Synthesis of Both Enantiomers of Chiral Phenylalanine Derivatives Catalyzed by Cinchona Alkaloid Quaternary Ammonium Salts as Asymmetric Phase Transfer Catalysts.

Lei Jin,Xin Chen,Shuai Zhao

doi:10.3390/molecules23061421

Abstract

A practical synthesis of both enantiomers of unnatural phenylalanine derivatives by using two pseudoenantiomeric phase transfer catalysts is described. Through asymmetric α-alkylation of glycine Schiff base with substituted benzyl bromides and 1-(bromomethyl)naphthalene under the catalysis of O-allyl-N-(9-anthracenmethyl) cinchoninium bromide (1f) and O-allyl-N-(9-anthracenylmethyl)cinchonidium bromide (1i), respectively, a series of both (R)- and (S)-enantiomers of unnatural α-amino acid derivatives were obtained in excellent yields and enantioselectivity. The synthetic method is simple and scalable, and the stereochemistry of the products is fully predictable and controlled: the cinchonine-type phase transfer catalyst 1f resulted in (R)-α-amino acid derivatives, and the cinchonidine-type phase transfer catalyst 1i afforded (S)-α-amino acid derivatives.

Highlights

Unnatural α-amino acids are important building blocks for synthesis of peptides, pharmaceutical molecules and natural products
We are interested in unnatural α-phenylalanine derivatives [9] because they are the key building blocks for synthesizing a series of dipeptides as allosteric antagonists of the β2 -adrenergic receptor (β2 AR) [1] in one of our ongoing research projects
Chiral unnatural α-phenylalanine derivatives were synthesized through the asymmetric α-alkylation reaction of N-(dibenzylidene)glycine tert-butyl ester (2) [23,24] with substituted benzyl bromides catalyzed by a phase transfer catalyst

Summary

Introduction

Unnatural α-amino acids are important building blocks for synthesis of peptides, pharmaceutical molecules and natural products. Unnatural α-phenylalanine derivatives have been the subject of numerous investigations for their extensive distribution in biological active compounds. CPD-15A5, which is a small-molecule negative allosteric modulator (antagonist) for the β2 -adrenergic receptor (β2 AR) [1], contains a (S)-3,5-dibromophenylalanine subunit (Figure 1). ADEP 4, which shows potent antibacterial activity against multidrug-resistant pathogens [5,6], has a (S)-3,5-difluorophenylalanine sidechain. We are interested in unnatural α-phenylalanine derivatives [9] because they are the key building blocks for synthesizing a series of dipeptides as allosteric antagonists of the β2 -adrenergic receptor (β2 AR) [1] in one of our ongoing research projects

Objectives

Methods

Results

Conclusion