Dissertation/Thesis Abstract

Synthetic studies on silyl glyoximines, alternaric acid, and quaternary donor site cyclopropanes
by Slade, Michael Christopher, Ph.D., The University of North Carolina at Chapel Hill, 2011, 243; 3477648
Abstract (Summary)

Silyl glyoxylates were converted to a variety of nitrogenous derivatives and their suitability for three component coupling reactions was investigated. Silyl glyoximines bearing electron-rich or -neutral N−aryl groups were suitable electrophiles for addition of sp3-hybridized alkyllithium nucleophiles. The relatively unstudied [1,2]-aza-Brook rearrangement serves as a key mechanistic feature for the generation of a glycinate enolate for second-stage electrophilic trapping, which could be accomplished with aldehyde, cyanoformate, or anhydride electrophiles. These reactions thus demonstrate the ability of silyl glyoximines to serve as dipolar glycinate linchpins complementary to their silyl glyoxylate parents. To the best of our knowledge, the use of an aza-Brook rearrangement to enable multicomponent coupling is without precedent.

The ability of silyl glyoxylates to serve as effective linchpins for the union of nucleophiles and electrophiles at a glycolic acid junction has been leveraged in synthetic efforts toward the total synthesis of alternaric acid, a biologically active natural product. The second-stage glycolate aldol reaction with the aldehyde that directly affords the aldol subunit in the natural product suffers from poor diastereoselectivity. Efforts to overcome this obstacle demonstrated that a wide variety of substituents are tolerated on the aldehyde electrophile, and exert varying degrees of stereochemical control. Significantly, a method for generating functionalized vinyl nucleophiles suitable for efficient three component coupling reactions has been established, increasing the convergency of the route and expanding known reactivity patterns of silyl glyoxylates.

A diastereoselective synthesis of pentasubstituted tetrahydrofurans via a Lewis acid catalyzed (3 + 2)-annulation of quaternary donor site cyclopropanes and aldehydes is described. Yields (up to 95%) and diastereoselectivities (up to 99:1) are in some cases competitive with related (3 + 2)-annulation reactions of tertiary donor site cyclopropanes, despite the increased hindrance and reduced steric differentiation between the substituents on the donor site. Chirality transfer studies are consistent with the operation of a similar mechanism for both quaternary and tertiary donor site cyclopropanes, and demonstrate the impact of the stability of carbenium ion character at the cyclopropane donor site on the reaction course. Significantly, it is still possible to obtain highly enantioenriched tetrahydrofuran products from enantioenriched cyclopropane starting materials.

Indexing (document details)
Advisor: Johnson, Jeffrey S., Crimmins, Michael T.
Commitee: Brookhart, Maurice S., Forbes, Malcolm D., Templeton, Joseph L.
School: The University of North Carolina at Chapel Hill
Department: Chemistry
School Location: United States -- North Carolina
Source: DAI-B 73/01, Dissertation Abstracts International
Subjects: Organic chemistry
Keywords: Annulation reactions, Multicomponent coupling reactions, Silyl glyoxylates
Publication Number: 3477648
ISBN: 978-1-124-94382-4
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