Synthesis of β-hydroxy-α,α-disubstituted amino acids through the orthoamide-type overman rearrangement of an α,β-unsaturated ester and stereodivergent intramolecular SN2′ reaction: Development and application to the total synthesis of sphingofungin F

Tomoya Sugai, Shunme Usui, Shun Tsuzaki, Hiroki Oishi, Daichi Yasushima, Shoko Hisada, Takahiro Fukuyasu, Takeshi Oishi, Takaaki Satou, Noritaka Chida

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Abstract

The development of a two-step synthesis for β-hydroxy-α,α- disubstituted amino acid derivatives from cyclic orthoamide is reported. The first step is the orthoamide-type Overman rearrangement of an α,β-unsaturated ester to give a sterically hindered α,α-disubstituted amidoester. The α,β-unsaturated ester is known to be a challenging substrate in the conventional Overman rearrangement due to the competitive aza-Michael reaction. However, suppression of the aza-Michael reaction is realized by two factors; 1) the high reaction temperature, and 2) an alkyl substituent at the α-position. The second step is stereodivergent intramolecular SN2′ reaction for the installation of a hydroxy group at the β-position. Either syn- or anti-type SN2′ reaction is possible by simply changing the reaction conditions. The developed method can provide all four possible stereoisomers of the β-hydroxy-α,α-disubstituted amino acid, and is successfully applied to the total synthesis of sphingofungin F.

Original languageEnglish
Pages (from-to)594-607
Number of pages14
JournalBulletin of the Chemical Society of Japan
Volume91
Issue number4
DOIs
Publication statusPublished - 2018 Jan 1

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ASJC Scopus subject areas

  • Chemistry(all)

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