Asymmetric amination of α,α-dialkyl substituted aldehydes catalyzed by a simple chiral primary amino acid and its application to the preparation of a S1P1 agonist

Qiong Xiao; Yifan Tang; Ping Xie; Dali Yin

doi:10.1039/c9ra06210f

Asymmetric amination of α,α-dialkyl substituted aldehydes catalyzed by a simple chiral primary amino acid and its application to the preparation of a S1P₁ agonist

RSC Adv. 2019 Oct 18;9(57):33497-33505. doi: 10.1039/c9ra06210f. eCollection 2019 Oct 15.

Authors

Qiong Xiao¹, Yifan Tang², Ping Xie¹, Dali Yin¹

Affiliations

¹ State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Department of Medicinal Chemistry, Institute of Materia Medica, Peking Union Medical College, Chinese Academy of Medical Sciences Beijing 100050 PR China yindali@imm.ac.cn.
² Beijing Union Pharmaceutical Factory PR China.

Abstract

The chiral catalytic amination of an α,α-dialkyl substituted aldehyde usually proceeds with low enantioselectivity. We selected naphthyl-l-alanine as the catalyst and observed improved enantioselectivity for the amination. Using this method, racemic α-methyl-α-benzyloxypropanal was aminated to give chiral serine derivatives in 74% ee, which was further increased to >99% ee after recrystallization. Moreover, we also successfully synthesized a chiral phosphonium salt 9 for the preparation of one α-substituted alaninol compound 14 as an S1P₁ agonist in high overall yield.