Synthesis of (10Z)- and (10E)-19-fluoro-1alpha,25-dihydroxyvitamin D3: compounds to probe vitamin D conformation in receptor complex by 19F-NMR

To study the interaction of vitamin D with its receptor by 19F-NMR, (5Z,10Z)- and (5Z,10E)-19-fluoro-1alpha,25-dihydroxyvitamin D3 were synthesized starting from vitamin D2 via electrophilic fluorination of vitamin D-SO2 adducts as the key step. Regio- and stereoselective electrophilic fluorination at C(19) of vitamin D-SO2 adducts was achieved under the conditions using (PhSO2)2NF and bulky bases. The stereochemistry of the addition and elimination of SO2 of various vitamin D derivatives was studied in detail. SO2 causes Z-E isomerization of the 5,6-double bond of vitamin D and adds to the resulting (5E)-isomer from the sterically less hindered side opposite to the substituent at C(1). Elimination of SO2 from 19-substituted vitamin D-SO2 adducts proceeded exclusively in a suprafacial manner with respect to the diene part under either thermal or reductive conditions. Dye-sensitized photochemical isomerization of 19-fluorovitamin D derivatives was studied in detail. The rapid isomerization at the 5,6-double bond was followed by the slow isomerization at the 10,19-double bond to yield the (5E,10Z)-isomer (by nomenclature of the 1-OH derivatives) as the major product. (10Z)- and (10E)-19-Fluorovitamin Ds were also interconverted thermally probably via the corresponding previtamin D by 1,7-sigmatropic isomerization.     

Synthesis of an optically active intermediate for A-ring of 19-nor- 1α,25-dihydroxyvitamin D3

An optically active intermediate 5 for A-ring of 19-nor-1a,25-dihydroxyvitamin D3 2 has been synthesized in five steps, starting from readily available, inexpensive D( )-xylose 6 with good yield.     

Catalytic asymmetric syntheses and biological activities of singly dehydroxylated 19-nor-1alpha,25-dihydroxyvitamin D(3) A-ring analogs in cancer cell differentiation and apoptosis

BACKGROUND: 1alpha,25-Dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) has been shown to modulate not only proliferation and differentiation, but also apoptosis in malignant cells, indicating that it could be useful for treating cancer. Little information is available concerning the structural motifs of the 1alpha, 25(OH)(2)D(3) molecule responsible for modulation of differentiation and apoptosis, however. We set out to synthesize singly dehydroxylated A-ring analogs of 19-nor-1alpha,25(OH)(2)D(3) in a catalytic asymmetric fashion, and to investigate their biological activities in leukemia HL-60 cells. RESULTS: A series of singly dehydroxylated 19-nor-1alpha,25-dihydroxyvitamin D(3) A-ring analogs were synthesized using a combinatiorial sequence of regioselective propiolate-ene reaction and catalytic asymmetric carbonyl-ene cyclization. Surprisingly, the analogs could be clearly divided into two categories; one group, bearing 1alpha-hydroxy or 3beta-hydroxy groups in the A-ring, were potent differentiators and the second group, bearing 1beta-hydroxy or 3alpha-hydroxy groups, were potent stimulators of apoptosis. CONCLUSIONS: We have clearly identified the structural motifs of 19-nor-1alpha,25(OH)(2)D(3) analogs responsible for differentiation and apoptosis in HL-60 cells. These findings will provide useful information not only for development of therapeutic agents for treatment of leukemia and other cancers, but also for structure-function studies of 1alpha,25(OH)(2)D(3).     

