INTRAMOLECULAR CYCLOADDITION STRATEGIES FOR
THE CONSTRUCTION OF POLYCYCLIC CYCLOPENTANOIDS
a thesis presented by
SORAB ANTONY BAPUJI
in partial fulfilment of the requirements
for the award of the degree of
DOCTOR OF PHILOSOPHY
OF THE
UNIVERSITY OF LONDON
BARTON LABORATORY
CHEMISTRY DEPARTMENT
IMPERIAL COLLEGE
LONDON SW72AY MAY 1989 Abstract
This thesis comprises three major sections.
Firstly, a review of the syntheses of triquinane sesquiterpenoids is presented.
Particular emphasis has been placed upon recent synthetic strategies and methodology
developed.
The second section outlines a synthetic strategy for construction of the p-isocomene
skeleton which features an intramolecular [jc2 s +ji2 s ] cycloaddition of an olefin and
an in situ generated ketene or keteniminium salt as the key step. Contemporaneous
model studies conducted while the precursor was in the assembly stage indicated that
such an approach was experimentally very demanding.
The third section deals with a fundamental study designed to achieve the equivalent of a
Diels-Alder type synthesis for five-membered rings and involves a novel
intramolecular application of the palladium (0) or nickel (0) catalysed [2te+2 cycloaddition of an olefinic or acetylenic component with a suitably constructed alkylidene cyclopropane. The nature of the metal and ancillary ligands on the catalyst and the resulting control of regiochemistry are discussed in terms of a probable mechanism for this reaction. Approaches towards the elaboration of the carbocyclic skeleton of p-isocomene using this methodology are discussed. » (i) Acknowledgements I would like to take this opportunity to thank my supervisor and friend, Dr. Willie Motherwell, for his relentless support, strong encouragement and kindness throughout the course of my work. I am indebted to the technical staff at Imperial College, who include John Bilton and Geoff Tucker for mass spectra, Ken Jones and his staff for microanalyses and Dr. Dick Sheppard for his advice and work on the high-field n.m.r. experiments. I would also like to thank my colleagues in the Barton, Whiffen and Perkin labs. - both past and present - for their help, friendship and knowledge. I am particularly grateful to my proof readers for their meticulous efforts: Dennis, Gavin, John, Matt, Andy, Mike, Dave and Rob. I wish to express a special thank you to Dr. Richard Lewis, who has given me much time and invaluable guidance. I am grateful to Prof. Steve Ley whose equipment I have frequently used. And lastly, thanks are also due to Prof. S. M. Roberts and Dr. P. Myers for their help throughout this research, and also to Glaxo for providing financial support. To my family, for their love and support. Abbreviations Ac - Acyl AIBN - Azobisisobutyronitrile aq- - aqueous IL-BuLi - a-Butyllithium I-B u L i - 1-Butyllithium COD - Cycloocta-1,5-diene Cp - Cyclopentadienyl DAMP - Diethyl diazomethyl phosphonate d b a - Dibenzylideneacetone DBU - Diazobicyclo[5.4.0]undec-7-ene DMAP - N,N-Dimethyl-4-aminopyridine DM90 - Dimethyl sulphoxide eq. - equivalent h - hour HMPA - Hexamethylphosphoric triamide iP r - isopropyl LDA - Lithium diisopropylamide mcpba - m-Chloroperbenzoic acid min - minute Ms - Methanesulphonyl n.m.r. - Nuclear magnetic resonance n.0.e. - Nuclear Overhauser effect PCC - Pyridinium chlorochromate PPTS - Pyridinium p-toluenesulphonate py - Pyridine RT - room temperature TBAF - Tetra-a-butylammonium fluoride (iv) TBDMS t-Butyldimethylsilyl THF Tetrahydrofuran THP Tetrahydro-2H-pyran-2-yl TMS Trimethylsilyl Tol Tolyl Ts p-Toluenesulphonyl (V) Conlenls Abstract ( i ) Acknowledgements (ii) List of Abbreviations (iv) Chapter One A Review of Recent Synthetic Strategies and Methodology of Selected Polyquinane Sesquiterpenoids 1.1 Introduction 1 1.2 Linear Triquinanes 2 1.2.1 Hirsutene 2 1 .2 .2 The Capnellene Group 7 1 .2 .3 Coriolin 1 1 1 .2 .4 Hirsutic Acid 1 4 1.3 Angular Triquinanes 1 5 1.3.1 Isocomene Sesquiterpenes 1 5 1.3.2 Silphinene 3 6 1 .3 .3 Pentalenene 4 2 1 .3 .4 Pentalenic Acid 5 0 1 .3 .5 Senoxydene 5 4 1 .3 .6 Silphiperfolene and Related Congeners 5 5 1 .3 .7 Subergorgic Acid 6 0 1 .3 .8 Conclusions 6 2 References 6 4 Chapter Two The Intramolecular Ketene-Olefin Approach to Polyquinanes 2.1 Historical Background 68 2 .2 A Model Study 74 2 .3 Construction of the Monocyclic Precursor 7 7 Chapter Three The Intramolecular Transition Metal Catalysed [2jc+2 ct] Approach to Polyquinanes 3.1 Introduction 8 3 3 .2 Strategy Towards Construction of an Acyclic Precursor for a Bicyclo[3.3.0]octane Framework 8 9 3 .3 Construction of Acyclic Precursors for Bicyclo[4.3.0]nonane Frameworks 9 4 3 .4 The Palladium (0) Catalysed Reaction 9 5 3 .5 The Nickel (0) Catalysed Reaction 11 0 3 .6 An Approach to a Precursor Biased Towards Proximal Cleavage 11 7 3 .7 Initial Synthetic Strategies in the Direction of the Isocomene Framework and Perspectives 1 21 Experimental 128 References 1 7 2 Chapter One A Review of Recent Synthetic Strategies and Methodology of Selected Polyquinane Sesquiterpenoids 1.1 Introduction Traditionally the chemistry and stereochemistry associated with six-membered ring systems has played a dominant role in synthetic organic chemistry, no doubt in part, because of the widespread occurence of this structural feature in many biologically important natural products. By way of contrast, prior to the early nineteen-sixties, polycondensed cyclopentanoid natural products were relatively rare, and hence developement of synthetic strategy to such systems was understandably overshadowed by a pre-occupation with their six-membered ring counterparts.1 By the mid seventies, however, the area of polyquinane chemistry was on the verge of an explosive growth period. There were several underlying reasons for this surge of interest in molecules whose frameworks featured mutually fused cyclopentane rings.2 In the first instance, comparatively little attention had been paid to methodology for annulation of one five-membered ring to another. The intellectual challenge of developing suitable protocols of this type was reinforced by a need arising throughout organic synthesis. Thus, the isolation of new substances in classical natural product chemistry possessing the di- or triquinane skeletons was of considerable interest to the synthetic chemist as was their biosynthesis from farnesyl pyrophosphate or related precursors. In the realms of non-natural product synthesis, there was a growing fascination for the possibly unusual physical and chemical properties of then unknown spherical compounds such as dodecahedrane. In addition, many novel polycyclopentanoid allylic systems of theoretical interest were yet to be synthesized. 1 The proliferation of review literature in this area, even with the lifespan of the present thesis, has been considerable, and it would be unrealistic to attempt to reproduce it here. Therefore, in order to place the studies described herein in their proper context, we have elected to highlight the key features relating to cyclopentanoid construction in several natural product systems. 1.2 LiQ£2I__ Triauinanes 1.2.1 Hirsutene Scheme 1 ?—O n OH ( 1) (3) Hirsutene (1) is the simplest member of a group of fungal metabolites possessing the linearly fused cis-anti-cis-tricvclo [6.3.0.02’6] undecane carbon skeleton.3 Other members with this framework include capnellene (2)16 and coriolin (3).25 As a result of the antibiotic and antitumour properties displayed by some of these triquinanes, new methods of annulation are constantly being devised for their construction. A formal [3+2] cyclisation was used by Magnus and Quagliato4 to produce bicyclic enone (4), although the yield was poor (38%). Stepwise methylene cyclopentane annulation followed by reduction produced (±)-hirsutene (Scheme 2). 2 o AgBF4 H ------► / (4) H SPh 1. MeLi 1 2. H g C l^ Thus the key step in Little's synthesis5 involved an ingenious intramolecular 1,3- diyl trapping reaction of an activated biradical diylophile (Scheme 3). 3 In terms of synthetic efficiency, reactions in which two or more C-C a bonds can be created in the same reaction are most attractive. This method has also been applied to coriolin synthesis.6,7 The intramolecular [3+2] nitrone-olefin cycloaddition by Funk,8,9 employed in the stereospecific construction of the hirsutene framework, was of interest in that heating the mixture of nitrone isomers resulted in only one adduct. With regard to cyclopentanoid formation, however, only one carbon-carbon bond is formed in this ring closure reaction (Scheme 4). o - Schem e 4 In contrast, the increasingly predictable behaviour of kinetically controlled radical cyclisation reactions was elegantly extended by Curran to tandem cyclisation reactions.10 The overall result is that the tricyclic skeleton is assembled in a single step from a monocyclic precursor (Scheme 5). However, the cis-anti-cis geometry can only be controlled by the non-trivial task of setting up the requisite 3.5-trans disposition of the starting cyclopentane. 4 *fcu£nH AffiN 8 3 % Schem e 5 In addressing the problem of entering the optically active series Hua employed condensation of a chiral sulphoxide with an enone during an asymmetric synthesis of (+)-hirsutene.11,12 At the time, its absolute configuration was not known; thus the synthesis enabled this to be established. Oxidation and selenoxide elimination followed by chromic oxidation and a cuprate addition to the resulting enone provided a side chain. This was elaborated to the tricyclic framework (Scheme 6). Scheme 6 OCOMe TnIS OH 4 : 1 86% yield 94% ee Tor OH H 5 Ley employed an organoselenium-mediated cyclisation reaction using N- phenylselenophthalimide (NPSP) and tin tetrachloride (Scheme 7).13,14 Since both the cis-anti-cis (6) and the unwanted cis-syn-cis (7) isomer were produced methods for elaborating the cis-svn-cis isomer were investigated in order to increase the overall yield of hirsutene. Ultimately, oxidation of the cis-syn-cis isomer to the selenoxide followed by elimination gave (8), which was hydrogenated under reductive rearrangement conditions to give (6). Scheme 7 In a beautifully concise approach by Weedon and co-workers cyclooctannulation was achieved by a one-pot photochemical [7c2s+tc2s] cyclisation and in situ retro aldolisation (Scheme 8).15 This was then followed by a transannular intramolecular McMurray-type reduction which neatly and quickly set up the hirsutene skeletal framework in only two steps. Scheme 8 O O 1. TBDMSC1, base 2. TiClo, K 1.2.2 The Capnellene Group (.)_A9(12)-Capnellene (2) is a marine sesquiterpene isolated in 1978 by Djerassi.16 It is the parent hydrocarbon and presumed biosynthetic precursor of the capnellanes, a group of poly-hydroxylated derivatives isolated from the same source: the soft coral Capnella imbricata. Details of their biological profile are not presently known, however it has been suggested that the capnellanes act as chemical defence agents to inhibit the growth of microorganisms.17 7 Scheme 9 H (2) Pattenden and Birch used an intramolecular photocycloaddition and subsequent transannuiar cyclisation in their synthesis of epiprecapnelladiene.18,19 This approach suffered from a marked lack of stereocontrol in the Lewis acid mediated carbocationic cyclisation. Three isomers resulted from this step (Scheme 10). An interesting series of pericyclic reactions have been used by the Mehta group20 in producing the pentacyclic dione (9); the caged dione precursor was formed by a Diels-Alder reaction and subsequent intramolecular photochemical cycloaddition. Thermolysis produced the required linear triquinane structure (Scheme 11). o o (9) A most unusual illustration of the olefin metathesis reaction forms the key step in the Grubbs approach to (±)-A9(12)-capnellene.21 The metallocyclobutane (10) was rearranged to the cyclobutene enol ether (11), which was finally subjected to ring expansion (Scheme 12). The Ikegami group developed an efficient method for the construction of the bisallylic 9 m alcohol unit common to the capnellane group of alcohols.22,23 The first total synthesis of A9(12)-capnellene-8|5t1 Oa-diol (12) and A9^12)- capnellene-3p,8p,10a-triol (13) was undertaken (Scheme 13). Aldolisation using a wide range of acidic and basic reagents was unsuccessful. It was apparent that the positon of equilibrium lay towards the starting materials. Subsequently this problem was mitigated to attain a mediocre yield by trapping the intermediate ketol with trimethylsilyl trifluoromethanesulphonate and eliminating hexamethyldisiloxane (Scheme 14). 1. NaBH4-CeCl3 R=H, 2. TBDMSCl-imidazole 3. dibal 4. acetylation OAc V OTBDMS Schem e 14 Lastly, a novel [3+2] annulation strategy has been tried in order to set up the bicyclo [6.3.0.0 2*6] framework using an in situ-aenerated Wittig reagent (Scheme 15).24 Schem e 15 The yield of (14) was only 10%; the ring opened cyclopentanone accounted for most of the remaining product. 1.2.3 Coriolin Coriolin (3) was first isolated in 1969 from fermentation broths of the basidiomycete Coriolus consors 25 The antibiotic and antitumour activities of coriolin (3) and diketocorioiin B (15), as well as their challenging structural features, continue to attract the attention of synthetic chemists (Scheme 16). 11 Scheme 16 Magnus and co-workers were the first to realise that an intramolecular variant of the Pauson-Khand reaction could be used in an efficient way for a formal synthesis of coriolin.26 A separable mixture of the bicyclo [3.3.0] octenone (16) and its epimer (17) were obtained (Scheme 17). This reaction proceeded yia a cobalt metallocycle followed by migratory insertion of carbon monoxide and reductive elimination. It is fortunate that coriolin possesses the oem-dimethyl group which facilitates the reaction by the Thorpe-lngold effect since further studies have shown a marked decrease in yield without this feature In a short synthesis of a key (±)-coriolin precursor Koreeda and Mislanker27 constructed the bicyclic fragment (18) utilizing alkylation of a dianion (Scheme 18). Scheme 17 TBDMSO C 02((X))8 CO, heptane sealed tube Schem e 18 The Demuth synthesis of coriolin28 involved regioselective photochemical rearrangement of the diketone epimers (19a) and (19b) to the tricycles (20a) and (20b) (Scheme 19). The resultant cyclopropyl ring, at a later stage, underwent regiospecific cleavage with lithium in liquid ammonia and the final ring was constructed by an alkylation step and subsequent aldol condensation. 13 Scheme 19 • 1.2.4 Hirsutic Acid Hirsutic acid C (21) was isolated from Stereum hirsutum and Stereum complicatum (Scheme 20).29 Schem e 2 0 14 The Greene synthesis30 is of interest inasmuch as it uses cyclobutanone precursors. Furthermore, asymmetric hydroboration followed by oxidation was employed to obtain the chiral ketone (-)-(22) in 90% e.e. This was subsequently elaborated to (23) by ring expansion and hence linked to a route previously established in the racemic series (Scheme 21). Schem e 21 H l.(+)-Ipc£H several ------> i H ^ o r steps M e 02C H 3. C i0 3.py2 1.3 Angular triquinanes 1.3.1 Isocomene Sesquiterpenes Isocomene (24) was first discovered by Zalkow31 by isolation from the toxic plant Isocoma Wriqhtii: its structure was confirmed by x-ray analysis of the corresponding diol (Scheme 22). The synthesis constitutes a significant challenge by virtue of the three contiguous quaternary chiral centres. 15 Scheme 22 (24) One of the first syntheses of (±)-isocomene was carried out stereospecifically by Paquette and Han.32 Ironically, a minor product of the deprotection of the acetal (25) was the required tricycle (26) (19%). However, by using a tin tetrachloride- promoted ring closure the aldehyde (from deprotection of (25) ) could be converted to (26) with much greater efficiency (95%) (Scheme 23). In the same year Oppolzer and co-workers33,34 also published a total synthesis of (±)-isocomene: an intramolecular ene reaction was used to construct one of the five- membered rings by cyclisation of a terminal alkene onto a bicyclo [4.3.0] nonene (Scheme 24). However, this required a ring contraction to be carried out at a later stage. Furthermore, it was unfortunate that the requisite product (27) was obtained in the key step as a minor product in only 17% yield. No stereoisomers of (27) were detected. This was in agreement with the examination of the two transition states. In the exo-orientation (II) strong repulsion between the C-1 methyl group and the bridging allylic methylene group was apparent. Thus the desired endo-orientation (I) avoided this steric crowding (Scheme 25). Scheme 23 1. LDA 2. PhSeCl Me^CuLi ------► 3. mcpba 4. hexane A Me H ^ N H ^ H p K £ 03 triethylene glycol A isocomene (24) 17 Me 1. LiAlUj 2. ArSeCN / Bi*P / py 1. Naiq 2. 80 °C Me P -isocomene (49) isocomene (24) Scheme 24 18 It is hardly surprising that other products arose from the thermolysis step, judging from the poor yield of product (27). The bicycle (28) was produced by a retro ene reaction in 15% yield. (29) was present in a major 22% yield (Scheme 26). Scheme 25 : The Transition States Leading to the Formation Tricycle (27) O o endo Schem e 2 6 (2 8 ) (2 9 ) 19 A completely different approach and an interesting variant on the transannular cyclisation strategy was carried out by exposure of the bicyclo [6.3.0] undecene derivative (30) to trifluoroacetic acid.35 In this case the regioselectivity of the epoxide opening, which was mandatory in setting up the [6.3.0.01,5] system, was controlled by the proximal carbonyl group (Scheme 27). Schem e 27 Me TFA ------► P O C l* p y 11 a -M e at C-2 P-M e at C-2 It was claimed that hydrogenation of (31) produced the epimer at C-2 with the methyl group in the a-position, a requisite towards isocomene. However, this has met with much controversy; it is more likely that hydrogenation would occur yia the exo face, and not the endo face. This would give rise to the p-epimer at C-2, the analogous 20 # intermediate for epiisocomene (32), shown in Scheme 28. Later, this had, in fact, been shown to be the case: hydrogenation of (33) resulted in (34a); from a high field n.m.r spectrum (34b) was present in less than 5%. Conversion of the hydrogenated mixture to the hydrocarbons followed by purification gave rise to p-epiisocomene (35) (Scheme 28).36 Schem e 28 The hindrance of the endo face was further demonstrated by Paquette32 (vide supra) whereby nucleophilic attack by dimethylcopperlithium solely occurred yia the more exposed exo face. A particularly concise approach to the bicyclo [3.3.0] octane skeletal framework was evident in Pirrung's synthesis,37 in which controlled carbocationic rearrangement of the bicyclo [4.2.0] system (36) was used to generate the tricyclic skeleton (37) in 21 spectacularly high yield (Scheme 29). Another significant feature, which has been used in other polyquinane frameworks, is the use of the intramolecular [k 2 s +7i2 s ] photocycloaddition. Schem e 2 9 O O p T s O H P h H , A A different strategy from a formal synthesis using classical and unsophisticated methodology was carried out by Dauben and Walker.38 However, the route is merited by virtue of its simplicity and efficiency. In one step two of the rings were constructed utilizing a Weiss-Cook condensation. The expected problem of ketone differentiation in (38) was overcome by initially forming the diketal and partially hydrolysing it to the monoketal (Scheme 30). 22 o O MeQ?C>>_i>JL >_^. OC^Me CQzEt ------►- pH 6 .8 , aq.MeOH O 1. 