Total synthesis of 275A lehmizidine frog skin alkaloid (or of its enantiomer)

A concise asymmetric total synthesis of the potentially bioactive 275A lehmizidine frog skin alkaloid (or of its enantiomer) is described. Key features of the protocol include an acyliminium butenyl Grignard addition and a seven-membered intramolecular reductive amination step. Both reactions ensure a high degree of diastereocontrol, with installation of the same relative configuration at the C3, C5 and C10 stereocentres as in the natural product 275A. Despite this total synthesis, the absolute configuration of the natural product remains unknown, due to the lack of specific rotation data for alkaloid 275A.

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(2S,5R)-Benzyl 5-(but-3-enyl)pyrrolidine-2-carboxylateC16H21NO2Ee 100%[α]D25=-39.2 (c 1.0 CHCl3)Source of chirality: diastereoselective synthesis and chromatographic separationAbsolute configuration: (2S,5R)

(2S,5R)-Dibenzyl 5-(but-3-enyl)pyrrolidine-1,2-dicarboxylateC24H27NO4Ee 100%[α]D25=-64.8 (c 1.0 CHCl3)Source of chirality: diastereoselective synthesis and chromatographic separationAbsolute configuration: (2S,5R)

(2R,5S)-Benzyl 2-(but-3-enyl)-5-(hydroxymethyl)pyrrolidine-1-carboxylateC17H23NO3Ee 100%[α]D25=-45.4 (c 1.0 CHCl3)Source of chirality: diastereoselective synthesis and chromatographic separationAbsolute configuration: (2R,5S)

(2R,5S)-Benzyl 2-(but-3-enyl)-5-(tosyloxymethyl)pyrrolidine-1-carboxylateC24H29SNO5Ee 100%[α]D25=-43.4 (c 1.0 CHCl3)Source of chirality: diastereoselective synthesis and chromatographic separationAbsolute configuration: (2R,5S)

(2R,5R)-Benzyl 2-(but-3-enyl)-5-(7-(tert-butyldimethylsilyloxy)heptyl)pyrrolidine-1-carboxylateC29H49NO3SiEe 100%[α]D25=-41.8 (c 1.0 CHCl3)Source of chirality: diastereoselective synthesis and chromatographic separationAbsolute configuration: (2R,5S)

(2R,5R)-Benzyl 2-(7-(tert-butyldimethylsilyloxy)heptyl)-5-((E)-5-oxohex-3-enyl)pyrrolidine-1-carboxylateC31H51NO4SiEe 100%[α]D25=-38.2 (c 1.0 CHCl3)Source of chirality: diastereoselective synthesis and chromatographic separationAbsolute configuration: (2R,5S)

(3R,5S,10R)-3-(7-(tert-Butyldimethylsilyloxy)heptyl)-5-methyloctahydro-1H-pyrrolo[1,2-a]azepineC23H46NOSiEe 100%[α]D25=-27.9 (c 1.0 CHCl3)Source of chirality: diastereoselective synthesis and chromatographic separationAbsolute configuration: (3R,5S,10R)

7-((3R,5S,10R)-5-Methyloctahydro-1H-pyrrolo[1,2-a]azepin-3-yl)heptan-1-olC17H33NOEe 100%[α]D25=-38.9 (c 1.0 CHCl3)Source of chirality: diastereoselective synthesis and chromatographic separationAbsolute configuration: (3R,5S,10R)

(3R,5S,10R)-3-(7-Bromoheptyl)-5-methyloctahydro-1H-pyrrolo[1,2-a]azepineC17H32BrNEe 100%[α]D25=-33.6 (c 1.0 CHCl3)Source of chirality: diastereoselective synthesis and chromatographic separationAbsolute configuration: (3R,5S,10R)

(3R,5S,10R)-5-Methyl-3-(non-8-ynyl)octahydro-1H-pyrrolo[1,2-a]azepineC19H33NEe 100%Source of chirality: diastereoselective synthesis and chromatographic separation[α]D25=-19.2 (c 1.0 CHCl3)Absolute configuration: (3R,5S,10R)