Investigating the π-Facial Discrimination Phenomenon in the Conjugate Addition of Amines to Chiral Crotonates: A Convenient Basis for the Rational Design of Chiral Auxiliaries

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Abstract

This paper is concerned with the nature of the chiral inducer in the high pressure-induced conjugate addition of amines to auxiliary-tethered crotonates. Almost complete stereocontrol was obtained in the addition of diphenylmethanamine to crotonates derived from the “arylmenthol” auxiliaries 18a, 18c, and 4 bearing an o-methoxyphenyl, p-phenoxyphenyl, or β-naphthyl substituent, respectively. This high efficiency has been attributed to the predominance of stacked conformations in such crotonates, a hypothesis supported by the 1H NMR spectra, calculated energy of conformational optima of the corresponding crotonates, and X-ray crystal structure of 5a. The arene and enoate appendages are roughly coplanar, separated by 3.4−4 Å. In contrast, only moderate selectivities could be achieved using various trans-2-arylcyclohexanols (27, 28, 2c, 29) as auxiliaries. In these cases the efficiency appears to be seriously compromised by the “widening V” arrangement exhibited by the two π-systems, as shown in the X-ray crystal structures of crotonates 5h and 5k. The sense of stereochemical induction of this conjugate addition has been determined by condensing diphenylmethanamine with enantiopure crotonate (+)-5a. The adduct 9a was converted to amino alcohol (S)-11, of known configuration. This correlation is consistent with the preferential attack of the amine to the less sterically hindered enoate π-face of (+)-5a, in its s-trans conformation. Finally, the stereochemistry of the proton transfer was determined by adding N,N-dideuteriodiphenylmethanamine to crotonate (±)-5a. The stereochemical outcome of this addition is consistent with the anti-addition of the incoming nitrogen nucleophile and the deuterium atom.

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