The [1,2]-Brook rearrangement: novel carbon-carbon bond forming reactions and application to the total synthesis of zaragozic acid C Public Deposited

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  • March 21, 2019
  • Nicewicz, David Andrew
    • Affiliation: College of Arts and Sciences, Department of Chemistry
  • I. Catalytic Cyanation/Brook Rearrangement/C-Acylation Reactions of Acylsilanes A tandem nucleophile-catalyzed cyanation/Brook rearrangement/C-acylation has been developed. Phase transfer cocatalysts facilitate cyanide-catalyzed reactions between acylsilanes and cyanoformates to afford protected tertiary carbinol products. A catalytic cycle is proposed involving cyanation of an acylsilane, [1,2]-Brook rearrangement, and C-acylation of the derived carbanion by a cyanoformate ester. The reaction offers an efficient method for the preparation of functionalized, unsymmetrical malonic acid derivatives. II. Catalytic Enantioselective Acylation of (Silyloxy)nitrile Anions New catalytic enantioselective cyanation/[1,2]-Brook rearrangement/C-acylation reactions of acylsilanes with cyanoformate esters are described. Catalysts for this transformation were discovered via a directed candidate screen of 96 metal-ligand complexes. Optimization of a (salen)aluminum complex revealed significant remote electronic effects and concentration effects. The scope of the reaction was investigated by using a number of aryl acylsilanes and cyanoformate esters. Chemoselective reduction of the reaction products afforded new enantioenriched alpha-hydroxy-alpha-aryl-beta-amino acid derivatives and beta-lactams. This reaction provides a simple method for the construction of new nitrogen-containing enantioenriched chiral building blocks. III. Three Component Coupling Reactions of Silylglyoxylates, Alkynes, and Aldehydes: A Chemoselective One Step Glycolate Aldol Construction A single-pot three-component coupling reaction of silylglyoxylates, terminal alkynes, and aldehydes in the presence of ZnI2 and Et3N is presented. The products of the reaction, densely functionalized silyl-protected glycolate aldols, can be converted to the corresponding acetonides in a one-pot deprotection/ketalization sequence. Mechanistic experiments suggest that the zinc acetylide reacts with the silylgyloxylate in a chemoselective manner. Using an unoptimized (+)-N-methylephedrine and Zn(OTf)2 system, moderate levels of enantioselectivity for the title reaction was achieved. IV. Application of the Silylglyoxylate Glycolate Aldol Reaction: Progress Toward the Total Synthesis of Zaragozic Acid C A review of the literature concerning previous approaches to the zaragozic acids is presented. A highly diastereoselective single step double aldol reaction of vinylmagnesium bromide, tert-butyl tert-butyldimethylsilylglyoxylate, and tert-butyl glyoxylate to afford an advanced intermediate with the potential for further elaboration to zaragozic acid C was explored. Subsequent manipulations set the stage for an intramolecular aldol which constructed a key epsilon-lactone and supplied all of the required atoms of the zaragozic acid C core.
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  • Johnson, Jeffrey
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  • University of North Carolina at Chapel Hill
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