Regioselective Asymmetric a,a-Bisalkylation of Ketones via N-Amino Cyclic Carbamate Chiral Auxiliaries: Methodology Development and Application to the Total Synthesis of both (+)- and (-)-Stigmolone and Apratoxin D

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2012

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Wengryniuk, Sarah Elizabeth

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Coltart, Don M

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Abstract

The α-alkylation of ketones is a transformation of central importance to organic synthesis. Our lab recently introduced the N-amino cyclic carbamate (ACC) chiral auxiliaries for asymmetric ketone α-alkylation. ACCs provide significant advantages over existing asymmetric ketone alkylation methods as they are easy to introduce, both deprotonation and alkylation can be run at relatively mild temperatures, stereoselectivity of alkylation is excellent and auxiliary removal is facile. A unique feature of ACCs is their ability to control the regioselectivity of deprotonation through what we have termed Complex Induced Syn-Deprotonation. In what follows, we describe several projects relating to the development and synthetic application of ACCs.

An optimized synthesis of our most successful ACC auxiliary was developed, including an improved method for the formation of the key N-N hydrazide bond.

A detailed mechanistic investigation of four ACC auxiliaries was conducted, examining the regio- and stereoselectivity of the alkylations at the level of the ACC hydrazone. This work culminated in a theoretical study of ACC auxiliaries, conducted through a collaboration with the Houk Group at UCLA.

We also describe the use of ACCs in the development of the first method for the regiocontrolled asymmetric α,α-bisalkylation of ketones. The method proceeds in excellent yield and with >99:1 diastereoselectivity. This method was also extended to the asymmetric α,α,α',α'-tetraalkylation of ketones, enabled by the development of a mild, epimerization-free LDA-mediated isomerization of the α,α-bisalkylated ACC hydrazones.

Additionally, we discuss three synthetic applications of the ACC α,α-bisalkylation methodology. We report an asymmetric formal synthesis of (+)- and (-)-stigmolone, as well as two approaches to the polyketide fragment of the novel cyclic depsipeptide apratoxin D, which have led to the completion of the first asymmetric total synthesis of apratoxin D.

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Wengryniuk, Sarah Elizabeth (2012). Regioselective Asymmetric a,a-Bisalkylation of Ketones via N-Amino Cyclic Carbamate Chiral Auxiliaries: Methodology Development and Application to the Total Synthesis of both (+)- and (-)-Stigmolone and Apratoxin D. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/5574.

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