Iminium activation hydrogen-transfer

With regard to the mechanism we assume that, similar to the dehydrogenase (Fig. 1), the ketimine 1 will be activated by protonation through Brpnsted acid 5 which results in the formation of a chiral ion-pair, an iminium ion A. Subsequent hydrogen transfer from the dihy-... 

The use of iminium-catalysis to facilitate highly asymmetric transfer hydrogenations has already been covered in some detail previously (Sect. 3.2.1) (203-205, 210) and the interested reader is referred to the original literature cited therein. Besides iminium activation in combination with Hantzsch dihydropyridines as hydride donors, the use of chiral phosphoric acids in... 

The possible reaction mechanism for a cascade olefination-hydrogenation reaction is illustrated in Scheme 1.21. First, the reaction of proline with ciis-isomer 67 generates the iminium cation 68, which reacts with electrophile 64 via a Mannich-type reaction to generate Mannich product 69. A retro-Mannich or base-induced elimination reaction of amine 69 would furnish active olefin 70. The subsequent hydrogen-transfer reaction is dependent on the electronic nature of the in situ-generated conjugated system or, more precisely, the HOMO-LUMO gap of reactants 65 and 70. 

Hypothesizing that primary amine catalysts, due to their reduced steric requirements, might be suitable for the activation of ketones, we studied various salts of a-amino acid esters. (For pioneering use of primary amine salts in asymmetric iminium catalysis involving aldehyde substrates, see Ishihara and Nakano 2005 Sakakura et al. 2006 for the use of preformed imines of a, 3-unsaturated aldehydes and amino acid esters in diastereoselective Michael additions, see Hashimot et al. 1977.) We have developed a new class of catalytic salts, in which both the cation and the anion are chiral. In particular, valine ester phosphate salt 35 proved to be an active catalyst for the transfer hydrogenation of a variety of a, 3-unsaturated ketones 36 with commercially available Hantzsch ester 11 to give saturated ketones 37 in excellent enantiose-lectivities (Scheme 28 Martin and List 2006). 

Fig. 1. Representation of the proposed catalytic activation. Aspartate D165 pro-tonates the a-iminoglutarate to form an iminium ion which after hydride transfer from NADH results in the formation of the amino acid glutamate (left). Active site of a GDH crystal structure the glutamate is located in a hydrogen bond distance from the catalytically essential D165 (right)...

The past 35 years have seen both the asymmetric hydrogenation and asymmetric transfer hydrogenation of imines develop into useful methods for the synthesis of chiral amines. Particularly, focused research over the past 15 years has led to highly enantioselective examples of both reaction types and has added aza aromatics, activated imines, and iminium cations to their purview. In addition, the asymmetric hydrogenation and asymmetric transfer hydrogenation of imines have both been apphed to total syntheses. Because they are necessarily isomeri... 

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