Stereoselective reductions with macrocyclic NADH models Ulrik Gran,* Olof WennerstroÈm and Gunnar Westman Department of Organic Chemistry, Chalmers University of Technology, S-412 96 Go Èteborg, Sweden Received 19 June 2000; accepted 27 June 2000 Abstract Macrocyclic NADH models with two (C 2 symmetry) or four (D 2 symmetry) nicotinamide units comprised in a ring have been prepared and found to reduce activated carbonyl compounds in good yields and high enantiomeric excess. The roles of magnesium ions as a cocatalyst and the temperature have also been investigated. The smaller, C 2 -symmetric macrocycle gave 96% ee upon reduction of ethyl benzoyl- formate whereas the best result with the larger D 2 -symmetric model was 81% ee for the reduction of methyl benzoylformate. # 2000 Elsevier Science Ltd. All rights reserved. 1. Introduction Nicotinamide adenine dinucleotide (NAD + /NADH) is a coenzyme which takes part in many biological oxidation±reduction reactions, 1 such as the conversion of ketones and aldehydes to alcohols and vice versa. These reactions are catalyzed by enzymes commonly named dehydrogenases. The reduction of ketones has been of major interest when mimicking the chemistry of NAD + /NADH. The enzymatic reduction of a prochiral ketone carried out by NADH proceeds via a selective transfer of one of the two diastereotopic hydrogens in the dihydropyridine ring of NADH. The hydrogen is transferred stereoselectively to the ketone, thus generating a chiral alcohol. Since the ®rst asymmetric reduction using an NADH model reported by Ohno et al. in 1975, 2 there has been a large number of dierent approaches to NADH mimicking. 3 The general concept is to start with nicotinamide and then modify it, for example, by introducing various chiral auxiliaries in the amide or methyl groups at C-2 and C-4 in the dihydropyridine ring. The NADH models presented in this report are designed by a supramolecular approach, where the substrate to be reduced is bound into a hydrophobic pocket of the model. The models comprise a chiral cavity as a substrate binding site to keep the substrate in a ®xed orientation during the reaction, which should give good control of the stereoselectivity. Several nicotinamide units are incorporated in the macrocyclic framework which creates this hydrophobic pocket. 0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved. PII: S0957-4166(00)00248-2 Tetrahedron: Asymmetry 11 (2000) 3027±3040 * Corresponding author. E-mail: gran@oc.chalmers.se