1,2·BIS ITRIME THYLSILYLOXY)CYCLOBU TENE : A STUDY OF AC YLAT ION METHODOLOGY AND SYNTHET IC APPLICATION

1,2·BISITRIME T HYLSILYLOXY)CYCLOBU TENE:A STUDY OF ACYLAT ION METHODOL OGY ANDSY NTHET ICAPPLICATION

by DEANW.STRICKLAND

B.Sc.(Honours) 1991 Memori alUniv er sity ofNewfoundland

St.John's,Newfoundland

Athe sissubmitted tothe SchoolofGraduate Studies in partial fulfilmen talthe requ ir ementsforthedegree of

Master's ofScie nce

Departmen t ofChemistry Memori alUniversityofNewfound land

51.John's,Newtomctand.Canada Aug uSl1996

©1996

1+1

Nahona ll,hrary 01Canada

ACQLJiSlhonsand Directioneesacqulsilionset BibliographICscocceBranch dC5servcesbibhographiqw s

.~,."M.r~jIr~,Sl".~,1 395,IlJQW~lIIr1glon

~t7;~~Dr'lo1r.o ~r:c:.~Qrol"'oOJ

The author has granted an irrevocable non-exclusive licence allowing the National Library of

Canada to reproduce, loan,

distribute or sell copies of his/herthesis by any means and in any form or format, making this thesisavailable to Interested persons.

The author retains ownership of the copyright in his/herthesis. Neither the thesis nor substantial extracts fromitmay be printed or otherwise reproduced without his /herpermission.

L'auteur a eccorde une licence irrevocable et non exclusive permettant

a

^la Blbllorheque nationale du Canada de reprodulre ,

p-eter,

distribuer ou vendre des copies de sa these de quelque manrere et sous quelque forme que ce soit pour mettre des exemplaires de cette these

a

^la disposition des personnes Intereaseea.

L'auteurconservela propriete du droit d'auteur qui protege sa these.Ni la these ni des extraits substantiels de celle-c! ne doivent etre lmprtmes ou autrement reproduits sans son autorisation.

ISBN0-612-17 650-9

Canada

.ji- Ab strac t

Kuwajima and co-workershave reported thatthereaction of a ketal and t.z-bisttrimethylsilylcxyjcyclobutene(1) in the presence of aLewis acid catalyst with subsequent rearrangementof the cyclobutanone intermediate with tnuuorcaceticacid affords 2,2-disubstitu led1,3-cyclopentanedionesin reasonable yields. We havefound Ihat substituents,such as methyl groups,in thea-position to the spiro center significantlyreducethe yield of product tn addition,substitutionof the t.z-emanediolmoietyof the ketal with groups such as methyl and phenyl alsoreduces product yields.

Synthesisof the precursorsof the juvenilehormone 6-ethyl-10- methyldodeca-S,9-dien-2-oneof the mothCecropiain ourfirst approach involve d theadditionof anethylgroup to 2·elhyl-2-methylcyclopentane-1,3-dione(71) andreduction with sodiumoorobydrtoeto afford80as a precursorfor a Grob- type fragmentation .Analysisof 80using nmr and X-raycrystallography indicatedthe structureshown inFig ure 5.The alternativeapproachtothe precursorsorthe juvenilehormoneinvolvedthe reduction of 71withsodium borohydride with subsequent introduction ofthe ethylmoietyto generate 89.

However,introduction ofIhe ethylgroup proved tobeirreproducible .Both of our

~ij,-

strategie sfocusedon theconstruction of the correct relativestereochemistryto enablea Grab-typefragmentation toproduce the correct doublebond isomerof 69.

Model studiestowardthe synthesis offred ericamycin A focusedon 12+2]

photochemical additionsof1withvarious enones. in particularwith spiro[3- cyclopentene-t.t'anoeoj-z.s-ctcne(99).However,while testscarriedoul between a simpleenoneand1provided limitedresults.the reaction between99 and1afforde donlystarti ngmateri al

-iv - Ackn owledg ements

Thereareagrealmany individualsand groups 10whomJowe an eternal deb!ofgralitudefor helpingin thecompletion of thisdocumenl Iwould liketo thankmy supervisor.Or.JeanBurnell,fortheopportunityto work in hislabs and10 engage in researchon severalchallengingprojects.

No thesi sis possible without theefforts andskillsof manyindividual s:

thankstobothDr.ChetJablonski and Ms.Nath alieBrunet forNMR spectra,and Iwishto thankNathalieforbeinga dear.dearfriend.beingakindred spirit,and just listeningduring someof the"difficult times";Dr.BrianGregory and Miss MarionBaggs are gratefullyacknowledged for providingme with mass spectra.

good adviceand understand ing.andthebestshortbread cookies;and Dr.John Bridsonfor X-Raycrystall ographic work.

I alsowish to thank theDepartmentofChemistry andOr.JeanBum ellfor financial support.In addition,thesecretarialstaff ofJoanSquires,ViolaHead.

Teresa Barker.MaryTaplin. and CarolynHawkins is moslappreciatedfortheir kindnessand understandin g.I wouldalso like10thank Chemistry Stores, especia lly Bon nieSmith,forunwa ivering cooperationin the procur ement of chemica ls andequipment.

The faculty and staff of the Department of Chemistry,Sir WilfredGrenfell College is most gratefully acknowledged.In particular,Iwould like 10thank Dr.

RobertHaines and Mr.BillLayden forproviding me with space to write this thesis and for instrumentationto collect data.In addition,(hanks toDr. Julian Du st for many helpfulconversationsand thanks to Mrs. Debbie Wheeler for allowingmeto shareher office. Finally.thanks to everyone in thelab, staff.and faculty forbringing backthe joy of science to a soulthat had lost the faith.

Finally,I wish to thankmy academicfamily:my labmates.My heartfelt gratitude is extended 10Tracy Jenkins, Jim Gillard.Yong·Jin Wu, andPei·Yi ng Uufor helpingwith technicaladvice andencouragement.Specralthanksare givento RonBuckle and LoriBurry for helpingto keep the dreamalivefor as long as possible. for sharing many greatrestaurants, for the great conversations, an dfor being kind to someonewho truly appreciatedit

Title....

Abstract...

TableofContents

... ... ....i .ii

Acknowledgements.... .. tv

Table of Contents vi

Ust of Figures . Ust ofTables..

. viii

... .ix

Glo ssary ofAbbreviations,.... x

Dedication... xi

Chapter1.Bis-acytation ofKetars

Introdu ction... 2

II. Results andDiscu ssion. 7

III.

IV.

SterleBulkoftheketarsAlCOholMoiety.

b. a-Substiluenls...

c. AromaticSubstrates....

Conclusions ..

ExperimentalSection...

.. a

...10

...20 ...15 ...17

Chap ter2.Synthetic Application s

Section A:SyntheticApproaches to thePrecursor sof the Juven ile HormonesofCecropia

-vti- IntrOduction...

ii. ResultsandDiscussion.

.33

. 42

Approach 1... 42

Approach2 50

iii. Conclusions 55

II. SectionB:ModelStudies Towardsthe Synlhesisof FredericamycinA

lntroduction.. 56

ii. Re sults andDiscussion... 63

iii. Conclusions 65

III. Experimental Section. . 66

SectionA.... . 66

ii. SectionB.. . . 73

References.

Appendix .

. 77

...••BO

Figure1 Figure2.

Figure3

Figure 4.

Figure 5.

Figure6.

-viii·

Listof Figures

StericHindrance inAllackof1,.•...••.

Stabilizat ionofCaroocation...

Comparision of1_'YI/Olld>eInteractionsBetween28 and29... ... ... ...••...

Coordinat ion of BorohydrideAdditiontothe

Ketone... . .

X-rayCry stal Structureof80 . NOED Spectrumof89.

10 18

20

46 47 52

Table 1.

Table2.

-fx - Listof Tables

13Cnmr ShiftsofDiones28and29...

Comparisonof13ComrShift &.ofCompounds19,80.

and89....

19

53

APT El GCMS

mp MgSO.

SOCI2

TFA

TLC TMS oar

Glossaryof Abbreviations

Attached proton test

Ethyl

Gas chromatography-massspectrometry Ultraviolet irradiation

Infrared spectroscopy Meltingpoint Magnesiumsulfate

Massspectrometry,massspectrum Sodiumhydrogen carbonate Nuclear magneticresonancespectroscopy ThionylChloride

Trifluoroacetic acid

Thin layer chromatography Trirnethylsilyl Narrow

Inloving memory ofGram...

