THE ORGANIC

CHEMISTRY OF

DRUG SYNTHESIS

Volume 7

DANIEL LEDNICER

North Bethesda,MD

THE ORGANIC

CHEMISTRY OF

DRUG SYNTHESIS

THE ORGANIC

CHEMISTRY OF

DRUG SYNTHESIS

Volume 7

DANIEL LEDNICER

North Bethesda,MD

Publishedby John Wiley& Sons,Inc., Hoboken,New Jersey

Publishedsimultaneously in Canada

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CONTENTS

Preface xi

1 OPEN-CHAIN COMPOUNDS 1

1. Peptidomimetic Compounds / 2

A. Antiviral ProteaseInhibitors / 2

1. Human ImmunodeﬁciencyVirus / 2

2. Human Rhinovirus / 9

2. Miscellaneous PeptidomimeticCompounds / 11

References / 19

2 ALICYCLIC COMPOUNDS 21

1. Monocyclic Compounds / 21

A. Prostaglandins / 21

B. Antiviral Agents / 25

C. Miscellaneous MonocyclicCompounds / 29

2. Polycyclic Compounds:Steroids / 31

A. 19-Nor Steroids / 31

B. Corticosteroid RelatedCompounds / 34

vii

3. Polycyclic Compounds / 38

References / 40

3 MONOCYCLIC AROMATICCOMPOUNDS 43

1. Arylcarbonyl Derivatives / 43

2. Biphenyls / 47

3. Compounds Relatedto Aniline / 50

4. Compounds Relatedto Arylsulfonic

Acids / 53

5. Diarylmethanes / 58

6. Miscellaneous MonocyclicAromatic Compounds / 60

References / 67

4 CARBOCYCLIC COMPOUNDS FUSEDTO A

BENZENE RING 69

1. Indenes / 69

2. Naphthalenes / 73

3. Tetrahydronaphthalenes / 74

4. Other benzofusedcarbocyclic compounds / 79

References / 81

5 FIVE-MEMBERED HETEROCYCLES 83

1. Compounds withOne Heteroatom / 83

2. Compounds withTwo Heteroatoms / 91

A. Oxazole andIsoxazoles / 91

B. Imidazoles anda Pyrrazole / 94

C. Thiazoles / 99

D. Triazoles / 103

E. Tetrazoles / 109

References / 112

6 SIX-MEMBERED HETEROCYCLES 115

1. Compounds withOne Heteroatom / 115

A. Pyridines / 115

B. Reduced Pyridines / 117

C. Miscellaneous / 119

viii CONTENTS

2. Compounds withTwo Heteroatoms / 121

A. Pyrimidines / 121

B. Miscellaneous Six-MemberedHeterocycles / 133

References / 136

7 FIVE-MEMBERED HETEROCYCLES FUSEDTO

ONE BENZENE RING 139

1. Compounds withOne Heteroatom / 139

A. Benzofurans / 139

B. Indoles / 141

C. Indolones / 148

D. Miscellaneous Compoundswith

One Heteroatom / 153

2. Five-Membered Ringswith Two Heterocyclic

Atoms / 156

A. Benzimidazoles / 156

B. Miscellaneous Compounds / 158

References / 160

8 SIX-MEMBERED HETEROCYCLES FUSEDTO

ONE BENZENE RING 163

1. Compounds withOne Heteroatom / 163

A. Benzopyrans / 163

B. Quinolines andTheir Derivatives / 167

C. Quinolone AntibacterialAgents / 172

2. Compounds withTwo Heteroatoms / 176

A. Benzoxazines / 176

B. Quinazolines / 178

C. Miscellaneous Benzo-FusedHeterocycles / 184

References / 186

9 BICYCLIC FUSED HETEROCYCLES 189

1. Compounds withFive-Membered Rings Fused

to Six-MemberedRings / 189

A. Compounds withTwo Heteroatoms / 189

B. Compounds withThree Heteroatoms / 191

C. Compounds withFour Heteroatoms / 195

CONTENTS ix

2. Compounds withTwo Fused Six-MemberedRings / 208

3. Miscellaneous Compoundswith Two Fused

Heterocyclic Rings:Beta Lactams / 213

References / 215

10 POLYCYCLIC FUSED HETEROCYCLES 217

1. Compounds withThree Fused Rings / 217

2. Compounds withFour Fused Rings / 228

3. Compounds withFive or MoreFused Rings:

Camptothecins / 230

References / 232

Subject Index 233

Cross Index ofBiological Activity 241

Cumulative Index 245

x CONTENTS

PREFACE

The ﬁrst volumeof The Organic Chemistry ofDrug Synthesis was orig-

inally visualizedas a singlefree-standing bookthat outlined thesyntheses

of mostdrugs thathad beenassigned non-proprietary namesin 1975at the

timethe bookwas written.Within ayear orso ofpublication in1977, ithad

become evident that agood manydrugs hadbeen overlooked.That andthe

encouraging reception of the original book led to the preparation of a

second volume. That second book notonly made up for the lacunae in

the original volume but also covered additional new drug entities as

well. With that secondvolume assignment of non-proprietary names by

USAN became thecriterion for inclusion. Thatbook, published in 1980,

thus included in addition all agents that had been granted USAN since

1976. What hadbeen conceived as a single bookat this point became a

series. The roughly 200 new USAN coined every ﬁve years over the

next few decades turned out to nicely ﬁt a new volume in the series.

This then dictated the frequency for issuing new compendia. After the

most recent book in the series, Volume 6, was published in 1999, it

became apparent that a real decline in thenumber of new drug entities

assigned non-proprietary names had set in. The customary half-decade

interval betweenbooks was apparently nolonger appropriate.

A detailedexamination of the 2005edition of theUSAN Dictionary of

Drug Names turned up 220 new non-proprietary names that had been

assigned since the appearance of Volume 6.Many of these compounds

represent quitenovel structural types ﬁrstidentiﬁed by sophisticated new

cell-based assays.This clearlyindicated theneed for thepresent volumein

the seriesThe Organic Chemistry ofDrug Synthesis.

This new book follows the same format as the preceding volumes.

Compounds are classed bytheir chemical structures rather than by their

biological activities. This is occasionally awkward since compounds

with the samebiological activity but signiﬁcantly differentstructures are

relegated to different chapters, a circumstance particularly evident with

estrogen antagonists that appear in three different chapters. The cross

index found at the end of the book, it is hoped, partly overcomes this

problem. Thesyntheses are discussed froman organic chemist’s pointof

view, accompaniedby the liberal use of ﬂowdiagrams. As was the case

inthe precedingvolumes, athumbnail explanationof thebiological activity

of eachnew compound precedesthe discussion of itsbiological activity.

Several trends in the direction of drug discovery research seemed to

emerge duringthe preparationof thisbook. Mostof thepreceding volumes

included one ormore therapeutic classes populated by manystructurally

related potential drugs.Volume 6 for example describedno fewer than a

half dozen HIV-proteaseinhibitors and a similar numberof the “triptan”

drugs aimedat treating migraine.The distribution oftherapeutic activities

in thepresent volumeis quite distinctfrom thatfound in theearlier books.

Thisnew set,for example,includes asizeable numberof antineoplasticand

antiviral agents.These twocategories together infact accountfor just over

one third ofthe compounds in the presentvolume. The antitumor candi-

dates are further distinct in thatspeciﬁc agents act against very speciﬁc

tumor-related biological end points. This circumstance combined with

mechanism baseddesign in other diseaseareas probably reﬂectthe wide-

spread adoption of in-vitro screening in the majority of pharmaceutical

research laboratories.

The use of combinatorial chemistry for generating libraries to feed

in-vitro screens has also become very prevalent over the past decade.

This book is silent on that topic since compounds are only included

when in a quite advanced developmental stage. Some of the structures

that include strings of unlikely moieties suggest that those compounds

may havebeen originally preparedby some combinatorial process.

The internethas played a majorrole in ﬁnding thearticles and patents

that were required to put thisaccount together. The NIH-based website

PubChem was anessential resource for ﬁnding structures ofcompounds

that appear in thisbook; hits more often than not includeCAS Registry

Numbers. References to papers on the synthesis of compounds could

sometimes be foundwith the other NIH sourcePubMed. The ubiquitous

Google wasalso quite helpful for ﬁndingsources for syntheses. In some

xii PREFACE

of the earlier volumes,references to patents were accompaniedby refer-

ences to the corresponding CAS abstract since it was often difﬁcult to

access patents. The availability of actual images of all patents from

either the U.S. patent ofﬁce (www.uspto.gov) or those from European

elsewhere (http://ep.espacenet.com) has turned the situation around.

There wasalways the ratherpricey STN onlinewhen all else failed.

This volume,like its predecessors,is aimedat practicing medicinaland

organic chemistsas wellas graduate andadvanced undergraduatestudents

in organic and medicinal chemistry.The book assumes a good working

knowledge of syntheticorganic chemistry and some exposureto modern

biology.

Asa ﬁnal note,I wouldlike toexpress myappreciation tothe staffof the

library inBuilding 10 of theNational Institutes of Health.Not only were

they friendlyand courteous but theywent overboard infulﬁlling requests

that wentwell beyond theirjob descriptions.

PREFACE xiii

CHAPTER 1

OPEN-CHAIN COMPOUNDS

Carbocyclic or heterocyclic ring systemscomprise the core of chemical

structures of the vastmajority of therapeutic agents. This ﬁnding results

in the majority ofdrugs exerting their effect by their actions atreceptor

or receptor-like sites on cells, enzymes, or related entities. These inter-

actions depend on the receiving site being presented with a molecule

that has a well-deﬁnedshape, distribution of electron density, and array

of ionic or ionizable sites, which complement features on the receptor.

These requirements arereadily met by the relativelyrigid carbocyclic or

heterocyclic molecules. A number of important drugs cannot, however,

be assigned to one of those structural categories. Most of these agents

act asfalse substrates forenzymes that handlepeptides. The centralstruc-

tural featureof these compoundsis an open-chainsequence that mimicsa

corresponding featurein the normal peptide. Although these drugsoften

contain carbocyclicor heterocyclic rings intheir structures, thesefeatures

are peripheral to their mode of action. Chapter 1 concludes with afew

compounds thatact by miscellany and mechanismsand whose structures

do notﬁt other classiﬁcations.

The OrganicChemistry ofDrug Synthesis, Volume7. By DanielLednicer

1. PEPTIDOMIMETIC COMPOUNDS

A. Antiviral Protease Inhibitors

1. Human Immunodeﬁciency Virus. The recognition of acquired

immune deﬁciencysyndrome (AIDS)in the early1980s andthe subsequent

explosion ofwhat had seemedat ﬁrst to bea relatively raredisease into a

major worldwide epidemic,lent renewed emphasis to thestudy of virus-

caused disease. Treatment of viral disease is made particularly difﬁcult

by the factthat the causative organism, the virion, doesnot in the exact

meaning of the word, replicate. Instead, it captures the reproductive

mechanism of infected cells and causes those to produce more virions.

Antiviral therapythus relieson seekingout processes thatare vitalfor pro-

ducing those new infective particles. The ﬁrstdrugs for treating human

immunodeﬁciency virus (HIV) infection comprised heterocyclic bases

that interfered with viral replication by interrupting the transcription of

viral ribonucleic acid (RNA) into the deoxyribonucleic acid (DNA)

required by the host cell for production of new virions. The relatively

fast developmentof viral strains resistantto these compounds hasproven

to bea major drawbackto theuse of thesereverse transcriptase inhibitors.

The drugsdo, however,still form animportant constituentin the so-called

cocktails used to treatAIDS patients. Some current reverse transcriptase

inhibitors are described in Chapters 4 and 6. The intense focus on the

HIV virus revealed yet another point at which the disease may be

tackled. Like most viruses,HIV comprises a packet of genetic material,

in this case RNA, encased in a proteincoat. This protein coat provides

not onlyprotection from the environment,but also includes peptidesthat

recognize features on hostcells that cause the virion to bind to the cell

and a few enzymes crucial for replication. Many normal physiological

peptides are often elaborated as a part of a much larger protein.

Specialized peptidase enzymes are required to cut out the relevant

protein. This proved to be the case with the peptides required for

forming the envelopes for newly generated virions. Compounds that

inhibit the scission of the protein elaborated by the infected host, the

HIVprotease inhibitors,have provideda valuableset ofdrugs fortreatment

of infectedpatients. The synthesisof four of thosedrugs were outlinedin

Volume 6of this series. Work oncompounds in this classhas continued

apace as evidenced by the half dozen newprotease inhibitors that have

been grantednonproprietary names since then.

As noted in Volume 6, the development of these agents was greatly

facilitated by adiscovery in a seemingly unrelated area.Research aimed

2 OPEN-CHAIN COMPOUNDS

at developmentof renininhibitors aspotential antihypertensive agentshad

led tothe discovery of compoundsthat blocked theaction of this peptide

cleaving enzyme. The aminoacid sequence cleaved by renin was found

to be fortuitously the same asthat required to produce the HIV peptide

coat. Structure–activity studies on renin inhibitors proved to be of great

value for developingHIV protease inhibitors. Incorporation ofan amino

alcohol moiety proved crucial to inhibitory activity for many of these

agents. This unit is closely related to the one found in the statine, an

unusual amino acid that forms part of the pepstatin, a fermentation

product thatinhibits protease enzymes.

This moietymay be viewedas a carbonanalogue of thetransition state

in peptidecleavage. The fragment isapparently close enoughin structure

to such an intermediateas to ﬁt the cleavage site in peptidaseenzymes.

Once bound, this inactivatesthe enzyme as it lacks thescissile carbon –

nitrogen bond. All ﬁve newer HIV protease inhibitors incorporate this

structural unit.

One scheme for preparing a key intermediate for incorporating that

fragment begins with the chloromethyl ketone(1) derived from phenyl-

alanine, in which the amine is protected as a carbobenzyloxy (Cbz)

group. Reduction of the carbonyl group by means of borohydride

affords a mixtureof aminoalcohols. The major synisomer 2 is then iso-

lated. Treatmentof 2 with baseleads to internal displacementof halogen

and formationof the epoxide (3).

1. PEPTIDOMIMETICCOMPOUNDS 3

The corresponding analogue (4) in which the amine is protectedas a

tert-butyloxycarbonyl function (t-BOC)comprises the startingmaterial for

the HIV protease inhibitor amprenavir (12). Reaction of 4 with

isobutyl amine leads to ring openingof the oxirane and formation of the

aminoalcohol (5). The thus-formed secondary amine in the product is

convertedtothe sulfonamide(6)byexposure top-nitrobenzenesulfonylc hlor-

ide.The t-BOCprotectinggroup isthen removedby exposureto acidleading

to the primary amine(10). In a convergent scheme, chiral3-hydroxytetra-

hydrofuran( 8)is allowedto reactwith bis(N-succinimidooxy)carbonate(7).

The hydroxyl displacesone of the N-hydroxysuccinimide groupsto afford

the tetrahydrofuran (THF) derivative (9)equipped with a highly activated

leavinggroup. Reactionof thisintermediate withamine 10leadsto displace-

ment of the remaining N-hydroxysuccinimide and inc orporation of the

tetrahydrofurylmoiety asa urethane(11). Reductionof the nitrogroup then

affordst heprotease inhibitor(12).

Much thesame sequenceleads toa proteaseinhibitor thatincorporates a

somewhat morecomplex furyl function-linked oxygen heterocyclic.This

fused bis(tetrahydrofuryl) alcohol (16) was designed to better interact

with a pocketon the viral protease. Theﬁrst step in preparing thisinter-

mediate consists ofreaction of dihydrofuran (13) with propargyl alcohol

and iodosuccinimide to afford the iodoether (14). Free radical dis-

placement of the iodine catalyzed by cobaloxime leads to the fused

4 OPEN-CHAIN COMPOUNDS

perhydrofuranofuran (15).The exomethylene groupin the productis then

cleaved by means of ozone; reductive workup of the ozonide leads to

racemic16. The opticallypure single entity(17) is thenobtained byresol-

ution ofthe initial mixture ofisomers with immobilized lipase.

Thatproduct (17)isthen convertedto theactivatedN-hydoxysuccinimide

derivative 18 as in the case of the monocyclic furan. Reaction with

theprimary amine 10used toprepare amprenavirthen leadsto theurethane

(19). Reductionof thenitro groupthen affords darunavir

(20).

The synthesis of theamprenavir derivative, which is equipped with a

solubilizing phosphate group, takes a slightlydifferent course from that

used forthe prototype. Theprotected intermediate 5 usedin the synthesis

of 12 isallowed to react withbenzyloxycarbonyl chloride to provide the

1. PEPTIDOMIMETICCOMPOUNDS 5

doubly protected derivative 21, a compound that bears a t-BOC group

on one nitrogen and a Cbz grouping on the other. Exposure to acid

serves toremove the t-BOC group,affording the primary amine22. This

compound is then condensed with the activated intermediate 9 used in

the preparation of the prototype to yield the urethane 23. Catalytic

hydrogenation then removes the remaining protecting group to give

the secondary amine 24.Reaction as before with p-nitrobenzenesulfonyl

chloride gives the sulfonamide 25. This intermediate is allowed to

react with phosphorusoxychloride under carefully controlled conditions.

Treatmentwith aqueous acidfollowed bya secondcatalytic hydrogenation

affords thewater soluble proteaseinhibitor fosamprenavir (26).

The preceding threeantiviral agents tend to differ formeach other by

only relativelysmall structuraldetails. Thenext proteaseinhibitor includes

some signiﬁcant structural differences though it shares a similar central

aminoalcohol sequence that is presumably responsible for its activity.

Construction of one end of the molecule begins with protection of the

carbonyl function inp-bromobenzaldehyde (27) as its methylacetal (28)

by treatmentwith methanol inthe presence ofacid. Reactionof that inter-

mediate withthe Grignard reagentfrom 4-bromopyridineleads to unusual

6 OPEN-CHAIN COMPOUNDS

displacement ofbromine from the protected benzaldehydeand formation

of thecoupling product. Mildaqueous acid restoresthe aldehydefunction

to afford29. Thiscompound isthen condensed withcarbethoxy hydrazine

to formthe respective hydrazone;reduction of theimine function leadsto

the substituted hydrazine (30). Reactionof 30 with the by-now familiar

amino-epoxide (4)results in oxirane openingby attack ofthe basic nitro-

genin the hydrazine(30) andconsequent formationof theaddition product

31. The t-BOC protecting group is then removed by treatment with

acid. The ﬁnal step comprises acylation of the free primaryamine in 32

with the acid chloride from the O-methyl urethane(33). This last com-

pound (32) is a protected version of an unnaturala-aminoacid that can

be viewed as valine in with an additional methyl group on what had

been the side-chain secondarycarbon atom. Thus, the protease inhibitor

atazanavir (34)is obtained.

A terminal cyclic urea derivativeof valine is present at one terminus

in lopinavir(43). Preparationof thisheterocyclic moiety beginswith con-

version ofvaline (35) to its phenoxycarbonylderivative by reaction with

the corresponding acid chloride. Alkylation of the amide nitrogen with

3-chloropropylamine in the presence of base under very carefully con-

trolled pH results in displacement of the phenoxide group to give the

1. PEPTIDOMIMETICCOMPOUNDS 7

urea intermediate (37). This compound then spontaneously undergoes

internal displacementof chlorine to formthe desired derivative (38).

The statine-like aminoalcohol functionin this compound differs from

previous examples by the presence of an additional pendant benzyl

group; the supporting carbon chain is of necessity longer by one

member. Condensation ofthat diamine (39),

protected at oneend as its

N,N-dibenzyl derivative, with2,6-dimethylphenoxyacetic acid (40) gives

the corresponding amide (41). Hydrogenolysis then removesthe benzyl

protecting groupsto afford primary amine 42. Condensationof that with

intermediate 34affords the HIV proteaseinhibitor 43.

8 OPEN-CHAIN COMPOUNDS

2. Human Rhinovirus. Human rhinoviruses are one of the most fre-

quent causes of that afﬂiction that accompanies cooling weather, the

common cold.This virusalso consistsof asmall strand ofRNA enveloped

in apeptide coat. Expressionof fresh virionsin this case dependson pro-

visionof the properpeptide bythe infectedhost cell.That inturn hingeson

excisionof that peptidefrom thelarger initially producedprotein. Protease

inhibitors have thus been investigated as drugs for treating rhinovirus

infections. The statine-based HIV drugs act by occupying the scission

site of the protease enzyme and consequently preventing access by the

HIV-related substrate.That binding is,however, reversible inthe absence

of theformation ofa covalentbond between drugand enzyme.A different

strategy wasemployed in the research thatled to the rhinovirus protease

inhibitor rupinavir(58). The moleculeas a wholeis again designedto ﬁt

the proteaseenzyme, asin thecase ofthe anti-HIV compounds.In contrast

to thelatter compound,however, thisagent incorporates amoiety that will

forma covalentbond withthe enzyme,in effectinactivating itwith ﬁnality.

The evocativeterm “suicide inhibitor” has sometimes been usedfor this

approachsince both thesubstrate anddrug are destroyed.

The mainpart ofthe somewhatlengthy convergentsynthesis consists of

the constructionof the fragmentthat will formthe covalent bondwith the

enzyme. The unsaturated ester in this moiety was designed to act as a

Michael acceptor for a thiol group on a cysteine residue known to be

present atthe active site. Thepreparation of thatkey fragment starts with

the protected form of chiral 3-amino-4-hydroxybutyric acid (44); note

that the oxazolidine protecting group simply comprises a cyclic hemi-

aminal ofthe aminoalcohol withacetone. The ﬁrststep involvesincorpor-

ation of a chiral auxiliary to guideintroduction of an additional carbon

atom. The carboxylic acid is thus converted to the corresponding acid

chloride andthat reactedwith the (S)-isomer ofthe by-nowclassic oxazo-

lidinone (45)to give derivative46. Alkylationof the enolatefrom 46with

allyl iodidegives the correspondingallyl derivative (47)as a singleenan-

tiomer. Thedouble bond isthen cleaved withozone; reductive workupof

theozonide affordsthe aldehyde (48).Reductive aminationof thecarbonyl

group with 2,6-dimethoxybenzylamine in the presence of cyanoboro-

hydride proceeds tothe corresponding amine 49. This last stepin effect

introduced a protected primary amino groupat that position. The chiral

auxiliary grouping is next removed by mild hydrolysis. The initially

formed amino acid (50) thencyclizes to give the ﬁve-membered lactam

(51). Treatmentunder stronger hydrolytic conditionssubsequently serves

to open the cyclic hemiaminalgrouping to reveal the free aminoalcohol

1. PEPTIDOMIMETICCOMPOUNDS 9

(52).Swern-type oxidationof the terminalhydroxyl groupin thislast inter-

mediate affords an intermediate(53) that now incorporates the aldehyde

group requiredfor building the Michael acceptorfunction. Thus reaction

of that compoundwith the ylide from ethyl 2-diethoxyphosphonoacetate

adds twocarbon atoms and yieldsthe acrylic ester(54).

The remainingportion of themolecule is preparedby the condensation

of N-carbobenzyloxyleucine with p-ﬂuorophenylalanine to yield the

protected dipeptide (55). Condensation of that intermediate with the

Michaelacceptor fragment (54)under standardpeptide-forming conditions

leads tothe tripeptide-like compound (53).Reaction of 53 withdichloro-

dicyanoquinone (DDQ) leads to unmasking of the primary amino group

at the end of thechain by oxidative loss of the DMB protecting group.

Acylationof that functionwith isoxazole(55) ﬁnallyaffords therhinovirus

protease inhibitorrupinavir (58).

10 OPEN-CHAIN COMPOUNDS

2. MISCELLANEOUS PEPTIDOMIMETIC COMPOUNDS

Polymers of the peptide tubulin make up the microtubules that form the

microskeleton of cells. Additionally, during cell division these ﬁlaments

pull apartthe nascentnewly formed pairof nuclei.Compounds thatinterfere

with tubulinfunction and thusblock this processh av eprovided somevalu-

ablea ntitumorcompounds. Thevinca alkaloiddrugs vincristineand vinblas-

tine, forexample, block the self-assemblyof tubulin into thoseﬁlaments.

Paclitaxel,more familiarly knownas Taxol, interestinglystabilizes tubulin

and in effect freezescells into mid-division. Screening ofmarine natural

products uncovered the cytotoxic tripeptide-like compound hemiasterlin,

which owed its activity to inhibition of tubulin. A synthetic program

based onthat lead ledto the identiﬁcation oftaltobulin (69), anantitumor

compound composed, likeits model, of sterically crowdedaminoacid ana-

logues.T hepresence ofthe nucleophile-acceptingacrylate moietyrecalls 58.

Onearm of theconvergent synthesisbegins withthe constructionof that

acrylate-containing moiety. Thus, condensation of the t-BOC protected

a-aminoaldehydederived fromvaline withthe carbethoxymethylene phos-

porane (60) gives the corresponding chain extended amino ester (61).

