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Synthesis 2005(15): 2533-2543  
DOI: 10.1055/s-2005-872075
PAPER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of 24,24-Ethanovitamin D3 Lactones Using Ruthenium-Catalyzed Intermolecular Enyne Metathesis: Potent Vitamin D Receptor Antagonists

Nozomi Saitoa, Manami Masudaa, Hiroshi Saitob, Kazuya Takenouchib, Seiichi Ishizukab, Jun-ichi Namekawab, Midori Takimoto-Kamimurab, Atsushi Kittaka*a
a Faculty of Pharmaceutical Sciences, Teikyo University, Kanagawa 199-0195, Japan
Fax: +81(426)853713; e-Mail: akittaka@pharm.teikyo-u.ac.jp;
b Teijin Institute for Bio-Medical Research, Tokyo 191-8512, Japan
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Publication History

Received 25 March 2005
Publication Date:
20 July 2005 (online)

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Abstract

Novel vitamin D receptor antagonists, 24,24-ethanovitamin D3-26,23-lactones 6 and 7 and their 2α-functionalized analogues 6a-c and 7a-c were synthesized and their biological activities were evaluated. The triene structure of vitamin D3 was constructed using Pd-catalyzed alkenylative cyclization of A-ring precursor enynes 12 and 12a-c with the CD-ring bromo-olefin counterpart having 24,24-ethano-α-methylene-γ-lactone on the side chain (21 or 22). The CD-ring precursors 21 and 22 were efficiently synthesized via Ru-catalyzed intermolecular enyne metathesis of 15 with ethylene to give dienone 17 followed by cyclopropanation. The VDR antagonistic activity of the newly designed vitamin D3 lactones 6 and 7 increased to 2.8 times that of TEI-9647 (2) in a HL-60 cell differentiation evaluating system. Moreover, introduction of three substituents, that is, a methyl (6a and 7a), a 3-hydroxypropyl (6b and 7b), or a 3-hydroxypropoxyl group (6c and 7c) into the C2α position of 6 and 7, resulted in marked enhancement, up to 19 times, of the antagonistic activity toward VDR.

Key words

vitamins - antagonist - lactones - ruthenium - metathesis - enynes

20

Crystal data of 20 are as follows: C21H34BrO2, space group P212121, Z = 4, a = 7.785 (6), b = 9.445 (9), c = 27.35 (2) Å, V = 2010 (2) Å3, Dcalcd = 1.313 g/cm3, R1 = 0.063 for 16610 reflections [I > 3.00s (I)], wR2 = 0.068 [I > 3.00s (I)]; structure solution and refinement were performed using Direct Methods (SIR92) and full-matrix least-squares on F, respectively. Diffractometer Rigaku RAXIS-RAPID, graphite monochlomated CuKα (λ = 1.54187 Å).