Enzymatic desymmetrization approach

Improved efficiency in the synthesis of 24 was ultimately achieved via an enzymatic desymmetrization approach (Scheme 7). In the key step of this route, an asymmetric oxidation of achiral amine 41 promoted by monoamine oxidase (MAON) under an oxygen atmosphere afforded intermediate 42. In this streamlined process, sodium bisulfite was included in the enzymatic oxidation mixture to effect direct conversion to sulfonate 44. Treatment of 44 with sodium cyanide provided the trans-nitrile 43 as a single diastereomer in approximately 90% yield from pyrrolidine 41. As in the second-generation synthesis, the nitrile is hydrolyzed to the methyl ester under Pinner conditions (HCI, methanol). In the manufacturing process, the product was converted to its free base using NaOH, then crystallized as the HCI salt from i-propanol and methyl t-... 

Biocatalysis plays a central role in the manufacturing of statin side chains (Figure 6.2). A first set of approaches exploits enzymatic desymmetrization reactions, for example, of the methoxyacetyl ester of glutaric acid diethyl ester with commercially available a-chymotrypsin as explored by Ciba SC with a yield of 94% and enantiomeric excess of up to 98% [1]. In the optimized procedure, the substrate was available in a concentration of 1 M at an enzyme/substrate ratio of 7% (wt/wt), and the reaction took approximately a day. The subsequent steps to the final acetonide also involved a pig-liver esterase (PLE) catalyzed selective hydrolysis of the methoxyacetyl group (Figure 6.2a). 

Wang, M.X., Liu, C.S., and Li, J.S. 2001a. Enzymatic desymmetrization of 3-alkyl- and 3-arylglutaronitriles, a simple and convenient approach to optically active 4-amino-3-phenylbutanoic acids. Tetrahedron Asymmetry, 12 3367-73. 

In another approach, ketone 228 was obtained in optically pure form by an enzymatic desymmetrization and a stereoselective epoxidation [91] (Scheme 47). A sequential reduction of epoxide and the carbonyl group gave diol 229, which was... 

Asymmetric synthesis with lipases and esterases can basically be performed by two different approaches - the desymmetrization of prochiral or meso compounds and the enzymatic kinetic resolution of racemic mixtures. The main bottleneck of kinetic resolutions, product yields of maximum 50%, can be overcome if an in situ racemization of the starting material is possible. In this case all starting material can theoretically be converted to the desired product [34],... 

The or-analogue 159 has been made by a Pd-catalysed reaction involving an allylic phosphate as reactant, whilst others have also described routes to 159, its hydrogenated analogue, and the enantiomer and diastereoisomers of this, using enzymic desymmetrization to introduce chirality the products were evaluated for their ability to inhibit tumour necrosis factor-a. A chemo-enzymatic approach has also been used to make the cyclopropane-fused analogue 160 and... 

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