The application of recombinant pig liver esterase isoenzymes was key to successfully obtaining the (3S,5S)-diastereomer, which shows activity as an anti-Mannich catalyst. The asymmetric Mannich reaction is an important carbon-carbon bond-forming step in the synthesis of chiral molecules containing nitrogen. The resulting β-amino carbonyl compounds act as valuable synthons in the preparation of many natural products with useful biological properties. Consequently, the demand for Mannich reactions that selectively deliver anti- or syn-products with high enantioselectivity is high.
Among the variety of available organocatalysts, proline is one of the most commonly used and provides easy access to syn-products in Mannich type reactions. Enantioselective anti-Mannich reactions catalysed by pyrrolidine derivatives are, however, considerably rare. Furthermore, as the industrial use of proline-organocatalysts is limited — because of high catalyst loadings — there is a growing demand for more efficient proline analogues.
The novel synthetic route presented here was developed by Professor Masterson’s group at the University of Southern Mississippi and utilises recombinant pig liver esterase (rPLE) isoenzymes and a new stereoselective cyclisation strategy. This route provides access to two diastereomers of 5-benzyl substituted Ca-methyl-b-proline in their optically pure forms (Figure 1).
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