6 N HC1, HOAc 2. KF.2Hp, Mel 3. HOCH£(Me)£H^OH, TsOH 4. TsOH, 5 % aq. Me^O X 1. NH^H 3 KOH, COzH ( H O C H £ H ^ , COzMe 205 °C 2. H p + 38a X, Y = 0 Schem e 30 38b X, Y = < o —* 38c X = O, Y = < ° " ^ < o— ' Selective protection of the least hindered ketone in (39) followed by a Wittig reaction and subsequent isomerisation furnished the allylic methyl group (Scheme 31). Deprotection lead to a common intermediate in the Paquette-Han route.32 > 23 Scheme 31 1. HSCH^CHjSH, BF3.OEt2 2. lAmONa, Ph 3P+MeBf 3. TsOH 4. Mel, MeCN, CaC0 3 A five step synthesis of (±)-isocomene was implemented by Wender and Dreyer.39 Employment of an arene-olefin meta-photocycloaddition produced a mixture of two readily interconvertible isomers (40) and (41) (Scheme 32). 24 Scheme 32 hv, 450 W Hanovia Vycor, cyclohexane RT 4h 25 There are several possibilities for the meta-cycloaddition (Scheme 33) : C-l, C-9 C-9, C-l Scheme 33 26 C-1, C-9 and C-9, C-1 were disfavoured because of the C-6, C-13 steric interactions. The C-2, C-8 mode took preference over the C-8, C-10 mode by virtue of the directing influence of the C-1 methyl substituent. Two modes of C-2, C-8 addition are possible (Scheme 34): Schem e 34 R P exo endo It was considered likely that the exo orientation would predominate over the more difficult to achieve endo alignment. Also, it was further assumed that the methyl group at C-7 would adopt a pro-a orientation since the methyl-methyl repulsive interaction that would develop in the pro-p case would be unfavourable (Scheme 35). 27 Scheme 35 pro-a pro-p Wenkert and Arrhenius40 chose to rearrange an oxycyclopropane to a cyclobutanone as their key reaction in a seventeen step synthesis. A mundane aldol condensation produced the bicycle (42) (Scheme 36). 28 The relief of strain in the transformation of (43) to (44) contracted the six- membered ring to the requisite cyclopentane nucleus (Scheme 37). Schem e 37 1. CH^HI^ Et^Zn 2. C1O3, py, AcOH ------► 3. LDA 4. TMSI 5. CH jIj Et^Zn 30% H2S04 ------hexane via 29 However, a further ring expansion of the cyclobutanone was necessary in order to furnish the angular triquinane framework (Scheme 38). Schem e 38 (44) 1. MeSCHjLi 2. Mel NaH 1. LiAlH4 2. nBuLi, ClPCOKNMe^ 3. Li / EtNH2 (±)-isocomene (24) A more elegant example of cyclopropanation, which was done intramolecularly, was followed by ring expansion in one step. This was reported by Hudlicky in the synthesis of (±)-isocomenic (45) and (±)-epiisocomenic acid (46).41 The key reaction featured a vinylcyclopropane to cyclopentene rearrangement. Flash vacuum pyrolysis of the diastereomeric mixture (47) resulted in the tricyclic ketone (48) as a single diastereomer in 64% yield (Scheme 39). 30 Scheme 39 1. (COCl) 2 2. MeCHN2 Vycor, PbCOj, 580 °C, 0.05 mmHg Stereospecific hydrogenation, followed by a modified Wittig reaction gave a mixture of (49a) and (49b) (9:1) at 0 °C. However, in refluxing toluene (49a) was completely epimerized to the thermodynamically more stable isomer (49b). Straightforward hydrolysis of (50b) produced (±)-isocomenic acid (45). However, epimerization was observed in the case of (50a) to yield both (±)-isocomenic acid (45) and (±)- epiisocomenic acid (46). This problem was circumvented by reduction to the alcohol and re-oxidation to (±)-epiisocomenic acid (46) alone (Scheme 40). 31 Pd(Q O h 2 Scheme 40 '■/# ■«# EtC^C Et02C (48) CH^Ph* PhMe, lAmOH, lAmONa HO 2C (±)-epiisocomenic acid (46) Esters (49a) and (49b) have also been converted to the corresponding hydrocarbons : isocomene (24), epiisocomene (32), p-isocomene (51) and p-epiisocomene (35) (Scheme 41 ).42 32 Scheme 41 (4 9 a) (49 b) 1. LiAIH4 1. LiAlH4 2. TsCl, py 2. TsCl, py 3. UAIH4 3. LiAlH4 w 1' Another example of an epoxide-carbonyl rearrangement similar to that used by Wenkert40 (vide supra) was employed in a chelation-controlled fashion.43 The syn- epoxide (52) was synthesised yia a short stereospecific sequence, and upon treatment with lithium bromide rearranged regiospecifically to the ketone (53) in 81% yield (Scheme 42). 33 Schem e 4 2 (±)- p-isocomene (51) (±)-isocomene (24) An interesting cascade rearrangement has been carried out by Fitjer and co workers44 using thermodynamic control. Dispiro [3.0.4.2] undecane (54) was synthesized (Scheme 43): The reaction was monitored by 1H-n.m.r. spectroscopy. The initial kinetic products formed were the propellane (±)-modhephene (55) and triquinane (56). However, after three days (±)-isocomene (24) was obtained in a significant yield along with > 35 triquinanes (56) and (57) (Scheme 44). Schem e 4 4 After 10 m ins; After 76 h ; 1.3.2 Silphinene Silphinene (58) was initially reported in 1980 by Bohlmann and Jakupovic45 from Silphium perfoliatum (Scheme 45). Several syntheses have been published; the first two successful approaches were by Paquette46 and Ito.47 36 Scheme 45 »« (±)-silphinene (58) Paquette and Leone-Bay's seventeen step synthesis commenced with a bicyclo [3.3.0] octane and again used the Marfat-Helquist conjugate addition (Scheme 46). Direct conversion of (59) to (58) was not possible; straightforward hydrogenation would have led to the wrong epimer. By contrast, acid-catalysed epoxide opening of (60) ensured stereospecific rearrangement to (61), with the secondary methyl group occupying the more thermodynamically stable position. Ito's route showed close similarity to that of Paquette. As his key strategy Sternbach48 used the classical concept of latent functionality. Thus the intramolecular Diels-Alder cyclisation was employed to construct an unrelated bicyclic framework in which the enol ether functioned as a masked carbonyl moiety. Subsequent ozonolysis and intramolecular aldol cyclisation produced the requisite framework of the tricyclo [6.3.0.04,8] undecene system (Scheme 47). > 37 Nft, K £ O y triethylene glycol Schem e 4 6 38 Scheme 47 68 % • « CHO Unfortunately (62) was formed in a significant proportion as a by-product of the decarboxylation step. The final product was obtained in 19% overall yield (Scheme 48). 39 Scheme 48 1. Jones 2 . Pb(OAc )4 Cu(OAc>2.Hp py 1. Me^CuLi 2. K2CO3 1' In just three steps (±)-silphinene has been produced from an enone by arene-olefin meta-photocycloaddition (Scheme 49).49 Irradiation of (63) using Vycor-filtered light from a mercury arc lamp gave adducts (64) and (65) in a 1:1 mixture in 70% yield. Optimal conditions for the reductive cleavage of the cyclopropane ring were established using lithium in methylamine at -78°C to provide (±)-silphinene together with a regioisomer (66) in a 9:1 ratio (74% combined yield). 40 Scheme 49 > 41 1.3.3 Pentalenene (+)-Pentalenene (67) (Scheme 50), isolated from Streptomyces griseochromogenes in 1980, is the parent hydrocarbon of the pentalenolactone family antibiotic fungal metabolites. Synthetic interest in this particular compound has arisen because of its role as a key precursor to pentalenolactone.50 Matsumoto51 has obtained pentalenene in 20% yield from humulene (68). Mercuric oxidation followed by sodium borohydride reduction yielded an oxiran. This underwent a series of carbocationic rearrangements to give pentalenene (Scheme 51). 42 Scheme 51 Paquette hsd also reported the synthesis of (67)50 although the major product was epi-pentalenene (69). The overall synthetic strategy and methodology employed bears close resemblance to the group's synthesis of isocomene. The bicyclic enone was formed in an efficient manner by a [jt2s+rc2s] cycloaddition of dichloroketene followed by a ring expansion using diazomethane; this method was developed by Greene and used in hirsutene synthesis (Scheme 52).52 43 Zn/AcOH RT 1. MeMgBr 2. Qjj Me^S 3. HOCH2CH2OH, TsOH t 1. pyH.OTs, ) 44 Unfortunately the final 1,4-addition of cuprate to the enone produced the wrong stereochemistry at C-9. Generation of the enone (70) and reduction using a multitude of reducing agents gave the same result. However, the system (PPhgJgRhCI / Et 3SiH showed some improvement. Wolff-Kischner reduction yielded the two hydrocarbon epimers (69) and (67) (Scheme 53). Schem e 53 45 Piers53 constructed the rings in the same sequence as Paquette and also utilized a 1,4-nucleophilic addition to an enone for the construction of the final ring. A novel methylene cyclopentane annulation method was employed to generate an exocyclic double bond. It was hoped that reduction of this double bond would improve the yield of the required epimer, compared with Paquette's endocyclic double bond reduction (Scheme 54). Schem e 5 4 1. MeLi 2. MgBr2 Cl 3. CuBr. Me^S O H H KH l.H ^P t AcOH 2. MeLi O 3. pTsOH H H a) Rj = M e; R2= H (71) b) Rj = H ; R2= Me a : b = 42: 58 46 Catalytic hydrogenation of (71) reduced not only the exo-methylene group but also effected contemporaneous hydrogenolysis of the cyclopropane ring to furnish the gem dimethyl groups. Although there was a slight improvement in the proportion of required epimer, the formation of an epimeric mixture demonstrated, once again, that stereochemical control at C-9 was somewhat problematic. The Pattenden route54 involved Lewis acid-catalysed transannular cyclisation of a bicyclo [6.3.0] undecadiene (72) (Scheme 55). Schem e 55 OTBDMS 47 This, in turn, was produced by the now familiar theme of intramolecular [7e2s +te2s] photocycloaddition followed by ring expansion. This latter step is of interest because it implies that the regioselectivity of the fragmentation is controlled yia formation of a specific protonated complex. A similar cyclisation has been adopted by Mehta55 using an aldol cyclisation to construct the bicyclic skeleton. Another example of the intramolecular Pauson-Khand cycloaddition is its impressive use in a highly stereoselective synthesis of (±)-pentalenene by Schore and Rowley (Scheme 56) 56 It was suggested that stereochemical control was brought about by the interaction between the C-9 endo substituent and the propargylic methylene group (Scheme 57). 48 Scheme 57 exo methyl substituent endo methyl substituent: steric interaction This contrasts with Magnus's use of a bulky alkyne substituent in order to effect stereochemical control (Scheme 58)57, since the directing element is already inherently present. Schem e 58 TBDMSO 49 1.3.4 Pentalenic acid Schem e 5 9 petalenic acid (73) deoxypentalenic acid (76) m Pentalenic acid (73) (Scheme 59) has also been shown to be a key intermediate in the biosynthesis of pentalenolactone,58 hence its synthetic interest. Crimmins59 has carried out a synthesis employing a stereoselective photocycloaddition which sets up three of the required stereocentres in a single step. Subsequent reductive cleavage produced a spirobicyclo [4.4] nonane framework (74) (Scheme 60). This was converted to dione (75) which was used as a common intermediate to (±)-pentalenene (67), (±)-deoxypentalenic acid (76) and (±)- pentalenic acid (73) (Scheme 61). > 50 Scheme 60 O CO^Me C02Et Li-NH-*, -78°C 73% total if 1. HC1, AcOH, A 2. MeOH, pTsOH, (MeO)^CH a) Rj=Me, Rf=H b) RpH, R^Me (75) ) 51 Scheme 61 1. LDA, C0 2 1. MeSO^Cl, E t^ (75) 2. HC1 2.DBU 3. CH^ 2 \ 1. LDA, C0 2 1. LDA, Mel 2. H* 2. Li - NH3 3. CHjNj 4. NaBH 4 CO2H 1. H2 -Pd(C) (±)-pentalenic acid (73) 2. MeSO^Cl, 1. pMeC6 HpC(S)Cl Et3N 2. 200 °C, 25mmHg 3. DBU 4 . KOH J (±)-deoxypentalenic acid (±>pentalenene (67) in an attempt to implement an intramolecular Diels-Alder strategy Fukumoto and co workers60 carried out, in fact, an intramolecular tandem conjugate addition of bis- 52 enone (77), efficiently forming two rings in a single step (although not in a concerted fashion) (Scheme 62). Schem e 6 2 1. HCOjEt, NaOMe 2. pMeCgH^O^ EtaN 3. hv, MeOH 1. KOH, MeOH 2. NaH, Li - NH3 3. CHjNj, MeOH Me02C Me02C 1. LDA, PhSeCl 2. HP2,AcOH previously reported route Following the reaction indicated that the tricycle (78), and its C-10 epimer, were gradually transformed into a mixture of silyl enol ethers, hence annulation proceeded 53 via a double Michael reaction and not yia an intramolecular Diels-Alder reaction of the siloxydiene. 1.3.5 Senoxydene This new sesquiterpene was isolated in 1979 from Senecio oxvodontus by Bohlmann and Zdero.61 The initial structural assignment (79) (Scheme 63) was incorrect, as later shown by Paquette62 in an unambiguous, stereocontrolled synthesis. Isomers with different gem-dimethvi substituent positions were prepared, none of whose proton n.m.r. spectra matched that of the natural product.63 Schem e 63 (7 9 ) (8 0 ) (81) Aldol condensations were used to effect the final ring closure in each case (79), (80) and (81). Ito and co-workers64 began a synthesis of the proposed structure (79); this served to reinforce its incorrect assignment. The same group also carried out a synthesis of (82), the epimer of the proposed senoxydene, which also was not identical with that from nature. Asakawa65 has also produced (82) (Scheme 64). The senoxydene enigma still remains unresolved. Along with silphinene, silphiperfol-6-ene (83) was also isolated from the roots of ♦ Silphium perfoliatum.45 The related ketone 5-oxosilphiperfol-6-ene (84) was obtained and characterised shortly afterwards, originating from the stems of Espeletiopsis quacharaca (Scheme 65).66 Paquette first reported the synthesis of (83).67 The main outline of the route was an alkylation of an activated ketone, aldol condensation, 1,4-cuprate addition to an enone followed by another aldol cyclisation (Marfat-Helquist annulation) (Scheme 66).68,69 However, the absolute stereochemistry of the molecule was determined by basing the synthesis on (fl)-(+)-pulegone (85)70 and hence using the methyl group as a stereochemical marker. The initial spectroscopic structural assignment was also confirmed. By taking advantage of symmetry, it was possible to devise a precursor whereby the initial alkylation step gave the same product m an SN 2 or Sfg2' mechanism. As pyridinium chlorochromate oxidation has been shown to yield (84)66, this synthesis formally constitutes one of (-)-5- oxosilphiperfol-6-ene. 55 1. NaH, caL KH several OH 1. pMeC^HpC(S)Cl, py 2.180 °C, 24 mmHg Naprp7» ------» 3. N p* H p, K p 0 3 AcOH, A cp H O C H p H p H H 56 In a further use of the arene-olefin meta-photocycloaddition Wender and Singh71 have described the total synthesis of (±)-silphiperfol-6-ene (83), (±)-7pH- silphiperfol-5-ene (86) and (±)-7aH-silphiperfol-5-ene (87). Three five memebered rings were formed in one step. The synthesis is concise (7-8 steps), providing each compound in 5-10% overall yield (Scheme 67). (88) and (89) were found to be photochemically interconvertible, however complete equilibration was not possible because of competing decomposition of the compounds. As in the case of hirsutene, the angularly fused skeleton is also amenable to construction using the kinetically controlled tandem radical cyclisation method (Scheme 68).72 Two of the five-membered rings are therefore constructed in a single step thus avoiding the sequential annulations so often used. The precursor to the key step was constructed by successive alkylations followed by a Grignard addition. In the event, however, tributyltin hydride-promoted cyclisation produced the undesired (90b) epimer (90a:90b/1:3). Moreover, the two isomers were difficult to separate. This problem was eventually solved by ketalisation prior to cyclisation which produced the requisite isomer in the major proportion (91a:91b/2.5:1). Furthermore, the ketalised products were readily separable by chromatography. Subsequent deprotection and reduction produced (±)-silphiperfol-6-ene (83) and 9-epi-silphiperfol-6-ene (92) in 66-80% yields. 57 Scheme 67 58 Scheme 68 r ~ \ pyHOTs HOCH^CH^OH ^ ------ I nBujSnH 59 1.3.7 Subergorgic acid Subergorgic acid (93) was isolated in 1985 from the Pacific coral Subergorgia suberosa by Fenical and co-workers.73 It is manifested by its cardiotoxic activity. Recently, a stereoselective total synthesis of (±)-(93) has been reported by Iwata sL aL.74 Schem e 69 O H, OH 1. hv, allene 1. MsCl, py 2. L-selectride 2. NaBH* MeOH ^ ^ ...... r ^ S 1 1 3. OsO^ NaI04 ...... yL o — V— ' ^ y ° 1. PPTS, Me^CO | 1. NalO^ MeOH 2. MeOCH^Cl, (iPr)^IEt 1 2. Et-jN, CCL4 w o' N / 3. LDA, PhSSPh 3 f > l 3. 3N HC1 M OM O^ \ / 4. MsCl, EtgN O r SPh 60 The ubiquitous [2+2] photocycioaddition set up the required stereochemistry of the ring junction methyl group (Scheme 69). Two different routes were used for the introduction of the C-4 methyl group: path A ( (95):(96)/6:1 ) and the improved path B ( (95):(96)/20:1 ). The synthesis was completed by ring cleavage, reclosure and reoxidation (Scheme 70). Schem e 7 0 path A Li-NH-j (95) RpH, Rj=Me i Hp^NaOH (96) RpMe,R2=H | i MepuLi CHO 1. piperidine O, O acetate (9 5 ) Zn-AcOH 2. NaClOj, 2-methyl-2-butene, '''Me NaHpO^BuOH H 61 1.3.8 Conclusion The foregoing description, albeit brief and highly selective, has been used to illustrate the major types of strategy which have been employed in the polyquinane area. Careful perusal of these examples from the tactical standpoint does, however, reveal several features of considerable interest. Thus, reaction schemes including successive annulation sequences and typically involving an aldol type ring closure or related reaction as the one-bond final ring forming step are, of necessity, linear, long and relatively low yielding. By way of contrast, plans which use cycloaddition reactions in which two or more o bonds are formed in a single reaction are much more efficient, in this latter respect the [tc2s +tc2s ] photocycloaddition, especially in the intramolecular mode,18,19,37,59,74 has served particularly well. Elaboration of these adducts does however necessitate either a ring expansion protocol, such as that developed by Greene52, or alternatively a suitable bicyclo [4.2.0] product which may be elaborated by ring opening and reclosure to the [3.3.0] skeleton (Scheme 71) 48,74 ring opening Schem e 71 62 The meta photocyclisation of arenes developed by Wender39,49 is also a beautiful reaction but once again the adducts require additional steps to unmask the cyclopentane ring. A similar argument may also be advanced against the use of the Diels-Alder reaction in polycyclopentanoid synthesis since the resultant cyclohexene derivative is, in general, only of value in subsequent ozonolysis as an aldol precursor. Of the most vast and ever increasing number of new methods available, the intramolecular version of the Pauson-Khand reaction and the tandem radical cyclisaton reaction, albeit with the limitations already discussed, would seem to offer especially useful and potentially general solutions for polyquinane construction. It should never be forgotten that methods for formation of five-membered rings should not be viewed as a mere extrapolation of those available for six-membered rings. The combination of torsional and ring strain invalidates such analogies. In summary, the development of a cyclopentane annulation reaction which would be equivalent to the versatile power of the Diels-Alder reaction in terms of regio- and stereocontrol still represents a worthwhile challenge. 63 References 1. B. M. Trost, Chem. Soc. Revs.. (1982), 11, 141 2. L. A. Paquette, Topics in Current Chemistry. (1984), 119, 1 3. S. Nozoe, J. Furukawa, U. Sankawa and S. Shibata, Tetrahedron Lett.. (1976), 195. 4. P. Magnus and D. A. Quagliato, Organometallics. (1982), 1, 1243 5 . R. D. Little and G. W. Muller, J. Am. Chem. Soc.. (1981), 103, 2744 6. R. D. Little, G. L. Carroll and J. L. Petersen, J. Am. Chem. Soc.. (1983), 105, 928 7. L. V. Hijfte, R. D. Little, J. L. Petersen and K. D. Moeller, J. Pro. Chem.. (1987), 52, 4647 8. R. L. Funk and G. L. Bolton, J. Org. Chem.. (1984), 49, 5021 9. R. L. Funk, G. L. Bolton, J. U. Daggett, M. M. Hansen and L. H. M. Horcher, Tetrahedron. (1985), 41, 3479 1 0. D. P. Curran and D. M. Rakiewicz, J. Am. Chem. Soc.. 