Enantioselective
Desymmetrization of 2‑Aryl-1,3-propanediols
by Direct O‑Alkylation with a Rationally Designed
Chiral Hemiboronic Acid Catalyst That Mitigates Substrate Conformational
Poisoning
posted on 2021-03-15, 14:34authored byCarl D. Estrada, Hwee Ting Ang, Kim-Marie Vetter, Ashley A. Ponich, Dennis G. Hall
Enantioselective
desymmetrization by direct monofunctionalization
of prochiral diols is a powerful strategy to prepare valuable synthetic
intermediates in high optical purity. Boron acids can activate diols
toward nucleophilic additions; however, the design of stable chiral
catalysts remains a challenge and highlights the need to identify
new chemotypes for this purpose. Herein, the discovery and optimization
of a bench-stable chiral 9-hydroxy-9,10-boroxarophenanthrene
catalyst is described and applied in the highly enantioselective desymmetrization
of 2-aryl-1,3-diols using benzylic electrophiles under operationally
simple, ambient conditions. Nucleophilic activation and discrimination
of the enantiotopic hydroxy groups on the diol substrate occurs via
a defined chairlike six-membered anionic complex with the hemiboronic
heterocycle. The optimal binaphthyl-based catalyst 1g features a large aryloxytrityl group to effectively shield one of
the two prochiral hydroxy groups on the diol complex, whereas a strategically
placed “methyl blocker” on the boroxarophenanthrene
unit mitigates the deleterious effect of a competing conformation
of the complexed diol that compromised the overall efficiency of the
desymmetrization process. This methodology affords monoalkylated products
in enantiomeric ratios equal or over 95:5 for a wide range of 1,3-propanediols
with various 2-aryl/heteroaryl groups.