ENANTIOGENIC TOTAL SYNTHESES OF (-)-INDOLIZIDINES (BICYCLIC GEPHYROTOXINS) 205A, 207A, 209B, AND 235B VIA THE INTRAMOLECULAR DIELS-ALDER REACTION OF A CHIRAL N-ACYLNITROSO COMPOUND

A general protocol for the enantiogenic total syntheses of a series of the 5-substituted 8-methylindolizidine class of alkaloids from the arrow poison frog, i.e., (-)-indolizidines 205A (1), 207A (2), 209B (3), and 235B (4), is described, in which a key step is the asymmetric intramolecular Diels-Alder reaction of the chiral N-acylnitroso compound 8 leading to the bicyclic oxazinolactam 7 which was utilized as a versatile common chiral intermediate for the preparation of these alkaloids. Subsequent introduction of the C-5 (in future) side chain was elaborated by means of a completely stereocontrolled process involving a Grignard reaction followed by reduction with NaBH4 in acidic media. The bicyclic oxazines 20a, 24, and 26 thus obtained were then subjected to reductive N-O bond cleavage followed by cyclodehydration using PPh3/CBr4/Et3N, which provided the (-)-enantiomers of the title alkaloids.