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Synthetic approach to the agelasimines Dotse, Anthony Kwabla 1992

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SYNTHETIC APPROACH TO THE AGELASIMINESByANTHONY KWABLA DOTSEB.Sc.(Hons.), University of Science and Technology, 1985M.Sc., University of London, 1990A THESIS SUBMITTED IN PARTIAL FULFILLMENT OFTHE REQUIREMENT FOR THE DEGREE OFMASTER OF SCIENCEInTHE FACULTY OF GRADUATE STUDIESDEPARTMENT OF CHEMISTRYWe accept this thesis as conformingto the required standardTHE UNIVERSITY OF BRITISH COLUMBIAAugust 1992Anthony Kwabla Dotse, 1992In presenting this thesis in partial fulfilment of the requirements for an advanceddegree at the University of British Columbia, I agree that the Library shall make itfreely available for reference and study. I further agree that permission for extensivecopying of this thesis for scholarly purposes may be granted by the head of mydepartment or by his or her representatives. It is understood that copying orpublication of this thesis for financial gain shall not be allowed without my writtenpermission.(Signature)Department of  ChemistryThe University of British ColumbiaVancouver, CanadaDate 27th August 1992DE-6 (2/88)11ABSTRACTAside from the structural interest and the success achieved inannulation methods as exemplified in schemes 6 and 7 in thislaboratory, synthetic work on the agelasimines A and B and theirquartenary 9-methyladenine derivative (44) was encouraged by thepresence of a variety of biological activities in these natural products.Another aim of this thesis is to confirm the generality of thesynthetic method as applied to the total synthesis of ambliol B (48).Copper(I) mediated conjugate addition of allylmagnesiumbromide to 3,4-dimethy1-2-cyclohexen-l-one (63), followed bytrapping of the enolate generated with trimethylsilyl chloride,produced the silyl enol ether (62), which was converted to theMannich base (61). Oxidation of this compound with m-CPBA gavean amine-oxide intermediate which eliminated N , N -dimethylhydroxylamine to give the enone (60). Conjugate additionof the novel vinylgermane cuprate (19) to this enone and treatmentof resultant ketone (80) with iodine gave the iodide (59). Thisiodide was employed as the cyclization precursor to the trans-fusedsubstituted bicyclo[4.4.0]decananol (58). Cyclopropanation of theexocyclic double bond in (58) occurred chemoselectively and gavethe cyclopropane (67). The remaining double bond was ozonizedand the ozonide cleaved to generate an aldehyde which was reducedto the primary alcohol (93). Hydrogenolysis of the cyclopropanering of this diol provided the diol (55), which is a possible precursorMe2N(61).)Me3Ge0(80)Me3Si(63)(62)Me3Ge 	 Cu(CN)Li(60) (19)(93)H(55)111for the synthesis of the agelasimines A (42), B (43) and theirquartenary 9-methyladenine derivative (44).) OH     (59) (58) (67)X. (44)Purino-derivative of (42 and 43).,"X. (42) 	 '= OHivAgelasimine A"444'X = (43) 	 1•1/NAgelasimine BTABLE OF CONTENTSPageABSTRACT 	 iiTABLE OF CONTENTS 	 vABBREVIATIONS 	 v iACKNOWLEDGMENTS 	 ixI . 	 INTRODUCTION 	 11.1 	 General 	 11 .2 Background and Proposals 	 2II. DISCUSSION 	 122.1 Synthetic Approach to the Agelasimines 	 122.1.1 Introduction 	 122.1.2 Synthetic Planning 	 1 62.1.3 Synthesis of the gem-Dimethyl Intermediate(55), a possible precursor to the agelasimines 192.2 Conclusion 	 3 7III . EXPERIMENTAL 	 4 03.1 General 	 4 03.2 Experimental Procedures 	 4 6I V . REFERENCFS 	 6 2viLIST OF ABBREVIATIONSAc	 acetylAPT	 attached proton testAq	 aqueousa t m	 atmosphere(s)9-BBN	 9-borabicyclo[3.3.1Thonaneb p	 - boiling pointb r	 - broad (spectral)Bu	 - n-butylt-Bu	 - tert-butyl`C	 - degree Celcuiscalcd	 - calculatedcat	 - catalytic / catalystCI	 - chemical ionisation (in mass spectrometry)cm -1	- wave numberCOSY	 - correlation spectroscopym-CPBA - meta -chloroperoxybenzoic acid5	 - chemical shift in parts per million downfield fromtetramethylsilaned 	 - doublet (spectral)ED50	 - dose that is effective in 50% of test subjectsEI	 - electron impact (in mass spectrometry)equiv	 - equivalent(s)Et	 - ethyleV	 - electron volt(s)FT	 - Fourier transformviig	 - gram(s)glc	 - gas-liquid chromatographyh	 hour(s)HMPA	 hexamethylphosphoramideHz	 hertzit	 infraredJ coupling constant (in NMR)L liter(s)LDA	 lithium diisopropylamideA	 microM	 moles per literm	 multiplet (spectral)Me	 methylm g	 milligram(s)min	 minute(s)MHz	 megahertzmol	 mole(s)mmol	 millimole(s)MS	 mass spectrometryn m r	 nuclear magnetic resonanceP h	 phenylp p m	 parts per millionq quartetr t	room temperatures	 singlet (NMR)soln	 solutiont	 triplet (spectral)viiiTf2NPh - N-phenyltrifluoromethanesulfonimideTHE	 tetrahydrofurantic	 thin layer chromatographyTMS	 trimethylsilyl, tetramethylsilanetorr	 - 1 nun HgixACKNOWLEDGMENTSGratitude is hereby being expressed to my advisor, Dr. EdwardPiers, who was helpful, academically, during the course of this study.His guidance, patience and perfectionistic attitude towards researchsaw this work to its present stage.May I say "Thank You" to all other academic staff, technicalstaff and my colleagues who contributed in one way or the other.Acknowledgement is made to Ingrid Ellis for the weekendhours spent on my behalf typing most of this thesis.Finally, thanks are due to my daughter, Selasie and her mum,Empress, who were of constant support, emotionally, and have keptspirits and hopes very high so far.xThis thesis is dedicated to the memoryofmy mum,Celestine Kwasiwor Kuebunyaandmy aunt (guardian),Margaret Aku KuebunyaxiThere is excitement, adventure, and challenge, and there can be greatart in organic synthesisR. B. WoodwardIn Perspectives in Organic Chemistry1INTRODUCTION1.1 GeneralWe are now in an era of both the synthesis of new molecules ofever increasing complexity and in the development of new methodswhich allow more precise control over the formation of new bondsand the stereochemistry of the product. Nature provides thesynthetic chemist with a vast array of complex structures whosesyntheses are justifiable and well-defined goals. The total synthesisof natural products requires chemists who are able to invent neworganic reactions, control relative and absolute stereochemistry in apredictable manner, and realize success in reaching clearly definedtargets of research.Organic reagents possessing two reactive sites (one nucleophilicand one electrophilic, or two nucleophilic or two electrophilic centres)are becoming increasingly important in organic synthesis. Thesespecies have been used as reagents by employing the two reactivepositions in the novel synthesis of complex and functionalizednatural products. They are referred to as "bifunctional conjunctivereagents" 1 or "multiple coupling reagents"2 and have been used forcyclizations. This involves coupling with bifunctional substratesintermolecularly followed by an intramolecular step. The reactionsare usually polar in nature resulting in the reactive sites of thereagents being termed "donor" (d) and "acceptor" (a).32No attempt will be made in this thesis to give examples of theuse of these reagents in total synthesis of natural products since suchexamples are numerous, some of which can be found in thereferences numbered 4 - 12.1.2 Background and ProposalsFor the past decade, investigations conducted in our researchlaboratories produced a group of vinylstannanes 1 3 and avinylgermane, 20 which have been employed as bifunctionalconjunctive reagents. Thus, regioselective addition of trimethyl-stannylcopper-dimethyl sulphidel 4 to 1-alkynes produced co-chloro-2-trimethylstannyl-1-alkenes (1), where n = 1, 2.(1) Me3SnCu.Me2S, THF,Me0H, -78°C, 2.5h,  Me3SnonOH0°C, 3h,on 	 (2) aq. NH 4CI (pH 8)I Ph 3P, CCI4 ,Et3 NMe3Sny, on(1)Scheme 1As precursors of bifunctional conjunctive reagents, thesevinylstannanes possess donor (d) and acceptor (a) sites and as such3Me3Sn, 	 1On  ad 	71T2--=(2)are synthetic equivalents of donor-acceptor synthons (2).These reagents have been utilized in the construction of 5- and6-membered rings, through conjugate addition to cyclic enones.Thus, 4-chloro-2-trimethylstannylbut-l-ene (3) 1 was convertedMe3Sn 	 Cl 	 (1) MeLi, THF, -78°C Li(CN)Cu(2) CuCN, -63°CCI( 3 )	(4)(4)CI4C0H(6)1 KH,THF, r.t.THF, -78°CH( 5 ) 4readily into the novel cuprate (4) which added to the cyclic enone(5). A subsequent intramolecular alkylation generated a thirdcyclopentane ring 15 to provide the angularly fused triquinane (7),as shown in scheme 2.5-Chloro-2-trimethylstanny1-1-pentene (8), a homologue of(3) and a synthetic equivalent of the 1-pentene d 2 , a5 synthon (9),has also been employed in annulation.M e3SCI aH2    (8) (9)For example, 5-chloro-2-lithio-l-pentene (10), obtained bytransmetalation of (8), was converted to Grignard and/ororganocopper reagents, which added conjugatively to the enone (11).Intramolecular alkylation at the a-position of the ketone (12)produced a mixture of the cis- and trans-fused bicyclic compounds(13a) and (13b) 16 as indicated in scheme 3This useful and important methodology was employed in acomplementary fashion by reversing the order of deployment of thepotential acceptor site (alkyl halide) and the potential donor site(vinylstannane). Such annulation strategies were utilized in theformation of the diene (18), the enone (25), and compoundscontaining allylic angular hydroxyl groups (eg, (30), (32), (33)).5MeLi, THF,-78°C, 15 min.CI(1 0)M e3SCI( 8 )(A) (1) MgBr.Et20,THF, -78°C(2) CuBr.Me2SOR(B) (1) n-Bu3P, THF,-78°C,(2) CuBr.Me2S,(3) 0(11)-78°C --■ -40°C(4) NH4CI, H2O(13b) (13a)Scheme 3(12)Thus, cyclic a -methoxycarbonyl ketones (14) have beenalkylated conveniently with the acceptor site of the iodo analogue(15) 17 of reagent (8). After the conversion of these alkylatedproducts (16) into enol trifluoromethanesulphonates (17),palladium(0)-assisted cyclization afforded the diene systems (18).18=RCO2me cat.