Cal-B-catalyzed alkoxycarbonylation of a-ring stereoisomeric synthons of 1alpha,25-dihydroxyvitamin D3 and 1alpha,25-dihydroxy-19-nor-previtamin D3: a comparative study. first regioselective chemoenzymatic synthesis of 19-nor-A-ring carbonates

A comparative study of alkoxycarbonylation processes of both 19-nor-A-ring and A-ring stereoisomers of 1alpha,25-dihydroxyvitamin D3 analogues catalyzed by Candida antarctica lipase B (CAL-B) has been described. The presence of the methyl group in the A-ring at C-2, as in 3-6, has a determining role in the regioselectivity of the biocatalysis, mainly allowing the hydroxyl group at C-5 position to react. For the 19-nor-A-ring stereoisomers 7-10, which lack the C-2 methyl group, the configurations at C-3 and C-5 have a high influence in the selectivity exhibited by CAL-B. Thus, each couple of enantiomers showed opposing regioselectivities depending on the C-3 configuration. When C-3 possesses an (S)-configuration, enzymatic alkoxycarbonylations took place at the C-5-(R) or C-5-(S) hydroxyl groups. However, if the chiral centers at C-3 are (R), CAL-B alkoxycarbonylated the C-3-(R) hydroxyl group independently of the configuration at C-5. The corresponding carbonates are useful A-ring precursors of 1alpha,25-dihydroxyvitamin D3 analogues, selectively modified at the C-1 or C-3 positions. In addition, an improved synthesis of cis A-ring synthons 5 and 6 is described using a Mitsunobu methodology.     

Efficient synthesis of novel 1alpha-amino and 3beta-amino analogues of 1alpha,25-dihydroxyvitamin d(3)

Convenient synthetic routes to 1alpha-amino-25-hydroxyvitamin D(3) (3) and 3beta-amino-3-deoxy-1alpha,25-dihydroxyvitamin D(3) (4), novel analogues of vitamin D(3) bearing an amino group at the C-1 or C-3 position, have been developed starting from (S)-(+)-carvone. Construction of the A-ring fragments was accomplished by selective enzymatic hydrolysis of a diester intermediate and introduction of the amino group under Mitsunobu conditions.     

Efficient convergent synthesis of 1alpha,25-dihydroxyvitamin D3 and its analogues by Suzuki-Miyaura coupling

[reaction: see text] 1alpha,25-Dihydroxyvitamin D(3) was synthesized by the Suzuki-Miyaura coupling of the A-ring intermediate 1, which was efficiently prepared from readily available 1,7-enyne 2, with the corresponding boronate compound of the C,D-ring portion. The method was applied to prepare des-C,D analogues of 1alpha,25-dihydroxyvitamin D(3).     

Catalytic asymmetric synthesis and anticancer effects of the novel non-calcemic analog of vitamin D, 2α-fluoro-19-nor-22-oxa-1α,25-dihydroxyvitamin D3 in metastatic lung carcinoma

1α,25-Dihydroxyvitamin D₃ (1α,25-D₃) has potent antiproliferative and anti-invasive properties in vitro in cancer cells. However, the major limitation to its clinical use is that it causes hypercalcemia. Therefore, vitamin D analogs with potent cell regulatory effects but with weaker calcemic effects than 1α,25-D₃ are required. Among them, 22-oxa-1α,25-D₃ and 19-nor-1α,25-D₃ have anti-cancer effects with relatively low calcemic effects. Modifications at the C-2α position of the A-ring also produced analogs with a unique biological profile. Not only the side-chain but also the A-ring modification thus generates a unique analog with potent cell regulatory effects and low calcemic activity as well. We report here that the hybrid 1α,25-D₃ analog, synthesized via the highly regio- and stereo-selective ring opening 2α-fluorination and catalytic asymmetric carbonyl-ene cyclization, with 2α-fluoro, 19-nor, and 22-oxa modification exhibits unique cell regulatory activities against the development of metastatic lung carcinoma.     

6-s-cis locked analogues of the steroid hormone 1alpha, 25-dihydroxyvitamin D(3). Synthesis Of novel A-ring stereoisomeric 1, 25-dihydroxy-3-epi-19-nor-previtamin D(3) derivatives

