SPIROIllKETO niC

A SYNTlllniCSTUDYOFSOME TRIQUINANENATURAL PRODUCTSAND MICROBIAL REDUCTION

OF PIW CHIRALSPIROIllKETONES

by

YANYIZIIU

H.St:.(Honours),East China Universityof Chemical Technology, Shanghai. People'sRepublic of China, 1986

/\thesis submitte dtothe School of Graduate Stud ies in partialfulfill mentofthe

requ irement sforthe degreeof Muster of Science

Department of Che mistry Memorial UniversityofNewfoundland

51.John's. Newfoundland

March 1993

©

HI

NahonalL,brary

ctceocce B,blrolhcqllc r"1TIOl1.l1c duC"nadOl Acquisihor.sand Duectonocs acqLJI$'IIOIISct BiblIOgraphic Services Branch desservicesblbhogl"p11IQlI\~

395Wclilnglon51,ecl 395,".'WI>II'~ll""

~1~~4()il~"o ~~,~~~~"" .,,,ol

The author has grar.~ed an irrevocable non-exclusive licence allowing the National Library of Canada to reproduce, loan, distribute or sell copies of his/herthesisbyany means and in any form or format, making this thesisavailableto interested persons.

The author retains ownershipof the copyright in his/herthesis.

Neither the thesis norsubstantial extracts from it may be printed or otherwise reproduced without his/herpermission.

L'auteura accorde unelicence irrevocable et nan exclu sive permettant

a

la Blbllothequ e natianale du Canada de repraduire,preter,distribuerau vendre des copiesdesa these de quelque manlere et sous quelque forme quecesoit pour mettredesexemplairesdecette these

a

la dispo sition des personneslnteressees.

L'auteur conse rve laproprlete du droll d'auteur qui protege sa these. Ni la theseni desextraits substantiels de celle-cl ne doivent etre imp rimes au autrement reproduit s sans son aulorisation.

ISBN 0-315-86635-7

Canada

AllST RACT

The firstha lf of th isthesis describes un approachIIIthesynthesis uf a group oftriquinane sesquiterp encs.with{±ldco xypcut nlcuic:1I,:i llas the particula rtarget.The synthesisstarted from read ilyuvuilabl cisophoronc.

The centralquaternarycenterof the nnrurulprod uctW:ISestablishedin:1lI earlyste pbyadoubleucylat lonreac tionnilu cyc tohcx cnc derivative.

Cleavageof the double bondwas followedbyrcclosurcIn afive- membered ring.Therelati vestereochem istryatastcrcogcui mcthinc was controlledbycatalytichydrogenation.Anintrumolc culuraldolreact ion wasused to cyclizethethirdringofthetriquinnucmoiety.Thercmuiuing steps to (±)-deox:ypenlalenicacid weremodeledin reactionsleadin gInII.

keto este rsand inreductionsoftheketone moiet y ofu [f-kcroester.

Thesecond partofthe thesisprovides thercsults ofchirulreductions ofLf-c y clo pen ta nedione derivativ esusing baker'sYCi ISt.The seriesof diketonesthatwa s examine dincluded7.9,9-trimcthylspi wf4.5Idee-7-enc- l.a-dione.Theyeas t reductionofthiscompou ndto (4S,5R)-4-hydrnlty- 7.9.9-tri methyls p; ro[4.5 ]dec-7 -en-l-one(23)proceed ed withhigh fuciul selectivityand enantio selectivity .usdeterminedbyanana lysistlfthe correspond ingMo sher'sester[(+)-a-me thoxy-a-tri tluu rllmcthylphc nyl- acetatederivative).The facialselectivitywas compared withthutIll'the chemical reduc tio n usingsod ium bo rohydridc.Theabsolutestereo- che mistrywas establishedfromCDspec traandanXvn-ystructure,The transfo r mation ofcom pound 123into (4/?5S)- 4-hyd roxy-4,7,lJ,lJ- tetra met hy!spiro[ 4.5Jdec -7-en-l-one, an optically active form nf an intermediate in the triqu ina nc synthe sis, requ ire d four steps.

ACKNOWLEDGEMENTS

The authorwi:hcs10tha nk:

Pro fess o r 0.1. Burnell, my supervisor. for his gu ida nce. encourageme nt andhel p thro ughthecourseofmy studies:

Professor C.R.Jablonski.ProfessorB. Gregory, Professor A.R.

Stein.ProfessorJ.N.Bridsonand thetechn ical staffof theChemistry De pa rt men t.Miss M.Baggs and Ms.N.Brunet. fortheprovis ionof the spccrruldata. andMr.Zhongxi nZhoufor help withCDspectra;

Dr.Y.T.Ma,myhusband , forhisgrea t influenceand interest inmy work;

Pro fessorJ.N.Brid sonand ProfessorR.Helleur,my supe rv iso ry cOlll111 iIlCC, forthei r valuablecomments;

allmembers ofProfessorBurnell 's group fortheir kind hel p and fun;

Memo ria l Univer sit y ofNewfound landand Pro fessorDJ,Burnell forfinancial support.

Itt

Till e...

Abstract

TABL EOF CONTENTS

. i

...ii ,u

Acknowle dgements iii

Tableof Contents...

List of Figures . ListofSchemes..

List ofTables

. iv

.. vi

.. .. ... ... ... .... ..viii

GlossaryofAbbreviations ix

Dedication.

ChapterI. A Synthe ticStudy of SomeTriquinuneNaturalProducts...1

L In trod uction... . .. ..1

II.Resultsand Discussion 15

Ill. Experim ental .::4

Chapter2. MicrobialRedu ctionofProcbir ulSpirodikcton cs 61

I. Introdu ction 61

II.Result s andDiscussion 72

III. Expe ri mental

References . Appendix..

...lJ1

... 110 ...117

LISTOF FIGURES

Fig/lreI. MS spec trumofcompo un d57 1 6

Figllrt!2. MSspectrumofcompound58 16

Figllrl'3. I HNM Rspectrumofcompound66 22

Fi,r.:/lre4. IHNM Rspectrum ofcompound 67...•...•...•...•23 Figure 5. IHNMRspectrumofcompound 72... . .30 Figure6, IH NMR spectrumofcompound 71(CDCl3) 31 fig/In:7. IHNMRspectrum ofcompound71(C6D6)... .. 3t fig/In:l~. IHNMRspectra of123and117n plus Eu(hfc)3 76 Figure9. IHNMRspectrumof123(with Mosher'sester) 77· Figure10. IHand19FNMRspectraof124aand124b(with

Mosher'sester) 79

FiJ:lIl"eJ J. CDspectra of122and130 86

FiKlIreJ2. X-Raystructure130Mosher'sester 87

ngure/3. CDspectrumof129 89

Figure14. X-Raystructure134 89

Figure/5. XiRoy structure137 91

LISTOF SCHEMES

SchemeJ. Biosynthesisof pcntalenenederivatives A

Scheme 2. Crimmins' synthes is oflb tl

Scheme3. Fukumoto'ssynthesis of lb 9

Scheme 4. Yndav's synthesis ofan angulartriquinunc 11

Scheme 5. Burnell'ssynthesisof2 1J

u

Scheme 6. Formati on of 57 from .56 Scheme7. MSfragmentationof57 andS8 Scheme8. Formationof60from57 . Scheme9. Formatio nof 63from60 .

...15 ...17 ...IX ..11) Scheme10.Formatio nof66und 67from63 20 Scheme11.Facialselectivityonhydrogenationof63 andfi4 27 Scheme12.Formation of71from66and

n

from 67 2H Scheme 13.Formation of73from71and 74front72 J5 Schem e14.Formation of1bfrom 73... . 37 Scheme15.Modelstudyof p.k eto esterfor mation of77from 76 3X Scheme16.Formation of~.ketoesterfrom74 ami72... . JIJ Scheme17.(3-Ketoesterred uctionstudies on77and7M .40 Scheme18.Yeastreductionof 2.2-di alkyl1.3·cyclopcntam:dillllcby

Kosmol.. . ....,(12

Scheme 19. Yeastreductionofz.z-dtsubsrnutcdt.j -cyclopcntaned ionc

by Brooks... . Jl]

Scheme20.Brooks' synthes is ofanguidine(96).. .. 66 Scheme21.Mori's synthesisof(lS,5R)-karahanaether (109)... ..fJlJ

Scheme 22. Mcthyllltbiumadd itionandNuBH4reductionof60 71 Sd m ne23.Mcth yllith ium add itionandNuBH4reductionof118 71

Sd~f!I1/('24.Baker'syeastreduct ion of121 72

Sd/(!me25.Principle ofyeastreduction:fac'nlselectivityand

enuntiosclectivity . ..73

Scheme2r,.Baker's yea stred uc tionof 60.. .... . 74 Scheme 27.Baker'syeastredu ction of118... .. 77 Scheme 28.Bak er's yeast reduct ionof125.126,127and128 81 Sdu'11/e29. Principleof chemical reduction: facialselectivit y.... ..82 Sctunne30.Baker'syeastreduction on 126... ..87

Schnne 3/.Fo rmationof 137from123 90

LIST OF TABLES

Table I. IHNMRdata.fur 66.... ...:!·I

Table 2. IHNMRdata fur()7.... . 25

Table3. 13CNMRdatafor66and67.... ...2(}

Table 4. lHNMRdata for71.... . .\:!

