Synthesis of all possible A-ring diastereomers at the 1- and 3-positions of 1alpha,25-dihydroxy-2beta-(3-hydroxypropoxy)vitamin D3 (ED-71) using C2-symmetrical epoxide as a common starting material.
The active vitamin D3, 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3), is now well recognized as a potent regulator of cell proliferation and differentiation in addition to possessing a regulatory effect on calcium and phosphorus metabolism. From research on the synthesis of 1,25(OH)2D3 analogs with the goal of separating these biological activities, we have already reported two characteristic analogs of active vitamin D3, namely 1alpha,25-dihydroxy-22-oxavitamin D3 (OCT) and 1alpha,25-dihydroxy-2beta-(3-hydroxypropoxy) vitamin D3 (ED-71). OCT, a 22-oxa analog obtained from modification of the side chain of 1,25(OH)2D3, has been used clinically as an injection for the treatment of secondary hyperparathyroidism underlying renal insufficiency and as an ointment for the skin disease, psoriasis. OCT has also been reported to exhibit antiangiogenic activity, exerting antitumor effects without producing serious side effects such as hypercalcemia. On the other hand, ED-71, which possesses a hydroxypropoxy substituent at the 2beta-position of the A-ring of 1,25(OH)2D3, has more potent biological effects on bone compared to 1 and phase III clinical studies for bone-fracture prevention have been completed. To explore structure activity relationship between ED-71 and related analogs, significant attention was now focused on the diastereomer of 3 at both the 1- and 3-positions of the A-ring, namely 3-epi-ED-71, 1-epi-ED-71 and 1,3-diepi-ED-71. All possible A-ring diastereomers at the 1- and 3-positions of ED-71 were synthesized using C2-symmetrical epoxide as a common starting material by convergent Trost methodology.
Kubodera
Noboru
N
Disease Area Strategy Department 2, Chugai Pharmaceutical Co. Ltd., 2-1-1, Nihonbashi-Muromachi, Chuo-ku, Tokyo 103-8324, Japan. kuboderanbr@chugai-pharm.co.jp
Hatakeyama
Susumi
S
D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D004852:Epoxy Compounds / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism; D014807:Vitamin D / Q000031:analogs & derivatives
D004852:Epoxy Compounds; D014807:Vitamin D; D002117:Calcitriol; C547512:eldecalcitol