Intramolecular Sakurai Condensation

The intramolecular Sakurai condensation (IMSC) can be considered as one of the most powerful synthetic tools for the stereocontrolled construction of polysubsti-tuted tetrahydropyran rings [48-50]. Using this methodology, the synthesis of five- [51-54] or seven-membered [55, 56] rings, their nitro analogues [57, 58] and spiro [59] compounds is possible. 

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Recently, a new multicomponent condensation strategy for the stereocontrolled synthesis of polysubstituted tetrahydropyran derivatives was re-published by the Marko group, employing an ene reaction combined with an intramolecular Sakurai cyclization (IMSC) (Scheme 1.14) [14]. The initial step is an Et2AlCl-promoted ene reaction between allylsilane 1-50 and an aldehyde to afford the (Z)-homoallylic alcohol 1-51, with good control of the geometry of the double bond. Subsequent Lewis acid-media ted condensation of 1-51 with another equivalent of an aldehyde provided the polysubstituted exo-methylene tetrahydropyran 1-53 stereoselectively and... 

In summary, the SMS reaction is a truly efficient process, possessing a broad scope and applicable to a number of carbonyls, allylsilanes, alcohols (silyl ethers) or amines. Its usefulness has been validated in several total syntheses and demonstrated by the preparation of chiral homoallylic alcohols. During the development of the SMS reaction, Melkafia and Marko [48] realized that the homoallylic alcohol (ether), if connected to an allylsilane, would form novel annelating agents that would lead to tetrahydropyran derivatives via condensation with carbonyl compounds. This reaction was called IMSC for intramolecular Sakurai cydization and will be discussed in the next section. 

Nowadays, the intramolecular Sakurai cyclization stands as one of the most suitable methodologies for the assembly of such subunits [62-64], However, in 1991, when Marko et al. [48] initially published the TMSOTf-catalyzed condensation (ISMS) of aldehyde 105 with TMS-ether 106a, the results of this reaction were far from perfect (Scheme 13.40). Indeed, this condensation resulted in the formation of three products. Surprisingly, not only the expected product 107 was formed, but the isomerized adducts 108 and 109 were also present in the reaction mixture. 

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