-,-

Chapter 1 Sis-acylationof Ketals

-2- INTRODUCTI ON

In1977Kuw ajimaand co-workers'publisheda gaminalacylation procedureforthe conversion ofacetatsand aldehydesinto1,3.

cyclopentanedion e derivatives through anintermediatepinacol.The valueof this methodis intherapid gen erationof a five -m ember edring that possesses two ketonefunctions.Inthisprocess, thereis the formati on of aquaternary center froma ketone,andtheformationofa spirocente r from a cyclicketone An example ofthe reactionis shownin Scheme1with benzaldehyde as the substrate.1,2.Bis(t rimelhylsilyloxylcyclo bulene²(1) in the presence ofthelewis acidTiC I~reects with benzaldehydeto afford the cyclobut anone 2.This compound thenrearrangesto3upontreatmentwith tnnucrcaceticacid(TFA) in a yieldof 76% overboth steps.'

rg/H

⁺

Sche me 1

OHOSiMe3 Me3SIO

'==f _o

OSIMo3 TIC~

©JiV0 0

~

H 2

'::" ~O

^TFA

I

~'H _

-3-

Kuwajima¹note dthai avariety ofLewis acids,e.g.TiCI",BF,.EI20,and le!l;.~ul yla mmonj umfluoride,couldaccomplishthe firs tstep. Inaddition, Kuwejma'showedthatthe resultant1,3-cyclopenlanedione couldbe subjecte d to hyoroxioe -indccedcleavage10afford av-ketoacid.asshow nintheexample inSch eme2

Sch em e 2

In1984, Kuwajimaet af.'upd atedtheir earlierprocedure,andthey assessed morecarefullya numberof differentparamete rsin vo lved in this qeminalacylation.The nature of thelewisacidprovedtobeimportant inthe formationof the cyclobutanone.Itwasfound thaiTiCI"was the most effective lewis acid Ihattheytestedfor reacti ons of1with alde hydes and aliphatic acela ls,whereas BF3.Et₂₀was marc effective with reactiveacetalsandketats.

An importantparameter inlhechoiceof the acid forthe rearran gmenl of the intermediate pinecclwasthe ease ofremoval of excessacid uponwork-up.

Trifl uoroacetic acidwas favoured for thisreason.Eve nthoug h acidicmedia suchas n-toluenesuttontcacid(pTsOH)inhot benzene,BF₃.Et₂₀,and trimethyl silyltrifla le(TMSOTf)indichloromelh ane werehighlyeffective, they

·4·

were nOIas easilyremoved dur ingwork-up.

Theoverallprocess withaketal substrateisbelievedto occurvia the rrecnenlsm showninScheme3.Thefirststepis complexationofaketal

TMS

1 \0 8 6 J

~

^{'-BF' TMS}

^I

¹

J

TMS

I

e

o

O""BF,

e 0 g e c:!.

^o-.TMS

r

^O-TMS

BF"'OJ 0 BF,

'0x H0

- 'V'U I..--'

Sch eme3

oxygenwiththelewisacid.Next,thereis acondensationbetween1andthe ketalcomplex10giveacyclobutanone intermediat e.Complexatio naltha other ketaloxygen the n allowsfortherearrangementof the cyclobul ano ne

-5-

intermedi ateto th e1,3-cy dopentanedion e.Apointworthnotingisthat Kuwajimastaledthaithereaction0/1 an d ketones does notoccurin eithe rbasic Ofacidic media

Wu andBurnell'"were thefirst,10 belater followedbyAyyangaret af }to reportamodification10the Kuv.tajimaprocedure whereby alargeexcess ofa Lewis acid leddir ectlyfrom aketa ltoa1.3-<:yclopentaned ionewithoutthe necessit y ofisolati on of the cyclobutenon e.

A numberof group s have capitalizedupon the gaminel acylation methodol ogy,Some examples follow.Anderson andLees incorp or aled the methodto generatetheC-ringinafunctionalizedaromaticsystem5in 39% yield from4inaroute towardana logs ofltichotheeane6,asshow ninScheme4.

TMSO OTMS

1 .0

M{: ^o

^{OCHOC H'J}

CH, H,

Scheme4

U FA

B

·6·

Wu andBumel~use dthespi ro-ann ulal ionof7to8(Sc hem e 5)10 introduceoneofthe ffve-merrceredringsofthefragrant sesquilerpene iso kusimon ein 85%yield.

Scheme 5

Burnelland Wu' also used thismethod10generatetheO-rin gof a-meuesve sea-t,3,5,B,14- p enlaen -17-on e.an estrone analog.Reactionof9 with1gav e a1,J..cycJopentanedion e,which wasimmediatelycycliz e dagain10 provide the C-ringin anove rallyie ld0191%yield.as shown in Sch eme 6

TMSO

oms ~ o

1 . 0 0 ",, -

BF3.E120 2. TFA CH3

10 Scheme6

Finally,Kavashand Mariano^llemplo yedthe strategyto genera tethe inte rmediat e12in 73%yieldfrom thealdehyde11inthe construct ionof the harringtoninering system.asdepic t e dinScheme7.

·7-

0611TMSOO OTMS 06n

t ^?'I)

^'_BF3_E1_'O

_{t~ 1}

^OH

CU CHO 2 TFA 0 :::'" :7

" 0

/

/ /

O~

( 1 N

o '>-

I

tBuCOO Scheme7

II. RESULTS AND DISCUSSION

Desp itethereactionparame ters lhatwereconsidere dbyKuwajima and co-workers1,3and the exam plesof theinco rporatio n ofthis methodin to sy nthesis ,there remained a needtodefinemorecle arlyotherparameters involvedinthereaction.For instance,wha t influen ce wouldthenature of the ketalhave upontheoutco meofthereaction? Thus,athoroughstudywas init ialedinourlabo ratory.Onepointshou ld be mentionedhere bef oredeta ilsof these stu di es arepresented.Difficultieswere encountered inlocati ng som eof the 1,3-cyc lopenta nedion e products onIh in-layerchromatography(tIc)plate s.

ThedikGtone produ ctswerealmost invisiblewith theusualvisualiz at ion

-8-

techni ques,i.e.,uvlight.t,.an dacidsprays..InOfdef'to get aro u ndthisproblem.

it was sometimesnecessary(0allowthecolumnfractions10 concentrateby evapo ration.Inothercases,gasetrom alogra phy-mass spectrometry (GeMS) wasus ed10analyze each columnfraction.

tL B. SterieBulkof the Keta l'sAlcoholMoiety

Kuwajimaused methylor ethyl ket elsinhis seriesof examples Kuwajima didnotemployketafsderived fromt.z -euenecnctwhic hIs themostcommonly seen exampleofaketalinsyn th esis.Thus,itwasimportantforusto demo n strateth eformationofthe1,3-d ikelone14fromtheketal13deriv edfrom cycIoh exanon e.Ketal 13wastr eatedwith 2.5equivalentsof1and 15 equivalentsofborontrif luorideemerateat _78°C.Thesolutionwasthen warmedto roomternp e renreov ernight.a'ldaqueouswor1l.-opafforded the 1,3- cycIo p entanedione14in96%yield,asdepicte dinSch e me 8

TMSO OlMS

n 0

0

^{·780C _SF,.El20rt}

o~o

13 14

Schem eS

-9-

Itwa sfoundth aitheuse ofa bulkieralcoholmoietyfortheketal dra maticallyre<lJcedtheyieldofthe 1,3-cyclopentan edione. Itisunlikelythat ther eisany electronic effectat'NOfkhere fortworeasons.First.met hylgroups arenotsign ificantelectrondonorsviainduction.Secondly,themethyl group s areseparatedfromthereac tingcen t erbytwobonds.In the case shown in Scheme 9,thecon ve rsionof theketa l 15in t othe diane16 proceede din only 48% yield.Burnell andco-w orkers"alsofoun dthatincr easin gthestereuolkby rep la cingthe methylsin15 with phe nylgrou psprecludedcon version ofthis ketal

15 16

Scheme9

1016.ThJs,abulkyketalcanserve asa protectinggrQl4)fortheketonein nese gemina lacylati o nreac tions.Thisisim portantbecauseworKbyJenkins ' o dem onstratedthatt.a-cycicoemenecncrescanindee d be formeddirectlyfrom ketones.In the caseof 15,stericco n gestionaffectsthe additi onofthe1,2- (bistr imethylsilyloxy)cyclobutene to theketal,accordin gtoCase 1 and/orCase 2 asdepictedin Figure 1.In eithersituation,somepartafthakelal15 isin very

-10-

closeproximityto the1,2·(bistrimethylsilyloxy)cyclobuteneand muststerlcauy hinderreaction.

Case 1

TMSO~c~Ji

CH,

~OTMS

Case2 Figure1: SterieHindrancein Attack of 1

II.b.cr-Sub stituents

Theuse of a ketalIhat issubstitutedon the1,2-elh anedio lmoiety is nola commonsynthet icsituation,butex-substitutionis oftendesirable. Thus, we decide dtotest the effectofincreasingthe sterle bulk of the subst rate by the introductio nof cx-subst iluents. Thefirst of these wasIhereaction ofthe kelal17, derive dfrom racemic 3-methy lno nan-4-oneand1,2-ethanediol.Kelal17 was converted to18as shown in Scheme 10 in only a28% yield.Thiswasa substantially lower yield Ihan was obtaine dinthe reaction of keta l 13.However, anothercolumnfractionof the reaction of17affordeda secondproduct 19asa mixtu re ofdiastereome rs in15% yield. The'Hnmrspect rumof this compound

·11-

TMSO OlMS

l 'o []

~ ~

17

~ ^o

^{3 ',0}

10 9 6 7

• "

·780C _f."

