Leucascandrolide Mukaiyama aldol reaction

The asymmetric vinylogous Mukaiyama aldol reaction was applied in several natural product syntheses, such as macquarimicins <2003JA14722, 2004JA11254>, leucascandrolide A <2002AGE4098, 2003JOC9274>, and dactylo-lide <2005AGE3485>. 

Aldehydes undergo a Mukaiyama-aldol reaction followed by a Prins cyclization with the highly reactive allylsilane 329 to afford jy -2,6-tetrahydropyrans 330 that feature an oeo-methylene group at C-4 (Equation 140, Table 12). This Mukaiyama-aldol-Prins (MAP) cascade cyclization has been used to form a key bis-tetrahydropyran intermediate during the total synthesis of leucascandrolide A <2001JA8420>. Similarly, titanium tetrabromide mediated MAP reactions afford 4-bromo tetrahydropyrans <20030L3163>. 

Rychnovsky reported synthesis of Leighton s macrolide 201 of leucascandrolide A, wherein the key reaction is the Mukaiyama aldol-Prins cascade reaction (Sect. 2.4). In this cascade reaction, oxonium cation, required for the Prins reaction, is prepared by a Lewis acid-mediated Mukaiyama aldol reaction of alkyl vinyl ether with aldehyde. Usually, alkyl vinyl ethers are not suitable for Mukaiyama-aldol, because of oligomerization of the resulting oxonium cation. Rychnovsky resolved this issue by trapping the cation with an intramolecular nucleophile, which resulted in Prins cyclization. 

Kopecky, D. J., Rychnovsky, S. D. Mukaiyama Aldol-Prins Cyclization Cascade Reaction A Eormal Total Synthesis of Leucascandrolide A. J. Am. Chem. Soc. 2001, 123, 8420-8421. 

Kopecky and Rychnovsky also targeted leucascandrolide A to demonstrate their Mukaiyama Aldol-Prins (MAP) method (Scheme 38) [78]. The MAP reaction generates an oxocarbenium intermediate from an enol ether and an aldehyde, which is capable of imdergoing a Prins cyclization with the pendant allylsilane. Aldehyde 278 (from Scheme 73, Eq. 1) in the presence of enol ether 142 and boron trifluoride etherate underwent the MAP cascade without incident. The reaction mixture was treated with sodium borohydride to reduce any of the unreacted aldehyde and simplify purification. Desired alcohol 143 was then isolated in 78 % yield as a 5.5 1 mixture of diastereomers. 

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