Table5. IHNMR data for72... ...\.1 Table6. 13CNMRdatafor71and72... . .\,1 Table7. t3CNMRdatafor73and74. . .16

tll ll

Table8. Reduction of~-kc tocsterbyNuBH4/MC I:!.. .. ..11 Table9. Reductionofprochim l2.2-disuostitutcJ1..1-cy,,:lnrClll'lIlc-

(Honesbybaker's yeas tandby NaBH4.... ...M Table 10. Bake r's yeast reduction... ...x.\

TableJ1. Comp arison ofyeastandchemicalreductions X"I

IX

Glossaryof Ahbreviation s

APT Attachedprotonlest CD Circulardichroism COSY ^rH_IH Correlation spectrum DBU I,H-Diazabicyc1oI5.4.0Jundec~7~ene D1B,\L Diisobutyluluminumhydride GCM S Gus chromatography-massspectrometry I-IMPA Hexnmethylphosphorurnide

II< Infrared (spectroscopy)

LDA LithiumdiisopropyJamide M" Methyl

lllp Meltingpoint MS Mass spectrometry NBS N·Bromosuccinimide

NMR Nuclear magneticresonance(spectroscopy) nOc NuclearOverhau sereffect

Nu Nucleophile

PeC Pyridiniumchlorochromate I'TSA para-Toluenesulphonic acid TBDMSCI tert-Butylchlorodimethylsilane TFA Trifluor ouceticacid THF Tetrahyd rofu m n TLC Thin layer chromatography TMSCI Cblorotrimethylsilane UV Ultravio let(spectroscopy)

Tomydear parent s

Chapte rI

A SYNTHETICST UDYOFSOMETRIQ UINAN ENATU RAL I'I{()J>UCT S

I. Introduction

OUfultimategoal wasthe synthesisofdeoxypentalenicacid(J b).

which is amem ber ofalargeclass ofmetabolit es containing the tricyc!o[6 .3.0.04,8jundecune skeleto n, closelyrela tedmolecules are deoxypentalcnicacidglucuron(la ),'pentalen ene (2),2,3 andpentalenic acid (3).4,5

H 5 :4 .1

" ~ COOR

~ _{7'" :1}

~ll

10

OH III It

=

HO-r---?-7-OH

-...J--

^0--.L-COOH

Ih R

=

^H

Hq 1;1

. > ( b - - -COOH

r \ )

Thisgroupof angularlyfused triquinoncs ;llsuincl udesisocomcn c

(~),6,7silphinene(5),8.95-oxosil phipe rfotene(6),10.IIsnbcrgorgic

acid(7).12•13the unique diterpcnelaurcneuelH)I·t 1;\1 (the onlyknown

IlO OC-cb

" y..

a

~

a ~

^__on

10

~ ~

~ClK )J1 V ,1;-<> I. )

n II

naturall yoccurringfenestrane),theunusualscstertcrpcnc rctigerunicacid (9),16.17andcrinipe llin (10).18.19 Intensiveresearchon pcntalcnenc (2),pentalenic acid(3),deo xypcnmlenic ad dOb).and dccxypcntalc nic

acid gJucuron fla)hasresultedfromthe ir demonstrat ed rolein the biosynthesisufthe sesqui terpeneantibioticpentalenolactone (11).20.21 Setaet al.2•4 isolatedpentalenicacid(3)fromStreptomyceschromofusc us andpernulcncne(2)fromS.'griseochromog enes . Takahas hiet01.1obtained dcoxypentalenicacidglucuron(Ia)fromS.omiyaensis,S.olbofaciens,and S.viridlfacie ns. Dcoxype ntalenicacidglucuro n (la)displayed antitumor activity againstSarco ma180in mice. Penrale nclacton e(11)wasisol ated fromseveralspeciesofSireptomyces20suchasS.chromofus cus,S.

griseochmmogenes.S.baarnensis.S.arenaeandS.roseogriseus.These are rareexamplesofcyclic terpcn oid antibioticsprod ucedbyprokar yotic organism s.Pent alen olnc ton e(11) wasreport edto exhibit poten tand specific antiviralaClivity.22 StudiesinCane's 2 3laboratoryhave shown.

that pema lenol actone(11) is atime-dep endent.irre versible inactiv ntorof glyccrulde hyde-Scphosp hatedehydrogenase,whoseinhibito ry actionisdue In a spec ificreactionwithall fo uractive-s itecystei nesof the tetram eric enzyme.They alsocarriedoutextensivestudiesonthebiosynthesis of2.3.

1:1.lband 11as shown in Scheme1.24 _Famesyldiphos phate(12)was enzymaticallycyclizelrtopentalenene(2),theparent sesqu iterpene.Several oxidativ esteps frompentalenene(2) ledtodeo xypentalenic acidglucuron (la),deoxypentalenic acid(l b)andpenta lenolactone(11).

Additionalinterest hasrecentlybeendire cted towardthesynthesisof these structurally intriguingmolecules.

In 19 86.Crimm ins andcoworkersffreportedthetotalsynthe sis of (±)-c.lt::oxypcnti:llenicacid (lb)(Schem e2) to ge ther with(±)·penta le nene 2).and(t)-peat al enicacid (3).Akey step inthe(±).deoxypentalenicacid

Schemel Biosynthesisofpcntnlcnenederivatives

R ^I

^,ropp

12

HQ.. ~

>(O--COOH

~

>(b-C

H

O OH _

1--) _o

14 H

I

>(b-C O O H

b~) _o ----

15

><:t)--COOJ< ','

~

ill R =glucuronic acid Ih R = H

II

I

>(b-mo ll

1-)

_o

13

-lli-

.

'

' \ COOII

\ ,

b 1-)

o 11

(lh)synthesiswas anovel conjugateadditicn-cycloacylationsequenceon anacctylenic diester 16. Treatmentof 16 withth eappropriateGrignard reagent in the pre se nce oftetramethylet hylenediarnine(TMEDA) and cllppcr(l) iodideled to diene 17.Convers ionof17to dienediester 18 was readi lyaccomplis he d by selective ozonolysis of the electron -ric h trisubst ituted double bondto yield an aldehyde,whichwasimmediate ly condensedwith(carbethoxy~methy leneHriphe nylphosphoranetoprovide 18.Irradiation ofdiene18withUVlight resultedinsmoo thcycloadditio n to produce 19 asa10:3: 1 (l9a:19b :19c)mixture.Reduc tive cleavage of thecyclobutaneringof19was accomplishedbytreatmen twith lithium in liqu id ammoniato produce~-ketoesters20a and 20b ina ratioof13: 1.

Following hydrolys is-decarboxylationof fl-ketoester20b, esterif ication- andcyclization inbase generatedthe triquin ane skeleto n 21.Selective kemlizutio nof 21gave compound 22.After reducing the carbony l funct ionof 22with lithium in ammonia, hydrolys is of theketal provided ketoalcoho l 23 . Mesylationofthis compound23ketone foll o wedby treatment with 1.8·d iazabicyclo[5.4.0 ]und ec-7-ene (DBU)produced enone 24. Enone24was treated withexcess LOA andC02 followedby esterificatio nwith diazomethan e (CH2N2)togiveketo ester 25. Sodium bcrohydridereductionof2Sproceededto giveallylic alco hol 26, wh ic h was catalytically hydr ogenated to alcohol 27.Mesyl ation of thealcoholand eliminationwithDBU yielded methyldeoxype nralenate 28.The tota l synthesis ofdeoxype ntalenic acid (I b)was achieve dbyhydrolysis of28in aqueous potassium hyd roxide . Crimmins' synthesiswas accomplished in a 101.11of twen ty steps.

Scheme2 Crimmins'synthesis of (±)-deoxy pentale nicucidOb)

o XCOOCH~ Me~C=CH(CH1).1CHMeM gC!

=

COOCH,TMEDA.CuI.THF 16

# CODClh

'"

17

19

^g;\P=C'IICO, Et

>ffi ~OO~

,; , ,)

19a,b

o

COOM,

~COO_Et

^{_ _}

. .. hu

.--"-/

19c

o

# coocu,

~ (OOEI IN

j

^{Li/ NH,}

~

HO^Rt

^R,

^{-...::,.• .. -OOM'c a DEt}

20.Rt=H. R_2=CH, 20bRt=CH,. R,=H'

1)hydrolysis o X 21

-co, >OJ

3) McOH/H2S04

4) t-BuOK .

SI(CH,DH ),II'TSA ~ 21X= O 22X=(OC II,),

22

o

O C O O M O

N

25

I

^NaSH,

011

m - C O O M O

N

26

> ( I ) - C O O H

N

Ib

LOA,CO, CH,N,

Pd-C,H ,

IO%KOH

>oj

~

23

j

^21MsCl,Et3N

^DBU

x::6 N

24

>0::.>-

OH ^COOMe

N

27

I ~

> ( I ) -COOMe

A0

28

In 1988 Fukum otoandcowor kers.Jlreporte dtheto tal synthesis

or

(±)-deoxype ntalenicacid(l b:'Ising a diffe rentap proach(Scheme.\1.The key ste pin this synthesiswasan intramole culardoubleMichael reaction.

Thus. treatmen tofbis-encne29withchlorotrimeth ylsilunc.triethylamine.

andzincchlori degavetwo separable dias tercomcrs .\0andJI.Boththe yieldandthe ratioof thosetwo isomersdepended onthe rcnction te mpera tureandthe solve nt. Com pound30 wastransfor med into compound32with ethyl formateintfupresence ofsodium mcthoxidc.

Diazo-e xchangeusingp-toluene sul pbonylazide andtriethylami ne gave diazo-ke tone33.Irradi ation of 33inmetha nolpro duced amixtureIll'the two sep a rable keto esters 34and35in a ratioof3.6:1.Reductionofthe ketone group of 34toameth ylenewas achievedbydirhiouccmlformation and desul furizati on with Raney nickel.Selencnylntionof36 followedby oxidativeelimination furnish edmethyl deo xypcntulcuutc (2M).Hytlrnlysis ofthe methyl estercompletedthe synthesisof deoxypcntalcnicucld(I h).

This syn thesis wasfinishedinatotaloffifteen ste ps including six.~Iepsttl 29.During thesynthes is. two stepseach pro duceddiastcreomcric mixtures ofcompounds.

Thechallenges in the synthesisofth is groupofnatural productsarc toestab lishtheangular triqui nane skeletonitself andto obtainthe correc t relative sterechemistryatC-9.Therearc anumbe r ofapproachestothe synthesis ofangulartriquinaneske leton.Recen tly, arudicai-mcdiutcd approachwas reportedby Yndav aridcoworkcn;25 (Sc heme4).The requiredbromo acetal 40wa s preparedfrom2·methuxycydopem-2-cn·l·

one(37).AGrignard reagent.preparedfro mbute nylbro m ide.wasadded

Sche me3 Fukumoto'ssynthesisof (±}-deoxypentalenicacid(lb)

29

O ~+O~

H 0 H 0

30 31

I

HCO , EtlN aOMe

,.-y.

