Total Synthesis of 25-Hydroxy Vitamin D₃Northern Portion, Involving Tandem Conjugate Additions

Abstract

New approaches to 25-hydroxy vitamin D building blocks 7 and 8 have been developed. Tandem acid-catalyzed conjugate addition of ketene acetal 2d or 2c and acceptors 3 and then 11 yielded 5b (76% from 3) or 22 (64%), respectively, with the proper relative configuration on C20, C17, and C13 (steroid numbering, all compounds are racemic). The trans-hydrindan ring junction in 16 and 27 has been secured by chirality transfer in palladium-catalyzed hydrogenolysis of formates 15 and 26. Treatment of 16 with N-bromoacetamide followed by NaOH yielded a mixture of 8β,9β- and 8α,9α-epoxides 18 in a ratio of ca. 2:1, which was tosylated and reduced with lithium aluminum hydride without separation. The required diol 20 and its isomer 21 were obtained. In a complementary approach, 27 was oxidized into 8α,9α-epoxide 29 with a new reagent composed of m-CPBA, KF, and 2,6-di-tert-butyl-4-methylphenol. Opening of the epoxide ring in 29 with thiophenoxide anion followed by oxidation afforded dihydroxy sulfone 31. The latter was reduced via the respective dimesylate, and then the protective benzyloxy group was removed yielding 8.

Diastereoselective Approaches to trans-Hydrindane Derivatives − Total Synthesis of 8-(Phenylsulfonyl)de-A,B-cholestane Precursors to 25-Hydroxyvitamin D3

“…The ketene acetal 6 [a mixture of (E) and (Z) isomers in a ratio of 95:5] prepared as described earlier [8] was treated with 2-methylcyclopent-2-one (5) in the presence of trityl hexachloroantimonate (TrSbCl 6 , ca. 5 mol%) and the adduct 7 was subsequently treated in situ with the α,β-unsaturated ketone 8.…”

“…The experiments described had shown that, of the scrutinized candidates, (phenylthio)methyl vinyl ketone (8) was the Michael acceptor of choice. It was important that the adduct 9 was formed as the dominant product, easy to purify by chromatography.…”

“…[6] In certain systems, intermolecular conjugate addition reactions have triggered sequential transformations giving rise to complex annulation products. [7] We have recently reported on the application of two MukaiyamaϪMichael reactions in tandem [8] for a convergent synthesis of the hydrindane derivative 2 (Scheme 1), which served as the key building block for a synthesis of 1α,25-dihydroxyvitamin D 3 (1). Treatment of ketene acetals 6 with 2-methylcyclopent-2-en-1-one (5) in the presence of trityl hexachloroantimonate as catalyst gave the intermediate adduct, which was treated in situ with methyl vinyl ketone (4) as the second Michael acceptor.…”

Enantioselective Total Synthesis of a trans‐Hydrindane Rings/Side‐Chain Building‐Block of Vitamin D − Asymmetric Induction in an Acid‐Catalyzed Conjugate‐Addition Reaction

“…AlMe 3 /tBuSH; 2. 2,2-dimethoxypropane, TsOH, 56%, 96% ee; (b) as reported; [36] (c) Sharpless asymmetric dihydroxylation, 18 into 20: AD-mix-α, 76% yield (after distillation), Ͼ 95% ee; 19 into 21: DHQ-PHAL, K 3 Fe(CN) 6 , K 2 CO 3 , OsO 4 , 54%, 96% ee and 14, 8%; (d) 2,2-dimethoxypropane, TsOH, 16, 89%, 17, 96%; (e) AlMe 3 /tBuSH, 76%…”

“…The solvent was evaporated. The residue was purified by chromatography on silica gel (25 g, hexanes/EtOAc, 15:1), and the main fraction was distilled in a kugelrohr apparatus (165°/ [36] 19 (2.14 g, 10.00 mmol), Na 2 SO 3 (15 g). Reaction time 6 h. The product was extracted with dichloromethane (5 ϫ 30 mL) and purified by chromatography on silica gel (100 g, hexanes/ EtOAc Asymmetric dihydroxylation of the thioester 19 using commercially available AD-mix-β [37,38] …”