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

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.

N‐Sulfinyl Amines as a Nitrogen Source in the Asymmetric Intramolecular Aza‐Michael Reaction: Total Synthesis of (−)‐Pinidinol

“…Flash column chromatography was performed with the indicated solvents on silica gel 60 (particle size: 0.040-0.063 mm). 1 H, 13 C, and 19 F NMR spectra were recorded on a 300 MHz spectrometer. Chemical shifts are given in ppm (d), referenced to the residual proton resonances of the solvents or fluorotrichloromethane in 19 F NMR spectroscopic experiments.…”

“…[13] Additionally, this interaction would also explain the difference in selectivity found between substrate (S S )-4 c ( Table 3, entry 1) and (R S )-4 d (Table 3, entry 6), which contains a tBu group attached to the sulfoxide, since in this case only steric effects are operating.…”

Organolithium/Chiral Lewis Base/BF3: a Versatile Combination for the Enantioselective Desymmetrization of meso‐Epoxides

“…89°C (2-propanol) (ref. [54] 90°C, 2-propanol). Recrystallization from EtOH afforded white crystals of racemic material.…”

Correlation between pressure and steric interactions in organic reactions

“…21 The asymmetric conjugate Michael-like addition of amines to chiral bulky crotonates is essentially accessible only under high pressure. 22 Interestingly, efficient stereo-and enantioselectivity are achieved at 1.4 GPa since the diastereoisomeric excess increases from 10% at ambient pressure to 98% at high pressure. Very recently, hindered quaternary centers have been made accessible via highpressure asymmetric Michael addition of chiral imines to crotonates.…”