Six novel 2-substituted analogues of 1alpha,25-dihydroxy-19-norvitamin D(3), 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 (2alpha or 2beta) was determined by (1)H NMR experiments and compared to DeLuca's 2-methyl- and 2-ethyl-1alpha,25-dihydroxy-19-norvitamin D(3). Thus, the synthesized 2alpha-(3-hydroxypropyl)-1alpha,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 beta-isomer 8b had only a 3% affinity. Both 2alpha-allyl- and 2alpha-propyl-1alpha,25-dihydroxy-19-norvitamin D(3) (6a and 7a) and their 2beta-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.
VitaminsVitamins U 0900 Efficient and Convergent Coupling Route for the Short-Step Synthesis of Enantiopure 2α-and 2β-Alkylated 1α,25-Dihydroxy-19-norvitamin D 3 Analogues. -Key steps in the novel synthesis are the radical introduction of the 2-alkyl side chain onto thiourethanes such as (II) and the C5-C6 coupling using Julia olefination. -(YOSHIDA, A.; ONO, K.; SUHARA, Y.; SAITO, N.; TAKAYAMA, H.; KITTAKA*, A.; Synlett 2003, 8, 1175-1179; Fac. Pharm. Sci., Teikyo Univ., Sagamiko, Kanagawa 199-01, Japan; Eng.) -Mais 41-220
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