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Synlett 2003(8): 1175-1179
DOI: 10.1055/s-2003-39908
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Akihiro Yoshida, Keiichiro Ono, Yoshitomo Suhara, Nozomi Saito, Hiroaki Takayama, Atsushi Kittaka*
Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Kanagawa 199-0195, Japan
Fax: +81(426)853714; e-Mail: akittaka@pharm.teikyo-u.ac.jp;
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Publication History

Received 11 April 2003
Publication Date:
11 June 2003 (online)

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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

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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.