I. Enantioselective Acylation of Silyl Ketene Acetals through Fluoride Anion-Binding Catalysis II. Development of a Practical Method for the Synthesis of Highly Enantioenriched Trans-1,2-Amino Alcohols

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I. Enantioselective Acylation of Silyl Ketene Acetals through Fluoride Anion-Binding Catalysis II. Development of a Practical Method for the Synthesis of Highly Enantioenriched Trans-1,2-Amino Alcohols

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Title: I. Enantioselective Acylation of Silyl Ketene Acetals through Fluoride Anion-Binding Catalysis II. Development of a Practical Method for the Synthesis of Highly Enantioenriched Trans-1,2-Amino Alcohols
Author: Birrell, James Andrew
Citation: Birrell, James Andrew. 2013. I. Enantioselective Acylation of Silyl Ketene Acetals through Fluoride Anion-Binding Catalysis II. Development of a Practical Method for the Synthesis of Highly Enantioenriched Trans-1,2-Amino Alcohols. Doctoral dissertation, Harvard University.
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Abstract: A highly enantioselective acylation of silyl ketene acetals with acyl fluorides was developed to generate useful α,α-disubstituted butyrolactone products in high yield and excellent enantioselectivities. This transformation is promoted by an arylpyrrolidino thiourea catalyst and 4-pyrrolidinopyridine and represents the first example of enantioselective thiourea anion-binding catalysis with fluoride. Mechanistic investigations revealed both catalysts to be necessary for reaction to occur, suggesting the thiourea aids in the generation of the key N-acylpyridinium/fluoride ion pair. The outstanding hydrogen-bond-accepting ability of fluoride is likely important in this regard. In addition, a strong dependence on both the N-acylpyridinium counteranion and the substituents on the silicon group of the silyl ketene acetal were observed, highlighting the importance of the silicon-fluoride interaction. A cyclic oligomeric (salen)Co–OTf complex was used to catalyze a highly enantioselective addition of phenyl carbamate to meso-epoxides to afford protected trans-1,2-amino alcohols. The use of an oligomeric (salen)Co–OTf complex as the catalyst and aryl carbamates as nucleophiles was crucial to the development of this reaction protocol. This method is amenable to large-scale synthesis due to the low catalyst loadings and high concentration used, its operational simplicity, and the use of inexpensive, commercially-available starting materials. To demonstrate the synthetic utility of this protocol, optically pure trans-2-aminocyclohexanol hydrochloride and trans-2-aminocyclopentanol hydrochloride were prepared on a multigram scale using only 0.5 and 1 mol% catalyst loading, respectively.
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Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:10973940
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