Direct and Enantioselective Aldol Reactions Catalyzed by Chiral Nickel(II) Complexes

Abstract

A direct and asymmetric aldol reaction of N-acyl thiazinanethiones with aromatic aldehydes catalyzed by chiral nickel(II) complexes is reported. The reaction gives the corresponding O-TIPS-protected anti-aldol adducts in high yields and with remarkable stereocontrol and atom economy. Furthermore, the straightforward removal of the achiral scaffold provides enantiomerically pure intermediates of synthetic interest, which involve precursors for anti-a-aminob-hydroxy and a,b-dihydroxy carboxylic derivatives. Theoretical calculations explain the observed high stereocontrol.Scheme 1. Direct and enantioselective carbon-carbon bond-forming reactions from carbonylic compounds.

Stereocontrolled Aldol-Like Reactions Involving Oxocarbenium Intermediates

“…Following a thorough assessment of the experimental conditions, it was finally established that TIPSOTf-mediated reactions of N -acyl-1,3-thiazinane-2-thiones with aromatic aldehydes catalyzed by 2–10 mol% of [( R )-Tol-BINAP]NiCl 2 ( ent -169 ) allowed for the isolation of enantiomerically pure ( ee 90–99%) anti aldol products 171 – 182 in high yields (Eq 20 in Scheme 46 ). 65…”

“…In turn, the reaction features a remarkable stereocontrol as the diastereoselectivity is usually larger than 80:20, and the enantioselectivity is predominantly over 97% (Scheme 46 ). 65…”

A catalytic enantioselective stereodivergent aldol reaction

“…In general, the challenge of chemoselectively activating the pronucleophilic carbonyl in the presence of the acceptor aldehyde has been circumvented by the judicious selection of acidic pronucleophiles such as activated ketones and aldehydes, or through the use of non-enolizable aldehyde acceptors. An alternative direct-type approach involving the chemoselective activation of latent pronucleophilic carbonyls in situ has provided a more general solution to this challenge (17)(18)(19)(20)(21)(22). In particular, malonic acid half thioesters (MAHTs) have proven to be powerful latent pronucleophiles, which undergo decarboxylation under mild conditions to generate the active enolate in a catalytic aldol reaction (23)(24)(25)(26).…”