Exposure to acid serves to remove the protecting group to reveal the

primary amine (62). Condensation of that intermediate with the tertiary

butyl-substituted aminoacid 33, usedin a previous example leads to the

protected amide (63); the t-BOC group in this is again removed with

acid unmasking the primary amino group in 64. Construction of the

other major fragment ﬁrst involves addition of a pair of methyl groups

2. MISCELLANEOUSPEPTIDOMIMETIC COMPOUNDS 11

to thebenzylic position of pyruvate(65). This transform isaccomplished

under surprisingly mild conditions by simply treating the ketoacidwith

methyl iodide in the presence of hydroxide. Treatment of product 66

with methylamine and diborane results in reductive amination of the

carbonyl group, and thus formation of a-aminoacid 67 as a mixture of

the two isomers. Condensationof that with the dipeptide-like moiety64

under standard peptide-forming conditions gives the amide 68 as a

mixture of diastereomers. The isomers are then separated by chromato-

graphy; saponiﬁcationof the terminal esterfunction of the desired(SSS)-

isomer affordsthe antitumor agent taltobulin(69).

The alkylatingagent cyclophosphamide is oneof the oldestU.S. Food

and Drug Administration (FDA)-approvedantitumor agents, having been

in use inthe clinic for well over fourdecades. Though this chemothera-

peutic agent is reasonably effective, it is not very selective. The drug

affects manysites and is thusvery poorly tolerated. Overthe years, there

has been much research devoted to devising more site-selective related

compounds. It wasestablished that a heterocyclic ringin this compound

is openedmetabolically and then discarded. Theactive alkylating metab-

olite comprises the relatively small molecule commonly known as the

“phosphoramide mustard”.

12 OPEN-CHAIN COMPOUNDS

This resultopens the possibility ofdelivering this active fragmentor a

related alkylatingfunction in a largemolecule that would itselfbe recog-

nized by an enzyme involved in cancer progression. As an example, it

was observed that many types of cancer tissues often have elevated

levels of glutathione transferase, the agent that removes glutathione. A

version of the modiﬁed natural substrate, glutathione, which carries a

phosphoramide alkylating function, has shown activity on various

cancers. Reaction of bromoethanolwith phosphorus oxychloride affords

intermediate 70. This compound reacts without puriﬁcation with bis-2-

chloroethylamine to give the phosphoramide (71), which is equipped

with two sets of alkylating groups. Compound 71 is then reacted with

the glutathioneanalogue 72, in which phenylglycinereplaces the glycine

residue normally at that position. The bromine atomin intermediate 71

is apparentlysufﬁciently more reactivethan the chlorines inthe mustards

so thatdisplacement by sulfur preferentiallyproceeds to 73.Oxidation of

the sulﬁdewith hydrogen peroxide affordscanfosfamide (74).

11,12

The D(R) isomer of theamino acid N-methyl-D-aspartate, more com-

monly known as NMDA servesas the endogenous agonist at a number

of central nervous system (CNS) receptor sites. This agent is not only

involved in neurotransmission, but also modulatesresponses elicited by

other neurochemicals. A relatively simple peptide-like molecule has

been found to act as an antagonistat NMDA receptors. This activity is

manifested in vivoas antiepileptic activity. Thisagent in addition blocks

the nerve pain suffered bymany diabetics, which is often called neuro-

pathic pain. The synthesis begins by protecting the unnatural

D-serine

2. MISCELLANEOUSPEPTIDOMIMETIC COMPOUNDS 13

(75) asits carbobenzyloxyderivative 76. Thisis accomplishedby reacting

75 with the corresponding acid chloride. Reaction of the product

with methyl iodide in the presence of silver oxide alkylates both the

free hydroxyl and the carboxylic acid to give the ether ester (77).

Saponiﬁcation followedby couplingwith benzylamine leadsto thebenzy-

lamide (78). Hydrogenolysis of the Cbz protecting group(79) followed

by acylationwith acetic anhydride affordslacosamide (80).

Asnoted inthe discussionof canfosfamide,alkylatingagents havea long

historyas a classof compoundsused in chemotherapy.The trendis toattach

the activeelectrophillic groupsto moleculesthat willdeliver themto speciﬁc

sites. Asimple alkylating agent, cloretazine (83),is beingactively pursued

becauseof its promisingantitumor activity.Exhaustive methanesulfonation

of hydroxyethylhydrazine withmethanesulfonyl chloride yieldsthe N,N,O-

trimesylate (81).Reaction ofthis intermediatewith lithium chlorideleads to

displacementof the O-mesylateby chlorine andformation ofthe alkylating

group in 82. Treatmentof 82 with the notorious methylisocyanate (MCI)

yields theantitumor agentcloretazine (83).

14,15

14 OPEN-CHAIN COMPOUNDS

The relatively simple homologue of taurine, 3-aminosulfonic acid

(84a), also known as homotaurine, is ana ntagonistof the neurochemical

gamma-aminobutyric acid (GABA). Homotaurine has been foundto sup-

press alcoholism in variousanimal models. Speculation is that this occurs

because ofits activity againstGABA towhich it bearsa some resemblance.

The calcium salt (84b)oftheN-acetyl derivative has been usedto help

alcoholics maintain abstinence from alcohol by preventing relapse. The

compound is prepared straightforwardly by acylation of homotaurine in

the presence of calcium hydroxide and acetic anhydride.

The product,

acamprosatecalcium (84b), wasapproved by FDAfor use in theUnited

States in2004.

A relatively simple derivative of phenylalanine shows hypoglycemic

activity. This compound, nateglinide,is usually prescribed for use as an

adjunct to either metformin, or one of the thiazolidine hypoglycemic

agents. Catalytic reductionof the benzoic acid(85) leads tothe correspond-

ingsubstituted cyclohexaneas amixture ofisomers. Thiscompound isthen

esteriﬁed with methanol to give the methyl esters (86). Treatment with

sodium hydride leads 86to equilibrate to themore stable transisomer 87

via its enolate. Condensation of 87 with the ester of phenylalanine (88)

yields nateglinide(89) after saponiﬁcations.

The hypoglycemicagent repaglinidemay looselybe classedas apeptid-

omimeticagent, becauseitessentially showsthesame activityas nateglinide.

The actualsynthetic routeis difﬁcult todecipher from thepatent in whichit

2. MISCELLANEOUSPEPTIDOMIMETIC COMPOUNDS 15

is described. No description is provided for the origin of the starting

materials. It isspeculated that condensation ofthe protected monobenzyl

ester (90)withdiamine91 wouldleadtotheamide(92).Hydrogenolysis

of thebenzyl ester in theproduct would affordthe free acid.Thus ,repagli-

nide (93)would be obtained.

Formationof bloodclots isthe naturalprocess thatpreservesthe integrity

of the circulatorysystem. Damage to the vasculature sets off an intricate

cascade of reactions. Thesereactions culminate in the formation ofa ﬁbrin

clot that seals the damaged area preventing the further loss of blood.

Surgery, heart attacks, and other traumatic events lead to inappropriate

formation of clotsthat can result in injury by blocking the blood supply

to organs and other vital centers.The drugs that have traditionally been

used to prevent formation of clots, coumadin and heparin have a very

narrow therapeutic ratio,necessitating close monitoringof blood levels of

these drugs in patients. One of theﬁrst steps in the formation of a clot

involves the binding of ﬁbrinogen to speciﬁc receptors on the platelets

that start the process. A number of ﬁbrinogen inhibitors have recently

been developedwhose structure is basedon the sequence of aminoacids

in the natural product. Two more recent compounds, melagartan,and

xymelagartan, both contain the amidine (or guanidine) groups that a re

intended tomimic the similar function inﬁbrinogen and that characterize

this classof drugs.

The synthesisof these agentsbegins with thehydrogenation ofphenyl-

glycine t-BOCamide (94) to thecorresponding cyclohexyl derivative95.

The freecarboxyl group is thencoupled with the azetidine (96)to afford

16 OPEN-CHAIN COMPOUNDS

the amide(97). Saponiﬁcation withlithium hydroxide yieldsthe free acid

(98). The carboxyl group in that product is then coupled with the

benzylamine(99), wherethe amidinegroup atthe paraposition isprotected

as the benzyloxycarbonyl derivative to give intermediate 100. The

protecting group on the terminal amino group is then removed by

hydrolysis withacid (101). The primaryamine in this lastintermediate is

then alkylated with benzyl bromoacetate. Hydrogenolysis removes the

protecting groups on the terminal functions in this molecule to afford

melagartan (102).

Intermediate 100 serves as the starting material for the structurally

closely related ﬁbrinogen inhibitor xymelagartan. Hydrogenation over

palladium on charcoal removes the protecting group on the amidine

function (103). This compound is then allowed to react with what is

in effect and unusual complex ester of carbonic acid (104). The basic

nitrogen on the amidine displaces nitrophenol, a good leaving group

to afford106. Regiochemistry is probablydictated by thegreater basicity

of the amidine group compared to the primary amine at the other end

of the molecule. The amine is then alkylated with the triﬂuoromethyl-

sulfonyl derivative of ethyl hydroxyacetate. Reaction of this last inter-

mediate (107) with hydroxylamine result in an exchange of the

substitutent on the amidine nitrogen to form an N-hydroxyamidine.

Thus, xymelagartan (108) is obtained.

This drug is interestingly

rapidly converted to 102 soon after ingestion and is in effect simply a

prodrug for the latter.

2. MISCELLANEOUSPEPTIDOMIMETIC COMPOUNDS 17

Drugs that inhibit the conversion of angiotensin 1 to the vasocon-

stricting angiotensin 2, the so-called angiotensin converting enzyme

(ACE) inhibitors, block the action of angiotensin converting enzyme,

one of a series of zinc metalloproteases. A closely related enzyme

causes the degradation of the vasodilating atrial natriuretic peptide. A

compound that blocks both metalloproteases should in principle lower

vascular resistance and thus blood pressureby complementary mechan-

isms. A drug that combines those actions, based on a fused two-ring

heterocyclic nucleus, omapatrilat, is described in Chapter 10. A related

compound that incorporates a single azepinone ring shows much the

same activity. The synthesis begins by Swernoxidation of the terminal

alcohol in theheptanoic ester 109. Reaction of theproduct 110 with tri-

methylaluminum proceeds exclusively at the aldehyde to afford the

methyl addition product (111). A second Swern oxidation, ﬂowed this

time by methyl titanium chloride, adds a second methyl group to

afford the gem-dimethyl derivative(112). Construction of the azepinone

ring begins by replacementof the tertiary carbinol in 112 with anazide

group by reaction with trimethylsilyl azide and boron triﬂuoride.

Hydrogenation of the product (113) reduces the azide to a primary

amine andat the same timecleaves the benzyl esterto the corresponding

acid (114). Treatment of this intermediate with a diimide leads to for-

mation of an amide, and thus the desired azepinone ring (115). The

18 OPEN-CHAIN COMPOUNDS

phthalimido function, which has remained intact through the preceding

sequence, is now cleaved in the usual way by reaction with hydrazine.

The newlyfreed amine is again protected,this time as ittriphenylmethyl

derivative. The anionon the amide nitrogen from treatment of116 with

lithium hexamethyl disilazane is then alkylated with ethylbromoacetate;

exposure to triﬂuoracetic acid (TFA) then cleaves the protecting group

on the other nitrogen to afford 117. The primary amino group is

acylated with (S )acetylthiocinnamic acid (118). Saponiﬁcation cleaves

both the acetyl protection group on sulfur and the side-chain ethyl

ester to afford gemopatrilat (119).

REFERENCES

1. D.P. Getmanet al., J.Med. Chem. 36,288 (1993).

2. R.D. Tung,M.A. Murcko, G.R.Bhisetti, U.S. Patent5,558,397 (1996). The

scheme shown here is partly basedon that used to prepare darunavir and

phosamprenavir dueto difﬁculty indeciphering the patent.

3. A.K. Ghosh,Y. Chen, TetrahedronLett. 36, 505(1995).

4. D.L.N.G. Surlerauxet al., J.Med. Chem. 48, 1813(2005).

5. L.A. Sobrera,L. Martin, J.Castaner, Drugs Future,23, 22 (2001).

REFERENCES 19

6. G. Boldet al., J.Med. Chem. 41, 3387(1998).

7. Fora schemefor thisintermediate seeD. Lednicer,“TheOrganic Chemistryof

Drug Synthesis”,Vol. 6, JohnWiley & Sons,Inc., NY 1999,pp. 12,13.

8. E.J. Stoneret al., Org.Process Res. Dev.4, 264 (2000).

9. P.S. Dragovichet al., J.Med. Chem. 42,1213 (1999).

10. A. Zasket al., J.Med. Chem. 47, 4774(2004).

11. L.M. Kauvar,M.H. Lyttle, A. Satyam,U.S. Patent5,556,942 (1996).

12. A. Satyam, M.D. Hocker, K.A.Kane-Maguire, A.S. Morgan, H.O. Villar,

M.H. Lyttle,J. Med. Chem.39, 1736 (1996).

13. J.A. McIntyre,J. Castaner, DrugsFuture 29, 992(2004).

14. A. Sartorelli,K. Shyam, U.S.Patent 4,684,747 (1987).

15. A. Sartorelli,K. Shyam, P.G.Penketh, U.S. Patent5,637,619 (1997).

16. J.P. Durlach,U.S. Patent 4,355,043(1982).

17. S. Toyoshima,Y. Seto, U.S.Patent, 4,816,484 (1989).

18. W. Grell, R.Hurnaus, G. Griss, R. Sauter,M. Reiffen, E. Rupprecht, U.S.

Patent, 5,216,167(1993).

19. See Ref.7, pp. 15–18.

20. L.A. Sobrera,J. Castaner, DrugsFuture, 27, 201(2002).

21. J.A. Roblet al., J.Med. Chem. 42, 305(1999).

20 OPEN-CHAIN COMPOUNDS

CHAPTER 2

ALICYCLIC COMPOUNDS

The slimnessof this chaptervery aptlyreﬂects the importanceof aromatic

and heterocyclic moieties as cores for therapeutic agents. This section

includes severalagents thatdepend onthe presenceof on asingle alicyclic

group fortheir activity. Though afew of the compoundsincluded in this

chapter do include a benzene ring, that group does not seem to play a

major role intheir biological activity. Sizeable chapters weredevoted in

the earlier volumesin this series to thediscussion of drugs based on the

steroid nucleus. Thisarea, in common with the prostaglandinsthat open

this chapter, has received relatively little attention in recent years. A

handful ofsteroids thus round outthis section.

1. MONOCYCLIC COMPOUNDS

A. Prostaglandins

The discoveryof the prostaglandinsin the mid-1960s ledto an enormous

amount ofresearch inboth industrial andacademic laboratories.

Much of

this workwas arguablybased onthe mistakenpremise thatthese hormone-

like compounds would provide the basis for the design of major new

classes oftherapeutic agents. Analogywith the largenumber ofimportant

The OrganicChemistry ofDrug Synthesis, Volume7. By DanielLednicer

drugs thathad emerged from manipulation of thestructure of the steroid

hormones providedat least some ofthe impetus for researchon the pros-

taglandins. The expectation of majorclasses of new drugs was to some

extent dispelled bythe ﬁndings in the late1960s that prostaglandins and

other productsderived from arachidonic acidtended to mediate injurious

responses, such asinﬂammation rather than hormonaleffects. In spite of

this, several compounds based on this structure have found uses in the

clinic. Theseinclude, for example, misoprostol,a drug based onthe ben-

eﬁcial effect of this class of compounds on the mucous lining of the

stomach.This compounddiffers fromthe naturallyoccurring prostaglandin

E (PGE)by the removalof the sidechain hydroxyl toone carbon furthest

from thecyclopentane and presenceof an additionalmethyl groupon that

position. Othercompounds basedon thisstructure provideseveral ophthal-

mic products. These topicalprostaglandins are used to lower intraocular

pressure in glaucoma patients. They are believed to cause the outﬂow

of ﬂuidwithin the eye bybinding to speciﬁc intraocularreceptors. These

compounds are classed as PGFs. Since both ring oxygens comprise

alcohols.

Miso

rotol

Theﬁrst two agents,both usedto lowerintraocular pressuredue toglau-

coma, differ from naturalprostaglandins by the presence of an aromatic

ring at the end of the neutral side chain. Construction of the terminal

group on travoprost (9) starts with the reaction of the anion from

methyl dimethoxyphophonate with the aryloxy acid chloride (1).

Displacement of halogen affords product 2. Treatment of 2with strong

base leads to formation of the corresponding ylide. A key intermediate

for the synthesis of many prostaglandinsis the so-called Corey lactone.

This compound,shown as itsdibenzylcarboxylic ester (3), providesfunc-

tionality forimmediate attachment of theneutral side chain aswell as, in

latent form a junction point for the addition of the carboxylic acid

bearing side chain.Reaction of this reactive speciesfrom 2 with 3 leads

to the condensation product of the ylide with the aldehyde. The trans

22 ALICYCLIC COMPOUNDS

stereochemistryof thenewly formed oleﬁnfollows fromthe normalcourse

of thisreaction. Reductionof the side-chaincarbonyl groupwith zinc bor-

ohydride givesthe alcohol5 after separationof theisomers. Reaction with

mild baseresults in hydrolysis ofthe diphenyl ester protectinggroup (6).

The newlyrevealed alcohol,as wellas that onthe sidechain, are thenpro-

tected as theirtetrahydropyranyl ethers by reaction withdihydropyran in

the presenceof acid (7).Controlled reduction ofthe lactone ringwith dii-

sobutylaluminum hydride (DIBAL-H) stops at the lactol stage (8).

Condensation with thezwitterionic salt-free ylide, 4-triphenylphosphino-

butyrate, results in condensation with the open aldehyde form of the

lactol. The “salt free” conditions of this reaction account for the

formation of the new oleﬁn with cis stereochemistry. The acid is then

converted to its isopropyl ester by reaction of the carboxylatesalt with

isopropyl iodide.There is thus obtainedtravaprost (9).

(CH

POCH

BuLi

CH=O

Separate

ZnBH

Dihydropyran

TsOH

THPO

OTHP

DIBAL-H

THPO

CF3

OTHP

1. (C

)

(CH

)

–

2. (CH

)

CHI

3. H

CH(CH

)

Therather simplerophthalmic prostaglandinlatanoprost (10),

carriesa

simple benzenering directlyat theend of theside chain.The amide ofthis

drug is said to be better tolerated because of the absence of an acidic

carboxyl group. Reactionof 10 with 1,8-diazobicyclo[5.4.0]undec-7-ene

1. MONOCYCLICCOMPOUNDS 23

(DBU)ﬂowed bymethyl iodideleads tothe correspondingmethyl ester11.

Heating11 with ethylamineleads toester interchangeand formation ofthe

ethyl amidebimatoprost (12).

NHC

DBU

A PGErelated compound, lubiprostone(23) displays a quitedifferent

spectrum ofactivity. This compoundhas been recentlyapproved fortreat-

ment of chronic constipation and is being investigated for its effect on

constipation-predominantirritable bowelsyndrome. Ithas beenascertained

that the drug interactswith speciﬁc ion channels in the GI tractcausing

increased ﬂuid output intothe lumen. Starting material for the synthesis

(13) comprises yet another variant on the Corey lactone. Condensation

CH=O

THPO

NaBH

DiBAL

)

(CH

)

–

THPO

1. CrO

2. AcOH

tBuOK

24 ALICYCLIC COMPOUNDS

of thisaldehyde withthe ylidefrom thediﬂuorinated phosphonate14 leads

to theaddition product15. Thedouble bond inthef oleﬁnhas theexpected

transgeometry thoughthe nextstep, hydrogenation,makes thispoint moot.

Sodiumborohydride thenreduces theside-chain ketonefunction to give17

as amixture ofisomers. Thelactone is thenreduced tothe keylactol inthe

usual fashionby means of diisobutyl aluminumhydride. This compound

is thencondensed with the ylide obtainedfrom reaction ofthe zwitterion

4-triphenylphosphoniumbutyrate to give the chain-extended oleﬁn (19).

The carboxylic acid in this intermediate is next protectedas the benzyl

ester by alkylationof its salt with benzylchloride. Oxidation of the ring

alcohol by means of chromium trioxide followed by exposure to mild

acid to removethe tetrahydropyranyl group establishes theketo –alcohol

PGE-likefunction in theﬁve-membered ring(21). Catalytichydrogenation

of this last intermediate at the same time reducesthe remaining double

bond and removes the benzyl protecting group on the acid to give the

open-chain version (22)of the product. The electron-withdrawingpower

of theﬂuorine atoms adjacentto the side-chain ketonecause the carbonyl

carbon to becomea reasonable electrophile. Theelectron-rich oxygen on

the ring alcohol thusadds to this to give a cyclichemiacetal. This form

(23), greatlypredominates in product23.

B. Antiviral Agents

The enzymeneuraminidase plays akey rolein the replicationof inﬂuenza

viruses. Newlyformed virions form blister-like budson the inside ofthe

host cell membrane.This proteolytic enzyme, known as sialidase,facili-

tates scission of thebase of the bud and thus release of thenew virion.

Research on structurally modiﬁed neuraminidase congeners culminated

in the development of a derivative that blocked the action of the

enzyme. This complex dihydropyran, zanamivir (24), was found to be

effective against inﬂuenza viruses and most notably avian inﬂuenza A

(H5N1), better known as bird ﬂu. The lengthy complex route to that

drug encouraged the search for alternative structures that would ﬁt the

same site. Twomore easily accessible agents basedon carbocyclic rings

that havethe same activity as thenatural product based drugs havebeen

identiﬁed todate.

There hasbeen much recent anxiousspeculation that the birdﬂu virus

will mutateto aform that willspread from personto person. Aworldwide

inﬂuenza epidemic,at worst comparableto that which followedthe Great

War, couldwell bethe net resultof such anevent. The efﬁcacyof theﬁrst

carbocyclic neuraminidase inhibitor, oseltamivir (34), knownfamiliarly

1. MONOCYCLICCOMPOUNDS 25

by itstrade nameTamiﬂu, hasfocused considerable attentionon thisdrug.

A signiﬁcant amount ofwork has been devoted to its preparationin the

expectation of the very large quantities that would be required in the

event that the pandemic materializes. The choice of starting material is

constrained by the fact that virtually every carbon atom on the six-

membered ring in the molecule bears a chirallydeﬁned substituent. All

the early syntheses start with either shikimic (25) or gallic acid from

plant sources. A typical approach involves construction of the epoxide

27 asan early step. Shikimicacid is ﬁrst convertedto its ethyl ester.The

two syn disposed adjacent hydroxyl groups are then tied up as the

acetonide (26) by reaction with acetone. The remaining free alcohol is

then converted to its mesylate by means of methanesulfonyl chloride.

Hydrolysisof the mesylatefollowed byreaction withbase leads tointernal

displacement of the mesylate and formation of the key epoxide (27).

The freehydroxyl group is thenprotected as its methoxymethylene ether

(MEM) (28). Reaction with the nucleophile (sodium azide) then serves

to open the oxirane to give the azide (29). The next series of steps in

essence establishes the presence of adjacent trans disposed amino

groups. The freehydroxyl is thus ﬁrst converted to amesylate; catalytic

hydrogenation then reducesthe azide to a primary amine (30).This dis-

places the adjacentmesylate to form an aziridine (31).Treatment of this

intermediateor aderivative withacetic anhydridethen affordsthe activated

intermediate (32).

AcHN

MEMO

1. MsCl

2. H

MEMO

MsO

MEMO

AcHN

1. MsCl

2. H

3. B

–

282930

AcHN

NHAc

33 34

26 ALICYCLIC COMPOUNDS

Sodium azideagain opens a strainedreactive three-memberedring. There

isthus obtained the acetamido azide(33). Repeatof thesequence, mesylate

formation followed by catalytic hydrogenation leads to formation of a

new aziridine (33), in which the ring has moved over by one carbon

atom. Reaction of this lastintermediate with 3-pentanol in the presence

of base leads to opening the aziridine ring to give the corresponding

ether. Theazide in this last intermediateis again reduced withhydrogen.

Finally (34)is obtained.

6–8

The importance of thisdrug to meet a potential worldwide pandemic

has attracted the attention of academic chemists. This ﬁnding has

resulted in the development of a relatively short but elegant synthesis.

The approach is notable in that it does not involve difﬁcult to obtain

natural product starting material and completely obviates the use of

potentially explosiveazide intermediates. The ﬁrststep involves building

the carbocyclic ring equipped with a chiral carbon atom that will

determine the stereochemistry of the many remaining ring substituents.

