Highly Enantioselective Hydrogenation of Enamides Catalyzed by Chiral Phosphoric Acids

Abstract

A highly enantioselective hydrogenation of enamides catalyzed by a dual chiral-achiral acid system was developed. By employing a sub-stoichiometric amount of a chiral phosphoric acid and acetic acid, catalyst loadings as low as 1 mol% of the chiral catalyst were sufficient to provide excellent yield and enantioselectivity of the reduction product.Enantioselective hydrogenation is one of the key transformations to produce chiral compounds in academia and in the chemical industry. 1 As a new direction in this research field, enantioselective hydrogenation catalyzed by organocatalysts with Hantzsch esters as the reducing agent has emerged as an attractive strategy due due to its environmentally benign nature. 2 Recently, chiral Brønsted acids 3 were reported as highly efficient catalysts for the hydrogenation of ketimines, α,β-unsaturated aldehydes and nitroolefins by the research groups of Rueping, List, MacMillan and others. 4 Likewise, our recent interest in chiral phosphoric acid-catalysis 5 included a report whereby α-imino esters could be reduced in the presence of a VAPOL phosphoric acid-catalyst (A2) to prepare chiral α-amino acid esters with excellent enantioselectivities. 5aAlthough the reductive amination of ketones and the hydrogenation of ketimines catalyzed by chiral Brønsted acids were achieved in high enantioselectivities, these reactions were limited primarily to reactants derived from aniline and its analogues. As a result, the deprotection of jantilla@cas.usf.edu. Supporting Information Available. Experimental procedures, characterization, chiral HPLC conditions, and spectra. This material is available free of charge via the Internet at http://pubs.acs.org. the aromatic group to reveal the amino group can be relatively difficult, requiring somewhat harsh reaction conditions such as those methods that use ceric ammonium nitrate (CAN), rendering these methods less synthetically appealing (eq. 1, Scheme 1). Attractive features of enamides are their relative stability and ease in handling. Additionally, when considering Nacyl enamide substrates, the acyl group of the reduction product can be easily removed under standard procedures in good yield. Therefore, due to these considerations such enamide precursors have become popular substrates for preparing chiral amines through standard metalcatalyzed hydrogenation. 1 Herein we would like to report our results on the asymmetric hydrogenation of enamides with high enantioselectivity using chiral phosphoric acid catalysis (eq. 2, Scheme 1). NIH Public AccessWe initiated our studies on the hydrogenation of enamide 1a by using the achiral phenylphosphinic acid (A1) as the catalyst, with 1.1 equivalents of Hantzsch ester dihydropyridine 2 as the reducing agent. We were pleased to find that in the presence of 10 mol % of A1, at ambient temperature, the reaction took place smoothly in an argon atmosphere to provide a 95% isolated yield of the desired product amide 3a (entry 1, Table 1). However, when we replaced the achiral catalyst A1 with chiral phos...

Selecting Chiral BINOL‐Derived Phosphoric Acid Catalysts: General Model To Identify Steric Features Essential for Enantioselectivity

“…Reactions with imines bearing large N‐substituents favor Type I pathways; a preference for E or Z depends on how accessible the configuration is. If the Z configuration is energetically inaccessible the reaction proceeds via a Type I  E pathway, the correct catalyst has large proximal and medium AREA(θ) 10, 11, 12, 13c, 14b, 19, 20, 21, 22, 40, 41, 42, 43, 44, 45, 46, 47. However, reactions involving displaced nucleophiles the best choice of catalyst has large proximal and small AREA(θ) 5, 8, 9, 30, 31, 48, 49, 50, 51, 52, 53.…”

The mechanism investigation of chiral phosphoric acid-catalyzed Friedel–Crafts reactions – How the chiral phosphoric acid regains the proton

“…BINOL-phosphoric acids are well-known catalysts with excellent yield and enantioselectivity in many organic reactions such as Friedel-Crafts [1], Strecker-type [2], Mannich-type [3] and Aza-Diels-Alder reactions [4], as well as the reduction of imines [5] and enamides [6], the allylboration of aldehydes [7]. Therefore, computational studies for the organocatalysis reactions of BINOLphosphoric acid have received much more attention by some research groups, like those of the Goodman et al [8], You et al [9], Yamanaka et al [10], Himo et al [11] and Shi groups [12].…”

Imine and iminium precursors as versatile intermediates in enantioselective organocatalysis

“…67 Having observed a significant retardation of reaction rate when lowering catalyst loading from 5 to 1 mol % during initial optimization, they postulated that the addition of an achiral acid as a co-catalyst might accelerate the tautomerization of the starting material, but not interfere with the hydrogenation step. Indeed, the addition of 10 mol % of acetic acid accelerated the reaction greatly and the hydrogenation products were obtained in excellent yields and enantioselectivities (Scheme 42).…”