§

^" OI""\OH

• 0

+ Os 5

10

•

8 7

"

Sch eme10

includedsignalsatli4.26and3.8 5,which wereconsistentwith Ihe presenceof

an2-hyd roxyethyl groupderivedfro m1,2-ethanediol.The free 1,2.ethanediol fro m!hereacnonmusthaveattackedthet.a-csciccenteneorcnemoietyof1810 fo rce openthe ringand generatetheester .

Anotherexamplewas theketal20,which was exposedtothesame conditions asinScheme11.Noneoflhe expected 1,3-eyclopentanedione21

n

^{TMSO OIMS}

-r ^>

^BF3,Et20

^{D~ ~o}

20 -78o e ---....r.1. 21 Scheme 11

was isolatedafter d1romatography.Instea d.the ester22was obtainedin19%

yie ldasIhe only identified materiat.asind icatedin Sch eme12.Th is had to

-12- TMSO OTMS

o

BF3·Et20 _780C- .r.t.

20 Schem e 12

have been formed from 21,also by the attack of the 1,2-elhanediol. Clearly,the 1,3-c ycl opentanedione was fairlyreactive even thoughitwas sterfcafty hindered. Given the results ofScheme10andSc heme 12,it was clear thatthe s e moleculeswere undergoinga phenomenonsimilar:0 what Kuwajima1notedin the originalpuallcettonwhichdescribedthe formation ofv-ket oacids through base-induced cleavage.In ourcase, we were victims of a variationofthis phenomenon wherebythe 1,2· ethane d iolrele a sed fromthe ketal acted asa nucteophlte and forced an acid-inducedcleavage,the postulatedmech anism of which is showninSchem e 13.Significantly,for the transfor mationto the ester to occur,the desiredt.a-cscrccentenecnonemust have be-engenerated first;the retro- ald oJoccurred subsequently. Although this appearsto be a problem, it is one that is easilysolved by makinguse of the increased stenc bulkof the2,3~

butanediol. Therefore,wereturned to the dimethyl diolketalswith theidea that the presence of the two methyl groups would decrease the nucleophiJicity of tho dialand wouldthen preventthe destruction ofthe 1,3-cyclopentanedione.When

-13 -

O~O'

^BF3

~ '--/' -

20

D~O, e

~~'''BF3

x - a o-x '---.I

~

22

)

SCheme13

!hedimelhyl-substitut ed ketal23 was exposed10thesamecondlticns asin Scheme14therewas a 56%conversionto21asdetermined bynrnr.However, attempts10pu rifylhe sample by columnchrom atographyfailed,largelydueto decomposition of thediketone on the sil ica. Indeed,we found that1 ,3-diketon e productsderivedfrommore substitutedketalswereall prone to decomposition. Given thatwealso haddifficulties in 'v i sualiZing'the1,3-diketonesbytic,

23 Sch em e 14

lMSO OlMS

o

·780C__r.t.

~O

21

chromatography of these materials was rathertricky andcouldtherebyexplain lower yields.We believethatrecoveries couldbe enhance difone were to carry on withthenext synthetic step withoutrig orous pu rificationaltha1,3-diketane stage.

An u-substitutedcyclic ketal24wassubjectedto the standardreaction condition s(as definedin theExperimental Section),whichaffordedthediane25, but in only36% yield(Scheme15). Therewas nonect the openeddiane

n

^{lMSO OlMS}

'D

^BF3.E120

⁰ ~O

24

-rsec

----...rt 25

Sch eme15

material.However,the yield was stillfar bel owthatafthaunsubsliluted case

·15-

The reasonbehindthiswas lhat themethylgroupwaslocated on oneside of the ring In order for the 1,2-bis(tri methylsily loxy)cyclob uteneto approach,itmust have attackedin theposition antito the methylgroup.However,there was stilla great dealof etertchindrancetothe approach of the cycrobutene.Ifthe cyclob utenewere toapproach syntothe methylgroup,thester!c hir:dran ce wouldhavebeencon siderably worse.Thus. thenetresultwas thatthe approachwas blockedandthe reactionratedropped significantl y.

We decide dtolookatamore complex cyclic example that alsohad anQ.

J ,---,

OH OH pTsOH

'.SO O OT" ~I

BF3·El20

~

.780 C _ rt 26

Scheme 16

-16-

c-memy tgroup.Hydrogenation of(R)-carvone gave tetrahy drocarvoneas a1:1 mixture ofepimers(Scheme16).Ketalizatton of thismixturewith 1,2-elhaned iol and pTsOHproce ededsmoothlywith concomitanteplmenzeuon ofthe a-center to yieldanapproximately 10:1mixture of epimericketals 26and27, withthe major productbeingthethermod yna micallypreferred isomerwithboththe methyl andthe isop ropyl groupsequatorial. Reaction ofthis mixtu rewith1took placemore slowly than withketa113,butthedesireddike tone producI 28was isolated in modestyieldafterchromatography.Itis synthetically importantto note thatthe relativestereochemistryaboutthecyclohexanoneringwas maintaine d in this reaction,andifanyepimeric diane29was produced, it wasin a quantitythat was undetectable.This was consistentwith equatoria laddition onto the retal centerand subsequentrearrangementwithout eliminationto an intermedia tevinyl ether. Therelativestereochemis tryofthereact ion of26is in contrastwith the reaction oftetrah ydrocarv onemixtu re directly wilh 1underthe ketone conditions.(The nmr datathatshowshowthe relativestereochemistry wasdeter mined ispresent ed below.)This processgave theisomer29very predomi nately,butthis re su lthas not yet bee nrationalized in termsof a mechanism."Jenkins reacted1withthe1:1 mixlure ofketonesunder acidic condilions in whichthe ketonesshouldhave beeninterco nvert ible by epimerization of thea.stereogeniccenter.A2.2:1mixtureofdialswasisolated,

::::)01

fi!!0

and thenrearrangementof thismixture with ltifluoroaceticacidprovidedvery

r-d

30 0

~

^1:1

1 0 ( ::

~ " 22~

':f:

^0'

'1::

^0'

Slower! TFA TFA!raster

~

^{/ \ 28}

Scheme17

very minor major

predominate lydiane29.Thus,thereaction proceededunderthe kineticregime summarized inSch em e17.Ifthe ketone reaction wasalso by equatorial attack,Iethen1mustapproach the reacting carbonylsyn tothe axialmethyl, an eventthat appearsto invitesteric hindrance.We can offertwo explanations, both of which haveimportant syntheticramifications forthe(room temperature)

-18-

ketone versus Ihe (·760c)ketaltechnology .Firstly,Iheketone epimer mustin fact haveasignificantpopulation ofbothisomers 3Dand31at room temperature.Whereasthe isomer 30shouldbe thermOdynamicallypreferred, 31is less than 0.2 kcal/molhigherin energy,bulitis completely unencumbered for equato rialattackby1.Thus,by this rou te,the majorintermediate should be 32, not33as originallyclaimed." Compound 32isthe same as there sult of axialattack by1onisomer 30.Secondly,whereasisomer30should indeedbe etericatly hindering towardsin com ing1,Iheinitial complexatio nwith Lewis acid maybe greatlyfacilitated bythe fact Ihat the axialmethylcan provide hyperconjugat ivestabilizationof theintermediatecarboca tion.as shownin Figu re2. Inthe case where theintermediate has anaxial methyl,the

o

#

Figure2:Stabilizationof Carbocation

re arrangement of th e inte rmediate tothe 1,3·dik etone proceeds ata significantly higher rate. The reason forthisis that in this interme diate thereis a large steric inte ractio nbetween the cyclobutanone moietyandth ea-methyl. This congestionwill forcetherearr angementto proceedata higherrate than for

-19- theequ atorial intermedi ateinorder10alleviate thestrai n.

Theassignme ntoftherelati ve stereo chemis try of28and29 was done by comparingthe13Cnmrspectraof28 with the diketone29,generated direc tly fromtheketone throughthe procedureof JenkinsandBumell. ' oThese differences are consistentwitha'1₀-=111interactionfrom an axialsubstituent (methyl)in29.¹¹Table1assignsthe13Cnmr signals for both Tabl e 1:"c nmr Shift sof Dio nes28and29

Diketone 13C nmr Shifts

Assignment 28 2'

C·1orC-4 217.8 214.6

C·1orC-4 216.7 214.1

C·2orC-3 35.7 34.3

C-2orC-3 35.4 34.7

C-5 60.5 60.8

C-6 36.0 32.7

C-7 28.5 27.6

C-8 29.3 22.1

C-9 36.5 36.6

C-l 0 35.4 25.2

C-11 17.7 14.6

C-12 32.2 31.7

C-13orC-14 19.6 19.7

C-13orC-14 19.2 19.4

-20-

compounds.The signalsforcarbonsca andC~10andfor the methylgroup at C-6for29shouldbecompared withthe same 13Cnmr signalsfor28.

Wh&nthe structu resshownin Figure 3 are considered,one cansee thatin the case of 29,thereareY; .UCMinteractions whereas in28,there are no such interactions.

