Stereoselective Synthesis of Four Calcitriol Lactone Diastereomers at C23 and C25

Abstract

23S,25R)-Calcitriol lactone is a major metabolite of vitamin D 3 , but its synthesis has been far less well investigated than that of 1α,25(OH) 2 vitamin D 3 , the active form of vitamin D 3 , even though the lactone is present at a significant level in serum. This paper describes stereoselective syntheses of natural calcitriol lactone and its diastereomers at C23 and C25. This work features (i) the diastereoselective Reformatsky-type crotylation of aldehyde 25 in the presence of chiral ligand L2 to construct the stereochemistry at C23 and (ii) the diastereoselective epoxidation of homoallylic-allylic alcohol 31 to control the stereochemistry at C25. These key reactions allowed us to synthesize CD-ring synthon 30 with all four stereoisomers, and these were further converted into calcitriol lactones 3a−3d by reaction with ene-yne-type A-rings 33 in the presence of a palladium (0) catalyst.

Chemical Synthesis of Side‐Chain‐Hydroxylated Vitamin D3 Derivatives and Their Metabolism by CYP27B1

“…The 26‐hydroxylated CD–ring compounds 12 a and 12 b were synthesized from the triols (23 R ,25 S )‐ 19 a and (23 S ,25 R )‐ 19 b , as reported by our group [19] (Scheme 6). The 1,2‐diol moiety of the triols 19 was protected with acetone in the presence of PTS, followed by reduction of the secondary alcohol at C23 using the Barton method via xanthate to give 20 a and 20 b in 50 % and 48 % yield through two steps, respectively.…”

Differential diagnosis of vitamin D–related hypercalcemia using serum vitamin D metabolite profiling

“…Given the potential importance of measuring a terminal catabolite of 25‐OH‐D 3 metabolism, 25‐OH‐D 3 ‐26,23‐lactone, and the initial 1,25‐(OH) 2 D 3 catabolic pathway product, 1,24,25‐(OH) 3 D 3 , formed by CYP24A1, we synthesized or generated biologically, novel calibrators and deuterated internal standards d 3 ‐25‐OH‐D 3 ‐26,23‐lactone and d 6 ‐1,24,25‐(OH) 3 D 3 to enable quantitative measurement of these metabolites. ( 16,18 ) Unlabeled forms were also available to confirm the identity of peaks observed in serum samples.…”

“…We employed a combination of IE and LLE to expand the number of vitamin D metabolites that can be quantified by isotope-dilution enable quantitative measurement of these metabolites. (16,18) Unlabeled forms were also available to confirm the identity of peaks observed in serum samples.…”

“…Vitamin D metabolites presented in conventional units (ng/ml or pg/ml) can be converted to SI units by multiplying by 2.3 to 2.5 mmol/L or pmol/L, respectively. (16,18) Unlabeled forms were also available to confirm the identity of peaks observed in serum samples.…”

Peroxygenase-Catalyzed Selective Synthesis of Calcitriol Starting from Alfacalcidol

“…All active vitamin D3s are mainly used clinically for the treatment of chronic renal insufficiency, parathyroidism, rickets, chondromalacia, and bone lesions caused by abnormal vitamin D3 metabolism. Calcitriol, for example, is 500–1000 times more active in calcium absorption, compared with 25-hydroxyvitamin D3 ( Figure 1 ) [ 8 , 9 ]. In addition, calcitriol is also used as an antitumor agent, fat emulsion, sebum secretion promoter, etc.…”