Synthesis of a Vitamin D₃Hydrindan Ring−Side-Chain Building Block, Involving Tandem Conjugate Addition and Alkylation Reactions

Abstract

: Vitamin D3 hydrindan ring−side-chain building block 4 (racemic) has been synthesized from ketene acetal 12 (derived from 6-methylheptanoic acid), 2-methylcyclopent-2-en-1-one (13), allyl methyl carbonate, and dimethyl methylphosphonate. The Mukaiyama−Michael conjugate addition of 12 and 13 yielded the adduct 11 (lk) accompanied by ca. 10% of its diastereomer. Allylation of 11 with allyl methyl carbonate in the presence of palladium catalyst afforded 10. The latter was transformed into enol lactone 26, which on treatment with 2 equiv of lithium dimethyl methylphosphonate and then 1 equiv of acetic acid provided 4.

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

“…The relative configurations at the three new asymmetric centres formed during these reactions were ascribed on the grounds of the Mukaiyama stereochemical model, [2] observations on the reaction of silylated cyclopentanone enols with electrophiles, [14] and our own experiences. [3] Some approaches that would allow utilization of a Michael acceptor bearing the phenylsulfonyl group were examined next. In an attempt to prepare phenylsulfonylmethyl vinyl ketone (11) by oxidation of 8, only polymeric material was obtained.…”

“…[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.…”

The Allylic Alkylation of Ketone Enolates

“…The stereochemical outcome of the reaction can be controlled by neighboring groups, as described in the total synthesis of a vitamin D building block by Wicha et al [32] They utilized a (Z)-configured allyl carbonate, which isomerized during the reaction to yield the (E)-configured allylated product (Scheme 20). The reaction proceeded diastereoselectively, delivering 90 % of the desired anti-isomer.…”

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

“…The thioester 16 was transformed into the ketene acetal 28 (Scheme 7) in the usual way, [44] and the product was purified by a short-path distillation. A mixture of (E)-and (Z)-isomers in a ratio of 89:11 was obtained.…”