Total Synthesis of Thyrsiferyl 23-Acetate, a Specific Inhibitor of Protein Phosphatase 2A and an Anti-Leukemic Inducer of Apoptosis

Abstract

A convergent synthetic entry to the squalenoid polyether system has been developed and applied to the biologically active marine natural products thyrsiferyl 23-acetate (1a), thyrsiferol (1b), thyrsiferyl 18-acetate (1c), and thyrsiferyl 18,23-diacetate (1d). This involved the separate construction of two advanced intermediates representing the C1−C15 (4) and C16−C24 (5) domains, followed by their organochromium-mediated coupling, installation of the tertiary alcohol at C15, and manipulation of the C18 and C23 acetate moieties. The C1−C15 (4) intermediate containing the three tetrahydropyranyl rings (A−B−C) was derived from two preconstructed tetrahydropyran-containing units representing the functionalized A (C2−C6) and C (C10−C14) rings (6 and 7, respectively). The bromotetrahydropyranyl A ring was obtained via bromoetherification of the hydroxyalkene 16, which was synthesized from (2R,3R)-epoxy geraniol. The C ring was stereoselectively constructed by acid-catalyzed opening of the hydroxy epoxide 32, derived from d-glutamic acid. Intermediates 6 and 7 were joined using organochromium conditions, and ketone and hydroxyl functionalities were installed at carbons 7 and 11, respectively. Closure of the B ring was accomplished stereoselectively by formation of species derived from a C7, C11 keto-alcohol and in situ reduction of a tetrahydropyranyl oxonium. The complementary tetrahydrofuran D (C19−C22) ring was obtained from a geraniol-derived tertiary hydroxy alkene (44) via a stereoselective Re(VII)-induced syn-oxidative cyclization. The side chain appended to the D ring was elaborated into trans-alkenyl iodide 5 under Takai reaction conditions. CrCl2-mediated coupling of aldehyde 4, containing the secondary bromide at C3 of the natural products, with iodide 5 bearing acetate moieties at C18 and C23, installed the C15−C16 carbon−carbon bond. The resultant C15 allylic carbinol was converted into an α,β-saturated ketone, and the final methyl group was added stereoselectively using methylmagnesium bromide. Saponification of the C18 acetate yielded 1a, whereas cleavage of both C18 and C23 acetates gave the triol 1b. This modular entry into the squalenoid−polyether system may facilitate further evaluation of the antileukemic, apoptosis-inducing, protein serine/threonine phosphatase 2A inhibitory and anti-multidrug resistance activities of the thyrsiferol-derived natural products.