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

摘要

(u0001)-Loline (1) was synthesized via a pathway that employed intramolecular [4 u0001 2] cycloaddition of annacylnitrosodiene, 25 or 26, as a key step. The acylnitrosodienes, which were used in situ, were obtainednby oxidation of the corresponding hydroxamic acids, 17 and 24, and these were prepared from eithernglucose via aldehyde 9 or more directly from (S)-malic acid (18). The endo dihydrooxazines 27 and 29,nobtained in a mixture with their exo stereoisomer, were transformed by reductive N–O bond cleavagenand reannulation into pyrrolizines 34 and 35. The latter was subjected to Sharpless aminohydroxylationnin the presence of (DHQD)2PHAL to give 50 along with its regioisomer 51. N-Methylation of tosylnamide 50, followed by mesylation of alcohol 52 and reduction of the γ-lactam 53 with borane, affordednpyrrolizidine 54. Cleavage of the p-methoxybenzyl ether and subsequent thermal treatment of 55 resultednin intramolecular etherification to yield N-tosylloline (57). Final reductive cleavage of the N-tosyl residuenproduced (u0001)-loline, characterized as its dihydrochloride.