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BSttig and T. Hudlicky, Tetrahedron. (1981), 37, 4359 35. S. Chatterjee, J. Chem. Soc.. Chem. Commun.. (1979), 620 36. L. D. Kwart, M. Tiedje, J. O. Frazier and T. Hudlicky, Synth. Commun.. (1986), 16, 393 3 7 . M. C. Pirrung, J. Am. Chem. Soc.. (1979), 101, 7130 38. W. G. Dauben and D. M. Walker, J. Org. Chem.. (1981), 46, 1103 39. P. A. Wender and G. B. Dreyer, Tetrahedron. (1981), 37, 4445 4 0 . E. Wenkert and T. S. Arrhenius, J. Am. Chem. Soc.. (1983), 105, 2030 65 41. R. P. Short, J.-M. Revol, B. C. Ranu and T. Hudlicky, J. Pro. Chem.. (1 9 8 3 ) , 48, 4453 42. B. C. Ranu, M. Kavka, L. A. Higgs and T. Hudlicky, Tetrahedron Lett.. (1984) , 25, 2447 4 3 . Y. Tobe, T. Yamashita, K. Kakiuchi and Y. Odaira, J. Chem. Soc.. Chem. Commun.. (1985) , 898 44. L. Fitjer, A. Kanschik and M. Majewski, Tetrahedron Lett.. (1988), 29, 5525 45. F. Bohlmann and J. Jakupovic, Phytochemistry. (1980), 19, 259 46. A. Leone-Bay and L. A. Paquette, J. Org. Chem.. (1982), 47, 4173 4 7 . T. Tsunoda, M. Kodama and S. Ito, Tetrahedron Lett.. (1983), 24, 83 48. D. D. Sternbach, J. W. Hughes, D. F. Burdi and B. A. Banks, J. Am. Chem. Soc.. (1985), 107, 2149 49. P. A. Wender and R. J. Ternansky, Tetrahedron Lett.. (1985), 26, 2625 50. G. D. Annis and L. A. Paquette, J. Am. Chem. Soc.. (1982), 104, 4504 51. S. Misumi, T. Ohtsuka, Y. Ohfune and K. Sugita, Tetrahedron Lett.. (1979), 31 52. A. E. Greene, Tetrahedron Lett.. (1980), 21, 3059 53. E. Piers and V. Karunaratne, J. Chem. Soc.. Chem. Commun.. (1984), 959 54. G. Pattenden and S. J. Teague, Tetrahedron Lett.. (1984), 25, 3021 55. G. Mehta and K. S. Rao, J. Chem. Soc.. Chem. Commun.. (1985), 1464 5 6 . N. E. Schore and E. G. Rowley, J. Am. Chem. Soc.. (1988), 110, 5224 5 7 . P. Magnus and L. M. Principe, Tetrahedron Lett.. (1985), 26, 4851 58. K. Sakai, T. Ohtsuka, S. Misumi, H. Shirahama and T. Matsumoto, Chem. Lett.. (1981), 355 59. M. T. Crimmins and J. A. DeLoach, J. Am. Chem. Soc.. (1986), 108, 800 6 0 . M. Ihara, M. Katogi, K. Fukumoto and T. Kametani, J. Chem. Soc.. Chem. Commun.. (1987), 721 61. F. Bohlmann and C. Zdero, Phytochemistry. (1979), 18, 1747 6 2 . L. A. Paquette, R. A. Galemmo, Jr., and J. P. Springer, J. Am. Chem. Soc.. (1983), 105, 6975 66 6 3 . L. A. Paquette, R. A. Galemmo, Jr., J.-C. Caille and R. S. Valpey, J. Pro. Chem.. (1986), 51, 686 64. T. Tsunoda, Y. Kabasawa and S. Ito, Tetrahedron Lett.. (1984), 25, 773 65. M. Tori, R. Matsuda and Y. Asakawa, Bull. Chem. Soc. Jpn.. (1985), 58, 2523 66. F. Bohlmann and J. Jakupovic, Phytochemistry. (1980), 19, 259 67. L. A. Paquette, R. A. Roberts and G. J. Drtina, J. Am. Chem. Soc.. (1984), 106, 6690 68. A. Marfat and P. Helquist, Tetrahedron Lett.. (1978), 4217 6 9 . J. C. Stowell, J. Org. Chem.. (1976), 41, 560 70. J. N. Marx and L. R. Norman, J. Org. Chem.. (1975), 40, 1602 71. P. A. Wender and S. K. Singh, Tetrahedron Lett.. (1985), 26, 5987 72. D. P. Curran and S.-C. Kuo, J. Am. Chem. Soc.. (1986), 108, 1106 73. A. Groweiss, W.Fenical, H. Cun-heng, J. Clardy, W. Zhongde, Y. Zhongnian and L. Kanghou, Tetahedron Lett.. (1985), 26, 2379 7 4 . C. iwata, Y. Takemoto, M. Doi and T. Imanishi, J. Org. Chem.. (1988), 53, 1623 67 Chapter Two The Intramolecular Ketene-Oleffn Approach to Polvouinanes 2.1 Historical Background As we have argued in the introduction, it is practical to form two o bonds in a single reaction, particularly in the case of smaller rings and polycyclic systems where there may be much strain during the final ring-closing step. Furthermore, the choice of a single cycloaddition reaction not only reduces the number of synthetic steps but also, particularly if the mechanism is concerted, allows the added bonus of stereoselectivity. Pericyclic reactions, such as the Diels-Alder reaction, are valuable methods in organic synthesis. Intramolecular versions of such reactions have been extensively developed over the past decade1 and shown to be valuable for the synthesis of polycyclic compounds. We were intrigued, however, that no attempt had been made to develop the intramolecular [2+2] cycloaddition into a similarly extensive general synthetic method. Hence, as illustrated for the case of p-isocomene (1), a strategy for disconnection was envisaged using this methodology (Scheme 1). It is noteworthy that the relative stereochemistry of the three chiral centres generated during the cycloaddition to produce (3) should be entirely controlled by the stereochemistry of the C-2 methyl group in (2). o (2) Scheme 1 Examination of the literature at the planning stage showed that intermolecular ketene-olefin cycloadditions were well documented. In general, the intermolecular cycloaddition proceeds in poor yield with ketene itself, and instead, activated ketenes with electron-withdrawing substituents, such as chlorine are preferred.2 Dichloroketene, in particular, has been shown to yield a vast array of 1,1- dichlorocyclobutanone adducts; examples include reaction with cyclopentadiene,3 indene,4 pent-1-ene,5 cyclohexene,5 styrene,5 and ethyl vinyl ether.5 Methylchloroketene6 and ethylchloroketene7 also undergo reaction with cyclopentadiene. Furthermore, the syntheses discussed in the review often employed an intermolecular [2+2] ketene-olefin cycloaddition. By way of contrast, the intramolecular variant had been little explored8a,b at that time. 69 It is a measure of the rapid progress of modern science, although disappointing to record, that almost as soon as our programme had been initiated further studies in this area began to proliferate in the literature, culminating towards the end of this thesis in a recent review entirely devoted to the intramolecular [2+2] variant8b. Thus, Yates and Fallis9 produced (5) when acyl chloride (4) was treated with triethylamine in refluxing benzene (Scheme 2). The yield, however, was only 18 %. Scheme 2 Later, the substituted bicyclo [3.2.0] heptanone (6) was formed in 65 % yield (Scheme 3 ).10 Ph COC1 Et3N Toh RT (6) Scheme 3 70 Subsequently Ghosez11 investigated a wide range of precursors including both ketene- olefin and keteniminium salt-olefin cycloadditions (Scheme 4). H H Scheme 4 The greater electrophilicity of keteniminium salts led to higher yields than those obtained yia use of the corresponding ketene. Tricyclic systems could also be synthesized. 71 At the same time Snider and co-workers12 were routinely carrying out intramolecular [2+2] ketene-olefin cyclizations using (alkenyloxy)acetyl chlorides (Scheme 5). H Me Me Scheme 5 63 % It was also noteworthy that, while alkenes in which the internal olefinic carbon atom was more highly substituted also reacted to give bicyclo [3.2.0] heptanes; those in which the terminal carbon was more highly substituted yielded bicyclo [3.1.1] heptanes (Scheme 6). Vinylketenes have also been shown to undergo [2+2] cycioaddition with olefins intramolecularly (Scheme 7).13 There are also examples of angularly fused14 and linearly fused15 triquinanes. Finally, Corey8 has recently carried out a total synthesis of (±)-retigeranic acid (7) employing the intramolecular [2+2] ketene-olefin cycloaddition under exceptionally mild conditions to produce (8) in 80 % yield (Scheme 8). 73 In our case the project was undertaken on two simultaneous fronts. Firstly, a model precursor was synthesized in order to become acquainted with, and to optimize, the experimental conditions. At the same time, the construction of the framework for the tricyclic skeleton was commenced. 2.2 A Model Study The preparation of 7-methyl bicyclo [3.2.0] octan-1-one (9) was selected in the first instance as a suitable model study (Scheme 9). This route commenced with the elegant protocol developed by Schreiber for ozonolysis and selective acetalisation16 of 1-methylcyclohexene. The reaction was conveniently followed by n.m.r. by monitoring the disappearance of the alkene (5 5.35 ppm). The methine triplet of the acetal was clearly visible (5 4.4 ppm, J 5 Hz). Methylenation using a-butyllithium as base17 gave rise to (10) (42 %). However, when the Wittig transformation was performed using potassium hydride in dimethylsulphoxide18 the yield increased to 72 %. In situ deprotection was followed by Jones oxidation19 to yield the olefinic acid (11) (73 %), which was converted to the corresponding acid chloride (12) in 54 % yield through the very mild procedure involving use of oxalyl chloride with dimethylformamide as a catalyst.20 74 Scheme 9 1. O^MeOH, -78 °C 2. pTsOH 3. Me^S 74% CH^Ph3 DMSO (COCl)2, PhH, DMFcat % (12) (9) With the obtainment of the unsaturated acid chloride (12), the stage was now set to attempt the crucial intramolecular ketene-olefin cycloaddition. Reactions were routinely carried out under high dilution conditions using slow addition of triethylamine as base to benzene solutions of the acid chloride. However, in spite of extensive experimentation, the desired cyclobutanone (9) was never formed in more than trace amount, as evidenced by infra-red monitoring of the crude reaction products for the presence of the four-membered ring carbonyl group at 1780 cm~1. Our attention was therefore directed towards the generation of the more reactive keteniminium salts. Accordingly, the acid chloride (12) was converted to the pyrrolidine amide (13) which is an apposite precursor of the keteniminium salt (14) (Scheme 10). Once again however, in spite of repeated efforts involving very slow syringe addition of trifluoromethanesulphonic anhydride (0.02 M in dichloromethane) to dilute solutions of the amide and collidine no evidence was adduced for the formation of the required cyclobutanone. Hydrolytic work up merely afforded the stating amide. Ketenes have a tendency to dimerize21 hence it was important to use conditions of high dilution in order to keep the ketene concentration low. However, at low concentrations the acid chloride is obviously more susceptible to hydrolysis. This is especially true of the keteniminium salts because of their enhanced electrophilic character. 76 COC1 RT (12) (13) 55% 1. collidine 2. ( CF^O^A Scheme 10 Although every effort was made to achieve the rigorously anhydrous conditions required, the presence of adventitious water, particularly on a small scale and operating under high dilution, is probably responsible for the failure to achieve cycloaddition. Direct experience of the difficulty in generating and handling keteniminium salts was available in our laboratory in the person of a postdoctoral colleague from the Ghosez group who confirmed that such apparently simple cycloaddition reactions were often very difficult to realise in practice. 2.3 Construction of the Monocyclic Precursor At the same time synthetic approaches to the tricyclic nucleus were being performed (Scheme 11). Retrosynthetic analysis suggested that we take advantage of the symmetry of the formal dehydration products of the addition of a carbanion to 2,5- dimethylcyclopentanone since, irrespective of the mode of elimination, formation of the same endocyclic product would be predicted to occur on grounds of ring strain. A Wittig approach was envisaged and hence 2,5-dimethylcyclopentanone22,23 (15) and ethyl 5-bromo-2-methylpentanoate24 (18) were prepared. The preparation of (15) commenced with the alkylation of 2- (methoxycarbonyl)cyclopentanone by methyl iodide (Scheme 12). The resulting monoalkylated product (16) was then converted in a one-pot process to the 2,5- dimethyl derivative (17) by a methoxide-catalysed reverse Dieckmann cleavage and subsequent recyclization in the opposite sense by removal of methanol.22 It was found that distillation had to be continued for a further 0.5 h after the temperature had reached 134 °C in order to effect complete recyclization. The sodium enolate was subsequently quenched with methyl iodide to give 2,5-dimethyl-2- (methoxycarbonyl)cyclopentanone (17). Decarboxylation yia the enol was then effected by hydrolytic treatment with aqueous sulphuric acid.23 78 1. NaOMe, MeOH Scheme 12 A 15 h 2. -MeOH 3. Mel 4 . H30* 'r o O 20 % aq. In terms of the second fragment required, attempted partial alkylation of ethyl propanoate with 1,3-dibromopropane to give (18) led only to ethyl 2-methyl-3- oxopentanoate (19) arising from self-condensation of the ester (Scheme 13). O o o OEt Scheme 13 92% 09) 79 However, this problem was readily overcome by conducting the alkylation at a lower temperature and employing the bulky t-butyl ester as substrate (Scheme 14).24 Scheme 14 t-Butyl 2-methyl-5-triphenylphosphoniumpentanoate, bromide salt, was then prepared in 72 % yield by heating equimolar proportions of t-butyl 5-bromo-2- methylpentanoate (20) and triphenylphosphine25 and coupling with 2,5- dimethylcyclopentanone was attempted using Wittig methodology 26 Generation of the desired ylide was then accomplished using potassium dimethylsulphoxyl anion as the base (Scheme 15). However, n.m.r. monitoring of reaction aliquots showed that the olefin-forming reaction was very slow and low-yielding; only a trace of alkene had formed after three days and there was little increase after ten days. Although other potential olefin-forming reactions such as the Peterson27 and Julia28 reactions could have been attempted, the competing basicity of the necessary carbanion was deemed to be a problem and these were not attempted for the trisubstituted alkene (21). Other alternatives including metal halogen exchange of the corresponding iodo ester or use of the small, linear acetylide anion as shown in Scheme 16 were also considered in an effort to reduce the problems associated with the sterically encumbered but neutral phosphorus ylide. Scheme 16 The coupled product (21) was to be hydrolysed to the acid while simultaneously isomerizing the double bond to the endocyclic position. Mild conditions would furnish the acid chloride (22)20 from which the ketene (23) and keteniminium salt (24) would be generated as described above (Scheme 17). However, this approach was peremptorily abandonned at this stage not only because of the low yields in the model study, but more importantly, because the increasing usage, and success, of this methodology in the literature meant that such a strategy would no longer bear originality. 81 Instead, we ventured forth to investigate newer and more exciting prospects for the direct construction of cyclopentanoids, as detailed in the next chapter, which did not require the additional steps inherent in further ring expansion from cyclobutanones. Scheme 17 Chapter Three The Intramolecular Transition Metal Catalysed f27c+ 2q1 Approach to Polvauinanes 3.1 introduction As we have argued in the preceding chapters, the strategy of using an intramolecular cycloaddition reaction for direct construction of the tricyclic nucleus of angularly fused polyquinanes is certainly the most attractive, particularly when two a bonds are formed in a single reaction. An even more economical approach than the tc2s + it2a cycloaddition, however, would be the homologous [3 + 2] cycloaddition reaction, which avoids the necessity for a further ring expansion protocol (Scheme 18). Scheme 18 Examination of the recent literature in this context reveals that the intermolecular version of the palladium (0) catalysed Ntrimethylenemethane-likeN reaction of electron deficient olefins with 2-trimethylsilylmethylallylic acetates (Scheme 19) has proven to be extremely useful.29 83 Pd (0) Pd MeC>2C MeC^C Scheme 19 However, extension of this reaction to the intramolecular mode is synthetically unattractive in terms of appropriate precursor construction. Our attention was therefore captivated by an alternative reaction first discovered by Noyori30 and extensively investigated by Binger31 involving reaction of an alkylidene cyclopropane and an olefinic acceptor and catalysed by a nickel (0) or palladium (0) complex. The essential features of this reaction are summarised in Scheme 20. Ni(0) Aa proximal cleavage (bondb) / = \ Scheme 20 From the mechanistic standpoint, we were particularly intrigued by the fact that this reaction does not involve the generation of an analogous trasition metal complex to that involved in the Trost29 trimethylenemethane chemistry (Scheme 19). Thus, reaction of the differentially substituted norbornadiene derivative proceeds with equal facility at both the electron rich and the electron poor double bonds (Scheme 21 ),32 whereas use of the Trost reagent would lead to exclusive attack at the a,p unsaturated ester. Pd(0) CC^Me Scheme 21 The curious contrast between the behaviour of nickel and palladium catalysts in terms of preferred proximal and distal cleavages has already been alluded to in Scheme 20 and was reason for further mechanistic interest. Closer examination of the body of work on the intermolecular variant in synthetically more useful situations featuring alkyl and aryl substituted reagents reveals however why this formally efficient reaction has failed to gain in popularity (Scheme 22). In the first instance, self-reaction of the alkylidene cyclopropane may dominate, either to give rearranged dienes or dimeric adducts.33 Regiochemically, the situation 85 is complicated not only by the possibility of proximal or distal addition, but also by further alkyl group scrambling in the alkylidene cyclopropane derived intermediate and completely confounded by the presence of regioisomers with respect to the olefinic acceptor component. In terms of stereochemical control, while good evidence is available that the initial geometry of the olefinic acceptor is preserved in the adducts, little information is available concerning the outcome in terms of polyalkylated alkylidene cyclopropanes. Clearly, such a reaction is of little use to the preparative chemist. We reasoned however, that many of these problems could be totally avoided through use of the intramolecular variant of this reaction. This could therefore become, in its own right, an extremely powerful tool for the construction of complex molecular systems. The immense body of literature on the intramolecular version of the Diels- Alder reaction,1 with its subtle mechanistic variants on the basic theme, such as the asynchronicity of bond making and conformationally biased preferences for the formation of exo adducts, serves to illustrate that simple extension to the intramolecular mode may be of immense value. Initial work in our group34 (Scheme 23) on the palladium (0) catalysed distal cycloaddition of a diphenylmethylene cyclopropane derivative provided the first example of such a reaction and established the validity of this concept. In this instance however, the precursor for cyclisation was carefully designed, not only to benefit from the Thorpe-lngold effect35 of the gem-dimethyl group, but also to feature the use of the diaryl substituted cyclopropyl derivative which facilitates cleavage of the carbon-carbon bond in the cyclopropane ring32. 