- Total synthesis of 1α,25-dihydroxyvitamin D3 (calcitriol) through a Si-assisted allylic substitution
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Herein, we describe a versatile and efficient total synthesis of 1α,25-dihydroxyvitamin D3 (calcitriol). The synthetic strategy relies on an unprecedented Si-assisted SN2′-syn displacement of carbamates by cuprates to set the challenging pivotal quaternary methyl group at the fused-ring junction of the CD-trans-hydrindane core. Other key transformations involve the catalytic asymmetric reduction of an α,β,γ,δ-unsaturated ester with CuH to generate the natural steroidal configuration at C20 and a Pauson-Khand cyclization to form the CD-ring skeleton. This strategy enables the syntheses of novel analogs for structure-function studies and drug development.
- López-Pérez, Borja,Maestro, Miguel A.,Mouri?o, Antonio
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Read Online
- Preparation method of 25-hydroxyvitamin D3, 1alpha, 25-dihydroxyvitamin D3 and isotope internal standard compound thereof
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The invention discloses a preparation method of 25-hydroxyvitamin D3 and 1alpha, 25-dihydroxyvitamin D3 and an isotope internal standard compound thereof. The preparation method comprises the following steps: a compound III is subjected to SO2 conjugate protection, O3 oxidation, NaBH4 reduction, iodination ring opening, conjugate addition with acrylate, and reaction with a methyl Grignard reagentor isotope labeled methyl Grignard reagent, a silicon protecting group is removed under the action of TBAF, and a product is obtained through ultraviolet irradiation configuration inversion under thecatalysis of 9-acetyl anthracene. The method is good in reaction selectivity, high in total yield, simple and convenient to operate and short in isotope introduction step, and the isotope utilizationrate is greatly increased.
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Paragraph 0102-0103; 0111-0114
(2020/08/27)
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- A single mutation at the ferredoxin binding site of P450 Vdh enables efficient biocatalytic production of 25-hydroxyvitamin D3
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Vitamin D3 hydroxylase (Vdh) from Pseudonocardia autotrophica is a cytochrome P450 monooxygenase that catalyzes the two-step hydroxylation of vitamin D3 (VD3) to produce 25-hydroxyvitamin D 3 (25(OH)VD3) and 1α,25-dihydroxyvitamin D 3 (1α,25(OH)2VD3). These hydroxylated forms of VD3 are useful as pharmaceuticals for the treatment of conditions associated with VD3 deficiency and VD3 metabolic disorder. Herein, we describe the creation of a highly active T107A mutant of Vdh by engineering the putative ferredoxin-binding site. Crystallographic and kinetic analyses indicate that the T107A mutation results in conformational change from an open to a closed state, thereby increasing the binding affinity with ferredoxin. We also report the efficient biocatalytic synthesis of 25(OH)VD3, a promising intermediate for the synthesis of various hydroxylated VD3 derivatives, by using nisin-treated Rhodococcus erythropolis cells containing VdhT107A. The gene-expression cassette encoding Bacillus megaterium glucose dehydrogenase-IV was inserted into the R. erythropolis chromosome and expressed to avoid exhaustion of NADH in a cytoplasm during bioconversion. As a result, approximately 573 μg mL-1 25(OH)VD3 was successfully produced by a 2 h bioconversion. Copyright
- Yasutake, Yoshiaki,Nishioka, Taiki,Imoto, Noriko,Tamura, Tomohiro
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p. 2284 - 2291
(2013/12/04)
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- Hydroxylation of CYP11A1-derived products of vitamin D3 metabolism by human and Mouse CYP27B1
