Catalytic asymmetric defluorinative allylation of silyl enol ethers

Abstract

The stereocontrolled installation of alkyl fragments at the alpha position of ketones is a fundamental yet unresolved transformation in organic chemistry. Herein we report a new catalytic methodology able to...

Lewis-Base-Catalyzed N-Allylation of Silyl Carbamate Latent Pronucleophiles with Allylic Fluorides

“…We established the concept of latent pronucleophiles to address this central problem in enantioselective Lewis base catalysis in reactions of N-centered nucleophiles (Scheme a) . Foundations for this concept were set in the pioneering work on Lewis-base-catalyzed C-allylations with allylic fluorides by Shibata, an approach which was recently also explored by the Companyó group . In our proof of concept study, N-silyl heterocycles were used as less nucleophilic surrogates of N-centered nucleophiles thus allowing for enantioselective allylation in the presence of chiral Lewis base catalysts of low nucleophilicity (Scheme a) .…”

“…Although a dynamic kinetic resolution can not be ruled out based on this experiment alone, we find it unlikely to operate under the reaction conditions. The slow racemization of MBH fluorides in the presence of (DHQD) 2 PHAL has been observed in the absence of silyl Lewis acid, , presumably via reversible conjugate addition of the catalyst/elimination of the fluoride. In the presence of silyl Lewis acid, the C–F cleavage process promoted by the silyl Lewis acid would result in creation of a Si–F bond, making the racemization of the allylic fluoride by back attack of the fluoride less likely to occur.…”

“…11 Foundations for this concept were set in the pioneering work on Lewis-base-catalyzed Callylations with allylic fluorides by Shibata, 12 an approach which was recently also explored by the Companyógroup. 13 In our proof of concept study, N-silyl heterocycles were used as less nucleophilic surrogates of N-centered nucleophiles thus allowing for enantioselective allylation in the presence of chiral Lewis base catalysts of low nucleophilicity (Scheme 2a). 11a Limitations of this concept, however, became evident when silylated ammonia or alkyl amines were used as pronucleophiles (Scheme 2b).…”

“…Further investigations were geared toward the use of chiral Lewis base catalysts to achieve enantioselective allylations. We focused on dimeric cinchona alkaloid derived catalysts that have shown good levels of stereocontrol in related reactions. − , Optimization effort focused on the identity of the catalyst, catalyst loading, solvent, stoichiometry, and temperature (see Supporting Information). With the interplay of high yield and high enantioselectivity, the optimal reaction conditions involved the use of 10 mol % of (DHQD) 2 PHAL in the presence of excess of the pronucleophile in chlorobenzene at room temperature (Scheme ).…”

“…Previous mechanistic work on allylation of silyl enol ethers with allylic fluorides has invoked a concerted mechanism for the substitution reaction with the delivery of the nucleophile via a highly ordered ternary transition state featuring a six-membered chair-like arrangement involving the silyl enol ether and C–F bond of the allylic fluoride. , Such a mechanistic scenario applied to silylated N-centered nucleophiles would require a four-membered transition state . In contrast, the mechanism proposed for allylation of pyrroles with allylic fluorides involves a formation of ammonium ion followed by the delivery of the anionic nucleophile .…”