Metal‐Free, Organocatalytic Asymmetric Transfer Hydrogenation of α,β‐Unsaturated Aldehydes

Abstract

Selective reduction without metals: An imidazolidinone salt effectively catalyzes the highly enantioselective biomimetic transfer hydrogenation of α,β-unsaturated aldehydes to give the saturated analogues using a synthetic dihydropyridine cofactor (see scheme). Remarkably only one enantiomer forms regardless of the configuration of the enal starting material. Asymmetric catalytic hydrogenations are used in the large-scale industrial production of pharmaceuticals and fine chemicals and also by all living organisms. While chemical hydrogenations require metal catalysts or the use of stoichiometric amounts of metal hydrides,1 living organisms typically rely on organic cofactors such as nicotinamide adenine dinucleotide (NADH) in combination with metalloenzymes.2 Until now, metal-free catalytic asymmetric hydrogenations have been unknown in chemical synthesis and seem to be rare in nature.3 Here we show that a small organic molecule effectively catalyzes a highly enantioselective biomimetic transfer hydrogenation of α,β-unsaturated aldehydes using a synthetic dihydropyridine cofactor. This reaction is the first example of a completely metal-free transfer hydrogenation of olefins.7 We could also show that enantioselective iminium catalysis of the reaction is in principle possible. Iminium catalysis has recently been introduced as a powerful organocatalytic method for carbonyl transformations such as conjugate additions and cycloadditions.8 We have now completed an extensive screening of several synthetic and commercially available Hantzsch dihydropyridines and chiral ammonium salt catalysts and report here on an efficient enantioselective variant of our transfer hydrogenation. Entry Starting Product Yield [%] e.r. material 1 1 1 77[a] 95:5 2 1 1 89 98:2 3 1 1 83 (from (E)-5 c) 97:3 80 (from (Z)-5 c) 97:3 81 (from (E)/(Z)- 5 c (1:1)) 97:3 4 1 1 90 97:3 5 1 1 85 97:3 6 1 1 86 96:4 Like our nonasymmetric variant, the enantioselective reactions are generally clean and highly chemoselective, and carbonyl reduction or aldolization products were not detected. We also investigated the influence of the stereochemistry at the double bond. Remarkably, when we subjected both the isolated pure E or Z isomers of 4-nitro-substituted derivative 5 c to our reaction conditions, the same R enantiomer of product 8 c was obtained and with the same enantiomeric ratio of 97:3. Similarly, (E)/(Z)-5 c mixtures always gave the same result and, independent of their exact ratio, all furnished (R)-8 c in 97:3 e.r. Thus, our process is enantioconvergent, a highly desirable yet rare feature of a catalytic asymmetric reaction, where a mixture of stereoisomers furnishes only one product enantiomer. As a practical consequence of this feature, the unsaturated aldehyde starting material of our reaction may be used as a mixture of E and Z isomers as obtained from common synthetic procedures such as the Wittig reaction. Mechanistically, we assume the reaction to proceed by formation of iminium ion 9, which presumably isomerizes quickly via dienamine 10 (Scheme 1). The following rate-determining hydride transfer from dihydropyridine 6 to enal (E)-9 via transition state A proceeds faster than to (Z)-9 [k(E)>k(Z)] and, as a result, saturated aldehyde (R)-8 is formed predominantly. Proposed mechanism of the organocatalytic asymmetric transfer hydrogenation. In summary we have described the first completely metal-free catalytic asymmetric transfer hydrogenation. In our iminium catalytic reaction α,β-unsaturated aldehydes are highly efficiently reduced by means of transfer hydrogenation from a dihydropyridine. Attractive features of the process are 1) its high yields, chemo-, and enantioselectivities, 2) its enantioconvergence, and 3) its simplicity and practicability. Applications in the synthesis of natural products, pharmaceuticals, and fine chemicals may be envisioned. General procedure for the asymmetric transfer hydrogenation reaction: To a stirred solution of α,β-unsaturated aldehyde 5 (0.5 mmol) in dioxane (7 mL) at 13 °C was added catalyst 7 (20.4 mg, 0.05 mmol, 10 mol %) and, after five minutes, crystalline dihydropyridine 6 (129.2 mg, 0.51 mmol). After a reaction time of 48 h the mixture was poured into distilled water (20 mL) and extracted with dichloromethane (2×15 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The product was isolated by flash chromatography (SiO2, ethyl acetate/hexane) to give the saturated aldehyde product 8. Aldehydes 5 a–f were synthesized according to previously reported methods and their analytical data as well of those of aldehydes 8 match literature values.9 The absolute configuration of (R)-8 f was determined by measurement of its optical rotation and comparision to the literature value.10 Enantiomeric ratios were determined by chiral stationary phase GC-analysis.