Efficient and Convergent Coupling Route for the Short-step Synthesis of Enantiopure 2α- and 2β-Alkylated 1α,25-Dihydroxy-19-norvitamin D₃ Analogues

Abstract

Novel efficient synthesis of several enantio-pure 2-alkyl­ated 1α,25-dihydroxy-19-norvitamin D₃ analogues through radical introduction of 2-alkyl chain and C₅-C₆ position coupling using Julia-type olefination as key steps was established starting from commercially available (-)-quinic acid as a chiral pool.

Key words

total synthesis - vitamin D - radical reactions - Julia reactions - coupling

References

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1

New address: A. Yoshida, The Noguchi Institute and Japan Chemical Innovation Institute (JCII), Itabashi-ku, Tokyo 173-0003, Japan. Y. Suhara, Kobe Pharmaceutical University, Higashinada-ku, Kobe 658-8558, Japan

7

In fact, Wittig reaction of our phosphine oxide 9 (R = CH₂CH=CH₂) with the known 8-keto CD-ring derivative did not proceed. See also ref.^6d

13

In the literature,^6d oxidation of 2-hydroxyl derivative 10 followed by a Wittig olefination-hydrogenation sequence was reported for a 2-ethylation strategy. However, Wittig reaction provided the 2-ethylidene product only in 18% yield, and the subsequent chemoselective hydrogenation gave a 2-ethyl analogue in ca. 45% yield.