Thus, 2 þ4 cycloaddition of acrylate 5 to cyclobutadiene in the pre-

sence of the pyrrolidine derivative (36) as a chiral catalyst affords the

ester (37)as a virtually pure opticalisomer. The ester groupis then con-

verted to an amide (38) bysimple interchange with ammonia. Reaction

with iodine underspecial conditions leads to the nitrogencounterpart of

an internal iodo-lactonization reaction and formation of the bridged

iodolactam (39). The amide nitrogen is then protected as its tert-

butoxycarbonyl derivative. Dehydroiodination with DBU introduces a

double bond giving 41. Free radical bromination of that intermediate

with N-bromosuccinimide (NBS) proceed with the shift of the oleﬁn

to give the allylic bromide 42. Dehydrobromination with cesium oxide

introduces an additional double bond in the ring. The presence of

ethanol leadsthe lactam ring toopen at the sametime. (For ease invisu-

alization, the product diene (43) is drawn both as produced and in the

orientation that matchesthat in the scheme above.) The secondnitrogen

required for theproduct is introduced by an unusualnovel reaction. The

product (44) obtained from treatment of diene 43 with acetonitrile and

NBS in the presence ofstannic bromide can be rationalized by positing

initial addition ofbromide to the oleﬁn toform a cyclic bromoniumion;

addition of the unshared pair of electrons on the nitrile nitrogenwould

account for the connectivity. Hydrolysis of the initial imine-like inter-

mediate would account for the observed product 44. Treatment with

base leads to internal displacement and formation of the aziridine ring

in 45. Reaction as above with 3-pentanol followed by removal of the

t-BOC group affords oseltamivir (34).

1. MONOCYCLICCOMPOUNDS 27

AcHN

t-BOCN

DBU

t-BOCN

NBS

AIBn

t-BOCN

CsO

t-BOCHN

EtOH

NBA

SnBr

t-BOCHN

AcHN

t-BOCHN

NHAc

(t-BuOCO)

Neuraminidase blocking activity is interestingly retained when the

central ringis contracted byone carbon atom. Notethat the cyclopentane

ring in the antiviral agent peramivir (53) carries much the same

substituents as its cyclohexane-based counterpart. The presence of the

guanidine substituent, however, traces back to the tertrahydropyran

zanamivir (24). The relatively concise synthesis of peramivir starts by

methanolysis of the commercially available bicyclic lactam 46.

Reaction of the thus-obtained amino-ester with t-BOC anhydride leads

to the N-protected intermediate (47).The key reaction involves addition

of both a functionalized carbon substituent and a hydroxyl group in a

single step. Reaction of the nitroalkane (48) with phenyl isocyanate

leads to the formation of a nitrone. That very reactive species then

undergoes 2 þ3 cycloaddition to the double bond in the cyclopentene

(47). The isoxazolidine (49) is the predominant isomer from that

reaction. Catalytic hydrogenation then cleaves the scissile nitrogen-

to-oxygen bond leading to ring opening and formation of the corre-

sponding aminoalcohol. This compound is converted to acetamide (50)

with acetic anhydride. The ring amino group is next revealed by

removal ofthe t-BOC group by means ofacid to yield 51. Anexchange

reaction of that primary amine with pyrazole carboxamidine (52) then

introduces the guanidine group. Thus the antiviral compound 53

is obtained.

28 ALICYCLIC COMPOUNDS

2. (t-BuOCO)

1. CH

t-BOCNH

N OH

1. H

2. Ac

tBOCNH

NHAc

NHH

N=C=O

C. Miscellaneous Monocyclic Compounds

The venerabledrug theophylline has been used totreat asthmatic attacks

for many years.Research on the mechanism of action ofthis purine led

to the discoverythat it actedby blocking the action ofthe enzyme phos-

phodiesterase (PDE).The clinical utility ofthis compound pointed tothe

potential of PDE inhibitorsas a source for new drugs. Modern method-

ology has ledto the subdivision of PDEreceptors into a numberof sub-

types, each of which seems to beinvolved in the regulationof a discrete

organ system. It is of interestthat a newly developed PDE inhibitor, in

this case speciﬁc for PDE 4, has shown clinical activity in alleviating

the symptoms of chronicobstructive pulmonary disease. This ﬁnding of

course involves the same organ that led to the discovery of the ﬁeld

many decades ago. Theﬁrst sequence in the synthesis of this newPDE

inhibitor comprises homologation of the benzaldehyde (54) to phenyl-

acetonitrile (56). Reduction of the aldehyde in the presence of lithium

bromide gives the corresponding benzyl bromide; displacement of

halogen by reaction with potassiumcyanide gives the substituted aceto-

nitrile (56). Condensation of thatintermediate with ethyl acrylate in the

presenceof base leadsto Michaeladdition oftwo moleculesof the acrylate

and formationof the diester (57).Treatment of thislast intermediate with

strong base leads to internal Claisen condensation with consequentfor-

mation ofthe carberthoxycyclohexanone derivative 58.Heating the keto-

ester with acid initially leads to hydrolysisof the ester to an acid. This

decarboxylates underreaction conditions to givethe cyclohexanone (59).

Condensation of the ring carbonyl group in this intermediate with the

anion from 1,3-dithianeleads to 60, inwhat in effect comprises addition

1. MONOCYCLICCOMPOUNDS 29

to the ringof a carbon atomat the acid oxidationstage. Oxidation of the

sulfur atoms in this intermediatewith mercuric chloride in the presence

of methanol converts that carbon to the methyl ester. The product in

which the nitrile and carboxyl are cis to each other predominate in an

11: 1 ratio over the trans isomer, probably reﬂecting thermodynamic

factors. Saponifaction of the ester group completes the synthesis of

cilomilast (61).

CH=O

KCN

1. CH

HgCl

2. NaOH

NaOC

The vitaminA related compound,all trans retinoic acid,is a ligandfor

cells involved in epithelial cell differentiation. It has found clinical use

under thename tretinoin(62), for treatmentof skin diseases,such asacne,

and foroff-label applicationas a skinrejuvenation agent.The recentlydis-

covered closelyrelated 9-cis isomer inaddition binds toa different set of

receptors involved in skin cell growth. This new compound has been

foundto controlproliferationof somecancercells. Thedrug isthusindicated

for topical use in controlling the spread of Kaposi sarcoma lesions.

Reductionof theester groupin compound63, whichincorporates therequi-

site future9-cis linkagewith lithiumaluminum hydride, leadsto thecorre-

spondingalcohol. Thiscompound isthen oxidizedtoaldehyde 64by means

of manganesedioxide. Condensation ofthe carbonyl groupwith the ylide

derived bytreatment of thecomplex phosphonate(65) adds therest of the

carbon skeleton(66). Saponiﬁcationof theester thengives thecorrespond-

ing acid,alitretinoin (67).

30 ALICYCLIC COMPOUNDS

1. LiAlH

2. MnO

CH=O

66; R = C

67; R = H

NaH

2. POLYCYCLIC COMPOUNDS: STEROIDS

The ﬁrst ﬁve volumes in thisseries each feature a separate chapter that

bearsthe title Steroids.The steadydiminution ofresearch on thisstructural

class isillustrated bythe regularly decreasingextent of thosechapters. By

thetime Volume 6appeared, thediscussion ofsteroid-based drugstakes up

but a section in the chapter on Carbocyclic Compounds. The relatively

small amount of research devotedto this area is reﬂected in the present

volume as well. The compounds thatfollow are organized by structural

class as they each display quite different biological activities from one

another.

A. 19-Nor Steroids

Virtually all known antiestrogens comprise non-steroidal compounds

based more or less closely on triphenyl ethylene (see ospemifene,

Chapter 3). Tamoxifen ranks as the successstory in this class of drugs

having found widespread use inthe treatment of women suffering from

estrogen receptorpositive breastcancer. It isthus notable thata derivative

of estradiolitself, which carriesa very unusualsubstituent, also actsas an

estrogen antagonist.Unlike its non-steroidforerunners, all ofwhich show

some measure of agonistactivity, this agent is devoid of any estrogenic

activity. Conjugate1,4 addition of the Grignard reagentfrom long-chain

bromide 69 to the dienone 68 affords the 7-alkylated product 70 as a

mixture ofepimers at the newlinkage. The 7-a isomer isseparated from

the mixturebefore proceeding; the hydroxylgroup at the endof the long

chain is then unmasked by hydrolytic removal of the silyl protecting

group. Reactionwith cupric bromideserves toaromatize ring A;saponiﬁ-

cation with mild base preferentially removes the less sterically hindered

acetate at the end of the long chain. Acylation by means of benzoyl

chloride convertsthe phenolto thecorresponding ester72.

The synthetic

2. POLYCYCLICCOMPOUNDS: STEROIDS 31

route fromthis pointon is speculativeas details arenot readily accessible.

Reaction of this last literature intermediate (72) with methanesulfonyl

chloride would then lead tomesylate 73. This group could then be dis-

placed by sulfuron the ﬂuorinated mercaptan (74). Controlledoxidation

of sulfur,for example, withperiodate, would thenlead to the correspond-

ing sulfone. Saponiﬁcation ofthe ester groups at the 3 and17 positions

would afford the estrogenantagonist ﬂuverestant,(75).

Note that this

speciﬁccompound is butone froma sizeablegroup ofsimilarly substituted

estradiol derivativesthat shows pureantagonist activity.

OAc

tBu

OAc

tBu

1. H

2. Ac

OAc

1. CuBr

2. NaOH

3. C

COCl

OAc

1. HS

2. [O]

3. OH

–

OSO

Synthesis of19-norandrostanes, whichcarried afunctionalized benzene

ring atthe 11 position, ledto the surprising discoveryof compounds that

antagonized the action of progestins and glucocorticoids. One of those

compounds, mifepristone (76), more familiarly known as RU-486, was

quicklyenveloped incontroversy, asa resultof itsuse forterminating preg-

nancy bynonsurgical means.A morerecent example,asoprinosil (84)isa

more selectiveprogesterone antagonist withreduced binding to glucocor-

ticoid receptors.Treatmentof the diene77, atotal synthesisderived 19-nor

32 ALICYCLIC COMPOUNDS

gonane, with hydrogen peroxide,results in selective reaction at the5,10

double bond to give the epoxide 78. The proximity of the acetal

oxygens atthe 3 position accounts forthe regiochemistry of theproduct;

attack from the more open a-side accounts for the stereochemistry.

Condensation of 78 with the Grignard reagent from the methyl acetal

of p-bromobenzaldehyde in the presence of cuprous salts leads to

conjugate addition to the 11 position with concomitant shift of the

double bond to the 5,9 position (79). Construction of the side chain

at the 17 position starts with the addition of the ylide from the tri-

methylsulfonium iodide to the carbonyl group give the oxirane 80.

Reaction of the productwith sodium methoxide opens the epoxide ring

to give the ether –alcohol 81. Alkylation of the hydroxyl group at 17

with methyl iodide and base affordsthe bis(methyl ether) 82. Exposure

of that intermediate to acid leads to hydrolysis of the acetal protecting

groups on the ketone at3 as well as the aromatic aldehyde; the tertiary

alcohol on the AB ring junction dehydrates under those conditions,

restoring the double bond (83). Reaction of this last intermediate with

hydroxylamineleads to formationof thealdoxime in a95 :5 (E)/(Z)ratio.

(CH

)

OCH

Mg,Cu

(CH

)

tBuOK

ONa

OCH

ONa

TsA

OCH

O=HC

OCH

2. POLYCYCLICCOMPOUNDS: STEROIDS 33

The puriﬁedisomer (84)

is currentlyused in theclinic asa treatment for

endometriosis, as wellas other conditions related to excessprogesterone

stimulation.

The total synthesisbased 17-ethyl norgonane, levonorgestrel(85), has

been in usefor many years. The corresponding oximehas recently been

introduced as the progestational component of an oral contraceptive.In

the absenceof aspeciﬁc reference,it maybe speculatedthat thecompound

norelgestimate (86),is prepared bysimply reactioning 85with hydroxyl-

amine in analogy to the preparation of the corresponding 17 acetoxy

derivative.

HON

B. Corticosteroid Related Compounds

The soybeansterols thatcomprise one ofthe principal sourcesfor proges-

tins andcorticoids consist almostentirely ofa mixture ofstigmasterol and

sitosterol. The lackof a double bond in the side chainrenders the latter

useless as a starting material since that function is key to the Upjohn

process for removing the long terpinoid side chain present in these

sterols. Asa result, tonnage quantitiesof this steroid thusaccumulated in

a Kalamazoo storage lot over the years. A microorganism was ﬁnally

found inthe late1970s thatwould feedon thisrich sourceof carbon, meta-

bolizing thefatty side chainat the 17 positionand at thesame time intro-

ducing an oxygen function at position 9 that could be used later to

introduce thecrucial double bond inring C. Considerable workwas then

devoted todeveloping methods for building upthe highly functionalized

two-carbon side chains found in corticoids at the now bare17 position

found in these biodegradation products. One of the intermediates from

one of those schemes has interestingly recently becomes a drug in its

own right. Wet macular degeneration, one variant of the disease that

leads to loss of vision withage, is marked by excessive growth of new

blood vessels in the retina. This process, neovascularization, in effect

destroys photoreceptor areas of the retina. The drug, anecortave (95),

which needs to be administered locally within the eyeball, inhibits the

34 ALICYCLIC COMPOUNDS

growth ofthose new bloodvessels thus savingstill-intact areas theretina.

Thesequence for preparationof the agentbegins withthe conversionof the

ketone at 3 toits enol ether 88, for example, with methylorthoformate.

Addition ofcyanide tothe carbonylat 17initially leadsto a mixtureof epi-

meric cyanohydrins.Conditions were developedfor converting thisto the

desired isomer 89, by crystallization under equilibrating conditions.The

17b cyanoisomer isapparently less solublethat itsepimers. The hydroxyl

group at17 is thenprotected as itstrimethylsylyl ether (90).Reduction by

meansof diisobutylaluminumhydridefollowedby proticworkupconvertsthe

cyanogroup toan aldehyde.Condensation ofthis intermediatewith theanion

from methylenebromide probably leadsinitially to adduct92. Excess base,

lithium diisopropylamide (LDA),is thought to removeone of the bromine

atoms.The resultingintermediatethen rearrangestogivethe observedbromo-

ketone. Removalof the protectinggroups leads todiketone 94, whichlacks

only oxygen atpositon 21. Displacement of bromineatom at that position

with sodiumacetate completesconstruction ofthe corticosteroidside chain

at position17.

Thus 96is obtained.

(CH

)

KCN

AcOH

(CH

)

SiCl

OTMS

CH=O

OTMS

DIBAL-H

OTMS

LDA

OTMS

LiO

NaOAc

OCOCH

Topically appliedcorticosteroids have provenvery effective intreating

asthma. The amount of drug from the inhaled dose that reaches the

small airways has a critical effect on relieving asthmatic episodes. The

acetal at positions 16,17 of the diol (97) with acetone,

desonide, has

2. POLYCYCLICCOMPOUNDS: STEROIDS 35

long been indicated for treating asthma. It has recently been found

that the acetalcontaining cylcohexane carboxaldehyde penetrates further

into the small airways. The ﬁrst step in this brief sequence comprises

reaction of the syn diol (96) with isobutyric anhydride to afford the

triply esteriﬁed intermediate 97. Reactionof this compound with cylco-

hexane carboxaldehyde in aprotic solvent in the presence of acid leads

to formation of the acetal by a transesteriﬁcation-like sequence. The

presence of the very bulky alkyl groups on the esters favors formation

of that isomer of the acetal in which the cyclohexane is oriented away

from the face of the steroid. The product (98) thus predominantly

comprises the desired isomer. Saponicationof the remaining ester at 17

followed by separation from the small amount of epimeric acetal then

affords cicledesonide(99).

–

Separate

Replacement of carbon4 in androstane by nitrogenleads to androgen

antagonists. These drugs have proven useful for treating a condition

marked byexcess androgen orsensitivity there to sucha benign prostatic

hypertrophyand even hair loss. Earlierexamples arecovered inVolumes 5

and 6 of this series.Synthesis of the most recent example starts byfor-

mation of the amide between steroid carboxylic acid 100 and 1,4-

bis(triﬂuoromethylaniline) (101) via the acid chloride. Ring A is then

36 ALICYCLIC COMPOUNDS

opened to the correspondingketo acid (102) by oxidation of the double

bond in ring A by means of permanganate.Reaction of that compound

with ammonia at elevated temperature can be visualized as proceeding

through an amide–enamine, such as 103. Amide interchange closes the

ring to form the enamide 104. Catalytic hydrogenation followed by

reaction withDDQ completes the synthesisof dutasteride (105).

100

101

KMnO

102

104

NOC

103

2.DDQ

1.H

105

Vitamin D actually consistsof aset ofclosely relatedcompounds whose

structures arebased on the steroidnucleus with an opened ringB. These

compounds control variousmetabolic processes from bone deposition to

skin growth. One of the vitamins(D3), calcitrol, has been used to treat

psoriasis and acne. A recent semisynthetic Vitamin D congener has

shown an improvedtherapeutic index over the naturalproduct. The syn-

thetic sequenceto thisanalogue hingeson selective scissionof theisolated

double bond inthe side chain. Thekey step thus involvesinactivation of

the conjugated diene centered on ring A. This is accomplished by

formation of a Diels– Alder-like adduct between the starting material

106, in which the hydroxyl groups are protected asthe diisopropylsilyl

ether and sulfur dioxide.

Ozonolysis of the adduct 107 followed by

work-up of theozonide, gives the chain-shortenedaldehyde. Heating the

product restoresthe diene byreversing the originalcylcoaddition reaction

(108). The carbonyl group is then reduced to the alcohol by means of

borohydride andthe resulting alcohol converted toits mesylate 109. The

chain is next homologated by ﬁrst displacing the mesylate with the

anion form diethylmalonate. Saponiﬁcation of the estergroups followed

by heating the product in acid cause the malonic acid to lose carbon

dioxide. Thus, the chain extended acid 110 is obtained. The carboxyl

2. POLYCYCLICCOMPOUNDS: STEROIDS 37

group is next converted to the activated imidazolide by reaction with

carbonyl diimidazole. Condensationof this intermediate with pyrrolidine

gives the corresponding amide. Removal of the silyl protection groups

with ﬂuorideleads to ecalcidine (111).

RO OR

R=Si(CH(CH

))

RO OR

1. O

2. heat

RO OR

CH=O

106 107 108

RO OR

109

1. NaBH

2. CH

OSOCH

2. NaOH

3. HCl

RO OR

110

1. CDI,

–

HO OH

111

3. POLYCYCLIC COMPOUNDS

A sequiterpinoid fulvenefrom the Jack O’Lantern mushroomwas found

some years ago to show verypromising antitumor activity in a number

of in vitro assays. This compound,Iludin S (112) was, however, found

to be too toxic in follow-up in vivo tests to be considered for further

development. Thesemisynthetic analogueirofulven (114)is far bettertol-

erated and has been taken to the clinic where it demonstrated activity

against several tumors. Though a total synthesis has been published,

the compound is most efﬁcientlyprepared by semisynthesis from Iludin

S itself. Treatment of thenatural product withdilute acid leads to lossof

the elements of water and formaldehyde in what may be considered a

reverse hydroformylation reaction to yield intermediate 113. Reactionof

that productwith formaldehyde in dilute acidin essence reverses thelast

reaction, though with a different regiochemistry. Formaldehyde thus

38 ALICYCLIC COMPOUNDS

adds to thelast open position of the extendedeneone system. Thus, 114

is obtained.

112

113

114

C=O

Pain receptors become sensitized during inﬂammation or from a

related stimuli, and consequently often release glutamate. That amino

acid then acts on NMDA receptors on neurons, and in the process

further sensitizes those to pain stimuli. This sequence then causes

the pain to become chronic. Speciﬁc NMDA antagonists would thus

be expected to relieve chronic pain by interrupting that chain.

Consequently, such compounds would offer a potentially nonaddictive

alternative to the opiates currentlyused to treat chronic pain. Reductive

amination of the acetaldehydederivative 116 with monocarbobenzyloxy

ethylenediamine (116) leads to the now-disubstituted ethylenediamine

116. Reaction of this amine with the commercially available cyclo-

butenedione derivative 117 leads to replacement of one of the ethoxy

groups in 117 by the free amino group in 116 by what is probably

an addition– elimination sequence to afford the coupled product 118.

NHCO

115

CH=O

116

NaCNBH

NHCO

116

117

NHCO

118

119

120

(CH

)

SiBr

121

3. POLYCYCLICCOMPOUNDS 39

Reduction of thisintermediate by hydrogen transfer from1,4-cyclohexa-

diene in the presence of platinum leads to loss of the carbobenzoxy

group and formation of the transient primary amine 119. The terminal

primary amino group in that product then participates in a second

addition–elimination sequence to form an eight-membered ring (120).

Treatment of this intermediate with trimethylsilyl bromide then cleaves

the ethyl etherson phosphorus to givethe free phosphonic acidand thus

perzinfotel (121).

REFERENCES

1. See, for example, Chemistry of the Prostaglandins and Leukotrienes,

J.E. Pike,D.R. Morton, Eds.,Raven Press, NY,1985.

2. J. Castaner,L.A. Sobrera, DrugsFuture 25, 41(2000).

3. See D. Lednicer, The Organic Chemistryof Drug Synthesis, Vol. 6, John

Wiley &Sons, Inc., NY1999, p. 98.

4. D.A. Woodward, S.W. Andrews, R.M. Burk, M.E. Garst, U.S. Patent

5,352,708 (1994).

5. L.A. Sobrera,J. Castaner, DrugsFuture 29, 336(2004).

6. C.U. Kimet al., J.Am. Chem. Soc. 119,681 (1997).

7. C.U. Kimet al., J.Med. Chem. 41, 2451(1998).

8. N. Bischofberger, C.U. Kim, W.Lew, H. Liu M.A. Williams, U.S.Patent

5,763,483 (1998).

9. Y.-Y. Yeung,S. Hong, E.J.Corey, J.Am. Chem. Soc. 128,6310 (2006).

10. Y.S. Babuet al., J.Med. Chem. 43,3482 (2000).

11. S.B. Christensenet al., J.Med. Chem. 41, 821(1998).

12. M.F. Boehm, M.R. McClurg, C. Pathirana, D. Mangelsdorf, S.K. White,

J. Herbert,D. Winn, M.E. Goldman,R.A. Hayman, J.Med. Chem. 37, 408

(1994).

13. J. Bowler,T.J. Lilley, J.D.Pittman, A.E. Wakelin,Steroids 54, 71(1989).

14. G. Schubert, W. Eiger, G. Kaufmann, B. Schneider, G. Reddersen,

K. Chwalisz,Semin. Reprod. Med.23, 58 (2005).

15. A.P. Shroff,U.S. Patent 4,027,019(1977).

16. J.G. Reid,T. Debiak-Krook, TetrahedronLett. 31, 3669(1990).

17. S. Bernstein,R. Littell, J.Am. Chem. Soc. 81,4573 (1959).

18. J. Calatayud,J.R. Conde, M.Lunn, U.S. Patent5,482,934 (1996).

19. K.W. Batchelor,S.W. Frye,G.F. Dorsey, R.A.Mook, U.S.Patent 5,565,467

(1996).

40 ALICYCLIC COMPOUNDS

20. R. Hesse,U.S. Patent 4,772,433(1988).

21. R.H. Hesse,G.S. Reddy, S.K.S.Setty, U.S. Patent5,494,905 (1996).

22. T.C. McMorris,Y. Hu, M.Kellner, Chem. Commun.315 (1997).

23. T.C. McMorris,M.D. Staake, M.J.Kellner, J. Org.Chem. 69, 619 (2004).

24. W.A. Kinneyet al., J.Med. Chem. 41,236 (1998).

REFERENCES 41

CHAPTER 3

MONOCYCLIC AROMATIC

COMPOUNDS

Free-standingbenzene ringshave providedthe corefor avery largenumber

ofbiologically activecompounds.This ubiquitousunit providestherigid ﬂat

skeletonon whichto attachfunctionalgroups andalsomanifests theelectron

density required forrecognition at various receptor sites. Theubiquitous

occurrence of aromatic rings in endogenous effector molecules as, for

example, the chatecholamines,is a reﬂection of this importance. The30

odd drugs described in Chapter 3 represent a wide variety ofstructural

types; their biological activities are equally diverse. Consequently, it is

often not readilyapparent just which parts of thestructures form part of

the pharmacophore.Thus, compounds areincluded in thischapter largely

on the basisof structure. The grouping in the discussions that followare

admittedly somewhatarbitrary.

1. ARYLCARBONYL DERIVATIVES

A relativelysimple benzamide inhibitor ofphosphodiesterase 4 has proven

useful for treating congestive obstructive pulmonary disease (COPD).

The synthesisof this compound beginsby alkylation of thefree phenol on

aldehyde 1with chlorodiﬂuromethane inthe presenceof base.Oxidation of

The OrganicChemistry ofDrug Synthesis, Volume7. By DanielLednicer

the carbonyl group in 2 with hypochlorite followed by reaction with

thionyl chloride leads to the acid chloride (3). Condensation of the

last intermediate (3) with the substituted aminopyridine (4) affords the

benzamide roﬂumilast(5).

