Ring synthesis Ireland-Claisen rearrangement

In the enantioselective total synthesis of p-lactone enzyme inhibitor (-)-ebelactone A and B, I. Paterson and coworkers constructed seven stereocenters and a trisubstituted alkene plus a very sensitive p-lactone ring. The backbone of their strategy applied an aldol reaction / Ireland-Claisen rearrangement sequence and used minimal functional group manipulation. The Ireland-Claisen rearrangement was performed in the presence of an unprotected ketone moiety and set a precedent for this protocol. The diastereoselectivity was 96 4, indicating highly ( )-selective silylketene acetal formation. 

Funk et al. reported an early example of lieterocycle synthesis via a ring contraction of a azalactone via an Ireland-Claisen rearrangement (Scheme 4.99) [87]. Since the lactone was 10-membered, the rearrangement occurred exclusively via the boat transition state to afford the cis piperidine diastereomer. The product was elaborated in several steps to a protected version of meroquinene, an intermediate in cinchona alkaloid syntheses. 

In 1977 Still and Schneider used an Ireland-Claisen rearrangement of a 3° allylic ester in the synthesis of ( )-frullanolide (Scheme4.102) [93]. Rearrangement to the j8-pyrrolidinomethyl ester was followed by Cope elimination to the exo-methylene lactone. Stereocontrol of the alkene was of course not an issue in this case since the alkene was confined within a ring. 

Knight et al. have employed a ring contraction via the Ireland-Claisen rearrangement of an aryl lactone to generate a 2,3,4-trisubstituted tetrahydrofuran intermediate in the synthesis of ( )-samin (Scheme 4.143) [138], The rearrangement proceeded via a boat transition state of the cyclic -silyl ketene acetal. 

Very recently, Hong et al. [48] used the chelation-controlled Ireland-Claisen rearrangement of 89 in their synthesis of carbovir analogues 91. Herein, again the ring was closed via ring-closing metathesis. 

Fujiwara et al. extended their methodology to the synthesis of optically active medium rings [17]. As outlined in Scheme 3.6, the use of L-serine-derived oxazolidi-nones in Ireland-Claisen rearrangement resulted in the generation of the optically active dienes 66a-c. Exposure of 66a-c to [Ru]-II catalyst resulted in the formation of dihydropyrans, oxepines, and oxocines in reasonable yields. A secondary benefit of the cyclization reaction was that the auxiliary was removed in the course of the cyclization. 

Taking advantage of the likewise mild conditions of the Ireland version of the Claisen rearrangement, easily accessible ester or lactone bonds may be transformed via their enolates into C—C bonds. In the case of cyclic systems, the ring size may be varied by the position of the double bonds. Recently Funk et al. made use of this often applied principle for the synthesis of tricycle 76 (shown in Scheme 18) (76). 

Still and Schneider have described" a total synthesis of ( )-frullanolide (82) in which the lactone ring is constructed by an enolate Claisen rearrangement of the type developed by Ireland s group, followed by iodolactonization, viz. (83) - (84). 

Ireland and co-workers, in their synthesis of the prostanoid skeleton, have described the use of the ester enolate modification of the aliphatic Claisen rearrangement to produce the cyclopentane ring C-8—C-12 bond, viz. (74) ->(75). Conversion of the silyl ester (75) into the lactone (76), with a trace of acid, followed by reduction with DIBAL and aldol cyclization, then led to the prostanoid (77) (Scheme 20). 

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