M'OOC '.~

H 0 35

:\..-

TsN,JE.,N

R

HO "'"

H

0

32

\

,.-y.

M'OOC~

H 0 34

~

I LDAJPhSeCI ~

2 H;P 2 McOOC~

,', r-\....

M ,ooc--<=t{<

H 0

34

MOOOC--ctx ~

if

28

I

^KOHlMeOH

lb

BF.fEt .!O

~

McOOC--l-fv

~~ I'S 0

35

j

^{Ib llcyNi}

36 10

II Scheme4 Yadav's synthes isofan angular triquinane

CH,=ChCCH, hMgBr

Jl /"-.. _

V -'"

s;

42 '"

!CH]MgBr

"c$

43

45 Jones 90%TFA

38 jDlBAL

OH NBS. CH,=CHOE,

A/"-.._

V - '"

39 37

OEt

~ O~D'

~

⁴⁴

^~IOHo

~

40

I

^NaBH]CNAIBN: BuJSnH

~.

⁴¹

I,

to37 to give 2·(4-b uteny l)cyc1o pen t-2- e n-l-un c (38).Reductionof .lH with DIBA Lproduceddiencl 39, whic hW:lSfurther conve rted10 the de sired bromoaceml 40 using NB Sandethylvinylether.Treatme nt of-Ill withsodiu mcynnoborohydrideinthepresence of a catalyticuuuunu(I f

trib utylti n hydride led to the expected mixed cyclic acctul

a

l,Hemiace tal 42wasobtai nedbyhydrolysis of ethylnccmla lwith90¹jf.rrtfluoroaccnc acid. Reaction of42with methyl magncsiul1!bro mide produce ddiol ·U, wh ichwas convertedto diketone 44byJones oxidation.Thedesiredt)- methyl- tricycl o[6.3.0.01, 5}undec.4-e n-3-one loiS)was ob tained hy trea t mentof 44with20%potassiu m hyd ro xideinethano l.

Our syntheticapproac h to thetriq uinnncskeletonwas bused on the successfulsynthesis ofthe(±)- pental~nene(2)by Wu anti BurncliJ u (Sche me 5).Ketalisatio n of3-ethy l-5,5-d imethylcydohcx -2-cn- l-onc(4 6) wit hethyleneglyco lprovidedket al47. Treatmentketal 47 with 1,2- bis( tri methylsily loxy)cyclobute ne (48 )26and borontrifl uorid e cthc nuc afforde dthespiro-di ketone49.Themon o- alcohol 50W;lSobtainedby ad di tionofmethyllith iumto49. Ozonolysisof50. the ncycli zationwith pTSAas the catalyst pro vided51. The conjugated double bondW;\S redu ced using Birch condi tio ns. Hydro genation andaldolco ndcns ut iou gave amixtur e ofthe tricyclicprod ucts53 and54. whichwcre separa ted.

Start ingwith53.cata lytic hydrog enation , sodiumborchydride reduct ion and acid catalysed dehydrationresulted inproduc t2.

Eventho ughourapproa c htodeoxypent alcnic acid (lh) was designedtoparallelthe route to pentalene ne(2),itcouldalso lead tu pentalen ene (2) itselfbya slig htmodifica tionof thelust steps.We

13 Sche me5 Burnell'ssynthes isof(±)-pentalenene (2)

~

^{46 (CH,oH),.pTSA ~}

8

47 OTMSj

48

c(

^SF,.Et,O

OTMS

53 54 MeLi

I) fl,.Pd-C 2) NaSH, 3)pTSA 51

13S

511

j

^{2)I)0pTSA, .Me,S}

~

conce ntrated on thesynthesisof compound55.whichwould beonlyafew steps fromthe naturalproduct.The result sufourwork1U\ \';lnlthe totu l synthes is ofdeoxy pentale nicacid {Ib).includingSU IIlCmodel studies for the finalsteps,are presentedinthischapter(Ifthethesis.

()

0 <"00' "

N

55

II.ResultsandDiscussion

Scheme6 Formation of57from S6

I:;

56 57 58

Thesynthesisstarted from the readily availablestarting material.

iso phoronc (56).Kctalisation wascarriedout withethylene glycol inthe presenceof I'-Ioluenesulphonicacid(PTSA)(Sche me 6).The reaction producedamixtureoftwopoorlyseparableketals57and 58.Thedesired isomer 57 W::lS the major compone nt as determined by gas

Ihromutography-mass spec tro metry(GeMS).Somestarting materi al alwaysremainedno matter howlong thereactionwas run, andsome oligomeric material wasfo rmedwhen thereactiontime wasincre ased .Vr;,;

Finally optedtorunthe reactionfor 12-14hours.The solventwas evaporatedand the productswere distilled undervacuumto removethe yellow color.111e crudecolorlessoil was thennash chrom atographed,The ketal5',wasalwaysa majorisomer. buttheratioofthe two isomers varied withthe reactiontime.GeMSanalysisindicatedthatthe someof the ketalproductwashydrolysedback10thestartingmaterial 56.andsomeof theketal57 isomerized10ketalS8duringchro mato graphy.Theisomeric

ketals could beclearlydistinguishedbytheir massspectra(FiguresIand 2).

Figure1 MSofcompound57

OI. 11

'"

Ie.

. ..

~ sae

~

.. _, .. ^,

lIN ...

I U V' ..

'J j ( , ^r

I¹⁷ ) '(

»

" 8' IN Ii':' 141 1'1

"I . .~h .,I

Figure2 MSofcompoundS8

Theketal57 hallitsbasepeakatmlz86(C4H60 2·+).whicharose viuthe homolyticretrc-Diels-Alderre action of57.Likewise.thebase peakatml z 126inthe massspectrumof58 could be assignedto a fragmentwiththe formu laC7HIO 0 2'+(Sche me7).In thelHNMR spectra.the vinylproton(H·8)ofthe ketal 57resonated at 05.17.while thevinyl prolan (H-6)of theketal58was at05.34.

Scheme 7 MSfragmentationof 57and58

~ n-r ^:>

57

^{"" 0}

m/ z

^{r> ,(}

86

^iT

⁺

^yy

n-r ^{i T}

A ^{,J o~ r>}

⁺

^)l

58 mlz126

Treatmentofthismixture of ketalswiththreeequivalentsof1.2·

his(lrim elhylsilyloxy)cycl obutene 48 andalargeexcessofboro n trifluorideetherateproceeded.viaan intermediate cyclobutanone59,to afford inasingleoperationtherearranged,spiro-annulated diketone60 (Scheme8).

17

Scheme 8 Formationof 60from57

I~

1 \ ~

~

^{o 4'0}

^{- - --}

^{XO,(CH~hO 4' OTMS}

^{- -- -}

57 59

Thisreactio n hasnow beenextensivelystudied inomlaboratory.

Howe ver,Kuwaj ima andco-workersc" tics!reportedthisreaction.They dem on stratedthatunder Lewisacidcatalys isaketal reactswith 1,2- bis(trim ethylsil ylo xy)cycl obut en e (48)toprovid ethe cyclohutauoue.

whichcanbe rearra nged inthe presence oftritluo roaccticncid(T PA) In yielda spirodiketone. OUf method employs:\singlestep andlend sIIIa superi oryieldbyprolongingtreatmentofthe ketalwith 4H andbyusing a largeexcess ofboron trifluoride etherate.28-30

With the diketone60in hand,weintrod ucedthefinalmethyl group.

At-7SoCadditio nof meth yllithi umtothe spiro dikctonc60 prod uce d monoalcoho l 61as the majorproduct (Scheme 9). From previous studies inour laboratory.Ll weknew thatmcth yllith ium woulduuuckonlyOIlC ketone,nomatterhow manyequivalen ts of methyllithiumwereused.The 13C NMRspectrumof theproduct showedonlyonecarbonylsigna lat{) 220.5,and there was a resona nce for a quaternarycarbo nbearingan hydroxy atB77.7.

Ozonolysisof61 cleaved the double bond,andreductio nofthe ozonidewith dimeth ylsulflde yielded the aldehyde 62.Because compo und

Scheme9 form ation of63from 60

60

63

61

n ~~HO H>0-x

62

19

62 wasnot very stab le,withoutanypurificatio nP:TS Awasadded to induce smoothcycliza tionandconcomita nt dehydrat ion giving the diketone 63. The do ublebondthatresult edfrom dehydrationdidnotmoveinto conju gationwiththe ring ketone.The I HNMRspectru mof63 showe d two ulkcnic resonances: onefo ran unco nju gated doublebond proton at13 5.76(IU.dd,H~3)andtheother for a conjugated doublebondprct on at0 6.69 (1H. s,H·7).The H·3 signalwas coupled totwoH·2signals(J=3.3 Hz)andto 4-CH3(J

=

1.8Hz).Thefactthatonedoublebondin 63 remained unconju gated was proba blyfor tworeasons.In this arrangeme nt

thedoublebond ismor e subs tituted.•md thisshapeinvolves less stcric compression.since C·4issp2 the4-CH3does not eclipseeitherC-6 or C-9.

Scheme10Formation of66and67from63

20

,

~

^{9 ....}

^v

⁶³

^A

⁶¹

^{o o}

^Li/NH,

^{- -}

+ either:

~ ^{... :}

^•66

^{\ .. {}

⁰

I

^H,lPd

ffi··( / x "

67

qro >rr

or: + .. . ~o

68 69

The conjuga teddoublebond of 63was red uced using Birc h condi tions to furnish an exclusive product,the enedio ne 64(Scheme 10).

Inthisreaction, a stereogeniccenteratC-6 wasproduced.Nuclear Ovcrhauscreffect(nOe) measurements were not successfulin indicating the relat ivestereochemistry,becausein its IH NMR spectru m thechemica l shifts of 4-CH3, H-9 and 1-1-7 were very similar.Differentso lvents, suchas C6D6andCSDSN.were tested ,butthey all failedto separatethesesignals.

