Capnellenes intermediates

In a typical example of aliphatic cyclizations, already discussed in Section 5.2, the enamine 675 is alkylated by silylated methyl 4-chloroacetoacetate 747 a [2] to give, via 760 and subsequent ehmination of pyrrolidine, the unsaturated bicycHc /9-ke-toester 761 in, as yet, only 30-40% yield [1]. Analogously, the bicycHc system 1408 with an additional 6-keto group is silylated to 1409 and cyclized via 1410, in an overall yield of 42%, to the tricyclic capnellene intermediate 1411 [3] (Scheme 9.1). An alternative synthesis of bicyclic compounds Hke 761 is given elsewhere [3 a]. 

The silyl enol ethers 209 and 212 are considered to be sources of carbanions. and their transmetallation with Pd(OAc)2 forms the Pd enolate 210. or o.w-tt-allylpalladium, which undergoes the intramolecular alkene insertion and. 1-elimination to give 3-methylcyclopentenone (211) and a bicyclic system 213[199], Five- and six-membered rings can be prepared by this reaction[200]. Use of benzoquinone makes the reaction catalytic. The reaction has been used for syntheses of skeletons of natural products, such as the phyllocladine intermediate 214[201], capnellene[202], the stemodin intermediate 215[203] and hir-sutene [204]. 

Scheme 30. Curran s synthesis of ( )-A9<12,-capnellene [( )-2] construction of intermediate 155.

The Tebbe reagent reacts with some alkenes. The tricyclo[5.3.0.0] ring 207 was obtained nearly quantitatively by domino alkene metathesis and carbonyl alkenation of the norbomene-type ester 205 with the Tebbe reagent. This interesting reaction to give the intermediate 206 can be explained by the kinetic preference of the Tebbe reagent for the strained double bond over the ester. Alkenation of the ester in 206 produces 207. Capnellene (208) has been synthesized by applying this reaction as a key reaction [65],... 

Three new chirality centers are formed with high enantio- and complete diastereoselectivity in the course of the reaction of the enol triflate 37 to the bicyclo [3.3.0]octane derivative 38 (Scheme 11) [15]. In this transformation, the intermediate 39, formed by oxidative addition, leads to the cationic palladium-7r-allyl complex 40, which is finally converted to the isolated product 38 by regio- and diastereoselective nucleophilic addition of an acetate anion. The bicyclic product 38 is of interest as a building block for the synthesis of capnellene sesquiterpenes. 

Other intramolecular aldol reactions have been reported. In the first total synthesis of A -capnellene-8/ ,10a-diol and A -capnellene-3y3,8/3,10a-triol Shibasaki et al. reported that excess la with Et3N effects the cyclization of intermediate 16 giving 17 in 42 % yield (Sch. 15), although a wide variety of different acidic and basic reagents meet with failure [46]. 

Although it probably did not involve a Heck reaction per se, Balme and co-workers employed an interesting tandem reaction in their construction of A 2) capnellene (147) (Scheme 6-26) [54J. Presumably vinyl iodide 144 undergoes initial oxidative addition with the palladium(O) catalyst to furnish a cr-alkenylpalladium(n) intermediate that is complexed to the pendant alkene. Intramolecular addition of the soft malonate nucleophile to this complex, from the opposite face, followed by reductive elimination, then provides tricycle... 

In the laboratory of V. Singh a novel and efficient stereospecific synthesis of the marine natural product capnellene from p-cresol was developed. After rapidly assembling the desired carbon framework, it was necessary to remove the carbonyl group from the tricyclic intermediate which was accomplished using Barton s deoxygenation procedure. 

In cases that provide a mixture of alkene regioisomers or in which the less-substituted alkene is desired, control of the position of the new alkene is possible using a trialkylsilyl group to direct its introduction. Desilylation is generally preferred over deprotonation, and the known (3-cation stabilizing effect of a silyl group helps to reduce side reactions resulting from the intermediate aUyl cation. The silicon-directed Nazarov cyclization has been made use of twice in a synthesis of the sesquiterpene A -capnellene 349 (3.221). ... 

Asymmetric carbopalladation can also be combined with other reactions to give domino asynunetric processes. A group selective example from a synthesis of ( capnellene 216 features the cyclization of the alkenyl triflate 210 (Scheme 32). The resultant TT-allylpalladium intermediate has effectively been captured with a variety of nucleophiles including acetate anion for the synthesis. A domino Suzuki coupling/in-tramolecular Heck reaction converts ditriflate 212 into tricycle 213 in modest yield with 85% The transformation accomplises an annnelation, two carbon-carbon bond... 

