Stereoselective Quaternization of α-Amino Phenylacetonitriles Mediated by a Remote Sulfinyl Group

Abstract

Enantiomerically pure alpha-substituted alpha-amino phenylacetonitriles have been readily prepared from 2-p-tolylsulfinylbenzaldimines following a two-step sequence: a moderately stereoselective hydrocyanation of the imines and a completely stereoselective quaternization of the resulting diastereoisomeric mixture of alpha-amino phenylacetonitriles with different alkylating or acylating reagents in the presence of KHMDS. Theoretical calculations support a stereoselectivity control exerted by the remote sulfinyl group, as long as it is responsible for the conformational preferences of the benzyllithium intermediates, which suffer the attack of the electrophiles to the less hindered diastereotopic face.

Stereodivergent Quaternization of 2‐Alkyl‐2‐p‐tolylsulfinylacetonitriles: NMR Spectroscopic Evidence of Planar and Pyramidal Benzylic Carbanions

“…When LHMDS was used as the base in THF at À78 8C, the reaction evolved with moderate stereoselectivity yielding a 74:26 diastereoisomeric mixture of 7 aA and 7 aB (Table 1, entry 1). [16] The use of CH 2 Cl 2 as the solvent determined a decrease in the stereoselectivity (Table 1, entry 2), whereas the addition of [12]crown-4 ether had scarce influence on the diastereoisomeric ratio (d.r.) (Table 1, entry 3).…”

“…Keywords: asymmetric synthesis · carbanions · chirality · diastereoselectivity · NMR spectroscopy triles [12] (2, Y= NHBn) and potassium hexamethyldisilazane (KHMDS) also evolved in a highly stereoselective way [Scheme 1, Eq. (2)] allowing the creation of chiral benzylic quaternary centers with high optical purities.…”

Stereocontrolled reactions mediated by remote sulfoxides: Formation and reactivity of enantiomerically pure benzylic centers

“…Thus, the reactions of the corresponding silylated cyanohydrins with lithium or potassium HMDS, generated a benzylic carbanion that reacted with different electrophiles, both acylating and alkylating reagents, to form quaternary chiral centers in an almost complete stereoselective SCHEME 5 way and very high yields (Scheme 5b) [15]. Even better results were obtained starting from N-benzylα-amino nitriles, [16] which provided optically pure compounds containing quaternary carbons at C-α (Scheme 5c).…”

Enantioselective Synthesis of α-Quaternary Amino Acids by Alkylation of Deprotonated α-Aminonitriles

“…In contrast, (4S,5S)-5-amino-2,2-dimethyl-4-phenyl-1,3-dioxane (1) proved to be highly effective and provided excellent diastereoselectivities of up to 99:1. In contrast to the also highly efficient 2-sulfinylarene type auxiliary employed by Ruano and coworkers, 41 it can be removed by oxidation after hydrolysis of the nitrile function permits a straightforward access to α-quaternary arylglycines. 42,43 Auxiliary 1 had been successfully employed by Weinges et al [42][43][44] for the synthesis of α-amino acids by means of a diastereoselective crystallization of its Strecker products with aldehydes or ketones followed by hydrolysis and oxidative degradation of the chiral template.…”