Design of N-Spiro C₂-Symmetric Chiral Quaternary Ammonium Bromides as Novel Chiral Phase-Transfer Catalysts:  Synthesis and Application to Practical Asymmetric Synthesis of α-Amino Acids

Abstract

A series of C(2)-symmetric chiral quaternary ammonium bromides 10 and 11 have been designed as a new, purely synthetic chiral phase-transfer catalyst, and readily prepared from commercially available optically pure 1,1'-bi-2-naphthol as a basic chiral unit. The details of the synthetic procedures of each requisite chiral binaphthyl subunit have been disclosed, and the structures of the assembled N-spiro chiral quaternary ammonium bromides 11a and 11f were unequivocally determined by single-crystal X-ray diffraction analysis. The reactivity and selectivity of these chiral ammonium bromides as chiral phase-transfer catalysts have been evaluated in the asymmetric alkylation of the benzophenone Schiff base of glycine ester 7 under mild liquid-liquid phase-transfer conditions, and the optimization of the reaction variables (solvent, base, and temperature) has also been conducted. Further, the scope and limitations of this asymmetric alkylation have been thoroughly investigated with a variety of alkyl halides, in which the advantage of the unique N-spiro structure of 11 and dramatic effect of the steric as well as the electronic properties of the aromatic substituents on the 3,3'-position of one binaphthyl moiety have been particularly emphasized. Finally, the potential synthetic utility of the present method for the practical asymmetric synthesis of structurally diverse natural and unnatural alpha-amino acids has been demonstrated by its successful application to the facile asymmetric syntheses of (S)-N-acetylindoline-2-carboxylate, a key intermediate in the synthesis of the ACE inhibitor, and l-Dopa (l-3,4-dihydroxyphenylalanine) ester and its analogue.

The Basic Principle of Phase‐Transfer Catalysis and Some Mechanistic Aspects

“…The most studied area in the asymmetric phasetransfer catalysis is that of asymmetric alkylation of active methylene or methine compounds with alkyl halides, in an irreversible manner. The reaction mechanism illustrated above is exemplified by the asymmetric alkylation of glycine Schiff base (Scheme 1.5) [8].…”

Design of Sophisticated Bidentate Lewis Acids and Organocatalysts for Fine Organic Synthesis

“…Switching the catalyst to (S,S)-20c and sterically more hindered (S,S)-20d further increased the enantioselectivity to 96% ee and 98% ee, respectively, and virtually complete stereochemical control was achieved using (S,S)-20e as catalyst. 21,22 The lower chemical yield (79%) with (S,S)-20e was ascribed to the intervention of enolate oxidation by aerobic oxygen and was improved to 90% by simply performing the reaction under argon atmosphere. In the case of a reactive alkyl halide, the catalyst loading can be reduced to 0.2 mol % without loss of enantiomeric excess.…”

“…In the case of a reactive alkyl halide, the catalyst loading can be reduced to 0.2 mol % without loss of enantiomeric excess. 22 (S,S)-20e is the catalyst of choice for the preparation of a variety of essentially enantiopure ¡-alkyl-¡-amino acids by this transformation (Scheme 22). Facile asymmetric synthesis of ¡-alkyl-¡-amino acids, which is usually inaccessible by enzymatic processes, becomes feasible by employing appropriate electrophiles such as ortho-disubstituted benzyl bromides.…”

Enantioselective Total Syntheses of Several Bioactive Natural Products Based on the Development of Practical Asymmetric Catalysis

“…[195][196][197][198][199][200] Later, Corey [201][202][203] and Lygo [204][205][206][207] independently greatly improved this catalyst system. [208][209][210] Although many types of chiral phase-transfer catalysts have been developed, Cinchona alkaloid derivatives give more impressive enantioselectivity for a range of reactions than do other catalysts, with few exceptions, [213][214][215][216][217][218][219][220][221][222] such as N-spiro binaphtyl derivatives. [213][214][215][216][217] The major drawback of these catalysts is the difficulty in modifying the catalyst structure for further improvement of selectivity and reactivity or further application to other types of catalytic asymmetric reaction systems.…”