O CH=O

CHCl

CHO

O CH=O

1. NaClO

2. SO

CHO

O CO

CHO

The discovery of the “statin” mevalonic acid synthesis inhibitors

focused new attention on control of blood lipid levels as a measure to

stave off heart disease. A number of compounds have been found that

treat elevated lipidlevels by other diverse mechanisms. The phosphonic

acid derivativeibrolipim (9)is believedto lower thoselevels byaccelerat-

ing fattyacid oxidation.The phosphorus-containingstarting material7 can

in principle be obtained by the Arbuzov reaction of a protected fromof

p-bromomethylbenzoic acid (6) with triethylphosphate. Removal of the

protecting group and conversion of the acid to an acyl chloride then

affords 7. Condensation of this intermediate with substituted aniline 8

leads tothe hypolipidemic agent (9).

P(OC

)

ClOC

44 MONOCYCLIC AROMATICCOMPOUNDS

Redblood cellsinpatients afﬂictedwith sickle-cellanemiashowa reduced

capacityfor holdingoxygen. Theadventitiousdiscoverythat thelipid lower-

ing agentc loﬁbrate(10) possessed some antisicklingactivity led to further

investigationof relatedcompounds. Itwas foundthat thisunexpected activity

of these agents resulted from their bringing about an increased oxygen-

carrying capacity of normalblood cells. One of the compounds from this

work, efaproxiral (15), isnow used to deliver oxygen to hypoxic tumor

tissuest oimprove theefﬁcacy ofradiation therapy.Oxygen, whosepresence

is crucialto thegenerationof cell-killingradicals, isoften inshort supplyin

solidtumors. Reactionof thearylacetic acid(11) withthionyl chlorideleads

to the correspondingacyl chloride. Condensation of thatintermediate with

3,5-dimethylaniline leads tot heanilide 14. Treatment ofthat product with

acetone and chloroform in the presence of strong aqueous base adds the

dimethyl acyl function to the phenol group. Thus, 15 is obtained.

This

unusual reaction can be visualized by assuming intitial formation of a

hemiacetalbetween thephenol andacetone (a);displacement ofthe hydroxyl

by the anion from chloroform wouldlead to the intermediate (b);simple

hydrolysiswou ldthen convertthat groupto a carboxylicacid.

COR

11; R = OH

12; R = Cl

N CH

(CH

)

CHCl

–

CHCl

HCl

Overthe pastfewyears,it hasbeenestablishedthat severalapparentlyquite

unrelateddrug classes owetheir activityto effects ona sharedbiochemical

system.The blood lipidlowering effectof the ﬁbrates, suchas, 10,andthe

hypoglycemic actionof the recently introducedhypoglycemic thiazolidine-

diones bothtrace backt oaction onsubtypes of theperoxisome proliferator-

activatedreceptors (PPAR),which regulates lipidand glucose metabolism.

Research targeted atPPAR has led to several novelhypoglycemic agents,

whichare unrelatedstructurallyto drugsprevious usedto treatdiabetes.

1. ARYLCARBONYLDERIVATIVES 45

Thesynthesis ofthe ﬁrstof thesestarts withthe formationofthe enamide

(18)from tyrosine(16) and2-benzoylcyclohexanone(17). Treatmentof that

product withpalladium on charcoal leads todehydrogenation of the ene-

amide ring with consequentaromatization. Condensation of the terminal

hydroxyl groupon the side chainin the substituted oxazole(21) with the

phenolfunction on20in thepresenceof triphenylphosphineand diethylazo-

dicorboxylate (DEAD)leads to formation ofan ether bond. Thisreaction

affordsthe hypoglycemic agentfarglitazar (22).

)

P, DEAD

An aryl carbamate replacesthe tyrosine moiety in a relatedanalogue.

The preparation of this compound ﬁrst involves activation of the side-

chain oxygen in the sameoxazole used above (21) by conversion to its

mesylate (21a) bymeans of methanesulfonyl chloride. Thisintermediate

21; R = H

21a; R = OSO

CH=O

1. H

NCH

2. NaBH

OCH

46 MONOCYCLIC AROMATICCOMPOUNDS

is used to alkylate the phenol group on p-hydroxybenzaldehyde (23).

Condensation of the aldehyde group in 24 with glycine methyl ester

leads to the corresponding imine.Reduction of that function with boro-

hydride yields the intermediate 25. Acylationof the amino group in 25

compound withp-anisyl chloroformate (26) yieldsmuraglitazar (27).

A verysimple triketone has proven usefulfor treating the raregenetic

disease tyrosinemia. The drug alternately known as nitisinone (30)or

orfadin actually bearsa very close relation to apesticide. The analogue

in which methylsulfonyl replaces the triﬂuoromethylgroup, mesotrione,

is an important corn herbicide. Acylation of cyclohexan-1,3-dione,

shown as an enol (28) with acid chloride (29), leads in a single step

to 30.

28 29 30

2. BIPHENYLS

Excision of malignanttumors comprises ﬁrst line treatment for cancer of

solid tissues. This procedurenot infrequently misses small fragments of

the tumor that may have broken off before surgery from the principal

site of thedisease. These fragments, metasteses,often proliferate at quite

remote locations where they cause much ofthe pathology of cancer. A

series of proteolytic enzymes present in tumor cells, known as matrix

metalloproteinases, help establish growth of these metasteses at the

newly invaded sites; these proteases are also involved in the formation

of new blood vessels that will nourish the invasive cell masses.

Consequently, considerableresearch has been devotedto matrix metallo-

proteinases as a target for anticancer drugs. Clinical results with these

compounds haveto date produced equivocalresults.

Constructionof one biphenyl-basedmetaloproteinase inhibitorstarts with

theFriedel– Craftsacylationof 4-chlorobiphenyl(31)with itaconicanhydride

(32).Attack proceedson the lessinactivated ringto givethe acylatedproduct

(33). Michaeladdition ofphenylmercaptan to theexomethylene groupgives

theproteinase inbitortanomastat (34).

2. BIPHENYLS 47

AlCl

31 32 33

Research onthe prostaglandins several decades agorevealed a second

pathway in the arichidonic acids cascade. Products from this alternate

route consistedof long-chain fattyacids instead ofthe cyclic prostanoids.

Subsequently,it wasascertained thatthese straight-chainacids, calledeico-

sanoids,reacted with endogenoussulfur-containing oligopeptides,such as,

glutathione, to form aseries of compoundscalled leukotrienesthat elicited

allergic reactions. These were found to be the same as the previously

known slow-reactingsubstance ofanaphylaxis (SRS-A). Drugsthat coun-

teract this factor wouldprovide an alternate means to antihistamines for

dealing with allergies. The majority of antagonists developed to date

consist of long-chain compounds that terminate in an acidic function.

This last comprises a tetrazole ratherthan a carboxylic acid in virtually

allcompounds reportedto date.A veryrecent entryinterestingly terminates

in acarboxylic acid.The convergent synthesisstarts withthe alkylation of

the enolatefrom resorcinolmonomethylether (35) withpropyl iodide.The

use ofaprotic conditionsfavors alkylationon carbonover oxygento afford

(36). The enolate fromthis product is then used to displacethe halogen

atom in o-ﬂuorobenzonitrile to give the aromatic ether. The nitrile is

then hydrolyzed to the corresponding acid with potassium hydroxide.

Treatment ofthat product with methanolin the presence ofacid converts

the latter to its methyl ester. The O-methylether in the product is then

cleaved withboron tribromide to affordthe phenol (39). Synthesisof the

second half of the compound begins with the reduction of the acetyl

group in 40 to an ethyl group (41) with tirethylsilane. Bromination of

this intermediatewith NBS proceeds,as expected at theposition adjacent

to the benzyl ether to afford 42. The side chain that will connect the

two halves isthen put in place by alkylatingthe free phenol group with

1-bromo-2-chloroethane (43). Reaction of the aromatic bromo function

in thislast intermediate withp-ﬂuorophenylboronic acid (44)leads to for-

mation ofthe biphenyl group and thus45. The Finkelstein reaction,with

potassium iodide, leads to replacementof chlorine by the better leaving

group, iodine in 46. Alkylation of the enolate from the acid moiety

39 with iodide in 46 completes construction of the framework.

48 MONOCYCLIC AROMATICCOMPOUNDS

Saponiﬁcation of the methyl ester followed by hydrogenolysis of the

benzyl ether completes the synthesis of the leukotriene B

antagonist

etalocib (47).

BuLi

1. KOH

2. MeOH

)

SiH

NBS

B(OH)

36 37

3. BBr

1. 39

2. NaOH

45; R = Cl

46; R = I

3. H

The discovery,close tohalf acentury ago thatbeta adrenergicreceptors

fellinto two broadclasses, ledto majoradvances indrug therapy.Agonists

that acton beta 2 receptors, forexample, include the majority agents for

treating asthma.The large numberof beta blockers actas beta-1 selective

adrenergic antagonist.The discoveryof a thirdsubset of bindingsites, the

beta-3 receptorshas led to acompound that providesan alternate method

to currently available anticholinergicagents for treating overactive blad-

ders. There is some evidence too that beta-3 agonists may have some

utility in treating Type II diabetes. Synthesis of the compound begins

with construction of thebiphenyl moiety. Thus, condensation of methyl

m-bromobenzoate (48) with m-nitrophenylboronic acid (49) in the pre-

sence of palladium leads to the coupling product (50). The nitro group

is then reduced to the correspondingamine (51). Alkylation of 51 with

the t-BOC protected 2-bromoethylamine (52) leads to intermediate 53.

Treatment with acid removes the protecting group to give the primary

amine (54). Condensation of this last product with m-chlorostyrene

oxide leads to formation of 56, a molecule that incorporates the aryl

2. BIPHENYLS 49

ethanolaminemoiety presentin thegreat majorityof compoundsthat acton

adrenergic receptors.Thus, solabegron (56) isobtained.

(HO

PdP(C

)

NHCO

C(CH

)

NHCO

C(CH

)

50; R = O

51; R = H

3. COMPOUNDS RELATED TO ANILINE

The structures of many monocyclic aromatic compounds have little in

common; the same is often thecase for their biological activities. They

are consequently grouped here on the basis of some shared structural

element rather thanbiological activity. The three compounds thatfollow

have incommon a nitrogen atomattached to thebenzene ring.

Awide variety ofcompounds weretested aslipid-lowering agentssome

ﬁvedecades agowhen associationbetweenheart diseaseand hyperlipdemia

wasestablished. Oneof themoreeffective agentsdiscoveredin thecourse of

thisresearch wasthe endogenoushormone thyroxin.Use of thiscompound

wasseverely limitedby itseffect onmetabolic functionandcardiac activity.

More detailedrecent researchhas the thyroidreceptor, likethose for many

other hormones, exists asa pairof subtypesthat areunevenly distributed.

One ofthese, the b-receptor,is virtuallyabsent in cardiactissue. Research

hasthus startedto identifycompounds aimedat thisreceptor. Thesynthesis

ofa selectiveblocker fortheb selectiveagent axitirome(66), startswiththe

reactionof the dianisylioidonium salt(57) with thenitrophenol (58)in the

presenceof acupric salt togive theproduct fromdisplacement ofiodine by

the phenoxideto give thediaryl ether (59).Acylation of intermediate(59)

withp-ﬂuorobenzoyl chloride (60)in thepresence oftitanium tetrachloride

yieldsthe benzophenone(61). Reactionintermediate(61) withboron tribro-

mide thenserves to cleavethe methyl ether (62).Catalytic hydrogenation

serves toreduce thenitro group toafford aniline (63).This intermediateis

50 MONOCYCLIC AROMATICCOMPOUNDS

then treated with ethyl oxalate (64) to afford the oxamic ester 65. The

carbonylgroup isthen reducedto thecorresponding alcohol;saponiﬁcation

affordsthe hypolipidemic agent66.

OCH

–

COCl

1. BBr

2. H

1. NaBH

2. NaOH

62; R = O

63; R = H

Thefew drugscurrently availablefor treatinghair lossact byvery different

mechanisms, Finasterideand structurally relatedsteroids act to diminishthe

effect oftestosterone, the hormoneclosely associated withmale pattern hair

loss. Themechanism of actionof the olderhair growth stimulant,minoxidil

(67) onthe other hand, is believedto involve the compound’svasodilatory

activity. The more recent hair growth stimulant, namindinil (74), also

shows vasodilatoraction. It is ofnote that the nitrogen-richfunctionality in

the lattersomewhat resemblesa ring-opened versionof 67. Thesynthesis of

the newer compound reﬂects the current trend to prepare drugs in chiral

form. Onebranch in theconvergent scheme thusinvolves preparationof the

complex alkyl group as a single enantiomer. Thus reductive alkylation

(R)-a-methylbenzylamine (69), with pinacolone (68), gives the secondary

amine as a mixture of diastereomers. These are then sepa ra ted by

3. COMPOUNDSRELATED TO ANILINE 51

chromatography.Catalytic hydrogenationof the appropriatediastereomers leads

to scissionof thebenzylic carbon-to-nitrogen bondto affordthe (R)-amine (71)

as a single isomer. Construction o f the second part of the molecule starts

by additionof sodiumcyanamide to theisothiocyanate (72),itself, forexample,

available fromreaction of the anilinewith thiophosgene. The thioureaproduct

(73)is then condensedwith thechiral amine (71)to afford74.

1. Separate

2. H

N=C=S

NaNCN

HN N

The activityagainst urinaryincontinence ofthe adrenergicbeta-3 recep-

toragonist solabegron(56) was notedabove. Anagent thatacts ona subset

of alpha receptors, speciﬁcally, alpha-1A/1L receptors, has also shown

activity on the same clinical end point. The synthesis starts with

Mitsonobu alkylation ofthe nitrophenol (75) with trityl protectedimida-

zole carbinol (76) to yield the ether (78). The nitro group on the

benzene ringis thenreduced byany of severalmethods (79).The resulting

aniline is then converted to the corresponding sulfonamide (80), by

reaction with methanesulfonyl chloride. Hydrolysis with mild acid then

removesthe trityl protecting groupto afford dabuzalgron (81).

C(C

)

DEAD

C(C

)

C(C

)

SnCl2

C(C

)

52 MONOCYCLIC AROMATICCOMPOUNDS

4. COMPOUNDS RELATED TO ARYLSULFONICACIDS

Thetitle for thissection aptlyillustrates thealmost arbitrarycriteria usedto

group potentialdrugs in thischapter. The fewentries in this sectioncom-

prise an interestingcontrast to afull sizeable chapter that wasdevoted to

sulfonamide related drugs in Volume 1of this series. Arylsulfonic acid

derivedmoieties formed anessential partof thepharmacophore invirtually

every one of the 40 odd antibacterial, diuretic, and antidiabetic agents

described in that chapter. In the case at hand, by way of contrast, this

functionality is no more than a convenient handle by which to coral a

group of compoundswith otherwise widely divergent structures, aswell

as biologicalactivities.

A benzene ring that contains two sulfonic acid groups, as well as a

nitrone, iscurrently being investigated asa treatment for stroke.The free

radical scavengingproperties of this compound, disufenton (89),will, it

is hoped,translate into neuroprotectiveaction on brain tissuewhen admi-

nistered during the ﬁrst6 h after a cerebralstroke. The synthesis of this

compound starts withthe preparation of the highlysubstituted hydroxyl-

amine (86).Thus, reaction of benzaldehydewith tert-butylamine leads to

imine 83. Oxidation of intermediate 83 with m-perchlorobenzoic acid

(MCPBA) gives theoxazirane (84); this rearranges to thecorresponding

nitrone (85)on heating. Hydrogensulﬁde then servesto reduce thatinter-

mediate tothe requisite hydroxylamine(86). In asomewhat unusual reac-

tion, treatment of2,4-dichlorobenzaldyde with sodium sulﬁte atelevated

temperature leads to displacement of each of the halogens by sulfur to

give the disulfonicacid (88) as its sodium salt.This S

2-like reactionis

probablyfacilitated by thelowered electrondensity atthe 2and 4positions

of the startingbenzaldehyde (87). Reaction ofthe products (88) with the

intermediate (86),leads toformation of thenitrone (89)by hydroxylamine

interchange. Thus89 is obtained.

CH=O

NC(CH

)

NC(CH

)

NC(CH

)

MCPBA

NC(CH

)

Heat

C(CH

)

CH=O

NaO

C(CH

)

4. COMPOUNDSRELATED TO ARYLSULFONICACIDS 53

Elastase isan inﬂammatoryprotease associated withlung injurycaused

by infection orany of a number ofother tissue insults. Inhibitors of this

enzymewould thusbe expectedto aid intreatment oflung injuries.A com-

pound that includes a sulfonamide linkage has shown activity against

neutrophil elastase.Protection of the phenol in p-hydroxyphenylsulfonate

(90)asitstert-butyl ester (91),comprises the ﬁrststep in theconstruction

of anelastase inhibitor.The sulfonate functionis then activatedas thesul-

fonyl chloride (92)by reaction with thionylchloride. In the otherarm of

the convergent scheme, condensation of o-nitrobenzoyl chloride ( 93)

with glycine benzyl ester (94)leads to the second half of the molecule.

The nitro group in this intermediate is then reduced to an amine with

iron inthe presence of acid.Reaction of the newlyrevealed amino group

with sulfonyl chloride in 92 yieldsthe corresponding sulfonamide (97).

Hydrogenolysis of the benzylprotecting group affords the free acid and

thus sivelestat(98).

NaO

(CH

)

COCl

NaO

C(CH

)

ClO

C(CH

)

COCl

C(CH

)

Fe/HCl

C(CH

)

The potentialantimetastatic activity of inhibitorsof metalloproteinases

has generatedconsiderable work in thearea as noted inthe discussion of

tanomastat (34).The very differentstructure of the inhibitorprinomastat

(107) illustratesthe considerablestructural freedom thatseems to existfor

inhibitors ofthese enzymes. Displacementof halogen in 4-chloropyridine

(99) by phenoxide leads to the diaryl ether (100). Reaction of inter-

mediate 100with chlorosulfonic acid affordsthe sulfonyl chloride (101).

54 MONOCYCLIC AROMATICCOMPOUNDS

Construction ofthe thiomorpholine moietystarts by protectionof the car-

boxylic acidin penicillamine (102) byreaction with hexyldimethylsilane

(Dmhs). Condensationof 103 with 1,2-dichloroethane leadsto formation

of theheterocyclic ringby sequential displacementof halogen by nitrogen

and sulfurto yield 104. Reactionof intermediate 104 withthe benzophe-

none (101), leadsto formation of the sulfonamide (105). Mildacid then

serves toreveal the free carboxylicacid (106). This functionis then con-

verted tothe acid chloridewith oxalyl chloride.Treatment of thisreactive

intermediate withhydroxylamine leads to acylation onnitrogen to afford

the proteinaseinhibitor 107.

102

Dmhs =C6H13(CH3)2Si

Dmhs

103

DBU

104

100

ClSO

101

ClO

Dmhs

105

106

O NHOH

1. (COCl)

2. NH

107

Endothelins comprisea groupof vasoconstrictivepeptides generatedby

the endothelium of blood vessels, as well as other tissues. Studies on

inhibitors or frank antagonist suggest that such compounds will be of

value in treating various cardiovascular diseases. The synthesis of an

antagonist starts by forming a sulfonamide linkage. Thus, reaction of

o-bromobenzenesulfonyl chloride (108)with aminoisoxazole (109) gives

the sulfonamide (110). The somewhat acidic sulfonamide function is

then tied up as its methoxymethylene (MOM) derivative. Lithium –

halogen interchange of the bromine in 111 followed by reaction with

trimethyl borategives the borateester (112). Mild acidleads to thecorre-

sponding boricacid derivative.Reaction ofthat compoundwith the substi-

tuted bromobenzene (114) in the presence of a palladium– triphenyl

phosphine complex leadsto aryl coupling and formationof the biphenyl

(115).The MOM groupis lostalong theline, mostlikely duringhydrolysis

of the borate ester. Reductive amination of the aldehyde function in

4. COMPOUNDSRELATED TO ARYLSULFONICACIDS 55

115 withmethylamine givesintermediate 116. Acylationof the secondary

amine withpivaloyl chlorideaffords thecorresponding amide andthus the

endothelin receptorantagonist edonentan (117).

108

109

110

MOM

111; MOM = CH

OCH

(CH

MOM

1. BuLi

3. (CH

(HO)

MOM

112

113

O = HC

114

O = H

Pd, (C

)

[H]

115 116 117

Cholesterol isnot absorbed from theintestine as such, butneeds to be

esteriﬁed ﬁrst. This process requires a special enzyme, ACAT (acyl-

CoA: cholesterol acyltransferase). Inhibitors of this enzyme should

provide a means of reducing serum cholesterol levels by limiting the

amount absorbedfrom thediet. The inhibitoravasamibe (125)is included

in thissection though the sulfur-containingfunction, which comprises an

unusual sulfonamide linked through oxygen rather than carbon.

Chloromethylation of commercially available 1,3,5-triisopropylbenzene

(118) withformaldehyde and hydrogenchloride affords the chloromethy-

lated derivative ( 119).Displacement of the benzylic chlorine bycyanide

gives thecorresponding nitrile (120).The cyano groupis thenhydrolyzed

with baseto givethe arylaceticacid (121). Theother branchof theconver-

gent synthesis starts with reaction of the hindered phenol (122) with

isocyanosulfonyl chloride to give the O-sulfonated product (123).

Hydrolysis thenleads to O-sulfonamide (124). Acylation ofintermediate

124 with the acid chloride obtainedfrom acid 122 and thionyl chloride

leads tothe ACAT inhibitor(125).

56 MONOCYCLIC AROMATICCOMPOUNDS

OCNSO

HCl

KCN

HOH

–

OCN

118 119 120 121

122 123 124

125

The pHof intracellularspace isknown to fallduring ischemicepisodes,

heart surgery, and other events that compromise cardiac function. This

encourages entryof sodium and calcium intocardiac cells. The resulting

calcium overloadmay then compromisecontractile function. The recently

developedantiarrhythmic agent cariporide(130) has beenfound toact by

speciﬁcally inhibiting the sodium–proton exchange that leads to further

injury. Chlorosulfonationof p-isopropylbenzoic acid leads to thechloro-

sulfonyl derivative (127). Treatment of intermediate 127 with sodium

sulﬁte in base serves to reduce the newly introduced function to the

126

ClSO

ClO

127

HHO

128

NaOH

1. SO

2. H

C N

129130

4. COMPOUNDSRELATED TO ARYLSULFONICACIDS 57

sulfenicacid (128). Alkylationby meansof baseand methylbromide gives

the corresponding arylmethyl sulfone (129). The carboxylicacid is then

activated as the acid chloride by treatment with thionyl chloride.

Reaction of this intermediate with guanidine gives the aroyl guanidine

(130).

5. DIARYLMETHANES

Prolonged treatmentof cancer patients with chemotherapeuticagents not

infrequently results in the development of drug resistance. The small

number of malignant cells that survive exposure to the drug proliferate

and become the dominant population. A farmore serious case involves

the development of cell lines that develop resistance to more than one

class ofdrugs, acondition known asmultidrug resistance.The structurally

relativelysimple compound tesmilifene(133) has beenshown to enhance

the antitumor activity of severalclasses of chemotherapy agents against

multidrug resistant cancers. The mechanism of actionof this drug is as

yet unclear. Thiscompound is prepared by alkylation ofp-benzylphenol

(131) with2-chlorotriethylamine (132).

N(C

)

131

132

133

N(C

)

Moving theside chain bearing theamino group tothe benzylic carbon

leads to compoundswith very different activities.Anticholinergic agents

speciﬁc formuscarinic receptorshave provento be veryuseful for treating

urinaryincontinence. The synthesisof arecent examplespeculativelystarts

with theFries rearrangementof theester (134) tothe benzophenone(135).

This compound is thentreated with the organometallic reagent obtained

O O

134

135

AlCl

CH(CH

)

CH(CH

)

BuLi

CH(CH

)

CH(CH

)

CH(CH

)

CH(CH

)

137

138

136

58 MONOCYCLIC AROMATICCOMPOUNDS

from 2-chloroethyl diidopropyl amine (136) to afford the benzhydrol

(137). Hydrogenolysis over palladium would then afford tolterodine

(138).

The releaseof largeamounts of theneurotransmitter glutamateduring a

stroke lead to ﬂood nerve cell receptors, such as that for N-methyl-

D-

aspartate (NMDA) causing excessive stimulation. The NMDA receptor

antagonists have as a result been investigated as agents for preventing

some ofthe injury from strokes.Relatively small changesin the structure

of tolterodine,lead toan NMDAantagonist. Condensationof 3,3-diﬂuoro-

benzophenone (139) with the lithio reagent from acetonitrile yields the

benzydrol (140). The nitrile group isthen reduced to the corresponding

amine by means of diborane. Treatment with acid leads to loss of the

tertiary hydroxyl group and formation of the oleﬁn (141). The double

bond is reduced by catalytichydrogenation (142).

