Asymmetric aldol additions: use of titanium tetrachloride and (-)-sparteine for the soft enolization of N-acyl oxazolidinones, oxazolidinethiones, and thiazolidinethiones.

Asymmetric aldol additions using chlorotitanium enolates of N-acyloxazolidinone, oxazolidinethione, and thiazolidinethione propionates proceed with high diastereoselectivity for the Evans or non-Evans syn product depending on the nature and amount of the base used. With 1 equiv of titanium tetrachloride and 2 equiv of (-)-sparteine as the base or 1 equiv of (-)-sparteine and 1 equiv of N-methyl-2-pyrrolidinone, selectivities of 97:3 to > 99:1 were obtained for the Evans syn aldol products using N-propionyl oxazolidinones, oxazolidinethiones, and thiazolidinethiones. The non-Evans syn aldol adducts are available with the oxazolidinethione and thiazolidinethiones by altering the Lewis acid/amine base ratios. The change in facial selectivity in the aldol additions is proposed to be a result of switching of mechanistic pathways between chelated and nonchelated transition states. The auxiliaries can be reductively removed or cleaved by nucleophilic acyl substitution. Iterative aldol sequences with high diastereoselectivity can also be accomplished.

Formal total synthesis of (+)-trehazolin. Application of an asymmetric aldol-olefin metathesis approach to the synthesis of functionalized cyclopentenes.

An asymmetric synthesis of the aminocyclopentitol pseudosugar of trehazolin has been completed. The synthesis hinges on an asymmetric aldol-ring closing metathesis strategy to construct the five-membered ring with control of both the relative and absolute stereochemistry.

An aldol approach to the synthesis of the EF fragment of spongistatin 1.

A synthesis of the C29-C51 fragment of spongistatin 1, containing the E and F rings, has been completed. The approach relies on four diastereoselective aldol additions and an asymmetric glycolate alkylation to establish eight of the eleven stereogenic centers. The intact chlorodiene side chain was appended by a Lewis acid catalyzed addition of an allylstannane to an epoxy enol ether.