A simple and efficient enantioselective route to 2,6-disubstituted piperidines: synthesis of (2R,6S)-isosolenopsin A and (2S,6R)-isosolenopsin

The enantioselective synthesis of 2,6-cis-disubstituted piperidine alkaloids, (2R,6S)-isosolenopsin A 2 and (2S,6R)-isosolenopsin 5 from fire ant venom is described. Starting from the dodecanal and decanal, the synthesis presents two key steps. The first step involves Keck allylation to afford the chiral homoallylalcohol with the required stereochemistry and the second key step consists of Grubbs olefin cross metathesis. The synthesis was achieved in five steps with 44% overall yield.

The enantioselective synthesis of 2,6-cis-disubstituted piperidine alkaloids, (2R,6S)-isosolenopsin A and (2S,6R)-isosolenopsin of fire ant venom is described.Figure optionsDownload as PowerPoint slide

(R)-Pentadec-1-en-4-yl 4-methylbenzenesulfonateC22H36O3S[α]D = +9.6 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (4R)

(R,E)-2-Oxoheptadec-3-en-6-yl 4-methylbenzenesulfonateC24H38O4S[α]D = +9.0 (c 0.25, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3E,6R)

(S,E)-6-Azidoheptadec-3-en-2-oneC17H31N3O[α]D = −2.6 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3E,6S)

(S)-Tridec-1-en-4-yl 4-methylbenzenesulfonateC20H32O3S[α]D = −13.5 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (4S)

(S,E)-2-Oxopentadec-3-en-6-yl 4-methylbenzenesulfonateC22H34O4S[α]D = −22.9 (c 0.75, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3E,6S)

(R,E)-6-Azidopentadec-3-en-2-oneC15H27N3O[α]D = −3.6 (c 1.0, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3E,6R)