Strategies for Catalyzing Sterically Hindered Stereoselective Matteson Homologations

Abstract

In Chapter 1, we describe the development of an iterative Matteson homologation reaction with catalyst-controlled diastereoselectivity. This work relies on the development of a catalyst capable of efficiently catalyzing the homologation of secondary boronic esters. This reaction was applied to the selective synthesis of each stereoisomer of benzestrol, a bioactive compound with estrogenic activity featuring three contiguous stereocenters. The eight different stereoisomers were assayed to determine their binding affinities for the estrogen receptor α (ERα), and the absolute configuration of the compound that exhibited uniquely high activity was determined. In Chapter 2, we provide further biological characterization of all eight benzestrol stereoisomers and propose a structural rationale for the uniquely high binding activity of the most potent isomer. Two cellular activity assays, proliferation of ER-positive breast cancer cells and stimulation of estrogenic gene activity, demonstrate that the potencies of the eight isomers parallel their binding affinities as described in Chapter 1. In all cases, only one isomer exhibited high activity. A small-molecule crystal structure of the highly active isomer was examined, revealing conformational flexibility within the solid-state crystal lattice. Computational modeling of each isomer bound to ERα established that calculated binding energies and internal torsional energies correlate with experimentally measured binding affinities and potencies. The modeled binding conformation of the most active isomer was shown to overlay well with that of the well-studied, potent, non-steroidal estrogen, trans-diethylstilbestrol, making similar key interactions in the ERα ligand-binding pocket. In Chapter 3, we describe our ongoing efforts to develop an enantioselective, catalytic Matteson homologation to access tertiary α-chloro pinacol boronic esters from commercially available boronic esters and 1,1-dichloroethane. Relative to previous work on secondary boronic esters and the iterative homologations presented in Chapter 1, this system initially exhibited significantly lower reactivity. We present efforts to enhance the yield and enantioselectivity of this reaction, achieving up to 55% yield with 83% ee. Enantioselectivities as high as 89% were observed in reactions with lower yields. Additionally, we describe an observed negative correlation between yield and selectivity and propose a kinetic hypothesis to account for this trend. Finally, we explore the reaction scope and the potential to transform tertiary α-chloro pinacol boronic esters into other tetrasubstituted stereocenters via enantiospecific chloride and boron elaboration.