86 Pd(0) or ------► + Ni(0) distal \ proximal Pd(0)orNi(0) mode scrambling Ni(0) + regioisomer \ + 3 other + 3 other regioisomers regioisomers Scheme 22 87 PtKdtakPCO—<)3, A ,100 °C or (Ph$>)fd + sonicadon 1:1 mixture of diastereomers 1:1 mixture Scheme 23 80% Towards the end of the work described in the present thesis, a second example of the intramolecular reaction was reported by the group of Nakamara (Scheme 24).36 Ni[COD]2or ------** P d C l^ h ^ disobutylalumnium hydride (distal cleavage) Scheme 24 88 3 .2 Strategy Towards Construction of an Acyclic Precursor for a Bicvclo[3.3.01octane Framework Initially, we chose to study a simple model cyclisation reaction leading to the bicyclo[3.3.0]octane skeleton and featuring the energetically more demanding case of a simple alkylidene cyclopropane which did not possess the added advantage of aromatic substitution (Scheme 25). Moreover, the choice of acetylenic terminus would permit variation in terms of increasing electron acceptor power in the series H < SiMe3 < C 0 2Me and also allow a detailed study of the influence of the metal and the concentration and nature of the ancillary ligands. MeC^C Me02C Z Z=H, SiMe3, C O ^e Scheme 25 A simple convergent approach to the required precursors involving sequential alkylation of dimethyl malonate derived anions with propargyl bromide and a 2- methylenecyclopropylcarbinyl derivative was envisaged (Scheme 26). The formation of the alkylidene cyclopropane involved a precedented37 addition of methylchlorocarbene to a double bond followed by dehydrohalogenation. Initial efforts employed the trimethylsilyl ether of allyl alcohol, 1,1-dichloroethane, and n-butyllithium as base, to give (25). These were thwarted, however, by 89 problems of substrate volatility resulting in a low yield of isolated product (13 %). (34 % based on recovered starting material). PO Cl£HCH3 ------► ^ c' base (PsSiMej (25) ) base x Scheme 26 P = protecting group X = leaving group We therefore opted to prepare the higher molecular weight derivative (26) by the route outlined in Scheme 27, which also possessed the advantage that the more electron rich trisubstituted double bond would be more susceptible to addition of methylchlorocarbene. Careful experimentation was required in order to achieve the indicated yields. Firstly, the yield in the chlorocarbene addition product (26) was markedly improved from 30 % to 75 % by sequential generation of two portions of the lithium carbenoid. (Interestingly, use of a large excess of 1,1-dlchloroethane initially was less successful). 90 1. C1£HCH3 OSiMePh2 OSiMePh2 74% Scheme 27 K+ lBuO'/DMSO TBAF OH ------ Competing deprotection of the silyl ether was also noted in the potassium tert- butoxide promoted elimination. Hence a work up procedure was developed which involved deprotection with fluoride anion to give the alcohol (27) directly. And so the stage was set for the conversion of the primary alcohol (27) to an electrophilic derivative suitable for alkylation with the known38 malonate fragment prepared by reaction of dimethyl malonate with homopropargyl bromide. Unfortunately, reaction of the hydroxyl group with para-toluenesulphonyl chloride in pyridine afforded the derived tosylate (28) as an extremely labile substance which was prone to spontaneous decomposition between 35 °C and 40 °C upon attempted reduced pressure solvent removal. 91 \ X / OT! — (28) OTs' OTs i J tertiary homoallylic allylic cation assistance ■ i f+ ring J expansion c h 2+ Scheme 28 With hindsight, the fragility of this compound is readily appreciated (Scheme 28). Cyclopropyl carbinyl tosylates are known to be a reactive class of compounds39 under solvolytic conditions. In the case of tosylate (28), participation by the neighbouring carbon-carbon bond is especially favoured since it leads to a tertiary allylic cation by virtue of the gem-dimethyl group. In addition there is the possibility of homoallylic participation from the exomethylene double bond of the alkylidene cyclopropane. Efforts were nevertheless made (Scheme 29) to react tosylate (28) with the anion derived from the propargyl malonate (29). The combination of a relatively unreactive carbanion component with the superactive tosylate was however unsuccessful and no evidence was found for formation of the derived carbon-carbon bond. 92 Scheme 29 MeO^C l.NaH x - MeO^C 2.(28) (29) Attempted preparation of the corresponding bromide (30) from the tosylate (28) by an exchange reaction with sodium bromide in acetone led to the formation of an inseparable mixture of products which n.m.r analysis indicated to contain not only the desired bromide (30) but also the rearranged diene (31). (30) In view of these problems, it was therefore decided to investigate the homologous carbon series, in which cyclisation would yield the hydrindane skeleton (Scheme 30). Scheme 30 93 3 .3 Construction of Acyclic Precursors for Bicvclor4.3.01nonane Frameworks The required exomethylene cyclopropane was readily assembled by the route shown in Scheme 3 1 39 In this case however, the experience gained in the early nor-methvlene series was used to advantage. Thus, selection of the tetrahydropyranyl ether (32) of but-3-en-1-ol ensured that this group was not lost under the relatively harsh dehydrohalogenation conditions. Additionally, the "insulation" from neighbouring group participation provided by the extra methylene carbon atom allowed direct conversion of the alcohol to the iodide using the extremely mild triphenylphosphine- imidazole-iodine combination,41 without the necessity of including a tosylation step. 1. (Q ) , H* (88%) 2. C1^CHCH3 3. nBuLi (32) 11 4. repeat 2. and 3. 76 % from THP Scheme 31 K+tBuOV DMSO 1.H+/Hp ------X 2. PhgP/iy imidazole H (34) X = OH (86%) (33) 88% (35) X = I (72 %) 94 Formation of the final carbon-carbon bond was then effected smoothly and in high yield by alkylation of the propargyl malonate (29) with iodide (35) using sodium hydride in dimethylformamide (Scheme 32). Deprotonation of the terminal acetylene (36) with n-butyllithium followed by quenching of the resultant anion with either chlorotrimethylsilane or methyl chloroformate42 then afforded the required series of precursors for intramolecular cyclisation. Scheme 32 3.4 The Palladium (0) Catalysed Reaction Attention could now be focused on the key transition metal catalysed cycloaddition reaction in a possible distal mode (Scheme 33). Palladium was selected in the first instance for study in a possible distal mode reaction (Scheme 33) in combination with the acetylenic ester (38), since intermolecuiar reactions featuring this electron deficient partner appeared to be highly efficient. 95 ? Pd(0) catalyst (38) ------» distal mode Scheme 33 In terms of detailed catalyst and ancillary ligand selection, close scrutiny of the large number of intermolecular reactions fails to reveal any useful predictive guidelines. Thus, a variety of starting palladium (0) complexes may be employed in combination with a range of phosphines or phosphites differing in electron donating ability. Finally, and quite remarkably, as exemplefied in Scheme 34, the structure of the # major product may even be altered merely by changing the concentration of the same trialkylphosphine ligand. This reaction type may truly be classified as a "black-box" art. Following on from our work in the energetically easier diphenyl methylene cyclopropane cyclisations34 we elected to use bis(benzylideneacetone) palladium (0) as the metal catalyst, and to follow an observation made in intermolecular cases32 • that better yields may be obtained by pumping a solution of ajducts into a preheated solution of the catalyst. We were also able to benefit from the designed intramolecularity of the system by running reactions at dilute substrate concentrations, typically of the order 0.02-0.05 M, thus eliminating any possibility of competing dimerisation reactions. 96 R Ligand (eq) Yield (%) I II m IV (%) (w.r.t. metal) Ph 1.0 85 13 16 71 Ph 4.0 86 49 39 12 Me 1.0 83 20 12 48 20 A systematic study of the concentration and nature of the ancillary phosphorus ligands was then made, (Table 1), from which some mechanistic conclusions may be drawn (vide infra). From the immediate practical standpoint however, this allowed the optimisation of experimental conditions whereby through use of eight equivalents of triisopropylphosphine with respect to palladium and a two hour reflux, it was possible to isolate a novel product in 41% yield. Mass spectral and analytical data served in the first instance to establish that the structure was isomeric with that of the starting alkylidene cyclopropane (38), while the infra-red spectrum displayed two ester carbonyl absorptions at 1 733 cm"1 97 (saturated) and 1 710 cm'1 (unsaturated) and the absence of an acetylenic ester stretch. Initial examination of the 1H n.m.r. spectrum lent considerable credence for the formation of a bicyclic product of the desired type (39). Thus, the absence of the cyclopropyl protons present in the starting material (38), the appearance of three distinct carbomethoxy groups, and the presence of two exomethylene protons were all in accord with the properties anticipated for a rigid bicyclic structure. Possible products involving endocyclic double bond isomerisation (such as (40) and (41) ) were also readily dismissed by noting the absence of any vinylic methyl groups (Scheme 35). (39) (40) (41) Scheme 35 Similarly, a sequence involving isomerisation of the alkylidene cyclopropane to diene (42) followed by intramolecular Diels-Alder reaction to give (43) was considered to be improbable because of the absence of the expected 10 Hz olefinic coupling between the two olefinic protons1 (Scheme 36). 98 Ha (42) Scheme 36 Further n.m.r. investigation of this compound was therefore undertaken. The 13C data indicated the presence of four sp2 centres, three of which are disubstituted and one of which is terminally olefinic, as demonstrated by a DEPT 135 experiment (Scheme 37). Four methylene groups are also present. The DEPT experiment also showed that there are four carbon centres bearing an odd number of protons. Since three of these are methoxy groups, as is evident from the 1H n.m.r. spectrum (Scheme 38), then it follows that there exists one methine proton. These data support the structure (39). Proton decoupling experiments were necessary to complete the assignment of 1H chemical shift values and to evaluate the complex couplings. The two protons at 3.35 ppm were consistent with an isolated methylene group whose couplings are to the olefinic protons (4.99 and 4.915 ppm) (Scheme 38). In addition, this pair of sp2 protons is coupled only to the proton at 3.12 ppm (Table 1). This multiplet has large couplings with protons at 1.35 and 2.12. Protons at 1.35, 2.12, 2.45 and 1.94 ppm are all mutually coupled (Scheme 39). The magnitudes of the coupling constants suggest that these four protons constitute two adjacent methylene groups. The proton at 4.24 ppm has a large coupling with that at 2.35 ppm. Again, the relatively uncomplicated splitting of the former proton suggests that this is a separated methylene entity. 99 Scheme 37 13C Chemical Shift Values o f t C 29.3 b 30.7 | 50 fl 170.6 O o Scheme 38 1H n.m.r. spectrum for the product formed by Pd (0) catalysis Scheme 39(T) Coupling constants (Hz) of the Pd(0) bicycle H The decoupling experiments support the assignment of proton chemical shift values in Scheme 40; these are also in accord with the two dimensional proton-proton correlation spectrum. In conclusion, the results of these studies are entirely consistent with structure (39), the product of a palladium (0) assisted cycloaddition. 102 Scheme 39 (ii) In the case of the trimethylsilyl acetylene (37) a reflux period of 72 h was followed by column chromatography (5% diethyl ether/petrol) of the crude residue from the reaction mixture. 1H n.m.r. analysis revealed that the major fraction (34 mg) contained two compounds (2 sets of ester signals) which co-ran on t.I.c. No starting material was recovered. Mass spectral data showed a parent molecular ion isomeric with that of the starting material. Not surprisingly, there was present a ring opened uncyclised product, as indicated by several olefinic peaks and the loss of the cyclopropyl protons. An acetylene was also present in this mixture (2.9 ppm (CH2C=C) and 2 177 cm"1 (infra-red) ). 103 3 .1 2 a: values interchangeable H H Chemical Shift Values Scheme Scheme 40 104 More interestingly, by comparison with the spectrum of the product arising from the acetylenic ester, the presence of remarkably similar signals (4.92, dd, olefinic; 4.85, dd, olefinic; 3.15, m; 2.45, m; 2.1, m; 1.9, m and 1.3 ppm, m) strongly suggested that an analogous bicyclic product had been formed. At this juncture, it is appropriate to return in some detail, to the mechanistic implications of this reaction, and in particular to the conclusions which may be drawn from a careful study of the ancillary phosphorus ligands (Table 1). From the outset, we were convinced that the nature of the phosphine itself would prove to be vitally important, particularly in respect of the superior donor ability of phosphines when compared with the less electron rich phosphites. We were also aware that the attainment of a relatively hindered series of intermediates might be strongly influenced by the cone angle43 of the phosphite and hence predicted that trimethyl phosphite could well be superior to the more bulky triisopropyl phosphite. In the event, examination of the results in Table 1 reveals that these conclusions were largely misconceptions. Firstly, we note that use of palladium (0) bis(dibenzylideneacetone) in the absence of any phosphorus ligand is totally ineffective. Although the complex was reported32 to be thermally stable B£r we have found that reflux under an inert atmosphere led to deposition of metallic palladium. Secondly, as implied above, the electronic nature and bulk of the phosphorus ligand is relatively unimportant. In the final analysis, the most critical factor would appear to be the relative concentration of the phosphorus ligand in the system. 105 Table 1 Entry Cyclisation Phosphorus Reaction Products Recovered Precursor (a) Ligand Conditions (% yield) Starting Temp./Time Material (°C) / (h) (% yield) 1 ( 3 8 ) none 1 1 0 1 2 trace >50 2 ( 3 8 ) A 1 eq 1 1 0 4 complex none m ixture 3 ( 3 8 ) A 1 eq sonication 8 trace >95 4 ( 3 8 ) A 4 eq 1 10 1 2 2 5 none 5 ( 3 8 ) A >4 eq 1 10 1 2 3 5 3 0 6 ( 3 8 ) B 4 eq 1 10 3 0 2 5 none 7 ( 3 8 ) C 1 eq 1 1 0 5 trace 1 5 8 ( 3 8 ) C 4 eq r.t. 1 2 none 1 0 0 9 ( 3 8 ) C 4 eq 1 1 0 2 2 4 0 none 1 0 ( 3 8 ) C 8 eq 1 1 0 2 41 none 1 1 ( 3 6 ) A 4 eq 1 1 0 9 0 complex none m ixture 1 2 ( 3 7 ) A 4 eq 1 10 7 2 41 none Cycloaddition reactions of acetylenic hydrindane precursors (36), (37) and (38) catalysed by Palladium (0) bis(dibenzylideneacetone) (10 mole % with respect to substrate) in toluene at 0.02 - 0.05 M concentrations of substrate. (a) number of equivalents of phosphorus ligand with respect to catalyst: A = triisopropyl phosphite; B = trimethyl phosphite; C = triisopropyl phosphine. 1 0 6 In this respect, the intramolecular variant differs markedly from its intermolecular counterpart. In the latter case best results are normally obtained using a oneione molar ratio of palladium catalyst and phosphine or phosphite ligand; a higher concentration of phosphorus ligand leads to rapid and complete inhibition of the reaction.44 There are several possible explanations for this concentration reversal in the intramolecular case, which are best illustrated by consideration of possible mechanistic pathways, (Scheme 41) for a hypothetical cyclisation involving tetrakis(triphenylphosphine) palladium (0). Irrespective of the fact that the true fascination of this reaction lies in unscrambling the series of possible intermediates involved in sequential carbon-carbon o bond formation the importance of the phosphine ligands occurs at the beginning and at the end of the catalytic cycle. Thus, sequential displacement of two triphenylphosphine ligands and olefin coordination is certainly required to bring the alkylidene cyclopropane and the unsaturated acceptor together. The first step is almost certainly coordination of the unsaturated acceptor to the palladium as indicated, since back bonding should result in a stronger complex in this instance. In the last stage of the reaction where reductive elimination of a metallocycle is required at least one of the two "departed" triphenylphosphine molecules must return to give either a catalytically active los. triphenylphosphine palladium (0) species or the starting tetrakis(triphenylphosphine) complex. 107 rearrangement; a bond formation 11 108 The importance of the return of the phosphorus ligands in the fate of a nickel metallocyclopentane has been studied by Grubbs45 (Scheme 42) who demonstrated that three possible reaction pathways are controlled by ligand concentration. Thus, p- hydride elimination is observed from the 14 electron three coordinate complex (I), reductive elimination from the 16 electron four coordinate complex (II) and conversion to a bis-ethylene complex requires the availability of an 18 electron five coordinate species such as (III). Scheme 42 With these facts in mind, the considerable advantage of being able to operate at higher phosphorus ligand concentrations in the intramolecular case becomes apparent. Thus, in the intermolecular reaction use of greater than one equivalent of ligand with respect to palladium considerably diminishes the possibility of the metal finding both an acceptor olefin and an alkylidene cyclopropane and hence reaction is effectively quenched. 109 In the intramolecular case however, as soon as complexation of the acceptor olefin to palladium (0) has occurred the next stage of the reaction is entropically favoured by the immediate presence of an alkylidene cyclopropane in the same molecule. In the present study this is also reinforced by the Thorpe-lngold35 effect of the geminal carboxymethyl groups. Furthermore, the increased phosphorus ligand concentration will not only promote the desired reductive elimination at the expense of competing p-hydride elimination pathways (as in Scheme 42) but will also ensure that the catalytically active species (for example Pd(PPh 3 )3 ) does not undergo decomposition to deposit metallic palladium. In this way, the turnover number and catalytic efficiency is improved by comparison with intermolecular cases. A final point of interest from the results in Table 1 is that the cycloaddition reaction certainly prefers a more electron deficient olefin. Thus, while cycloadducts were obtained from the carbomethoxy and silyl substituted alkyne derivatives (38) and (37) reaction of the parent alkyne afforded an extremely complex mixture from which no cyclised product was isolated. 3.5 The Nickel (0) Catalysed Reaction At this stage, we were also intrigued with the exciting possibility of obtaining a second regioisomer from the same alkylidene cyclopropane through use of the nickel (0) catalysed proximal cycloaddition (Scheme 43), the appropriate geometry being derived by a "simple" rotation around a carbon-carbon single bond. Me02C| MeC>2C C02Me Me02C (38) Me02C Pd (0) Ni (0) distal 9 proximal i 1 (39) Scheme 43 In terms of the ideal geometry for such a reaction, we were well aware that the relative orientation of the electron deficient olefin and the alkylidene cyclopropane did not correspond to that deduced by the elegant deuterium labelling studies of Noyori2b for the bis(acrylonitrile) nickel (0) catalysed reaction of the parent exomethylcyclopropane with methyl acrylate (Scheme 44). Reaction was nevertheless attempted. As anticipated from the work of Noyori2 and Binger3 , reactions proceeding yia the smaller and more labile nickel (0) complexes may be conducted at much lower temperatures. In the event, use of nickel (0) bis(cyclooctadiene) at room temperature led to the formation of a novel cycloadduct whose spectra immediately revealed that it was not identical to that derived through use of palladium. An unoptimised yield of 20 % was obtained. Interestingly, in this case, use of ancillary phosphine or phosphite ligands appears to lead to complete inhibition of the reaction. 111 £ f D CC^Me MeC^C (CH^HCN^i (0) Scheme 44 70% Me02Cr XD d A detailed spectral examination of the product was then undertaken. As in the case of the palladium adduct, infra-red and mass spectral analysis confirmed that the acetylenic ester was absent and that a monomeric isomeric structure had been formed. Once again the n.m.r. spectrum revealed the presence of three non-equivalent carbomethoxy groups, an exomethylene type carbon-carbon double bond and the absence of any vinylic methyl groups as would also be anticipated for the proximal mode adduct (44). The 13C data of the Ni(0) cyclised product revealed a compound which contains three carbonyl groups and four olefinic centres, one of which is a terminal alkene group (Table 2). There are four methylene groups. Additionally, the presence of a methine- bearing carbon was confirmed by a DEPT 90 experiment (Scheme 45). The 13C data support a bicyclic adduct. 