Asymmetric synthesis of (+)-loline, a pyrrolizidine alkaloid from rye grass and tall fescue

(+)-Loline (1) was synthesized via a pathway that employed intramolecular [ 4 + 2] cycloaddition of an acylnitrosodiene, 25 or 26, as a key step. The a cylnitrosodienes, which were used in situ, were obtained by oxidation of th e corresponding hydroxamic acids, 17 and 24, and these were prepared from e ither glucose via aldehyde 9 or more directly from (S)-malic acid (18). The endo dihydrooxazines 27 and 29, obtained in a mixture with their exo stere oisomer, were transformed by reductive N-O bond cleavage and reannulationin to pyrrolizines 34 and 35. The latter was subjected to Sharpless aminohydro xylation in the presence of (DHQD)(2)PHAL to give 50 along with its regiois omer 51. N-Methylation of tosyl amide 50, followed by mesylation of alcohol 52 and reduction of the gamma -lactam 53 with borane, afforded pyrrolizidi ne 54. Cleavage of the p-methoxybenzyl ether and subsequent thermal treatme nt of 55 resulted in intramolecular etherification to yield N-tosylloline ( 57). Final reductive cleavage of the N-tosyl residue produced (+)-loline,ch aracterized as its dihydrochloride.