(Ph3P)4Pd,/ R0n s°H 	 THFSO2CF3CO2Me"I,On z RFT(17)SnMe36CO2Me',/,On:. 	 (2)	 nMe3 	 Onz RFT 	 I(14) 	 (16)(15)O2Me (1) KH, THF,  SnMe31 LDA, THF,Tf2NPh(18) (i) n . 1, R . H or Me;(2)n.2,R.HorMe;(3)n=3,R.H.Scheme 4The use of the bifunctional conjunctive reagents discussed sofar was extended in another useful way by interconverting theirdonor and acceptor sites. In such a way the activity of the reactivesites themselves have been reversed. This idea was successfullyexecuted by our group in a five-membered ring annulation methodinvolving the use of the vinylgermane cuprate (19) as a syntheticequivalent of the 1-butene a2 ,d4 synthon (20). 19Me3GeCu(CN)Li 	 =1..._.— 	 a 	 cH2d(19)	 (20)(1) , THF, 	 0(21)(19)7Thus 1,4-addition of reagent (19) to the cyclic enone (21)produced the 1,4-adduct (22) as an intermediate to the keto vinyliodide (23). Palladium(0)-catalyzed cyclization produced compound(24) which under the reaction conditions, was isomerized into theenone (25).GeMe3Me3Gey•Cu(CN)Li(2) Me3SnCI, -78°C,H2O, NH4CI(1) (PPh3 )4Pd (16 mole %)THF, r.t.-.1	(2)t-BuOK, THF / t-BuOH(24)t-BuOK, t-BuOH,r.t.(22)1 12 , CH 2Cl2 ,r.t.0I(23)(25)Scheme (5)Recent reports in our laboratory documented the successfulpreparation of bicyclic systems possessing an allylic angular(1) LDA, THF, 0°C,(2)Bu3S 	 CI(26)	 •••(3) Na104 , THF, H2OjriBu 30(27)I t-BuOK, t-BuOH,THF; MelNNMe2H0(29)n-BuLi, THF,4, -63°C8hydroxyl group,20,26 the double bond being endocyclic or exocyclic.The preparation of the product (30) containing an endocyclic doublebond began from the bifunctional reagent (26), which is derivablefrom the corresponding alcohol. 21 The keto vinylstannane (27),resulting from the usual alkylation 18 with the vinylstannyl chloride(26), was methylated (28) with t-BuOK in t-BuOH and THF followedby MeI addition. Iodine treatment produced the keto vinyl iodide(29), which was smoothly cyclized to (30) upon treatment with n-BuLi (2.5 equiv).12, CH2Cl2r.t.SnBu 3 (30) I A = -OCH 2C(CH3)2CH20- I(Scheme 6)10t::%'60jLn SnMe3R 12, CH2Cl2ARAlCol.. )n 	 +rt.0 0(31)n-BuLi, THF, -78°CROH9The exocyclic equivalent of (30) was also accessed using themethodology described above. The bifunctional reagents employedwere (15) and its one-carbon lower homologue (81). Hence startingfrom the alkylated substrates mentioned earlier, 18 the intermediateketo vinyl iodides (31) were cyclized into the products (32) a n d(33).(32)	(33)I A = -OCH2C(CH3)2CH20- In = 1, R = H; both cis and trans,n = 2, R = Me; only cis product.Scheme 7The successful execution of these annulation processes and thefact that the methylenecyclopentane, methylenecyclohexane, theirmore stable endocyclic isomers and the allylic angular hydroxylmoiety are structural units in the terpenoid family of naturalH(36).0O2Me(37)R = NH—CHO(38)R = N 4=-C- (39)10products, encouraged us in our goal towards the total synthesis ofnatural products.In africanol (34), 8 the methylcyclopentane ring could beprepared by hydrogenation of the correspondingmethylenecyclopentane moiety, whilst the gem-dimethylarrangement in 3a,5a-dihydroxychiliolide (41),23 the agelasiminesA (42) and B (43) 24 and their quartenary 9-methyladeninederivative (44) 25 are theoretically achieved by cyclopropanation ofthe methylenecyclohexane ring, followed by hydrogenolysis of thecyclopropane ring. The other representative natural products ofinterest are (±)_09(12)_capnellene (35) ,4,22 (i_j_ pentalenene (36), 5(±)-axamide-1 (37) and (±)-axisonitrile (38), 6 (-)-methyl kolavenate(39), 9 and A9 ( 12)-capnellene-5a,88,10a-triol (40). 22N(42) X = 	 IN1" NH(43) X = (  HO`%'' OH1 1(44) X .It was in fact an interest in the synthesis of the trans-fusedbicyclic natural products containing an angular, allylic hydroxylfunction that initiated the work described in this thesis.(46)(45)OH 	 16 1412II DISCUSSION2.1 Synthetic Approach to the Agelasimines2.1.1	 IntroductionThe isolabdane diterpenoids, possessing the general carbonskeleton (45), are a class of terpenoids which biogenetically arederivable from geranylgeraniol (46). Formally (45) could beregarded as being formed via a 1,2-methyl shift involving themigration of the methyl group at C-10 to C-9 followed by 1,2-hydride shift from C-5 to C-10. The clerodane skeleton (47) isformed by methyl group migrations at two positions, from C-4 to C-515(47)in addition to the C-10 to C-9 migration. There is also the 1,2-hydrideshift from C-5 to C-10 following the C-10 to C-9 methyl migration.A small number of diterpenoids possessing the isolabdane1 3skeleton have been isolated from terrestrial and marine organisms.Notable examples are ambliols B (48) and C (49) isolated fromDysidea amblia (de Laubenfels) samples collected by hand usingSCUBA at 20-30 m at Scripps Canyon and Pt. Loma, La Jolla, CA, byFaulkner et. al.26 a ,b 3a ,5 a -Dihydroxychiliolide (41) was isolatedfrom the aerial parts of Chiliotrichium rosmarinifolium (voucher RMK9399, U.S. National Herbarium, Washington). 23 In 1984, Faulkner et.al. 25 extracted and determined the structure of an unusual purino-diterpene (44), an artifact derived from an unstable base that wasthe major antimicrobial metabolite of Agelas mauritiana. Themethanolic extract of this sponge from Enewetak showed significantantimicrobial activity against Baccilus subtilis and Vibrioanguillarum. Recently,24 Fathi-Afshar and Allen isolated two noveladenine derivatives of a bicyclic diterpenoid, agelasimine A (42) andagelasimine B (43) from the orange sponge Agelas mauritiana. Thismarine sponge was collected from Enewetak Atoll at 15 meterdepths.Aside from the structural interest and the success achieved inannulation methods as exemplified in schemes 6 and 7 in thislaboratory, synthetic work on the agelasimines A and B wasencouraged by the presence of a variety of biological activities inthese natural products. Both compounds have been reported 24 toshow cell growth inhibition properties when tested against L1210mouse leukemia cells in vitro (ED50 = 2-4 gg/mL). Their effect on thesmooth muscle relaxation of rabbit gut and beef coronary arteryX. (44) 	 ".NX. (42)X. (43)He(41)14(49)X = (48)iHtissues (ED50 = 3-10 11,M) was also confirmed. These two compoundsalso have the ability of inhibiting nucleoside transport into rabbit(51)15erythrocytes (IC50 = 6-14 µM). The most interesting biologicalactivity tested was the reversal effects on rat aorta ring preparationsof various neurotransmitters and other substances. It is anticipatedthat both agelasimines will be active Ca 2+-channel antagonists as wellas a 1 adrenergic blockers.The synthetic aspects of isolabdane diterpenoids had remainedunexplored until 1990, when our group reported the first totalsynthesis of one of these substances, called ambliol B (48).26c Likeambloil B, the agelasimines contain a gem -dimethyl moiety adjacentto an angular hydroxyl functionality. Therefore, similar methodologywas applied towards our synthetic studies on the agelasimines.For some background work on clerodane synthesis, the readeris referred to publications describing the synthesis of (+ )m a in g ay icacid (50),27 (-)-methyl kolavenate (39), 9 linaridial (51) 28 and (+) -15 ,16 -epoxy-cis-cleroda-3,13(16),14-triene (52).27O2Me(39) (50)16(52)2.1.2	 Synthetic PlanningFor the synthesis of the substituted t r a n s - f u s e dbicyclo[4.4.0]decane (58) by the already documented annulation, thepreparation of the a-methylene ketone (60) became mandatory.From a synthetic point of view (scheme 8), this substance isderivable from a conjugate addition29 -trapping 30 -alkylation 3 1procedure 26 c ,32 , provided that the introduction of the allyl group to3 ,4-dimethy1-2-cyclohexen- 1 -one (63) is stereoselective in thedesired sense, that is, trans to the 4-methyl group. Fortunately, inthis respect, we could utilize the straight-forward result of Piers andMarais26c and also that of Danishefsky. 32 These authors reported thatthe conjugate addition of vinylmagnesium bromide andpentenylmagnesium bromide, respectively, generated ametalloenolate species.	 These were silylated to afford trappedproducts similar to (62), stereospecifically.