112 Scheme 45 DEPT 90 experiment for the cyclised product formed by Ni (0) catalysis i m 113 Table 2 1 Data of the Ni (0) product 172.6 C=0 (flfijn-diester) 53.1 MeO 171.0 C = 0 (afiLm-diester) 5 2 .6 MeO 166.4 C=0 (unsaturated ester) 51.5 MeO 155.5C=C 47.6 methine 1 5 5 .4 C=C 37.1 methylene 1 3 4 .0 0 = 0*0 On Me 3 5 .0 methylene 1 0 4 .3 H2£=C 32.8 methylene 56.9 (M e0 2C)2£ 32.1 methylene 1 H n.m.r data support a bicyclic structure. Decoupling experiments were necessary in order to evaluate the coupling constants (Table 3). The signals corresponding to the methoxy groups and exo-methylene protons were readily discernable. However, nOe experiments were undertaken (Scheme 46) to determine the position of the exo-methylene group. Hence, irradiation at 4.73 ppm (low field exo-methylene) was found to enhance the group of signals between 3.6 and 3.8 ppm (Scheme 47). There was also a strong enhancement of the signal at 4.85 ppm. Irradiation at 4.85 ppm (high field exo-methylene) caused enhancement of this same region (3.6 to 3.8 ppm) and the multiplet proton at 2.76 ppm. Similarly, there was also a strong enhancement of the neighbouring exo-methylene proton (4.73 ppm). Irradiation at 3.76 ppm (methoxy group of the unsaturated ester) gave rise to a strong nOe of the signal at 4.73 ppm. 114 Table 3 1H n.m.r data of the Ni(0) compound 4.85 1H, s, exo-methylene (£& to unsaturated ester) 4.73 1H, s, exo-methylene (trans to unsaturated ester) 3 .7 6 3H t s, M e02C (unsaturated ester) 3.69 3H, s, Me02C (flfijn-diester) 3.67 3H, s, Me02C (flfim-diester) 2.81 1H, m, J 4 and 15.5 Hz, 2 .7 6 1H, m, J 2, 4 and 4 Hz, 1-Hp (equatorial) 2 .2 6 1H, d, J 15.5 Hz, 2.21 1H, m, J 3.5, 3.5 and 15 Hz, 1.72 1H, m, J 3.5, 4, 12.5 and 12.5±1 Hz, 1.58 2H, m, J 2, 3.5, 12.5±1 and 14 Hz, 1 .4 6 1H, m, J 12.5, 14 and 15 Hz N.b. One proton lies beneath the unsaturated ester signal. These nOe results indicate that the exo-methylene group is situated at the 2-position (Scheme 47). Furthermore, the chemical shift of one of the 1-H protons has now been established (2.76 ppm). The fact that only one, and not both, of the 1-H geminal protons is enhanced suggests that the five-membered ring is considerably puckered. A molecular model indicated that this proton is in the 1-Hp (equatorial) position. Attempted irradiation of each of the aani-dimethoxy groups (3.67 and 3.69 ppm) in turn was not selective because of the very close similarity in chemical shift. However, there was some enhancement of the signal at 4.73 ppm. 115 Scheme 46 nOe studies on the nickel (0) catalysed product U,!' 116 Irradiation of the signal at 2.26 ppm caused very strong enhancement at 2.81 ppm. There was a strong nOe at 2.76 ppm and some enhancement in the methoxy region. The splittings of the signals at 2.26 and 2.81 ppm are consistent with an isolated methylene group. It is noteworthy that the proton at 2.81 ppm is split only once. The proton at 2.3 ppm is also split by long-range couplings. Because of the complexity of the 1H n.m.r. spectrum definitive assignment of every proton was not possible. In the final analysis, it can be said that the summation of the entire spectroscopic data is wholly consistent with the formation of an isomeric bicyclic adduct in the proximal mode. 3 .6 An Approach to a Precursor Biased Towards Proximal Cleavage In tandem with these studies, initial efforts were also made to construct a constrained precursor for proximal mode cyclisation (Scheme 48). H Ni (0) ------► ? Scheme 48 A key element in our planning was that the carbon-carbon double bond of the alkylidene cyclopropane should be accessible by Homer-Wadsworth-Emmons technology46 using the cyclopropyl phosphonate (45) either in reaction with a simple lactol followed by further elaboration a i m reaction with a suitable aldehydic 117 fragment (46). The cyclopropyl phosphonate (45) had already been prepared in our group47 by copper (I) triflate catalysed addition of diethyl diazomethylphosphonate (47) to cyclopentene. These considerations are summarised in Schemes 49 and 51. Scheme 49 Generation of the a-lithio phosphonate using n-butyilithium as base followed by reaction with the 8-lactol (48)48 failed however to give any trace of olefin (Scheme 49), and so our attention was directed towards preparation of the acyclic aldehyde fragment (46). This proved to be readily accessible by a two step sequence involving reaction of the same lactol (48) with carboethoxytriphenylphosphorane to give the alcohol (49) followed by oxidation with pyridinium chlorochromate49 (Scheme 50) which furnished the desired precursor (46). OH OH EtQ2C (49) PCC H Scheme 50 Et02C Use of the aldehyde (46) in conjunction with the cyclopropyl phosphonate (45) under the standard basic conditions of the Wadsworth-Emmons reaction failed however to generate the necessary trisubstituted double bond (Scheme 51). Indeed, attempted isolation of the intermediate p-hydroxyphosphonate (50), prior to exchange of the metal counterion,50 led to isolation of an intermediate in which even the carbon- carbon double bond of the unsaturated ester unit was absent. Spectral evidence was consistent with the formation of the Michael adduct (51) derived by the addition of the intermediate alkoxide anion. Although formation of the first carbon-carbon bond in the phosphonate coupling reaction was an encouraging sign, since the resultant Michael reaction of the alkoxide is inherently reversible, suitable experimental conditions to promote olefination were not discovered and further studies in this series were not made. 119 \ Scheme 51 3 .7 Initial Synthetic Strategies in the Direction of the Isocomene Framework and Perspectives While the aforementioned fundamental studies were still in progress, we also set out to achieve our stated objective of constructing the tricyclic angularly fused nucleus of p-isocomene. A variety of possible monocyclic precursors for either proximal or distal cyclisation and varying in relative disposition of the alkylidene cyclopropane and unsaturated olefinic acceptor may be envisaged (Scheme 52). O « Scheme 52 We chose however to examine the possibilities inherent in the p-substituted enone (52) which may be retrosynthetically derived as shown (Scheme 53) from a variety of readily assembled precursors in a highly convergent way. 121 R R Scheme 53 R=Ph, H J> O Y = Li Y = I X X X = Br (1,4 addition) X = OMe (1,2 addition) exchange In order to facilitate distal cleavage of the cyclopropyl ring the construction of the diphenylmethylene cyclopropane was commenced (Scheme 54). The cyclopropyl phosphonate (55) was formed by carbene insertion into the silyl protected alcohol (54). Despite many repeated efforts and rigorous precautions of oxygen exclusion (thourough degassing of reactants and solvents) the yield was poor (19%; 95% based upon recovered starting material). Moreover, when this cyclopropanation was attempted on the tetrahydropyranyl protected alcohol (56) only recovered starting material was obtained. 122 Scheme 54 PhjMeSiCl, Et3N 95% DAMP, 0 °C Cu(I)OTf CH£12 II P(OEt)2 OTHP The attempted alkylation of benzophenone with cyclopropyl phosphonate (55) led to the recovery of the aromatic ketone and the formation of diphenylmethylsilanol (57), instead of the expected methylene cyclopropane (58) (Scheme 55). 123 Scheme 55 O II P(OEt)2 OSiPh2Me OSiPh2Me (55) Ph^eSiOH (57) In order to establish whether the lack of success lay with the initial coupling or with the elimination step of the intermediate we considered it sagacious to try and isolate the {3-hydroxyphosphonate (59) (Scheme 56). Unfortunately, no coupled product was obtained; starting material was recovered in greater than 90%. Scheme 56 O II P(OEt)2 OSiPh2Me OSiPh2Me (55) It now remained to pursue the route employing the unsubstituted methylene cyclopropane analogue. Construction of the simple carbon homologue of the alkylidene cyclopropane was entirely straightforward. The yields for the various steps are indicated in Scheme 57 and require no further comment. 124 Scheme 57 (95 %) 1. C^CHCHj 2. nBuLi 3. q £ H C H 3 4. nBuLi l r C l KO'Bu, DMSO f H OTHP ------OTHP (61) (80%) (60) (57 %) The known vinylogous acid bromide (53) was then prepared using a standard reaction51 of cyclopentane-1 f3-dione with triphenylphosphine dibromide. initial efforts to forge the necessary carbon-carbon bond centered around conversion of the iodide (63) to the corresponding cuprate reagent52 yia metal halogen exchange followed by a conjugate addition-elimination sequence (Scheme 5 8 )53 125 Consideration was then given to the possibility of reversing the polarity in this reaction through use of a vinyllithium reagent which could formally be derived by metal halogen exchange of a suitably protected derivative of the ketone (Scheme 59). Such a strategy has been employed in the homologous cyclohexyl series.54 Protection of the bromo enone through ketalisation with ethylene glycol and pyridinium para- toluenesulphonate was however unsuccessful. 1 2 6 Scheme 59 At this stage, although a variety of alternative techniques and strategies were still available for coupling of the cyclopentanoid fragment and the alkylidene cyclopropane, the constraints of time prevented further work. In retrospect however, the present thesis has demonstrated that the intramolecular variant of the alkylidene cyclopropane-olefin cycloaddition reaction may be successfully applied in the energetically more demanding case of cyclopropanes which do not possess judiciously placed aromatic rings to favour carbon-carbon bond cleavage. An even more exciting prospect however is that the choice of the metal provides a further control element which can be used to control regiochemistry. In this respect, the cyclisation can therefore be considered to be even more flexible than the intramolecular Diels-Alder reaction. Much work remains to be done in determining the more subtle stereochemical factors and in unravelling mechanistic aspects. The dream of controlling four stereochemical centres around a five-membered ring and using an optically active catalyst to control enantioselectivity may yet be possible. 127 Experimental Infrared spectra were recorded on a Perkin Elmer 983G grating infrared spectrophotometer as thin films or as dichloromethane solutions. 1H n. m. r. spectra were recorded at 89.55 MHz on a Jeol FX 90Q, at 250 MHz on a Brucker WM-250, at 270 MHz on a Jeol GSX 270 instrument and at 500 MHz on a Brucker AM-500, with tetramethylsilane or chloroform as internal standard. 13C n. m. r. spectra were recorded at 22.51 MHz on a Jeol FX 90Q, at 67.9 MHz on a Jeol GSX 270 instrument and at 125.8 MHz on a Brucker AM-500 instrument using deuterochloroform as internal standard. Mass sectra were recorded on a VG Micromass 7070B instrument using electron impact as the ionisation techique. Elemental microanalysis was performed in the Imperial College Chemistry Department microanalytical laboratory. Analytical thin-layer chromatography was performed on precoated glass-backed plates (Merck Kieselgel 60 F25 4 ); developing utilized u.v., acidic ammonium molybdate (IV) or iodine. Preparative column chromatography was performed at low positive pressure on Merck Kieselgel 60 (230-400 mesh). "Silica" refers to this grade of Kieselgel. "Petrol" refers to redistilled light petroleum ether (b.p. 40-60 °C) and "ether" to diethyl ether. Ether, tetrahydrofuran, xylene, toluene and benzene were distilled from sodium-benzophenone ketyl under argon immediately prior to use, unless otherwise specified. Dimethylformamide and dimethylsulphoxide were distilled from calcium hydride at reduced pressure and stored over 4A sieves under an argon atmosphere. Dichloromethane was freshly distilled from phosphorus pentoxide under an argon atmosphere prior to use. 1,1-dichloroethane was passed through a pad of potassium carbonate before distillation from phosphorus pentoxide and storage over 4A sieves under an argon atmosphere. Pyrrolidine, pyridine, collidine, diisopropylamine and 128 triethylamine were dried by distillation from potassium hydroxide and storage over sieves under an argon atmosphere. Triisopropyl phosphite and triisopropyl phosphine were distilled under reduced pressure from sodium and stored over 4A sieves under an argon atmosphere. Trimethyl phosphite was first treated with sodium, then decanted prior to distillation under reduced pressure and storage under an argon atmosphere over 4A sieves. Imidazole was recrystallised from dichloromethane- petrol. Brine refers to a saturated aqueous sodium chloride solution. Organic phases were dried over magnesium sulphate or anhydrous sodium sulphate and concentrated using a rotary evaporator at water pump pressure. 129 1.1 -Dimethoxyheptan-6-one. O OMe s OMe 1- Methyl-1-cyclohexene (9.8 g, 0.102 mmol) was dissolved in methanol (150 ml) and cooled to -78 °C. The solution was ozonised for a period of 6 h (0 2 rate : 90 dm3ir1; potential difference = 180 v), then stirred with p-toluenesulphonic acid (0.25 g) for 2 h at room temperature. Dimethyl sulphide (6.2 g, 0.1 mmol, 1.0 eq) was added and stirring was continued overnight. The solution was concentrated under reduced pressure to one half of its volume and then stirred with a solution of 10% aqueous sodium hydrogen carbonate. The mixture was extracted with ether and the organic layer was washed with water and dried (Na2S 0 4 ). Distillation of the residue afforded 1.1-dimethoxvheptan-6-one55 (12.9 g, 74 mmol, 74 %) as a colourless liquid, b.p 60-62 °C/0.3 mmHg. vmax(NaCI) 2 942, 2 829, 1 713 (C=0), 1 437, 1 363 and 1 128 cm'1, 5H(90MHz; CDCI3) 4.4 (1H, t, J 5 Hz, (MeO)2CJi- ), 3.30 (6H, s, MeO), 2.45 (2H, t, J 7 Hz, 5-H2), 2.10 (3H, s, MeC=0), 1.2-1.8 (6H, m, 2- H2, 3-H2, 4-H2). 1.1-Pimethoxv-6-methvlhept-6-ene (10). (10) Usino n-butvllithium as base n-Butyllithium (3.8 ml of a 1.45 M solution in hexanes) was added dropwise to a 130 stirred solution of methyltriphenylphosphonium bromide (2.0 g, 5.5 mmol, 1.1 eq) in tetrahydrofuran (35 ml), which had been precoled to -78 °C. Stirring of the bright, lemon yellow mixture was continued for a further 1.5 h, then a solution of 1,1-dimethoxyheptan-6-one (0.87 g, 5.0 mmol,1.0 eq) in tetrahydrofuran (5 ml) was added, when the yellow colour rapidly disappeared. The reaction mixture was slowly allowed to warm to room temperature over a 5 h period, after which it was quenched with water (30 ml) prior to extraction with petrol. Triphenylphosphine oxide was removed by filtration. Partial removal of solvent and cooling of the petrol phase overnight in a fridge enabled more triphenylphosphine oxide to be removed. Reduced pressure removal of solvent and column chromatography (silica-10% ether/petrol) of the crude residue afforded 1.1 -dimethoxy-6-methylhept-6-ene (10) (0.40 g, 2.32 mmol, 46 %) as a colourless oil. vm ax(NaCI) 2 938, 2 828, 1 647 (C=C), 1 449, 1 374 and 1 128 cm'1, 8H(90MHz; CDCIg) 4.69 (1H, s, C=CH2), 4.66 (1H, s, C=CH2), 4.36 (1H, 1, J 5.5 Hz, (MeO)2CH.- ), 3.31 (6H, s, MeO), 2.02 (2H, t, J 7.2 Hz, 5-H2), 1.71 (3H, s, Me), 1.60 (2H, m, 2-H2), 1.5- 1.25 (4H, m, 3-H 2 , 4-H2 ), nL/2. 174 (0.1%, M-+ ), 173 (0.6, M.-H), 143 (4, M.- OMe), 142 (3, M.-MeOH), 75 (100, +CH(OMe)2 ), (Found: C, 69.85; H, 11.95. C i 0 ^ 2 0 ^ 2 recluires C, 69.72; H, 11.70 %). Using dimethylsulphoxide anion as base Dimethylsulphoxide (70 ml) was added to potassium hydride (6.58 g, 64 mmol, of a 35 % w/w suspension in oil). After stirring for a 0.5 h period a solution of methyl triphenylphosphonium bromide (23.2 g, 57.6 mmol) in dimethylsulphoxide (50 ml) was added to give a yellow solution. Stirring was continued for 1 h after which a solution of 1,1-dimethoxyheptan-6-one (10.0 g, 57 mmol) in dimethylsulphoxide (50 ml) was added. Work up was effected after 14 h by pouring the mixture into water (250 ml), extracting it with petrol, drying the organic phase (MgS04) and concentrating it at reduced pressure. Column chromatography (silica-7% ether/petrol) of the crude mixture afforded (10) (7.0 g, 41 mmol, 72 %). 131 6-Methylhept-6-enoic acid (11). Jones' reagent (prepared from chromium trioxide (10.6 g, 10.7 mmol), water (40 mi) and sulphuric acid (7 ml, cone.), precooled in ice) was added dropwise to a rapidly stirred mixture of the alkene (10) (1.00 g, 5.8 mmol) in ether (20 ml, commercial), and water (10 ml), precooled to 0 °C. After 3 h the reaction mixture was quenched by the dropwise addition of 2-propanol (5 ml, precooled in ice). Extraction with ether was followed by washing with water and drying (M gS04) of the organic layer. Reduced pressure removal of solvent and bulb-to-bulb distillation of the residue (oven temp. 150-155 °C/0.8-1.5 mmHg, lit.56 b.p.83°/0.4mm) yielded 6-methvlhept-6-enoic acid (11) (0.60 g, 4.2 mmol, 73 %). vmax(NaCI) 3 500-2 600 (C02H), 2 950, 1 707 (C=0), 1 647 (C=C), 1 412 and 1 374 cm-1, 8H(90MHz; CDCI3) 11.15 (1H, broad s, C02H), 5.00 (1H, d, J 1.3 Hz, C=CH2), 4.67 (1H, d, J 1.3 Hz, C=CH2 ), 2.37 (2H, t, J 7.2 Hz, 2-H2 ), 2.03 (2H, t, J 7.6 Hz, 5-H2), 1.70 (3H, s, Me), 1.65-1.55 (2H, m, 3-H2), 1.55-1.4 (2H, m, 4- H 2 ), m Jz. 142 (6%, M.+ ), 124 (14, ML-H2 0 ), 82 (100, M .-H2 C = C (O H )2 ). 6-Methvlhept-6-enovl chloride (12). Oxalyl chloride (0.24 g, 1.9 mmol, 1.1 eq) was added to a stirred solution of the acid (11) (0.24 g, 1.7 mmol, 1.0 eq) and dimethylformamide (50 pi, cat.) in 132 dichloromethane (5 ml) at room temperature. Stirring was continued for 1 h after which solvent was removed under reduced pressure. Bulb-to-bulb distillation of the crude residue (oven temperature 115-120 °C/0.8-1.0 mmHg) afforded 6- methylhept-6-enoyl chloride (12) (0.15 g, 0.90 mmol, 54 %), vmax(NaCI) 2 938, 2 866, 1 795 (C=0), 1 646 (C=C), 1 450, 1 402 and 1 372 cm-1; this reported compound10 was used without further purification. N-(6-Methylhept-6-enoyhpyrrolidine __ (13).- A solution of pyrrolidine (142 mg, 2.0 mmol, 2.2 eq) in dichloromethane (4 ml) was added to a solution of the acid chloride (12) (145 mg, 0.90 mmol) in dichloromethane (6 ml), whilst stirring at room temperature. After 3 h the reaction mixture was acidified with 10 % hydrochloric acid (6 ml) and this aqueous phase was extracted with ether. The combined organic layers were washed with a solution of saturated aqueous sodium hydrogen carbonate, water and dried (M gS04). Reduced pressure solvent removal and column chromatography (silica-20% ether/petrol) of the residue produced the requisite amide (13) (97 mg, 0.50 mmol, 55 %), which was used without further purification. vm ax(NaCI) 2 938, 2 873, 1 635 (C =0, C=C) and 1 437 cm'1, 6H(90MHz; CDCIg) 4.7 (2H, s, C=CH2), 3.4 (4H, m, 2'-H2, 5'- H2), 2.3 (2H, m, 2-H2), 2.1-1.9 (6H, m, 5-H2, 3'-H2, 4'-H2), 1.7 (3H, s, Me), 1.5 (4H, m, 3-H2, 4-H2). 133 Attempted cyclisation of 6-methylhept-6-enoyl chloride H21 ? (12) (9) Triethylamine (44 mg, 0.43 mmol, 1.1 eq) was added dropwise to a solution of the acid chloride (12) (63 mg, 0.39 mmol) in dichloromethane (30 ml, constituting a 0.01 M solution of (12) ) at room temperature. After 2 h the solvent was removed and the crude products were subjected to column chromatography (silica-10% ether/petrol). The second fraction, which comprised several faint and poorly-defined spots, showed a sharp peak at 1780 cm'1, which is characteristic of the desired cyclobutanone. Attempted cyclisation of N-(6-Methvlhept-6-enoynpvrrolidine (13) A solution of trifluoromethanesulphonic anhydride (76 mg, 0.27 mmol, 1.2 eq) in dichloromethane (15 ml) was added over a 20 h period to a solution of the amide (13) (44 mg, 0.23 mmol constituting a 0.015 M solution) and collidine (33 mg, 0.27 mmol, 1.2 eq) in dichloromethane (15 ml) at reflux. The mixture was then stripped of solvent and refluxed with 30 % hydrochloric acid (15 ml) for a period of 2 h. The cooled reaction mixture was extracted with ether and the organic phase was dried (M gS 0 4 ). Infra-red spectral examination of this mixture indicated the absence of a cyclobutanone and confirmed that the major carbonyl peak was characteristic of the starting amide (13). 