Two new chiral, non-racemic sulfoxide containing 1,3 amino -alcohol synthons: Application to the total synthesis of (+)-Negamycin.

Abstract

The 1,3 amino alcohol structural unit is found in a wide variety of natural products. We have prepared two types of 1,3 amino alcohol synthons and demonstrated how to functionalize one of them in the total synthesis of (+)-Negamycin. A new route to protected beta-amino sulfoxides demonstrated by the synthesis of [2<italic>S</italic>, <italic>R</italic>_S] and [2<italic> R</italic>, <italic>R</italic>_S]-2-<italic>t</italic>-butoxycarbamidopropyl <italic> p</italic>-tolyl sulfoxide, [2<italic>S</italic>,<italic>R</italic>_S]-2-<italic>t</italic>-butoxycarbamido-3-methylbutyl <italic>p</italic>-tolyl sulfoxide, and [2<italic>R</italic>, <italic>R</italic>_S]-<italic> N</italic>-acetyl-2-amino-2-phenylethyl <italic>p</italic>-tolyl sulfoxide is described. The protected beta-amino sulfoxides are shown to be suitable precursors for both optically active beta amino acids and alpha amino aldehydes. All diastereomers in optically active form of the 1,3 amino alcohol synthon [<italic>R</italic>_S]-4,5-epoxy-2-<italic>t</italic>-butoxycarbamidopentyl <italic> p</italic>-tolyl sulfoxide are described. Key reactions involve the Mitsunobu inversion of the [<italic>R</italic>_S]-4,5-epoxy-2-hydroxypentyl <italic> p</italic>-tolyl sulfoxides to the [<italic>R</italic>_S]-4,5-epoxy-2-azidopentyl <italic> p</italic>-tolyl sulfoxides, and the subsequent chemoselective Staudinger reduction of the azides to the [<italic>R</italic>_S]-4,5-epoxy-2-aminopentyl <italic> p</italic>-tolyl sulfoxides. The total synthesis of (+)-Negamycin demonstrates how this synthon can be functionalized. Key steps involve the formation and alkylation of the diamion of [2<italic>R</italic>, 4<italic>R</italic>, <italic>R</italic>_S]-4,5-epoxy-2-<italic> t</italic>-butoxycarbamidopentyl <italic>p</italic>-tolyl sulfoxide with methyl chloroformate and subsequent removal of the sulfoxide to produce methyl [3<italic> R</italic>, 5<italic>R</italic>]-3-<italic>t</italic>-butoxycarbamide-5,6-epoxyhexanoate without affecting the epoxide. This compound was manipulated to give (+)-Negamycin in 20% overall yield from the synthon. All diastereomers in optically active form of the 1,3 amino alcohol synthon <italic> N</italic>-<italic>tert</italic>-butoxycarbonyl-[<italic>R</italic>_S]4,5-imino-2-methoxypentyl <italic>p</italic>-tolyl sulfoxides are described. The key step in the synthesis is the stereocontrolled reductive cyclization of the azidohydrin [<italic>R</italic>_S]-5-azido-4-hydroxy-2-methoxypentyl <italic> p</italic>-tolyl sulfoxide to the aziridine proceeding through the Staudinger-Blum reaction. The potential 1,3 diamino synthon [2<italic>R</italic>, 4<italic> S</italic>, <italic>R</italic>_S]-bis-<italic>N</italic>₁-<italic> N</italic>₂-<italic>tert</italic>-butoxycarbonyl-4,5-imino-2-aminopentyl <italic> p</italic>-tolyl sulfoxide was also prepared with this methodology. The aziridines were chemoselectively opened at the terminal position without side reactions, the former under mild push-pull conditions analogous to the Bajwa reaction, and the latter with higher ordered methyl and phenyl cyanocuprates.