Enantioselective Alkali Metal Catalysis

Abstract

In Chapter 1, we chronicle the discovery of enantioselective, catalytic 1,2-boronate rearrangements for the synthesis of α-chloro pinacol boronic esters from readily available boronic esters and dichloromethane. Chiral thiourea dual–hydrogen bond donors were initially found to promote enantioselective Matteson homologations, albeit with poor reproducibility. Systematic investigations of the fate of the thiourea led to the discovery that lithium-isothiourea-boronate derivatives were being generated in situ as highly enantioselective catalytically active species. The optimal lithium-isothiourea-boronate catalyst displays significant generality in the rearrangement of primary alkyl migrating groups, affording synthetically valuable α-chloro boronic ester products with consistently high enantioselectivities. The chiral building blocks produced in these reactions can undergo two sequential stereospecific elaborations to generate a wide assortment of trisubstituted stereocenters. The catalyst is proposed to act as a structurally rigid chiral framework that precisely positions two lithium cations to enable a dual-lithium–mediated chloride abstraction. In Chapter 2, we detail the development of carbonimidothioate reagents for the convergent synthesis and stereochemical characterization of isothiourea-boronate derivatives. Aminolysis of these carbonimidothioate derivatives to afford arylpyrrolidine-tert-leucine–derived isothiourea-boronate derivatives is promoted by Lewis bases. A network of side reactivity resulting from loss of a thiol during aminolysis is proposed, and this side reactivity is diminished by modification of the alcohol leaving group. The scope of a kinetic resolution of a racemic carbonimidothioate reagent is examined. Diastereopure carbonimidothioate reagents with chiral auxiliary leaving groups are synthesized and applied to the crystallography-free identification of isothiourea-boronate diastereomers. In Chapter 3, we describe the development and mechanistic study of an asymmetric potassium-isothiourea-boronate–catalyzed Wittig olefination of 4-substituted cyclohexanones with non-stabilized phosphorus ylides to afford highly enantioenriched axially chiral alkenes. The optimal Lewis acid catalyst features an unusual macrocyclic amide-potassium-boronate chelate that enables the ligand framework to accommodate a large metal cation within a rigid chiral environment. Remote substituent effects on olefination rate and enantioselectivity are attributed to the induction of an intramolecular oriented electric field. A catalytic cycle is established based upon kinetic analysis of the catalyzed olefination by cryogenic UV-visible spectroscopy. These studies provide evidence consistent with inhibition of the Lewis acid catalyst by the oxaphosphetane intermediate, with key implications for the development of future transformations using this family of alkali metal-based catalysts. Computational studies indicate that the enantiodetermining cycloaddition proceeds via a stepwise polar 1,2-addition to afford a potassium betaine complex, consistent with historical proposals on the mechanism of poorly stereoselective lithium-salt–mediated Wittig olefinations.