YanU to

molh"J#J0

\ CH3

~ \ 0

28

Ygaueheto

m'th\~ :

I -,

0 CH, "-

/ Ygaucheto

Yant!10 Ygaucheto 29 met hyl methyl C-8anclC_10

Figure3:Comparisonof'Y.n~I'Yg.uc~. lnteractionsBetween28 and 29

II. c. Aromatic Substrat es

Evidence fromotherexamples studiedin our group sho wedthaithe presenceofana-double bond reduced yields of 1,3-cyc lopentanediones very drastica lly relative tothe saturatedcompounds."This ledto ourexaminationof the aromaticketal34as shown inSche me 18.Ketal 34was smoothlyconverted to the 1,3-cyclopentanedione 35in a syntheticallycreditable yieldof 77%.

11islikelyin the cases of<l.p-unsaturated compoundsthaipolymerizationis

Scheme18

-»: n

o

34

-21-

TMSO OTMS

o ;=()=O

CJ~

35

responsible for poor yields.Obviously,this is notthecase with acetophenone as itis nollikelyto polymerize, thuseliminetinq analternatereaction pathway.

III. CONCLUSIONS

From these results,itispossible 10draw afew genera lizations.The first of theseis thaiincreasingthe steriebulk of the glycolmoiety ofIhe ketal retards conversion of the ketal 10Ihe dtcne.The lmplicetion ofthisis clear:in casesin whicha molecule containstwoormoreketene functionsonemayselectively ketanze one site with a verybulky glycol.Thaiparticular reaction centerwill not be convertedasreadily toa t.S-cyclo penten edlc ne,anditcanthen be deprolec ted for othersynthetic transformations. Another conclusionthatwe can drawis thatthe presenceof ana-substituentwill reducethe yieldofproduct, and,in the case of someacyc licsubstrates, none ofthediketonecanbe isolated.In the samecaseswherewehave c-substituents onacyclicmolecules, the incorporationofabulk y glyco lsignificantlyimpedesthe degradation ofthe

-22-

t.a-cyc lcpe n tanedlone productsby subsequentattackby the liberatedglycolto give the keto-e ster.Thu s,we can concludethat the choiceof the glycol can offer choices interms ofproduct distributions.The veryfeature of slade bulk thatlowers product yieldsin"unsubstilu led"ketals canactuallyserveto bolster isolable yieldsof1.a-cyctopen tanedlone products whenusedincases of a- subst itute dacyclic ketels . Thisperhap sleads 10 thebroadlesson ofthisstvdy:

thisrea ction is very sensitiveto the sterieenvironment. Thus, any synthesis employi ng th is methOdologywillhave 10 take thi s factor inlo accountas il can provide substanti albarrierstosyntheticutility. However.this informationalso permits onetoincorporat e ahigh degreeof selectivityinB synth esis,which can manifestitself both intermsofshortersyntheticschemes and in the degreeof elegance of the design.Finall y. we can conclude thatthe failureof the conjugated ketones/ketalsto give acceptable yields isnotdueto the unsaturation itself,Le.possible stabiliza tionofcerboceuo ns. be cause acetophenone behaves normally.Onemightpredict thatinsubstra tes thatmay beunsa tura tedbut not enolizablethat thereactionwill proceednormally,also.

-23- IV. EXPERIMENTALSECTION

General Proced ur es

Kelals were obtainedbythe acid-catalyzed actionof alarg eexcess of t.z-ethaneololin benzenewithazeotropicremoval ofwater.Reagenl 1was preparedby the procedureof Bloomfieldand Nelk e.!

Allbis-acylation reacti ons were carriedout under aninertatmosphereof nitrogenusingdichloromethane distilledfromcalciumhydrideasth e solvent.

Flash columnchromatog raphy("chromatograp hy")employed230-400mesh silica gelwith hexane and anincreasing proportion ofethy lacetateas eluent.

The ratiosof ethy lacetale/ hex ane

are

reported below.Nuclear magnetic resonance(omr)spectrawererecordedon a GeneralElectric GE30Q-NB(300 MHz for'H)spectrometer.The lHnmr spectrawere acquiredin solutions of deute riochloroform(CDCI3).Couplin gconstants(J)arereport edin Hz.The13C nmr spectra (75MHz) were alsoacquiredinCDCI3, and chemical shifts are relative 10the solvent(6 77.0).13C nmrshifts are sometimes follow ed in parenthe sesby the number of attached protons onthatcarbon,whic hwere derived from anattache d prot on test(APT)and/o r heter onuclearcorrelation (HET-CO RR)spectra. Assignments quoted for the 'H and13Cnmrspectrais givenwhen thesearereasona bl yreliable and consistentwith the correlatio n spectra.Wheneve r possibl e,assignments havebeencorrobor atedby theuseof

-24~

ChemWindowsC~13NMRMo dule version1.2 (Softshell)and gNMRfor Windowsversion 3.6(CherwellScientific). Assignment of 'Hand1JC spectra are accordingto an arbitrary numerical scheme chosenfor ease of identification and are indicatedonthe compound structureinth e Appendix of nmr spectra.

Low and highresolutionmass spectral (MS) data were obtainedfrom a V.G.

Micromass 7070HSinstrume ntusingelectronionizationat 70 eV.Infrared(ir) spectra wereacquired as thinfilms using aMattson PolarisFT~I Rinstrument, andintensi tiesare notedas (s), (m), (w), (brlfor strong,medium,weak,and broad,respectively.AHewlett-P ackard model 58 90 gas chroma tograph, equippedwith a 12.5 m fused-silicacapillary colu mnwithcrosslinked dimelhylsilicone as the liquid phase,couple dto amodel 5970 mass selective cetectorwas used forgaschromato graphy..massepecuome tric(GCMS) analyses. Melli ngpoints (mp)were obtaine don a Fisher-Jo hns instrument and are uncorrected.

GeneralReac tionProcedure.To a cooledsolution (_78°C) of a keta l andBFJ.Et20(15equiv.) in dichloromethane(20ml) was addeddropw isea solutio nof 1(3 equiv.)indichtoromelhane(10ml).The reactionmixture was stirred overni ghtduringwhich timeth e temper atur e was allowed torise to room temperature (rt).The reactio nmixturewaspoured into ice-water,and the organiclayerwaswashedsuccessively with water(x2),with a saturated

-25-

aqueous solution ofNaHCO ),and then witha satur a tedNaCI solution(Y2).The organiclayerwas driedoveranhyd rous MgS0 4<filtered.andconcentratedin

vacuo .

This is hereafterreferredtoas'standardwork-up',Flash chromatogr aphy afforded the 1,3-cyclopenlanedione s.Standardvisua lization methods oflieplate sproveddifficultor ineffective inlocati ng the1,3- cyclopentanediones.Insomecases,the1,3<yclopentanedioneswere found usingGeMSanalysis.

Spiro[4.5]decane·1,4-dion e(16)

Toa stirredsolutionofket al 15(0.26 9, 2.0mmel)andBF3.El zO (3.7ml, 30mmel) in CH_2CI₂(20ml)at-76acwa s addedasolution of1(2.0ml,6.0 mmol )inCH₂CI₂(8.0rnL).There action mixturewasallowed to warmtort overnight and stan dard work:-upled,afterdlromat ography(10190),to spi ro(4.5 )decan e- 1,4-dione16(183 mg,72%)as a solid:mp60-61 DC(In.¹²mp 61 ~2 "C):irv_ .:1755(w)and 1720cn-',lHnmr6:1.4-1.7(10H,brm, C-6 H2, C-7Hl•C-BHl,

c-s

H2•C-10H₂),2.68 (4H, S,C-2 H₂,C-3H₂);13Cnmr05:215.8 (C- 1,C-4 ),55.9(C-5),34.3 (C-2,C-3),29.2(C-a),24.9 (C-6,C-l0),20.4(C-7, C-9) ;MS:166(100,M'),137 (25),124 (32),112 (61),111 (46),85 (46),81(37), 67 (74),56 (44).Exact mass calcu la tedfor C'oHU02:166.0993 ;found: 166.0985.

-26-

2-{1-Methylpropyl)-2 -penty lc yc lopentane-1,3-dione(18)and2- Hyd ro xy ethyl6-mPlhyl-4-oxo -5.pe ntyloclano a tefig)

To a stirredsolution ofkelal17(0.22mg,1.1mmoI)andBF3.Et:O(2.0 mt..16mmol)inCH~CI2(20ml)at -78 · C was added asolution of1(0.68 mL, 3.3mmol)inCH;:CI:(8.0mL).The reactionmixturewas allowedto warm10rt overnightandstandard work-up led,afterchromatography(15185),to 2-(1- methy lpropyl)-2-penlylcyclopenl an e-1,3-dione18(0.07g, 28%)asavery pale yellowliquid,and,in alater fractioncollectedby passing pure ethyl acetate throug hthe column.2-hydroxyel hyIS-mel hyI4-oxo-5-pentyloetanoate19(46 mg.15%)as an oil.For18:ir'J",..:1719cm'','Hnmr6:2.66(4H.narm,C-4 H2•

C-SH:),1.80-1.61(3H,m),1.45 (1H,m,C-6HI ). 1.31'().9 5(7H,m),0.92(3H,d, J=6.9Hz,C-14H,),0.B5(3H,t,J=7.2Hz, C-13H,or3H,I,J=7.0Hz.C~

H3),0.83(3H,t,J=7.0Hz. C-6H3 or 3H,I,J=7.2Hz,C-13 H:J;13Crmrs:

218.5(C-1",C-3),218.1(C-1orC-3),64.1(C-2),41.0(C-11), 36.9(C-7 '"C·

8),36.8 (C-7orC-8),32.9(C-10orC-12),32.2(C-l0orC-12).244 (C-4,C-5), 22.2(C-9),13.9 (C·14),13.2(C-13),12.3(C-6);MS:noM' , 195(34),169(53), 168(25),154 (33),139 (54),126(28),125 (56),112 (100),69 (27),55 (65),41 (80).Exactmasscalculated forCI2H1902(M'-C2^Hs):195.1384;found:195.1380.

