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

Abstract

Asymmetric catalytic hydrogenations are used in the largescale 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 a,b-unsaturated aldehydes using a synthetic dihydropyridine cofactor.Industrially, metal-catalyzed hydrogenations are the most often used catalytic asymmetric processes. The complete removal of metal impurities from the reaction product, though difficult, is generally required in the production of pharmaceutical intermediates because of toxicity concerns. [4] Organocatalysis is a rapidly growing area of research, and one of its advantages is the general lack of metals.[5] We have recently developed an amine-catalyzed nonasymmetric transfer hydrogenation of a,b-unsaturated aldehydes 1 with Hantzsch ester 2 [Eq. (1)]. [6] This reaction is the first example of a completely metalfree 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.We found that upon treating aromatic, trisubstituted a,bunsaturated aldehydes 5 with a slight excess of dihydropyridine 6 and a catalytic amount of MacMillan imidazolidinone salt 7 at 13 8C in dioxane, the corresponding saturated aldehydes 8 were obtained in high yields and excellent enantioselectivities [Eq. (2), Table 1].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-nitrosubstituted 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

Old Yellow Enzyme-Catalysed Asymmetric Hydrogenation: Linking Family Roots with Improved Catalysis

“…Common synthetic routes for cis-hydrogenation are accomplished via homogeneous chiral catalysts composed of precious metals such as rhodium (Rh), ruthenium (Ru) or iridium (Ir), and phosphine ligands such as chiral monoand di-phosphines, C 2 -symmetric bisoxazoline ligands or C 2 -symmetric N-heterocyclic carbenes, respectively [3]. In comparison, synthetic methods for asymmetric trans-hydrogenation to afford the stereo-complementary products are scarce [4].…”

MacMillan’s Imidazolidinones: Powerful Chiral Organocatalysts

“…A small collection of chiral imidazolidinone salts have been shown to be widely efficient for a broad range of asymmetric transformations such as Friedel-Crafts alkylation, 2 Diels-Alder cycloaddition, 3 hydrogenation of a,bunsaturated carbonyl compounds 4 and cascade catalysis. 5 Furthermore, these chiral imidazolidinones can be used for the classical enamine activation of ketone or aldehyde 6 in aldol or addition reactions.…”

“…14 (E) Organocatalytic reduction of a,b-unsaturated aldehydes was performed by List and and co-workers. 4 The iminium generated in situ reacted with the Hantzsch ester hydride donor to provide enantiomerically pure hydrogenated aldehydes. The authors noticed that the enantiomeric excess is not related to the geometry of the double bond.…”

Asymmetric organocatalytic reductions mediated by dihydropyridines

“…Interestingly, both 14 and its (Z)-isomer 17 (and even 1 : 1 mixtures of 14 and 17) furnished the same product enantiomer in almost identical yield and enantioselectivity. 34 Scheme 3 The first enantioselective organocatalytic reductions.…”