Catalytic Stereoconvergent Synthesis of Homochiral β-CF3, β-SCF3, and β-OCF3 Benzylic Alcohols

Abstract

We describe an efficient catalytic strategy for enantio- and diastereoselective synthesis of homochiral β-CF₃, β-SCF₃, and β-OCF₃ benzylic alcohols. The approach is based on dynamic kinetic resolution (DKR) with Noyori-Ikariya asymmetric transfer hydrogenation leading to simultaneous construction of two contiguous stereogenic centers with up to 99.9% ee, up to 99.9:0.1 dr, and up to 99% isolated yield. The origin of the stereoselectivity and racemization mechanism of DKR is rationalized by density functional theory calculations. Applicability of the previously inaccessible chiral fluorinated alcohols obtained by this method in two directions is further demonstrated: As building blocks for pharmaceuticals, illustrated by the synthesis of heat shock protein 90 inhibitor with in vitro anticancer activity, and in particular, needle-shaped crystals of representative stereopure products that exhibit either elastic or plastic flexibility, which opens the door to functional materials based on mechanically responsive chiral molecular crystals.

Figure 1

(A) Bioactive compounds with β-CF₃ alcohol or amine motifs. (B) Synthetic strategies toward homochiral β-CF₃ secondary alcohols.

Figure 2

Optimized transition state geometries en route to the four stereomeric products 2a taking place with R_Ru,λ structural arrangement of the (S,S)-C2 catalyst active form (see text). The relative free energies are given in kcal·mol^–1. Some attractive and repulsive interactions are highlighted by green and red symbols, respectively. Noncritical H atoms are omitted for clarity.

Figure 3

(a) Three-point bending experiment with elastically flexible needle-shaped crystal of 2p. (b) Crystal packing of 2p, view along c-axis. (c) Bent plastically flexible crystal of 2o. (d) Crystal packing of 2o, view along b-axis.

Scheme 1. Further Synthetic Transformations of Stereopure DKR-ATH Products 2