The primary amino

group can then be converted to the N-methyl derivative by any of a

number of procedures,such as, treatment with formaldehyde andformic

acid. Thenthe NMDA receptor antagonistdelucemine (143) is obtained.

139

LiCH

1. BH

2. H

140

141

142

NHCH

143

The ﬁrst product from one of the branches of the arachidonic acid

cascade comprises a bridged bicylic compound where a pair of oxygen

atoms form one of the rings. One route from this leads to the

familiar ﬁve-membered ring prostaglandins; an alternate path leads to

thromboxanes, one of the principal injurious products of the cascade.

Compoundsthat block thromboxaneswould beuseful in treatingthe vaso-

constricting and platelet aggregating action of this compound. The

synthesis ofa recent thromboxanes A

receptor antagoniststarts with the

Wittig condensation ofthe ylide from v-phosphinocarboxylic acid(145)

with the ketone (144) to give the oleﬁn (146). The reaction apparently

5. DIARYLMETHANES 59

proceeds to give exclusively to the (E) oleﬁn isomer. Acid hydrolysis

removes the acetyl protection. Reaction of that intermediate with the

cyanoimidate 148 leads to displacement of one phenoxy groups by the

amine in 147. This reagent may be viewed formally as the phenol

acetal of cyanamide formate. Reaction of the intermediate 149 with

tert-butylamine displaces the remaining phenoxy group to form the

corresponding cyanoguanidine.Thus terbogrel (150) isobtained.

CONH

144

)

P(CH

)

CONH

145

146 147

148

149

150

(CH

)

CNH

(CH

)

CNH

tBuOK

6. MISCELLANEOUS MONOCYCLIC AROMATIC

COMPOUNDS

Damage toperipheral nerves,termed peripheral neuropathy,is among one

of themore common consequences ofdiabetes; it may alsobe caused by

Parkinson’s diseaseor various toxins.Neurophilins areagents that reverse

that conditionand encourage newnerve growth. Thesmall molecule tim-

codar (157) has shownpromising activity in animal models andseveral

early clinical trials. Aldol condensation of pyridine-4-carboxaldehyde

(152) with acetone dicarboxylic acid (151) proceeds to the keto acid

(153).This transient intermediatedecarboxylates underreaction conditions

to afford the bis(enone) 154. Hydrogenation over platinum proceeds to

give the saturated ketone (155). Treatment of 155 with benzylamine in

the presence of cyanoborohydride leads to the product from reductive

amination (156). Acylation with hydrocinnamoyl chloride affords the

amide 157.

60 MONOCYCLIC AROMATICCOMPOUNDS

151

CH=O

152

C CO

153 154

155

NaBH

156

157

The discovery several decades ago of the nontricyclic antidepressant

drugs, exempliﬁed by Prozac (ﬂuoxetine), has revolutionized society’s

view of depression. Use of these agents has mushroomed to the point

where they are indiscriminately consumed to overcome moods induced

by mild disappointments. The enormous market for drugs that act by

this mechanism has led to the introduction of a host of more or less

closely structurally analogues. A very recent stereoselective synthesis

for one of these drugs, (S,S)reboxetine (166), starts with the commer-

cially available chiral (S )-3-aminopropanediol (158). Acylation with

chloroacetyl chlorideleads to the amide(159). Treatment of intermediate

159 withstrong base result ininternal displacement ofhalogen with con-

sequent formation ofthe morpholine ring (160). Reduction ofthe amide

function with the hydride Red-Al forms the desired morpholine (161).

The secondary amino group is protected as its t-BOC derivative (162)

by acylation with t-BOC chloride. The next step involves oxidation of

the primary alcohol with the unusual reagent combinationconsisting of

2,2,6,6-tetramethylpiperidinyl-N-oxide (TEMPO) and trichloroisocya-

nuryl chloride. Thus aldehyde 163 is obtained. Condensation of this

with diphenyl zinc,obtained by treating phenylmagnesiumbromide with

zinc bromide,affords the secondary carbinol(164). The same reactionin

the absence ofzinc leads to recoveryof unreacted aldehyde. Thedesired

diastereomers was formed in an 3 :1 ratio with its isomer. The ﬁnal

piece could be added by conventional means, for example, by reaction

with 2-ethoxyphenol inthe presence of DEAD and carbon tetrachloride.

Reaction of 104 with the chromyl reagent (165) followed by oxidative

6. MISCELLANEOUSMONOCYCLIC AROMATIC COMPOUNDS 61

removal ofchromium by iodine gavethe product in highyield. Removal

of the t-BOCprotecting group with triﬂuoroacetic acid(TFA) completes

the synthesis of(166).

158

159

160

Red-Al

161

162

OCOtBu

O=HC

OCOtBu

[O]

)

OCOtBu

163

164

(CO)

165

166

2. TFA

tBuOK

tBuOCOCl

Many, if not most, cancer chemotherapy agents can be considered

selective toxinswith a rathernarrow therapeuticindex. Theadministration

of these agentsis quite frequently accompaniedby nausea and vomiting,

the reﬂex whereby the body seeks to reject toxins. Classical antiemetic

compounds, such as the phenothiazines, have little effect on chemo-

therapy inducedemesis. The morerecently introduced serotoninantagon-

ists are far more effective. They however, are, not universallyeffective

and elicit severe CNS side effects in some patients. A pair of closely

related antiemetics act by a very different mechanism: these drugs

oppose emesis byacting as antagonists at tachykininreceptors. The syn-

thesis of the common moiety starts with aldol-like condensation of the

anion from the acetonitrile (168) generated with a strong basewith the

ester group on the piperidine (167). Heating the product (169)from

that reaction with strong acidleads to hydrolysis of the nitrile group to

the corresponding acid. The transient intermediate then decarboxylates

to afford theketone (170). Reaction of 170 with brominethen gives the

bromoketone (171). This undergoes spontaneous internal displacement

of bromine by the piperidine nitrogen. The formation of this bridge

leads tothe quinuclidine (172)as a quaternarysalt. The benzylprotecting

group on nitrogen is then removed by hydrogenolysis over palladium

to yield the substituted quinuclidone (173). Reductive amination with

2-methoxy-4-isopropylbenzylamine (174) affords ezlopipant (175); the

same reaction using 2-methoxy-4-tert-butylylbenzylamine leads to

maropitant (176).

27,28

62 MONOCYCLIC AROMATICCOMPOUNDS

167

Base

168 169

170

171172173

175

OCH

H3C

OCH

174

176

OCH

CH3

Mostparadigms fortreating Parkinson’sdisease involveincreasing dopa-

mine levels at synapsesin the brain. Administration of dopamine itself is

ruled outs incethe polarity of thiscompound prevents it fromcrossing the

blood–brain barrier. Dopamine,like most neurotransmitters, istaken back

bythe presynapticﬁber afterit hastriggered action.A compoundthat inhibits

thisprocess wouldas aconsequenceinc reaselevelsof dopaminein thesynap-

ticcleft. Thestarting material(177) fora dopaminereuptake inhibitor infact

comprisesthe free acid formof cocaine. Hydrolysis inmild acid servesto

removethe benzoate(178). Reaction ofthis hydroxyl acidwith phosphorus

oxychloride leads toloss of the hydroxyl and formationof the conjugated

acid. This compound is the n converted to its methyl ester (179).

Condensation withthe Grignard reagentfrom 3,4-dichlorobromobenzenein

the presence of copper leads to conjugate addition of the organometalic

6. MISCELLANEOUSMONOCYCLIC AROMATIC COMPOUNDS 63

reagentand formationof 180.The estergrouping isnext reducedto thecorre-

sponding carbinol(181). Swern oxidationwith oxalylchloride then leadsto

aldehyde 182.Treatment of this intermediatewith O-methylhydroxylamine

leads tothe O-methlyloxime. Thusthe dopaminereuptake inhibitorbraso-

fensine (183)isobtained.

177

HCl

178

1. POCl

179

2. CH

180

LiAlH

181

MgBr

182

(COCl)

ONH

183

Both the older tricyclic antidepressants and the more recent drugs

related to ﬂuoxetine owe their efﬁcacy to interaction with receptors

for the neurotransmitters epinephrine, serotonin, and dopamine. The

184

185

186

Base

1. SO

2. NaN

187

188

LiAlH

189

COCl

190

LiAlH

191

64 MONOCYCLIC AROMATICCOMPOUNDS

antidepressant igemsine(191) actsby some otheras yetundeﬁned mecha-

mism. Thecompound is described asa ligand forsigma receptors, a sub-

class ofopiate receptors notassociated with pain pathways.Alkylation of

the anionfrom 2-phenylbutyricacid withthe allylic halide(185) yieldsthe

acid (186). The carboxylic acid is then converted to the corresponding

azide by reaction in turn with thionyl chloride and sodium azide.

Heating this compound inan aprotic solvent then affords the isocyanate

rearrangement product.Reduction with LiAlH

gives theN-methylamine

189. Thiscompound isthen acylatedwith theacid chloride fromcyclopro-

pyl carboxylic acid (190). Reduction of the amide, again with hydride,

gives theantidepressant 191.

Virtuallyall estrogen antagoniststhat havebeen inthe clinicincorporate

a basic sidechain in the form ofan tertiary-aminoethoxy aromatic ether.

An exception, published in the 1960s,reported that the amine could be

replaced by a glycol.

The estrogen antagonist ospemifene (195) takes

this one step further. Antiestrogenic activity is retained when the basic

192

NaOH

193

194

CCl

,(C

)

N(CH

)

195

196

6. MISCELLANEOUSMONOCYCLIC AROMATIC COMPOUNDS 65

ether in the antagonist toremifene (196)

is replaced by a simple

hydroxyethyl group.This agent is prepared starting withan intermediate

(192) used to prepare 196. Alkylation of the phenol in 192 with

the choroethanol benzyl ether affords 193. The free hydroxyl at

the end of the chain is then converted to the halide (194)by

reaction with carbon tetrachloride and triphenyl phosphine. Removalof

the benzyl group by means of hydrogen over palladium then affords

195.

There is some evidence that points to an association between

Alzheimer’s disease and a deﬁct in brain acetylcholine levels.

Considerable attention has thus focused on cholinesterase inhibitors as

potential drugs for treating theafﬂiction. The preparation of a relatively

simple inhibitor is prepared by acylation of the benzylamine (197)

with chloroformamide (198). The resulting urethane is then resolved

to affordrivastigmine (199).

(CH

)

(CH

)

197 198 199

The lipidemic compound ezetimibe (207), whose structure differs

markedlyfrom the ACATinhibitor avasamibe (125),discussed previously,

also inhibits absorption ofcholesterol from the gut. The keyto the con-

struction of thiscompound involves formation of anazetidone. Enamine

formation betweenthe p-benzyloxybenzaldehyde (200) and aniline(201)

provides one of the required reactants, imine 202. This compound is

then treated witha half-acid chloride of ethyl adipate(203) and triethyl-

amine. In all likelihood, this ﬁrst dehydrohalogenates under reaction

conditions to form the substituted ketene. The transient intermediate

reacts withthe imine in a2 þ 2cylcoaddition to afford afour-membered

ring and thus204. The reaction proceedsto give the trans isomeralmost

exclusively. The ester group is then hydrolyzed by means of lithium

hydroxide. Condensation with the zinc reagent formed in situ from

p-ﬂuoromagnesium bromide and zinc chloride affordsthe ketone (205).

The carbonyl group is thenreduced with diborane to afford the alcohol

(206). Removal of the benzyl protecting group by hydrogenolysis over

palladium ﬁnallyaffords 207.

66 MONOCYCLIC AROMATICCOMPOUNDS

200

O=HC

OCH

201

OCH

C6H

202

OCH

COCl

203

204

C=O

1. LiOH

MgBr

ZnCl

OCH

205

OCH

Pd/C

206 207

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9. J.S. Sawyeret al., J.Med. Chem. 38,4411 (1995).

10. K.H. Donaldson,B.G. Shearer, D.E.Uehling, U.S. Patent6,251,925 (2001).

11. J. Malm,Curr. Pharm. Design 10,3525 (2004).

12. N. Yokoyamaet al., J.Med. Chem. 38,695 (1995).

13. K.S. Atwal,U.S. Patent 6,013,668(2000).

14. R.L. Cournoyer,P.F. Keitz,C. O’Yang,D.M. Yasuda,U.S. Patent6,057,349

(2000).

REFERENCES 67

15. L.A. Sobrera,P.A. Leeson, J.A. Castaner,M. del Fresno, DrugsFuture 29,

240 (2002).

16. K. Imaki,Y. Arai, T.Okegawa, U.S. Patent5,017,610 (1991).

17. L. Bender,M.J. Melnick, U.S. Patent5,753,653 (1998).

18. N. Murugesanet al., J. Med. Chem. 46, 125(2003).

19. H.T. Leeet al., J.Med. Chem. 39,5031 (1998).

20. H.-J. Lang,A. Weichert, H.-W.Kleeman, H. Englert,W. Scholtz,U. Albus,

U.S. Patent5,591,754 (1997).

21. L.J. Brandes,M.W. Hermonat, U.S.Patent 4,803,227 (1989).

22. N.A. Johnsson,B.A.Sparf, L.Mikiver, P.Moses, L.Nilvebrant, G.Glas, U.S.

Patent 5,382,600(1995).

23. S.T. Moe, D.L. Smith, K. By, J.A. Egan, C.N. Filer, J. Label. Comp.

Radiopharm. 41,535 (1998).

24. R. Soyka, B.D. Guth,H.M. Weisenberger, P. Luger, T.H. Muller,J. Med.

Chem. 42,1235 (1999).

25. R. Zelle,M. Su, U.S.Patent 5,840,736 (1998).

26. E. Brenner,R.M. Baldwin, G.Tramagnan, Org. Lett.7, 937 (2005).

27. J.A Lowe,U.S. Patent 5,451,586(1995).

28. I. Fumitaka,H. Kondo,M. Nakane,K. Shimada, J.A.Lowe, T.J.Rosen, U.S.

Patent 5,807,867(1998).

29. L.A. Sobrera,J.A. Castaner, DrugsFuture 25, 196(2000).

30. G.G. Aubardet al., U.S.Patent 5,034,419 (1991).

31. D. Lednicer,D.E. Emmert,S.C. Lyster,G.W.Duncan, J.Med. Chem.12, 881

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32. D. Lednicer,The OrganicChemistry ofDrug Synthesis,Vol. 5,John Wiley&

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33. M. DeGregorio,V. Wiebe,L. Kangas, P.Harkonen, K. Vaananen,A. Laine,

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68 MONOCYCLIC AROMATICCOMPOUNDS

CHAPTER 4

CARBOCYCLIC COMPOUNDS

FUSED TO A BENZENE RING

The nucleus ofa modest number of newcompounds comprise a two- or

three-ring fusedsystem, one of whichconsists of a benzenering. As was

the case for free-standing benzene rings in Chapter 3, the annelated

rings in mostinstances serve merely as supportsfor the pharmacophoric

substituents.

1. INDENES

Imidazolines havea venerablehistory asa-adrenergic agents. Compounds

that includethis group variouslyact as a

- anda

-agonists orantagonists

depending on the substitution pattern in the rest of the molecule. The

indene fadolmidine (5), is an effective a

-agonist that blocks pain

responses. The compound does not cross the blood –brain barrier as a

resultof its hydrophobiccharacter; ithas asa consequencebeen developed

as adrug for useas a spinalanalgesic. Preparationof the compoundstarts

with a crossed version of the McMurray reaction. Thus treatment of a

mixture of the indanone (1) with N-benzyl protected imidazolecarbox-

aldehyde (2) in the presence of TiCl

, preformed from TiCl

and zinc

powder, gives thecoupling product 3. Catalytic hydrogenation serves to

The OrganicChemistry ofDrug Synthesis, Volume7. By DanielLednicer

both reduce thedouble bond and to remove thebenzyl protecting group

(4). Reaction of4 with hydrogen bromide then cleaves themethyl ether

on benzeneto afford the freephenol and 5.

O=HC

TiCl4

HBr

The antidepressantcompound lubazodone (8)illustrates the breadthof

the structuralrequirements for serotonin selectivereuptake inhibitors; the

structure of thisagent departs markedly from that of ﬂuoxetine,the ﬁrst

drug in this class. The compound at hand also exempliﬁes the current

trend forpreparing drugs in chiral form.Thus reaction of theindanol (6)

with the mesylate from chiral glycidic oxide in the presence of base

leads to the epoxypropyl ether(7) with retention of chirality. Treatment

intermediate 7 with aminoethylsulfonic acidcloses the morpholine ring.

Product 8consists of pure (S) enantiomer.

OSO

Alzheimer’s disease,as notedearlier, isassociated withdecreased levels

of acetylcholine in thebrain. Mostof the drugsthat have beenintroduced

to date for treating this disease thus comprise anticholinergic agents

intended to raisethe deﬁcient levels byinhibiting loss of existingacetyl-

choline. A compound-based on an indene perhaps surprisingly, shows

70 CARBOCYCLIC COMPOUNDSFUSED TOA BENZENE RING

anticholinergic activity, and has been proposed for treatment of

Alzheimer’s disease. Condensation of piperidinealdehyde (10) with the

indanone (9) leads to the oleﬁn (11). Catalytic reduction removes the

double bondto afford donepezil (12).

O=HC

More recentwork indicates thatmonoamine oxidase (MAO) inhibitors

may be usefulas well. The indene ladostigil (17)is intended to address

both ofthose targets; the compound thusincorporates a carbamate group

associated with anticholineric activity and a propargyl moiety found in

MAO inhibitors. The synthesis involves juggling protecting groups

on two reactive functions. Thus, reaction of amino-indanol (13) with

bis-tert-butoxy carbonate affords the corresponding t-BOC protected

derivative14. Treatmentof derivative14 with N-methy-N-ethylcarbamoyl

chloride affords the O-acylated carbamate (15). The t-BOC protecting

group is then removed by means of hydrogen chloride to give the free

amine (16). Reaction of16 with propargyl bromide gives 17. This drug

also consists of asingle (R) enantiomer; it is not clear from thesource

at whichstage the resolution takesplace.

NHCO

BOC

tBuO

NHBOC

HCl

1. INDENES 71

The hormonemelatonin (30) isintimately involvedin the diurnal cycle

with levelsrising late inthe day priorto sleep. Congenershave asa result

been preparedin thesearch fora sleepinducing drugs.Ramelteon (29),an

indene that incorporates several structural features of the hormone, has

been approved bythe FDAas a sleepingaid. Theﬁrst part ofthe synthesis

involves constructionof the ethylamine sidechain. Thus condensation of

indanone (18)with theyilde from2-diethoxyphoshonoacetonitrile attaches

the requisitetwo carbon chain(19). The nitrile isthen reduced tothe cor-

responding primaryamine (20) bymeans of Raneynickel. This drug also

follows the current trend toward achiraly deﬁned substance. Reduction

of the double bond with rhodium in the presence of the chiral catalyst

2,2

-bis(diphenylphosphino)-1,1

-binaphthyl (BiNAP) affords the intermedi-

ate (21)asthe(S) enantiomer.This compoundis thenacylated withpropionyl

chloride toafford 22. The remainderof the scheme involvesconstruction

of thefused furan ring.Bromination proceeds atthe slightly lesshindered

position. The methoxy group is then cleaved with boron tribromide to

yield the bromophenol (23). Alkylation of the phenol with allyl

POCH

BiNAP

COCl

NHCOC

1. Br

2. BBr

NHCOC

200°C

NHCOC

O=HC

NaBH

NHCOC

/Pd

1. CH

2. TEA

NHCOC

NHCOCH

72 CARBOCYCLIC COMPOUNDSFUSED TOA BENZENE RING

bromide proceedsto the allylether (24). Heating compound24 leads toa

Claisen rearrangementto the C-allyl derivative(25); bromine atthe other

ortho positionprevents formation ofthe alternate undesiredisomer. Ozoniza-

tion followedby reductive workupleads to 26; treatmentof the aldehyde

with sodium borohydride reduces that function to an alcohol providing

27. Theblocking bromine atomis thenreplaced by hydrogenby meansof

hydrogenation overpalladium to yield 27. Constructionof the furan ring

starts byconversion of the primaryalcohol to its mesylatewith methane-

sulfonyl chloride. Treatment of the product with triethylamine (TEA)

formsthe phenoxide,which thendisplaces themesylategroup. Thisinternal

displacement formsthe furanring. Thus,ramelteon (29) isobtained.

2. NAPHTHALENES

The parathyroidglands comprise one ofthe principal centers for regulation

of calcium levels. The parathyroidhormone secreted by those glands into

the bloodstream directlycontrols levels of calcium and phosphorus.In the

normal course ofevents, low levels of calciumwill result in release ofthe

hormone andvice versa.Patients with kidneydisease whoare on dialysis,as

well as thosewith parathyroid gland neoplasms, tend to havesigniﬁcantly

elevatedcalcium levels,a conditionthat canlead to hypertensionand conges-

tiveheart failure.Astructurally relativelysimplenaphthalene derivativelowers

parathyroidlevels by bindingto calcium receptorson the gland.Reaction of

commercially available (R)-ethyl-a-naphthylamine (31) with the aldehyde

(32) affordsthe Schiff base (33).Reduction of intermediate 33with cyano-

borohydride leadsto thecalcium mimeticcompound cinalcet (34).

O=HC

33 34

NaCNBH

It isnow recognizedthat protein kinasesplay animportant role inintra-

and intercellular communications. These enzymes are consequently

directly involvedin cell proliferation.The p38 kinase, forexample, regu-

lates the production of key inﬂammatory mediators. Excess expression

of thisfactor isinvolved inthe pathologyof rheumatoidarthritis, psoriasis,

and Crohn’s disease. A rather complex protein kinase inhibitor, which

2. NAPHTHALENES 73

includes a substituted naphthyl moiety, has shown preliminary in vivo

activity.The convergentsynthesis startswith constructionof a heterocyclic

fragment. Condensationof the keto-nitrile(35) with p-tolylhydrazine(36)

proceeds togive the pyrazole( 37).The overall transformcan be rational-

ized byinitial formation ofa hydrazone; additionof the remaining hydra-

zine nitrogento the nitrilewould then formthe pyrazole ring.Reaction of

this intermediatewith phosgenethen convertsthe primaryamine to aniso-

cyanate(38). Theother branchof thescheme ﬁrstinvolves alkylationof the

t-BOC protectednaphthylamine (39) in thepresence of basewith chloro-

ethyl morpholine(40). Exposure to acidthen cleaves thet-BOC group to

affordthe freeamine (41). Addition of theamino groupin thisintermediate

to the reactive iscocyanate in 38 connects the two halves via a newly

formed ureafunction. Thus, the p38 kinaseinhibitor doramapimod (42)

is obtained.

(CH

)

(CH

)

tBuOCHN

1. Base

2. H+

COCl

(CH

)

(CH

)

N=C=O

37 38

3. TETRAHYDRONAPHTHALENES

Drug therapyfor treating Parkinson’s diseaseinvolves supplementing the

deﬁcient levelsof dopamine inthe brain thatcharacterize thedisease. The

blood–brain barrier virtuallydictates thatthe agentsneed to belipophillic;

74 CARBOCYCLIC COMPOUNDSFUSED TOA BENZENE RING

dopamine itselfis too hydrophilic topenetrate the brain fromthe circula-

tion. A tetrahydronaphthalene derivative that incorporates one of the

phenolic hydroxyls,as well as anethylamine-like sequence of dopamine,

showsthe sameactivity asthe neurotransmitter.The lipophilicityof rotigo-

tine (52) allowsit not only to cross the blood–brain barrier, but to also

reach thecirculation when administeredtopically. The drugis in factpro-

videdin a skinpatch formulationthat providesprolongedblood levels. The

preparation ofthis dopaminergic agent begins withthe conversion of the

dihydroxynaphthalene (43) to its methyl ether by means of dimethyl

sulfate. Treatment of 44 with sodium in alcohol initially leads to the

dihydro intermediate (45).The regiochemistry follows from the factthat

only the right-hand ring has twoopen positions in a 1,4 relationship to

the methyl ether for forming the initial metal adduct. Treatment of 45

with acid then hydrolyzes the enol ether to afford the b-tetralone (46).

The carbonyl group is next converted to a Schiffbase (47) by reaction

with propylamine. Catalytic hydrogenation of the intermediate then

affordsthe secondaryamine. Thisintermediate isresolved viaits dibenzoyl

tartrate salt (48). The methyl ether in the (S) enantiomer is cleaved by

means of hydrogen bromide to give the corresponding phenol (49).

Reaction with anactivated form of 2-thienylacetic acid(50) followed by

reduction ofthe amide (51)with diboranegives the correspondingtertiary

amine, 52.

