Cautions in the synthesis of prostaglandins. C9→C15 acetate migration

Abstract

In the present communication we would like to focus on some difficulty which may be encountered in the final steps of the classical prostaglandin E1 synthesis through enone I (Scheme 1) [1–5]. This approach implies a sequence of reactions, namely reduction of the keto group in enone I to hydroxy, protection of diol IV as bis-tetrahydropyranyl (THP) ether, hydrolysis of the acetate and ester groups, oxidation of the 9-hydroxy group, and removal of the THP protecting groups. The synthesis of PGE1 according to this reaction sequence was described in [6]. The necessity of careful adherence to the conditions at the step of protection of diol IV should also be noted. It is desirable to use freshly distilled anhydrous reagents and solvents and ensure fairly fast reaction completion (in ~1–2 h). In some experiments during the THP protection of diol IV, especially when the reaction was slow, partial migration of the acetyl group from C to C with formation of C-acetate VI was possible (Scheme 2). The resulting bis-THP ethers V and VI were mixtures of diastereoisomers detected as a diffuse spot by TLC. After alkaline hydrolysis, Collins oxidation, and deprotection of the hydroxy groups, that mixture was converted into a mixture of PGE1 and enone VII which cannot be separated by silica gel chromatography. When mixture V/VI was subjected in succession to alkaline and acid hydrolysis, prostaglandin F1α (VIII) was obtained with a good overall yield. Examples of 1,2 and long-range acyl group migrations, including those occurring in prostaglandins, have been well documented [7–11]. However, despite obvious structural and functional differences between PGE1 and enone VII, it is surprising that these compounds are characterized by very similar Rf values in TLC with different eluent systems and that they almost cannot be separated by chromatography using simple columns with different lengths and efficiencies. ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 1, pp. 140–142. © Pleiades Publishing, Ltd., 2014. Original Russian Text © N.S. Vostrikov, V.V. Loza, N.K. Selezneva, M.S. Miftakhov, 2014, published in Zhurnal Organicheskoi Khimii, 2014, Vol. 50, No. 1, pp. 144–146.