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

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.