Asymmetric Synthesis of the Tetraponerine Alkaloids

• Published in: Journal of organic chemistry Vol. 82; no. 13; pp. 6689 - 6702
• Main Authors: Davies, Stephen G, Fletcher, Ai M, Houlsby, Ian T. T, Roberts, Paul M, Thomson, James E
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 07.07.2017; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Organic; Physical Sciences; Science & Technology; BETA-AMINO ACIDS; LITHIUM AMIDES; DIASTEREOSELECTIVE CONJUGATE ADDITION; ENANTIOSELECTIVE SYNTHESIS; AZA-MICHAEL ADDITION; DOUBLE CYCLOISOMERIZATION; RING CLOSING METATHESIS; (+/-)-TETRAPONERINE T6; STEREOSELECTIVE-SYNTHESIS; ALPHA,BETA-UNSATURATED ESTERS
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/acs.joc.7b00837

The asymmetric syntheses of all eight tetraponerine alkaloids (T1–T8) were achieved using the diastereoselective conjugate additions of lithium amide reagents in the key stereodefining steps. Conjugate addition of either lithium (R)-N-allyl-N-(α-methylbenzyl)­amide or lithium (R)-N-(but-3-en-1-yl)-N-(α-methyl­benzyl)­amide to tert-butyl sorbate was followed by ring-closing metathesis of the resultant N-alkenyl β-amino esters, reduction to the corresponding aldehydes, and reaction with tert-butyl (triphenyl­phosphoranylidene)­acetate. Subsequent conjugate addition of the requisite antipode of lithium N-benzyl-N-(α-methylbenzyl)­amide to the resultant α,β-unsaturated esters gave a range of diamines for elaboration to T1–T8 via a sequence involving reduction of the ester moiety to give the corresponding aldehyde, olefination, tandem hydrogenation/hydrogenolysis, and cyclization upon reaction with 4-bromobutanal to give the tricyclic skeleton.