-27-

For19:irv.".,: 3457 (br),1736 (5),1709 (5)cm': 'Hnmr0:4.26(2H,m, C-15H2 ),3.85(2H.nar m,C·16 H2l . 2.96-2.38(6H,m),1.76-1.05(11H,m), 0.96-0.84 (9H,narm).

2-Hydroxyethyl5,6-dimethyl-4.oxoheptanoate(22)

To a stirredsoluti onof ketal20(0,26 g, 2.0mmol)and BF₃.EI₂₀(3.7mL, 30 mmol)inCH_2Clz (20 mtjat-78°C wasadded asolutionof1(1.6 mL,6.0 mmo1) in CH₂CI₂(8.0mL l .The reaction mixture was allowe d10warm tort overnig h t.Standardwork-up led, after chromatog raphy(5/95),to 2-hydroxyMhyl 5,S·d ime thyl-4-oxohepta noale22(59 mg,14%) as a pale yellowliq uid:irv; ..:

3459 (br ),1737,1711 em";'H nmr5:4.2 3(2H, nar m,C-10 Hz),3.82(2H,nar m.C-11 H1 ),.2. 80 (2H,t,J

=

6.7Hz,C-2Hz), 2.6(1H,very br.OH),2.60(2H,I, J

=

^{6.7Hz,C-3 H}1),2.36(1H,quintet,J=7.0Hz,C-S H,),1.97(1H, octet,J=

6.B Hz,C-6HI)'1.04 (3H.d,J:,:7.0Hz,

c-s

H, ),0.91 (3H, d,J=6.7Hz,

c-t

or C~8H_{3) ,}0.87(3H,d,J=6.8Hz,C-7or C-BH,);I' C nmr05:213.3(C-4),173.1 (C-l), 66.1(C-l0),60.9(C-l 1),52,7(C-5),36.4(C,1), 30.2(C-2),27.8(C-6), 21.2(C-7orC-8), 18.7(C-7orC-B), 12.8(C-9);MS:noM',199 (2),186(2),174 (7),155 (22),145(24), 112(21),101(100),85(24),71(73),45(29),43 (70).

Exactmasscalcul ated for C8H 1(O.(M+-C,H₆vleMcLaffe rt y):174.0 89 2;found:

174.0890.

-28 -

2-Methy l -2-(met hy lethyl )c yclopentane-1,3·dio ne(21)

To a stirredsolutio nof ketal23(390 mg, 7.46 mmo!)and BFJ E1P (4.5 ml,37 mmol) in CH_2CI2(20 rnl)al-78 °C was addeda solutionof1(2.0mL,7.4 mmol)andCH2CI2(8.0mt.).Thereaction mixturewas stir redfor 27 h during which timethe mixturewarmed10rt.Standa rdwork-upgave a mixtureof the spirodiketone and startin gmateriel.Therefore.BF3.Et20(4.5ml,37mmol)and 1(2.0 ml,7.4mmol) wereaddedagaintoa CH₂CI₂(20 ml)solution of the mixture . Afterstirringfor 19 h,standa rd work-upwas executedon thereaction mixture,affor de d213mg(56%)of aproductIhat'Hnmrre vealedwa s very predom inantl y21,Attemptstopurifythis mixture by chromatographyled larqely to its destruction;howeve r,asmall amount (50mg)ofhomo genou s21was recovered:irv",p:1759(m),1721(s)cm'':'Hnmr.3:2.74 (4H,symmet ricalm.C·

4H_2,C·5H2),2.01 (1H,seplet,J

=

^{6.9Hz,C·7HI ),1.06(3H,s,C-6}H3),0.93 (6H.d,J;::6.9Hz.C·8H_3,C-9HJ ) ;13Cnmr05:216.8(C-1, C·3 ),59.5 (C· 2), 356 (C-4,C-5),33.8(C-ll),17.3(C-7,C-8),15.3 (C-g);MS:154 (28,M'),139 (100).

112 (24),111(32),83(2 5),56 (18),55 (27),43 (12),41 (2 0) Exactmass calculated for C,H1.0^2:154,0993;found:154.09 89.

6· Methylsp iro [4. 4 ]n onane.1.4-dione(25)

To a stirredsolutionofkel al24(0.35g.2.5mmol)and BF3,Et20(4.5mt.

-29-

37 mmol)in CH_2CJ₁(20mL) at -78'"Cwas aaddedasolution of1(2.0mL,7.4 mmol)in CH_1Cl₁(B.Oml).The reaction mixturewas allowedto warm tort overn ightandstandardwork-upled,after chromatography (15/8 5).106- melhylspiro[4.4)nonane·1,4-dione25(146mg,36%)as a colourless liquid:ir

\I...:1718ern",'Hnmr6:2.8 1-2.57(4H,brm.C-2H2•C-3H2),2.25(1H.brm.

C-6H,),1.85 (5H,br m), 1.54(1H,brm), 0.95(3H,d,J

=

^7.2Hz,C-l0H,);'3C nmre:217.3(C-l0' C-4), 216.6(C-lo' C-4), 66.7(C- 5),46.9(C-7),36.2(C-6), 35.6 (C-2

0'

^{C-3),34.5(C-2}

0'

^{C-3),33.5(C-9),246(C-8),15.2(C-l0);MS:16 6}

(64,MO),151(100),125 (15),109(52), 95(41),81(20),67(41),55(3 1),41 (30).Exact mass calculatedforCloHl~02:166.0993;fou nd:166.0997.

(6R,9 S)-6·M ethyl.9-(methy lethyl~piro I4.5]d ecane -1,4-dione(28) To a stirredsolutionof ketal26(500 mg.2.52mmol)and BF,.Et10 (4.6 mL, 381TVTlOI) in CH:CI2{20mL)al-76°C was added a solutionof1(1.6mL.6.3 mmol)in CH₂CI₂(8.0ml).Thereactionmixtu rewas allowedto warm tort overn ight.Standardwork-upled,afterchroma tography(7193),to6-methyl-9·

(methytelhyl)spiro[4.5}decane-1,4-dione28as ayellowoil(204mg, 36%):ir v....,:1717ern":lHnmr 6:2.92-2.49 (4 H,complexm,C·2H2,^C-3H2),1.81(3H, m),1.57(3H,mj,1.39(1H,m,C--6H₁).1.28-1.00 (2H. rn, C-9H₁,C- 12H₁₎,0.63 (3H,d,J

=

^6.7Hz,C-13H3or C-14HJ),0.82 (3 H, d,J

=

6.7Hz,C-13H_JorC-14

-30-

H3),0.75 (3H,d,J=6.0Hz,(;-11H3 ) ;

"c

nmrs:217.8(C-1 or C-4), 216.7(C·1 orC-4),60.5(C-5), 36.5(C-9),36.0(C-12),35.7(C-6 ),35.4(C-2,C-3) ,32.2(C- 6),29.3(C-7), 28.5 (C-10), 19. 6 (C-13OrC-14),19.2(C-13 or C-1'),17.7(C- 11);MS:222 (3,WI,179(1), 138(10 ),125 (15),106(48),105(2 3),91 (100), 86 (25), B4 (40), 43 (31).Exact masscalculatedforC,~Hn02:222.1619,found: 222.1614.

For the ketal (6R,9S)-6-Methyl-9-(methylethyl}-1,4-

dioxaspiro[4.5]decane(26):'HnmrIS:3.98-3.91(4H,complex m,C-11H2,C-12 H2),1.79-1.73(1H,m),1.70-1.58 (3H,complexm),1.50-1.30(3H,complexmj.

1.14-0.96(2H,complex m),0.92-0.84 (9H, complexm,

c-e

H3,C-9 H3 .C-10H₃) :

"c

nmris:11 1.3 (C-1),65.3(C -11orC-12),64.8 (C-11orC-12), 41.6(C-2), 39.9 (C';;), 39.0(C-4),32.3 (C-7),32.0(C-5 ), 28.5(C -3 ), 19.7(C-ll or C-9),19.5 (C-B or CoS),13.9 (C-10) .

2-Methyl-2-p h enyl-1,3.cyclo p enta ned io ne (35)

To a stirredsolutionofketal34(232 mg, 1.43 mmol)andBF3.Et20 (2.6 mL,21mmol) inCH2CI 2(30 mL)at·78°C was added a solution of1(1.1mL,4.3

mmol)in CH2CI2(6.0 mL). Thereactionmixturewarmed10rtovemight and then itwaspoured intowater.The organiclayerwas washed with water(x2)and saturatedNaCI solution,andtheorganiclayer wasdried overanhydrous

-31-

magnesiumSUlfate,filtered,andthe sol....entwasremovedinvacuo.