(60) (61)17(63);)-■Me3Si(62)Scheme 8At this stage it was expected that we could take advantage ofthe reaction of silyl enol ethers with preformed Mannich salts. Thisoccurs regiospecifically to give keto amines (61) as substrates to thea -methylene  ketone (60). In this intermediate, the relativeconfigurations of two of the four contiguous stereogenic centres at C-5, C-8, C-9 and C-10 in the natural products have been set up. Theallyl moiety and the a -methylene group have been put in place so asto make further side chain manipulations possible.As already documented in our group by Marais, thebifunctional conjugate reagent (19), the synthetic equivalent of a 1-butene d2 ,d4 -synthon (65), is expected to add to the enone (60). A18series of appropriate transformations would then be expected to give)  )           (60)  OH       (58) (55)Scheme 9the trans-fused bicyclic product (58) predominantly or exclusively4 6 a (scheme 9).Cyclopropanation of the exocyclic double bond in (58) wouldgive (67) (see pages iii and 32), allowing for the manipulation on theremaining double bond to access the ketone (56) or the iodide (54).From the ketone (56), target products (42-44) would be accessiblevia Wadsworth-Emmons-Horner olefination followed by appropriatetransformations.: OH(54)+    z OH(42 - 44) (53) j X19	OH	 E OH	(56)	 (42 - 44)An alternate route would be to couple33 the iodide (54) withthe vinyl iodide (53), generously supplied by Jacques Roberge, tosynthesize an intermediate that would serve as a suitable precursorfor the same targets.2.1.3	 Synthetic Studies on the AgelasiminesThe studies started from the preparation of 3,4-dimethy1-2-cyclohexen-1 -one (63) according to standard methods, 34 which were20modified to give an optimum yield of 81%. This compound hasspectral properties identical to those reported by Dauben et. a1.35A copper(I)-catalyzed conjugate addition of allylmagnesiumbromide (64) to the enone (63) in the presence of HMPA/Me3SiC1 30did not produce the required 1,4-adduct but rather the 1,2-additionproduct (68) in 83% yield. The presence of the OH group wasindicated by a strong absorption peak in the it spectrum at 3366cm -1 . This was confirmed by a peak at 8 69.9 in the 50 MHz 13 C nmrspectrum. The vinyl proton in the ring appeared at 8 5.31 as a broadsinglet in the 1 H nmr spectrum (400 MHz, CDC13). This result is notunexpected, since earlier reports 29a ,b have documented this. Gooddonor solvents such as THE have been known to retard or inhibitconjugate addition.The dienol (68) could serve as a viable precursor to the silylenol ether (62) via an anionic oxy-Cope rearrangement36,37,38followed by trapping37 a of (69) with trimethylsilyl chloride asshown in Scheme 10.        -Or  WO'  OH   TMS(68)	 (69) 	 (62)Scheme 1021Having failed to effect the conjugate addition by Cu(I)-catalysis,attention was drawn to earlier experiments whereby 0.5equivalent39a of a Cu(I) species was employed to improve the yieldsof the 1,4-adducts when 3-methyl-2-cyclohexen-l-one (71) and 1-acetylcyclohexene (72) were substrates. 39 b The usual 0.25equivalent of Cu(I) gave significant amounts of 1,2-addition to thecarbonyl group.(71) (72)When this approach was extended to our system, both 1,2- and1,4-addition products were obtained in the ratio of 1:1. However, itwas found that use of 1.0 equivalent of CuBr.Me2S gave exclusively1,4-addition, and the silyl enol ether (62) was produced andpurified40 in 86% yield (scheme 11). The silyl enol ether andterminal olefin frequencies appeared at 1668 cm -1 , 1252 cm-1 and1641 cm-1 , 910 cm-1 , respectively, in the it spectrum. The presenceof one tertiary and one secondary methyl group was indicated at 80.80 (s, 3H) and 0.82 (d, 3H, J = 7 Hz), respectively, in the 1 H nmrspectrum (400 MHz, CDC13). The presence of four vinyl protons wasalso indicated by signals at 8 4.65 (br s, 1H), 8 4.92-5.05 (m, 211) and5.68-5.84 (m, 111). According to literature precedence,26c ,29c ,32 therelative configuration of the two chiral centres present in the (62)2 2could be assigned with confidence and were correct for the eventualsynthesis of the target natural products (42-44).Due to the unstable nature of the silyl enol ether (62), itshydrolysis product, the ketone (70) is always isolated as a sideproduct. This ketone was fully characterized. The it spectrum(70)showed peaks at 1714 cm -1 , 1640 cm-1 and 916 cm-1 . 1 H nmrspectroscopy (400 MHz, CDC13) showed the presence of one tertiaryand one secondary methyl group at 3 0.71 (s, 3H) and 0.88 (d, 3H, J =8 Hz), respectively. The vinyl protons resonated as multiplets in theregion 8 4.94-5.10 (2H) and 5.68-5.81 (1H). The keto carbon-atomwas confirmed in the 13 C nmr spectrum (100 MHz, CDC13) at 8 212.1.The exact mass determined for Ci1H180 was 166.1358 and compareswell with the calculated value of 166.1361. Microanalysis gave C78.80 and H 10.80 as against the theoretical value of C 79.47 and H10.91.Now that we had successfully prepared the silyl enol ether(62), its reaction with methyllithium at room temperature for 30040Or 00 .?AgBr, CuBr.Me2S(63)HMPA, Me3SiCI, THF, -78°CMe3Si(62)I MeLi, THF, 0°C23min, according to the procedure of Stork and Hudrlik,41 generatedthe enolate (73) with positional specificity (scheme 11). This enolate )Me2W=CH2 I(74)Mee THF, -78°C (61) (73)Scheme 11was then allowed to react with dimethyl(methylene) ammoniumiodide (74, Eschenmoser's salt42 ) following Danishefsky'smethod. 3 1,32 This was followed by acidic (1N HC1) work-up andbasification (5% aq. Na2CO3) to afford a 96% yield of the Mannichbase (61), which consisted of an epimeric mixture at the C-2position. The it (neat) spectrum of the keto amine (61) revealedpeaks at 1715 cm-1 for keto group and at 1639 cm -1 for olefin group.The 1 H nmr spectrum (400 MHz, CDC13) showed that the correctproduct had been isolated. Prominent peaks in the spectrum at 82.15 and 2.20 (s, s, ratio 2.2:1, 6H) are assignable to the methyl)	)filtration, silica gel(75)  (60)24groups of the Me2N moiety. The chemical ionization (CI) massspectrum of this compound gave prominent fragments at 224 (M+ i-1, 2.3%), 223 (M+, 4.3%), and 58 (CH2=N+Me2, 100%).Because of its instability, the crude keto amine mixture (61)was oxidized without further purification with m -chloroperoxybenzoic acid in dichloromethane 26 c ,43 to form thecorresponding labile N-oxide (75). This material was passed througha short column of silica gel to produce the a-methylene ketone (60)in 85% yield, after purification and distillation (scheme 12).Surprisingly, this biselectrophile was stable compared to its lowerhomolog (vinyl in place of allyl), prepared in our group by Marais. 26 cResonance frequencies in the it spectrum at 1695 cm -1 and 1610cm -1 indicated the presence of the a,(3-unsaturation. The terminalolefin gave rise to an absorption at 1640 cm -1 . The 1 H nmr spectrum(400 MHz, CDC13) of this enone showed resonance peaks at 6 5.15 (brs, 1H) and 5.84 (br s, 1H) due to the two methylene protons 13 to thecarbonyl group. Other assignments were as expected. The 13 C nmrspectrum (50 MHz, CDC13) indicated the carbonyl carbon at 6 203.7.)Me2(61)m-CPBA,	 IrCH2Cl2 , 0°C	 0-Scheme 122 5A minor compound, exhibiting a higher retention time on glc ascompared to (60), was also isolated. This material exhibited spectralproperties similar to those of (60), except that its a-methyleneprotons resonated at 8 4.76 (br s, 1H) and 4.97 (br s, 111) in its 1 11nmr spectrum (400 MHz, CDC13). The structure (76) 44 was assignedto this minor side product.(60)(76)In order to prepare the novel cuprate (19),26c a cold (-98 0 C )THF solution of (77), (0.05 M) 16c was treated with 2.00-1.95equivalents of tert-butyllithium and the resultant solution waswarmed to -780 C whereupon 1.1 equivalents of copper(I) cyanidewas added. Brief warming to -35 0C gave the cyanocuprate (19) as a(1) t-BuLi (2 eq.), THF, -98°Cme3Gelr	 I 	 p.- Me3Ge(2) CuCN, -78°C --II- -35°C(77) (19)26clear pale tan solution.The enone (60) was allowed to react with 1.6 equivalents ofthe cuprate (19) in the presence of three equivalents oftrimethylsilylbromide at -780C in THF for 2 hours (scheme 13, page28). The resulting silyl enol ether intermediate (78) was hydrolyzedand the reaction mixture was worked up. The crude 1,4-adduct(79), which consisted of two epimers in the ratio of 1:2.5, wasepimerized with 0.5 equivalents of potasium tert-butoxide in tert-butanol and THF to give the more stable isomer. Purification anddistillation of the crude oil gave a 50% yield of the ketovinylgermane (80). Evidence that the desired compound was indeedformed came from the it spectrum. The ketone function gave rise toan absorption at 1713 cm -1 , while the olefin function produced peaksat 1639 cm -1 and 916 cm-1 . The 1 H nmr spectrum (400 MHz, CDC13)of (80) exhibited a nine-proton singlet at 6 0.18 for the Me3Ge groupand three-proton signals at 8 0.55 (s) and 0.89 (d, J = 8 Hz) due to thetertiary and secondary methyl groups, respectively. Three vinylprotons can be found in the region 8 5.02-5.18 (m). The vinyl protontrans to the Me3Ge moiety appeared at 8 5.47 (m, 1H) whilst the fifthvinyl proton gave a peak at 8 5.73-5.88 (m). Compound (80)exhibited expected 13 C nmr spectral (50 MHz, CDC13) characteristics.During the epimerization of the crude mixture (79) (scheme13, page 28), the less stable isomer (82) was converted underthermodynamic conditions into the relatively more stable compound(81). It can be seen from the two conformational formulas that (82)(83)27has two axial and two equatorial substituents whereas (81) has onlyone axial and three equatorial substituents.11Geme3(82) (81)It should be noted that the exact equivalents of reagentsutilized in the preparation of (19) and subsequently (80) a r enecessary for best results. Deviations from these amounts gave thecoupling product (84) and the t-butyl conjugate addition product( 8 3 )M e3Ge GeMe3(84)The keto vinylgermane (80) (scheme 13, page 28) wasexpediently transformed into the corresponding keto vinyl iodide(59) by treatment with 1.1 equivalents of iodine indichl or o me th an e 4 5 at room temperature. After work-up and))(60)(19)	IP.