Howe ver,the relativestereochemistry of64wasdetermi ned afterthe next SICp.Ketone 64could notbecyclizedto65in eitheracid or basedue to the acidityof the C-2hydrogen s.Thus,the nnconjugated doublebond was also reducedbycatalytic hydroge nat ion , and in the processanother stcreogeniccenter atC-4was generated.Weobtainedtwo produc ts.which.

could have been thepair 66and 67,orthe pair68and 69. Thesetwo productswereseparated by carefulchromatograp hy.

1.3%nOe~

~ ^{4; ( H H3}

^67:

^{1,o :}

⁶

^{~ ... <}

⁰

Onlythe mino r product showed asignific ant oO e onH-6 on saturationof the4·CH 3 signa l. Thus, this minorprodu ct could only have

21

been67.As thetwo products were epimericonlyat C-4.therefore the majorproductwas66.

In theIHNMRspectrumof thismajorproduct66(Figure.1). the4- CH3 signallay bet weenthe two 8-CH)singlets.so;iwasdifficultIn saturateonly4-CH 3. Also. thechemicalshiftof the4-CH.1 tor(,6W;IS&

1.04(d, J=6.4Hz).and inco mpound 67 (Figure 4) itwas atis0.76(d.J

=

7.2Hz)sugges tingthat in67 the4-CH3 wasinboththe carbonyl amithe acetylgroups'shieldingregio ns. cons istentwith4-CH)on the "'.1'/1face.

Noted fromtheI3CNMRspec traldata.thechemica lshifts of 4-CI-I) (0 14.8)andC-9 (842.6)in66were at higherfield thanthe4-CI-I)(0 17.4) andC-9(8 51.2)incompound 67. because the4·CH3in ()7W;1S"(-illltiIn

e-9,butin 66.iteclipsedC-9.

.-J)Jl I '

J Figure3

i i i j

3

.JIll ,J I I I~J.J. ^J

23

o I '

PP !.!

Figure 4 IHNMRspectrumof compound 67

Most important.themajor reduction product66hadthe correct relativestereochemistry atC-4for thetargetsesquite rpenes.Theratio of compound 66 to 67was :!:1.Thespectraldataof both 66and67were assigned in detailbased onnOe difference spectra.attachedproton test (APT). 'H· I H, and. tH_13C two dimensional(20) NMRspectra. The assignmentsare listedinTables 1,2and 3.

TableIIHNMRdata forref-(4R.5R.6R)~6·;u:ctyl~.UU3­

trimethylspiro[4 .4lnonun-l-one (6 6)

3f f ) I

OH

, .t

¹¹

5 '6 \ .

4 '

°

... 9: S

position H·2

H·3

H-4 H·6 H-7

H·9

H-II 4·CH3 8·CH3 8-CH3

chemica lshift 2.45(m.ddd,J

=

1.2. 9,It).2I-1z)

2.15 (IH.m) 1.35(IH.m) I.M9(IH.m) 1.87(III.m) 3.75(IH.dd.1=6.2.D.6II,,)

1.55(IH.dd.l=6.12.3111.1 1.99(111. 10) 1.20 (lIl.d.l = 13.K1M 1.75(l1I.d.l=13.K111.)

2.1lO(3H.'J 1.04 (311.d.1 =6.4II,,)

1.03 1311. ,) 1.]()(311. 'I

Table2IHNMR datafor rel-(4R,5S,6S)-6-ac etyJ-4 ,8,8- trimethylspiroI4.4]nonan- l- o ne (67)

3 ~

5

' OH _JlI

'6\ .

4 : 0

9' 8

25

position H-2 H-3

H-4

H-6 H-7

H-9

H-II 4-CH3 8·CH3 8·CH3

chemical shift 2.20-2.42(2H,m)

1.60 (lH.m) 2.07(lH,m) 2.56 (lH,ddq,J=1.5, 7.2,14.4

Hz) 3.15(IH,dd,J=4.5,9.1 Hz) 1.71(lH,dd,J =4.5,13.5Hz)

2.24(lH,m) 1.74(lH,d,J = 13.5Hz) 1.91(lH,d,J =13.5Hz)

2.16(3H, s) 0.76(3H,d,J =7.2 Hz)

0.98(3H,5) 1.02 (3H. s)

Table 3 l3C NMR data forrel-(..IR .5R.(iR)-6 -ucctyl -..LS.S.

trirnethylspirol-l.elnonan-l-one(66 ) andrd-(....R.5S.6S)-6- acetyl-4,8,8-trimethy[spiro[4.4jno nan-l-one(67)

position'" 66 (.7

C-I(O) 220.4 :!21.J

C-2 (2) 35.9 12.9

C-3 (2) 27.1 :!6A

C-4(1) 38.2 W.2

C-5(0) 61.9 65.0

C-6(1) 55.5 55.1

C-7 (2) 43. 1 -14.0

C-8(0) 37.4 37.9

C-9(2) 42.6 51.2

c-io

(0) 208.7 210.X

C-II(3) 31.1 30.1

8-CH3(3) 29.4 29.2 Jl.9

4-CH3(3) 14.8 17.4

'"Numberofattached protons in parentheses

26

Scheme11Facialselectivity onhydrogenatio nof63and 64

27

64

o '\,.. 0

-~

66 maj or

63 70 69maj or

Catalytichydrogenationof 64appearedto take place with moderate fucialselectivity.Sinceits acetylgroupwas atsome distancefromthe doublebon d.hydrogenationcouldproceed mainly from thedirection shown in Scheme11.Previously,Wu31obtained isomer69,aC-4nod C- (, cpimerof66.bydirect hydrogenation of compound 63.Inthis casethe unccnj ugateddoublebondwasreducedfirst.Inthe intermediate compound 70 oneface ofthe cnonewasblockedby4-CH3 , so reductionofthe conjugateddoublebondwnsmainlyfrom theoppositeface.Butthis me thod compound69wasthemajoriso mer. andcompo und 68,whichhad the desiredrelative stereochemistryat C-4•wasthe minorisomer.Hence.

thereduction of theenoneviatheBirch conditionsgavethe betterracial selectivityandprovidedthe desiredcompound 66asthemajor isomer.

Sche me 12 For mat ionof71from 66and 72from(17

~( ^{... !}

⁰

~

^:

(

⁰

66 67

I

^'BuOK

I

^'BuOK

sv"

⁷¹

^>?

^{:72 II (J}

Conve rsions of66 to71and 67to 72 werecarried out inall intramolecularaldolring-closurefash ionusing potassiumterl·hutoxidcas thebase (Scheme 12).When the reactionwaskept atroomtemperatu re.Ill)

cycli zationproduct wasdetected fromboth TLC andGCMS.Howe ver . when thisreactionwascurriedoutatreflu x. The TLCre vealed anewspot that'vas veryclearlyvisible underUV.Thereaction was complete in I{J.

20 minutes.CarefulTLC monitoring wasrequired.The MSshoweda strong peakatmIl.43for the acetylgrou pin the start ingmuteriuls.This

fragmentwas not present intheproducts, anda molec ular ion atmlz 204 impliedcycliz ationto71and 72.

Both the majorisom er 71 and mino r isom er7'J,could be distinguishedfromtheirIHandl3CNMRspectra data.IntheIHNI\A'P spectra, the chemicalshiftof 9·CH3in72(Figure5)was at(50.'/6.

whereasin 71(Figure6)itwas at0 1.2 6.Alsonotedfromthe13eNMR spectraldata.the chemicalshifts of9-CH3(814.6) and C-? (039.4) in 71 wereuthigherfield than 9-CH3 (0 16. 6) andC-?(0 51.0) incompound

n .

This wasdueto9-CH)being y-antito C-?in 72,and y-eclipsedwith

c-?

in71.ThenOedata confirmed the relati vestereoc he mistry of compound 72with H-4synto 9-CH3. When9-CH)wassaturated,H-4had a10%nOe.

29

o

72

The nOe differen ce experiments failedoncompound71.becausein itsIHNMRspectrum the9-CH3signal wasbet weenthe two6-CH3signals.

Itwasdifficulttosaturate9-CH3.In C6D6 (Figure7) the 9-CH3 signaldid sepnrutefrom the two6·CH3peaks.butH-4 wasthenoverlapped with

otherprotonsigna ls.Thus.itwas confirmedthaicompoundIIhadthe correctstereoche mistry atC-9.

The completeassignments ofI HandI3C NMRdataof 71and 7J, based onIH_IHand 1H_13C 2DNMRspectraarc compiledin Tables..J..5 and 6.

I

4

Figure5 tHNMRspectrumofcompound

n

.10

r,I,'~--rr-=-= --,--r=-=--,-r=-,-~=r==r=~~4'~~~"=r=+-

6 4

Figure 6 IHNMRspectrum of compound 71

I

4

Figure7 IH NMR spectrum of compound71(C<;D6)

31

PPM

Table4 IHNMRdata forre/.(4 R.SR.9R)· 6.6.9 -

trimethyltricyclo( 6 .3.0.o-J.8]undcc·I -~Il-.'-tmc⁽⁷¹⁾

7 ^{~" :}

^1""S

^{6 'u}

^{., 0}

position chemica lshirt

H-2 5.77(ifi.s)

H-4 2,40(IH.d.J=9.6liz)

fI-S 1.71(Ill.Ill)

1.94(IH.m)

f1-? 1.26(I H.~.J=1).511/.)

1.6J(IH.~.J=1).5111.)

