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

Abstract

(+)-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 reannulation into pyrrolizines 34 and 35. The latter was subjected to Sharpless aminohydroxylation in the presence of (DHQD)₂PHAL to give 50 along with its regioisomer 51. N-Methylation of tosyl amide 50, followed by mesylation of alcohol 52 and reduction of the γ-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.