Efficient syntheses of A-ring synthons 24 and 32 are described from hydroxy ester 16, which is easily available on a preparative scale from (-)-quinic acid. Key features of the syntheses were (a) the ability to selectively perform desilylations in the presence of p-nitrobenzoate esters and (b) the excellent yield and complete stereospecificity with which the configuration of alcohols 16, 18, and 26 could be inverted under Mitsunobu conditions. Thus, A-ring synthons 24 and 32 were both prepared in 35-38% yield (eight steps) from the common precursor 16. The coupling of A-ring synthons 24 and 32 with the appropriate CD-ring/side chain fragment 7 provides access to novel 6-s-cis locked analogues of steroid hormone 1alpha, 25-dihydroxyvitamin D(3): 1alpha, 25-dihydroxy-3-epi-19-nor-previtamin D(3) (37) and 1beta, 25-dihydroxy-3-epi-19-nor-previtamin D(3) (38), which are unable to undergo rearrangement to the respective vitamin D form by virtue of the absence of the C-19 methyl group. Compounds 37 and 38 can be used as tools for studying the genomic and nongenomic mechanisms of action of the previtamin form of the hormone 1alpha, 25-dihydroxyvitamin D(3).     

Efficient and versatile synthesis of novel 2alpha-substituted 1alpha,25-dihydroxyvitamin D(3) analogues and their docking to vitamin D receptors.

Novel 2alpha-substituted 1alpha,25-dihydroxyvitamin D(3) analogues with 2alpha-alkyl and 2alpha-hydroxyalkyl groups were systematically synthesized from D-xylose. Their conformation on binding to the ligand binding domain (LBD) of the vitamin D receptor was analyzed. It has been found that the 2alpha-hydroxypropyl group best fits the cavity of the LBD, and the binding activity is three times higher than that for the natural hormone.     

2 alpha-(3-hydroxypropyl)- and 2 alpha-(3-hydroxypropoxy)-1 alpha,25-dihydroxyvitamin D3 accessible to vitamin D receptor mutant related to hereditary vitamin D-resistant rickets

Hereditary vitamin D-resistant rickets (HVDRR) is a genetic disorder caused by mutations in the vitamin D receptor, which lead to resistance to 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)]. We found that the A ring-modified analogues, 2alpha-(3-hydroxypropyl)- and 2alpha-(3-hydroxypropoxy)-1alpha,25(OH)(2)D(3), (O1C3 and O2C3) can bind better than the natural hormone to the mutant VDR (R274A), which similar to the HVDRR mutant, R274L, had lost the hydrogen bond to the 1alpha-hydroxyl group of 1alpha,25(OH)(2)D(3).     

Candidate Trail Attractants of Reticultermes lucifugus: Stereoselective Syntheses of (3Z, 6E,BE)-(3Z, 6E, 8Z)-and (3Z, 6Z, 8Z)-3,6,8 -Dodecatrien-1-OL1

Stereoselective syntheses on a gram scale of (3Z,6E,8E)-, (3Z,6E,8Z)-and (3Z,6Z,8Z)-3,6,8-dodecatrien-1-ol, 8, 9 and 10, respectively, are described. A key step of the synthesis of 8 consisted of a copper-mediated coupling reaction between 4-(2-tetrahydropyranyloxy)-1-butynylmagnesium bromide (15) and the mesyl ester of (2E,4E)-2,4-octadien-1-ol (14). A similar copper-mediated reaction between 15 and the mesyl ester of (E)-2-octen-4-yn-1-ol (19) was used to construct the C-12 carbon skeleton of 9. On the other hand, the synthesis of 10 was based on a palladium-promoted reaction between (Z)-1-bromo-1-pentene (23) and the organozinc bromide derived from 3,6-heptadiyn-1-yl acetate (27).     

Stereoselective synthesis of (Z)-2-fluoro-1-alkenyl(phenyl)iodonium tetrafluoroborates

[reaction: see text] (Z)-2-Fluoro-1-alkenyl(phenyl)iodonium salts were stereoselectively prepared by the reaction of alkynyl(phenyl)iodonium salts with aqueous HF in good yields. The method is applicable to the synthesis of fluoroalkenyliodonium salts having functional groups such as ketone, ester, and chloride. (Z)-2-Fluoro-1-alkene, (Z)-2-fluoro-2-alkenoate, and (Z)-beta-fluoroenyne could be stereoselectively prepared from the fluoroalkenyliodonium salt.