(2) Me3SiBr, THF, -78°C(1) Me3Ge Cu(CN)LiMe3Ge28purification, the keto vinyl iodide (59), homogeneous by tic and glc,was obtained in 91% yield (scheme 13). The compound (5 9 )exhibited all the expected resonances in both its it (neat) and 1 H nmr(78)H2O, NH4CI)Me3Ge 	 " 	 t-BuOK, 	 Me3Get-BuOH, THF, r.t.(80) (79)12,CH2Cl2 ,r.t.)klr'X)'(59)Scheme 13(400 MHz, CDC13) spectra. Ir absorptions for the ketone group and2 9the vinyl group were observed at 1712 cm -1 and 1638 cm -1 ,respectively. That for the iodo-substituted double bond appeared at1617 cm-1 . In the 1 H nmr spectrum, two diagnostic multiplets forthe iodovinyl protons appeared at 8 5.67-6.02. These signals aresignificantly downfield from those of the corresponding resonancesfor the precursor vinylgermane (80), thus confirming that thegermane moiety had been replaced by the more electronegativeiodine atom. The 13 C nmr (50 MHz, CDC13) spectrum confirmed thetypes and the total number of carbon atoms present.As discussed previously, the keto vinyl iodide (59) is theprecursor to the required substituted trans-fusedbicyclo[4.4.0]decananol (58) (scheme 14). Attention was thereforeturned to achieving this transformation by the addition of 2.4equivalents of n-butyllithium at -78 0 C to a THE solution of (59).Within 15 min, smooth cyclization had occurred. Work-up,chromatographic purification and distillation provided the alcohol(58) in 87% yield as a single product.Evidence that (58) was indeed produced came from a varietyof spectral data. The it spectrum of this compound exhibited an 0-Hstretching absorption at 3426 cm -1 . The olefin absorption appearedat 1639 cm-1 . The 400 MHz 1 H nmr spectrum of (58) revealed thepresence of two methyl groups resonating at 8 0.85 (d, 3H, secondaryMe, J = 8 Hz) and 0.88 (s, 3H, tertiary Me). The protons on theexocyclic double bond showed resonance absorptions at 8 4.65 (br s,1H) and 4.73 (br s, 1H), whilst the vinyl protons of the ally! group(85)1OLi(86)30gave rise to resonances in the region 8 4.90-5.05 (m, 211) and 5.62-5.75 (m, 1H). In the 13 C nmr spectrum, the tertiary carbinol carbonof (58) produced a signal at 8 73.6.Despite the highly nucleophilic character of n-butyllithium, it isinteresting to note that direct reaction of this reagent with thecarbonyl group did not occur. Thus the reaction of n-butyllithium toeffect iodine-metal exchange at the low temperature was faster thanits reaction with the nonconjugated ketonic carbonyl group presentin (59) .46b)n-BuLi (2 eq.),THF, -78°C(59)H2O OH(58)(Scheme 14)The spectroscopic data derived from the cyclization product3 1(58) did not provide conclusive evidence regarding thestereochemistry at the ring junction of this material. However,precedence has been set by cyclization studies by Marais26c thatsuch systems yield products of the desired stereochemistry.Cyclization is expected to take place via conformer (85). For stericreasons, attack on the carbonyl atom by the vinyllithium moiety willtake place from the equatorial face to give the transient trans- fusedlithium alkoxide (86). This species, upon protonation, would give(5 8) . In the case of axial facial attack by the approachingvinyllithium moiety on the carbonyl carbon, a 1,3-diaxial interactionwith the axially oriented methyl would be experienced, destabilizingthe transition state.The annulation sequence was, therefore, highly stereoselectiveand in view of the stability ascribed to conformer (85), the desiredstereochemical relationships at the four diastereomeric carbon atomsin (58) can reasonably be assigned, though the ultimate confirmationof this will be made after the completion of the total syntheses of thenatural products. The tra n s -fused bicyclic skeleton of theagelasimines (42-44) had also been correctly installed.Before any synthetic manipulations of the allyl group of (58)could be carried out, it was necessary to convert the exocyclic doublebond into a relatively unreactive cyclopropane moiety.The use of diethylzinc47 a instead of zinc-copper couple48 forthe cyclopropanation of olefins was reported by Furukawa et. al. In3 21972, Miyano documented evidence that the presence of oxygengreatly accelerates the cyclopropanation. 49 Thus, treatment of a drybenzene solution of (58) with diiodomethane-diethylzinc in thepresence of dry oxygen gave a 90% yield of the cyclopropane (67) asa colourless oil. The it spectrum of (67) indicated absorptions at3075 cm -1 , 3001 cm -1 and 1015 cm -1 characteristic of thecyclopropane ring. The 0-H stretch and the olefin absorptions wereindicated between 3599-3514 cm -1 and at 1637 cm-1 , respectively.This compound exhibited four characteristic high field multiplets inits 400 MHz 1 H nmr spectrum at 6 0.00-0.10, 0.15-0.24, 0.48-0.58and 0.60-0.69, indicative of the protons on the cyclopropane ring.The protons attached to the vinyl moiety showed resonances in theregion 8 4.95-5.05 (m, 2H) and 5.68-5.84 (m, 1H), confirming that thecyclopropanation was site-selective.Et2Zn, CH2 I2 ,02, PhH, 0°C, 30 min.OH (58)	(67)As reported by Marais 20,26 c in a related reaction, longerreaction times gave poor yields of (67) and an unwanted sidereaction, possibly involving cyclopropanation of the allyl groupdouble bond. Additionally, in our hands, quenching of the reaction3 3mixture with the usual aqueous NH4C1-NH4OH (pH 8) provided thedesired product (67) and another compound (87) in the ratio of 1:6.Evidence for the structure of compound (87) came from theabsence50 of the hydroxyl and cyclopropane groups as indicated byits it and 400 MHz 1 H nmr spectra. The multiplet in the region 82.50-2.72, integrating for two protons, is attributable to the allylic(87)protons of the newly generated side chain. The two CH2I protons areobservable in the region 8 3.01-3.19 as a multiplet and are coupledto the adjacent protons as indicated in a COSY experiment. All otherresonances are as expected. The CI mass spectrum revealed peaksand their fragments as follows: 358 (M+, 1.6%), 317 (M+-allyl,80.8%), 316 (M+-42, 78.9%), 231 (M+-I, 10.4%), 189 [M+-(I + ally!),100%].With some experimentation on the method of quenching thereaction mixture, it was found that the use of a 0.1 M aqueous34solution of sodium thiosulphate effectively eliminated the by-product (87) formation.The next steps of the planned syntheses were to involvehydroboration of the double bond of (67), hydrogenolysis of thecyclopropane ring into a gem-dimethyl moiety and oxidation of theprimary alcohol group into an aldehyde (90). These conversionswere to be followed by reaction of the aldehyde with methyllithiumand the oxidation of the intermediate secondary alcohol (91) toprovide (56), our targeted Wadsworth-Emmons-Horner substrate(scheme 15).(OH 	 OH./)H	":      OH        (67)	(88)	(89)OH	OH	z OH(56)	(91)	(90)Scheme 1535Hence, treatment of (67) with 2.0 equivalents of 9-BBN in THEgave an organoborane intermediate. Unfortunately, during theoxidative work-up, 51 all the solvent was lost from the reactionmixture, leaving an intractable (gummy) material. All attempts toisolate the desired product (88) proved futile.It was at this stage of the synthesis that Jacques Robergegenerously supplied a quantity of the vinyl iodide (5 3) . Thesynthetic pathway (54 42-44) outlined on page 19became more appealing compared to the one in Scheme 15. Thepreparation of the compound (55) therefore became mandatory.This could, in theory, be conveniently accessed via a sequence ofreactions involving initially the reductive cleavage of the ozonideintermediate derived from (67) , 52 followed by reduction53 of thealdehyde (92) to produce the diol (93). 54It was to the double bond in (67) that attention was directed(scheme 16). Ozonolysis52 of this double bond generated an ozonidewhich was cleaved by dimethyl sulphide into the aldehyde (92).The crude aldehyde was then reduced with sodium boronhydride togive the diol (93) in 52% yield.That the expected product was formed was shown by thepresence of a two-proton multiplet in the region 8 3.54-3.73 of the1 H nmr spectrum of (93). These signals can be attributed to theC H20H protons. Other proton signals in the 400 MHz 1 H nmrspectrum are as expected.)H	s-(93)OH): OH(55)H2 (1.0 atm.), Pt02AcOH, r.t., 90 min.36(1)03, Me0H, -78°C(2)Me2S, r.t.