Siloxy Esters as Traceless Activator of Carboxylic Acids: Boron-Catalyzed Chemoselective Asymmetric Aldol Reaction

Abstract

The catalytic asymmetric aldol reaction of carboxylic acids is among the most useful reactions for the synthesis of biologically active compounds and pharmaceuticals. Despite the existence of many prominent reports, no general method is available to incorporate the aldol motif into complex carboxylic acids and their derivatives at late stages. Chemoselective catalytic asymmetric aldol reaction of multifunctional carboxylic acids is difficult to achieve, due to the high basicity required for enolization and the poisonous chelation of β-hydroxy acid products to Lewis acid catalysts. Herein, we identified that preconversion of carboxylic acids to siloxy esters facilitated the boron-catalyzed direct aldol reaction, leading to the development of carboxylic acid-selective, catalytic asymmetric aldol reaction applicable to multifunctional substrates. The asymmetric boron catalyst stereodivergently controlled the products’ stereochemistry depending on the catalyst’s chirality, not on the stereochemical bias of substrates. Computational studies rationalized the mechanism of the catalytic cycle and the stereoselectivity, and proposed Si/B enediolates as the active species for the asymmetric aldol reaction. The silyl ester formation facilitated both enolization and catalyst turnover through acidifying the α-proton of substrates and attenuating poisonous Lewis bases to the boron catalyst.

Visible-Light-Driven α-Allylation of Carboxylic Acids

“…The resulting boron enediolate can be in the form of either a diboron enediolate or a monoboron enediolate anion with an onium countercation. The structural ambiguity for the enolate intermediate is mostly due to low concentration of the ionized species in the equilibrium mixture . Irrespective of the nature of the countercation, the ene moiety of the enolate is formally π-conjugated with the ligand of the boron catalyst through the oxygen and boron atoms.…”