Catalytic Dynamic Kinetic Resolutions with N-Heterocyclic Carbenes: Asymmetric Synthesis of Highly Substituted β-Lactones

摘要

The conversion of a racemic substrate to enantioenriched products, commonly referred to as a kinetic resolution, is an established method with broad applications.'' Due to the intrinsic lack of efficiency with this strategy where the theoretical yield is only 50 %, many creative dynamic kinetic resolutions (DKRs) have been developed in which >99% yields are possible. For these processes, the rapid intercon-version between each enantiomer of a starting material provides an opportunity for a selective catalyst system'"*' to promote a desired reaction favoring only one enantiomer, assuming the interconversion is faster than the irreversible step. Both transition metal and enzyme-based DKR reactions have seen significant development over the past two decades. Dynamic kinetic resolutions based on organocatalysis are emerging as powerful and complementary approaches for the conversion of racemic substrates to products with high enantioselectivity. Organocatalytic DKRs have employed a wide variety of activation strategies, including Lewis bases, hydrogen bond donors, chiral Br0nsted acids, enamine/iminium ions, and peptide-based biaryl oxidations.' While N-heterocyclic carbene (NHC) catalysis has been used in very few cases of traditional kinetic resolutions'" or parallel kinetic resolutions, NHC-DKRs should provide significant new opportunities. Here, we report a new NHC-DKR with p-keto esters to generate highly substituted β-lactones' with excellent levels of stereoselectivity (Scheme 1). This unique process leverages the basic conditions necessary to generate the NHC catalyst from the azolium salt to promote racemization of the substrates.