Date of Award

2013

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Chemistry

First Advisor

Patrick J. Walsh

Abstract

A conventional approach in the construction of complex molecules is to use existing substrate stereochemistry to direct the introduction of new stereogenic centers. Since Cram's original studies 1952, the Felkin–Anh, Cornforth–Evans, and Cram-chelation models were developed and have been widely utilized to predict stereochemical outcomes in nucleophilic additions to aldehydes and ketones bearing a proximal chiral center. Specifically, nucleophilic additions to protected α- and β-hydroxy aldehydes and ketones is protecting group dependent. Small protecting groups such as methyl or benzyl undergo carbonyl addition via a chelation-controlled mechanism. In contrast, sterically encumbered silyl protecting groups preclude chelation and furnish Felkin/Cornforth addition products with few exceptions. One major drawback to this approach is that the overall synthetic approach is, including the choice of protecting group, is governed by the stereochemical outcome desired for the carbonyl addition step.

We have identified alkyl zinc halide Lewis acids capable of promoting chelation-controlled additions to α-silyloxy aldehydes and ketones, thus overriding the expected Felkin selectivity. A variety of organozinc reagents, including dialkylzincs, functionalized dialkylzinc reagents, and add to α- and β-silyloxy aldehydes and ketones with high selectivity for the chelation-controlled products in the presence of achiral alkyl zinc halides (RZnX) and triflates (RZnOTf). This method constitutes an alternate approach to employing enantioenriched stoichiometric auxiliaries, chiral catalysts, and optically active stoichiometric additives that have to be first synthesized and later separated from the product. Moreover, this method challenges the well-established paradigm used to understand and predict diastereoselectivity in these reactions.

Organohalides are known to coordinate to electron-poor metal complexes. However, there are few examples of chelation-controlled additions to α-halogenated carbonyl and imine derivatives. All of these examples involve hydride addition. We have achieved highly diastereoselective additions to N-Ts α-chloro aldimines, which represents the first diastereoselective halide directed C–C bond forming reaction. Alkyl and vinylzinc reagents undergo chelation-controlled additions to in situ generated α-chloro aldimines with good to excellent selectivity. Computational studies provide additional evidence for our proposed chelation transition state. The functionalized syn β-chloroamine products can be utilized in further multi-step and tandem reactions.

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