Efficient synthesis of 2-modified 1α,25-dihydroxy-19-norvitamin D3 with Julia olefination: High potency in induction of differentiation on HL-60 cells

Keiichiro Ono, Akihiro Yoshida, Nozomi Saito, Toshie Fujishima, Shinobu Honzawa, Yoshitomo Suhara, Seishi Kishimoto, Takayuki Sugiura, Keizo Waku, Hiroaki Takayama, Atsushi Kittaka

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Abstract

Six novel 2-substituted analogues of 1α,25-dihydroxy-19-norvitamin D3, 6a,b-8a,b, were efficiently synthesized utilizing (-)-quinic acid as the A-ring precursor. The C2-modified A-rings were prepared as 4-alkylated (3R,5R)-3,5-dihydroxycyclohexanones 12-15 from (-)-quinic acid based on radical allylation at the C4 position of methyl (-)-quinicate. The new type of the CD-ring coupling partner 23 was synthesized from 25-hydroxy Grundmann's ketone 19 to apply to the modified Julia olefination to construct a diene unit between the A-ring and the CD-ring. The coupling yields, including a deprotection step, were 47-62%. After the separation of the diastereomers based on C2 stereochemistry, the structure (2α or 20) was determined by 1H NMR experiments and compared to DeLuca's 2-methyl- and 2-ethyl-1α,25-dihydroxy-19-norvitamin D3. Thus, the synthesized 2α(3-hydroxypropyl)-1α,25-dihydroxy-19-norvitamin D 3 (8a) showed almost the same potency in binding to the bovine thymus vitamin D receptor (VDR) as the natural hormone 1, while its β-isomer 8b had only a 3% affinity. Both 2α-allyl- and 2α-propyl-1α,25-dihydroxy-19-norvitamin D3 (6a and 7a) and their 2β-analogues (6b and 7b) possessed a weak affinity for the VDR. The strong VDR ligand 8a was ca. 36-fold more potent in induction of HL-60 cell differentiation than 1, and interestingly, even the weaker ligand 8b showed a 6.7-fold higher potency in the cell differentiation activity than that of 1.

Original languageEnglish
Pages (from-to)7407-7415
Number of pages9
JournalJournal of Organic Chemistry
Volume68
Issue number19
Publication statusPublished - 2003 Sep 19

ASJC Scopus subject areas

  • Organic Chemistry

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    Ono, K., Yoshida, A., Saito, N., Fujishima, T., Honzawa, S., Suhara, Y., Kishimoto, S., Sugiura, T., Waku, K., Takayama, H., & Kittaka, A. (2003). Efficient synthesis of 2-modified 1α,25-dihydroxy-19-norvitamin D3 with Julia olefination: High potency in induction of differentiation on HL-60 cells. Journal of Organic Chemistry, 68(19), 7407-7415.