Chromatography (15/85)provided2-melhyl-2-phenyl-1,3-cyclopentanedione35 as ayellow oil(206mg,77%):ir\1m,, :1765(m),172 4em";'Hnmr5:7.38-7.25 (3H,m,C-B HI.C-9H"C -l0H,.),7.22-7.19 (2H,narm,C-?H"C-11H,),2.82 (4H,broadsymmetricalm, C-4H2 oC-SH2),1.43 (3H,s,C-12H3 );1JCnmris:

213.0(C-1,C-3),136.8 (C-6),129.3 (C-8,C-l0),127.9(C-7 , C-11),128.3 (C-9), 61.9(C-2),35.2 (C-4,C-5),19.7 (C-12);MS: 188(100,M-), 145(36),132 (32), 105(26), 104 (74), 103 (30),78(24), 77 (26),51(21),Exactmass calculatedfor C,2H,202:188.0837;found:188.0835.

-3? -

Chapter 2 SyntheticApplications

-33 -

SF.eTIONA:SYNTHETICAPPROACHES TO THE PRECURSORSOF THE JUVENILE HORMONESOFCECROPIA

INTRODUCTION

Fromthe examplesof syntheticapplicationsdescribed in Chapter1,itis clear thatth e bis-acyletionreaction ispotentiall y usefu lin the construct ionof variousnaturalproducts.Wesetoul to synthesizethe precur s ors of onesuch naturalproduct, namelythe juvenile ho rmone36of themothCecropia,as a furtherexam pleofthe syntheticutilityofthis typ e of reactionandto explorea

~o _3'

novelrouleto build this system.Ourapproachentaile dthe co nstructionof particularly substit ute d1.a-cvcrcpenteoecrcnesthat coul dundergocontrolle d Grab-typefrag mentati ons 10 affordcarbon-ca rbo ndou b lebondsin the correct positionsan din the correctgeometrica lisomers.This wouldbe a sign ificant challenge givenearlie rworkinour groupthatindicate d thatthe se typesof1,3- cyclope ntanedione sys tems areextremelylabile. Inaddition, we hadtoensure

-34-

thattheconstructionofthe1,3-c y clopen ta nedion es was selectiveenough so as topreve nt 100mu ch dtas terecmenccont aminationin the products,thereby ensurin gthatou rappro achwouldhave significa nt advantagesoveran approach incorpor atingWittig chemistry.

Anumberof gl'oupshaveworkedtowardthesetypesofnaturalproducts.

Manandco-workers"in1968 employeda linea rsequen ceofatt achments10 obtainmelhyI10-epoxy-7-€~hyl·3.1 1 -dimethyl·2.6·lridecadjenoate(37)ina15%

~C02'" _o

37

overall yie ld.The irsynthe sis sta rtedwith thead d itionof th e keto-ester 39 10 the bromo-al kene38 in thepresence afbase(Scheme191.Furthertransform ations

~Br

38

Scheme 19

3'

4

^C~Et

afforded anintermedi atemolecule 40.which underwenta Wittigreaction togive 41(Sch e m e 20).Thismaterialwa s thenepoxidi zedwith pefOxybenzoicacid10

- 35·

~cO:tMe

40 41

~CO'M'

_o

37 Sche me20

givea mixtureof epoxidizedmaterialthatinclud ed 37.A significantproblemwith this synthesiswas thelackofcontrolof the geometry of the doublebonds.

Separationof th e geometricalisomers was diff icult,whichreducedthe overall effectivenessofthe synthesis.

Hansonand Cochrane'"in 1971 reportedtwo alternativeapproachesto thesynthesisofthese hormones .One approach incorporatedflexibilitywith respect to chainlengthwhereas the otherprovidedahi gher degree of stereochemicalcontro l. The firstroute madeuseoftheGrigna rd addition of elhylmagnesi umbromidetothe ketone42.The tertiary alcohol 43 that resulte d underwentre a rrangement with aqueous HBrto yieldamixture ofalkenes 44an d 45in a1:3rat io,as seen inScheme21.Afterconversion of44and45into Grig~ardreagentsandadditio ntoano therequivalentof42withring-op ening

-36·

o

OH

if' c~r~~

42 43

44 45

Scheme21

under acid catalysis,lhe stage was set fora Wittig reactionbetwee n diethyl(melhoxycabonyl methyljphospllonateandtheketone46 10 afford47.

This materialwas then epox idizedto give the hormone 48.as seeninScheme 22.In thesecondapproach,care waslaken to control the geometryof the first

Scheme22

-37 -

do ub lebond.BUI-2-yn·1-ol49wasconvertedtoa-lcocbut-z-en -t -ot

su

by treatmentwithlithium aluminum hydride,sodium mel hoxide ,and iodine.

Alkylationof50withdielhyl cuprateafforded(Z)-3- me lhylpenl-2 ·e n-1-o 151,but in only15 % yieldfrom 49(Scheme23).Alt houghthiswas a stereospecific

~OH ~OH I

Scheme 23 49

51

so

syn thesis,theyieldofthealco hol was too low10carry throughthere mainder of the hormonesynthesis.Co nsequently,amixture of alcoholswas carried through a series of stepswhich,likethefir stroute,alsoinvolvedaWitlig cou pling.

In19 70 Findlayandco-workers"reportedalinear sequencethai also utilizedWittigadd itionsin the exten sionofthe chain.Inthis case,a tripleWittig cou plingsequencewasused,as shownin Scheme24.First, additionofthe pho sphoket al52 to 2-butanonegavea mixture of isomersthat included 53.

This,in turn,was coupledwithanotherequ iv alentof52togive54 after

-38-

53

Ph,p~L

52

(EtOb-P...C0

'ii

2Me

~Co,M' ~~O

"

\

"

Scheme 24

oeprctectlon.Addition ofsodium diethyl(melhoxycarbonylmal hyl)p hosphonsl e 55toketone54yielded the este r 56which,afterepoxidation, producedthe hormone57as aracemicmixture,in14%overallyield.

-39-

Kutne yeter" employe da similar Wittig coupling between 58and5910 afford60(Sch em e 25)in 72%yield.Unfortuna tely,theyieldfor the entire synthes iswas only0.07%.

58

O~Co,Me

59

~CO'Me

60 Scheme25

In1967,Trost and co-workers"reported another linearsequence involvingmultip leWittigre action s to produce61 startingwith 2-butanone ina

~CO'Me _{o ....}

_H

61 Sche me 26

-40-

racemic synthesis,whichis very similarin strategy to that ofFind lay (S c heme 26).

Finally.Coreyetal.' 8took a departurefromthe use of Wittigcoupling when they synthesized 63from 62.The synthesis consisted ofaseries of functional grouptransformationsand alkylationsto afford 63 in 8%overall yield (Sc heme27).

Scheme27

¢'----

CH3

62

~ I ""

^o,M.

o

63

We chose to pursue alinear approachto 37.However,wewou ldattempt to controlthe geometry of the carbon-carbondouble bondsby setlingupthe relative stereochemistry intheprecurs ors in such a way as toforce elimination to onegeometricalisomer.In accordwithour experience inthe formationof1.3- cyclopentanedic nes," our route for theconstructionof the precursors to37 (Sc hem e 28) wouldbegin with theform ation ofthe t.a-cvciccentenecncne 65 fromthe ketal64. Grignardaddition to65shouldafford 66, andthiscouldbe

-41 -

lMSO

o

OlMS ^BF3.Et20

6 .

^6S

H4?~

^mBH,

H~

67

"

j

H ¥ ^~o

.. _"

Scheme28

followe d byreductionof Iheremainingketone10yieldthe trans-dlol67.Then, conversionofthesecondary alcohol toa leavinggroup,withstereoche mical inver sion.wouldafford68.Thisprecursor could lhenopenviaaGrob-type¹⁹ fra g mentation 10 generate69selediv ely.Repetition ofthese stepswouldallow

fOl'theconstructionofthe remaininglink sin thecarbon chainof37 One import a ntcha nge 10this proposalcameoutofwork also carried outII"ourlabs byOr.TracyJenkins10whodevelopedconditions that permitted theqenera ton oft.z -cy c iopentenec none sdirectly from ketones.Note that the direct conversion of ketonesto 1,3-cyclopentanediones re ducesthenumberof stepsin

u us

synthetic approach.

u

RESULTSAND DISCUSSION

Appro ac h1

Directconversionofz-but ancn e70to the 1,3-cydopentane dlooe 71proce ededsmoothly,as seeninScheme 29,witha veryhigh degree01 reprod ucibilityofyields,typically 75-80% ona vanety of scales

Schem e29 70

1)BFJ.EI2011 •

o~o

2)H201BFJ.EI20

1

71

Columnchromatography wasnotnecessary to obtain71in a homogeneou s form.Instead,simple filtrationof tho black crudeproduct thr ough

a plugof activatedcharcoaland Florisit affordeda pale yellow oil that was suffi cientlypure to use inthe subsequentstep.