Kagechika, K. and Shibasaki, M. (1991) Asymmetric Heck reaction a catalytic asymmetric synthesis of the key intermediate for A -capneUene-3i3,8j8,10o -triol and A -capnellene-3/S,8/3,10a,14-tetrol. J. Org. Chem., 56,4093 (b) Kagechika, K., Ohshima, T. and Shibasaki, M. (1993) Asymmetric Heck reaction-anion capture process. A catalytic asymmetric synthesis of the key intermediates for the capneUenols. Tetrahedron, 49, 1773-82 (c) Ohshima, T., Kagechika, K., Adachi, M., et al. (1996) Asymmetric Heck reaction-carbanion capture process. Catalytic as5mmetric total synthesis of (—)-A LcapneUene. J. Am. Chem. Soc., 118, 7108-16 (d) Itano, W., Ohshima, T. and Shibasaki, M. (2006) Synthesis of the tricyclic core of 5a-capneUenols using asymmetric Heck reaction-carbanion capture process. Synlett, 3053-6. 

The cascade process was initially explored with prochiral trienyl iodide 44 (Scheme 16.11) [36, 37]. Mizoroki-Heck cyclization of this precursor produced -ally(palladium species 45, which was trapped by acetate at the least-hindered terminus of the ry -aWyl system to provide CM-bicyclo[3.3.0]octadiene 46 in 60% yield, albeit with very low enantioselectivity (20% ee). Attempts to use silver salts as halide scavengers in this reaction led to the decomposition of 44, presumably resulting from the sensitivity of the cyclopentadienyl moiety. Mizoroki-Heck cyclization of prochiral vinyl triflate 47 with Pd(OAc)2, (S)-BINAP and tetrabutylammonium acetate was more productive, giving diquinane product 48 in excellent yield and 80% ee (Scheme 16.12). The corresponding allylic amine 49 was obtained in analogous fashion using benzylamine as the nucleophile [38]. Allylic acetate 48 was elaborated in seven steps to triquinane /3-ketoester 50, an intermediate in Shibasaki and coworkers [39] earlier total syntheses of ( )-A -capnellene-3/3,8/3,10a-triol (51) and )-A. -c3i me ene-5p, P,l0a,lA-i xdiO (52). 

The use of carbanionic nucleophiles in the Mizoroki-Heck cyclization-/ -allyl nucleophilic trapping sequence allowed for streamlined access to the triquinane core common to various members of the capnellene family of natural products. For example, Shibasaki and coworkers obtained diquinane 57 in 77% yield and 87% ee by Mizoroki-Heck cy-clization of trienyl triflate 47 in the presence of malonate nucleophile 56 Scheme 16.14). It is notable that two new C-C bonds and three stereocentres are generated in this reaction. Eleven additional steps were used to convert intermediate 57 to ( )-A ( Ecapnellene (58). This first catalytic asymmetric total synthesis ( )-A d2). j pjjgjjgjjg achieved in 19 steps and 20% overall yield from commercially available materials. A related approach has recently been employed to prepare intermediates en route to capnellenols 53 and 54 (Scheme 16.12) [41]. 

The reaction, at room temperature (16 h), afforded the triquinane 37, a key intermediate in the synthesis of ( )A -capnellene, in 70% yield along with traces of the isomer having an internal double bond. Indeed, 37 could be converted to capnellene as a single isomer in three steps using conventional synthetic methods (50% overall yield). 

A variant on this approach is to incorporate the enantiotopic alkenes into a five-membered ring such as a cyclopentadiene. 3-Hydride elimination is then obviated, as a if-allyl complex 5.130 is formed after insertion, which may be intercepted by an added nucleophile, such as acetate (Scheme 5.39). Other nucleophiles, including carbon nucleophiles can also be used to intercept the tt -allyl intermediate (see Section 9.2.9). This chemistry was used in a synthesis of capnellene 5.137 (Scheme 5.40). The T]p-allyl intermediate 5.130 was intercepted with a functionalized malonate nucleophile 5.132. The malonate was used to construct the third five-membered ring of the natural product while one ester group was removed by Krapcho... 

The transannular cationic cyclization was the key transformation for biomimetic synthesis of the linear triquinane A -capneUene by Birch and Pattenden. It involved treating the cycloocta-1,5-diene or its exo-methylene isomer (i.e., 154) with BF3-Et20 to initiate the transannular cycH-zations to give A -capnellene and the two isomers 157 and 158 (Scheme 20.38). These products were derived from the same carbocation intermediate 156 of the transannular cationic cyclization and the major product A -capnellene was also formed by the isomerization of the bridgehead capnellene 158. 

Kagediika, K. and Shibasaki, M. (1991) Asymmetric Heck reaction a catalytic asymmetric synthesis of the key intermediate for -capnellene-3p,8p,10a-triol and A bcapnellene-3p,8p,10a,14-tetrol. /. Org. Chem., 56, 4093—4094. 

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