134 2.5-Dimethyl-2-(methoxycarbonvhcyclopentanone M 7). 2-(Methoxycarbonyl)cyclopentanone (10.Og, 70.4 mmol,1.0 eq) in xylene (50 ml) was added to sodium hydride (3.30g of a 57% suspension in oil, 78.4 mmol, 1.1 eq) at room temperature under argon and stirred for 2 h. Methyl iodide (50.0g, 352 mmol, 5.0 eq) was added and the mixture was stirred for 20 h; excess methyl iodide was subsequently removed by distillation until the stillhead temperature reached 136 °C. • Sodium methoxide in methanol (1.67g, 72.6 mmol of sodium in 100 ml methanol) was added to the cooled mixture in one portion, afterwards refluxing for 15 h. Methanol was removed by distillation. Once the mixture had attained a constant 134 °C, distillation was continued for a further 0.5 h. When the mixture had cooled to room temperature methyl iodide (50.0 g, 352 mmol, 5.0 eq) was added, and stirring was continued for a further 12 h. The reaction mixture was poured onto a mixture of crushed ice, water (50 ml) and hydrochloric acid (cone. 20 ml), stirred for 2 h, and then thoroughly extracted with ether, washed with saturated aqueous sodium metabisulphite, water, and dried (MgS04). Removal of solvent gave 2.5-dimethyl- 2-(methoxycarbonyhcyclopentanone22a (17), 11.8 g (mixture of isomers) (78 % yield of (17) ), containing 30 % xylene by n.m.r. vmax (NaCI) 2 966 (CH2), 2 874, 1 749 (C=0 ketone), 1 729 (C=0 ester), 1 454, 1 374, 1 264, 1 196 and 1 155 cm'1,8 H(90 MHz; CDCI3) 3.70 (6Ht s, MeO), 2.5-1.5 (5H, m, 3-H2, 4-H2, 5-H), 1.34 (3H, s, 2-Me). 1.28 (3H, s, 2-Me), 1.19 (3H, d, J 3.9 Hz, 5-Me), 1.11 (3H, d, J 3.9 Hz, 5-Me), mJZ. 170 (11%, M.+ ). 142 (95), 111 (48, M.- 135 M e 0 2 C), 101 (100, (MeO)(OH)C(Me)CH2+), 88 (65, MeCH=C(OH)(OMe)+), 83(50, MeCH(CO)CHCH2+), 69 (77), 55 (71) and 41 ( 86). 2.5-Dimethylcyclopentanone (15). p-Ketoester (17) (11.7 g, 69 mmol) was refluxed with 20 % aqueous sulphuric acid (100 ml) for 13 h after which the mixture was ether-extracted. The organic layer was washed with aqueous saturated sodium hydrogencarbonate, water and dried (M gS04). Distillation afforded 2.5-dimethvlcyclopentanone (15), a colourless liquid, as a mixture of isomers (4.5 g, 40 mmol, 57 %) (b.p. 70-72 °C/^.70 mmHg; lit.57 147 °C/750 mmHg). vmax (NaCI) 2 961, 2 870, 1 735 (C=0), 1 452 and 1 159 cm'1, 8h (90 MHz ; CDCI3) 2.3-2.0 (2 H, m, 2-H, 5-H), 1.3-1.9 (4H, m, 3- H2\ 4-H2'), 1.12 (3H, d, J 3.7 Hz, Me), 1.05 (3H, d, J 3.7 Hz, Me). Attempted preparation of ethvl 5-bromo-2-methvlDentanoate (18). n-Butyllithium (7.7 ml of a 1.4 M solution in hexanes) was added to diisopropylamine (1.1 g,11 mmol) in tetrahydrofuran (50 ml). After stirring for 15 min at room temperature; the mixture was then cooled to between -20 °C and -30 °C. Ethyl propanoate (1.0 g, 10 mmol, 1 eq, neat) was added. After 0.5 h the mixture was added to 1,3-dibromopropane (6.0 g, 32 mmol) in tetrahydrofuran (20 ml) at 136 the same temperature. The mixture was warmed to room temperature over 12 h. 10 % hydrochloric acid was added, stirring rapidly for 10 min then extracting with ether, washing with water, saturated aqueous sodium metabisulphite, water, saturated aqueous sodium hydrogencarbonate and finally drying (MgSC^). Reduced pressure solvent removal followed by distillation of the residue gave ethyl 2-methyl-3- oxopentanoate (19) as a yellow oil. (0.72 g, 4.6 mmol, 92 %) b.p. 55-60 °C/1- 1.5mmHg. vmax (NaCI) 2 978, 2 938, 1 740 (C=0 ester), 1 712 (C=0 ketone), 1 431, 1 375, 1 240 and 1 194 cm-1, 6H(90MHz; CDCI3) 4.20(2H, q, J 7.0 Hz, M eC J±2 0-), 3.52 (1H, q, J 7.0 Hz, (OC)MeJ±(CO) ), 2.56 (2H, q, J 7.8 Hz, CH 3 CJ±2 CO), 1.38 (3H, d, J 7.0 Hz, (OC)MjbH(CO) ), 1.30 (3h, t, J 7.0 Hz, M aC H2 0), 1.10 (3H, t, J 7.8 Hz, M&CH2 CO). ferf-Butvl 5-bromo-2-methylpentanoate (201. n-Butyllithium (56 ml of a 1.4 M solution in hexanes) was added to diisopropyiamine (7.6 g, 74 mmol, 1.1 eq) in tetrahydrofuran (80 ml), whilst stirring, over 20 min under argon at 0 °C. The mixture was cooled to -78 °C and t-butyl propanoate ( 8.8 g, 68 mmol, 1.0 eq) in tetrahydrofuran (10 ml) was added dropwise over 5 min. The mixture was stirred for 1.5 h after which 1,3-dibromopropane (27.4 g, 2.0 eq) in tetrahydrofuran (50 ml) at -78 °C was added and the mixture slowly warmed to 0 °C over an 18 h period. Hydrochloric acid (60 ml of 1.25 M) was added with rapid stirring and the mixture was extracted with ether, washed with saturated aqueous sodium bicarbonate and dried (MgSC^). Reduced pressure solvent removal followed by distillation gave terf-butyl 5-bromo-2-methvipentanoate (20) (11.8 g, 47 mmol, 69 %) b.p. 88-90 °C/3-3.5 mmHg as a colourless oil. This was used without further purification. vmax (NaCI) 2 974, 2 934, 1 723 (C=0), 1 456, 1 367, 1 252, 1 137 216 and 1 148 cm'1,8 H(250MHz; CDCI3) 3.41 (2H, t, J 6.7 Hz. BrCH2-), 2.34 (1H, m, CHMe), 1.9-1.4 (4H, m, BrCH2 CH.2 CtL2 -), 1-45 (9H, s, (CH3 )3 C-), 1.13 (3H, d, J 7.0 Hz, M-fi_CH), DL/Z. 235 (0.5%, 195 (2, B rC H 2 CH 2 CH 2 CHMeC(OH)2+), 177 (7, M-'BuOH), 149 (5, M.-,Bu0 2 C), 115 (5, 197-HBr), 69 (15, M.-HBr,-C0 2 Bu1), 57 (100, tell*). terf-Butvl 2-methvl-5-triphenvlphosDhonium pentanoate. bromide salt. OtBu OtBu t-Butyl 5-bromo-2-methylpentanoate (20) (11.8 g, 47 mmol, 1.0 eq) and triphenylphosphine (12.3 g, 47 mmol, 1.0 eq) were heated together under argon at 100 °C for 18 h. The glassy mass was dissolved in dichloromethane and triturated with ethyl acetate. After standing the mixture overnight to ensure further precipitation, the solid was filtered, washed (ethyl acetate) and dried in vacuo at 110 °C to give tert-butvl 2-methvi-5-triphenvlphosphonium pentanoate._bromide salt (17.5 g, 34 mmol, 72 %). Attempted coupling of terf-butvl 2-methyl-5-triphenylphosphonium pentanoate. bromide salt and 2.5-dimethylcyclopentanone (15) Potassium hydride (0.46 g of a 35 % w/w suspension in oil, washed once with ether: 4.0 mmol, 1.0 eq) and dimethylsulphoxide (12 ml) were stirred together under argon for 10 min at room temperature, after which the vigorous effervescence had subsided. A solution of t-butyl 2-methyl-5-triphenylphosphonium pentanoate, bromide salt (2.1 g, 4.0 mmol, 1.0 eq) in dimethylsulphoxide (16 ml) was added dropwise whereupon the mixture became dark orange. After complete addition the mixture had again become colourless. A solution of 2,5-dimethylcyclopentanone (15) (0.47 g, 4.2 mmol, 1.0 eq) in dimethylsulphoxide (6 ml) was added; the mixture was heated for 3 days at 55 °C with stirring, after which n.m.r analysis of a reaction mixture aliquot showed the presence of a triplet at 5.0 ppm and indicated that starting material was predominant. After 10 days the relative intensity of the triplet had increased slightly. The reaction mixture was cooled to 0 °C, poured into 15 % aqueous phosphoric acid (60 ml) and thoroughly extracted with pentane. The combined extracts were washed with water, dried (MgSC^) and the solvent removed under reduced pressure. Chromatography of the crude reaction mixture (a brown oil) (0.21 g) led only to the recovery of starting material. 3-(Trimethvlsilvloxv)prop-1 -ene. 2 ^ 1 OSiMe3 la 3 Triethylamine (28.8 g, 288 mmol, 1.1 eq) and chlorotrimethylsilane (31.0 g, 286 mmol, 1.1 eq) were added to a stirred solution of 4- dimethylaminopyridine (0.58 g, 4.7 mmol, 2 mol%) in dichloromethane (200 ml) under argon at 0 °C. Prop-2-en- 1 -ol (15.0 g, 258 mmol, 1.0 eq) was added dropwise over 5 min and the reaction mixture was subsequently stirred for 24 h before pouring onto a saturated aqueous solution of ammonium chloride. The aqueous phase was thoroughly extracted with diethyl ether and the combined organic layers were washed with water, dried (M gS 0 4 ) and the solvent removed. Distillation under an argon atmosphere gave 2 i 139 ftrimethvlsilyloxylprop-1 -ene (b.p 105-108 °C/760 mmHg, lit .58 1 0 8 -1 1 0 °C/760 mmHg) (14.3 g, 110 mmol, 43 %) as a colourless liquid. vmax (NaCI) 2 961, 2 862, 1 646 (C=C), 1 422, 1 252 (Me-Si), 1 089 (Si-O-C) and 843 (Si- O-C) cm'1, 6 h (90M H z ; CDCIg) 5.90 (1 H, ddt, J. 8.1, 8.1 and 3.9 Hz, 2-H), 5.83 (1 H, m, 1-H), 5.63 (1H, m, J1a>2 8 Hz, 1a-H), 4.1 (2 H, m, 3-H 2 ), 0.1 (9H, s, (CH 3 )3 Si), m/Z. 130 (1 %, M.+), 103 (5, M.-CH 2 CH), 73 (13, +CH 2 S i(C H 3 )2 ). 1 -Chloro-1 -m ethvl- 2 -trimethvlsilyloxvmethvlcvclopropane (25). MesSiO A solution of allyloxytrimethylsilane (5.0 g, 38 mmol) and 1,1-dichloroethane (4.2 g, 44 mmol, 1.2 eq) in ether (30 ml) under argon was cooled to between -30 °C and -40 °C prior to the dropwise addition of n-butyllithium (14.8 ml of a 2.6 M solution in hexanes, 1.0 eq) over a 2.5 h period. The mixture was then allowed to warm to room temperature and poured cautiously into water. The aqueous phase was extracted into ether, dried (Na2 S 0 4 ) and the solvent removed by distillation at atmospheric pressure. Further distillation of the residue yielded a fraction (b.p.^140 °C/atmos. press.), n.m.r. analysis of which revealed that all of the alkene had been consumed and that cyclopropyl protons were present (5^ 0 .8-1 ppm) in a several component mixture. 1-(DiDhenvlm ethvlsilvloxv)-3-m ethvlbut-2-ene. OH ______^ ° s iMeph2 140 3-Methyl-2-butene-1-ol (10.0 g, 116 mmol, 1.0 eq, neat) was added dropwise over a 10 min period to a solution of 4-dimethylaminopyridine (0.20 g, 1.6 mmol, 1 mol%), diphenylchloromethylsilane (30.0 g, 128 mmol,1.1eq) and triethylamine (13.1 g, 130 mmol, 1.1 eq) successively dissolved in dichloromethane (150 ml) under argon and subsequently cooled to 0 °C. The reaction mixture was allowed to warm to room temperature over 2 h after which it was poured into water and thoroughly extracted with dichloromethane. The organic layer was washed with brine, dried (MgS04) and the solvent removed under reduced pressure to give a crude product ( 86% yield) which was of high purity (> 90% by ^ H n.m.r.) and was used directly in the next step. vmax (NaCI) 3 068, 3 049, 3 0 2 1, 2 968, 2 912, 1 673 (C=C), 1 428, 1 380, 1 119 (Si-O-C), 1 061, 791, 737 and 718 cm-1, 8 h (90M H z ; CDCI3) 7.8-7.3 (10H, m, Ph2), 5.4 ( 1 H, t, J 6 Hz, Me2 C = C H ), 4.3 (2H, d, J 6 Hz, CH 2 0 ), 1.8 (3H, s, allylic methyl), 1.6 (3H, s, allylic methyl), 0.6 (3H, s, MeSi). 1 -Chloro-3-diDhenvlm ethvlsilvloxvm ethvl-1.2.2-trim ethvlcvclopropane 126). n-Butyllithium (34.7 ml of a 2.1 M solution in hexanes, 73 mmol, 1.3 eq) was added dropwise over a 2 h period to a stirred solution of diphenylmethylsilyl 2-methylbut- 2-enyl ether (16.1 g, 57.0 mmol) and 1,1-dichloroethane (8.2 g, 83 mmol, 1.4 eq) in ether (40 ml) under argon which had been cooled to between -30 °C and -40 °C. A second portion of 1,1-dichloroethane (8.2 g, 83 mmol, 1.4 eq) was then added before adding a further solution of n-butyllithium (34.7 ml, 73 mmol, 1.3 eq) over a 2 h period. The mixture was allowed to warm to room temperature, poured Into water, and thoroughly extracted with ether. Drying (M g S 04 ) and distillation of the residue 141 (<250 °C/0.07 mmHg) gave 1-chloro-3-diDhenylmethvlsilvlQxvmethyl-1.2.2- trim ethylcyclopropane (26) (14.4 g, 42 mmol, 74 %,) as a mixture of diastereomers (ratio 2:1 approx.). vmax(NaCI) 2 957, 1 428, 1 380, 1 119 (Si- O-C), 1 084, 1 061, 791, 737 and 699 cm"1, 8 h (90M Hz ; CDCI3) major isomer: 7.7-7.3 (10 H, m, Ph2), 3.9 (1H, d, J 3 Hz, CJ1HO), 3.8 1 ( H, d, J 3 Hz, CHHO), 1.6 (3H, s, gam-dimethyl), 1.3 (3H, s, MeCCI), 1.1 (3H, s, OfiJIL-di1methyl), 0.55 (1 H, d, J 3 Hz, cyclopropyl); minor isomer: 7.7-7.3 (10H, m, Ph2), 3.75 (1H, d, J 2 Hz, CHHO), 3.65 (1H, d, J 2 Hz, CHHO), 1.5 (3H, s, a£HL-dimethyl), 1.3 (3H, s, MeCCI), 1.0 (3H, s, gem-dimethyl). 0.7 (3H, s, MeSi), 0.55 (1H, d, J 3 Hz, cyclopropyl), m Jz. 329 (0.2 %, M_-Me), 309 (1, ML-CI), 227 (20, CH 2 O S iP h 2 C H 2 ), 197 (100, Ph 2 SiCH2), (Found: (M_-Me), 329.113 1. C i gH2 2 CIOSi requires M-Me 329.109 7). (3.3-Dimethyl-1-methylenecycloprop-2-yl)methanol (27). The silyl ether (26) (17.2 g, 50 mmol) was added dropwise over a 2 h period to a suspension of potassium t-butoxide (14.6 g, 120 mmol, 2.4 eq, sublimed once) in dimethylsulphoxide (50 ml) under argon maintained at 90 °C. After 20 h the mixture was poured into a solution of 2N hydrochloric acid, extracted with ether, and filtered through a pad of M gS04 . Most of the solvent was then removed by distillation at atmospheric pressure. Tetrabutylammonium fluoride (50 ml of a 1.1 M solution in tetrahydrofuran, 1.1 eq) was then added and stirring was continued overnight. 2N Hydrochloric acid was added to the reaction mixture which was then extracted with ether. The combined organic extracts were then dried (M gS04). The bulk of solvent 142 was removed at not less than 160 mmHg. Distillation of the residue gave (3.3- dim ethyl-1-methy lenecycloprop-2-yh methanol (27) (3.8 g, 34 mmol, 68 %), b.p. 65-70 °C /_20 mmHg, as a colourless oil. vmax (NaCI) 3 340 (OH), 2 950, 2 867, 1 747 (C=C), 1 445, 1 368, 888 (H2 C=C) cm"1,8 H(90MHz; CDCI3) 5.33 (1 H, d, J 2 Hz, H.HC-C), 5.29 (1H, m, HH.C-C), 3.75 (2H, m, CH 2 OH), 1.55 (1 H, m, cyclopropyl), 1.46 (1H, m, OH), 1.22 (3H, s, Me), 1.19 (3H, s, Me), m Jz. 113 (7 %, (M.+ H ) + ), 1 1 2 (4, L i), 111 (6, M_-H), 110 (3, M.-2H), 109 (4, M .-3 H ), 97 (18, M.-Me), 95 (100, Li-OH), 83 (10, Li-CH 2 OH), 81 (34, M.-CH 2 = C H 2 ,- H), 79 (51, M.-H 2 0,-Me), (Found: Li+, 112.088 8. C7 H120 requires M, 112.088 8). A tte m p te d ___ preparation___ a l___ 2.2-dim ethyi-3-(p-toiuenesuiphony I oxvmethvl)methvlenecvclopropane (28). OTs (27) (28) A solution of tosyl chloride (1.3 g, 6.8 mmol, 1.5 eq) in pyridine (6 ml), precooled to 0 °C, was added in portions to a solution of the alcohol (27) (0.50 g, 4.5 mmol) in pyridine (1 ml) and dichloromethane (6 ml) under argon at 0 °C. The reaction mixture was then stirred for 4 h after which it was added dropwise with vigorous stirring to an ice-cold solution of 2M sulphuric acid (10 ml) and crushed ice. Subsequent extraction with petrol (b.p. 30-40 °C) was followed by washing the combined extracts with ice-cold saturated aqueous sodium hydrogencarbonate and drying (M gS04 ) prior to solvent removal under reduced pressure in an ice-cold bath. Attempted column chromatography (silica-30/40 petrol) led to extensive product decomposition as shown by n.m.r. 6|_|(90MHz; CDCI 3 ) (crude spectrum) 8.0-7.1 (aromatics), 5.2 (exo methylene), 3.4-4 (CH 2 OTs), 2.5 (MeC 6H 4 ), 1 .2- 1.0 (4 methyl groups). Attempted preparation of 2.2-dimethvl-3-(bromomethv0methvlene cyclopropane m x - (28) (30) The crude tosylate (28) (prepared from 0.5 g, 4.5 mmol alcohol (27) ) in dichloromethane (5 ml) was added to a solution of sodium bromide (1.4 g, 14 mmol) in acetone (10 ml) and stirring was continued at room temperature overnight. The mixture was then poured into water, extracted with petrol (b.p. 30-40 °C), dried (M gS04) and chromatographed (silica- 1 00% petrol b.p. 30-40 °C), which affected a poor separation. N.m.r analysis indicated that a pure compound had not been obtained. vm ax (CH 2 C I2 ) 2 978, 2 951, 1 746 (C=C) and 1 375 cm'1, 8H(90MHz; COCI 3 ) 6.4 (m), 5.5 (m), 5.25 (2H, m, H 2 C=C), 5.1 (m), 3.2 (2H, m, CH2 Br), 1.40 (1H, m, cyclopropyl), 1.24 (3H, s, Me), 1.12 (3H, s, Me). Dimethyl but-3-vne-1.1-dicarboxvlate (29). Me02C Me02C Me02C MeQiC (29) Dimethyl malonate (25.0 g, 0.19 mol) was added to a solution of sodium methoxide (prepared from sodium, 4.45 g, 0.19 mol) in methanol (150 ml) under argon at 0 °C. Propargyl bromide (41.0 g of an 80 % w/w solution in toluene, 0.28 mol, 1.5 eq) was carefully added at such a rate as to maintain a gentle reflux. After 4 h the 144 reaction mixture was poured into water and thoroughly extracted with ether. The combined organic extracts were dried (MgS04) and solvent was removed under reduced pressure. Distillation of the residue yielded dimethyl but-3-yne-1. 1 - dicarboxylate (29) as a pale yellow liquid (11.1 g, 65 mmol, 34 %), b.p. 100-102 °C /^10 mmHg. vmax(CH 2 CI2) 3 303 (HC=C), 3 051, 2 955, 2 125 (C=C ),1 738 (C=0), 1 436, 1 342, 1 274, 1 240 and 1 159 cm'1, 5H(90MHz; CDCIg) 3.80 (6H, s, 2xMeO), 3.55 (1H, d, J 7.5 Hz, (Me0 2 C)2 CH), 2.80 (2 H, dd, J 2.5 and 7.5 Hz, C=CCJ±2), 2.05 (1H, t, J 2.5 Hz, O C R ), mJz. 170 (1 %, M +), 139 (34, M.- MeO), 111 (100, M .-M e 0 2 C), 110 (32, M_-Me0 2 C, -H), 79 (26, M.-Me0 2 C, - MeOH), 60 (40, C0 2 M e+), (Found: C, 56.57; H, 6.0 1. C8 H 1 0 O 4 requires C, 56.47; H, 5.92 %). Attempted alkylation of dimethyl but-3-vne-1,1-dicarboxylate f29) with 2 .2 - • dimethvl-3-(p-toluenesulphonyloxymethyl)methvlenecyclopropane (30). A solution of the malonate derivative (29) (0.34 g, 2.0 mmol) in dimethylformamide (5 ml) was added to a suspension of sodium hydride (93 mg of a 57 % w/w suspension in oil, 2.2 mmol; washed with ether (3x2 ml) ) in dimethylformamide (5 ml) with stirring under argon at 0 °C. After 10 min, the crude tosylate (28) (prepared from alcohol (27) 0.5 g, 4.5 mmol) in dichloromethane (5 ml) was added and stirring was continued for a further 1.5 h. The reaction mixture was poured into a saturated solution of aqueous ammonium chloride (35 ml), extracted with ether, washed with water, brine and dried (M gS04 ). Solvent was removed before purifying the mixture 145 by column chromatography (silica-10 % ether/petrol). Although n.m.r. revealed, as expected, the presence of the methylenecyclopropane fragment with loss of the tosylate group, no compound corresponding to the desired alkylation product was isolated. 1 -( (Tetrahvdro-2H-Dvran-2-vhoxv1but-3-ene. Concentrated hydrochloric acid (0.05 ml) was added to a mixture of 3-buten-1-ol (15.9 g, 221 mmol) and dihydropyran (19.5 g, 230 mmol) under argon at 0 °C with stirring, and the reaction mixture was allowed to warm to room temperature overnight. Sodium bicarbonate (1 g) was then directly added to the mixture; and stirring was continued for a further 10 min period. The reaction mixture was then thoroughly extracted with ether and the combined organic extracts were washed with brine and dried (M gS04 ). Removal of the solvent and distillation of the residue gave 1 -( (tetrahvdro-2H-pvran-2-vhoxv1but-3-ene (29.7 g, 190 mmol, 86 %) as a colourless liquid, b.p. 112-114 °OU2Q mmHg (lit.59 183-184 °C/760 mmHg). vmax CDCI3) 5.9 (1 H, m, C H = C H 2), 5.1 (2 H, m, CH=CM,2). 4.6 ( 1 H, m, 2'-H), 3.8 (2 H, m, 1-H2), 3.5 (2 H, m, 6’-H 2 ), 2.35 (2H, m, 2-H2), 2.0-1.3 (6H, m, 3’-H2 , 4’- H 2 and 5'-H2). 146 1 -Chloro-1 -methvl-2-(2-netrahvdro-2H-Dvran-2-vnoxvethvh— cyclopropane OTHP n-Butyllithium (90 ml of a 2.2 M solution in hexanes: 0.20 mol, 1.1 eq) was added dropwise over 3 h to a solution of the ether (32) (29.3 g, 0.188 mol) and 1,1- dichloroethane (20 g, 0.20 mol, 1.1 eq) in ether (170 ml) under argon whilst maintaining the reaction mixture between -30 °C and -40 °C. Stirring was continued overnight after which the reaction mixture was allowed to reach room temperature. At this stage 1H n.m.r. analysis of an aliquot showed that approximately 50 % conversion to the cyclopropane had been achieved. Subsequently, a second portion of 1 ,1 - dichloroethane (24 g, 0.24 mol) was added; the mixture was cooled as above and a solution of n-butyllithium (100 ml, 0.22 mol, 1.2 eq) was added dropwise over a 3.5 h period. The mixture was again stirred overnight, and allowed to warm to room temperature. 