(67) (92)NaBH4,CH2Cl2 / EtOH (1:1),0°C(93)Scheme 1616Hydrogenolysis of the cyclopropane ring55 of the diol (93) w asachieved by the use of H2 (1.0 atm),56 Pt02, and dry acetic acid atroom temperature for 90 min to yield (55), (60%).3 7This compound exhibited spectral properties identical withthose of the same compound prepared by Marais 2 0,26c as anintermediate towards the total synthesis of ambliol B. In particular,its it (CDC13) spectrum exhibited 0-H absorption in the region 3690-3609 cm -1 . The 1 H nmr (400 MHz, CDC13) spectrum indicated thefour methyl groups at 6 0.85, 0.86, 0.95 (s, s, s, 3H each) for thetertiary ones and 0.87 (d, 3H, J = 7 Hz) for the secondary one. Thetwo protons attached to the oxygen atom have chemical shift valuesin the region 8 3.55-3.70 (m), confirming the primary nature of thealcohol.Due to time constraints, the total synthesis of the naturalproducts, agelasimines A and B and their 9-methyl quartenarypurino derivative, could not be fully carried out. However, the stagehad been rightly set towards the achievement of such a goal.2.2 ConclusionThe bifunctional conjunctive reagents, the lower order cuprate(19) 26c and the a-methylene ketone (94),20,26c,31,32,44 are novelreagents employed in the total synthesis of natural products.5Me3Ge,irCu(CN)Li	0(19)	 (94)I)Ti—‹H -/L(53): OH(42 - 44)  +   : OH(54)3 8During our synthetic studies towards the total synthesis of theagelasimines (42-44), (19) was combined stereoselectively with(94, R = allyl) to produce the trans-fused bicyclic intermediate (58).This compound has the four contiguous stereocentres present in theagelasimines (42-44). A series of transformations gave the knowndiol (55),20,26c a possible precursor to the target natural products.iu 7OH(55)(58)It was anticipated that the diol (55) would be transformed intothe iodide (54) which upon palladium(0)-catalyzed coupling with thevinyl iodide, followed by appropriate transformations would producethe agelasimines (42 - 44),where X is defined as39N,11,.N R"IX = (42; R I = NMe, R H = H)= (44; R i = 0, 	 R H = Me:X = (43)4 0III	 EXPERIMENTAL3.1. 0	 General Procedure, Solvents and ReagentsProton nuclear magnetic resonance ( 1 H nmr) spectra wereobtained on deuteriochloroform solutions (unless stated otherwise)using a Varian XL-300 or Bruker models AC-200E or WH-400spectrometers. Signal positions are given in parts per million (6)from tetramethylsilane (TMS) as the internal standard. For thosecompounds containing trimethylstannyl, trimethylgermyl and/ortrimethylsilyl group, the resonance positions were determinedrelative to the deuteriochloroform signal (8 7.25).57 Couplingconstants (f-values) are reported in Hz and were measured onspectral spacings judged to be first order. 58 The spectra listed followthe order: chemical shift (ppm); (multiplicity, number of protons,assignment (where possible), coupling constants (Hz)). The tin-proton coupling constants Cis n-H) are given as an average of the117Sn and 119 Sn values.Carbon nuclear magnetic resonance ( 13 C nmr) spectra wererecorded on a Varian model XL-300 spectrometer at 75.3 MHz or onBruker models AC-200E at 50.3 MHz or WH-400 at 100.6 MHz, usingdeuteriochloroform as the solvent. Signal positions are given in partsper million (8) relative to the deuteriochloroform signal (8 77.0). 5 9Signals with negative intensities in an attached proton test (APT) areso indicated in brackets (-ve) following the chemical shift.4 1Infrared (ir) spectra were obtained on liquid films (neat,sodium chloride plates), chloroform solutions (0.1 mm sodiumchloride cells) or potassium bromide discs, employing a Perkin-Elmermodel 1710 Fourier transform IR spectrophotometer (internalcalibration), a Perkin-Elmer model 7108 spectrophotometercalibrated using the 1601 cm-1 band of a polystyrene film or aBomem Michelson 100 FT-IR spectrometer using internal calibration.Peak intensities are indicated by the following letters: vs = verystrong, s = strong, m = medium and w = weak.Low resolution and high resolution mass spectra were recordedwith a Kratos MS 50/DS 55 SM, and low resolution one with AEIM59/DS 55 SM, 70 eV, employing electron ionization (EI). Thedesorption chemical ionisation (DCI) spectra were recorded with aDelsi Nermag R10-10C and 10B mass spectrometer. The DCI data aregenerally accompanied by a chromatogram-like page which is theevaporation profile of the sample during heating of the DCI filament.All compounds which were subjected to high resolution massmeasurements were homogeneous by glc and/or tic analysis.For those compounds containing trimethylstannyl ortrimethylgermyl groups, the high resolution mass spectrometrymolecular weight determinations were based on 120 5n or 74 G erespectively and were made on the (M+-Me) peak. 60 Determinationsfor compounds containing tributylstannyl groups were made on the(M+-Bu) peak.604 2Microanalyses were performed in the MicroanalyticalLaboratory, University of British Columbia using a Carlos ErbaElemental Analyser 1106.Analytical gas-liquid chromatography (glc) analyses wereperformed on either a Hewlett-Packard model 5880 or a 5890capillary gas chromatograph, employing 25 m x 0.21 mm fused silicacolumns coated with cross-lined SE-54, both using flame ionizationdetectors.Thin-layer chromatography (tic) was performed oncommercially available aluminium backed sheets, precoated withsilica gel 60 to a thickness of 0.2 mm (E. Merck, type 5554).Visualization of the chromatogram was accomplished using one ormore of the following techniques: (a) ultraviolet light (254 nm tube);(b) iodine vapour stain; (c) heating with a hot gun a chromatogramthat had been stained with (i) a 5% aqueous solution of ammoniummolybdate in 10% aqueous sulfuric acid (w/v) or (ii) a 5% solution ofanisaldehyde in 95% ethanol that had been acidified with 5 ml conc.sulphuric acid or (iii) a 7% ethanol solution of vanillin that had beenacidified with 18.4 ml of 40% aqueous sulphuric acid (w/v).Conventional column (drip) chromatography, medium pressurechromatography, and flash chromatography, 61 as well as separationswith radial chromatography on Harrison ChromatotronTM models7924T and 7924C were done with 230-400 mesh silica gel (E. Merck,silica gel 60 PF-254 with calcium sulphate).4 3Distillation temperatures (uncorrected) were recorded as air-bath temperatures required for short path bulb-to-bulb (Kugelrohr)distillations.Melting points were measured on a Fisher-Johns melting pointapparatus and are uncorrected.All pure and dry solvents and reagents were obtained by usingestablished procedures. 62 Diethyl ether and tetrahydrofuran weredried with and distilled from sodium benzophenone ketyl.Dichloromethane and carbon tetrachloride were dried over anddistilled from phosphorus pentoxide. Diisopropylamine,hexamethylphosphoramide, triethylamine, benzene, trimethylsilylchloride and trimethylsilyl bromide were dried over and distilledfrom calcium hydride. The petroleum ether used was the fractionwith boiling point between 35-60°C .Hexamethylditin was obtained from Organometallics, Inc. andwas used without further purification unless coloured, in which caseit was distilled under aspirator vacuum (bp approximately 80°C )prior to use.Solutions of methyllithium in diethyl ether, n -butyllithium inhexane and t-butyllithium in pentane were obtained from theAldrich Chemical Co., Inc. and were standardized using the method ofKofron and Baclawski 63 and Suffert. 64 Solutions of potassium t-4 4butoxide in tetrahydrofuran and diethylzinc in toluene were alsoobtained from Aldrich Chemical Co., Inc.Cuprous bromide-dimethyl sulfide complex was prepared bythe method of House65 and Townsend.66 Old stocks of this materialwere purified by the method of Wuts 67 after they had been washedwith methanol.Commercially available dimethyl(methylene)ammonium iodide(Eschenmoser's salt)42 was recrystallized from tetramethylenesulphone and dried under vacuum (vacuum pump) at 50°C beforeuse.Aqueous NH4C1-NH4OH (pH 8) was prepared by the addition of100 ml of aqueous ammonium hydroxide (29-30%) to .1 L ofsaturated aqueous ammonium chloride.Lithium diisopropylamide (LDA) was prepared by the additionof a solution of methyllithium in ether (1.0 equivalent) to a solutionof diisopropylamine (1.6 equivalents) in dry THE at -78°C. Theresulting solution was stirred at 0°C for 10 mins before use.All other reagents and solvents were commercially availableand were utilized without purification unless otherwise stated.Cold bath temperatures were obtained by using the followingcombination of solvents and coolants68 : 27 g CaC12/100 ml H2O/dry4 5ice (-200C), 39 g CaC12/100 ml H20/dry ice (-350C), acetone-dry ice(-78°C) and methanol-liquid N2 (-98°C).Unless otherwise stated, all reactions were carried out under anatmosphere of dry argon using glassware that had been oven driedovernight or thoroughly flame-dried.4 6	3.2.0	 Experimental Procedure	3.2.1	 Synthetic Studies on Agelasimines.	 