The Domino Multicomponent Allylation Reaction for the Stereoselective Synthesis of Homoallylic Alcohols

• Published in: Accounts of chemical research Vol. 42; no. 2; pp. 367 - 378
• Main Authors: Tietze, Lutz F, Kinzel, Tom, Brazel, C. Christian
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 17.02.2009
• ISSN: 0001-4842; 1520-4898
• DOI: 10.1021/ar800170y

Stereoselective allylations of carbonyl compounds such as aldehydes and ketones are useful but challenging reactions in organic chemistry. The resulting chiral secondary and tertiary homoallylic alcohols or ethers are valuable building blocks in the synthesis of biologically active natural compounds and pharmaceuticals. Although researchers have developed several methods for the facially selective allylation of aldehydes, the stereoselective allylation of ketones still poses a severe problem. We have developed a highly diastereoselective domino multicomponent allylation reaction of a ketone and allyltrimethyl silane using the trimethylsilyl ether of a norpseudoephedrine or mandelic acid derivative as an auxiliary with a diastereoselectivity of up to 98:2. The reaction is performed at −78 °C in the presence of a catalytic amount of trifluoromethanesulfonic acid and leads to the corresponding tertiary ethers. The procedure can also be used for the allylation of aliphatic aldehydes with a diastereomeric ratio >99:1. Ketones give the 4,1′-syn product while the aldehydes give the reversed selectivity to yield a 4,1′-anti product. In addition, the reaction of γ-substituted allyl silanes with ketones yields a product with two stereogenic centers and an anti diastereoselectivity of >99:1. The homoallylic ethers formed in the domino multicomponent process can be used in further synthetic transformations: the auxiliary can serve as a protecting group or can be cleaved reductively to give the corresponding homoallylic alcohols. Based on a number of both experimental and theoretical studies of the reaction mechanism, we conclude that an intermediate oxocarbenium ion is formed in the reaction of ketones. The oxocarbenium ion is attacked by the allyl silane during the stereogenic step. Using density functional theory methods, we could trace the observed stereoselectivity phenomena back to open transition states (TSs) where there is no interaction between the silane’s trimethylsilyl group and the former carbonyl oxygen. On the contrary, the reaction with aldehydes forms an intermediate oxazolidinium salt, which explains the opposite selectivity. We have used the new allylation procedure in several total syntheses of natural products such as vitamin E, (+)-hydroxymyoporone, 5,6-dihydrocineromycin B, and polyoxygenated cembrenes.