Asymmetric catalysis with N-heterocyclic carbenes as non-covalent chiral templates

Abstract

N-heterocyclic carbenes are a class of persistent carbenes stabilized by adjacent heteroatoms that are part of a heterocycle. They play a central role in multiple enzymatic biosynthetic reactions that involve thiamine diphosphate. Inspired by this biocatalysis machinery, N-heterocyclic carbenes have emerged as one of the most versatile classes of organocatalysts for organic reactions. However, the asymmetric synthesis of carbon-carbon bonds through a non-covalent interaction mechanism has not been previously established for chiral carbenes. Here, we report an N-heterocylic carbene-catalysed, highly enantioselective process that uses weak hydrogen bonds to relay asymmetric bias. We find that catalytic amounts of hexafluoroisopropanol are the critical proton shuttle that facilitates hydrogen transfer to provide high-reaction rates and high enantioselectivity. We demonstrate that a successful asymmetric reaction of this type can be accomplished through a rational design that balances the pKa values of the substrate, the carbene precursor and the product.

Organocatalytic Reactions Enabled by N-Heterocyclic Carbenes

“…280 Recently, Chen and Huang demonstrated the stereoselective 1,4-addition of 1,3-dicarbonyl compounds to nitrostyrene derivatives. 281 Mechanistically, the reaction is believed to proceed via complexation between the free carbene and the cyclic enol form of the 1,3-dicarbonyl 266 , activating it. Then, the nitrostyrene approaches the complex and reacts via an ene-type mechanism.…”

Kooperative Katalyse mit N‐heterocyclischen Carbenen

“…B. ,d ass Catechol die katalytische Aktivitätv on NHCs bei der Addition von Acylanionen an Nitroalkene stark verbessert. [59] Xu und Mitarbeiter entdeckten, dass Säureadditive von Vorteil waren, um geringe NHC-Katalysatorbeladungenz ue rmçglichen, die Zersetzung des Katalysators zu verhindern und den Durchsatz des Katalysators zu steigern. Rodriguez, Coquerel und Mitarbeiter zeigten, dass die Zugabe von Essigsäure,um den Carbenkatalysator als Pyrroliumsalz zu maskieren, die Stereoselektivitätd es NHC-katalysierten Aldolschritts bei der Synthese von (1R)-Suberosanon steigerte.…”

Interaction of N‐Heterocyclic Carbenes and Simple Carbenes with Small Molecules (One to Three Atoms) Excluding Metals: Formation of Covalent C–X Bonds

“…Solvation of NHCs by alcohols through HBs has been reported as well as the importance of HBs in the asymmetric catalysis with singlet NHCs .…”