The next step was to introducethe ethylgroup (Sch eme30).Inorderto

71 Schem e30

CH3CH2MgBr

-

·78 0C-'OOC

79

achievemaximum facialselecti vitywithcomplete reactioninthe Grignard additionof elhylmagnesiumbromide,thereaction was carriedoutat low tcmperature overan extended period.AlthoughtwoGrignardadditionswere possiblebecause of the two ketone functions inth e substrate,we felt that reactionof oneketon e wouldreduce the sOlubili tyof this initial,desiredproduct, i.e.,the produ ct ofinitialadditionwould be muchless available fora second addition.This was indeedthe case,andtherewas a remarkabledegree of facial selectivityfound in the additio n.The13Cnmrspectrumof the crudeproduct mixtureindicatedthat therswas a significant factorfavourin g additio nto one face of theketone,whichlater proved tobe synto the methy lgroup.This was interestinginthatconventionalmeasures of "size",suchas equatorial/axial ratioson cyclon exane .suggest that there islittle difference.In Sche me 31,on e can see that in72,there aresignificant 1,3-diaxialinteractions whereasin

-44.

r;;j-

H-i-eH l ""-

eclipsed

CHJ - - _~

76

vJ

^CH.,

73

76

tt

Scheme31

78

conform er73themeth yl is intheequatorialpositio nandthere byeliminates repulsiveinteractions.Th e sameargumentis made withrespectto74and75 wheretheethylgroupreplacesthe methy lgroup.Onceagain.inthiscase,the

-45-

A-values formethyl and ethylgroups are nearlyidentical.20Thus, onewouldnot expect 10 observeany degree of selectivitywhereIhesetwo groupsareinvolved, If welook at76, one cansee seriousstericinteractionsno matter which conformer the moleculeisin. Makingthe extensionto77and78,one might thinkthatthereare sterie interactions that will make an arrangementsimilarto 76 thenorm.Inthe caseofthe two conformers77and78 there is an eclipsing interactio nbetween themethyl ofthe ethylgroupandthe geminalmethyl group.

Thereis a dramaticdifference inthaithismolecule has stericinteractions onlyin thecase of77, and thata simple rotationof abondallowsthe methylgroup of the ethylgrouptosit overtheface of the cyclopentane ring in the caseof18.

This wouldeliminatetheeclipsing stencinteractionswhich are encounteredin conformer 77.Since the caseof78isnow aviable situat ion, onecan seehow this methyl group nowblocks addition to the face ofthering syn tothe ethyl groupandtherebyfavour saddition to the face oftheringsynto themethyland thereforeantito theethylgroups, respectively.

Aproblem encountered at this stagewas one that wouldplaguethis approach all thewaythrough, namely the purificationofthemal erialby chromatography.Crude yieldsandspectraappe aredgood.However, substantialamountsof malerial were lost during chromatography. The polarity of an alcohol functionmayhavepermitted significant amounts ofmaterialto

adhereirreversiblytothe column.or thematerialwas simplydestroyed on silica gel.Thus.79was obta inedfrom71in only48%yield after clYomatography.

The next stage of the synthesisrequiredthe reductionof the second ketone(Scheme32).This wasaccomplishedwithsodium borohydrideatlow

o~

79

NaBH,.JMeOH

1\ . »<.

- H~ ""'OH

OOC _ rt

""' '''l

80 Sch eme32

temperamre.again toattainamaximumlevel of facial selectivi ty.On the surface when oneconsiders sterichindrance,thetwofaces ofthe ringare likely10be very similar.Howe ver,theborohy dride was expededfirstto coordinatewith the alcoh ol located atC..J,and then syn·additionof the hydride would producethe product with thetwoalcoholsin atrans arrangement,Figur e4.Thusthe

& ^o

Figure4:Coord inatedBorohydrideAdditiontoth eKetone reductionof the ketone ,79 affordedthe dial,80in only15%yield after column chromatography, but as befo re,ilwas thepurificati onthatled 10very major lossesofmaterial.Both 'Hand'3Cnmrofthe crude compoundsindicated virtually quantita tiveconversi on to80.Nowater was addedtoquenchthis

·47·

reactionas the methanolthatwas usedas eluentusuallycontained sufficient water10destroyany excess borohydride reagentaswell as the comolexec product.The reasoningbehindthis wasvery simp le:wefeltthat we wouldlose significant amounts ofmaterialif extraction from aqueous solutionwas required.

In addition.giventhatwe werelosinglargeamountsofmaterialsduring chromatography,wewereunwilli ngto loseanymore materialby addingan aqueous extraction slepto thepurificalion.

AnX·raycrystalstructureofcompound80confirmed the trans relationship ofthe alcohols(Figure 5).

Figure5:X-rayCrystalStruc tureof80

-48-

In compound 80,the two alcohol moietiesaretrans10 eachother,but for the Grabfragmentation, the leavinggroupmustbecisto the hydroxyl which will become the ketone.Thus.the secondary alcoholmustbe convertedto a good leavinggroup and the etereoceruc center mustbeinverted.Inan effort to evaluatemethods for accomplishing the task of converting the secondary alcohol of8010a halide,a number of the most promising mild techniques weretried, but none metwith any acceptable degree of success.These inclu ded the conversionof the 1-butanot 81to thet-bromobutane82into the presence of triphenylphosphine and bromine by Wiley and co-workers" as shownin Sch eme33.Downieand co-workers"also made use of mild conversion

~OH +(CeHshP + Br2 - (CeHsh PO + ~Br

81 Sch em e33

82

conditionsto convert 81to 1-chlorobutane83with triphenylphosphineand carbontetra chloride as seen in Sche me34.Olahand group23 published a

~OH 81 Scheme 34

+ (CeHshP + CCI4 - (CeHsb PO + ~CI 83

c5

64

~49~

+ M03SiCI + LiBr -

65 Sch eme35

method of convertingalcoholsto alky lbromides withtrimethylsilyl chlorideand lithiumbromide,Scheme 35.Thus,it was decidedto employ more vigorous conditions,as outline dinScheme 36.However,an lntrr - tabteblack

80 Scheme 36

SOClz

~py 86

product.composed of a very largenumberofcompoundsby tic,was obtained fromthis method,These preliminaryattemptsundersco re thefactthat these acycl ic1,3..cyclopentanedionesystemsareverylabile.Despi te earlysuccesses withfacialeelecuvity andyieldsof materials,itwas deci ded to approachthe Grobfragmentationprecur sor from anotherdirection.Thisdecision sprang from tworealities.First,the sod ium borohydride reductionof thesecond ketone was very slow, inthe orde r ofdays to complete. The second reason was theinability 10 convert the secondary alcohol to ahalogen effective ly.

·50·

Approach 2

like Approach1,Approach2 also set upa precurso rfor a Grab fragmentation.Thepreliminarysynthetictransformationswere carried out in the following manner.First,diketone71was red ucedwith sodium borohydr ide to87 in 55% yie ldafte r chromatography(Scheme 37). Hereagain the problemof

Scheme37 71

NaBIIoIMeOH

·78OC--rt

O~I "UH

87

purifyingcompounds that contain alcoholic sitescamebackto trouble us:a crudeyieldof 98% versus aniso lated yieldof 55%.Aswas the caseinour first approach,we had to try todemonstrate avery high leveloffaci al selectivityin a situationin whichA-values suggestedthat facialselectivitywouldbe very poor."

Again,the 13Cnmrspectrumof the crude product indicatedthai attack from one facewa s significantlyfavou red ,on the orderof93:7.The same arguments that appliedforselectiveadditionof the Grignard reagent to71apply here as well, that isto say,thatthe methylof theethylgroup will re st abovethe faceofthe ring and therebyblock additiontothatface of the ring.Thenextstagewas the protection thehydroxylgroupin67with chlorotr imet hyl silaneto give88in51% yield(S che me38).

~51 -

Withtheprotectedmaterial inhand,the way was pavedfor analkylation

87 Scheme 38

ICH3)3SiCI

--

^pyridine

OOC-rt

o n ·· ..

"OSIICH, b

?<]

88

by amodified Barbierreactionon the remainingketone.Thiswas achieved usingultrasonic irradiationof88inthe presenceofa 90:10lithium/sodiumalloy and iodoethane,to provide89inanisolated yieldof 37%(Scheme 39).This

°

⁰ ···0 Si(CH,b

?<'I

88 Scheme 39

Na/Li

~

- C HCH I HO"'" ....·..···OH 3 2 ....

I

"1)

89

reaction generatedan elhylli thium reagent. Adjustingthe shape ofthe flask did not impactonthereproducibility of thereactionnor did changing the solventto diethyl ether from tetrahydrofuran.In addition,anattempt al alkylationwith ethylmagnesiumbromideafforded only traceamountsof product. In89the two hydroxyls werecis asrequired,thus inversionof the secondary alcoholwasnot required.We couldmakethis assignmentof relativestereochemistryby

-52-

consideringthe13C nmr shiftsof79.80,and89asinTable2whereY~

interactions force the1~nmr signal further upfieldas compared 10 shiftswithOut theseinteractions.In addition ,thenudearOvernausereffectdifference spectrum(NOED) of thismoleculeshownin Figure 6show s thatsaturationof theC-2methylsignalafforded anenhancemen tof4%in the C-3hydrogen

Figure6:NOED Spectrum of89

signal.This demonstrates thatthemethylandtheC-3hydrogenare syn to one anothe r.The NOEDspectru malso shows enhance ment ofa protonsignalat0

- 53-

2.09that is assignedas lhe prolanatC-5issyn.However,asuttabteleaving groupwould have10beattache d10the secondaryalcoholtofacilitatethe Grab fragmentation.Theremoval of Ihe trimelhylsilylgroupduringthe courseof the sequence or duringwork-up came as a bonus. unfortunately,the alkylation step couldnolbe carriedout reproduciblyunder themodifiedBarbierconditions.

