Diastereoselective dynamic kinetic resolution process

Owing to the fully reversible equilibrium nature of the aldol addition process, enzymes with low diastereoselectivity will typically lead to a thermodynamically controlled mixture of erythro/threo-isomers that are difficult to separate. The thermodynamic origin of poor threo/erythro selectivity has most recently been turned to an asset by the design of a diastereoselective dynamic kinetic resolution process by coupling of L-ThrA and a diastereoselective L-tyrosine decarboxylase (Figure 10.47)... 

The hydrogenation of a-amino ketones was also a key step for the synthesis of three more pharma actives (Fig. 37.25). Roche [95] divulged a pilot process involving the hydrogenation/dynamic kinetic resolution of a cyclic a-amino ketone using an optimized MeO-biphep ligand. The Ru-catalyzed reaction was carried out on a 9-kg scale with excellent enantio- and diastereoselectivities, and very... 

Dynamic Resolution of Chirally Labile Racemic Compounds. In ordinary kinetic resolution processes, however, the maximum yield of one enantiomer is 50%, and the ee value is affected by the extent of conversion. On the other hand, racemic compounds with a chirally labile stereogenic center may, under certain conditions, be converted to one major stereoisomer, for which the chemical yield may be 100% and the ee independent of conversion. As shown in Scheme 62, asymmetric hydrogenation of 2-substituted 3-oxo carboxylic esters provides the opportunity to produce one stereoisomer among four possible isomers in a diastereoselective and enantioselective manner. To accomplish this ideal second-order stereoselective synthesis, three conditions must be satisfied (1) racemization of the ketonic substrates must be sufficiently fast with respect to hydrogenation, (2) stereochemical control by chiral metal catalysts must be efficient, and (3) the C(2) stereogenic center must clearly differentiate between the syn and anti transition states. Systematic study has revealed that the efficiency of the dynamic kinetic resolution in the BINAP-Ru(H)-catalyzed hydrogenation is markedly influenced by the structures of the substrates and the reaction conditions, including choice of solvents. 

The quinine derived thiourea 12 was found to be the most efficient catalyst, in terms of conversion and enantioselectivity, in the Michael-Michael cascade process between tra y-3-(2-mercaptoaryl)-2-propenoic acid esters and /ra 5-nitroalkenes [39]. The thiochromanes, containing three new stereocenters, were obtained with excellent enantio- and diastereoselectivity irrespective of the electronic namre and substitution pattern of the aromatic ring in the nitroalkene and in the thiol. Although the first sulfa-Michael step of the process was poorly enantioselective, it was also reversible, so that the enantiomeric mixture of the adducts underwent an efficient dynamic kinetic resolution due to a retro-Michael-Michael-Michael sequence (Scheme 14.10). 

A powerful application of this technology has been demonstrated by the conversion of racemic p-ketoesters to a single stereoisomer via asymmetric reduction combined with dynamic kinetic resolution. Cationic ruthenium complexes were employed in the conversion of 28 to 29, a key intermediate in the synthesis of carbapenem antibiotics (Scheme 14.10). Increased steric bulk on the aryl groups was required to give high diastereoselectivity as well as enantioselectivity, and this process was used for industrial production on a scale of 100 metric tonnes per year. 

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