Three-component coupling reactions of silyl glyoxylates, vinyl Grignard reagent, and nitroalkenes: an efficient, highly diastereoselective approach to nitrocyclopentanols.

The efficient synthesis of highly substituted cyclopentanols is an important task given the prevalence of this class of compounds in nature. Nitrocyclopentanols are of particular value due to the rich chemistry associated with the nitro group and their potential use as aminocyclopentitol progenitors. Aminocyclopentitols have generated considerable attention because of their significant biological activity and synthetic challenges presented by their often dense functionality and contiguous chiral centers. As such, the development of a flexible synthesis of functionalized nitrocyclopentanols would be a welcome addition to the synthetic toolbox. Herein we report the three-component coupling of silyl glyoxylates, CH2=CHMgBr, and nitroalkenes that selectively affords (Z)silyl enol ether products through a unique vinylogous Michael cascade. The resulting functionality enables the immediate implementation of a second-stage Henry cyclization for the expeditious, diastereoselective synthesis of functionalized nitrocyclopentanols. Silyl glyoxylates are conjunctive reagents for the union of complementary nucleophilic and electrophilic partners linked at a protected glycolic acid junction. The use of these reagents in coupling reactions with alkide and hydride nucleophiles and carbonyl secondary electrophiles has been documented. We endeavoured to expand the utility of silyl glyoxylate chemistry to include Michael acceptors as the secondary electrophile. Nitroalkenes were chosen by virtue of their highly electrophilic character and the synthetic versatility of the nitro functionality. The proposed transformation outlined in Scheme 1 involves the addition of vinyl Grignard to the silyl glyoxylate 1 to reveal, after [1,2]-Brook rearrangement, the (Z)-metallodienolate 2. This intermediate could act as a transient secondary nucleophile capable of engaging the nitroalkene 4 in a vinylogous Michael addition to provide enolsilane 6. As such, the combination of 1 and CH2=CHMgBr would function as the synthetic equivalent of the unusual a-keto ester homoenolate synthon, perhaps by way of the C-metalated tautomer 3 of the (Z)-metallodienolate (Scheme 2).