BINOL-Ti-Catalyzed Carbonyl-Ene Cyclization by Tuning the 6-Br-Ligand for the Synthesis of 2-Methyl-19-nor-22-oxa Vitamin D Analogue with Significant Differentiation Activity

Abstract

Transition state control in BINOL-Ti-catalyzed asymmetric carbonyl-ene cyclization by tuning the 6-Br-BINOL ligand completes the synthesis of the A ring of the 2-methyl-19-nor-22-oxa D 3 analogue (2), which shows the significant activity in differentiation of HL-60 cell.Basic research on the synthesis of analogues of the biologically active form of vitamin D 3 , 1a,25-dihydroxyvitamin D 3 [1a,25(OH) 2 D 3 ], has brought about the development of an important new field in medicinal chemistry. 2 A number of analogues have been synthesized and used to clarify the mode of action of vitamin D hormones and find new therapeutically useful compounds. These analogues are useful not only for calcium metabolism disorder and bone diseases, but also for differentiation of myelocytic leukemias and the treatment of psoriasis. 3 10-Oxo-19-nor-25(OH) 2 D 3 has been reported to exhibit a selective activity for differentiation of myelocytic leukemias. 4 19-Nor1a,25(OH) 2 D 3 also shows a selective activity profile, i.e., high potency in differentiation of malignant cells, but low calcitropic liability. 5 22-Oxa-1a,25(OH) 2 D 3 (OCT) shows a significant activity in the inhibition of cancer cell growth. 6 We have thus reported the hybridization analogue, 7 19-nor-22-oxa-1a,25(OH) 2 D 3 (1) on the basis of asymmetric carbonyl-ene cyclization 8b catalyzed by a binaphthol-derived titanium (BINOL-Ti) complex. 9 Recent papers 10 prompt us to report the synthesis of 2-methyl-19-nor-22-oxa vitamin D 3 analogue (2) 1,11 by tuning the chiral ligands for the ene cyclization 12 (Scheme 1) and the significant activity in differentiation of myelocytic leukemia, HL-60 cell.The preparation of the 2-methyl ene-cyclization substrate ((R,R)-3) is worth mentioning (Scheme 2). The allylic alcohol (7) was obtained through highly regioselective propiolate-ene reaction using triisopropylsilyl ethers (5) 13 (regioisomer ratio = 94:6) 14 with methyl propiolate (6) using EtAlCl 2 as the promoter. The ene substrate 3 was prepared in 96% ee via catalytic enantioselective epoxidation of allylic alcohol 15 (7) with (S,S)-diethyl tartrate (DET), O OBn OMPM OBn OMPM HO HO O OH OH HO O OH OH (R,R)-3 (R)-6-Br-BINOL-Ti

Strategies for the Synthesis of 19-nor-Vitamin D Analogs

“…Mikami and co-workers showed the synthesis of hybrid analogs of 2-methyl- ( 113a ) [ 39 ] and 2-fluoro-22-oxa-1α,25-(OH) 2 -19- nor -D 3 ( 113b ) [ 40 ] ( Scheme 20 ). One of the reasons that they synthesized fluorinated A-ring analogs was to investigate the VDR-binding conformation of the A-rings on the basis of 19 F NMR analysis.…”

Recent Results on A-Ring Modification of 1α,25-Dihydroxyvitamin D3: Design and Synthesis of VDR-Agonists and Antagonists with High Biological Activity

“…This compound showed a selective activity profile, combining high potency in inducing differentiation of malignant cells with very low, or no bone calcification activity [63]. Further modifications to the 19-nor A-ring were also studied, such as the deletion of one of the hydroxy groups [64,65], and the introduction of a functional group at the C2 position [66][67][68][69][70][71][72][73][74][75][76]. Recent studies revealed that 2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D 3 (2MD, 17a) induces bone formation selectively [69].…”

Synthesis of 2‐Methyl and Ethyl‐Substituted 19‐nor‐1α,25‐Dihydroxyvitamin D3 Analogues via the Cyclovitamin Strategy

“…In the 19‐ nor series, the synthesis of 5a , 6a , the corresponding 2‐hydroxymethyl analogues, and their 20‐epimers has been described via a Horner–Wittig reaction, known as the Lythgoe coupling,10 involving phosphane oxides such as 15 and 16 (Scheme ) 11,12. Mikami et al12b synthesized the A‐ring precursor 16 for 5a in a stereoselective fashion. DeLuca et al11 obtained a 1:1 mixture of 5a and 6a upon nonselective catalytic hydrogenation of 2‐methylene‐19‐ nor ‐1α,25‐dihydroxyvitamin D 3 (from 15 ) and separation by reversed phase HPLC.…”

“…DeLuca et al11 obtained a 1:1 mixture of 5a and 6a upon nonselective catalytic hydrogenation of 2‐methylene‐19‐ nor ‐1α,25‐dihydroxyvitamin D 3 (from 15 ) and separation by reversed phase HPLC. Application of the Lythgoe strategy in a stereoselective synthesis involving a 19‐ nor ‐2‐substituted phosphane oxide (steroid numbering) such as 16 is hampered by the fact that this particular A‐ring precursor no longer possesses a pseudo C 2 axis of symmetry as in 17 ; consequently, a control element12b for the 5,6‐double bond geometry relative to the configuration at C‐2 is required.…”