Experimental.Preparation of 3.4-dimethy1-2-cyclohexen- 1 -one (63). )o-3,4-Dimethylanisole (10.08 g, 73.5 mmol), dissolved in absoluteethano1 34a (50 mL), was added to cold (-78°C) liquid ammonia (250mL, freshly distilled over sodium). Lithium (3.0 g, 432 mmol) wasadded in small pieces and the blue solution was stirred for 2 h34b at-78 0C. Ammonium chloride (13 g, 243 mmol) was added carefully insmall portions and the mixture was left at ambient temperature untilall the ammonia had evaporated. Water (100 mL) was added to theresidue and the aqueous phase was extracted with Et20 (50 x 3 mL).Due to the very high volatility of the intermediate 4,5-dimethyl- 1 -methox y-1,4-cyclohexadiene, 34c solvent removal was carefully andpartially done (rotary evaporator, 35 0C). The residual solution wastreated with 50% hydrochloric acid (100 mL) and the resultantmixture was refluxed for 45 min.34d The mixture was cooled to roomtemperature, extracted with ether (3 x 50 mL), washed with brine (2x 20 mL), dried (MgSO4) and the solvent removed (rotaryevaporator). The residual oil was purified by flash chromatography4 7(300 g silica gel, elution with 70:30 hexanes-diethyl ether) anddistilled (air-bath temperature 90-95 0C/11 torr) as a colourless oil togive 7.43 g (81%) of the enone (63); it (neat): 2966 (m), 1674 (vs),1627 (m), 1255 (m), 861 (w) cm -1 ; 1 H nmr (400 MHz, CDC13) 8: 1.15(d, 3H, secondary Me, J. 8 Hz), 1.65-1.77 (m, 1H), 1.90 (s, 3H, Me),2.01-2.12 (m, 1H), 2.20-2.31 (m, 1H), 2.32-2.48 (m, 2H), 5.78 (br s,1H, Ha); 13C nmr (50 MHz, CDC13) 8: 17.7(-), 22.7(-), 30.3, 34.3(-), 34.5,126.3(-), 166.5, 204.1.Preparation of 1-Ally1-3.4-dimethy1-2-cyclohexen-l-ol (68)Hd OHTo a cold (-78 0C), stirred solution of allylmagnesium bromide(0.75 mL of a 1.0 M solution in THF, 1.5 equiv) in dry THF (2.2 mL)was added copper(I) bromide-dimethyl sulfide (5.2 mg, 5 mole %)and dry HMPA (0.21 mL, 2.4 equiv). 30a-f To this mixture was added,dropwise over 10 min, a solution of 3,4-dimethy1-2-cyclohexen-1-one (63, 61.4 mg, 1 equiv) and trimethylsilyl chloride (0.13 mL, 2.0equiv) in dry THF (0.4 mL). The reaction mixture turned orangeduring this addition. Stirring was continued for 4 h at -78 0 C. Drytriethylamine (0.14 mL, 2.03 equiv) and hexanes (2.0 mL) wereadded sequentially. The reaction mixture was allowed to warm toroom temperature and was poured into water (3.0 mL). The layerswere separated and the organic phase was washed with water (54 8mL). The organic solution was dried (MgSO4) and the solvent wasevaporated to give after flash chromatography (3.0 g silica gel,CH2C12, 0.5% Et3N), 68.4 mg (83%) of (68) as a colourless oil; it (neat):3366 (s), 3075 (m), 2935 (vs), 1665 (w),	 1640 (m),	 1439 (s),	 1377(m), 1131 (m), 989 (s),	 913	 (s), 845 (m) cm -1 ; 1 H nmr (400 MHz,CDC13) 8: 1.04 (d, 3H, secondary Me, J = 8 Hz), 1.35-1.90 (m, 4H), 1.69(s, 3H, Me), 1.52 (s, 1H, OH), 1.95-2.15 (m, 111), 2.26 (d, 2H, allylicCH2, J = 7 Hz), 5.05-5.15 (m, 2H, Hb and He), 5.31 (br s, 1H, Ha) 5.79-5.95 (m, 1H, Hd); 13 C nmr (50 MHz, CDC13) 6: 19.0(-), 21.5(-), 28.4,34.0(-), 34.3, 46.9, 69.9, 118.4, 127.3(-), 134.0(-), 142.2; Exact Masscalcd for Cii11180: 166.1357; found: 166.1352.Preparation of 3-allyl-cis-3.4-dimethyl-l-trimethylsiloxycyclo-hexene (6 2) H 	 HbAHdTo a cold (-780C), stirred solution of allylmagnesium bromide(15 mL of a 1.0 M solution in THF, 1.5 equiv) in dry THF (44 mL) wasadded copper(I) bromide-dimethyl sulphide (2.08 gm, 1.0 equiv). 3 9After the mixture had been stirred for 30 min, dry HMPA (4.2 mL,2.4 equiv) was added and the mixture stirred for 10 min. A solution4 9of 3,4-dimethy1-2-cyclohexen-l-one (63) (1.23 g, 1 equiv) andtrimethylsilyl chloride (2.56 mL, 2.0 equiv) in dry THE (8 mL) wasadded dropwise, over 10 min, to the mixture, during which time itturned deep red. Stirring was continued for 2 h at -78°C. Drytriethylamine (2.8 mL, 2.03 equiv) and hexanes (40 mL) weresuccessively added. The reaction mixture was allowed to warm toroom temperature and then was poured into cold water (0°C, 60 mL).After separating the layers, the organic phase was washed with coldwater (2 x 30 mL), dried (MgSO4) and concentrated. Flashchromatography (75 g silica gel CH2C12, 0.5% Et3N), 40 followed bydistillation (130-145 0 C/11 torr), provided 1.636 g (69%) of the silylenol ether (62) as a colourless oil; it (neat): 3076 (w), 2961 (s),1668 (s), 1641 (m), 1252 (vs), 1207 (s), 910 (s), 844 (vs) cm -1 ; 1 Hnmr (400 MHz, CDC13) 8: 0.15 (s, 9H, SiMe3), 0.80 (s, 3H, tertiary Me),0.82 (d, 3H, secondary Me, J = 7 Hz), 1.40-1.65 (m, 3H), 1.75-2.15 (m,4H), 4.65 (br s, 1H, Ha), 4.92-5.05 (m, 2H, Hb and He), 5.68-5.84 (m,1H, Hd); 13 C nmr (50 MHz, CDC13) 8: 0.0 (-), 14.9 (-), 22.3 (-), 27.2,29.4, 34.0 (-), 37.3, 45.7, 114.3 (-), 116.2, 135.7 (-), 149.2; Exact masscalcd for C14H260Si: 238.1753; found: 238.1752.H bsy HaA He0)x(70)5 0A second compound isolated (135 mg) alongside the desiredproduct was distilled (air-bath temp., 120-130 0 C/11 torr) andanalyzed for a hydrolysis product of the silyl enol ether (63). Thiswas characterized as 3-allyl-3,4-dimethylcyclohexanone (70); it(neat): 2963 (vs), 1714 (vs), 1640 (w), 1458 (m), 1244 (s), 916 (s)cm- 1 ; 1 H nmr (400 MHz, CDC13) 8: 0.71 (s, 3H, tertiary Me), 0.88 (d,3H, secondary Me, J = 8 Hz), 1.49-1.63 (m, 1H), 1.70-1.85 (m, 2H),1.86-2.00 (m, 2H), 2.03-2.15 (m, 1H), 2.19-2.35 (m, 3H), 4.94-5.10(m, 2H, Ha and Hb), 5.68-5.81 (m, 1H, He); 13 C nmr (100 MHz, CDC13) 8:14.7 (-), 18.8 (-), 30.5, 36.4 (-), 38.4, 39.9, 40.7, 45.6, 51.2, 52.2,118.2, 133.5 (-), 212.1; Exact mass calc'd for C1111180: 166.1358; C,79.47; H, 10.91; found: 166.1361; C, 78.80; H, 10.80.Preparation of 3-ally1-2-(Dimethylamino)methyl-cis-3.4-dimethyl-cyclohexanone (61) (CH3)2To a cold (00 C), stirred solution of the silyl enol ether (62)(325.1 mg, 1.37 mmol) in dry THE (6 mL) was added a solution ofmethyllithium in diethyl ether (1.1 mL, 1.4M, 1.1 equiv). Afterallowing the reaction mixture to warm to room temperature, it was5 1stirred for 1 h. The solution of lithium enolate41 so-formed wascooled (-78°C) and added via cannulation to a rapidly stirred, cold(-78°C) slurry of dimethyl(methylene)ammonium iodide, (74, 505mg, 2 equiv)42 in dry THE (9 mL).31,32,44 After allowing the reactionmixture to warm to room temperature, stirring was continued for 2.5h. Hydrochloric acid (1 N, 15 mL) and diethyl ether (10 mL) wereadded and the layers were separated. Thorough extraction of theorganic phase with 1 N hydrochloric acid and careful neutralizstion ofthe combined aqueous extracts with 5% sodium carbonate wasfollowed by CH2C12 (5 x 20 mL) extraction of the neutralized mixture.The combined extracts were washed with brine (20 mL). The layerswere separated and the organic phase was dried (MgSO4). Thesolvent was removed to give 291.1 mg (96%) of the crude keto amine(61) as a 2.2:1 mixture of epimers contaminated with thesubsequently desired elimination enone product (60) (16% by glc); it(neat): 3075 (w), 2966 (vs), 2821 (m), 2768 (m), 1715 (vs), 1639(w), 916 (m) cm-1 ; 1 H nmr (400 MHz, CDC13) 8: 0.54, 0.81 (s, s, ratio1:2.2, 3H, tertiary Me), 0.88, 0.92 (d, d, ratio 1:2.2, 3H, secondary Me,J = 8 Hz), 1.49-1.65 (m, 1H), 1.79-2.45 (m, 7H), 2.15, 2.20 (s, s, ratio2.2:1, 6H, NMe2), 2.50-2.63 (m, 1H), 2.85-3.04 (t, 1H, J = 12 Hz), 5.01-5.18 (m, 2H, Ha and Hb), 5.67-5.95 (m, 1H, H e ). The CI massspectrum gave prominent peaks at 224 (M+ + 1, 2.3%), 223 (M+,4.3%), 58 (100%). Because of its instability and the subsequentremoval of the epimeric stereocentre, this mixture was used withoutfurther purification in the next step.5 2Preparation of 3-allyl-cis-3.4-dimethy1-2-methylenecyclohexanoneLIUTo a solution of the keto amine (61) (1.46 g, 6.54 mmol) in dryCH2C12 (27.5 mL) was added m-chloroperoxybenzoic acid (3.39 g, 1.5equiv). 43 The reaction mixture was stirred for 20 min at 25 0 C andwas then filtered rapidly through a short column of silica gel, elutingwith 80:20 hexanes-diethyl ether. The solvent was removed fromthe combined eluate and the crude sample chromatographed on thechromatotron model 7924T (silica gel 60 PF - 254 with CaSO4, E.Merck). Concentration of the appropriate fractions, followed bydistillation (100-1200C/11 toff), afforded 989.6 mg (85%) of the a-methylene ketone (60) as a colourless oil; it (neat): 3076 (s), 1695(vs), 1640 (s), 1610 (s) cm-1 ; 1 H nmr (400 MHz, CDC13) 8: 0.97 (d, 3H,secondary Me, J = 7 Hz), 1.00 (s, 3H, tertiary Me), 1.59-1.70 (m, 1H),1.80-19.2 (m, 1H), 1.99-2.18 (m, 2H), 2.19-2.28 (m, 1H), 2.29-2.54(m, 2H), 4.99-5.10 (m, 2H, He and Hd), 5.15 (br s, 1H, Hb), 5.60-5.78(m, 1H, He), 5.84 (br s, 1H, Ha); 13 C nmr (50 MHz, CDC13) 8: 15.0 (-),22.0 (-), 26.4, 35.1, 37.1 (-), 43.9, 109.9, 117.8, 118.7, 133.8 (-),5 3153.1, 203.7; Exact mass calcd for C1211180: 178.1357; found:178.1361.A minor compound of higher retention time on glc was alsoisolated and analyzed to be the isomeric a-methylene ketone (76); it(neat): 2927 (vs), 1759 (vs), 1646 (vs), 1575 (w), 1527 (w), 1462 (s),1379 (s), 1254 (s), 1132 (s), 997 (s), 917 (s) cm -1 ; 1 H nmr (400 MHz,CDC13) 8: 0.94 (d, 3H, secondary Me, J = 8 Hz), 0.98 (s, 3H, tertiaryMe), 1.5-1.61 (m, 1H), 1.71-1.92 (m, 2H), 2.04-2.15 (m, 1H), 2.31-2.48 (m, 2H), 2.65-2.79 (m, 1H), 4.76 (br s, 1H Hb), 4.97 (br s, 1H, Ha),4.99-5.10 (m, 2H, He and Hd), 5.65-5.80 (m, 1H, He).Preparation of lithium	 (3-trimethylgermyl-3-butenyl)(cyano) cuprate (1 9) Me3GeNreCu(CN)Li5 4To a cold (-98°C), rapidly stirred solution of freshly distilled 4-iodo-2-trimethylgermy1-1-butene (77) (318 mg, 1.07 mmol) in dryTHF (13.3 mL, 0.05 M) was rapidly added a solution of tert-butyllithium in pentane (1.21 mL, 1.72 M, 1.95 equiv). The resultingyellow and cloudy solution was stirred at -98°C for 10 min and wasthen warmed to -78°C. Copper(I) cyanide (104.9 mg, 1.1 equiv) wasadded and the so-formed yellowish suspension was stirred at -78°Cfor 5 min. Brief warming of the reaction mixture to -35°C provided aclear pale tan solution of the lower order vinylgermane cuprate (19),which was recooled to -78°C and used immediately.Preparation of (2S*. 