Synthesis of N-methyl urocanates of hydroxyderivatives of isocembrol

Abstract

Alcohols were prepared by stereospecific hydroxylation of isocembrol and were esterified into N-methylurocanates, proposed biomimetics of taxol.Urocanic [3-(4-imidazolyl)prop-2-enoic] acid exhibits multifaceted biological activity and is formed in vivo as a result of histidine metabolism [1]. Its N-methylderivative is the acid component in the diterpene esters eleutherobin and sarcodictyins, metabolites of soft coral Eleutherobia sp. and Sarcodictyon roseum, which exhibit a taxol-like mechanism of cytotoxic activity [2]. In creating a combinatory library of sarcodictyins, it was discovered that removal of the N-methylurocanic acid or replacing its imidazole ring by oxazole, thiazole, or benzene sharply affected its cytotoxic activity [3]. Valdivones, eleuthesides that are not N-methylurocanate esters [4], have not been demonstrated to have similar properties. On the other hand, an eleuthesoid containing a benzene ring instead of menthane retains its cytotoxic activity [5]. It may be that the biological properties of eleutherobin and sarcodictyin are unique because they are also N-methylurocanate esters, which makes it probable that other accessible taxol biomimetics exist.Therefore, cembrane derivatives, which are proposed biogenetic precursors of eleuthesides [6], are promising diterpenoids for preparing N-methylurocanates. One of these derivatives, isocembrol (1), was isolated from Siberian cedar resin [7] and was studied for possible generation of the eleutheside carbon skeleton [8]. In contrast with this, we used hydroxy derivatives of isocembrol directly as the alcohols of N-methylurocanate esters.We studied the possibility of introducing selectively a secondary hydroxyl into the molecule because esterification of the tertiary alcohol of 1 is problematical due to steric hindrances and competing elimination. Scheme 1.

Reaction of isocembrol and alcohols on clay

“…Isomerization of 1 in formic acid that leads to the formation of bi-and tricyclic compounds [7], epoxidation by per-acids [8], and hydroxylation [9] were studied. Epoxidation of 1 by t-BuOOH in the presence of VO(acac) 2 was performed efficiently [10]. Further transformations of the resulting epoxy derivative were studied.…”