Chiral Proton Catalysis: Design and Development of Enantioselective Aza-Henry and Diels-Alder Reactions

Abstract

The proton (H+) is arguably Nature's most common Lewis acid and is utilized by many enzymes to carry out asymmetric transformations. These "natural" Brønsted acid catalysts have served as an inspiration to synthetic organic chemists for the development of both regioselective and stereoselective bond forming reactions. Inspired by Nature's elegance and motivated by the demand for inexpensive, robust and environmentally friendly catalysts, a Brønsted acid catalyst called the chiral proton was developed. This catalyst relies upon polar ionic hydrogen bonding for substrate activation and as a primary control element for enantioselection. The catalyst system was based on a coordination complex between a proton and a chiral, C2-symmetric BisAMidine ligand (BAM).

This complex has demonstrated the ability to both activate and control the absolute and relative stereochemistry in the addition of silyl nitronates to Boc-protected imines. It was further demonstrated that nitroalkanes could be used in place of silyl nitronates (aza-Henry reaction), eliminating the need for preformation of the nucleophile. In the latter reaction, the amount of catalyst could be reduced to as low as 1 mol% without loss of enantioselectivity, attesting to the BAM ligand's ability to sequester protons from bulk solvent. The products of this reaction provide access to enantioenriched 1,2-diamines. Furthermore, this catalyst system has been successfully applied to the enantioselective synthesis of both syn and anti α,β-diamino acids.

The chiral BAM-protic acid complexes were further applied to the stereoselective intramolecular hetero-Diels-Alder reactions of azadienes. These catalysts were found to influence both the endo/exo selectivity, as well as the facial selectivity of the [4+2] cycloadditions. The azadienes used in this study were modeled after the putative Diels-Alder precursors in the biosynthesis of the brevianamide class of natural products. In addition, a novel Diels-Alder reaction was hypothesized as an alternative route to the synthesis of oseltamivir phosphate (Tamiflu). A model system was chosen to examine the effectiveness of this route. The chiral proton catalyst was shown to catalyze this model reaction to produce the desired exo Diels-Alder adduct.