H·9 1.75 (I H.m)

H- IO 1.56(IH.In)

2.03C1H.Ill)

H-Il 2.56-2.65(2H.In)

6-CH3 0.K9Oil.s}

1.03(311.x}

9-CH3 1.06 C3H.~.J-13.511, ) .12

Table5 IHNMR dataforrel-(4R.8R,9S)-6.6.9- trimcthyltricyclo [6.3.0 .04.8]undec-l-en- 3-one (72)

~

1""' 3

8 0

9 " 6 \

33

position H-2 H-4 H-5 H-7

H-9 H-IO

H-II 6-CH3

9-CH3

chemicalshift 5.77(IH, brs) 2.69(lH.dd,J:5.7,8.4 Hz)

1.77-1.80 (2H.m) 1.47 (lH.d.J:12.9Hz) 1.61 (lH,d,J: 12.9 Hz) 2.11(IH.dq,J:7.2,14.1Hz)

1.60(lH,m) 2.27(lH.m) 2.54(2H.m) 0.93(3H,s) 1.02(3H,s) 0.76 (3H. d,J

=

^{7.2 Hz)}

Table6 13C NMRdataforrel-(4R.8R ,9R)·6.6.9-

trimethyltric yc lo[6.J.O.04,S]undec-l-en-3-o nc(71) ;'llllll"/.'/· (4U.SR, 9S)-6,6 .9-trimethyltricyc!o[6 .3.0.04.8111 ndec-l.cn-."\- o llc (72 )

position* 71 12

C-I(O) 19 4.4 192.2

C-2(I) 123.9 12J.X

C-3 (0 ) 214.7 215.2

C-4(I) 57.8 5J.9

C-5(2) 42.9 42.6

C-6(0) 41.0 425

C-7(2) 39.4 51.11

C-8 (0) 64.9 66.7

C-9(I) 41.3 411. 1

C-IO (2) 32.6 32,]

C-I I(2) 23.5 23.7

6-CH3 (3) 31.5 311.1

6-CH3 (3) 29.2 2H.9

9-CH3(3) 14 .6 16.6

*

Number of attachedprotons inparentheses

Catalytichydrog enationreduce dthe double bonds in 71and 72 (Scheme J3).Both products, 73and 74, showedcarbonylabso rpt ionat 17 36 cm-!for acarbo nylgroup inthe irJRspectra.BoththeIH and the J3C NMRspectrashowedno olefin icresonances . Detailed13CNMR assignme ntsarereported in Table7.

Scheme 13

~c ~c

71 73

7"

₇₂

>?"

74 35

"

Table 7 DCNMRdat u ofrel-{IR.4S.SR.9hHl.6.9 - trimethyltricycl o[ 6.3.0.04.8Iundccan- J-nne (74)and rel- (IR,4S,SR.9S)-6.6.9-trimcthyltricyc]oI6 .3.0 .04.NI undccan - j -onc(73)

position * 73 74

1(1) 45.7 46.0

2 (2) 46.8 4J.tl

J(0) 223.0 224.X

4(I) 59.4 53.6

5(2) 31.3 )~.7

6(0) 41.3 }9,6

7(2) 47.9 56.3

8(0) 62.7 M,l)

9 (I) 42.9 45.4

10 (2 ) 34.5

:n.2

II(2) 44.6 45.H

6·CH3 29.5,29. 2 29.7, 2X.l

9-CH3 15.5 14.tl

*Numberof attached protonsinpare ntheses

.16

Atthispoint, thetriquinaneskeleton hod beenefficientlyestablished.

Thenextfourplannedsteps todeoxypentalenicacid(lb) areshownin Scheme 14.

Scheme 14 For mationIb fro m73

37

73

>Q)-co~

~

28

\

Q

o ^C02Et

~

55

27

>Q:)-C O O H

~

lb

Thelast two steps to compo unds28andIbarcthe sumoasin Crimmins' synthesis.Two steps, to compounds55ami27.remainedto he studied.

Thefirstreactionwasdesignedto furnishthe

Ii.

keto ester 55.t\

coupleof methods werestudied. Fullis32reportedsomeacylatio nsuccess (61%)on cyclopentanone.whenitreactedwithdicthyldicnrhonatcwith potassium hydride in benzene [0ufforda ~· ket () ester produc t.

Mo.nder33,34usedmethyl cynnofo ruuuewith LDAasthe base011·7X°C, andthe f3-keto esterproductwasobtniued in71('/nyield.Inthis reaction therewasa competitionbetweenCr-ncylat ion:LIlJCeucylution.esp ecial ly for more sten cally hinderedketones. Howeve r.illa morerecentstudy Mander 35 discover ed that O-acyl<ltiun may be almost completely sup pressed bytheuse ofdiethyletherin the placeoftctrnhydrofuranax solvent,and thisresultedin prcd omiuuntformationofonlythe I'-ke to este r.Weexaminedthese method sin modelstudies. Fallis'method was test ed with norcamphor(Scheme15).

76

76

77

NoProdu ct !

We foundthat the reactionproceede d properlyin THFto yieldth e [f-keto este r. In contrast, inbenz e ne the reactiondidnot work.The product77 was a mixtureof stereoisomersina ratio of 8:5.IR absorption muximuat 1760 and 1724em-Iwereassig nedtotw ocarbo n yl s.No hydroxylabs o rptionwas found.Alsotherewasno double bond resonance in the 13C NMRspe ctrum. Therefo recompound77wasin theketoConn only.amino cnolcompoundexist. Both Fallis' and Mander'smethodswere appliedtocompound 74,andthe resultsare showninScheme16.

Scheme 16 For mationof~-ketoeste rfrom 74and 72

':'

W O C C H P I1OCOJ,O

~~II KHlbenzene unidentifi~compound

74 (CH30 h OCOh Ostartingmaterial KHrrHF

Gl,OCOCN

LOA/ether unidentifi~compound

>p:

^{: H0-I)}= . . , . . c - - - - unidentified compound^{Li/NH3•ether.tBuGH} 2) NCC0₂Me. ether C

72

39

Theunid entified compo unds.which were obtuiuedinsome of these reactio ns,werenot very stableunde rchromatographicco nditions. For all these compoun ds IHNMRrevealed thepresenceof maj or skeletal pieces . suchas an estergroup. 9-CH3and gem-dimethylgro uplitC-6.However, no clearHcl,H-2.orH-4 resonan c es.Theseproductswerepre sent as mixtu res. butitwasnotund erstood whetheror1101themixtures were the enolan d ketoforms. orO-acylat ionproduc ts.Itis worth mcutioning rhur the un ide ntifie dcompo und Ahada similarIHNMRspectrum10thut of unidentified compoundC exceptforadiffe rent estergroup. Howe verthe IRresults were not consiste nt.Compo und Ahad absorption maxima(lilly at176 6and171 2 em- I.Compound Chadabsorpti onmaxim a at 3475.

1747.1660.and 1621 cm-l ,andcompoundUli t3432.1735. 1662.am i 1660 em-I.

Schem e 17 l3- kcloeste rred uctionst udieson77 und78

411

&CO,CH

o

, . _

78

ttz-

^{77 0 COlEt- - -}

~

^{80 HOf!}

^co,Et

^{II +}

^{~ r~1I}

^{HI OIl}

^~CO,EI

Inafurtherstudy involvingreductionof Jl-keto esters,itwas revealedthatnoneof theseunidentifiedcompounds could bereducedby NaUH4.Nevertheless.thereductionofsimple rp.ketoesterderivatives was wellstudied withmodelcompounds77and78(Scheme17).Theratioof the(WI)isomericproductswasfoundtochangeupon theadditionofmetal chloridesCMCI2)(Table8),

Tab le8 Reduction ofp.ketoeste rsbyNaBH4/MCI2 Substrate Time NaBH4!MClz Yield³ Ratiob

min molarequivalents

30 NnBH4(1.0) 98 I:Z

0

6 C0 2CH.1 15 NaBH4(1.3)/ 100 Z:I

CnClz(Z.O) 78

10 NaBH4(1.0)/ 74 Z:I

CaClz(Z.O)

10 NaBH4(lJ)/ 70 5:1

MnClz(Z.O)

NaBH4 (1.0)/ 39 5:1

MnClz(Z.O)

1i~:EI

^{30 NaBH4(1.0) 90 7:1}

77

uyieldofreducedproductsasa mixture ofstereoisomers.

basdeterminedbyI HNMR.

41

Someofthesereductions werefairlystcrcosclcctivc. Forcompo u nd 78. NaBH 4gave aI::!ratioof hydroxyesters.butwith l\lnCl:! ..5:I rntio was obtai ne d.Amech anismhasbeenproposcdJ6.J⁷thatinvolves a mctnl complexwithtwo carbony ls.andN'IBH4chousi ngtheSYIIuruntifucc:

s)'11

ant i

The reaction conditio nswere varied with respect10themuurcof metal chlo ride andthereaction time . Addition ofMnCI2·41-1 2()ledhIthe best facialselec t ivity. Chan gingtherea ction timedid notaffect the prod uc t ratio. but it wasimport antin determinin g theyield .

The finalreact io ns thatwillfurnis htheestergroup ingoodyiel d will requirefur therstudy.Nevertheless. our approach10thetriquin un c ske leton. which waspresen tedhere, wusshort 18 steps)and with hi gh yields ineachstep. Furthe rmore ,the correct stereochemistry atC-9was obtained. Inde ed , while the final stages of the synthes is of (±J- deoxypentaleni c acid (lb)haveyettoberealiz ed. Wu31 has converte d ketone73into (±)-pe ntalenene(2)inthree stra ightforwar dsteps. Both the

workdescribedhere towards (±)-deoxy pentalenic acid (lb)andWu's synt hesis of(±)-pc ntalcnene(2)demonstratethe utilityofthe geminal acylution reactioninthe total synthes is of triquinanenaturalproducts.

43

III. EXPERIMENTAL

General

Both high and low resolutione.c.aronimpactmass spectraUIRMS . and LRMS) were recorde don a V.G. Micnuuass 70701-IS 1\1' 1S S spectromete r. Data nrc rep orted as11I/ : (rcluuvc intensity). Gas chromarog rnphy-massspectrometry(GeMS)data were recorde d on a Hewlett-Packa rd 5890 gaschromatographcoupled to amodel 5970mass selectivedetector,whic hwasequippedwitha 12.5IIIfused -silica capillary column with cross-linked dimethyl silicon e as theliquidphase.Fourier transform infrared OR)spectrawererecorded un a MuusonJ7finstrument.

