Direct Carbon--Carbon Bond Formation Through Reductive Soft-Enolization of α-Halothioesters and The Total Synthesis of (+)-Mefloquine

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Coltart, Don M

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Sauer, Scott J.

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2011-06-09T13:00:14Z

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2013-05-28T04:30:06Z

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2011

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Chemistry

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The direct addition of enolizable aldehydes and sulfonyl imines to α-halo thioesters to produce β-hydroxy/amino thioesters enabled by reductive soft enolization is reported. The transformation is operationally simple and efficient and has the unusual feature of giving high syn-selectivity, which is the opposite of that produced for the aldol addition with (thio)esters under conventional conditions. This method is tolerant to aldehydes and imines that not only contain acidic α-protons, but also towards electrophiles containing other acidic protons and base-sensitive functional groups. Moreover, excellent diastereoselectivity is achieved when a chiral non-racemic α-hydroxy aldehyde derivative is used. Using MgI2 and Ph3P, this method gives a wide range of aldol and Mannich products in good yields with high syn-diastereoselectivity. The products obtained from the reductive aldol and Mannich reactions are synthetically important intermediates in both polyketide and β-lactam synthesis, respectively, and can be readily derivatized to form many carbonyl derivatives through known manipulation of the thioester moiety.

Also, herein the asymmetric synthesis of (+)-mefloquine, a potent anti-malarial compound, is described. The synthesis is based on a key enantioselective Darzens reaction between a chiral α-chloro-N-amino cyclic carbamate (ACC) hydrazone and a quinoline-based aldehyde. This is a novel methodology developed by our lab, which gives a highly enantioenriched epoxide that can be further functionalized to give both enantiomers of mefloquine.

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https://hdl.handle.net/10161/3952

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Chemistry

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Organic Chemistry

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ACC

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aldol

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mannich

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mefloquine

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thioester

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Direct Carbon--Carbon Bond Formation Through Reductive Soft-Enolization of α-Halothioesters and The Total Synthesis of (+)-Mefloquine

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Dissertation

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24

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