Late‐Stage Diversification of Chiral N‐Heterocyclic‐Carbene Precatalysts for Enantioselective Homoenolate Additions

Abstract

A library of chiral triazolium salts has been prepared by late-state diversification of a triazolium amine salt. By utilizing a primary amine as a functional handle, a single triazolium salt can be transformed into a variety of chiral N-heterocyclic carbene precatalysts. This approach makes the preparation of chiral N-heterocyclic carbenes possible by a single-step modification of a triazolium salt, rather than the usual need for multistep organic synthesis and challenging heterocycle formation for each member of a catalyst library. We have screened these catalysts for control of diastereo- and enantioselectivity in a γ-lactam-forming reaction between α,β-unsaturated aldehydes and cyclic ketimines.

N-Heterocyclic Carbene and Brønsted Acid Cooperative Catalysis: Asymmetric Synthesis of trans-γ-Lactams

“…11,14 A plausible mechanism for our reaction is related as shown in Scheme 2. The enal 2 first reacts with carbene to generate Breslow intermediate.…”

“…10 Since then, investigations have documented their utility to prepare cis - γ -lactams, 8a,11 γ -butyrolactones, 12 cyclopentenes 8b–c,13 and heterocycles, 14 among others. 15 With few exceptions, 11d,12d,13b,15c the enantioselective control of homoenolates still remains challenging. Keeping this in mind, we turned our attention to homoenolate chemistry and the design of new types of chiral azolium salts to achieve products in high enantioselectivity.…”

Synthetic Approaches to Chiral Non-C 2-symmetric N-Heterocyclic Carbene Precursors

“…In 2011, the Bode group applied the Paal-Knorr reaction to introduce a pyrrole subunit into the triazole salt (Scheme 49). 102 This late-stage functionalization is strictly dependent on the substituents present in the dicarbonyl substrate 268. In general, ketoaldehydes 268a-d (R 1 = H) gave the products 269a-d in good yields.…”

Organocatalytic Asymmetric Transformations Involving the Cyclic Imine Moiety in Indole and Isoindole Related Heterocycles

“…12 that gave the highest enantioselectivity (73% ee ) gave the poorest diastereoselectivity (6:1) (Scheme ). Thereafter, several novel triazolium precatalysts were prepared and screened for control of diastereo‐ and enantioselectivity in the above γ‐lactam‐forming reaction by the same group . Disappointingly, no catalyst gave greater than 70% enantiomeric excess.…”