IHandI3Cnuclearmagneti c resonance(NMR)SpCClnIwere measured(in CDC I3unlessothe rw isenoted)ona GE300·N B (300MH I. for11-1and75 MHzfor13C ) spectrometer.Chem icalshif ts

«»

arcre po rtedillparis pe r mill ionfrom te trameth ylsilane (T MS).Chlo rofor m(un lessotherwisenoted ) wasusedastheinte rna lstand ard.IH: 67.27;13C: 0 77.0relative10TMS.

TM S wasused asthe internalstardard whe nthesolventshiftspectrawere record ed . Coupli ngconstants.J,areexpressedin Hert z(lIz ):II1Uarc re ported to within±0.2 Hz. The followingabbreviations urcused:

memultiplet,sesinglet.de doublet.tetrlplet,qequartct,bre broad.TIle13C NMRshiftarefollowedbythe number ofattached proton s,usdet ermine d byAttachedProton Test (APT) and heteronuclcar 20exper iments . Nucle a r Ove rh au ser effec t(oDe) diffe re nce experimentsweredone ondegas sed solut ionson theGE300-NBspectro mete r.

.,.

Flash chromatog raphywascarriedoutwithE. Mercksilicagel60 (230+400mesh)accordingto themethod describedbyStiIl.38 Thin layer chrom.uogrums<TLe)were exami nedunderultravioletlight(254 nm).Tl,e TLC plates were visualizedwith iod inevapor,orsprayedwith a solutionof phos phomoly bdicacid(10g ofMo03·H3P04,1.25g ofCe(S04)2,12mL concc mnucd H2S0 4.diluted10250mLwith H20 ),then theTLC plate was heated on ahot pIteo

Reagentgrade solventsweredistilled prior touse .Analytical grade dicth ylethe r(ethe r)and be nzen e (ACS)were used withou t further purification.Drydichl ororne thane and toluene were distilledfromcalcium hyd ri de. Dry tctr ah ydrof u ran (T HF) was dist ill ed from sod iu m bcnzophenone.

Most reactionswere carriedout under a positive pressure ofnitrogen

~~as.Reaction s whic h requi red anhydrousconditi onswereperfor med in oven-d riedglassware.whichwasassembledand allowed to coolwhilebeing purged withaninertgas.Allreactions were monitored by analytica lthin- layerchromatography(TLC).Allcompounds reported gavea single spot on TLC<till!werejudgedtobe>95%pureon the basis of both 11-1 NMR and GeMS.

45

7,9,9-Trimeth}'I-l,4-d ioxaspiro [4.5]d cc-7-cnc (57) :m d 7,9,9·Trim cthyl· l,4-dioxasp iro[4.5]dcc-6-cn cl58)

57 5K

Amixture of isophorone (5.0g.36mmol). ethylen eglycol(H.5ml..

155mmol), andpTSA(0,9g) inbenzenewas heatedatreflux overnight.As thewater wasformed,itwas removedbyaBarrettwatcr-sc punuor. Solid thensaturatedaqueoussodiumbicarbonatewereadded. Theuqueous layer was extractedwithether fourtimes .Thecombinedorganic layers were washed withbrine, driedover anhydrouspotassium curhon utc.filt ered.ami concentrated.The residuewasdistilled undervacuumtogivea colorless liquid (4.7g). Further purific ation was curr.ed out using flash chromatography (12-16%ethyl acetate inhexane)togiveacolorlessoil compose d ofa mixtureof7.9.9-trimethyl-IA-dioxaspiroJ4.5]dcc-7-ellc(57) and 7.9.9 -trimethyl- I,4-dio xaspiro[ 4 .5]dec- 6- enc (58)in aratioof10 :1 (1.52g,in30% yield.but64%based ontheconsumedstarli ngnnucrial).

For 57 :1HNMR:Ii1.04(6H,s, 9-C H3), 1.60 (2H,S,H-I0),1.67 (311,S,7- CH3), 2.14 (2H ,S,H-6), 3.95(4H,S,H-2and H-3),5.17[I H,S,IH );13C NMR:

s

^131.2(1),12 8.[ (0 ), 109.2[0),64.0(2, 2C), 43.5 [2),39.K (2),3],(, (0), 30.3 (3, 2C),23.4 (3); MSfrom GCMSmlz(%):IK2127 ,M+), 167 [16, M+-CH 3),154(1),139(7),123 [8), 96(34),K6 (100 ),67 (X),41 (13).The IHNMRofthe 6-eneisomer(58)isdifferentfrom thatof57atH-M(02.14.

2H.s}andH·6 105.34.IH, s); MS of 58fromGCM Sm/z (%):182 (4. M+).

16716.M+·CH 3 ), 149(I) ,137(12).126(100). 99 (9). 82(13).67 (3).4 1 (6 ).

7,9 ,9-Trimcthyls piro[4.5]dcc -7.e nc-l,4 -dione(60)

Borontrifluorideethcrate(7.0ml.,57mmal) and1.2-bis(trimethyl- silyloxy)cyclobutene(3.0ml.,11mmol)in10 mLofdichlcrome thanewere addedtoasolutionof7.9,9-trimethyl-I,4-dioxaspiro[4.5]dec-7-ene (622 mg, 3.42mmol)indichlorotnethane (60ml.).Themixture was stirred at-?SoC und ernitrogenovernightduringwhich timethemixture was allowedto attainroom temperature, andthenitwaspoured intoan ice-coldsaturated sodiumbicarbonatesolution.The aqueouslayer was extractedwith dichloromethanethree times.Thecombined organiclayerswere washed withsaturatedsodium bicarbonate, brine,driedoveranhydrous magnesium sulfate,filtered,andconcentrated. The residuewas separatedbyflash chrom utog raphy(10%-16%ethylacetateinhexane) togivethetitle compoundasa colorless oil(601mg,85%):IHNMR:0 0.94 (6H.s,9- CH».1.6 6 (2H.s.H· IO).1.76 (3H.s, 7·CH3).2.03(2H.s,H·6),2.59· 2,68 (2H,Ill.H·2 or H· 3). 3,02·3. 11 (2 H.m,H· 2 orH·» . 5.20(IH.s,H·8); 13C NM R:0214.2 (0, 2C),129.6(I),128.7 (0). 59,0(0).43,3 (2).34 .7(2.

zc),

)2,8(0),)0.1p,2C).29,1(2).23.6(3); MS from GCMSm/z (%): 206 47

nco.M+),19 1 (38, M+-CH3),17 8(\3),16.1 \7.1),145 \591,1 07 135),')[

(37),77(\9),4 1(2 1).

rel-(4R,SS)·4-Hydroxy-4,7,9.9.tch"umcth)')spiru[4.5]dcc-7-cn-I-on e«, I)

To a solutionof7.9.9-lrimethylspiro[4.5ldcc·7~cl1c-IA-lIinllc(XtJ7 mg,4.35mmol)in30ml,of dry etherat-?SoCundernitrogen was added 1.4 Mmethyllithium inether(16ml.,22mmol).The solutionbecame cloudy.Arterstirringfor2hours.the solutionwasslowlypouredinto icc- cold brine. Theaqueouslayerwasextractedwithethe rthreelimes.The combinedorganiclayerswe re washed withbrine ,driedover anhydrous magnesium sulfate.filtered,and concentrated. The residuewasscp.vnrcdhy nashchromatography(I2%~20%ethyl acetateinhexane)togivethetille compoundas a colorlessoil(803 mg.H3%):11-1NMR:0(J.IJOOil.x,I). CH3),1.00(3H,S,9-CH3),1.15 (3H,s.4-C1i3), 1.71(2H, d.J

=

4.5II"11- 10),1.74(3H,S,7-CH3),1.79 (2H,s,H-6),1.96(If!,m),2.21(211,m), 2.56 (lH,rn),5.19(IH, s,H-8);13CNMR;o220.5((),130.4 (I >,12X.7 (OJ,

~m~m~m~m~m~m~m~m 28.4(3), 24.1(3), 23.7 (3);MSfromGCM Sm/t:(% ) :222 (2,M+i, IX9 (IJ, 164 (4),149(7),123(13),99(32),83 (13),43(100 ).

I'el-(4R.5S)-4-Hydroxy-4.7.c. c-teuu methylspirol4.5]dec-7-en-I-one (321mg,1.45mmo!)in20mL of dichloromethanewas cooledto_78°C.

Ozonewas passedthroughthe solutionuntilthesolution turnedblue.Excess ozoneW.ISremoved by bubblingthe solutionwith oxygen.Dimethylsulfide (c«.6 IIlL)wasadded. and the mixturewasstirred undernitrogen overnight.

Thedichlo romethanewasevaporated.Theresidue wasredissolved in benzene (20 mL) and a catalyticamountof pTSA(ca.100mg) was added.

The mixturewasheatedatrefluxfor 2hours. The waterformedwas removedbyaBarrettwater-separator.After thesolutio n had cooled.

saturatedsodiumbicarbonatewasadded.The aqueouslayer was extracted withether threetimes. Theccmoinedorganic layerswere washedwith saturatedsodium bicarbonate,brine.dried overanhydrous magnesium sulfate. filtered. and concentrated. 'he residue was separated by flash chro matogruphy (2%acetoneinhexane) to provide63as a yellowoil(214 mg.71%):IHNMR:S 1.26 (3H,s. 8·CH3).\.30 (3H.s, 8-CH3).1.63(3H, dd.J

=

I.S, 2.4Hz. 4-CH3). 1.71 (lH.d,J

=

13.9Hz. H-9),1.91 (lH. d.J

=

13.9Hz.H-9),2.2." (3H. s.acetyl).2.88(IH.ddq,J=2.4.3.3.22.6Hz. H- 2), 3.1S (1H, ddq.J

=

^{2.4.3.3.22.6Hz.H-2l. 5.76(lH. dd.J}

=

^1.8.3.3Hz.

H-3).6.69 (IH,s. H-71;13C NMR:S 219.2(0),195.2(0),157.1 (I),142.6 49

(0), 141.6 (0), 121.4(1),68.3 (0).46.5(2).45.5 (0). 41.9(2).29.6( 3).29.0 (3),26.5(3).14.6 (3); MSfromGe MS11I/ :'(I:;') :21~(:\7.M+). 20J (\0.

