Asymmetric synthesis of (+)-lentiginosine using a chiral aziridine based approach

The synthesis of the indolizidine alkaloid, (+)-lentiginosine, is described. A key feature of the preparative route is the efficient and stereoselective construction of a dihydroxylated pyrrolidine via Sharpless asymmetric dihydroxylation of an aziridine-enoate, which was prepared from commercially available 1-(S)-α-methylbenzylaziridine-2-methanol. In addition, a regioselective aziridine-to-pyrrolidinone ring expansion process followed by a Wittig olefination was employed to construct a late stage pyrrolidine intermediate that was transformed into (+)-lentiginosine.

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((2S,3S,4R)-3,4-Dihydroxy-5-oxo-1-((R)-1-phenylethyl)pyrrolidin-2-yl)methyl acetateC15H19NO5[α]D24.5=+7.8 (c 0.20, MeOH)Source of chirality: 1-(S)-α-methylbenzylaziridine-2-methanol and stereoselective synthesisAbsolute configuration: (2S,3S,4R), 1-(R)

((2S,3S,4S)-3,4-Bis((tert-butyldimethylsilyl)oxy)-1-((R)-1-phenylethyl)pyrrolidin-2-yl)methanolC25H47NO3Si2[α]D24.5=+29.6 (c 0.25, CHCl3)Source of chirality: 1-(S)-α-methylbenzylaziridine-2-methanol and stereoselective synthesisAbsolute configuration: (2S,3S,4S), 1-(R)

(2S,3S,4S)-2-(4-(Benzyloxy)but-1-en-1-yl)-3,4-bis((tert-butyldimethylsilyl)oxy)-1-((R)-1-phenylethyl)pyrrolidineC35H57NO3Si2[α]D24.5=+67.6 (c 0.25, CHCl3)Source of chirality: 1-(S)-α-methylbenzylaziridine-2-methanol and stereoselective synthesisAbsolute configuration: (2S,3S,4S), 1-(R)

(1S,2S,8aS)-Octahydroindolizine-1,2-diolC8H15NO2[α]D19.8=+2.2 (c 0.17, MeOH)Source of chirality: 1-(S)-α-methylbenzylaziridine-2-methanol and stereoselective synthesisAbsolute configuration: (1S,2S,8aS)