146728-48-5Relevant articles and documents
Versatile synthesis and biological evaluation of 1,3-diamino-substituted 1α,25-dihydroxyvitamin D3 analogues
Oves, Daniel,Fernandez, Susana,Ferrero, Miguel,Bouillon, Roger,Verstuyf, Annemieke,Gotor, Vicente
, p. 928 - 937 (2007/10/03)
A concise route to 1α,3β-diamino-25-hydroxy-3-deoxyvitamin D3 (5) and 1β,3α-diamino-25-hydroxy-3-deoxyvitamin D 3 (6) has been developed starting from (R)- or (S)-carvone for the construction of the modified A-ring fragments. The con
Regioselective enzymatic syntheses of C-3 and C-5 carbonate A-ring stereoisomeric precursors of vitamin D
Oves, Daniel,Gotor-Fernandez, Vicente,Fernandez, Susana,Ferrero, Miguel,Gotor, Vicente
, p. 2881 - 2887 (2007/10/03)
The synthesis of selectively modified A-ring precursors for the preparation of 1α,25-dihydroxyvitamin D3 analogues by enzymatic hydrolysis reaction of corresponding dicarbonates has been accomplished. Thus, Candida rugosa lipase (CRL) was found to hydrolyze with high selectivity the C-3 carbonate of stereoisomers 4a,b, and 4d, furnishing C-5 vinyloxycarbonates 5a,b, and 5d. On the other hand, Chromobacterium viscosum lipase exhibit opposite regioselectivity with cis enantiomers 4c and 4d, catalyzing hydrolysis at the C-5 carbonate for 4c and at C-3 position for 4d. In addition, CRL catalyzes the alkoxycarbonylation reaction at C-3 of diol 3d affording the monocarbonate complementary to the one obtained by the enzymatic hydrolysis process.
Synthesis of monoacyl A-ring precursors of 1α,25-dihydroxyvitamin D3 through selective enzymatic hydrolysis
Gotor-Fernandez, Vicente,Ferrero, Miguel,Fernandez, Susana,Gotor, Vicente
, p. 1266 - 1270 (2007/10/03)
An efficient synthesis of monoacylated 1α,25-dihydroxyvitamin D3 A-ring precursors 15, 16, 18, and 19 has been described through an enzymatic hydrolysis process. Candida antarctica A lipase (CAL-A) hydrolyzes the C-5 acetate ester in trans stereoisomers 9 and 13, with complete and high selectivity, respectively. In the case of cis isomers 11 and 14, Chromobacterium viscosum lipase (CVL) is the enzyme of choice, exhibiting opposite selectivity for these two enantiomers. This lipase selectively catalyzes the hydrolysis at the C-3 acetate in diester 11 and at C-5 position in diester 14. It is noteworthy that through a hydrolysis reaction CAL-A and CVL allow the synthesis of the four A-ring monoacetylated precursors of 1α,25-dihydroxyvitamin D3, precursors which are complementary to those obtained by the enzymatic acylation process. In addition, with excellent yield CVL selectively hydrolyzes the C-3 chloroacetate ester instead of the C-5 acetate in diester 22, a key intermediate in the synthesis of new A-ring modified 1α,25-dihydroxyvitamin D3 analogues.
Selective acylation of A-ring precursors of vitamin D using enzymes in organic solvents
Fernandez,Ferrero,Gotor,Okamura
, p. 6057 - 6061 (2007/10/03)
Whereas Chromobacterium viscosum lipase (CVL) catalyzes selectively the acylation of the C-5 hydroxyl of the three stereoisomeric vitamin D A-ring precursors 2a, 3a and 3b, only the C-3 hydroxyl of the fourth stereoisomer 2b is acylated under the same conditions in organic solvent. In a convenient application, the racemic vitamin D A-ring precursor 4, possessing only the C-5 hydroxyl, was resolved using suitable conditions identified from the studies of 2 and 3.
Studies on the A-Ring Diastereomers of 1α,25-Dihydroxyvitamin D3
Muralidharan, K. Raman,Lera, Angel R. de,Isaeff, Shawn D.,Norman, Anthony W.,Okamura, William H.
, p. 1895 - 1899 (2007/10/02)
The three A-ring diastereomers 3b (compound HL), 4a (compound HJ), and 4b (compound HH), of the steroid hormone 1α,25-dihydroxyvitamin D3 (1α,25-(OH)2-D3, 3a, compound C) have been synthesized and biologically evaluated. (R)-Carvone was converted in seven steps to the enantiomerically pure A-ring enyne 7a.Palladium-catalyzed cross-coupling of the latter with the CD-ring triflate 8 resulted in silyloxy dienyne 10, which was converted in three steps to 1β,25-(OH)2-3-epi-D3 (4b).Oxidation of the latter with Dess-Martin reagent afforded trienone 6c, which upon reduction with sodium borohydride followed by thermolysis generated the 1α-epimer 4a.An identical sequence converted 1α,25-(OH)2-D3 to its 1β-epimer 3b via trienone 5c.Reduction of the latter with sodium triacetoxyborohydride followed by thermal isomerization regenerated the hormone 3a.Relative competitive indices (RCIs) of these analogues, which reflect their ability to bind to the chick intestinal nuclear receptor under in vitro conditions, were determined.Analogues 3b, 4a, and 4b had RCI values of 0.8 +/- 0.1 percent, 24.0 +/- 4.5 percent, and 0.22 +/- 0.01 percent, respectively, in comparison to 1α,25-(OH)2-D3 whose value is 100 percent by definiton.In addition, in vivo biological evaluation of these analogues was performed to determine their ability to induce intestinal calcium absorption (ICA) and bone calcium mobilization (BCM) in vitamin D deficient chicks.Analogue 4a was effective in stimulating ICA and BCM whereas analogues 3b and 4b exhibited little potency in eliciting these biological effects.
