A formal synthesis of optically active clavicipitic acids, unusual azepinoindole-type ergot alkaloids

An enantioselective synthesis of (-)-cis- and (-)-trans-clavicipitic acid m ethyl esters (15a,b) has been achieved. The key steps of the synthesis were 1) C-4 selective functionalization of the indole ring via directed lithiat ion of 1-(triisopropylsilyl)gramine (2), and 2) stereoselective alkylation of the lithiated (2R)-(-)-2,5-dihydro-2-isopropyl-3,6-dimethoxypyrazine (Sc hollkopf's bislactim ether (4) ( bislactim ether) (4) with 1-t-butoxycarbon yl-3-chloromethyl-4-[(E)-3-methoxy-3-methyl-1-butenyl]indole (10). The dias tereoselectivity of the latter reaction was found to be highly dependent on the coordinating ability of solvents or additives. The optically active am ino-alcohol 13, prepared by the mild acid hydrolysis of the alkylation prod uct 11a, was successfully converted to the azepinoindoles 14a, b by PPTS-ca talyzed dehydrative cyclization. During the course of the final deprotectio n of N-Boc group, an interesting cis-trans isomerization between 15a and 15 b, which proceeded via acid-catalyzed ring opening and recyclization at C-6 , was observed. (C) 1999 Elsevier Science Ltd. All rights reserved.