Design, synthesis, and evaluation of chiral thiophosphorus acids as organocatalysts

Abstract

A series of P-stereogenic chiral phosphorus acids (CPAs) were synthesized to determine the requirements for efficient asymmetric organocatalysis. In order to eliminate the need for C ₂-symmetry in common CPAs, various scaffolds containing C ₁-symmetrical thiophosphorus acids were chosen. These new compounds were synthesized and evaluated in the asymmetric transfer hydrogenation of 2-phenylquinoline. Although the efficacy of the thiophosphorus acids was disappointing for this reaction, the work should be useful for developing structural design elements.

Keywords: asymmetric; heterocycles; organocatalysis; phosphorus; synthesis.

Figure 1

Chiral phosphorus acids (CPAs) derived from BINOL, VAPOL, and SPINOL. R = H, Ph, 4-PhC₆H₄-, 4-β-naphthylphenyl, 9-anthryl, 3,5-dimesitylphenyl, 3,5-diphenylphenyl, 4-MeC₆H₄-, 4-CF₃C₆H₄-, 4-t-BuC₆H₄-, β-naphthyl, 3,5-t-Bu₂C₆H₃-, 2,4,6-Me₃C₆H₂-, 2,4,6-iPr₃C₆H₂-, Ph₃Si-, etc.

Scheme 1

The thiolic/thionic tautomeric equilibrium in thiophosphorus acids.

Figure 2

Project strategy and requirements for C₁-symmetrical CPAs.

Figure 3

BINOL CPA and C₁-symmetrical CPA targets 1–4.

Scheme 2

Synthesis of tryptophol-derived thiophosphorus acid 1.

Scheme 3

Synthesis of indole-derived thiophosphorus acid 2.

Scheme 4

Synthesis of N-biphenyl-DOPO CPA 4.

Scheme 5

Transfer hydrogenation of 2-phenylquinoline and transition-state proposed by Guinchard and coworkers [28].