Development of an Asymmetric Acetate Aldol Reaction with a Trifluoromethyl Ketone
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Abstract
We describe the discovery and development of a chiral auxiliary-controlled asymmetric acetate aldol reaction with a trifluoromethyl ketone. Chiral acetate 3d was prepared efficiently from (1S,2R)-1-amino-2-indanol. Reaction of the lithium enolate of 3d with trifluoromethyl ketone 2 afforded aldol adducts in 95% HPLC assay yield (by weight) with a 78:22 dr. The major isomer 5 was obtained via a robust crystallization method in 45% one-crop isolated yield with a >98.7:1.3 dr. Compound 5 was subjected to transesterification to give β-hydroxy ester 1. The cleaved auxiliary 7 was readily recovered by a direct crystallization/filtration method. Process optimization led to better volume efficiencies, improved isolation protocols, and less consumption of organic solvents, all contributing to enhanced throughput, reduced processing labor and time, as well as reduction in chemical wastes.
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