Table 2:Comparisonof13C nmr ShiftsofCompounds79,80,and 89 Compound13CnmrShifts

Assignment 79 80 89

c-i

222.5 79.7 80.9

C-3 82.6 85.1 86.5

C-2 55.4 49.8 51.7

C-5 33.8 29.5 30.8

C-4 30.1 33.1 35.5

C-9 28.4 28.7 27.7

C-6 23.4 26.3 21.4

C-8 16.8 13.6 19.6

C-7orC -10 8.9 9.4 9.0

C-7orC · 10 7.3 7.5 8.1

Thelackofsuccess witheitherapproachto thefragmentationprecursors precludedan evaluationof thisapproachto thecontrol ofgeometryofthe double bond. When theresults of Chapter1,particularlythe difficulty associated with workingwithsubstratesthathavec-alkylsubstituents,are consideredit ishighly

·54·

probable thai similarinfluences constrainboth approaches.In Approach 1,the sodiumborohydride reduclionof the ketoneto 80requiredan inordinateamount of time.Plausibly,the need for a long reductiontime arose from the sterie congestionnearthe reaction site.Despitethe relativelysmallsize of the molecule,the keyfea tures were all contiguous.These features includedone quaternary and one tertiarycenter,as well as the ketone/alcoholof79 and80 Giventhai lithium aluminum hydride is a more reactive reducingagent compared to sodium borohydride,itis likely that wouldbe less selective given the termsof the Reactivity-Selectivit yPrincip le.²'(Thus,thereduct ion would likely proceed morequickty but would nothave the degree of selectiv itythat is desired in this particularcase. In addition ,the difficulties foundin convertingsecondary alcoholsto halogens inthesubstrates that exhibited similar steric environments lentcredence 10thisid ea.Fina lly,the unreliabilityof the sana-alkylation was alsolikely a consequenceof steric encumbrance.In this case,not onlywasthe substrateitselfstericatlycongested,owing to the presence of the trimethylsityloxygroup, but the alkylating agenl wasfairlybulky.In any case,if the problems ofconv ersion/ inv ersion with a halogen or addingthe alkylating agent couldbe overcome,then theviability and valueof this slrategywill again becomeclear. Yet,despite the obviousproblems withthe syntheticapproaches, therewerevaluable results gained from thisexe rcise .First,thebis-acylation procedure worked welt by producinga 1,3-cyclopenlanedioneproductin very

-55-

reasonable yields.Experience from our labs indicatedproblems withlow molecularweightmoleculessuch as71interm sof product yield s.Due to the high volati lityof such smallmolecules.proceduresto removesolventoftenlea d to loss ofthe desiredproduct.Another significantdiscoverywas thevery high degree of facialselectivity ofboth Grignard additionsand sodiumborohydride redu ctions.In bothapproaches,therewasa veryhigh degree ofselec tivity for reacti onontothe lesserencenv hinde redfaceof the molecu le.Finall y, itisfairly cert ain that severecongestionencountered withina serie s ofcont iguously substit uted centers,such asthe casein thesemolecules,will offer potential problem stofu rthersynthe tic tran sformati ons.Of course,dependi ng upon the synthet icstrategy employed,this couldprove tobeeither a benefitor, in this case,adetriment.

iii. CON CLUSI ON S

Fromtheresultsof thesetwoattemptsatthesynthesisof the precursors 0' the juvenilehormones of Cecropia,itis possible10 draw some conclusions.

First,ithasbeen demonstratedthat conformationalfactorscan rend erthe usual measureof stericsize,i.e.A val ues , asfarasmethyland ethyl groups are conce rned,in adequate.We have exploitedthiseffect very successfully to reducediketon eswith ahigh degreeoffacialselect ivity.The secon d conclu sion wemaydrawis that the Grobfragmentationstrateg y appea rsto failbeca use of

the drastic conditionsrequir ed forthe generation ofa suitableleavinggroup even morerapidly destroys thesubstrate

II. SECTION8:MODEL STUDIESTOWARDS THESYNTHESISOF FREDERICAMYCINA

INTRODUCTION

Fredericamycin A92isachiral metaboliteisolated" fromStreptomyces griseusthatexhibits significantantitumor,antifungal,and cytotoxicactivil y.15It has been thelargetofbothtotal syntheses and of modelstudies.This

Fred ericamyc inA 92

compoundhas sixringsand includes a spiro-cent erand heavy functionalizalion interms of oxygenmoieties.Kellyand co-workers "werethe firstto synthesize (±)-fredericamycinA in1986in an overall yieldof 2%.They assembledthe ring

·57- system of92 from theprecursors&3and94(Sc h eme 40).

94

92 Schem e40

In 1989 Julia andco-workers" reported the deta ilsofa study of the construction oftheA-Bringsystemoffrederica mycinA(Schem e 41).In this work,the aroma ticester95was treatedwithdiethyl oxalate, which afforded 96in 55% yield,Compound96was thentransfor medin aseriesof step sto97.

·58-

Et~ MeN

95

97 Scheme 41

In 1988,Bacher er."reportedaseriesofDials-Alder model studiesof approachesto compoundssimilarto fredericamycinA Forexample.98was added to 9910afford100in62%yield (Sc heme42).

«

^OM'~OfMS

^o

⁺

MeO

~ ~

OMe eN

98 Scheme 42

«? ^\# '"

I - -

o

M.O

99 100

-59-

A key step inour strategytoward sfrecencamycnA wasto assemb le the A-B- C-O-E-Fring systemthroughaonctocnemtceraddition between99and1.

The relrosyn theli c analysispre sented inScheme43showshow this wouldbea key step.In our scenario.92iscons truct edfrom101,'Nhichcontainsthe

e-t·o-

E·Fringsyslem (Fortheconstructionof fredericamycinA,itwouldbenecessary

)

9Z

101

II

' - /

csS ° ( JJ:; ^6§(

"

Sch eme43

103 102

to use amore complex analog of99).•Compou nd101isitselfder ived from102 using aDiels-Ald erreec ncnwithOanishefs ky'sdiane.Thetelracyclic compound 102is the resu ltof cycIobutanebondcleava ge of103,whiChinturn isthedired

-60-

resultoftheprotocnemicatadditionOf1to the

mcscnc

enedione99 A simple exampleofthistypeofadd ition is provi ded by thewor1l.ofWilliamsandco- wor1<ers,JO inwhichtheycarried out an addition of1andlheenone104in he xane to afford theadduct 105in73% yiel dafterirradiatio n atO·Cwitha Corex-fitteredmedium-pressuremercury lamp fora period of 24hou rs(Scheme 44).Compo und105wasthen desily laledwithlelrab u lylammonium fluorideand

OTMS

0(

DlMS

104

hv

T~~G"" ~

""., ^{OTM S} Ii...·

o

105 Scheme44

oxidatively cleavedwithsodium pertodateto affordthe 1,4-d ione106in71%

yiel d(Scheme45).

T~~~OTMS

: ^o D - ^.

/'-

105 Scheme 45

¢O o

0

· r

106

-61·

Van Audenhoveandco-workers"alsoused th istechniquefortheir work towardcrs-nydnnoan esandcis-decallns.The photochemicaladditionswere carriedoutbetween1and enones suchas 107at room temperature in pentane or benzenewithirra d iation at350nm to affordanad duct,e.g .108in75%yield (Sch eme46).It isworth noting that the ratio of 1to107 was 4:1,whereasin the workof Williams(vid e supra),therali oof1 to 104was 1:1.2.Thus,avarietyof condi tions arepossible lorthis type ofreactio n.

OTMS

0(

OTMS

n ~ rh\

Mer-< _o Ii:{

TMSO Me 0

Scheme46

107 108

There are a few examplesin whicl1thistype of pnctochemicel addition has beeninc orporatedintoasynthesis.Acoupleofexamplesfollow.In 1984, Vandewalleandco-workers'"developed a route to (±) -3,4,5,5a.7 ,B,Bacr,Bba- octahydro-2aa,5a~-dimethyl-2H·naphtho[1 ,8-bclluran-2t6(2aH)-dione109via thekeyinter mediate111,which was generatedfromaphotochemicaladditionof 1and110ina ratioof 1,2:1in 80"!clyield(Sc heme47) followingphotolysisat 350nm.

-6 2 -

~

o 109

In anotherexample,AngleaandPinder»formedth eeocuct113from1

(YI

⁺TMSO OTMS

Y 0

^h,

o 11.

Scheme47

r+-h

^S

~s o

111

and112in24%yieldduringeffortstowardthe synthesisof(+)-balanilol (Schem e 48).Irradiation wascarriedou tatroom temperaturewithM immersion lampin a solutionot1and112(5:1.resped ively) inpentane.

TMSO OTMS

[ ]

113 Scheme48