M+-CH 3).175(96.M+-COCH 3).16 1 (23 ).147 (44).1J3 (43).119(IH).

105(22).91(25),77(16), 43(100).

- eus «,

,iR)·6·Acety l·4,8.8-trimclhy lsp iro{4.4 )Jum-.'· l'n- l-olic(M)

Lithium(ca.60 mg) wasaddedto liquidam monia(ca.50 IIlL)al _78°C . 6-Ac etyl -4,8,8-trimcthylspiro[ 4.4Jnona-J ,o-dic.:n-I-ollc(205lng, 0.939mmal)in THF(15 mL)was added whenthebathtemperature reached -35°C.Themixture wasstirred for35 minutesand then itwasquenchedby addition ofsolidammonium chloride untilthe bluccolor disappear ed.The ammonia was allowedtoevaporateat roomtemperature.Theresidu eW;IS partitionedbetweenetherand water.Theaqueous layerwasextracted with ethe r threetimes.

1h e

combinedorganiclayers werewashed withbrine.

driedover anhydrou smagnesi um sulfate.filtered,antico ncen trate d.The residue was dissolv edin dichloromethunc (40 mL) anti pyridinium chloroc hromate(pee,ca.500mg,2.3mmol)wasmktcd.The mixture was stirred atroomtemperature overnight.Ether wasaddedund the mixture was filtered througha padof silicage l.Separationill'theresid ue byflash chromatography(2% acetone inhexane)providedthetitle co mpound as a

yellow0;1(139mg. 67%):/ HNMR:81.14 (3H. s,8-CH) ).1.15 ()H .s, 8- CII)) .1.58(/H.d.AB.J=/4.1Hz.H-91.1.66-1.7 1(5H.m,4-CH3.H-7.

H-91.1.93/3H. s,acetyl). 2.04(IH.t.J

=

/3.1Hz.H-7).2.85 (/ H.ddq,J

=

2.4.4.8.2).4Hz.H-2 ). 2.98(IH.ddq.J

=

2.4. 5./.23.4Hz.H-2). 3.51(lH.

dd.J

=

6.) .13.5Hz. H-6). 5.70(lH. brs,H-3);1HNMR (C6D6 ):80.94 (JlI.s.8-CH)I. 1.10(3H.s.8-CH)). 1.30(IH.d.AB.J

=

14.1 Hz.H-9).

1.48-I. S515 H.m,4-CH3. H-7. H-9).1.5913H.s,H-II). 2.02(IH.t,J

=

13.GHz.H-7). 2.S2(2H.dq.J=2./. 4.5Hz.H-2). 3.43(lH.Jd.J

=

6.3.

13.5Hz.H-61. 5./9(I H.brs.H-3);IHNMR(CSD5N):81.02 (3H. s,8- CH)).1.10(3H.s. 8-CH3). 1.47(lH.d.AB.J

=

14.1Hz.H-9).1.60-1.65 (5H .m,4-C H3.H-7.H-9).1.90(3H.s,H-II).2.06(IH.t,J=12.9Hz.H- 7).2.90 (2/-1.dq.J

=

2.4.4.8Hz .H-2). 3.57(/ H.dd,J

=

6.3,13.5Hz).5.59 (IH.brs,H-31;13C NMR:8220.9 (0).207.7(0),144 .2(0),121.0(I), 64.0 (0).60.1(1),49.4(21.43.5 (2),41.5 (2),37.8 (0),29.7 (3),29.2 (3),28.7(l ), 15.4(3);MSfromGCMS mlz(% ):220 (II,M+),/77(41.M+-COCH3).

159 (9).149(13),121 (23).107(6 /),77 (31). 43(10m.

rei-(4R,5R,6R)-6-Acctyl -4,8,8-tri mcthylspiro[4.4]nonan-I -one(66)and rel- (4R,5S ,6S )-6-A cetyt-4,8,S·trimcthylsp iro[4 .4]non an-1-onc(67)

51

66 67

rel.(5 R.6R)-6-Ace tyl-4.S.8-trime thylspiro l4.4]no n-.t-cn -t-onc\9Nmg.

0.45 mmo!) wasdissolvedin drymetha nol(.V~JIlL)ami5%pullndium011 ca rbon(ca .250mg)was added. Themixture wasshakenunder50 psi pressureof hydrogenfor1.5hours and thenfiltered througha pad

or

silica gel.Theresidue was separated onasilic a gelCOIUlII llwith 4¹11.acetoneill he xane providingas a colorlessoil rt'l-HR,5 S.6S)-6- :u;et yl-4 .X.S- trimethyl s piro[4 .4 I-nona n- l-o ne (67) (Jtimg.311%)andrd-(4 R,5 R.hR)-6- ucetyl-4,8,8-trimethylspiroI4.41-nona n- l·one(66)(63mg.64%) .Fur the minorepimer (67):IR (film)"max:1733,17071.:1n-1;IIIand 13CNMRsee Table2and3; MSfromGeMSm/~(%):222(8,M+ ).207O.M+-C1-!3), 179(19, M+·COCH3),161 (33),152(60 ),137 (30 ), 123 (J5),I11)(17 ),10') (23) , 95 (36), 81(27),55(3 1), 43 (100).For the major cpimcr«(,6):IR (film) "max:1735.170 8 cnrl:IHand 13CNMR secTablesIuud 3;MS fromGCMSm/,(%):222 (3,M+):207(5, M+·CI·(3),179 (4,M+·COCI-I3), 161(13),152(99), 137 (56),123(21),110(64 ), 109 (25),95(22),HI(24), 55 (29),43(100).

rel.(4R,8R,9R).6,6 ,9.Trimethyltricyclo[6,3,O.04 ,81und c1;-1-cn-3-ollc(71 )

Potassiumrerr-bu toxide(76mg. 0.67 mmol) was added to asolution of rel-(4R,5R,6R )-6·acetyIA ,8 ,S·trimct hylspiro[4.4 lnunan- l·oIlC(70 mg.

0.32rnmcljin10 mLof benzene.Themixture was heated atreflu x for 20 minutes.Ithad a red co lor.Whenthesolution had cooled,10%Helinwater W~ISadded. Theaqueou s layer wasextra cted withethy lacetate three times.

The combined organic laye rs were washed wit hsaturate d sodium bicarbonate , driedover anhy drous magnes ium sulfate, filte red. and conce ntra ted.Theresidue was separa tedbyflash chromatog rap hy(2%

acetone- inhexane) toprovidethetitle compoundas a colorlessoil(45mg.

70%):IR(film)umux: 1704.1630 em-I: IH andI3C NMRsee Tables 4 and 6;MS from GCMS//liz(%):204 (6 1,M+),189(19 ,M+· C H3 ),176(9, M+·CO ),148 (100),133(58),107 (94), 91(78),77(49) ,41(60).

reJ-(4R,SR,95 )-6,6,9-Trirnethyltricyclo[6.3.0.04,8Jundec-l-cn-3-one(72)

PotassiumJert-buloxide(121 mg.1.07 mmol)was addedtoasolution of rd -(4R.5S.6S)- 6· acet yl-4,8,S-trimet hylspiro[4.4]non an-l- on e (110 mg, 0.500 mmol)in 10 ml,ofbenzene. Themixture was heated at reflu x for15 minutes.Ithadaredco lor.Whe n the solution hadcooled.10%Helinwater wasadded. Theaqueouslayer was extractedwithethyl acetatethree times.

Thecomb i ned organic layers were washed withsaturat ed sod ium bicarbonat eand brine,dried overanhyd rous magne sium sulfate,filtered,and concent rat ed.Theresidu e wassepara tedbyflash chroma togra p hy(2%

53

acetonein he xane) to provide the titlecompoundasu colorlcssnill(Hmg.

63%) :IR(film)umax:1703.1630cm-J:IHandIJCN~ I R^Sl'CTables$

and6;MSfromGCMS111/:'(%):104-(7.M+).1~9(2.~1+·CI1 3l.17(,(I.

M+-CO),148 (32),13) (28 ),107(69).91(68),77(58).41(IlXll.

re[.(IR.4S,8R,9S)-6.6,9-Trimcthyliricyclo((j_,. O.O-t.8Iundt'{':In-_1-unc(7J )

Toa solutionofrel-(4R.8R,9R)-6.6.9-trimclhyhrie ycluI 6. -'.U.1I4·~I ­ undec-l-en-3-one(43mg.0.21mmol)indrymethanol(25mL)wasadded 5%palladiumoncarbon(ca.200mg).and this wnsshakentinder50psi pressureofhydrogenforIhour.Themixture wasfilteredthroughapad(If silica gel,and thefiltrate wasevaporated .The residuewaspurifie don:'1

silicagelcolumnwith 4%acetonein hexaneproviding the titlecompound as acolo rless oil(43mg.98%):IR(film)umax:1736cm'l:If!NMR:0 0.97 (3H,d,J

=

6.7 Hz, 9-CH3),0.985 (3H.S,6-CfI3).1.0IClH.s,6-CIIJ), 1.32-1.37(3H.m),1.59-1.92 (5H.m), 2.05-2.14(211.mi.2.41-2.46 (211,mi.