(CH

)

OCH

NHC

Resolve

HBr

NHC

3. TETRAHYDRONAPHTHALENES 75

The effectson cell proliferationof retinoids hasled to theinvestigation

of structurally related compounds as potential antineoplastic drugs. The

ﬁnding manyyears ago thatthe cyclobexyl moiety inthe naturally occur-

ring compound canbe replaced by a tetrahydronapthalenehas simpliﬁed

work inthis area. It isof interest that ineach of the examplesthat follow

a benzene ring serves as a surrogate for the unsaturated carbon chain

found in natural retinoids. The tetralin-based compound tamibarotene

(59) has been tested as anagent for treating leukemias. Reaction of the

diol (53) with hydrogen chloride affords the corresponding dichloro

derivative (54). Aluminum chloride mediated Friedel –Crafts alkylation

of acetanilidewith thedichloride affordsthe tetralin (55).Basic hydrolysis

leads to the primary amine (56).Acylation of the primary amino group

with the halfacid chloride half ester from terephthalicacid (57) leads to

the amide(58). Basic hydrolysis ofthe ester grouping thenaffords 59.

HCl

NHCOCH

NaOH

ClOC

NaOH

The retinoid-like compound bexarotene (63)is approved for treating

skin lesions associatedwith T-cell lymphomas. The starting tetralin(60)

is probably obtained by alkylation of toluene with dichloride (54).

Friedel–Crafts acylation with the acid chloride (57), gives the ketone

(61). Thisintermediate isthen treatedwith theylide from triphenylmethyl-

phosphonium bromide. Thecarbonyl oxygen in the product (62)isnow

replaced by a methylene group. Saponﬁcation of the ester affords the

free acidand thus 63.

76 CARBOCYCLIC COMPOUNDSFUSED TOA BENZENE RING

ClOC

AlCl

)PCH

NaOH

6263

The saga of estrogenantagonists had its start in the mid-1960s when

several series ofcompound related to diethylstilbestrol wereinvestigated

asnonsteroidal antifertilityagents. The earlywork culminatedin thedevel-

opment of tamoxifen, anestrogen antagonist that was andstill is widely

used as adjuvant treatment forbreast cancer. The benzothiophene-based

analogue raloxifene, which retains some estrogenic activity, was intro-

duced more recently as a drug for treating osteoporosis. Other more

recent exampleswill befound scattered throughoutthis volume.A tetralin

ring formsthe nucleusof anotherrecent entry, lasofoxifene(74). Onesyn-

thesis for the penultimateintermediate starts with the formylation of the

desoxybenzoin (64) with ethyl formate and sodium ethoxide to its

sodium salt (65). In a convergent step, the benzyl chloride (66)is

allowed toreact with triphenylphosphine togive the correspondingphos-

phonium salt (67).Reaction of 67 with thesalt (65) leads directly tothe

product from coupling with the ylide as a mixture of isomers. This

mixture is then hydrogenated to give the ketone (68). Treatment of 68

with 3 equiv of aluminum chloride results in scission of the methyl

ether on the most electron-deﬁcient ether to give the phenol (69). This

compound is then cyclized to the corresponding dihydronaphthalene

with toluenesulfonic acid(TSA). The basic ether side chain requiredfor

antagonist activity is added byalkylation with 2-chloroethyl pyrrolidine

to afford, nafoxidine (72).Catalytic hydrogenation of this product gives

the tetralin(73).

Reactionof 73 withboron tribromideresults incleavage

of themethyl ether in thefused ring to give(74).

3. TETRAHYDRONAPHTHALENES 77

OCH

HCO

NaOC

OCH

CHO

P(C

)

65 6667

OCH

2.H

AlCl

TSA

BBr

The morerecent synthesisfor lasoxifene (74)takes avery different course.

The ﬁrststep comprises displacementof one ofthe halogens in1,4-dibromo-

benzene bythe alkoxidefrom N-2-hydroxyethylpyrrolidine75 inthe presence

of 18-crown ether to afford 76. Condensation of the lithium salt from 76

with 6-methoxytetralone (77) followed by dehydration of the initially

formed carbinol yields intermediate 78, which incorporates the important

basic ether. Reactionof this compound with pridiniumbromide perbromide

leads todisplacement of the vinylic protonby halogen and formationof the

bromide 79.Condensation ofthis product withphenylboronic acidin the pre-

sence ofa palladium catalys tleads tocoupling of thephenyl groupby formal

displacement ofbromine. Theproduct (79), isthen takenon to74 as above.

PyBr

B(OH)

[Pd]

78 CARBOCYCLIC COMPOUNDSFUSED TOA BENZENE RING

4. OTHER BENZOFUSED CARBOCYCLIC COMPOUNDS

Multidrug resistance,as notedearlier, is theall too prevalentphenomenon

where a patient’s resistanceto one class of cancer chemotherapy agents

comes to encompass mechanistically quite different drugs. Compounds

with awide variety of structural featureshave shown atleast preliminary

activity in resolving thisproblem. The structurally rather complex agent

zosuquidar (87) has shown promising activity against this problem.

Reactionof dibenzosuberone (80)with the diﬂuorocarbenefrom chlorodi-

ﬂuoroacetateaffords the cyclopropyladduct (81). Reductionof the ketone

with borohydride proceeds to afford the derivative wherein the fused

cyclpropyl andalcohol are onthe same side ofthe seven-membered ring.

ClCF

NaBH

SOCl

CH=O

TsO

4. OTHERBENZOFUSED CARBOCYCLIC COMPOUNDS 79

The carbinol (82) is then converted to the halide with thionyl chloride

apparently withretention ofconﬁguration (83). Displacementwith pipera-

zinemonoformamide leadsto thealkylated productin whichthe groupsare

now anti. Hydrolysisof the formamide grouping then affords secondary

amine 84. Ina convergent sequence, 5-hydroxyquinoline(85) is allowed

to react with thetosyl derivative of chiral glycidol. The epoxy groupin

the product (86) retains conﬁguration. Condensation of piperazine (84)

with the quinoline(86) opens the epoxide to afford87. Conﬁguration of

the alcohol is again retained asthe reaction takes place at the nonchiral

terminal ofthe side-chain to be.Thus, 87 is obtained.

Mostof the productsfrom thearachidonic acidcascade exertdeleterious

effects. Prostacylin(100) isa notableexception because ofits vasodilatary

activity. Thecompound is destroyedfar too quickly tobe used asa drug.

An analoguein whicha fusedtetralin moiety replacesthe furanand partof

the sidechain is approvedfor use asa vasodilator for usein patients with

pulmonary hypertension. The lengthy complex synthesis starts with the

protection of thehydroxyl group in benzylalcohol (88) by reaction with

tert-butyl dimethyl silyl (TMBDS) chloride (89). Alkylation of the

anion from89 (butyllithium) withally bromide affords90. Theprotecting

group isthen removed and thebenzylic hydroxyl is oxidizedwith oxalyl

chloride in the presence of triethylamine to give the benzaldehyde (91).

The carbonylgroup is thencondensed with theorganomagnesium deriva-

tive fromtreatment of chiral acetylene(92) with ethyl Grignard toafford

93. (The triple bond is not depicted in true linear form to simplify the

scheme.) The next few steps adjust the stereochemistry of the newly

formedalcohol in93. This groupisﬁrst oxidizedback toa ketonewith pyr-

idinium chlorochromate.Reduction withdiborane inthe presence ofchiral

2-(hydroxyl-diphenylmethyl)pyrolidine affords the alcohol as a single

enantiomer. This compoundis then again protectedas its TMBDS ether.

Heating 94 with cobalt carbonyl leads to formation of the tricyclic

ring system (95). Mechanisticconsiderations aside, the overall sequence

to the product (95) involves eletrocylic formation of the six-membered

ring from the oleﬁn and acetylenic bond, as well as insertion of the

elements of carbon monoxide toform the ﬁve-membered ring. Catalytic

hydrogenation of95 leads toreduction of the doublebond in the enone,as

well ashydrogenolysis of thebe nzylicTMBDS ether onthe six-membered

ring (96).Reduction of theketone thenleads to thealcohol apparentlyas a

single enantiomer. Acid leads to loss of the tetrahydropyrany protecting

groupto afford intermediate 97.The presence of labilegroups in thiscom-

pound precludes the usual methods, such as hydrogen bromide or boron

tribromide, forc leavingthe methyl ether. Instead,in an unusual sequence,

80 CARBOCYCLIC COMPOUNDSFUSED TOA BENZENE RING

the phenol(98) is obtained by treatmentof 97 withbut yllithiumand diph-

enylphosphine. Theproduct (98) isthen alkylated with2-chloroacetonitrile.

Hydrolysis of the cyano group to an acid ﬁnally affords the vasodilator

treprostinil (99).

14–16

100

OTMBDS

TMBDS = tBuMe

Si-

BuLi

[O]

CH=O

OTHP

93, THP=tetrahydropyranyl

1. [O]

2. BH

,Aux.

OTHP

OTMBDS

3. TMBDSCl

Co(CO)

OTHP

OTMBDS

OTHP

1. NaBH

9899

REFERENCES

1. A. Karjalainen,P. Huhtala, S.Wurster, M. Eloranta,M. Hillila, R.Saxlun d,

V. Cockroft,A. Karjalainen, U.S.Patent 6,313,322 B1(2001).

2. M. Fuji,T. Suzuki, S.Hayashibe, S. Tsukamoto,S. Yatsugi, T.Yamaguchi,

U.S. Patent5,521,180 (1996).

3. Y. Imura,M. Mishima, M.Sugimoto, J. Label.Comp. Radiopharm 27,835

(1989).

REFERENCES 81

4. M. Chorev, T. Goren, Y. Herzig, J. Sterling, M. Weinstock-Rosin,

M.B.H. Youdim,U.S. Patent 6,462,222(2002).

5. K. Chilma_Blair,J. Castaner, J.S.Silvestre, H.Bayes, Drugs Future28, 950

(2003).

6. B.C. VanWagenen, S.T. Moe, M.F.Balandrin, E.G. DelMar,E.F. Nemeth,

U.S. Patent6,211,244 (2001).

7. J. Reganet al., J.Med. Chem. 45, 2994(2002).

8. N.J. Cusack,J.V. Peck, DrugsFuture 18, 1005(1993).

9. Y. Hamada,I. Yamada,M. Uenaka,T. Sakata,U.S. Patent5,214,202 (1993).

10. M.F. Boehm,R.A. Heyman,L. Zhi,C.K. Hwang, S.White, A.Nadzan, U.S.

Patent 5,780,676(1998).

11. D. Lednicer,D.E. Emmert,S.C. Lyster,G.W.Duncan, J.Med. Chem.12, 881

(1969).

12. C.O. Cameron, P.A. Dasilva Jardine, R.L. Rosati, U.S. Patent 5,552,412

(1996).

13. J.R. Pﬁsteret al., Bioorg.Med. Chem. Lett.5, 2473 (1995).

14. P.A. Aristoff,U.S. Patent 4,306,075(1981).

15. P.A. Aristoff,U.S. Patent 4,649,689(1982).

16. P.A. Aristoff,U.S. Patent 4,683,330(1987).

82 CARBOCYCLIC COMPOUNDSFUSED TOA BENZENE RING

CHAPTER 5

FIVE-MEMBERED HETEROCYCLES

The speciﬁc chapterto which a given drugis assigned is to someextent

arbitrary. Morethan a fewcompounds in the precedingchapters included

a heterocyclic ringin their structures. Thatfragment more often that not,

however,comprised a cyclicbase, forexample, piperidine.The compound

in question wasnot classiﬁed as a heterocycle asit is quite likely that it

would show the same qualitative biological activity if that moiety was

replaced by a noncyclic base. Heterocyclic moieties do, however,seem

to play arole in the biological activity beyond simplyproviding a basic

center fora goodmany agents.Compounds 7and 18 provide aparticularly

apt example;the pyrrolidine ringin these enzyme inhibitorsacts as asur-

rogatefor a prolinemoiety thatoccurs in thenatural substrate.Compounds

meetingthat criterion willbe foundin thisand thefollowing sections.Note

thatclose to two-thirdsof thecompounds in thisvolume havebeen judged

to meetthat criterion and willbe met in thefollowing chapters.

1. COMPOUNDS WITH ONE HETEROATOM

The protease enzyme dipeptidal peptidase (DPP) is closely involved in

glucose control. This enzyme regulates levels of the hormone-like

The OrganicChemistry ofDrug Synthesis, Volume7. By DanielLednicer

peptide incretin, which stimulates release of insulin by cleaving the

molecule toan inactiveform. Inhibitionof DPPin effectextends theaction

of incretin. Thishelps prevent the increased levelsof blood glucose that

mark diabetes. The proteaseinhibitor vidagliptin (7), which is modeled

in part on the terminal sequence in DPP, has been found to sustain

levels of insulin in Type 2 diabetics. Inhibition is apparently reversible

in spite of the presence in the structure of the relatively reactive

a-aminonitrile function. Construction ofone intermediate in the conver-

gentsynthesis comprisesreactionof aminoadamantamine(1) witha mixture

ofnitric and sulfuricacid. Thisreaction affordsthe product2 fromnitration

of oneof the remaining unsubstitutedternary positions. Treatmentof this

product with strong base leads to solvolysis of the nitro group to give

aminoalcohol 3. Preparation of the other moiety involvesﬁrst acylation

of the pyrrolidine (4) with chloroacetyl chloride to give amide 5.

Reaction of that intermediatewith triﬂuoracetic anhydride (TFAA) con-

verts theamide at the 2position to the correspoundingnitrile. Alkylation

of theadamantamine (3) with 6proceeds on nitrogen toafford 7.

HNO

KOH

NH2

CONH

COCl

CONH

TFAA

A substituted pyrrolidine, which acts as a DPP inhibitor, comprises

another example in which this ring serves as a surrogate for proline.

This compound isbeing investigated as ananticancer drug as a result of

the ﬁnding that it inhibits growth of tumors in various animal models.

The structure of this compound is notable for the rare occurrence of

boron in the structure; in this case in the form of a covalently bound

boronic acid. The ﬁnal compound, talabostat (18), is comprised of a

single enantiomer. This isaccomplished in the case at handby a stereo-

selective synthesis ratherthan by resolution of theﬁnal compound or an

intermediate. The ﬁrst step in the synthesis comprises protecting the

amine in pyrrolidine (8) by conversion to its tert-butoxycarbonyl

(9, t-BOC) derivative with tert-butoxycarbonyl anhydride. Reaction of

84 FIVE-MEMBERED HETEROCYCLES

the productwith butyllithium generates ananion on carbon nextto nitro-

gen. Treatment of this compound with triethyl borate displaces one of

the ethoxy groups in the reagent to form a carbon –boron bond. The

product is comprised of a 1: 1 mixture of enantiomers. Hydrolysis of

this intermediatethen affords the correspondingboronic acid (10). Akey

step involvesformation of the acetal-like compoundof 12 with naturally

occurring (þ)pinanediol (11). The initial productis comprisedof twodia-

stereomersdue to thefact thatthe startingboronic acid(10) consistsof two

enantiomers. Thepair of diastereomersof 13are then separatedby recrys-

tallization.In the next step,the desiredisomer is coupledwith theto t-BOC

derivative from valine to give amide 16.The pinane diol group is then

removed by exchange with excess phenyl boronic acid.The ﬁnal com-

pound is converted to a salt (18) in order to avoid the formation of a

stable zwitterionbetween the amine and theboronic acid function. Thus,

18 isobtained.

Nt-BOC

t-BOC

1. BuLi

2. B(OC

)

B(OH)

3. H

COCl

1. C

B(OH)

2. HCl

B(OH)

(t-BuO)

As noted in Chapter 3, endothelins rank among the most potent

known vasoconstricting agents; they have been implicated in a number

of diseases including cerebral vasospasm and pulmonary hypertension.

The stereoselectivesynthesis of an endothelin antagonistbegins with the

1. COMPOUNDS WITH ONE HETEROATOM 85

establishmentof the chirallocus thatwill dictatethe remainingasymmetric

centers. Oxazolidone(20), derived fromvaline serves asthe chiral auxili-

ary forthat step. Condensation ofthe mixed-anhydride (19) frompipero-

nalacetic acid, with theanion from auxiliary 20, give the corresponding

amide (21). Treatmentof this intermediate with strong basefollowed by

tert-butyl bromoacetate leads to the alkylationproduct 22 as virtually a

single isomer. The auxiliary heterocycle is then removed by means of

lithium hydroperoxide to affordthe half ester (23). Reaction of 23 with

diborane selectively reduces the free acid to give the esteralcohol (24).

The hydroxyl group is thenactivated by conversion to its tosylate (25).

Treatment ofthat intermediate withanisyl hydroxylamine (26)in the pre-

sence ofcesium carbonate affordsthe O-alkylatedderivative 27. Theester

grouping isthen exchanged withmethylorthoformate to affordthe methyl

ester (28).Reaction ofthis last intermediatewith trimethylsilyl triﬂateand

butylamine in the presence of 1,2-dichloroethane presumably forms an

anion-like species on the carbon adjacent to the ester. This then adds

internally to theoxime carbon atom to yielda 1,2-oxazine. This product

(29) predominatesover the diastereomerin a 9: 1ratio.

COtBu

tBu

tBuO

LiOOH

tBu

BuLi

NaHMDS

tBu

OSO

OCH

27; R = tBU

28; R = CH

TMSOTf

OCH

Catalytic hydrogenation of 29 over palladium on charcoal results in

scission of the weak N22O bond and formation of aminoalcohol 30.

This compound is converted to a pyrrolidine by an internal alkylation

86 FIVE-MEMBERED HETEROCYCLES

reaction. Thus,reaction of the intermediatewith carbon tetrabromide and

triphenylphosphine presumably convertsthealcohol to abromide; internal

displacement by the primary amine forms the ﬁve-membered ring.

Alkylation of that amine with thecomplex bromo amide 32 affords the

endothelin antagonistatrasentan (33).

OCH

CBr

)

OCH

Researchon anticholinergiccompounds has experiencedsomething ofa

resurgence asa result oftheir utility intreating conditions suchas urinary

incontinence. Thestructures ofthese compoundsare quitevaried asshown

by darfenacin(44), which differs considerablyfrom other compoundsin

this class,for example,tolterodine (Chapter 3).The synthesis ofthis com-

pound (44)is also designedto produce asingle enantiomer. Heatinduced

decarboxylation ofproline (34) affords the keyintermediate 35 as apure

enantiomer. The amino group isthen converted to its tosylate (36) with

tosyl chloride; the hydroxyl group interestingly does not react under

those conditions. Convertingthat group to its derivativeis accomplished

by theMitsonobu reaction withmethyl tosylateto give thedoubly deriva-

tized intermediate 37. Condensationof 37 with the anion fromdiphenyl

acetonitrile (38), produced by reaction with sodium hydride, yields the

alkylation product 39. Treatment of this intermediate with hydrogen

bromide removes the protecting group on nitrogen. The nitrile is then

converted tothe corresponding amide withsulfuric acid. In a converging

scheme, acylation of benzofuran (41) with chloroacetyl chloride and

1. COMPOUNDS WITH ONE HETEROATOM 87

aluminum chloride yields the chloroketone (42). Reaction of that with

pyrrolidine(40) leadsto the alkylationproduct 43.Catalytic hydrogenation

over palladium reducesthe aryl carbonyl group toa methylene probably

via the initially formed labile benzyl alcohol. Thus the anticholinergic

agent 44is obtained.

heat

NSO

DEAD; Ph

NSO

NaH

1. HBr

2. H

CONH

Cl COCl

CONH

Protein kinasescomprise a series of closelyrelated enzymes that cata-

lyze the phosphorylationof hydroxyl groups in enzymes,which regulate

a widerange of physiological processes.Phosphorylation may eitherturn

the function of the target on or off. Inhibitors of the protein C kinases

(PKC) that are involved in cell proliferation have attracted particular

N(CH

)

Ruboxystaurin

88 FIVE-MEMBERED HETEROCYCLES

attentionas potential drugs.The complexfermentation productStaurosprin

is aPKC inhibitor thathas shownantineoplastic activity ina rangeof bio-

logical assays,but provedto be tootoxic for useas a drug.The somewhat

simpler analogue,ruboxystaurin shows greaterpotency and selectivityfor

speciﬁc PKCs. It has been pursued in the clinic to treat complications

from diabetes. The synthetic acyclic product enzastaurin (54)iseven

more speciﬁc,inhibiting asubclass of PKCsinvolved in cell proliferation.

Reaction ofthe pyridyl methylamine (45) with methylacrylate results

in Michael addition of 2 equivof the reagent to afford the diester (46).

1. tBuOK

2. LiOH

NC Cl

BCl

NaBH

heat

(COCl)

OCH(CH

)

1. COMPOUNDS WITH ONE HETEROATOM 89

Base-catalyzedClaisen condensationforms thedesired six-memberedring.

Heatingthat intermediatewith base leadsto saponiﬁcationof theester. The

beta ketoacid decarboxylates under reaction conditions to form 47.

Reductiveamination ofthe carbonylgroupin theketone inthis intermediate

withaniline wouldthen leadto the substitutedaniline (48).Treatmentof 48

withchloroacetontrile inthe presenceof borontrichloride leadsto acylation

onthe benzenering. Theregiochemistry isattributable tothestrongly acidic

reaction conditions thatinactivate the pyridine moiety. Aqueous workup

then affords thechloroacetyl derivative (49). The ketoneis then reduced

by means of sodium borohydride. On heating, the product undergoes

internal alkylation; the ﬁrstformed compound then dehydrates to afford

thesubstituted indole (50).

The nextstep inthe schemeinvolves construc-

tion ofthe pyrrolodione moiety. Therequired carbon atoms areadded by

acylationof 50withoxalyl chlorideto afford51.This compoundisthen con-

densed withthe imidate(52) fromindole acetamideto afford anintermedi-

ate,such as 53.The reactionmay bevisualized as involvingﬁrst formation

of an amide from imidate nitrogen with the acid chloride followed by

addition ofthe anion fromthe methylenegroup in 52to the carbonyl.The

initially formed pyrrolineis then dehydrated withstrong acid.

Thus, the

PKC inhibitor54 isobtained.

Leukotrienes, productsfrom onebranch of thearachidonic cascade, are

closely associated with symptoms of allergy, as well as asthma (see

Chapter 3, etalocib). The benzothiophene-based leukotriene antagonist,

zileuton, one of the ﬁrst agents in this class, is now on the market. A

related compound, atreluton (60), that omits the fused benzene ring

present in the prototype, shows improved potency and duration of

action over its predecessor. Condensation of benzyl bromide (55) with

the anion from thiophene and butyllithium in the presence ofthe Heck

catalyst [tetrakis(triphenylphosphine) palladium(0) gives the coupling

product 56. Reaction with NBS leads to the bromothiophene (57).

Condensation of that intermediate with the methyl– ethynyl carbinol in

the presence of triphenylphosphine, Heck catalyst, and cupric iodide

leads tothe couplingproduct 58. Therequisite functionalityis constructed

by ﬁrst replacing the hydroxyl next to the acetylene by nitrogen.

Mitsonobu-like reactionwith O,Nbis( phenyloxycarbonylhydroxylamine)

in thepresence of triphenylphosphine andDEAD affords 59.Reaction of

this intermediate with ammonia leads to displacement of both phenoxy

groups. This leads to formation of the free hydroxyl from the

O-carbonate and a ureafrom the phenoxy ester, yieldingthe leukotriene

antagonist 60.

90 FIVE-MEMBERED HETEROCYCLES

BuLi

(Ph

.Pd

NBS

(Ph

.P, PPH

, CuI

P, DEAD

2. COMPOUNDS WITH TWO HETEROATOMS

A. Oxazole and Isoxazoles

Thediscovery thatnon-steroid antiinﬂammatoryagents (NSAID)owe their

efﬁcacy to inhibition ofcyclooxygenase (COX),the enzyme thatcatalyzes

the formation of prostaglandins was followed some time later by the

ﬁnding that theenzyme occurred in several subtypes. Thealmost simul-

taneous discovery of speciﬁc inhibitors of COX-2, promised NSAIDS

that reduced inﬂammation that spared the production of prostaglandins

that maintainintegrity of the stomachwall. The enormous success ofthe

ﬁrst agent on the market celecoxib, led to detailed investigation of the

structure–activity relationship (SAR) of this class in competing labora-

tories. Minimumrequirement for activityseemed to involvetwo aromatic

ringson adjacent positionson aﬁve-membered heterocyle.The veryrecent

entry, tilmacoxib (67), shows that one of those benzene rings can be

replaced by cyclohexane. Condensation ofm-ﬂuorobenzyl bromide (62)

with the acidchloride (61) from cyclohexane carboxylic acidin the pre-

sence of the Heck reagent affords the ketone (63) that incorporates the

requisite two rings. Bromination proceeds on the benzylic position to

afford 64. This reactive halogen is displacedwith acetate to givethe key

2. COMPOUNDS WITH TWOHETEROATOMS 91

intermediate (65). Constructionof the heterocyclic ringinvolves reaction

of65 withammonium acetate.The reactioncan beviewed forbookkeeping

considerationsas proceeding throughthe initialreaction of ammoniumion

withthe ketoneto form animine. Thisimine cyclizeswith theadjacent car-

bonyl onthe acetateto afford66. Treatment of 66 withchlorosulfonic acid

gives thesulfonyl chloride; that sulfonylchloride is immediately allowed

to reactwith ammonia toyield the correspondingsulfonamide. This com-

pound thenaffords the COX-2 inhibitor67.

