ChemInform Abstract: Studies on Pyrrolidinones: Some Attempts to Improve the Synthesis of Methyl N‐(3,4,4′,5‐Tetramethoxybenzhydryl)pyroglutamate (HEI 81) by Using N‐Acyl Iminium Salts Methodologies.

Abstract

Some ways to use the N-acyl iminium salt methodologies to synthesize a new inhibitor of tubulin polymerization, methyl N- (3,4,4',5-tetramethoxybenzhydryl)pyroglutamate (HEI 81) were studied. The most interesting reactions utilize a new pyroglutamic lactone (3-(3,4,5-trimethoxyphenyl)dihydropyrrolo[1,2-c]oxazole-1,5-dione).J. Heterocyclic Chem., 39, 109 (2002).We recently described [1] the synthesis of azaanalogs 1 of the efficient anticancer agent podophyllotoxin (2) that interacts with tubulin at the colchicine (3) site [2]. From all the cyclic compounds synthesized, only the strict analog 4 of podophyllotoxin (2), yields inhibition of tubulin polymerization (IC 50 = 5 µM), but none had interesting antitumor activity in the standard NCI test [3]. Esters and acids 5 which are the starting materials for compounds 1 were also submitted to the same screening. 4,4', pyroglutamate (HEI 81) (6) emerged from these tests. The middle anticancer properties of HEI 81 (IC 50 = 4.1 10 -7 M (MCF-7 cells)) are interesting because of its atypical structure. This compound is related to combretastatin A-4 (7) [4] and phenstatin (8) [5] (Scheme 1), but to date it was assumed important that the junction of the aromatic rings in these series was realized by a sp2 carbon atom [5]. Important also is the 50-60°d ihedral angle between the aromatic rings of active compounds [6]. In HEI 81, a π-π interaction orients the methyl ester group just above the trimethoxyphenyl ring, imposing a dihedral angle of 49° [7]. In this paper, we report some attempts to obtain compound 6 stereoselectively by using an N-acyl iminium salt methodology.The previous synthesis of ester 6, starting from DLmethyl N-trimethylsilylpyroglutamate (9) yielded a 50/50 mixture of two racemics (Scheme 2) [1a]. The biologically active compound HEI 81 is the RR enantiomer [8]. In order to obtain the right configuration of the aromatic rings, we tried to utilize the methyloxycarbonyl group of methyl pyroglutamate to induce an asymmetric addition of anisole on an acyliminium salt 10E (Scheme 2). This approach is based on analog amidoalkylations of pyroglutamic acid derivatives. According to Roth [9], there are two reasons for a presumed stereoselectivity in such a reaction. 1: Steric hindrance of the methoxycarbonyl group on the lactam ring must direct the approach of the new aromatic ring as a nucleophile to the N-acyliminium ion from its opposite side. 2: The planarity requirements of the Nacyliminium cation, with less steric repulsion, is better fulfilled by the E rotamer 10 than by the corresponding Z rotamer. In the beginning of this work, the exact configuration of HEI 81 was not known thus all the reactions described in this paper were realized starting from DL pyroglutamic acid [8a].The first reaction based on Scheme 2 was realized by using silyl ether 11. The best yield of ester 6, among many other compounds, was 5 % (boron trifluoride etherate, 1 equivalent/dichloromethane/24 hours/20 °C) (Scheme 3). In order to test the reactivity of an aromatic other than anisol...