1H N.m.r. analysis at this stage showed a 70 % conversion to the desired product. A final portion of 1,1-dichloroethane (12 g, 0.13 mol, 0.7 eq) was added before cooling and adding n-butyllithium (40 ml, 0.09 mol, 0.5 eq) as described above over a 1.5 h period. The reaction mixture was then stirred overnight, and allowed to warm to room temperature. The solution was then poured into water (50 ml), stirred for 1.5 h and extracted with ether. The organic phase was thoroughly washed with water, brine, and dried (M gS04) and the solvent removed under reduced pressure. Distillation afforded 1 -chloro-1 -methvl-2-(2-(tetrahydro-2H-pvran- 2 -yhoxvethvh cyclopropane (32) (31.3 g, 0.143 mol, 76 % (88 % based upon recovered starting material) b.p. 80-84 °C/0.6 mmHg. vmax(NaCI) 2 938, 1 446, 1 120, 1 077 and 1 033 (C-O) cm'1,8 H(270MHz; CDCI 3 ) 4.62 ( 1 H, t, J 3.5 Hz, 147 2-H), 3.85 (2H, m, 2-H2), 3.5 (2H, m, 6'-H2), 2.0-1.4 (9H, m, 1-H2, 3-H, 3’- H 2 , 4'-H2 and 5’-H2 ), 1.61 (3H, s, Me), 0.91 (2H, m, 2 x cyclopropyl). This material was used for the next stage without further purification. 2-f2-ftetrahydro-2H-pyran-2-yl)oxyethyl)methylenecyclopropane (33). Cl 4' The tetrahydropyranyl ether (32) (30.0 g, 132 mmol) was added dropwise over 2.5 h to a stirred solution of potassium t-butoxide (30.8 g, 0.28 mol, 2.1 eq) in dimethylsulphoxide (60 ml) under argon at 80 °C. The mixture was then heated for a further 3 h after which it was cooled, poured into ice-cold water, and thoroughly extracted with ether. The combined organic extracts were washed with water, brine and finally dried (MgS04). Removal of the solvent under reduced pressure and subsequent distillation of the residue afforded 2-(2-(tetrahydro-2W-pyran-2- yhoxyethvhmethvlenecyclopropane (33) (21.2 g, 116 mmol, 88 %) b.p. 62-64 °C/1.2-1.3 mmHg. This was used without further purification. vm ax(NaCI) 2 943, 2 868, 1 743 (C=0), 1 440, 1 326, 1 077 and 1 036 cm'1, 8H(90MHz; CDCIg) 5.40 (2 H, m, CU.2 =C), 4.60 (1H, s, 2'-H), 3.76 (2 H, m, 2-H2 ), 3.53 (2H, m, 6'- H2), 2.0-1.1 (10H, m, 3'-H2, 4'-H2, 5'-H2, 1-H2 and cyclopropyl x 2), 0.79 (1H, m, cyclopropyl). 2-n-methvlenecycloprop-2-yhethanol (341. 148 The methylenecyclopropane (33) (21.0 g, 115 mmol) was added to a solution of p- toluenesulphonic acid (1.0 g, 4 mol %) in methanol (100 ml) under argon at room temperature. After 36 h, the reaction mixture was stirred with potassium carbonate (2.8 g) for 1 h . Methanol was then removed by distillation under argon at atmospheric pressure and water (30 ml) was added. The aqueous phase was thoroughly extracted with ether and the combined extracts were washed with water and dried (MgSC^). The ether was removed by distillation under argon at atmospheric pressure. Reduced pressure distillation of the residue yielded 2-(1- methvlenecvcloprop-2-yhethanol(34) (9.7 g, 99 mmol 86 %) as a colourless liquid, b.p. 82-86 °C/15-20 mmHg. This was used in the next step without further purification. vmax(NaCI) 3 330 (OH), 2 937, 1 744 (C=C) and 1 054 (C-O) cm"1, 8h (90M H z ; CDCI3) 5.40 (2H, m, CH2=C), 3.75 (2 H, d, J 6 Hz, 1-H2), 2.40 (1H, s, OH), 1.8-1.2 (4H, m, 2-H2 , cyclopropyl x 2), 0.85 (1H, m, cyclopropyl). 2-(2-lodoethvnmethylenecyclopropane (351. Triphenylphosphine (12.8 g, 49 mmol, 1.2 eq) followed by imidazole (3.34 g, 49 mmol, 1.2 eq) and finally iodine (12.4 g, 49 mmol, 1.2eq) were added to a stirred solution of the methylenecyclopropane (34) (4.00 g, 40.7 mmol) in acetonitrile/ether (1:3 v/v ; 400 ml) under argon which was maintained at 0 °C. After 1.5 h ether (300 ml) was added and the organic phase was washed with 5 % aqueous sodium metabisulphite, water, and dried (M gS04). Triphenylphosphine oxide was then removed by precipitation with petrol (b.p. 30-40 °C) and filtration. Solvents were then removed by atmospheric pressure distillation under argon. Bulb- to-bulb distillation (^.135 °C/^20mmHg) of the residue yielded 2-(2- iodoethyhm ethvlenecvclopropane (35) (6.1 g, 29 mmol, 72 %), as a colourless 149 liquid. vmax(NaCI) 3 066, 2 972, 2 923, 1 743 (C=C), 1 423 and 1 348 cm'1, 5 h (2 7 0 M H z ; CDCIg) 5.46 (1H, m, H2 C=C), 5.38 (1H, m, H2 C=C), 3.23 (2 H, t, J 7.3 Hz, 2-H2 ), 1.91 (2H, m, 1-H2 ), 1.57 (1H, m, cyclopropyl), 1.31 (1H, tt, J 2.2 and 9.0 Hz, cyclopropyl), 0.83 (1H, m, cyclopropyl), 8 q ( 6 7 .9 M H z ; CDCIg) 134.9 (H2C=£_), 103.8 (H2£_=C), 37.2 (C-1), 16.7 (cyclopropyl), 9.4 (cyclopropyl), 5.3 (C-2), m fz. 209 (36 %, M_H+), 81 (93, M_-1), (Found: M_H + , 208.982 8. CgHgl requires 208.982 7). Dimethyl 1-(methvlenecvcloproD-2-ynhex-5-vne-3.3-dicarboxvlate (361. MeC^C MeQ2C (29) The diester (29) (1.43 g, neat, 8.42 mmol, 1.4 eq) was added dropwise over 0.5 h to a suspension of sodium hydride (0.34 g, 8.1 mmol, 1.3 eq of a 60 % suspension in oil) in dimethylformamide (10 ml) at room temperature under argon and stirring was continued for a further 0.5 h until effervescence had ceased. The iodide (35) (1.27 g, 6.09 mmol) was then added in portions over a 0.5 h period and the mixture was stirred overnight. The reaction mixture was diluted with water and thoroughly extracted with ether. The combined organic extracts were washed with brine and dried (M gS04) and solvent was removed. Column chromatography (silica-5% ether/petrol) afforded the cyclization precursor dimethyl 1-fmethylenecvcloprop- 2-yl)hex-5-yne-3.3-dicarboxylate (36) (1.20 g, 4.81 mmol, 79 %). vmax(NaCI) 3 290 (C=C-H), 2 954, 1 751 (shoulder, C=C), 1 735 (C=0), 1 436, 1 273, 1 238 and 1 206 cm'1, 8H(270MHz; CDCI3) 5.43 (1H, m, H2C=C), 5.34 (1H, d. J l . 2 Hz, H2C=C), 3.74 (6H, s, MeO x 2), 2.80 (2H, d, J 2.7 Hz, 4-H2), 2.21 (2H, m, 2-H 2 ), 2.01 (1H, t, J 2.7 Hz, 6-H), 1.39 (1H, m, cyclopropyl), 1.24 (3H, m, 150 cyclopropyl; I-H 2), 0.74 (1H, m, cyclopropyl), 8 q (67.9MHz; CDCIg) 170.6 (C=0), 136.0 (£ = CH2), 102.9 (C=£.H2), 78.6 (C-5), 71.4 (C-6), 56.6 (C-3), 52.7 (MeO), 31.7 (C-1), 27.7 (C-2), 22.8 (C-4), 15.3 (cyclopropyl), 9.3 (cyclopropyl), (Found: C, 66.87; H, 7.30. C^H-igC^ requires C, 67.18; H, 7.25 %), mJZ. 250 (1 %, M.+), 218 (6, MrMeOH), 191 (13, M.-Me02C ), 190 (14, M r M e02C,-H), 187 (10, M-MeO,-MeOH), 179 (50, M -C02,-CH2C-CH), 148 (22, M.-C02,-Me0,-CH2C-CH), 131 (100, (Me02C)2CH), 79 (90, C6H7+), 59 (46, M e 0 2C+). Trimethyl 1-(methvlenecvcloprop-2-vhhex-5-yne-3.3.6-tricarboxvlate (38). n-Butyllithium (0.75 ml of a 2.4 M solution in hexanes; 1.8 mmol, 1.1 eq) was added over a 3 min period to a solution of the diester (36) (408 mg, 1.63 mmol) in tetrahydrofuran (5 ml) precooled to -78 °C under argon. The mixture was stirred for 5 min prior to the dropwise addition of methyl chloroformate (0.17 g, neat, 1.8 mmol, 1.1 eq). After 3 h the reaction mixture was warmed to room temperature over a period of 1 h and then poured into water (5 ml). The aqueous phase was thoroughly extracted with ether and the combined organic extracts were washed with brine and dried (M gS04). Removal of solvent followed by column chromatography (silica-10% ether/petrol) afforded the carbomethoxy derivative trimethvl 1- (methylenecvcloprop-2-vnhex-5-vne-3.3.6-tricarboxylate (38) (402 mg, 1.30 mmol, 80 %). vmax(NaCI) 2 995, 2 242 (C=C), 1 750 (shoulder, C=C), 1 736 (C=0, p-dicarbonyl), 1 716 (C=0, acetylenic), 1 434, 1 262 and 1 207 cm'1, 151 5H(270MHz; CDCIg) 5.43 (1H, m, H2C=C), 5.35 (1H, d, J 1.7 Hz, H2C=C), 3.75 (9H, s, MeO x 3), 2.96 (2H, s, 4-H2), 2.12 (2H, m, 1-H2), 1.42 (1H, m, cyclopropyl), 1.24 (3H, m, 2-H2, cyclopropyl), 0.74 (1H, m, cyclopropyl), 5c (67.9MHz; CDCI3) 170.2 (C=0, p-dicarbonyl), 153.7 (C=C£02Me), 135.9 (H2C = C_), 103.1 (H2£_=C), 83.6 (C-5), 75.3 (C-6), 56.4 (C-3), 53.0 ( (M£.02C)2C), 52.7 (C=CC02ML£L), 32.2 (C-1), 27.9 (C-2), 23.2 (C-4), 15.3 (cyclopropyl), 9.4 (cyclopropyl), ni/Z. 307 (0.1 %, M_-H), 245 (13, M_-MeO,- MeOH), 217 (34, M.-MeOCOH,-MeOH), 189 (44, M.-(2 x MeO),-Me02C), 179 (100, M-CH2C=CC02Me,-C02), 129 (64, MeO(CO)C(CO)OCH2+), 79 (78, M- (M e02C)2CCH2C=CC02Me) ), 59 (55, C02Me+), (Found: C, 62.48; H, 6.57. ^ 1 6 ^ 2 0 ^ 6 recP res C, 62.33; H, 6.54 %). Dimethyl 1 -(methvlenecvcloprop-2-yh-6-trimethvlsilvlhex-5-vne-3.3- ♦ dicarboxvlate (37). n-Butyllithium (0.46 ml of a 2.4 M solution in hexanes; 1.1 mmol, 1.1 eq) was added over a 3 min period to a solution of the acetylenic diester (36) (248 mg, 0.99 mmol) in terahydrofuran (4 ml) precooled to -78 °C under argon. After stirring for a further 5 min chlorotrimethylsilane (0.12 g, 1.1 eq) was added dropwise over a 2 min period. The reaction mixture was then stirred for 1 h at -78 °C before allowing to warm up to room temperature over 2 h and then poured into water. The aqueous phase was extracted with ether and the organic layer was washed with brine and dried (MgS0 4 ). Reduced pressure solvent removal followed by column chromatography 152 (silica-4% ether/petrol) gave the silyl derivative dimethyl 1- (methylenecvcloprop-2-vh-6-trimethvlsilvlhex-5-yne-3.3-dicarbQxylate (37), as a colourless oil (273 mg, 0.85 mmol, 85 %). vmax(NaCI) 2 956, 2 178 (CsC), 1 754 (C=C), 1 738 (C=0), 1 434, 1 250, 1 202 and 844 (C=CH2) cm"1, 8H(270MHz; CDCI3) 5.42 (1H, m, C=CH2), 5.35 (1H, m, C=CH2), 3.75 (6H, s, MeO x 2), 2.83 (2H, s, 4-H2), 2.18 (1H, m, 1-H2), 1.40 (1H, m, cyclopropyl), 1.23 (3H, m, 2-H2, cyclopropyl), 0.77 (1H, m, cyclopropyl), 5 q ( 6 7 .9 M H z ; CDCIg) 170.8 (C=0), 136.2 (H2C -£j, 103.0 (H2£=C), 101.2 (C-5), 88.2 (C-6), 56.9 (C-3), 52.8 (2 x MeO), 31.8 (C-1), 27.8 (C-2), 24.1 (C-4), 15.4 (cyclopropyl), 9.4 (cyclopropyl), (Found: M+, 322.159 4. C17H260 4 Si requires M 322.160 0), £072. 322 (1.1 %, M_+), 131 (37, (Me02C)2C H+), 73 (100, + C H 2 S iM e2 ), 59 (23, C 0 2 M e+ ). Typical run for the cvclization of trimethyl 1-(methylenecycloprop-2-ynhex-5- vne-3.3.6-tricarboxvlate (38) with palladium (0) bisfdibenzylideneacetonel and trialkyl phosphine/phosphite ligands PdCdba^ PhMe ------1 (iPr>3P, A CC^Me A solution of triisopropylphosphine (20 mg, 0.12 mmol, 40 mol%) in toluene (0.78 ml) was added to a solution of palladium (0) bis(dibenzylideneacetone) (17.8 mg, 31 pmol, 10 mol%) in toluene (2.00 ml) at room temperature under argon. (After a 5 min period the dark purple solution had become blood-red in colour; after a 0.5 h period the mixture had become a yellow colour). The mixture was heated to 110 °C 153 when after 10 min a solution of the ester (38) (94 mg, 0.31 mmol) in toluene (2.50 ml) was added dropwise over a 2 min period and refluxing was continued for a further 22 h. The reaction mixture was then filtered through a short pad of silica, eluting the pad with ether. Column chromatography (silica-10% ether/petrol) produced 1^ methylene-3.5.5-trimethoxycarbonylbicyclor4.3.01non-3^ne. (39) (19 mg, 0.062 mmol, 20 %), as a yellow oil. vmax(NaCI) 2 952, 1 733 (C=0, p- dicarbonyl), 1 710 (C=0, ap-unsaturated), 1 668 (C=C, exomethylene), 1 640 (C=C, conjugated), 1 432, 1 295, 1 247 and 1 112 cm-1, 5H(270MHz; CDCI3) 4.99 (1H, m, J 2.0 and 2.7 Hz, ijHC=C (cis. to ring methylene) ), 4.915 (1H, m, J 2.2 and 2.2 Hz, HJiC=C (cis. to methine) ), 4.24 (1H, dd, J 2.2 and 14.7 Hz, 4-Ha), 3.76 (3H, s, MeO (gem-diesterl ), 3.74 (3H, s, MeO (gfim-diester) ), 3.67 (3H, s, MeO (ap-unsaturated ester) ), 3.35 (2H, m, J 2.0, 2.2 and 2.9 Hz, 2-H2), 3.12 (1H, m, J 1.8, 2.2, 2.7 and 11-12 Hz, 8-H), 2.45 (1H, m, J 2.2, 2.2, 2.2 and 13.7 Hz, 6-Ha), 2.35 (1H, ddt, J 1.8, 14.7 and 2.9 Hz, 4-Hp), 2.12 (1H, m, J 2.2, 3.6 and 13.4 Hz, 7-Hp), 1.94 (1H, ddd, J 3.6, 13.7 and 13.7 Hz, 6-Hp), 1.35 (1H, m, 2.2, 11-12, 13.4 and 13.7 Hz, 7-Ha), 5C(125.8; MHz; CDCI3) 172.2 (C=0, p- dicarbonyl), 170.6 (C-O, p-dicarbonyl), 165.9 (C*C -£.02Me), 153.4 (C=C), 149.6 (C-C), 125.9 (C-3), 107.3 (H2£.«C), 56.1 (C-5), 52.9, 52.5, 51.3, 50.8 (3 x MeO, C-8), 39.7, 32.7, 30.7, 29.3 (CH2), m /i 308 (2%, M_+), 276 (100, M.-MeOH), 249 (9, M--Me02C), 216 (20, M_-MeOH,-Me02C), 189 (17, Mr 2xMe0,-Me02C), 129 (27, MeO(CO)C(CO)OCH2+), 59 (9, C02Me+), (Found: C, 62.19; H, 6.58. C-|0 H2 qO 0 requires C, 62.33; H, 6.54 %). (This general procedure was employed for dimethyl 1 -fmethylenecycloprop-2-vn- 6-trimethylsilylhex-5-yne-3.3-dicarboxyl ate (37) and dimethyl 1- (methylenecycloprop-2-yl)hex-5-yne-3,3-dicarboxylate (36) ). 154 Reaction of (38) with nickel (0) bis(cycloocta-1.5-diene) to produce 2-methvlene-3.5.5-trimethoxvcarbonvlbicvclof4.3.01non-3-ene (44) Me02C/ti M e C ^ C ^ ^ ------ (38) A solution of nickel (0) bis(cycloocta-1,5-diene) (2 mg, 7 pmol) in toluene (50 pi) was added to a stirred solution of the triester (38) (30 mg, 97 pmol) in toluene (2 ml) at room temperature under an atmosphere of argon. After a period of 0.5 h the reaction mixture was filtered through a short pad of silica using ether as eluant. Solvent was removed under reduced pressure and the crude residue was chromatographed (silica-20% ether/petrol) to produce recovered starting material (38) (11 mg, 36 pmol, 37 %) and a product (a yellow oil) (6 mg, 19 pmol, 20 % (32 % conversion based upon recovered starting material) ) whose spectral data were consistent with the structure (44). vmax(NaCI) 2 951, 1 736 (C=0, gem- diester), 1 704 (C=0, ap-unsaturated ester), 1 661 (C=C, exo-methylene), 1 595 (C=C, conjugated), 1 433, 1 355, 1 235, 1 103 and 735 cm-1, 5H(270MHz; CDCIg) 4.85 (1H, s, exo-methylene (cis to unsaturated ester) ), 4.73 (1H, s, exo methylene (trans to unsaturated ester) ), 3.76 (3H, s, Me02C (unsaturated ester), 3.69 (3H, s, Me02C (Ofim-diester) ) 3.67 (3H, s, Me02C (gem-diester) ), 2.81 (1H, m, J 4 and 15.5 Hz), 2.76 (1H, m, J 2, 4, and 4 Hz, 1-Hp), 2.26 (1H, d, J 15.5 Hz), 2.21 (1H, m, J 3.5, 3.5 and 15 Hz), 1.72 (1H, m, J 3.5, 4, 12.5 and 12.5 ±1 Hz), 1.58 (2H, m, J 2, 3.5, 12.5±1 and 14 Hz), 1.46 (1H, m, J 12.5, 14 and 15 Hz), 5c (125.8MHz; CDCI3) 172.6 (C=0, p-dicarbonyl), 171.0 (C=0, p- dicarbonyl), 166.4 (C=0, ap-unsaturated), 155.5 (C=C), 155.4 (C=C), 134.0 155 (C-3), 104.3 (H 2 C=C), 56.9 (C-5), 53.1, 52.6, 51.5 (3 x MeO), 47.6 (C- 8), 37.1, 35.0, 32.8, 32.1 (CH2), m Jz. 308 (12%, R +), 276 (12, ML-MeOH), 248 ( 1 2 , M .-M e 0 2 C,-H), 216 (14, M.-Me0H,-Me0 2 C), 189 (16, M.-Me0 2 C ,-2 x M e 0 ), 157 (11), 145 (10, 189-C02), 129 (20, MeO(CO)C(CO)OCH2+), 74 (37), 59 (57, Me02c + ), 45 (39), 31 (100, MeO+), 29 (41), (Found: M.+ 308.125 3. ^16H20°6 recllJires M. 308.126 0) 2-Hydroxytetrahvdro-2H-pyran (48). (48) Dibal (40 ml of a 1.5 M solution in toluene; 60 mmol, 1.0 eq) was added dropwise over a period of 0.66 h to a solution of 5-valerolactone ( 6.0 g, 60 mmol, 1.0 eq) in toluene (100 ml) maintained at -78 °C under argon. Stirring was continued for a further 10 min after which water (10 ml) was then added dropwise. The reaction mixture was slowly allowed to warm to room temperature. Ethyl acetate (6 ml) and sodium sulphate (1 g) were then added. The mixture was stirred for a 10 min period prior to filtration and washing of the solid sludge with toluene. Reduced pressure solvent removal followed by bulb-to-bulb distillation of the residue (oven temperature 100-110 °C/2-5 mmHg, lit.60 54-55 °C/3 mmHg) ) produced hydroxytetrahydro-2H-pyran (48) (4.43 g, 43.4 mmol, 73 %). vmax(NaCI) 3 393 (OH, broad), 2 944, 2 854, 1 441, 1 355, 914 and 901 cm'1, SH(90MHz; CDCIg) 4.95 (1 H, m, CH(OH) ), 4.70 ( 1 H, broad s, OH), 4.0 (1 H, m, 6-HaxO), 3.5 (1H, m, 6-HeqO), 2.0-1.4 (6H, m, (CH 2 )3 CH(OH) ). 156 Coupling of the lactol (48) with the phosphonate (45) n-Butyllithium (1.91 ml of a 2.3 M solution in hexanes; 44 mmol, 2.2 eq) was added dropwise over a 5 min period to a stirred solution of the lactol (48) (204 mg, 2.00 mmol, 1.0 eq) and the phosphonate (45) (436 mg, 2.00mmol) in tetrahydrofuran (30 ml) precooled to -78 °C under argon. The initial yellow colouration rapidly became colourless, however, the final solution was an orange-yellow colour. Stirring was continued for 2 h at -78 °C after which the solution was allowed to warm to room temperature overnight. The reaction mixture was then poured into a saturated solution of aqueous ammonium chloride, extracted with ether and dried (M gS04 ). Reduced pressure solvent removal was followed by column chromatography (silica- neat ethyl acetate) to yield diethyl (1-(1.5-dihydroxypentynbicyclof3.1 .Olhexvl) 1 -phosphonate (0.22 g, 0.69 mmol, 34 %), R^0.1 (ethyl acetate). 5H(90MHz; CDCI3) 4.20-3.95 (5H, 2 x d, J 7 Hz, (CH 3 CJi2 0 ) 2 P; CHOH), 3.60 ( 2 H, t, J 4.5 Hz, CH.2 OH), 2.1-1.9 (6H, m, Cj±2 CR 2 CR 2 (cyclopentyl) ). 1.8-1.5 ( 6H, m, CH 2 CH 2 CH 2 CH 2OH), 1.3 (6H, t, J 7 Hz, (CH3 CH 2 0 ) 2 P). This was used without further purification. Attempted elimination with potassium tert-butoxide A solution of potassium t-butoxide (21 mg, 0.19 mmol, 1.5 eq) in tetrahydrofuran (1 ml) was added over a 2 min period to a solution of diethyl (1-(1,5- dihydroxypentyl)bicyclo[3.1.0]hexyl) 1-phosphonate (43 mg, 0.13 mmol) in tetrahydrofuran (2 ml). (The first drop immediately produced a red colouration, 157 however the colour started to fade, becoming cloudy. After 15 min the reaction mixture had become a coarse, white suspension). The reaction mixture was then acidified (2N hydrochloric acid; 6 ml) and the aqueous phase was thoroughly extracted with ether and dried (M gSO ^. Thin-layer chromatography (neat ethyl acetate) of the organic layer revealed that all the starting material had been consumed and that only baseline material was present. Attempted elimination with sodium hydride A solution of diethyl (1-(1,5-dihydroxypentyl)bicyclo[3.1.0]hexyl) 1-phosphonate (38 mg, 0.12 mmol) in dimethylformamide (2 ml) was added to a stirred suspension of sodium hydride (47 mg of a 57 % suspension in oil: 27 mg, 0.64 mmol, 5 eq) in dimethylformamide (2 ml) maintained at room temperature under argon. Stirring was continued for a period of 1 h, after which the solution was heated at 90 °C for a 4 h period. The reaction mixture was then acidified and thoroughly extracted with ether. Thin-layer chromatography of the organic phase revealed only the presence of baseline material (neat ethyl acetate). Ethvl 7-hydroxyhept-2-enoate (491. (48) (49) A solution of (ethoxycarbonylmethylene)triphenylphoshine (6.12 g, 17.6 mmol, 1.2 eq) in acetonitrile (25 ml) was added to a solution of the lactol (48) (1.50 g, 14.7 mmol) in acetonitrile (25 ml) and refluxed under argon for a 48 h period after which the reaction mixture was then cooled and water (100 ml) was added. The cloudy suspension was extracted with ether, washed with water and dried (MgSC^). Reduced pressure solvent removal was followed by column chromatography (silica-65% 158 ether/petrol) to yield ethvl 7-hvdroxvheDt-2-enoate (49) (1.87 g, 10.9 mmol, 74 %). vmax(NaCI) 3 614 (sharp OH), 2 939, 1 708 (C=0), 1 651 (C=C), 1 368, 1 045 and 984 cm’1, 8H(90MHz; CDCI3) 6.96 (1H, dt, J 15.5 and 6.8 Hz, C H = C H C 0 2 Et), 5.83 (1H, dt. J 15.5 and 1.5 Hz, C M = C H C 02 Et), 4.18 (2 H, q, J 7.2 Hz, CH3 CU 20), 3.64 (2H, m, HOCH2), 2.22 (2H, m, CR 2CH=CH), 1.9 (1H, m, OH), 1.7-1.4 (4H, m, C R 2 C1±2 CH 2 0 H ), 1.29 (3H, t, J 7.2 Hz, C H 3 CH 2 0 ) (Found: C, 62.72; H, 9.53. C 9H 1 60 3 requires C, 62.76; H, 9.36 %), m/ 2. 172 (3%, M.+ ), 154 (4, M_- H 2 O). 