Pd(PPh

)

OCOCH

NaOCOCH

COCH

1. ClSO

2. NH

The large number of compounds that have been reported illustrate

the wide selection of heterocyclic ﬁve-membered rings that are com-

patible with COX-2 inhibitory activity. The oxazole ring can, for

example, be replaced by an isoxazole. Reaction of deoxybezoin (68)

with hydroxylamineaffords theoxime (69).Treatment ofthis intermediate

with 2 equiv of butyllithium followed by acetic anhydride goes to the

hydroxyl isoxazoline(71). The transformcan be rationalizedby assuming

that this proceeds via the O-acylatedintermediate (70). The anion from

the benzylic position would add to the acetyl carbonyl group to afford

the observed product. Reaction of this compound with chlorosulfonic

acid results in sulfonation of the aromatic ring nearest nitrogen.

The ﬁrst step probably comprises dehydration of tertiary alcohol in 71

under the strongly acidic conditions to give72. Subsequent addition of

ammonia converts the chlorosulfonicacid to the corresponding sulfona-

mide and thus valdecoxib (73).

Reaction of 73 with acetic anhydride

leads to acylation of the amide nitrogen, which increasesthe acidity of

that already acidic function. Treatment with base affords the water

soluble salt parecoxib (74),

which is suitable for use in injectable

formulations.

92 FIVE-MEMBERED HETEROCYCLES

BuLi

1. ClSO

2. NH

7273

1. Ac

2. NaOH

–

The immunesystem isbelieved to playa rolein rheumatoid arthritis,in

contrastto thefar morecommon osteoarthritis,whichis relatedto aging.An

agent that has immunosuppressive action has proven useful for treating

rheumatoid arthritis.This compound lenﬂunomide (77), canbe prepared

in asingle stepby acylationof p-triﬂuoromethylaniline (76)with the com-

merciallyavailable isoxazole (75).

The isoxazolering, itwas laterfound,

is readily cleaved in vivoto give the cyano ketone, teriﬂunomide (78).

Lenﬂuomides is consequently considered to be a prodrug for the latter.

Thisagent canbe preparedby condensationofthe sodiumsalt fromcyanoa-

cetone (79) with p-triﬂuoromethylphenylisocyanate (80),

itself readily

accessible fromthe aniline (76). Teriﬂunomide, isused in the clinic as a

potential drugfor relieving someof the effectsof multiple scelerosis.

75 76 77

7879 80

Metabolism

2. COMPOUNDS WITH TWOHETEROATOMS 93

B. Imidazoles and a Pyrrazole

By now, it is well established that “conazole” antifungal agents attack

fungi by inhibiting the synthesis of steroids essential to the fungal life

cycle. Virtuallyevery antifungal agentin this classincorporates an imida-

zole ringinto its structure. Thismoiety is thus, notsurprisingly, found in

the formof an enaminein a recentconazole. The startingmaterial for this

agent (83),could, for example,be prepared bybromination of thepropio-

phenone (81) followed by displacement of halogen with imidazole.

Alkylation of the enolate from the ketone with the side-chain fragment

(84), yieldsthe antifungal agents omoconazole(85).

81; R = H

82; R = Br

NaH

HistamineH

receptorshave beenfoundto modulatethe releaseofneuro-

transmitters, suchas acetyl choline, dopamine,and serotonin, involvedin

alertness and cognitive function. Compounds that act as antagonists at

those sitesfavor release ofthose neurotransmitters and resultin increased

alertness inanimal models. Antagonistswould hold promisefor treatment

of attentiondeﬁcit syndrome and relatedconditions including even poss-

ibly Alzheimer’sdisease. The ﬁrststep in the synthesistoward the antag-

onist cipralisant (92) comprises separation of the enantiomers of the

carboxylic acid 86. Tothis end, the acid is reacted with a chiralsultam

derived fromcamphor. Theresulting diastereomers(87) are thenseparated

by chromatography.Each of the diastereomericallypure derivatives, only

one of which is shown, is then treated in the cold with DIBAL-H to

afford the corresponding aldehyde (88). Reaction with the anion from

C-trimethylsilyl diazomethane gives the acetylene (89) in a single step.

The chainis then extendedby reaction ofthe acetylide anion withthe tri-

ﬂatederivative from3,3-dimethylbutanol. Exposureto strongacid servesto

remove the triphenylmethyl protecting groupon nitrogen. This last step

affords 92.

The absolutestereochemistry was derived fromX-ray struc-

ture determinationof one isomer ofthe sultam (87).

94 FIVE-MEMBERED HETEROCYCLES

)

CH=O

BuLI

HCl

DIBAL-H

(CH

)SiCHN

BuLi

The three part so-called cocktail used to treat HIV positive patients

typically comprise a proteinase inhibitor, such as those discussed in

Chapter 1;a nucleoside-basedreverse transcriptaseinhibitor, suchas those

in Chapter 6, and a non-nucleoside inhibitor of reverse transcriptase

(NNRTI). Most of the compounds in the ﬁrsttwo classes share a good

manystructural features withother agentsin the class.Chemical structures

of the various NNRTIs on the other hand have little in common.

Capravirine (103), is notable in the fact that it fails to include any of

the fused ring systems thatprovide the nucleus for other compounds in

this class. Chlorination of 3-methylbutyraldehyde (94) provides one of

the components for building the imidazole ring. For bookkeeping pur-

poses, thecondensation of94 with O-benzylglyoxal and ammoniacan be

OCH

93; R = H

94; R = Cl

OCH

, NaOH

–

OCH

100

OCH

101

HCl

102

ClSO

N=C=O

103

2. COMPOUNDS WITH TWOHETEROATOMS 95

envisaged as proceeding thoroughthe aminal (95) of the glyoxal. Imine

formation withdichloro reagent94 by displacementof halogen thenleads

to imidazole96. Reaction ofthat intermediatewith iodine inbase leads to

theiodo derivative(97). Displacementof iodineby theanionfrom dichlorol

sulﬁde (98) proceeds to give thethioether (99). The still-free imidazole

nitrogen isnext alkylatedwith 2-chloromethyl pyridineto afford101. The

benzyl protecting group on oxygen is then removed by treatment with

strongacid. Thethus-revealed carbinolin 102is condensed withchlorosul-

fonyl isocyanateto form the corresponding carbamate.Thus, the NNRTI

103 isobtained.

The imidazolering takesits place inthis exampleamong awide variety

of heterocyclic rings that serve as the nucleus for COX-2NSAID anti-

inﬂammatory compounds. Reactionof sulfonyl chloride (104), available

fromchlorosulfonation ofacetanilidewith tert-butylamine,gives thecorres-

ponding sulfonamide(105). The acetylgroup onnitrogen is thenremoved

by heatingwith strongbase togive the aniline(106). Reactionof 106 with

the ﬂuoroanisaldehyde (107)gives imine 108,which incorporatesthe two

adjacent aromaticrings characteristicof COX-2inhibitors. Reaction ofthe

imine with toluenesulfonyl isocyanate in the presence of potassium

carbonateleads to whatmay beviewed as2 þ3 cycloaddition ofthe nitro-

genanalogue of aketene toform theimidazole ring(109). Thisring isthen

chlorinated with N-chlorosuccinimide(NCS) possibly to adjust the elec-

tron densityon the heterocyclic ring. Heatingthis last intermediate (110)

with acid removesthe protecting group togive the free sulfonamide and

thus cimicoxib(111).

COHN

104

NC(CH

)

COHN

KOH

NHC(CH

)

O=HC

OCH

105

106

107

NHC(CH

)

NHC(CH

)

OCH

108

TsCH

N=C

NHC(CH

)

OCH

109

NCS

NHC(CH

)

OCH

HCl

110111

The enzymedopamine-b-hydroxylase, as thename indicates, catalyzes

hydroxylationof the sidechain ofdopamine in sympatheticnerves toform

96 FIVE-MEMBERED HETEROCYCLES

epinephrine. Direct antagonismof the enzyme shuts downproduction of

that neurotransmitter. This achieves an effect on the cardiovascular

systemmore directly thando either a-orb-blockers. Themost immediate

effect is manifestedas a decrease inblood pressure. The synthesisof the

speciﬁc hydroxylaseinhibitor nepicastat(122) starts byreaction of aspar-

tic acidwith triﬂuoroactetic anhydride. Thisreagent results in conversion

of theamine toits triﬂoroacetamidederivative andthe acidto ananhydride

(113). Reaction ofthis intermediate with 1,3-diﬂuorobenzene in thepre-

sence of aluminum chloride gives the Friedel– Crafts acylation product

(114). Catalytic hydrogenation then reduces the ketone to a methylene

group (115). Asecond acylation reaction, this time viathe acid chloride

leads to the tertralone (116). The new carbonyl group is again reduced

by meansof hydrogenation;saponiﬁcation thenremoves theprotecting tri-

ﬂuoroacyl groupto give the primaryamine (117) as asingle enantiomer.

Reaction ofthat amine with formaldehydeand potasium cyanide leadsto

formation of whatis essentially an a-aminonitrile, thenitrogen analogue

of acyanohydrin. The aminogroup is thentaken to aformamide by reac-

tion withbutyl fomate.Formylation ofthe carbon adjacentto thenitrile by

means ofethyl formateand sodiumethoxide putsinto place thelast carbon

for theimidazole ring (120).Reaction of thislast compound asits enolate

with thiocyanateforms the cyclic thiourea(121). Catalytic hydrogenation

serves toreduce the nitrileto the corresponding amino-methylenederiva-

tive andthus 122.

112

(CF

C0)

NHCOCF

113

AlCl

NHCOCF

1. PCl

2. AlCl

NHCOCF

114

115

116117

1. H

2. NaOH

NaCN

CHO

HCO

118

119

CHO

HCO

NaOC

120

KSCN

121

122

Collagenase enzymesare intimately involvedin the destruction ofcar-

tilage thataccompanies rheumatoidarthritis. Considerable attentionhas as

2. COMPOUNDS WITH TWOHETEROATOMS 97

aconsequence been focusedon ﬁnding inhibitorsof thatenzyme. Theﬁrst

step inthe convergent synthesisstarts by protection ofthe chiral hydroxy

acid (123)as its benzyl ester(124). The hydroxylis activated towarddis-

placement byconversion toits triﬂate 125.Reaction of125 with theanion

from theunsymmetrical malonate leads totriester 126.

The a-aminonitrile (127) from acetone and methylamine comprises

starting materialfor the heterocyclicmoiety. Reactionof 127 withchloro-

sulfonyl isocyanate and hydrochloric acid gives hydantoin (128).

Treatment of intermediate 128 with formaldehyde leads to a carbinol

from addition to the free amino group on the imidazole dione. The

hydroxyl groupis thenconverted tothe bromo derivative(129) withphos-

phorus tribromide.

Use ofthis intermediate (129)to alkylate theenolate

from 126yields 130. Catalytic hydrogenationof this product leadsto the

formation of thecorresponding ester-diacid by lossthe benzyl protection

groups ontwo of the esters.Heating this lastintermediate in thepresence

of N-methylmorpholinecauses thefree acidon the carbonbearing thetert-

butylester todecarboxylate (131).The desiredstereoisomer (131)predomi-

nates, in effect reﬂecting the selectivity of alkylation step (126! 130)

123

124

1. CH

2. PBr

125

ButO

NaH

126

127

128

129

tBu

130

NaH

131

– CO

132

HOHN

133

134

1. C

ONH

2. H

ClSO

N=C=O

98 FIVE-MEMBERED HETEROCYCLES

causedby thepresence ofthepreexisting adjacentchiralcenter. Thefree car-

boxylicacid is condensed with piperidineto form132. Theremaining ester

is then hydrolyzedin acid to affordthe acid (133). Reactionof 133 with

O-benzylhydroxylamine followedby hydrogenolysis of thebenzyl group

then leadsto thehydroxamic acid.Thus, thecollagenase inhibitor cipema-

stat (134)is obtained.

The discoveryof canabinol receptorshas ledto the searchfor synthetic

agonists and antagonists based on different structures from the hemp-

relatedproduct. One ofthe ﬁrstantagonists tocome out ofthose programs,

rimonabant (140) has shown activityas an appetite suppressant weight

loss agent. Addition of the anion from the propiophenone (135)tothe

anion from ethyl oxalate gives the enolate (136). Condensation of that

with 2,4-dichlorophenylhydrazine (147) results in formation of

imines between carbonylgroups and the basic nitrogenthus forming the

pyrrazole ring(138). Saponiﬁcation ofthe ester affordsthe corresponding

acid (139).This is thenreacted withN-aminopiperidine in the presenceof

DCC toform the amide 140.

135

(CO

)

BuLi

OLi

136

137

138139

NaOH

140

NHNH

C. Thiazoles

A relativelysimple thiazole hasbeen shown tobe a quitepotent antiinﬂa-

matoryagent. Darbufelone(143), whichis quitedifferent instructure from

all precedingNSAIDs inhibitsboth armsof thearachidonic acidcascade at

thevery inceptionof theprocess. Thisin effect shutsoff productionof both

prostaglandins andleukotrienes. This agentis prepared in a single stepby

condensation of substituted benzaldehyde 141 with the enolate from

thiazolone (142).

2. COMPOUNDS WITH TWOHETEROATOMS 99

CH=O

NaOAc

AcOH

141 142 143

Uric acidcomprises one of the principalproducts from metabolism of

endogenous nitrogen-containing compounds. Metabolic disorders that

cause this pyrimidine base to accumulate in the bloodstream can cause

gout, a painfulcondition that results from depositsof uric acid in joints.

The uricosoric thiazole febuxostat (147), like its venerable predecessor

allopurinol, inhibitsthe enzyme xanthine oxidase, whichis central to the

production ofuric acid.Febuxostat, whose structureis signiﬁcantlydiffer-

ent from its predecessor, has recently been introduced as treatment for

gout. Reaction ofthe dinitrile compound (144) with hydrogen sulﬁdein

base proceedsto convert the one ofthe two cyanide groupsto the corre-

sponding thioamide(145). Regioselectivityis speculativelydue toreaction

at the less hindered of the two nitriles. Condensation of this with the

diketo-ester (146) leads toformation of the thiazole ring. Saponiﬁcation

of theester completes the preparationof 147.

144

NaOH

145

O O

2. OH

–

147

146

Reactiveoxygen species releasedby neutrophilsmay playa rolein con-

ditions, such as inﬂammatory bowel disease and chronic pulmonary

obstructive disease. Athiazole that inhibits in vitro productionof super-

oxide by human neutrophilsis currently being investigated in theclinic.

In a convergent scheme, bromination of acyl pyridine carboxylic acid

100 FIVE-MEMBERED HETEROCYCLES

(148) affordsthe acyl bromide.The product is thenconverted to theester

(149), bytreatment with methanolin the presenceof acid. Catecholesters

undergo readyelectrophillic attack asa result of thehigh electron density

in the ring. Thus,reaction of diethyl catechol with isothiocyanate inthe

presenceof acid leadsto ringsubstitution. Theinitially formed thiocyanate

hydrolyzes tothe observed thiourea (150)under reaction conditions. Ina

classic method for forming heterocyclic rings, reaction of bromoketone

(149) with the thiourea (150) proceeds to the thiazole 151.

Saponiﬁcation ofthe ester then affordstetomilast (152).

148

1. Br

2. CH

149

KSCN

150

151

152

NaOH

Heterocyclic compoundsbearing nitro groupswere among someof the

earliest antiparasiticagents. Anitrothiazole hasrecently been approvedfor

treating diarrheadue to such infections.This rather venerablecompound,

nitazoxanide (155) is prepared in a single step by reaction of the acid

chloride (153)from aspirin with theaminonitrothiazole (154).

154

OCOCH

O NH

153

155

Many peptides contain reasonably reactive amines, as well as an

occasional free guanidine function. By the same token, the sugars that

2. COMPOUNDS WITH TWO HETEROATOMS 101

makeup polysaccharidecan beviewed asacetals ofaldehydes. Thesefunc-

tions on endogenous peptides and saccharides do occasionally interact

chemically to form cross-links. Accumulation of cross-linked proteins

withage is believedto leadto stiffeningof tissues.Some ofthese processes

maygo as faras toresult in pathologicchanges. Astructurally verysimple

thiazolium salthas shown activity inreversing such changes bybreaking

cross-links. The compound is probably prepared by reaction of

dimethylthiazole (156)with phenacylchloride (157). Theproduct alageb-

rium chloride(158) issaid toshow promise intreating effectstraceable to

loss oftissue elasticity.

156 157

158

The “glitazones”comprise alarge series ofantidiabetic compoundsthat

were introduced about a decade ago. The original hypoglycemic drugs

used forcontrol of Type2 diabetes weremarked bythe presence ofa sul-

fonyurea pharmacophore.This function isreplaced by athiazolidinedione

group in themore recent glitazones. The synthesis ofa very recent drug

candidate in this group begins with reduction of the carboxylic acid in

the naphthol(159) with diborane. Theresulting carbinol isoxidized back

159

1. BH

2. MnO

CH=O

160

161

162

163

102 FIVE-MEMBERED HETEROCYCLES

to analdehyde (160)by means ofmanganese dioxide. Aldol-typeconden-

sation of 160with the active methylene group inthiazolidinedione itself

leads to the unsaturated intermediate161. Next, catalytic hydrogenation

serves toreduce thedouble bond. Thefree phenol inthe other ringis then

alkylated with o-ﬂuorobenzyl chloride. Thus, the hypoglycemic agent

netoglitazone (163)is obtained.

D. Triazoles

Antifungal activity is retainedin compoundsin the“conazole” serieswhen

an additionalnitrogen atom is insertedinto the all-important heterocyclic

ring. The preparationof a triazole-based antifungal agent starts with the

construction of the pyrimidine ring. Thus, condensation of b-ketoester

(164) withformamidine leads topyrimidine 165. Treatment ofintermedi-

ate 165 with phosphorus oxychloride leads to the correspondingchlori-

nated compound (166).The key intermediate 168 couldbe obtained, for

example, by alkylation of 1,2,4-triazole with phenacyl chloride (167).

Addition of the enolate from treatment of the pyrimidine (166) with

strongbase to additionto the carbonylgroup in 168.The resultingtertiary

alcohol (169)is obtainedas amixture ofdiastereomers. Thechlorine atom,

having served its function, is now removed by catalytic hydrogenation.

Separation ofdiastereomers followedby resolution ofthe desired enantio-

mer pairaffords the antifungal agentvoriconazole (170).

O O

POCl

IDA

F F

1. H

2. Resolve

164

165

166

167

168

169

170

2. COMPOUNDS WITH TWO HETEROATOMS 103

A rathermore complex antifungal compound incorporatesin its struc-

ture both a triazole and a triazolone ring. The lengthy sequence begins

with displacement of chlorine in 171 by acetate. Reaction of the

product with the ylide from methyl triphenylphosphonium bromide

affordsthe methylenederivative (173).The acetategroup isnext saponiﬁed

to givethe free alcohol.The double bondis then oxidizedin the presence

L-ethyl tartrateto afford epoxide 174 asa single enantiomer. The ﬁrst

heterocyclic ring is now introduced by opening of the oxirane with

1,3,4-triazole properto afford 175. Reactionwith methenesulfonyl chlor-

ide givesthe corresponding mesylate (176).Treatment with base leadsto

formation of an alkoxide on the teriary carbinol; internal displacement

forms anew oxirane. This ringis then openedby the anion fromdiethyl-

malonate. Thealkoxide that is formed asthe initial product displacesthe

ethoxide group on one of the estersto form a lactone (178). Reduction

with borohydride takes both carbonyl groups to alcohols affording the

diol (179). This last intermediate (179) is again treated with toluene-

sulfonyl chloride toafford the bis(tosylate). Treatment with baseleads to

formationof an alkoxidefromthe still freetertiary alcohol.This compound

undergoes internal displacement ofone of the tosylate groups to form a

THF ring (180). The remaining tosylate function serves as a leaving

171

NaOCOCH

OCCH

172

1. (C

P=CH

2. NaOH

173

174

175

OSO

176

Base

177

NaOH

178

NaBH

179

1. TsSO

2. NaH

180

N N

181a

OTs

Ti(OiPr)

104 FIVE-MEMBERED HETEROCYCLES

group forthe nextreaction. This lastintermediate (180)is reacted withthe

diaryl piperazine(181a) inthe presence ofbase.

The thus formedphenoxide displaces the toluenesulfonateto form the

extended couplingproduct (181b). The nitrogroup is reduced tothe cor-

responding amine. That function is then reacted with phenoxycarbonyl

chlorideto give thephenoxy carbamate.Treatmentwith hydrazinedisplace

the phenoxide yielding the semicarbazone (182). Ethyl orthoformate

supplies the remaining carbon atom to form the triazolone (183). The

last step in the sequence comprises alkylation of the heterocyclic ring

with the chiral methoxymethyl protected 2,3-pentanediol 3-tosylate

(184). Thus,the antifungal agent posaconazole(185) is obtained.

181b

1. H

2. C

OCOCl

3. NH

182

184

NHNH

TsO

NN NH

183

185

Administration of cancer chemotherapeutic agentsis more often than

not accompaniedby serious bouts ofnausea and vomiting. Theserotonin

antagonists,such as ondansetron,were theﬁrst classof antiemetic drugsto

provide reliefto patients undergoing chemotherapy. The involvement of

substance Pin mediation of the emesisreﬂex offers another target inthe

search for compounds for treating nausea. The demonstration that the

substance P related neurokinin hNK-1is directly involved in that reﬂex

has ledto the searchfor speciﬁcantagonists. The stereoselectivesynthesis

of the antagonist aprepitant (200)begins with the preparation of chiral

p-ﬂuorophenylglycine (190). Coupling of the phenylacetic ester (187)

with the chiral auxiliary (186) affords the amide (188). The requisite

2. COMPOUNDS WITH TWO HETEROATOMS 105

nitrogenatom isthen introducedby treatingthe enolatefrom 188with tosyl

azide. Catalytichydrogenation thenreduces theazide to thecorresponding

primary amine (189).The chiral auxiliary, having done itswork, is then

removed. Thushydrolysis with base leads to aminoacid 190 as a single

enantiomer. The benzylprotection group is next introducedby reductive

alkylation with benzaldehyde. Reaction of the product (191) with

1,2-dibromoethane in thepresence of mild base leadsto formation of an

ester with the carboxylic acid and then alkylation on nitrogen, though

not necessarilyin thatorder. The netresult is formationof the morpholine

ring (192).Treatment of theproduct with Selectridereduces the estercar-

bonyl tothe aldehydeoxidation stage,present hereas a cyclicacetal (193).

186

187

188

189

TsN

KN(SiMe

)

1. H

2. LiOH

190

191

192

Selectride

193

ClOC

194

195

196

TiMe

199

200

197

198

CH=O

106 FIVE-MEMBERED HETEROCYCLES

Thering hydroxylgroup isthen acylatedwiththe ﬂuorinatedbenzoyl chlor-

ide (194)to yield ester195. Reaction withthe carbenoid species fromthe

Tebbereagent leadsto formalreplacement ofcarbonyl oxygenby amethyl-

enegroup toform the enolether (196).Catalytic hydrogenationreducesthe

enolto thecorresponding etherat thesame timedeleting thebenzyl protect-

inggroup. Thepresence oftwo adjacentchiral centersresult information of

product197 aslargely asingleenantiomer. Theremaining taskinvolves for-

mationof thependant pyrrazolonering. Alkylationof themorpholine nitro-

gen with substituted semicarbazide 198 leads to 199. Compound 199

undergoes internaldisplacement ofthe methoxy groupon nitrogen, which

results information ofthe triazolone ringand thus 200.

Thevirus that leadsto AIDSis renownedfor itsability todevelop resist-

ance toantiviral drugs. Successfultreatment depends insome measure on

ﬁnding agentsthat act onthe virus bynovel mechanisms. Currenttherapy

thus combines drugs that act on three different stages of the viral

201

202

NOH

203

ROH

204

ClCO

POCl

205

206

CONHNH

207

208

209

CH=O

212

210

211

NaB(OAc)

life cycle.A newclass ofagents depends onthe factthat thevirus needs to

bindwith speciﬁcreceptor siteson theimmune systemcells inorder togain

entryinto thesecells. Thevery recentantiviral agentmaraviroc(212) binds

to the same sites as HIV and thus prevents the very ﬁrst stage in the

2. COMPOUNDS WITH TWO HETEROATOMS 107

processof infection.Synthesis ofthis agentstartsby protectionof theamino

groupin the bridgedbicyclic amine (201).The carbonylgroup atthe other

end ofthe moleculeis then convertedto itsoxime. Treatment ofthis inter-

mediatewith sodiumin alcoholreducesthat groupto aprimaryamine (204).