3R*, 4S*)-3-ally1-3J—dimethy1-2-(4-trimethyl-germy1-4-pentenyl)cyclohexanone (80) Ha;(He(CH3)3GeHdTo a cold (-780C), stirred solution of the cuprate reagent (19)(1.6 equiv, prepared as described above) in dry THF (26.5 mL,0.05M) was added, dropwise and successively, trimethylsilylbromide (597 mg, 3 equiv) and a solution of 3-allyl-cis- 3 , 4 -dimethy1-2-methylenecyclohexanone (60) (236.2 mg, 1.0 equiv) inHb5 5dry THF (1 mL). The so-formed orange solution was stirred at -78 0 Cfor 2 h. Water (2 mL) was added and the reaction mixture wasallowed to warm to room temperature (30 min). Aqueous NH4C1-NH4OH (pH 8, 10 mL) and diethyl ether (10 mL) were added and themixture was stirred open to the atmosphere overnight. The layerswere separated and the aqueous phase was extracted thoroughlywith diethyl ether. The combined extracts were dried (MgSO4) andthe solvent removed to give 377.9 mg (78%) of the ketovinylgermane (79) that consisted of a 1:2.5 mixture of epimers at C-2, as determined by glc. This mixture was epimerized usingpotassium tert-butoxide (0.33 mL, 1.0 M, 0.5 equiv)53 a in THF. Flashchromatography (20 g silica gel, CC14-CH2C12 1:1.5) and thendistillation (160-180 0 C/1.0 torr) of the crude oil gave 241.3 mg(50%) of a single product (80); it (neat): 2968 (vs), 1713 (vs), 1639(w), 916 (w), 825 (m), 740 (m), 600 (m) cm-1 ; 1 H nmr (400 MHz,CDC13) 8: 0.18 (s, 9H, -GeMe3), 0.55 (s, 3H, tertiary Me), 0.89 (d, 3H,secondary Me, J = 8 Hz), 1.01-1.15 (m, 1H), 1.18 (m, 1H), 1.40-1.64(m, 2H), 1.65-1.78 (m, 1H), 1.79-1.88 (m, 1H), 1.89-2.20 (m, 1H),2.05-2.21 (m, 4H), 2.21-2.39 (m, 3H), 5.02-5.18 (m, 3H, Ha , Hb andH e ), 5.47 (m, 1H, Hd),45b 5.73-5.88 (m, 1H, He); 13 C nmr (50 MHz,CDC13) 8: -1.9 (-), 15.3 (-), 22.5, 28.3, 31.8, 36.4 (-), 37.6, 41.1, 42.5,45.4, 56.8 (-), 102.9, 118.3, 121.1, 133.6, 144.1, 212.2; Exact masscalcd for C18H310Ge (M+): 337.1587; found: 337.1585.Preparation of (2S*. 3R*. 4S*)-3-ally1-3.4-dimethy1-2-(4-iodo-4- pentenyl)cyclohexanone (59) 5 6HaHb_ 	 HeHX.HdTo a solution of the keto vinylgermane (80) (257 mg, 0.73mmol) in dry CH2C12 (14.6 mL) was added a solution of iodine in drydichloromethane (20.3 mL of a 0.04 M solution, 0.81 mmol) and theresulting deep red solution was stirred at room temperarure for 20h.45a Aqueous sodium thiosulphate (0.1 M, 14.64 mL, 1.46 mmol)was added and the organic layer was separated. The aqueous phasewas extracted with CH2C12 and the combined extracts were dried(Na2SO4). Solvent removal provided the crude keto vinyl iodide (59)(240.9 mg, 91%), homogeneous by tic and glc analyses. This wasfiltered (15 g silica gel, CH2C12) and the solvent removed (rotaryevaporator) to give pure (59) as a colourless oil (198.4 mg, 75%); it(neat): 3074 (w), 2962 (s), 1712 (vs), 1638 (w), 1617 (m), 893 (m)cm -1 ; 1 H nmr (400 MHz, CDC13) 8: 0.56 (s, 3H, tertiary Me), 0.90 (d,311, secondary Me, J = 8 Hz), 1.15-1.35 (m, 3H), 1.48-1.75 (m, 3H),1.80-1.90 (m, 1H), 1.90-2.02 (m, 1H), 2.12 (d, 2H, J. 9 Hz), 2.22-2.50(m, 411), 5.09-5.20 (m, 2H, Ha and Hb), 5.67 (m, 1H, H e ), 5.75-5.90 (m,111, He ), 6.02 (m, 111, Hd); 13 C nmr (50 MHz, CDC13) 8: 1.0 (-), 15.3 (-),21.3, 28.4, 31.7, 36.3 (-), 41.0, 42.5, 45.5, 45.8, 56.7 (-) ,112.4, 118.6,5 7125.4, 133.4 (-), 212.2; Exact mass calcd for C16H2501: 360.0952;found: 360.0951.Preparation of the trans-fused Bicyclo Allylic Alcohol (58)To a cold (-780C), stired solution of the keto vinyl iodide (59)(60 mg, 0.17 mmol) in dry THE (10 mL) was added a solution of n-butyllithium in hexane (0.25 mL, 1.6 M, 2.4 equiv). 46 The reactionmixture was stirred at -78 0 C for 15 min and water (4 mL) wasadded. The reaction mixture was allowed to warm to roomtemperature, and diethyl ether (15 mL) was added. The layers wereseparated and the aqueous phase was extracted several times withdiethyl ether. The combined extracts were dried (MgSO4), thesolvent was removed and the resulting oil distilled (145-160°C/1.0torr) to give 33.8 mg (87%) of the desired trans-fused allylic alcohol(58); it (neat): 3426 (m), 3075 (w), 2931 (vs), 1639 (m), 912 (s)cm -1 ; 1 H nmr (400 MHz, CDC13) 8: 0.80-1.10 (m, 2H). 0.85 (d, 3H,secondary Me, J = 8 Hz), 0.88 (s, 3H, tertiary Me), 1.14-1.80 (m, 8H),5 81.85 (m, 1H, possibly Hf or Hg) 1.96-2.20 (m, 3H, allylic CH2 protons,and Hg or Hf), 2.49 (m, 1H), 4.65 (br s, 1H, H e ), 4.73 (br s, 1H, Hd) ,4.90-5.05 (m, 2H, Ha and Hb), 5.62-5.75 (m, 1H, He ); 13 C nmr (50MHz, CDC13) 8: 15.9 (-), 17.1 (-), 21.6, 26.5, 27.9, 32.7, 36.4, 36.8 (-),40.1, 41.7, 48.6 (-), 73.6 (OH), 105.8, 116.9, 134.8 (-), 155.1.Preparation of the Cyclopropane (67)  HeHd"To a stirred solution of the allylic alcohol (58) (21.6 mg, 0.09mmol) in dry benzene (1 mL) at 25 0 C was added a solution ofdiethylzinc in toluene (0.24 mL, 1.1 M, 2.4 equiv). 4 7 Drydiiodomethane (22 'IL, 3.0 equiv) was added dropwise, and thereaction mixture cooled to 0 0C. After turning off the argon flow, dryoxygen was introduced into the space above the reaction mixturethrough a septum cap by means of an oxygen filled baloon containinga hypodermic needle as an outlet. Stirring was continued under theoxygen atmosphere at 0 0 C for 30 min.49 An aqueous solution ofsodium thiosulphate (0.1 M, 2 mL) and benzene (5 mL) was addedand the reaction mixture was allowed to warm to room temperature.5 9The layers were separated and the aqueous phase was extractedthoroughly with benzene. The combined extracts were dried (MgSO4)and the solvent was removed. The remaining crude oil was flashchromatographed (1.0 g silica gel, pet. ether-diethyl ether 95:5) togive 20.5 mg (90%) of the cyclopropane (67) as a colourless oil; it(neat): 3599 (w), 3514 (w), 3075 (m), 3001 (m), 2926 (vs), 1637(w), 911 (s) cm -1 ; 1 11 nmr (400 MHz, CDC13) 8: 0.00-0.10, 0.15-0.24(m, m, 11-1 each, protons on cyclopropane ring). 0.48-0.58 [m, 2H, one(or two) proton(s) on the cyclopropane ring, one proton un-assigned],0.60-0.69 (m, 1H, proton on cyclopropane ring). 0.78-0.90 (d, partlysuperimposed by s, 6H, secondary and tertiary Me groups), 1.11-1.45(m, 7H), 1.5-1.75 (m, 4H), 1.95-2.25 (m, 3H, Hg and allylic CH2protons), 4.95-5.05 (m, 211, Ha and Hb), 5.68-5.84 (m, 111, He).Preparation of the Cyclopropane Diol (93)HHaHHH bo 1Ozone was bubbled through a cold (-78°C), stirred solution ofthe alkene (67) (33.8 mg, 0.14 mmol) in methanol (7.0 mL) 52 a untila blue colour developed. 52b The solution was allowed to stand at60-78°C for 5 min. The excess ozone was removed by passing a streamof argon through the reaction mixture. Dimethyl sulfide (0.28 mL)was added and the colourless solution was warmed to roomtemperature. Stirring was continued for 2 h. The solution wasconcentrated under reduced pressure. The crude aldehyde soformed was redissolved in CH2C12 (10 mL) and absolute ethanol (10mL). This solution was cooled to 0°C and then was treated withNaB H4 (21.37 mg, 4.14 equiv).53 The mixture was stirred at 0°C for30 min, after which ether (40 mL) was added and the mixture wasfiltered through a plug of silica gel. The filtrate was concentratedand the residue was chromatographed on the chromatotron model7924C (hexanes-diethyl ether 3:1) to give 17.9 mg (52%) of the diol(93) as a colourless oil; 1 H nmr (400 MHz, CDC13) 8: 0.00-0.06, 0.18-0.26 (m, m, 11-1 each, protons on cyclopropane ring). 0.47-0.58[m, 2H,one (or two) cyclopropane ring proton(s), the other not assigned],0.59-0.72 (m, 1H, cyclopropane ring proton). 0.75-1.80 (m, 1411), 0.85(partly obscurred d, 3H, secondary Me, J = 7 Hz), 0.86 (s, 3H, tertiaryMe), 2.19 (m, 1H), 3.54-3.73 (m, 2H, Ha).Preparation of the Diol (55) OH6 1To a solution of the cyclopropane diol (93) (17.9 mg, 0.07mmol) in dry acetic acid (1.5 mL) was added platinum (IV) oxide(Adam's catalyst, -10 mole %).55 The reaction mixture was stirredfor 2 h, under an atmosphere of hydrogen (1.0 atmosphere), andthen slowly and cautiously neutralized with a cold (0°C), stirred,saturated aqueous solution of NaHCO3 (20 mL). After adding diethylether (10 mL), the layers were separated and the aqueous phasethoroughly extracted with diethyl ether. The combined extractswere dried (MgSO4) and the solvent removed to give a crude productwhich was flash chromatographed (1.0 g silica gel, hexanes-diethylether, 7:3). The product, (55) (60%), exhibited the followingcharacteristics: it (CDC13 soln): 3690 (w), 3609 (w), 2839 (vs), 1602(m), 1460 (w), 1147 (m) cm -1 ; 1 H nmr (400 MHz, CDC13) 5: 0.85, 0.86(s, s, 31-1 each, tertiary Me groups), 0.87 (d, partly obscurred, 3H,secondary Me, J = 7 Hz), 0.95 (s, 3H, tertiary Me), 1.02-1.80 (m, 16H),3.55-3.70 (m, 2H, H a ). This substance was found to bespectroscopically identical with the same compound preparedpreviously in our laboratory via a related synthetic sequence.26c6 2I V REFERENCES1. E. Piers and V. Karunaratne, J. Org. Chem., (1983), 48, 1774.2. D. Seebach and P. Knochel, Hely. Chim. Acta., (1984), 67, 261.3. 	 D. Seebach, Angew. Chem., Int. Ed. Engl., (1979), 18, 239.4a. E. Piers and V. Karunaratne, Can. J. Chem., (1983), 62, 629.4b. E. Piers and V. Karunaratne, Tetrahedron Lett., (1989), 45,10894c. G. Mehta, D.S. Reddy and A.N. Murty, J. Chem. Soc., Chem.Commun., (1983), 824.5. E. Piers and V. Karunaratne, J. Chem. Soc., Chem. Commun.,(1984), 959.6. E. Piers and B.W.A. Yeung, Can. J. Chem., (1986), 64, 2475.7. 	 