The stereoselective synthesis of the major oxygenated metabolites of trans-sobrerol (1) in optically active and/or racemic form is described.
(&)-trans-Sobrerol ( = (2RS, 6SR)-p-menth-6-ene-2,8-diol; l), a well known mucolytic agent, has been widely used for the treatment of chronic bronchopulmonary diseases [2]. In previous studies [3-51, one of us (P. V . ) demonstrated that 1 is extensively excreted in the free form and as conjugates, probably with glucuronic acid. Hydroxylation and oxidation of 1 at the allylic positions and, to a small extent, hydroxylation at Me-C (a), leading to 2-11 appear to be the metabolic pathway for 1 in man and in animals. It must be assumed that these biotransformations occur both simultaneously and successively. However, in the previous studies, no authentic samples were available for comparison, and structures were based on NMR and MS evidence. Since these metabolites might potentially contribute to the pharmacological and therapeutical properties of 1, we have prepared substantial amounts of them, in optically active and/or racemic forms'), to allow further characterization and pharmacological evaluation. Development of practical syntheses of oxidized metabolites of 1 has been hampered by the lack of methods for regio-and stereocontrolled introduction of oxygenated functions into ring positions of the p-menthane skeleton. Accordingly, a variety of standard procedures afforded only complex mixtures in which the target compounds were present in traces or not at all. Since acid-catalyzed rearrangement of a -pinene epoxide (12) affords smoothly trans- sobrerol(1) [6], we reasoned that analogous reactions of appropriately substituted a -pinene epoxides might provide the desired p -menthane derivatives.
I)
Part 2, see 111. ' ) Racemic and optically active forms are denoted (Exper. Part) by the letters a and b, respectively. Unless otherwise stated, the structural formulae of optically active compounds in this paper represent their absolute configuration.