Highly Enantioselective Synthesis of Fluorinated β-Amino Ketones via Asymmetric Organocatalytic Mannich Reactions: A Case Study of Unusual Reversal of Regioselectivity

 

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Abstract

The highly enantioselective direct Mannich protocol employing fluoroacetone, p-anisidine, and aldehydes catalyzed by 4-siloxyproline was developed, allowing efficient access for pharmaceutically important fluorinated β-amino ketones. On the basis of DFT calculations and mechanistic probes, the origin of an unusual reversal of regioselectivity was unraveled.

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DFT calculations were carried out with the Gaussian 09 package (Frisch M. J. et al. Gaussian 03, Revision D.01, Gaussian, Inc.: Wallingford, CT, 2004). The geometries for two enamines and two possible transition states which involved hydrogen bonding, are fully optimized by M06 method using 6-31G+(d,p) basis set. The geometries have been confirmed to be equilibrium geometries or transition states by the harmonic frequencies calculations at the same level of theory. The energy values in the gas phase are further calculated with M06/6-311++G(d,p) method based on the optimal geometries and corrected with the zero-point energy calculated from M06/6-31G+(d,p) method. Solvent effect from DMSO is mimicked by the PCM model and single point energy calculation is done with M06/6-311++G(d,p) with the gas phase geometry.

Normally, the Mannich reaction will proceed at the more substituted site, see ref. 8a. Reversal of regioselectivity was observed previously, see ref. 8b.