Pyrrolizidine alkaloid analogues. Synthesis of macrocyclic diesters of (±)-synthanecine a containing 12- to 16-membered rings

Abstract

The first macrocyclic diesters of 2,3-bis(hydroxymethyl)-1 -methyl-2,5-dihydropyrrole (2)[(±)-synthanecine A] with ring sizes of 12 to 16 have been prepared. Esterification of the imidazolide (6) of phenyl hydrogen adipate with (±)-synthanecine A was achieved at the 6-position. Treatment of the phenyl ester (7) with 1-(trimethylsilyl)imidazole and a catalytic quantity of sodium phenoxide produced the corresponding imidazolide and resulted in silylation of the free hydroxy group to afford the synthanecine A derivative (8). Attempted desilylation of the activated ester (8) followed by lactonisation failed and mixtures of oligomers were probably formed. In the successful route, treatment of (±)-synthanecine A (2) with thionyl chloride afforded (±)-3-chloromethyl-2-hydroxymethyl-1-methyl-2,5dihydropyrrolium chloride (3). Nucleophilic displacement of the allylic chloride was carried out with adipic (9a), pimelic (9b), suberic (9c), azelaic (9d), and sebacic (9e) acids in the presence of 1,8-diazabicyclo[5.4.0] undec-7-ene to yield the 7-monoesters (10a–e) of synthanecine A. Lactonisation of these monoesters was achieved via the pyridine-2-thiol esters to give the new macrocyclic diesters (4c–g) with ring sizes of 12 to 16 in low overall yield (12–16%). Improved yields (25–30%) of the dilactones (4c–g) were obtained after rigorous purification and crystallisation of the allylic chloride hydrochloride (3).