The development of a general catalytic asymmetric aldehyde alpha-alkylation reaction constitutes a major challenge in organic synthesis. Here, we report the first and successful approach toward its solution: (S)-alpha-methyl proline catalyzes the intramolecular alkylation of various halo aldehydes to the corresponding formyl cyclopentanes, -cyclopropanes, or -pyrrolidines in excellent yields and enantioselectivities. Most remarkably, racemization, aldolization, or catalyst alkylation do not occur to any significant extend, further illustrating the power, mildness, and profound selectivity of enamine catalysis.

32 years after the first, and still the only, catalytic asymmetric intramolecular aldol reaction was published in this journal, the proline‐catalyzed Hajos–Parrish–Eder–Sauer–Wiechert reaction is extended for the first time to catalytic asymmetric enolexo aldolizations. The process provides substituted cyclohexanes in excellent diastereo‐ and enantioselectivities. For example, heptanedial is converted into the corresponding cyclic anti‐configured aldol in 99 % ee (see scheme).

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

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