2.78(lH.dd,J

=

9.2,18.5 Hz);13CNMR:

s

223.0 (0),62.7(I)),59.4(I) , 47.9(2), 46 .8 (2), 45.7(I),44.6(2),42.9 (I),41.3({I),34.5(2),31.3 (2) , 29.5 (3), 29.2(3),15.5(3);MSfrom GCM Smlz(%):21)6(44 ,M+). 191 (37,M+·CH3),173(6),163(44,M+·COCH3),13 5()O),107(62),95 (71), 79 (49),55 (52),41(100),

rel-tIR,4S,8R,9R)-6,6,9-Trimcthyltricyclo[6.3.0.04,8]undecan-3.one(74)

TO:I solutionofrel-(4R.8R,9S)-6,6,9-trimethyltricyc lo[6.3.0,04,8 ]- undcc-t-cn-g-one(40mg.0.19mmoI) in drymethanol(25ml.)was added 5%palladiumoncarbon(ca.200 mg),and this was shakenunder50 psi pressure of hydrogenforI hour.The mixturewasfilteredthroughapad of silicagel andthetiltrate was evaporated. Theresidue was purified on asilica gelcolumnwith4%acetonein hexaneproviding the titlecompound as a colorlessoil(39mg. 98%):IR(film)umax:1736em-I:IHNMR:6 0,79 (3H.s, 6-CH3>.0.98(3H.d.J

=

^6.6Hz,9-CH3). 1.03 (3H.s. 6-C H3). 1.17 {l H, dd.J

=

6.\. 12.1Hz).1.43- 1.65(4H .m),1.70-1.94 (4H. m), 2.05 (lH, ddd,J

=

1.9,7 .3,19.\ Hz.H-2),2.43-2.50 (2H,m), 2.74(fH,dd,J=11.6,

\9.1Hz,H-2); DC NMR;6224.\ (0),60.9(OJ.56.3( 2),53.6(I),47.0 (2), 46,()(I). 45.S (2).45.4(I),39.6(0),33.2(2).32.7 (2). 29.7 (3).28.1(3), 14.0(3);MS from GCMS mlz(%):206 (24,M+).19\(\6.M+-CH 3),\63 (39.M+·CO CH 3).150 (51).124 (23).107 (62), 95(53). 81 (48). 41(100).

55

3·Carbox)'elh)'lbiqcl o(2.2.11heplan·2·o ne(77)

Asolutionof norcam phcr(126 I11g. 1.14 uuuu l)anddicthyl dicarbona te(0.34rnl.,2.3mmol)in4.0mLofTI-IF was addedtua stirred mixture of potassium hydride (500 mg.4.36111ll1UI..1"%oildispersion).

Afterreflux for1.5hours,10%Helinwaterwasadded<II(Joe. Theaqueous layer was extracted withethy lacetate threelimes.Thecomb inedorganic layers werewashedwithsaturatedsodiumbicarbomuc.driedoveranhydrous magnesiumsulfate.filtered. andconcentrated,Theresidue waspurifi edhy flashchromatography(5%acetoneinhexane) togivethetitlecompoundas

<I;yellow oil (153mg. 74%):IR (film)umux:1760.1724em-I:1HNMR

(8:5 mixtu re):8 1.28 (3H.t,J:7.2Hz),1.45-1.95(l2H,IIt),2. 19(III.I,) : 1.8Hz),2.23 (IH, ., ) :1.8Hz),2.65(IH,IIt).2.7fl(lH,IIt),2.1141111,~,}

:3.6Hz), 2.91(IH,m), 2.96(IH. m), 3.05(I H,~~,) : fl.6,4.5liz), 4.17 (2H,q. ) : 7.2Hz);13C NM R(8:5 mixture):8 209.7(1),!(,K.5(I)),167.5 (0),61.1(2),60.8(2).59.1(1), 57,7(I),50.0(I) ,4K.6 (I),39.211), 39.3III.

36.4(t), 35.7 (2).27.0 (2),24.1(2), 23.7(2),22.9(2),14.0(3);GC-MS001, (%):182 (9,M+), 154(74,M+-CO),137(Sf), M+-O CIl2C H31.1261')2 ), 108 (57),81(10),67 (49), 41(56);HRMSculcd. forC1l)ll14 ()3:IK2 ,fl'J42;

round:!82.0929 .

Reduction of 78with NaBH4inthe presenceofcalciumchloride

Anhyd rouscalc iumchloride(228mg.2.05mmol)was added10a solutionof methylz-oxocyctopemaneca rooxy lare(78)(140mg. 0.99mmol) in methanol(10mL),The mixture was stirredatroomtemp eraturefor 30 minutes,thencooled to DOC. Sodiumborohydride(50 mg .1.3mmol ) was adde d.Vigorousgas evolutionoccurred.Afterstirringfor 15 minutes ,the mixture waspoured into1MHel(10 roll.Theaqueous layer was extracted with ethyl ace tatefivetimes.The combinedorga niclayer s werewashed withsaturatedsodiumblcnrbc nnte.driedover sodiumsulfate,filtered ,and co nce ntrated. Theresidue waspurifiedbyflashchromatography05-2 l%

ethylnccuucinhexane) providingaminorisomer(41mg,29%)andamajor ixomer(101mg. 71%) in theratio1:2.4.Forthe minoriso mer:IR(film) umux:346 [, 1736.1437cm-l:IH NMR:81.60-1.69 (!H,m),1.76·1.82 (2H,m), 1.9\ -2.05 13H, m), 2.70IIH, dt,J

=

4.2,9.9Hz,H-I), 3.03(lH, d, J

=

3Hz, OH), 3.73 (3H,s. eOOMe),4.45(lH, dq,J

=

3.3,6.9Hz,H-2);

l.1e NMR:8175.3(0), 73.7(1),5 1.8(3), 49.4 (I),33.9 (2),26.3 (2),22,0

(2);MS

"if,

(%):\44 12, M+),127(3,M+-OH),116(29), 95 (\8),87 (100),

67(50),55(96), 41(6). Forthe majorisomer:IR(film) uma x: 3430, 1733, 14.16em-I:IHNMR:81.61-1.85 (4H,m),1.95-2 .09 (2H, m),2.47(IH,s, OH),2.67(1H,m.H-2), 3.7\(3H,s, eOOMe) ,4.38 (lH,q,J

=

6.6Hz,H- 2); DeNMR: 8\75.5 (0),76.3(I),54.4(3),51.8(I),34.1 (2), 27,1 (2),

57

22.0(2);MSm/z(%):145(I. M++l). 126(3.rvl+·HZO).116 (20). 1Uc26l.

95 (8). 87(98).67 (56). 55(100).4 1 (6).

Red uctionof78withNaBH4in thepresenceof mangan csctfl) chlori de

MnC12·4H20 (525 mg. 2.6511111101) was uddcd to asolution ofmethyl z-oxocyclcpentaneca rbo xylate (189 mg. 1.33mmol) in meth anol(10 m!.).

Themixturewas st irredatroomtemperaturefor30 minutes.thenitwas coole d toDOC,Sodiumborohydridc(64mg.1.7mmol) was added.Vigorous gas evolut ionoccur red .Afterstirring for 10minutes,themixtureW;IS poured into1M HCI(10 mL).The aqueouslayer wasextracted with ethyl acetate fivetimes.The combinedorg anic laye rs were washed withsaturated sodiu m bicarbonat e .dried oversod iu msulfate,filtered. andconcentrated.

Theresidu ewaspurifiedbyflashch romatograp hy(15~21%ethyluccmtc in hexan e)providingacolorlessoilcomposed ofu5:Imixtureoftwo products (133mg.70%);IR (film)umax:346 1.1736em-I.Fur theminor iso mer:11-1 NMR:Ii2.67 (lH.m,H-I),3.15(IH,brs,OH), 3.73OH,s.GCII] ),4.45 nu, m,H-2).Forthe major isomer :IHNMR: 02.2H(II I.hrs,OJ-I). 2.67 {lH,m.H-l).3.71 (3H.s,OC H3), 4.38(11-1.m,H·2).Othersignalswere evident at:Ii1.61-2.08 (6 H, m): 13CNMR:

s

175.4

«»,

175.3(lJ),7(,,)(Ij, 73.7(I),52.5 (3),51.8(I),49.4(I),34. 1(2),33.9 (2),27.1(2), 26.3(2), 22.0(2).

2a.-Hydroxy-3u-carhoxyethylbicyclo[2.2. 11heptane (80)and Zp-Ilydroxy-3p-car boxyethylbicyclo[2.2.1]heptane(81)

59

r~~02Et

~OH

KO H

~~"

81 OH

NaBH4 (21mg.0.56mmol)was addedto a solution of 3- carboxycthy lbicyclo [2.2. IJheptan-2-oneinmethanol(10 mL).The mixture was stirred for 30 minutes at roomtemperature.Thenthemixturewas poured into1MHel(10 mLl,The aqueouslayerwasextractedwithethyl acetate fivetimes.The combinedorganiclayerswerewashedwithsaturated sodiumbicarbonate.dried ov..rsodiumsulfate. filtered,andconcentrated.

Theresiduewaspurifiedbynashchromatography(to- 15% ethylacetatein hexane) providingayellowoilcomposed ofa7:1 mixtureoftwoproducts (H9mg.90%):IR(film)umax:3462.1731 ,1704em-I.Fortheminor iso mer(KO):IH NMR: 01.28(3H.t,J

=

7.2 Hz). 1.37(2H.m),1.40-1.50 (2H.ru),I.K2·2.00 (2H. m),2.39 (IH,m). 2.51(lH,brs), 2.74(IH.dd,J= 408.9.9Hz).4.17(2H. q.J=7.2Hz). 4.74(IH.d.J=6.3Hz);13CNMR:0 174.8(0).71.5 (I). 60.6 (2). 45.5(1).42.9 (I).41.0(I).35.8 (2), 24.5 (2).

19.5(2l,14.2 (3).Forthemajor isomer(81):lHNMR:01.27(3H,t,J=7.2 H,). 1.J9(lH,m).1.59(3H, m),1.88(lH.m),1.77(IH. d,J=3.0 Hz).1.99 (IH.JJ .J

=

2.7.3.9 Hz),2.33(IH,111).2.46(lH,m), 4.14(211.q.J

=

7.2 Hz). 4.43(IH. dd.J=3.9. 8.1 Hz); 13CNMR:0174.9(0),75.8(I).60.5 (2). 55.7(I),42.0(I).41.3(I).35.7(2). 29.7 (2).19.J(2).14.2 (3);MSml,

(\0):156(45.M+-CO).139 (18).128(16).110 (2.') .101(55l.~~ (2~l.S1 (37), 67(100),43(77).41(92);HRMScalcd.forCqH160:!l~I+-CO ):

156.1149;found:156.1151.

eo