A new strategy for the synthesis of hydroxylated pyrrolizidinic alkaloids by highly stereoselective indium-mediated allylation of pyrrolidinic aldehydes

Indium-mediated allylation of N-Cbz-l-prolinal 3, under Grignard conditions, was carried out with high yield and stereoselectivity (de = 90%) to afford intermediate (2S,1′R)-N-benzyloxycarbonyl-2-(1′-hydroxybut-3′-en-1′-yl)pyrrolidine 4, which was transformed in two steps into (1R,3R,7aS)-1-hydroxy-3-hydroxymethylpyrrolizidine 9. Commercial Cbz-l-proline was a source of functionalization and chirality.

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(2S,1′R)-N-Benzyloxycarbonyl-2-(1′-hydroxybut-3′-en-1′-yl)pyrrolidineC16H21NO3[α]D26=-56 (c 1, CHCl3)Source of chirality: l-proline and stereoselective synthesisAbsolute configuration: 2S,1′R (assigned by chemical transformation and NMR spectroscopy)

(2S,1′R,3′S)-N-Benzyloxycarbonyl-2-(3′,4′-epoxi-1′-hydroxybut-1′-yl)pyrrolidineC16H21NO4[α]D26=-47 (c 0.8, CHCl3)Source of chirality: l-proline and stereoselective synthesisAbsolute configuration: 2S,1′R,3′S (assigned by chemical transformation and NMR spectroscopy)

(1R,3R,7aS)-1-Acetyloxy-3-acetyloxymethylpyrrolizidineC12H19NO4[α]D26=-18 (c 0.4, CHCl3)Source of chirality: l-proline and stereoselective synthesisAbsolute configuration: 1R,3R,7aS (assigned by NMR spectroscopy)

(1R,3R,7aS)-1-Hydroxy-3-hydroxymethylpyrrolizidineC8H15NO2[α]D26=+1, [α]40526=+1.4 (c 0.8, MeOH)Source of chirality: l-proline and stereoselective synthesisAbsolute configuration: 1R,3R,7aS (assigned by NMR spectroscopy)