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 acylnitrosodienes, which were used in situ, were obtained by oxidation of the corresponding hydroxamic acids, 17 and 24, and these were prepared from either 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 stereoisomer, were transformed by reductive N-O bond cleavage and reannulationinto pyrrolizines 34 and 35. The latter was subjected to Sharpless aminohydroxylation in the presence of (DHQD)(2)PHAL to give 50 along with its regioisomer 51. N-Methylation of tosyl amide 50, followed by mesylation of alcohol 52 and reduction of the gamma -lactam 53 with borane, afforded pyrrolizidine 54. Cleavage of the p-methoxybenzyl ether and subsequent thermal treatment of 55 resulted in intramolecular etherification to yield N-tosylloline (57). Final reductive cleavage of the N-tosyl residue produced (+)-loline,characterized as its dihydrochloride.