127 (39, M_-EtO), 126 (64, M_-EtOH), 114 (13, E t0 2 CCH 2 C H=C H2+ ), 81 (100). Ethvl 7-oxohep1-2-enoate (461. A solution of the ester (49) (473 mg, 2.75 mmol) in dichloromethane (10 ml) was added to a stirred suspension of pyridinium chlorochromate (0.9 g, 4 mmol, 1.5 eq) and cellite (1.5 g) in dichloromethane (40 ml) at room temperature. Stirring was continued for a further 5.5 h after which the reaction mixture was diluted with ether (100 ml) and filtered through a pad of cellite, washing the pad with dichloromethane. The mixture was concentrated to approximately 10 ml and then it was added dropwise into a large volume of ether (200 ml). The cloudy suspension was then filtered through a florisil pad. The tarry cellite pad, from the previous filtration, was acidified with 2N hydrochloric acid (10 ml) and this aqueous phase was extracted with ether. The organic layers were combined and stripped of solvent. Column chromatography (silica-33% ether/petrol) afforded ethyl 7-oxohept-2-enoate (46), as a colourless oil (367 mg, 2.16 mmol, 78 %). (Acid-extraction of the tarry chromium residue was found to increase the yield by 9 %). vm ax(C H 2 Cl2 ) 2 940, 1 714 (C=0), 1 653 (C=C), 1 368, 1 252, 1 194, 1 159 and 1 043 c m '1 , 8 h ( 9 0 M H z ; CDCI3) 9.78 ( 1 H, t, J 1.3 Hz, CHO), 6.92 (1H, dt, J 15.5 and 6.9 Hz, * 159 C H = C H C 0 2 Et), 5.83 (1H, dt, J 15.5 and 1.5 Hz, C H =C H C 02 Et), 4.19 (2H, q, J 7.2 Hz, CH3 CH 2 0 ), 2.49 (2H, dt, J 1.0 and 6.9 Hz, CH2 CH=CH), 2.22 (2H, dt, J 1.3 and 6.7 Hz, CJ1 2 CH0), 1.85 (2H, m, CH2 CH 2 CHO), 1.29 (3H, t, J 7.2 Hz, CJd3 CH 2 0 ), m/Z. 170 (1%, M.+ ), 152 (5, M_-H2 0), 127 (41, 43 (McClafferty) ), 125 (56, Ll-EtO), 124 (64, M_-EtOH), 114 (82, Et02C C H 2C H = C H 2 + ), 99 (84, E t0 2 CCH=CH+), 81 (100), 68 (57, OHCCH=CHCH2+), (Found: M.+, 142.062 9. C 9H 1 4 O 3 requires M, 142.063 0). Attempted coupling of the phosphonate (45) and the aldehyde (461 * n-Butyllithium (0.85 ml of a 2.3 M solution in hexanes; 2.0 mmol,1.1 eq) was added dropwise to a solution of the phosphonate (45) (418 mg, 1.92 mmol, 1.1 eq) in tetrahydrofuran (20 ml) precooled to -78 °C. Stirring was continued for 15 min after which a solution of the aldehyde (46) (300 mg, 1.74 mmol) in tetrahydrofuran (1.5 ml) was added to the phosphonate solution over a period of 7 min. After stirring for a further 5 h, a solution of sodium t-butoxide (prepared from sodium hydride (0.60 g of a 57% suspension in oil; 0.34 g, 8 mmol, 4 eq) and t-butanol (545 mg) in tetrahydrofuran (10 ml) ) was added dropwise to the reaction mixture. This 160 mixture was allowed to warm to room temperature over a 1 h period. It was then poured into a saturated aqueous solution of ammonium chloride and acidified with 2N hydrochloric acid. The aqueous phase was extracted thoroughly with ether. The organic layer was then washed with water and dried (M gS04 ). Removal of solvent produced 0.7 g of a crude material (brown oil) whose n.m.r. spectrum was consistent with (51). 5 h (90M H z ; CDCIg) 4.1 (4H, m, P(OCtL2 CH 3 )2 ), 3.75 (2H, q, J 6.8 Hz, CH 3 C i± 2 0(CO) ), 1.9-1.7 ( 6H, m, CJ±2 CJtL2 CE 2 (cyclopentyl) ), 1.35 ( 6H, m, (CH 3 CH 2 0 ) 2 P), 1.25 (3H, m, CH3 CH 2 0 (C 0 ) ). 5-(Diphenylmethylsilyloxy)pent-1-ene (54). 2 4 OSiPh2Me la 3 5 (54) Pent-4-en-1-ol (10.25 g, 119 mmol, neat) was cautiously added dropwise to a solution of diphenylmethylchlorosilane (31.28 g, 134 mmol, 1.1 eq), triethylamine (14 g, 0.14 mmol, 1.2eq) and 4-dimethylaminopyridine (0.58 g, 4.6 mmol, 4 mol%) in dichloromethane, maintained at 0 °C. Stirring was continued for a further 24 h, after which the reaction mixture was allowed to warm to room temperature. It was then poured into water (200 ml). The aqueous phase was extracted with dichloromethane (2 x 250 ml) and the combined organic layers were dried (M gS04). Solvent removal was followed by column chromatography of the residue (silica-5% ether/petrol) which produced 5-fdiphenvlmethvlsilvloxvlpent-1 -ene (54) (31.65 g, 112 mmol, 94%). vmax(NaCI) 3 068, 2 936, 1 637 (C=C), 1 118 (Si- O-C), 790, 734 and 699 cm"1, 6H(270MHz; CDCI3) 7.6 (4H, m, aromatic), 7.4 (6H, m, aromatic), 5.78 (1H, m, 2-H), 4.98 (1H, m, J 1 a 2 16 Hz, 1 a-H), 4.94 (1 H, m, J1 2 9 Hz, 1-H), 3.74 (2H, t, J4|5 12 Hz, 5-H2), 2.14 (2H, m, 3-H2), 1.66 (2 H, m, 4-H 2 ), 0.64 (3H, s, MeSi), m J l 282 (4%, M.+), 267 (28, M.-Me), 204 (100, M_-PhH), 190 (31, M.-Me,-PhH), 199 (64, Ph2MeSiH + ), 121 (15, ¥ 161 P hM eSi+ ), 105 (2 1 , C6H4 Si+), (Found: C, 76.42; H, 7.86. C 1 8 H22OSi requires C, 76.54; H, 7.85 %). Diethvl 2-f3-fdiphenvlmethvlsilvloxv1prop-1 -yhcvclopropane 1 -phosphonate ( 5 5 ) . A 100 ml round-bottomed flask under an atmosphere of argon was charged with copper (I) triflate (92 mg, 0.18 mmol, 1 mol%), dichloromethane (40 ml, degassed) and the silyl ether (54) (4.41 g, 15.6 mmol). This mixture was then cooled to 0 °C prior to the addition of a solution of DAMP (2.56 g, 14.4 mmol, 0.92 eq) in dichloromethane (6.5 ml, degassed; a total volume of 10 ml) over a 72 h period. Stirring was continued for a further 18 h at room temperature after which solvent was removed from the reaction mixture under reduced pressure. The residue was chromatographed (silica-neat ether) to yield 1) recovered silyl ether (54) (3.54 g, 12.5 mmol, 80 %); 2) diethyl 2-(3-(diphenvlmethylsilvloxv)prop-1 - yhcyclopropane 1-phosphonate (55) (a) less polar isomer (0.487 g, 1.1 mmol, 7 %); (b) more polar isomer (0.76 g, 1.8 mmol, 12 %). (Total yield 19 % or 95 % based on recovered starting material (54) ). vm ax(NaCI) (same for both isomers) 2 930, 1 427, 1 389, 1 245 (P=0), 1 118 (Si-O-C), 1 029 (P-O-alkyl), 963, 790, 735 and 700 cm’1, fal less polar isomer: 8[_|(270MHz: CDCIg) 7.6 (4H, m, aromatic), 7.38 ( 6H, m, aromatic), 4.06 (4H, m, (CH 3 CJi2 0)2P ), 3.74 (2H, d, J 6.5 Hz, 3’-H2), 1.75-1.55 (5H, m, 2'-H2, 1 ’-H2, PCMJ, 1.31 (3H, t, J 7.3 Hz, (CH.3 CH 2 0 ) 2 P), 1.30 (3H, t, J 7.3 Hz, (CJ±3 CH 2 0 ) 2 P ), 1.15 ( 1 H, m, cyclopropyl), 1.05 (1H, m, cyclopropyl), 0.80 (1H, m, cyclopropyl), 0.63 (3H, s, MeSi), (Found: C, 63.91; H, 7.90. C 2 3 H 3 3 0 4SiP requires C, 63.86; H, 7.69 %), 162 (b) more polar isomer: 8h (270M H z ; CDCI3 ) 7.6 (4H, m, aromatic), 7.38 ( 6H, m, aromatic), 4.06 (4H, m, (CH 3 ChL2 0 ) 2 P ), 3.72 ( 2 H, d, J 6.5 Hz, 3’-H2), 1.67 (3H, m, 1 '-H2, PCM), 1.38 (2 H, m, 2’-H2 ), 1.31 (3H, t, J 7.0 Hz, (CJd3 CH 2 0 ) 2 P ), 1.30 (3H, t, J 7.0 Hz, (CJd3 CH 2 0 )2P ), 1.02 (1H, m, cyclopropyl), 0.63 (3H, s, MeSi), 0.54 (2H, m, 2 x cyclopropyl), (Found: C, 63.68; H, 7.88. C^HggC^SiP requires C, 63.86; H, 7.69 %). m/Z. 432 (0.2%, M.+), 417 ( 6, M.-Me), 355 (100, M.-Ph), 199 (56, MeSiPh 2 H+), 138 (14, (EtO)2 P O H + ), 108 (25, E tO P 02 + ), 91 (46, tropyllium cation), 81 (26, P(OH) 2 0 + ). Attempted alkylation of benzophenone using the phosphonate (551. v OSiPh2Me (58) n-Butyllithium (265 pi of a 2.4 M solution in hexanes; 0.64 mmol,1 .2 eq) was added dropwise to a solution of the phosphonate (55) (230 mg, 0.532 mmol) and TMEDA (77 mg, 0.66 mmol) in tetrahydrofuran (8 ml) precooled to -78 °C. Stirring was continued for a further 10 min by which time the yellow anion had become much darker in colour. A solution of benzophenone (210 mg, 1.15 mmol, 2.2 eq) in tetrahydrofuran (2 ml) was then added dropwise. The reaction mixture was stirred for a further period of 4 h after which a solution of sodium t-butoxide (prepared from sodium hydride (43 mg of a 60% suspension in oil: 26 mg, 1.1 mmol, 2.1 eq) and t-butanol (0.16 g, 2.1 mmol, 4.0 eq) in tetrahydrofuran (2 ml) ) was added dropwise. The reaction mixture was then allowed to warm to room temperature. After a further 6 h TBAF (0.55 ml of a 1.1 M solution in tetrahydrofuran) was added and stirring was continued for a 0.5 h period. Acetic acid (3 ml of a 10 % v/v aqueous solution) was then added dropwise and the quenched reaction mixture was poured into 163 water. The aqueous phase was thoroughly extracted with ether and the organic layer was dried (MgS04). Solvent removal was followed by column chromatography (silica-5% ether/petrol) of the residue which afforded recovered benzophenone (188 mg) and diphenylmethylsilanol (215 mg, 0.29 mmol, 55 %); 5H (9 0 M H z ; CDCI3) 7.7-7.2 ( 10H, m, aromatic), 2.8 ( 1 H, broad s, OH), 0.6 (3H, s, MeSi). Attempted isolation of the intermediate hydroxvphosphonate (59). n-Butyllithium (0.25 ml of a 2.4 M solution in hexanes; 0.54 mmol) was added dropwise to a solution of the phosphonate (55) (0.23 g, 0.54 mmol) and TMEDA (72 mg, 0.62 mmol, 1.1 eq) in tetrahydrofuran (5 ml) precooled to -78 °C. Stirring was continued for a 15 min period after which benzophenone (0.21 g, 1.1 mmol, 2.1 eq) in tetrahydrofuran (1 ml) was added over a 10 min period. Stirring was continued for a 3 h period, then glacial acetic acid (0.4 ml) was added dropwise. The reaction mixture was allowed to warm to room temperature, then it was poured cautiously into water. The aqueous mixture was thoroughly extracted with ether and the combined extracts were dried (M gS04). Solvent was removed under reduced pressure and the crude residue was chromatographed (silica-neat ether). The starting phosphonate (55) (RL0.25, neat ether) was recovered in greater than 90%. (There was also a trace (20 mg) of an unidentified product (Rf_0.8, 50% ether/petrol). N.m.r. analysis suggested the presence of a terminal alkene: SH 5.82 (1H, m, H2C=CH), 5.05 (1H, m, J 17 Hz), 4.98 (1H, m, J 8.5 Hz). * 164 1-f {Tetrahvdro-2H-Dvran-2-vhoxv)pent-4-ene. (5.61. 4 2 OH ( 5 6 ) 4’ Hydrochloric acid (0.05 ml) was added to a stirred mixture of pen-4-en-1-ol (10.3 g, 120 mmol) and dihydropyran (11.1 g, 131 mmol, 1.1 eq), which had been precooled to 0 °C. The reaction mixture was allowed to warm to room temperature overnight, after which sodium bicarbonate (2 g, solid) was added. Stirring was continued for 10 min, then the neutralised mixture was washed with brine and thoroughly extracted with ether. The organic phase was dried (M gS04 ) and solvent was then removed under reduced pressure. Distillation of the residue produced 1 ^ (Tetrahvdro-2H-pyran-2-yhoxy)pent-4-ene (56), as a colourless liquid (19.3 g, 114 mmol, 95 %), b.p^110 °C/U20 mmHg). vmax(NaCI) 2 939, 1 638 (C=C), 1 440, 1 351, 1 121, 1 034 and 910 cm-1, 5H(270MHz; CDCI3) 5.83 (1H, m, 4- H), 5.02 (1H, dt, J4(5a 17, J 1.7 Hz, 5a-H), 4.96 (1H, d, J4f5 10 Hz, 5-H), 4.58 (1 H, t, J 2.7 Hz, 2 -H), 3.9-3.7 ( 2 H, m, CH 2 0), 3.55-3.3 (2 H, m, CH 2 0 ), 2.14 (2H, m, 3-H2), 1.9-1.65 (4H, m, 3’-H2, 4'-H2), 1.55-1.45 (4H, m, 2-H2, 5'- H2), m /z 170 (1%, M_+), 85 (100, dihydropyranH+ ion), 69 (18, C H 2 CH = C H 2 CH 2 CH2+), 56 (10, 69-CH), 41(24), (Found: C, 70.69; H, 10.78. C 1 q H i 8O 2 requires C, 70.55; H, 10.66 %). Attempted cyclopropanation of 1-( fTetrahvdro-2H-pyran-2-yhoxy1pent-4-ene (56) with DAMP o I (EtO^P OTHP (56) * 165 A solution of DAMP (2.55 g, 14 mmol) in dichloromethane (2 ml; total volume 4.5 ml) was added over a 36 h period to a stirred mixture of a solution of the ether (56) (4.9 g, 29 mmol, 2.0 eq) and copper (I) triflate (0.25 g, 0.5 mmol, 2 mol%) in dichloromethane (10 ml) which had been precooled to 0 °C. The reaction mixture was then filtered through a short pad of silica, using ether as the eluant. Solvent was removed under reduced pressure.1 H N.m.r. analysis of the crude residue revealed that only the substrate ether (56) was present. 1 -Chloro-1 -m ethvl-2-(3-netrahvdro-2H-Dvran-2-v0oxvproDvn cyclopropane (60). Cl n-Butyllithium (21 ml of a 2.4 M solution in hexanes; 50 mmol) was added dropwise over a 3 h period to a stirred solution of the ether (56) (7.9 g, 46 mmol) and 1,1- dichloroethane (5.0 g, 4.3 mmol, 1.1 eq) in ether (45 ml), precooled to -35 °C. Subsequently, a second portion of 1,1-dichloroethane (5.0 g, 4.3 mmol, 1.1 eq) was added and a solution of n-butyllithium (21 ml, 50 mmol) was added dropwise over a period of 3 h. The reaction mixture was allowed to warm to room temperature after which it was poured into water and thoroughly extracted with ether. The organic phase was dried (M gS04) and solvent was removed under reduced pressure. Distillation of the residue afforded the starting material (56) (1.12 g, 6.6 mmol, 14 %), b.p. 50- 52 °C/0.5 mmHg and 1 -chloro-1 -m ethyl-2-(3-(tetrahydro-2H-pyran-2- yHoxypropyh cyclopropane. (60) as a colourless liquid (6.17 g, 26.0 mmol, 57 %; or 66 % based upon recovered starting material) b.p. 94-96 °C/0.5 mmHg. Column chromatography (silica-5% ether/petrol) of the crude residue also provided excellent purification. vmax(NaCI) 2 939, 1 441, 1 352, 1 200, 1 183, 1 120, * 166 1 077 and 1 033 cm-1, 8H(270MHz; CDCI3) 4.58 (1H, m, 2'-H), 3.8 (2H, m, CH20), 3.5 (2H, m, CH20), 1.9-1.45 (10H, m, 1-H2, 2-H2, 3'-]±2, 4,_a-2» 5'‘ R 2), 1-59 (3H« s» Me)» °-83 (2H, m» 2 x cyclopropyl), 0.62 (1H, m, cyclopropyl), (Found: C, 62.06; H, 9.09. C12H21C I02 requires C, 61.92; H, 9.09 %), m Jz. 231 (0.1%, M_-H), 196 (0.1, M.-HCI), 148 (0.5, M_-dhp), 102 (4, H2C=CCICH2CH=CH2+), 85 (100, dhpH+). 2-(3-(Tetrahvdro-2H-pyran-2-vl)oxypropyl)methylenecyclopropane (61). OTHP A solution of the ether (60) (5.61 g, 24 mmol) in dimethylsulphoxide (5 ml) was added over a 3 h period to a solution of potassium t-butoxide (5.6 g, 48 mmol, 2.0 eq) in dimethylsulphoxide (20 ml), maintained at 80 °C. The reaction mixture was then allowed to cool to room temperature, after which it was poured into water. The aqueous phase was extracted with ether and the organic layer was dried (MgSO^. Solvent removal and distillation of the residue produced 2-(3-fTetrahydro-2H- pyran-2-yhoxypropyn methylenecyclopropane (61) (3.77 g, 19.2 mmol, 80 %) b.p. 50-52 °C/0.5 mmHg. vmax(NaCI) 2 939, 2 868, 1 746 (C=C), 1 440, 1 352, 1 200, 1 035, 988, 884 and 815 cm’1, 8H(270MHz; CDCIg) 5.38 (1H, s, H2C=C), 5.31 (1H, m, H2C=C), 4.55 (1H, t, J 3.5 Hz, 2'-H), 3.9-3.7 (2H, m, CH20), 3.5-3.35 (2H, m, CH20), 1.9-1.3 11H, m, 1-H2, 2-H2, 3’-H2, 4'-H2, 5'-H2, cyclopropyl), 1.20 (1H, m, cyclopropyl), 0.70 (1H, m, cyclopropyl), (Found: C, 73.27; H, 10.51. C12H20O2 requires C, 73.43; H, 10.27 %), m /i 196 (0.5%, M.+), 85 (100, dhpH+), 95 (4, C7H110 +), 79 (13, C7HU +). * 167 3-M -methvlenecvcloproD-2-vhDroDanol (621. OTHP 3 1 (61) (62) A solution of the ether (61) (3.62 g, 18.4 mmol) and p-toluenesulphonic acid (0.6 g) in methanol (15 ml, commercial) was stirred at room temperature for a period of 2 h after which potassium carbonate (2 g, solid) was added. Stirring was continued for a further period of 20 min, then water was added and the mixture was thoroughly extracted with ether. The organic layer was dried (M gS04) and solvent was removed. Distillation of the residue produced 3-M-methylenecycloprop-2-yhpropanol (62), as a colourless liquid (1.61 g, 14.4 mmol, 78 %) b.p. 88-90 °C/_20 mmHg. Column chromatography (silica-35% ether/petrol) of the residue also afforded excellent separation. vmax(NaCI) 3 334 (OH), 2 933, 1 743 (C=C), 1 054 (C-O-H) and 885 (H 2 C=C) cm'1,8 h (270M H z ; CDCIg) 5.38 (1H, m, H2 C=C), 5.32 (1H, m, H2 C =C ), 3.65 ( 2 H, t, J 6.5 Hz, 1-H2), 1.90 (1 H, s, OH), 1.67 ( 2 H, m, 3-H 2 ), 1.5-1.3 (3H , m, 2 -H 2 , cyclopropyl), 1.2 (1H, m, cyclopropyl), 0.72 ( 1 H, m, cyclopropyl), 5c (67.5MHz; CDCI 3 ) 136.8 (H 2 £=C), 102.7 (H 2 C = £ ) , 62.5 (CH 2 OH), 32.4 (CH2), 29.3 (CH2), 15.3 (cyclopropyl), 9.4 (cyclopropyl), (Found: Li+, 112.088 5. C7 H 120 requires M., 112.088 8), m/z. 113 (7%, M.H+), 112 (4, ML+), 111 (2, M.-H), 97 (16, M_-Me), 93 (13, M_-H 2 0,-H), 79 (100, M.- MeOH,-H), 68 (1 6 , H2 C C (M e )C H = C H 2 ), 6 7 (3 4 , 68-H), 5 2 (2 1 , C4 H 5+ ). 2-(3-lodopropylVmethylenacycloDroane (63). 3 (62) (63) 168 The alcohol (62) (1.42 g, 12.7 mmol, neat) was added dropwise to a stirred solution of triphenylphosphine (4.16 g, 15.9 mmol, 1.25 eq), imidazole (1.01 g, 15.9 mmol, 1.25 eq) and iodine (4.03 g, 15.9 mmol, 1.25 eq) in acetonitrile (40 ml) and ether (100 ml). Stirring was continued for a 2 h period, then ether (100 ml) was added to the reaction mixture. The mixture was thoroughly shaken with a solution of saturated aqueous sodium thiosulphate. The aqueous layer was then thoroughly extracted with ether (2 x 150 ml) and the combined organic layers were washed with water and dried (M gS04). The solution was reduced to approximately one quarter of its volume, then petrol (b.p. 30-40 °C) was added in several portions. Triphenylphosphine oxide, which precipitated out of the solution, was removed by filtration. Reduced pressure solvent removal was followed by bulb-to-bulb distillation (oven temperature 95- 105 °C/7-7.5 mmHg) of the residue to afford 2 - ( 3 - iodopropyllmethylenecvcloproane (63) (2.51 g, 11.3 mmol, 89 %). Column chromatography (silica-neat petrol (40/60) ) of the crude residue also produced the iodide (63). vmax(NaCI) 2 925, 1 746 (C=C), 1 446, 1 223, 1 172, 1 021 and 888 (H 2 C=C) cm'1,8 h (270M H z ; CDCI3) 5.40 (1H. m, H2 C=C), 5.36 ( 1 H. m. H 2 C=C), 3.23 (2 H, dt, J 1.2 and 7.0 Hz. 3-H2 ), 1.95 (2 H, m, 1-H2 ), 1.6-1.3 (3H, m, 2-H 2 , 1 x cyclopropyl), 1.24 (1H, m, cyclopropyl), 0.81 (1H, m, cyclopropyl), 6c (67.5MHz; CDCIg) 136.1 (H 2£=C), 103.1 (H2 C=£), 33.8 (CH2), 33.5 (CH2), 14.6 (cyclopropyl), 9.5 (cyclopropyl), 6.6 (CH 2 I), mJz. 194 (59, M_-C 2 H4), 155 (24, +C H 2C H 2 1), 128 (8 , Hl+), 95 (100, M_-l), 67 (54, c 5 h 7 +). (Found: (M.-C2 H4)+, 193.959 2 . C5 H7I requires 193.959 3). 3^Bromo-2-methylcvclopent-2-enone (53). 169 A solution of bromine (7.84 g, 49.0 mmol, 1.1 eq) in benzene (10 ml) was added dropwise to a stirred solution of triphenylphosphine (12.9 g, 49.0 mmol, 1.1 eq) in benzene (450 mi), which had been precooled to 0 °C. Stirring was continued for a period of 1 h after which triethylamine (5.0 g, 49 mmol, 1.1 eq, neat) was added dropwise. The mixture was stirred for a further period of 20 min (by which time the orange-brown colouration had become whitish) and 2-methylcyclopenta-1,3-dione (5.00 g, 44.6 mmol, neat) was added dropwise. The reaction mixture was stirred overnight, then it was filtered through a short pad of silica, eluting with ether. Solvent was removed under reduced pressure and distillation of the residue produced 3-bromo-2-methylcvclopent-2-enone 5 3 (53) (2.16 g, 12.3 mmol, 28 %) _7 8 °C/^10 mmHg. vmax(NaCI) 2 923, 1 701 (C =0), 1 638 (C=C), 1 442, 1 376, 1 279, 1 066 and 616 cm"1, 6H(270MHz; CDCIg) 2.92 (2H, m, CH 2 CO), 2.54 (2 H, m, CH 2 CBr), 1.79 (3H, t, J 2.2 Hz, Me), mJz. 174 (64%, M_+), 95 (62, M.-Br), 67 (100, M.-Br,-C 2 H 4 ). Attempted _couplina of 2-(3-iQdoDroDvhmethvlenecyclopropane (631 with 3- bromo-2-methylcyclopent-2-enone (53). O o Br X ( 5 3 ) t-Butyllithium (1.02 ml of a 1.7 M solution in pentane; 1.2 eq) was added dropwise to a stirred solution of the iodide (63) (300 mg, 1.44 mmol, 1.0 eq) in pentane (12 ml), which had been precooled to -78 °C. Stirring was continued for 50 min after which the mixture was added to a solution of copper (I) iodide (137 mg, 0.5 eq) in tetrahydrofuran (12 ml) also maintained at -78 °C. After a period of 5 min a solution of the bromoenone (53) (280 mg, 1.60 mmol, 2.2 eq with respect to the lithium dialkyl cuprate) in tetrahydrofuran (2 ml) was added dropwise. Stirring was 170 continued for a further 10 min after which the reaction mixture was allowed to warm to 0 °C. This temperature was maintained for 1 h, then a saturated aqueous solution of ammonium chloride (1 ml) was added. The mixture was stirred for 5 min after which M g S 0 4 (0.5 g, solid) was added prior to filtration through a short pad of silica, using ether as the eluant. Solvent was removed and the crude residue was chromatographed (25% ether-petrol) to attain partial separation of the main component (109 mg). Analysis of the 1 H n.m.r. spectrum revealed new olefinic signals at 4.8 ppm, thus implying that there had been some destruction of the cyclopropyl ring. The vinylic methyl signal had disappeared. The methylene a to the carbonyl group was also no longer present. Examination of the infra-red spectrum revealed new peaks at 1707 and 1647 cm-1, suggesting the presence of a straight-chain ketone and a diene. Attempted dioxalane formation of 3-bromo-2-methvicvcloDent-2-ene (53) with ethylene glycol A solution of bromoenone (53) (1.95 g, 11 mmol) and ethylene glycol (1.25 g, 20 mmol, 1.8 eq) in benzene (150 ml) was refluxed with p-toluenesulphonic acid monohydrate (0.1 g), with provision for continuous azeotropic removal of water (Dean-Stark apparatus). 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