Date of Award

Winter 2009

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Chemistry

First Advisor

Patrick J. Walsh

Abstract

Enantioenriched secondary alcohols are ubiquitous moieties in natural products. The current methods to achieve their synthesis often times rely on complicated synthesis and isolation of fairly reactive and unstable organometallic reagents. To address these issues our group developed one-pot catalytic asymmetric methods toward the synthesis of E-allylic alcohols and diarylmethanols employing in situ synthesized functionalized Lewis acidic zinc reagents in the presence of chiral amino alcohols ligands. However, analogous methods for the synthesis of equally useful Z-allylic alcohols and diheteroaryl methanols were lacking. The reason why this task was more challenging is because en route toward the synthesis of the appropriate functionalized zinc reagents a Lewis acidic byproduct (lithium halide) was generated which would catalyze a racemic background reaction. The problem was addressed finding an additive, tetraethylethylenediamine (TEEDA), which could selectively inhibit the background reaction discriminating between the two Lewis acidic species present in the flask. The asymmetric addition could now take place giving the product in high yield and ee in one-pot. In the first chapter a novel catalytic asymmetric method for the synthesis of (Z)-disubstituted allylic alcohols is presented. Our one-pot procedure entails hydroboration of chloro alkynes and addition of a hydride source (t-BuLi), which results in formation of a (Z)-alkenylborane. Boron to zinc transmetalation of the alkenyl group with ZnEt2, addition of a chiral ligand, the inhibitor (TEEDA) and the substrate aldehyde results in formation of (Z)-allylic alcohols with excellent ee’s. In the effort of streamlining the synthesis of compounds with multiple stereocenters, tandem protocols were devised to synthesize cyclopropyl- and epoxy-alcohols. Finally a brief study for the synthesis of racemic Z-trisubstituted allylic alcohols is presented. In the second chapter we describe a method for the synthesis of diarylmethanols generating the desired arylzinc reagent in situ and adding it to both aromatic and heteroaromatic aldehydes. The one pot procedure entails lithium/halogen exchange, transmetallation with a zinc species, with generation of undesired LiCl that can be sequestered in situ by an additive (TEEDA). The functionalized zinc reagent, in the presence of the chiral catalyst (–)-MIB, adds to a variety of aromatic and heteroaromatic aldehydes in excellent ee, thus enabling the formation of highly desirable diheteroarylmethanols as well as many other compounds.

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