E. Piers and J. Renaud, Synthesis, (1992), 74.8a. B. Tursch, J.C. Braekman, D. Daloze, P. Fritz, A. Kelecom, R.Karlsson and D. Losman, Tetrahedron Lett., (1974), 9, 747.8b. L.A. Paquette and W.H. Ham, Tetrahedron Lett., (1986), 27,2341.8c. LA. Paquette and W.H. Ham, J. Am. Chem. Soc., (1987), 109,3 0 25.9. H. Iio, M. Monden, K. Okada and T. Tokoroyama, J. Chem. Soc.,Chem. Commun., (1987), 358.10. L.A. Paquette, R.A. Galemmo, Jr., J.-C. Caille and R.S. Valpey, J.Org . Chem., (1986), 51, 686.11. K. Yamada, Y. Kyotani, S. Manabe and M. Suzuki, Tetrahedron,(1979), 35, 293.12. T. Sugimura and L.A. Paquette, J. Am. Chem. Soc., (1987), 109,3 0 1 7.6 313a. E. Piers and J.M. Chong, J. Chem. Soc., Chem. Commun., (1983),934.13b. E. Piers and J.M. Chong, Can. J. Chem., (1988), 66, 1425.14a. E. Piers, J.M. Chong and H.E. Morton, Tetrahedron Lett., (1981),22, 4905.14b. E. Piers, J.M. Chong and H.E. Morton, Can. J. Chem., (1986), 65,7 8 .15. E. Piers, J.M. Chong and H.E. Morton, J. Chem. Soc., Chem.Commun., (1983), 935.16. E. Piers and B.W.A. Yeung, J. Org. Chem., (1984), 49, 4569.17. J. Hooz and S.S.H. Gilani, Can. J. Chem., (1968), 46, 86.18a. E. Piers, R.W. Friesen and B.A. Keay, J. Chem. Soc., Chem.Commun., (1985), 809.18b. E. Piers, R.W. Friesen and B.A. Keay, Tetrahedron Lett., (1991),47, 4555.19. E. Piers and P.C. Marais, J. Org . Chem., (1990), 55, 3454.20. P.C. Marais, Ph.D. Thesis, University of British Columbia,Vancouver, B.C., 1990.21. E. Piers, J.M. Chong, K. Gustafson and R.J. Andersen, Can. J.Chem., (1984), 62, 1.22. Y.M. Sheikh, G. Singy, M. Kaisin, H. Eggert, C. Djerassi, B. Tursch,D. Daloze and J.C. Braekman, Tetrahedron, (1976), 32, 1171.23. J. Jakupovic, S. Banerjee, F. Bohlmann, R.M. King and H.Robinson, Tetrahedron, (1986), 42, 1305.24. R. Fathi-Afshar and T.M. Allen, Can. J. Chem., (1988), 66, 45.25. T. Nakatsu, D.J. Faulkner, G.K. Matsumoto and J. Clardy,Tetrahedron Lett., (1984), 25, 935.26a. R.P. Walker, R.M. Rosser, D.J. Faulkner, L.S. Bass, H. Cun-hengand J. Clardy, J. Org . Chem., (1984), 49, 5160.6426b. R.P. Walker and D.J. Faulkner, J. Org . Chem., (1981), 46, 1098.26c. E. Piers and P.C. Marais, J. Chem. Soc., Chem. Commun., (1989),1222.27. T. Tokoroyama, K. Fujimori, T. Shimizu, Y. Yamagiwa, M.Monden and H. Iio, Tetrahedron, (1988), 44, 6607.28. T. Tokoroyama, M. Tsukamoto, T. Asada and H. lio, TetrahedronLett., (1987), 28, 6645.29a. H.O. House and J.M. Wilkins, J. Org. Chem., (1978), 43, 2443.29b. D.L.J. Clive, V. Farina and P.L. Beaulieu, J. Org. Chem., (1982),4 7, 2572.29c. F.E. Ziegler, G.R. Reid, W.L. Studt and P.A. Wender, J. Org . Chem.,(1977), 42, 1991.29d. N.L. Allinger and C.K. Riew, Tetrahedron Lett., (1966), 12, 1269.29e. A. Alexakis, J. Berlan and Y. Besace, Tetrahedron Lett., (1986),27, 1047.29f. E.J. Corey and N.W. Boaz, Tetrahedron Lett., (1985), 26, 6015.29g. E.J. Corey and N.W. Boaz, Tetrahedron Lett., (1985), 26, 6019.2 9h. K. Maruoka, K. Nonoshita and H. Yamamoto, Tetrahedron Lett.,(1987), 28, 5723.29i. H.O. House and W.F. Fischer, Jr., J. Org . Chem., (1968), 33, 949.Foulon and J.F. Normant, Tetrahedron, (1981), 36,30a. C. Chuit, J.P.2305.30b. C. Chuit, J.P.1385.30c. Y. Horiguchi,Tetrahedron3 Od. Y. Horiguchi,TetrahedronFoulon and J.F. Normant, Tetrahedron, (1981), 37,S. Matsuzawa, E. Nakamura and I. Kuwajima,Lett., (1986), 27, 4025.S. Matsuzawa, E. Nakamura and I. Kuwajima,Lett., (1986), 27, 4029.6 530e. C.R. Johnson and T.J. Marren, Tetrahedron Lett., (1987), 28, 27.30f. R.J.K. Taylor, Synthesis, (1985), 364.3 la. S. Danishefsky, T. Kitahara, R. McKee and P.F. Schuda, J. Am.Chem. Soc., (1976), 98, 6715.3 lb. S. Danishefsky, M. Prisbylla and B. Lipisko, Tetrahedron Lett.,(1980), 21, 805.32a. S. Danishefsky, M. Kahn and M. Silvestri, Tetrahedron Lett.,(1982), 23, 703.32b. S. Danishefsky, S. Chackalamannil, P. Harrison, M. Silvestri andP. Cole, J. Am. Chem. Soc., (1985), 107, 2474.33a. E. Negishi, D.R. Swanson and C.J. Rousset, J. Org. Chem., (1990),55, 5406.33b. E. Negishi and Z. Owczarczyk, Tetrahedron Lett., (1991), 32,6683.34a. J. Roberge, M.Sc. Thesis, University of Sherbrooke, Montreal, PQ,February 1988, page 56.34b. H.O. House, R.W. Giese, K. Kronberger, J.P. Kaplan and J.F.Simeone, J. Am. Chem. Soc., (1970), 2800.34c. K. Mori and M. Matsui, Tetrahedron, (1968), 24, 3127.34d. A. Pons, J.-C. Milhavet and J.-P. Chapat, Bull. Soc., Chim. Fr.,(1979), 7 -8(Pt. 2), 381.34e. S.K. Malhotra, D.F. Moakley and F. Johnson, Tetrahedron Lett.,(1967), 12, 1089.35. W.G. Dauben, G.W. Shaffer and N.D. Vietmeyer, J. Org . Chem.,(1968), 33, 4060.36. H.O. House, T.S.B. Sayer and C.-C. Yau, J. Org . Chem., (1978), 43,2153.6 637a. T.L. Macdonald, K.J. Natalie, Jr., G. Prasad and J.S. Sawyer, J. Org .Chem., (1986), 51, 1124.37b. R. Uma, K. Rajagopalan and S. Swaminathan, Tetrahedron,(1986), 42, 2757.37c. D.A. Evans, D.J. Baillargeon and J.V. Nelson, J. Am. Chem. Soc.,(1978), 100, 2242.37d. S. Swaminathan, K.G. Srinivasan and P.S. Venkataramani,Tetrahedron., (1970), 26, 1453.38a. D.A. Evans and J.V. Nelson, J. Am. Chem. Soc., (1980), 102, 774.38b. J.A. Oplinger and L.A. Paquette, Tetrahedron Lett., (1987), 28,5441.38c. L.A. Paquette, J. Reagan, S.L. Schreiber and C.A. Teleha, J. Am.Chem. Soc., (1989), 111, 2331.3 8d. R.K. Boeckman, Jr., D.M. Springer and T.R. Alessi, J. Am. Chem.Soc., (1989), 111, 8284.38e. L.A. Paquette and Y..-J. Shi, J. Org. Chem., (1989), 54, 5205.38f. L.A. Paquette, Angew. Chem. Int. Ed. Engl., (1990), 29, 609.39a. H. Andringa, I. Oosterveld and L. Brandsma, Synth. Commun.,(1991), 21, 1393.39b. S.A. Bal, A. Marfat and Paul Helquist, J. Org. Chem., (1982), 47,5045.40. I. Fleming and I. Paterson, Synthesis, (1979), 736.41a. G. Stork and P.F. Hudrlik, J. Am. Chem. Chem., (1968), 90, 4462.41b. G. Stork and P.F. Hudrlik, J. Am. Chem. Chem., (1968), 90, 4464.42. J. Schreiber, H. Maag, N. Hashimoto and A. Eschenmoser, Angew.Chem. Int. Ed. Engl., (1971), 10, 330.43. N.N. Schwartz and J.H. Blumbergs, J. Org. Chem., (1964), 29,1976.  6 744a. S. Danishefsky, M. Kahn and M. Silvestri, Tetrahedron Lett.,(1982), 23, 1419.44b. N. Holy, R. Fowler, E. Burnett and R. Lorenz, Tetrahedron,(1979), 35, 613.44c. J.L. Roberts, P.S. Borromeo and C.D. Poulter, Tetrahedron Lett.,(1977), 19, 1621.45a. H. Oda, Y. Morizawa, K. Oshima and H. Nozaki, Tetrahedron Lett.,(1984), 25, 3217.45b. H. Oda, Y. Morizawa, K. Oshima and H. Nozaki, Tetrahedron Lett.,(1984), 25, 3221.46a. E. Piers and P.C. Marais, Tetrahedron Lett., (1988), 29, 4053.46b. E.J. Corey and I. Kuwajima, J. Am. Chem. Soc., (1970), 92, 395.47a. J. Furukawa, N. Kawabata and J. Nishimura, Tetrahedron,(1968), 24, 53.47b. R.C. Gadwood, R.M. Lett and J.E. Wissinger, J. Am. Chem. Soc.,(1984), 106, 3869.48. H.E. Simmons and R.D. Smith, J. Am. Chem. Soc., (1959), 81,4256.49. S. Miyano and H. Hashimoto, Bull. Chem. Soc. Japan, (1973), 46,892.50. H.N.C. Wong, M.-Y. Hon, C.-W. Tse, Y.-C. Yip, J. Tanko and T.Hudlicky, Chem. Rev., (1989), 89, 165.51. H.C. Brown, E.F. Knights and C.G. Scouten, J. Am. Chem. Soc.,(1974), 96, 7765.52a. J.H. Hutchinson and T. Money, Can. J. Chem., (1987), 65, 1.52b. C.H. Heathcock, T.A. Blumenkopf and K.M. Smith, J. Org . Chem.,(1989), 54, 1548.53a. K. Tomioka, F. Masumi, T. Yamashita and K. Koga, Tetrahedron,(1989), 45, 643.6 853b. S.-H. Chen, R.F. Horvath, J. Joglar, M.J. Fisher and S.J.Danishefsky, J. Org. Chem., (1991), 56, 5834.53c. J.A. Marshall and R.H. Ellison, J. Org. Chem., (1975), 40, 2070.54. M.J. Fisher, C.D. Myers, J. Joglar, S.-H. Chen and S.J. Danishefsky,J. Org . Chem., (1991), 56, 5826.55a. C.W. Woodworth, V. Buss and P.v.R. Schleyer, J. Chem. Soc.,Chem. Commun., (1968), 569.55b. W. Oppolzer and T. Godel, Hel. Chim, Acta, (1984), 67, 1154.5 6. B.D. Challand, H. Hikino, G. Kornis, G. Lange and P. de Mayo, J.Org . Chem., (1969), 34, 794.57. R.W. Silverstein, G.C. Bassler and T.C. Morril, in "SpectrometricIdentification of Organic Compounds", 4th Ed., John Wiley andSons Inc., New York, 1981, page 235.58. R.W. Silverstein, G.C. Bassler and T.C. Morril, in "SpectrometricIdentification of Organic Compounds", 4th Ed., John Wiley andSons Inc., New York, 1981, page 192.59. R.W. Silverstein, G.C. Bassler and T.C. Morril, in "SpectrometricIdentification of Organic Compounds", 4th Ed., John Wiley andSons Inc., New York, 1981, page 288.60. J.L. Occolowitz, Tetrahedron Lett., (1966), 43, 5291.61. W.C. Still, M. Kahn and A. Mitra, J. Org . Chem., (1978), 43, 2923.62. D.D. Perrin, W.L.F. Armarego and D.R. Perrin, "Purification ofLaboratory Chemicals", Pergamon Press, Oxford, 1980.63. W.G. Kofron and L.M. Baclawski, J. Org . Chem., (1976), 41, 1879.64. J. Suffert, J. Org . Chem., (1989), 54, 509.65. H.O. House, C.-Y. Chu, J.M. Wilkins and M.J. Umen, J. Org .Chem.(1975), 40, 1460.66. A.B. Thei and C.A. Townsend, Synth. Commun., (1981), 11, 157.67. P.G.M. Wuts, Synth. Commun., (1981), 11, 139.6 968a. W.P. Bryan and R.H. Byrne, J. Chem. Ed., (1970), 47, 361.68b. A.M. Philips and D.N. Hume, J. Chem. Ed., (1968), 45, 664.


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