Constructionof thetriazolering ﬁrstinvolves acylationofthe aminewiththe

acidchloride fromisobutyric acidtoform theisobutyramide(205). Reaction

of205 withphosphorus oxychlorideconvertsthe amideintothe correspond-

ing chlorinated imine (206). Treatment with acylhydrazide leads to

addition–elimination of thebasic hydrazidenitrogen to theimino chloride

and thusformation of the imino–amide (207).Heating in the presenceof

acid leadsto reaction ofthe imino nitrogenwith the carbonyl group.This

closes thering and affordsthe triazole (208). Catalyticreduction removes

the benzylprotecting groupummasking the basicring nitrogen (209).In a

converging scheme, the ester in the peptide-like fragment (210)is

reduced to affordaldehyde 211. Reductive amination of211 with amine

209and sodium triacetoxyborohydride leadsto thecoupled product212.

Asubstituted 1,2,3-triazole ringprovidesthe pharmacophorefor ananti-

epileptic drug. Reaction of the 2,5-diﬂuorobenzyl bromide (213) with

sodium azideleads todisplacement of thebenzylic halogen andformation

of azide 214. Treatment of 214 with propargylic acid leads to a 2 þ3

cycloaddition reactionand thus formationof the 1,2,3-triazine ring(215).

The carboxylic acidis then converted to its amide viathe acid chloride.

Thus, theantiepileptic agent ruﬁnamide (216)is obtained.

213

NaN

F F

214

NNH

215

216

CONH

1. SO

2. NH

As notedearlier, protein kinasesplay apivotal role incell proliferation.

Inhibitors ofthese enzymesshow promiseas antitumoragents particularly,

those that show preference for malignant cells. The kinase inhibitor

mubritinib (221)is currently beingevaluated as adrug for treatingbreast

cancer. Theﬁrst step in theconvergent synthesis comprises displacement

of a leaving group, such as methanesulfonate, from a suitably protected

phenol (217) by 1,2,3-triazine proper. Removal of the protecting group

leads tothe free phenol (218). Preparation ofthe second moiety involves

reactionof one ofthe classicalmethods forforming ofan oxazole: reaction

108 FIVE-MEMBERED HETEROCYCLES

of ahalomethyl carbonyl groupwith an amide.Thus, condensation ofthe

cinnamic amide (219) with 1,3-dichloroacetone leads to formation of

oxazole 220, which retains a leavinggroup for a displacement reaction.

Treatment of 220 with the alkoxide from treatment of 218 with base

leads tothe corresponding ether (221).

219

220

O OSO

2. H

HO N

217

218

O N

221

E. Tetrazoles

Though the exactcause of Alzheimer’s disease is still unclear,evidence

points tothe utility of increasing acetylcholine(AcCh) levels for treating

that condition. Most approachesare aimedat devising inhibitorsof cholin-

esterase, the enzymethat destroys AcCh. A quite differenttack involves

developing compounds that havecholinergic activity in their own right.

The tetrazole alvameline (230), for example, was developed as a bio-

isostere of the muscarinic cholinergic compound arecoline (222). The

design devolves on the fact that the proton on a freetetrazole shows a

comparable to that of acarboxylic acid. Fully substituted tetrazoles

as in 230, may thus in some ways may be viewed as surrogate esters.

Alkylation ofnicotinonitrile (223) with methyliodide affords methiodide

224. Treatmentof this intermediatewith borohydridereduces itto tertrahy-

dropyridine (225) in which the position of the double bond mimics

that in arecoline. Reaction of 225 with ethyl chloroformate results

in N-demethylation and consequent formation of the corresponding

2. COMPOUNDS WITH TWO HETEROATOMS 109

carbamate. Thenitrile group isthen transformed toa tetrazole byreaction

with sodiumazide in the presenceof aluminum chloride,one of the stan-

dard proceduresfor buildingthat ring. Thesurrogate acidis then alkylated

with ethyl iodide to afford 228. Treatment with acid then removes the

carbamate onthe ring nitrogen(229). The methylgroup on thepiperidine

ring isrestored byreaction withformaldehyde andformic acid,under stan-

dard Clark– Eshweiler conditions. Thus, the muscarinic agonist 230 is

obtained.

222

223

224

NaBH

225

ClCO

NaN

AlCl

226

227

NaOH

228

HBr

229

230

HCO

A neurokinininhibitor whosestructure differsmarkedly fromaprepitant

(200) incorporates a substituted tetrazole ring. The synthesis of the

tetrazole-containing moietyof vofopitant (241) startby acylation ofsub-

stituted aniline231 withtriﬂuoroacetyl chloride toafford the amide(232).

Reaction of that under Mitsonobu conditions leads to the enol chloride

(233). Treatment of233 withsodium azide probabltystarts withaddition–

elimination of azide ion; this undergoes internal 1,3-cycloaddition

toform the tetrazolering. Catalytichydrogenation thenremoves thebenzyl

231

COCl

232

CCl

)

233

NaN

234

235

236

HCO

237

HMTA

AcOH

O=HC

110 FIVE-MEMBERED HETEROCYCLES

protecting group to reveal the free phenol (235). Reaction of 235 with

hexamethylene tetramine (HMTA) in acid leads to formylation at the

ortho position to give the substituted hydroxybenzaldehyde (236). The

phenol is next converted to the corresponding methyl ether (237), by

alkylation withmethyl iodidein the presenceof base.

Construction ofthe second part of themolecule starts with palladium-

catalyzed coupling of the substitutedpyridine (238) with phenylboronic

acid togive 239.Hydrogenation reduces boththe nitro groupand thesup-

porting pyridinering to afford 240 asthe cis isomer. Theenantiomers of

this arethen separated byresolution. The desiredisomer is thensubjected

to reductiveamination with aldehyde 237affording 241.

237

O=HC

B(OH)

238

239

240

resolve

NaB(OAc

241

The renin-angiotensinsystem plays a profoundrole in maintaining the

circulatorysystem. Elevated levelsof angiotensin IIare closely associated

with hypertension. Angiotensin converting enzyme inhibitors, the

so-called ACE inhibitors,lower blood pressure by preventinggeneration

of that enzyme from its precursor. These now-widely used drugs were

ﬁrst introduced starting almost three decades ago. Attention has turned

more recently to drugsthat actdirectly onangiotensin receptors. Theprep-

arationof one ofthese non-peptide agentsbegins with theformation of an

imidazole. Thus,condensation of the diamine242 with trimethoxybutyl-

orthoformate affords the heterocycle 243. The nitrile groups are then

hydrolyzed to the corresponding acids; these groups are then esteriﬁed

with ethanol (244).Reaction of intermediate 244with methylmagnesium

bromide leads to addition of but one of the ester groups. Thepresence

of the initial charged adduct arguably hinders addition to the second

ester. The free amino group on the imidazole is then allowed to react

2. COMPOUNDS WITH TWO HETEROATOMS 111

with the benzylic halide on the tetrazole-substituted biphenyl (246)to

afford the alkylated product (247). Saponﬁcation of the ester and

removal of the triphenylmethyl protectinggroup compeles the synthesis

of theangiotensin antagonist olmesartan (248).

242

(CH

243

1. NaOH

2. CH

244

MgBr

245

NC(C

)

246

NC(C

)

247

1. NaOH

248

2. H

REFERENCES

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K. Prasad, B.L. Mangold, M.E. Russel, T.A.Hughes, J. Med. Chem. 46,

2774 (2003).

2. S.J. Couttset al., J.Med. Chem. 39, 2087(1996).

3. S.J. Wittenberger,M.A. McLaughlin. TetrahedronLett. 40, 7175(1999).

4. P.E. Cross,A.R. MacKenzie, U.S.Patent 5,096,890 (1992).

5. M.M. Faul,E. Kobierski, M.E.Kopach, J. Org.Chem. 68, 5739 (2003).

6. W.F. Heath,J.H. McDonald, M. Paal, T.Schotten, W. Stenzel, U.S.Patent

5,672,618 (1997).

7. M.M. Faul, J.R. Gillig,M.R. Jirousek, L.M. Ballas, T. Schotten, A.Kahl,

M. Mohr,Bioorg. Med. Chem.Lett. 13, 1857(2003).

8. C.D.W. Brookset al., J.Med. Chem. 38,4768 (1995).

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10. J.J. Talleyet al., J.Med. Chem. 43,775 (2000).

11. J.J. Talleyet al., J.Med. Chem. 43,1661 (2000).

112 FIVE-MEMBERED HETEROCYCLES

12. R.R. Bartlett,F.-J. Kammerer, U.S.Patent 5,949,511 (1996).

13. P.T. Gallagher,T.A. Hicks, G.W.Mullier, U.S. Patent4,892,963 (1990).

14. K. Thiele,L. Zimgibl,M.H. Pfeninger,M. Egli,M. Dobler,Helv. Chim. Acta

70, 441(1987).

15. H. Liu,F.A. Kerdesky,L.A. Black,M. Fitzgerald,R. Henry,T.A.Ebenshade,

A.A. Hancock,Y.L. Bennani, J.Org. Chem. 69,192 (2004).

16. H. Sugimoto,T. Fujiwara, U.S.Patent 6,147,097 (2000).

17. C. Almansaet al., J.Med. Chem. 46, 3463(2003).

18. G.R. Martinez, O.W. Goodling, D.B. Repke, P.J. Teitelbaum,

K.A.M. Walker,R.L. Whiting, U.S.Patent 5,719,280 (1998).

19. H.R. Wiltshire,K.J. Prior,J. Dhesi, G.Maile, J.Labelled Cpd. Radiopharm.

44, 149(2001).

20. M.J. Broadhurstet al., Bioorg.Med. Chem. Lett.7, 2299 (1997).

21. F. Barth,P. Casellas, C.Congy, S. Martinez,M. Rinaldi, G. Anne-Archard,

U.S. Patent5,624,940 (1997).

22. W.A. Cetenko, D.T. Connor, J.C. Sircar, R.J. Sorenson, P.C. Unangst,

U.S. Patent5,143,928 (1992).

23. T.A. Robbins,H. Zhu, J.Shan, U.S. PatentAppl. 2005/0075503 (2005).

24. M. Chihiroet al., J.Med. Chem. 38, 353(1995).

25. J-.F. Rossignol,R. Cavier, U.S.Patent 3,950,351 (1976).

26. L.A. Sobrera,J. Castaner, M.del Fresno, J.Silvestre, Drugs Future27, 132

(2000).

27. R.O. Fromtling,Drugs Future 21,266 (1996).

28. J. Heeres,L. Backx, J.Van Custem, J.Med. Chem. 27,894 (1984).

29. J.J. Haleet al., J.Med. Chem. 41, 4607(1998).

30. M. Perros, D.A. Price, B.L.C.Stammen, A. Wood, U.S. Patent 6,667,314

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REFERENCES 113

CHAPTER 6

SIX-MEMBERED HETEROCYCLES

1. COMPOUNDS WITH ONE HETEROATOM

A. Pyridines

Agents that interact with cholinergic receptors have been extensively

investigated for the treatment of Alzheimer’s disease. Most of the

compounds discussed tothis point bind at muscarinic sites.An alternate

approach involves administration of agents that bind to cholinergic

nicotinic receptors. A compound closely related structurally to nicotine

itself is currently being investigated in the clinic. The synthesis of this

agent starts with the dihalogenated pyridine (2) obtained from nicotine

(1). Coupling ofthis with the monosilyl derivativefrom acetylene in the

presence of palladium: triphenyl phosphine and copper iodide replaces

iodine on the aromatic ringby the acetylene moiety 3. The chlorine on

the ring is then removed by reduction with zinc in acetic acid 4.

The silyl protecting group is then cleaved with ﬂuoride ion to afford

altinicline (5).

The OrganicChemistry ofDrug Synthesis, Volume7. By DanielLednicer

115

PdPh

PCl

CuI

iPr3Si

iPr

AcOH

As noted severaltimes in Chapter 5, aﬁve-membered ring containing

one ormore heteroatomscomprises the centralelement in agreat majority

ofCOX-2 inhibitorNSAIDs. Interestingly,that moietycan bereplaced bya

six-memberedpyridine ring.One ofthe twoadjacent ringsthat characterize

these agentsin this caseinclude a nitrogenatom. One ofthe routes tothis

agent startswith the nicotinicester (6).The ester groupis then reducedby

means ofDIBAL-H; backoxidation with manganesedioxide affordsalde-

hyde 7.Reaction with aniline anddiphenylphosphate gives adduct 8in a

reactionthat parallels formationof acyanohydrin. Treatmentof intermedi-

ate 8 withstrong base generates anylide on the carbonbearing nitrogen.

Condensation of 8 with benzaldehyde 9 leads toenamine 10 which now

contains two of the requisite rings. Hydrolysis of 10 leads to the

O)P

NHC

O=HC

1. DIBAL-H

2. MnO

ClCH

N(CH

)

N(CH

)

1. DMF

2. NaOH

3. HPF

tBuOK

116 SIX-MEMBERED HETEROCYCLES

ketone (11).The central ring isformed by a newlydevised pyridine syn-

thesis. The ﬁrst step involves reaction of chloroacetic acid (12) with

dimethylformamide (DMF);the initialadduct isthen convertedto itshexa-

ﬂuorophosphate salt (13). Condensation of 13 with ketone 11 involves

initial displacement of one of the dimethylamino groups bythe enolate

from 11 to give the open-chain adduct (14). Reaction with ammonium

hydroxide then closes the ring forming therequired pyridine. Thus, the

NSAID etoricoxib(15) is obtained.

B. Reduced Pyridines

Much efforthas beendevoted overthe yearsto deviselong acting formsof

drugs. Theoccasion does,however, sometimesarise where bloodlevels of

a drugbeing administered byinfusion need tobe cut offabruptly. Several

examples, suchas the b-blockeresmolol orthe analgesic agentremifenta-

nyl, includein their structurea function thatis quickly convertedto acar-

boxylic acid.This functional group both inactivatesthe drug and hastens

its excretion. Dihydropyridines comprise a large group of calcium

channel blockers usedto treat angina and hypertension.The short-acting

example, clevidipine(18) incorporates amethoxymethyl ester, afunction

that is readilycleaved to the correspondingacid by serum esterases. The

actual experimental details in patents

3,4

describe the preparation of this

compound bysimple alkylation of the monoester(16) with chloromethyl

butyrate (17). Thesesources are, however, mute as tosource of the half

ester startingmaterial.

O Cl

A verysimilar strategyunderlies the designof the opiate-like analgesic

alvimopan (30). Ileus, that is paralysis ofthe gastrointestinal tract, is a

common sideeffect fromsurgery. Theshock ofthe operationaccompanied

by heavy useof opiates causes a shut downof intestinal peristalsis. The

structure of that drug in effect comprises avery potent synthetic opiate

modiﬁed by apolar glycine residue. That lastmoiety keeps the drug out

of the CNS. Reversing postoperative ileus comprises one of the main

1. COMPOUNDS WITH ONEHETEROATOM 117

applications of this compound. The synthesis of this compound begins

with additionof the Grignard reagentfrom substituted the bromobenzene

(20) tothe piperidone(19). The hydroxylgroup isthen acylatedwith ethyl

chloroformate. Heating the resultingester (22) leads to formation of the

styrene (23). Treatment withbase under equilibrium conditions leads to

migration of the negative charge to the quarternary carbon adjacent to

the aromaticring. Addition of dimethylsulfate thus leads toalkylation at

that position.

Reaction of24 with sodiumborohydride leads toreduction

of whatis now anenamine, and thusformation of thesaturated piperidine

(25).The methyl groupis thenremoved usingchloroformate inthe modern

version ofthe Von Braun reaction.Treatment of product26, with methyl

acrylate leadsto Michael addition andformation of 27. The carbonadja-

cent tothe ester is nextconverted to its enolatewith lithium diisopropyl-

amine (LDA); addition of benzyl bromide leads to alkylation and

formation of 28. The ester (29) is then saponiﬁed. Condensation with

glycine esterfollowed by saponiﬁcationyields 30.

iPrO

OCO

iPrO

ClCO

Heat

iPrO

21 22

BuLi

(CH

)

iPrO

NaBH

iPrO

25 23

1. ClCO

2. HBr

NaOH

LDA

Glycine

DCC

Multidrug resistance,where atumor becomes immuneto a broadrange

of compoundswithout regardto their mechanismof action,comprises one

118 SIX-MEMBERED HETEROCYCLES

of themore importantpitfalls in cancerchemotherapy. Considerableeffort

has beendevoted toﬁnding drugs, so-calledchemosensitizing agents, that

reversethe process.The synthesisofone ofthese,biricodar(38)ispresented

inoutlineform omittingseveralprotection–deprotectionsteps.One armofthe

convergentscheme beginswitht heoxidationof trimethoxyacetophenone(31)

withselenium dioxideto affordthe correspondingacid (32).Compound 32is

thencondensedwith thesilylesterof pipecolicacidto affordthe amide;depro-

tection yields acid 33. Construction of the second m oiety involves ﬁrst

addition of the addition of an organometallic derivative of propargyl

bromide to but-3-ynal (34). The anion from removal of the acetylenic

protonswith strong baseis thentreated with 3-bromopyridine. Thisaffords

the product (36) fromdisplacement of halogenby the terminal acetylenic

carbon. Catalytichydrogenation thenleads to intermediate37. Esteriﬁcation

of theacid (33)with alcohol 37affords (38).

OCH

SeO

O CO

OCH

OC0H

Si(CH

)

OCH

N CO

2. H

O=HC

BrMg

1. BuLi

OCH

C. Miscellaneous

The design of the peptidomimetic antiviralagent (Chapter 1) ultimately

traces backto the fact thatstructures of these proteaseinhibitors in some

wayact as surrogatesfor thenatural substrateenzyme. The recentprotease

1. COMPOUNDS WITH ONEHETEROATOM 119

inhibitor antiviraldrug tiprinavir(52) notably departsfrom thispattern as

it omits thepeptide-like moiety present in theearlier agents; this drug is

also as aresult said to be activeagainst HIV strains thathave developed

resistance tothe peptidomimetic agents. Theconvergent synthesis begins

with the addition of the enolate from methyl acetate to the carbonyl

group in 39. The product (40) is then saponiﬁed and theresulting acid

resolved byway ofits ephedrine salt.Treatment ofthe desired enantiomer

with chloromethyl p-hydroxybiphenylgives the doubly alkylated deriva-

tive 41. Reaction of thatcompound with DIBAL-H results in reduction

of the ester toan alcohol (42). This function is thenback-oxidized with

hypochlorite in the presenceof tetramethylpiperidol N-oxide to give the

aldehyde (43).

1. CH

BuLi

2. NaOH

3. Resolve

OCH

ROCH

R = C

40 41

DIBAL-H

OCH

NaOCl

OCH

Preparation ofthe other majorfragment begins withKnoevenagel con-

densation ofm-nitrobenzaldehyde with dimethylmalonate to yielddiester

45. Treatment ofintermediate bromide45 withdiethyl zinc inthe presence

of cupric iodide leadsto conjugate addition of an ethyl group(46). The

diacid obtainedon saponiﬁcation of thatproduct then spontaneouslydec-

arboxylates onwarming. The product obtainedon esterifying theremain-

ing carboxylic function acid is next resolved by chromatography over a

chiral column. Condensation of the enolate from treatment of 47 with

the aldehyde in the other fragment affords the adduct (48). The newly

introduced hydroxylgroup is oxidized to theketone by means of pyridi-

nium chlorochromate toafford the b-ketoester (49). The biphenoxypro-

tecting group onthe tertiary alcohol is then removedby acid hydrolysis.

120 SIX-MEMBERED HETEROCYCLES

Reaction of this intermediate with base leads the anion of the newly

revealed hydroxyl groupto attack with the carboxylate inwhat amounts

to aninternal transesteriﬁcation. This stepforms the cyclic esterand thus

the requisite pyranonering (50). Catalytic hydrogenationof 50 results in

reduction of the nitrogroup to yield 51. Acylation of the newlyformed

amine with5-triﬂuoromethylpyridinium-2-sulfonyl chloride affords 52.

O=HC

Base

)

CuBr

1. HCl

2. CH

3. Resolve

ROCH

1. PCC

2. H

NaOH

2. COMPOUNDS WITH TWO HETEROATOMS

A. Pyrimidines

Thestructures ofall currentlyapproved gastricacid secretioninhibitors that

actas inhibitors ofthe sodium–potassium pump consistsof variouslysub-

stituted pyridylsulfonyl-benzimidazoles.A structurally very distinctcom-

pound based on a pyrimidinemoiety has much the same activity as the

benzimidazole-based drugs. Inyet another convergent synthesis,reaction

of b-phenethylamine (53) with acetic anhydride affords amide 54.

Treatment with polyphosphoric acid(PPA) then leads to ring closure to

form the dihydroisoquinoline(55). Sodium borohydride thenreduces the

enamine functionto afford fragment 56.

2. COMPOUNDSWITH TWO HETEROATOMS 121

In aclassic sequence for buildinga pyrimidine ring,the aniline (57)is

condensed withcyanamide. Addition ofthe basic nitrogento the nitrilein

the reagentleads to formation of theguanidine (58). Condensation of58

with methyl ethyl acetoacetate results in formation of the pyrimidine

(59); the residue of the carboxyl groupappears as an enol oxygen (59;

R ¼OH). Treatment of this intermediate with phosphorus oxychloride

replaces theenol oxygen by chlorine. Displacementof this last groupby

the basic aminein other moiety (56) leads to thecoupling product (61).

Thus, thesodium –potassium pumpinhibitor revaprazan is obtained.

PPA

NaBH

NCN

59; R = OH

60; R = Cl

2. POCl

A pyrimidine ring forms the nucleus for yet another nonnucleoside

reverse transcriptase inhibitor (NNRTI)active against HIV. This hetero-

cyclic ring is prepared in a manner analogous to that outlined above.

The startingguanidine (62) canbe prepared byreaction of 4-cyanoaniline

with cyanamide.Condensation of62 with ethylmalonate leadsto the sub-

stituted pyrimidine 63 in a single step. The enolic hydroxyls are then

POCl

122 SIX-MEMBERED HETEROCYCLES

replaced bychlorine by reactionwith phosphorus oxychloride. Treatment

of product64 with bromine replacesthe remaining hydrogenon the pyri-

midine ringby bromine(65). Reaction ofintermediate 65 withthe enolate

from 2,6-dimethyl-4-cyanophenol displacesone of the halogens forming

an ether linkage (66). The symmetrical nature of the pyrimidine ring

renders moot regiochemistry. Displacement of the remaining chlorine

with ammoniacompletes the synthesis ofetravirine (67).

The structureof the relativelysimple pyrimidone emivirine(71) might

suggest thatthis compoundis a classicalnon nucleoside reversetranscrip-

taseinhibitor. Detailed studieshave, however,shown thatinstead this com-

pound actsat thesame site asother NNRTIs. Base-catalyzedalkylation of

the pyrimidine (also called a uracil) (68) with ethyl chloromethyl ether

perhaps surprisinglytakes place atthe nitrogen ﬂankedby a singlecarbo-

nyl toyield 69.Reaction with asecond equivalentof base, thistime LDA,

followedby benzaldehyde resultsin additionof a benzylgroup tothe only

open-ring position.The reactionis then quenchedwith aceticanhydride to

afford the acetoxyderivative (70). Catalytic hydrogenationthen removes

the acetoxygroup to afford 71.

1. LDA

2. C

CH=O

AcO

3. Ac

The efﬁcacy and good tolerance of so-called statins has led to their

widespread use in the treatment of elevated serum cholesterol. These

agents act as a very early step in the endogenous synthesis of that

steroid. Thisinitial stage comprises reduction of theactivated carboxylic

acidgroup (COSCoA) (CoAis coenzymeA) inthe glutaric acidderivative

hydroxymethylglutaryl CoAto an alcohol (CH

OH); theproduct, meval-

onic acid, then goes on to the isoprene equivalent, isopentenyl pyro-

phosphate, inseveral more steps. Thispivotal reaction is catalyzedby an

enzyme hydroxymethylglutaryl CoA reductase(HMG –CoA); statins are

thus morecorrectly classedas HMG–CoA inhibitors.All approvedinhibi-

torsfeature aside chainthat mimicsthe HMG–CoA substrate.The remain-

der ofthe structureof drugsvaries widely rangingfrom thedecalins found

in the ﬁrst statins produced by fermentation to monocyclic heterocyclic

rings in some moreof the recently introduced drugs. The synthesisof a

statin based on apyrimidine ring begins with Knoevnagel condensation

2. COMPOUNDSWITH TWO HETEROATOMS 123