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CYP11A1 can hydroxylate vitamin D3 at carbons 17, 20, 22, and 23, producing a range of secosteroids which are biologically active with respect to their ability to inhibit proliferation and stimulate differentiation of various cell types, including cancer cells. As 1a-hydroxylation of the primary metabolite of CYP11A1 action, 20S-hydroxyvitamin D3 [20(OH)D3], greatly influences its properties, we examined the ability of both human and mouse CYP27B1 to 1a-hydroxylate six secosteroids generated by CYP11A1. Based on their kcat/Km values, all CYP11A1-derived metabolites are poor substrates for CYP27B1 from both species compared with 25-hydroxyvitamin D3. No hydroxylation of metabolites with a 17a-hydroxyl group was observed. 17a,20-Dihydroxyvitamin D3 acted as an inhibitor on human CYP27B1 but not the mouse enzyme. We also tested CYP27B1 activity on 20,24-, 20,25-, and 20,26-dihydroxyvitamin D3, which are products of CYP24A1 or CYP27A1 activity on 20(OH)D3. All three compounds were metabolized with higher catalytic efficiency (kcat/Km) by both mouse and human CYP27B1 than 25-hydroxyvitamin D3. CYP27B1 action on these new dihydroxy derivatives was confirmed to be 1ahydroxylation by mass spectrometry and nuclear magnetic resonance analyses. Both 1,20,25- and 1,20,26- trihydroxyvitamin D3 were tested for their ability to inhibit melanoma (SKMEL-188) colony formation, and were significantly more active than 20(OH)D3. This study shows that CYP11A1-derived secosteroids are 1ahydroxylated by both human and mouse CYP27B1 with low catalytic efficiency, and that the presence of a 17a-hydroxyl group completely blocks 1a-hydroxylation. In contrast, the secondary metabolites produced by subsequent hydroxylation of 20(OH)D3 at C24, C25, or C26 are very good substrates for CYP27B1.
- Tang, Edith K.Y.,Chen, Jianjun,Janjetovic, Zorica,Tieu, Elaine W.,Slominski, Andrzej T.,Li, Wei,Tuckey, Robert C.
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p. 1112 - 1124
(2013/07/19)
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- Continuous-flow synthesis of activated vitamin D3 and its analogues
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An efficient, two-stage, continuous-flow synthesis of 1α,25-(OH) 2-vitamin D3 (activated vitamin D3) and its analogues was achieved. The developed method afforded the desired products in satisfactory yields using a high-intensity and economical light source, i.e., a high-pressure mercury lamp. In addition, our method required neither intermediate purification nor high-dilution conditions. The Royal Society of Chemistry 2012.
- Fuse, Shinichiro,Mifune, Yuto,Tanabe, Nobutake,Takahashi, Takashi
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experimental part
p. 5205 - 5211
(2012/08/08)
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- TOPICAL PHARMACEUTICAL COMPOSITION CONTAINING A WATER-SENSITIVE ACTIVE PRINCIPLE
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A topical pharmaceutical composition including, as a pharmaceutical active agent, a water-sensitive compound in a solubilised form in a physiologically acceptable medium is described. A method for preparing such a composition, and uses thereof in dermatology are also described.
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- Metabolism of substrates incorporated into phospholipid vesicles by mouse 25-hydroxyvitamin D3 1α-hydroxylase (CYP27B1)
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CYP27B1 catalyzes the 1α-hydroxylation of 25-hydroxyvitamin D3 to 1α,25-dihydroxyvitamin D3, the hormonally active form of vitamin D3. To further characterize mouse CYP27B1, it was expressed in Escherichia coli, purified and its activity measured on substrates incorporated into phospholipid vesicles, which served as a model of the inner mitochondrial membrane. 25-Hydroxyvitamin D3 and 25-hydroxyvitamin D2 in vesicles underwent 1α-hydroxylation with similar kinetics, the catalytic rate constants (kcat) were 41 and 48mol/min/mol P450, respectively, while Km values were 5.9 and 4.6mmol/mol phospholipid, respectively. CYP27B1 showed inhibition when substrate concentrations in the membrane were greater than 4 times Km, more pronounced with 25-hydroxyvitamin D3 than 25-hydroxyvitamin D2. Higher catalytic efficiency was seen in vesicles prepared from dioleoyl phosphatidylcholine and cardiolipin than for dimyristoyl phosphatidylcholine vesicles. CYP27B1 also catalyzed 1α-hydroxylation of vesicle-associated 24R,25-dihydroxyvitamin D3 and 20-hydroxyvitamin D3, and 25-hydroxylation of 1α-hydroxyvitamin D3 and 1α-hydroxyvitamin D2, but with much lower efficiency than for 25(OH)D3. This study shows that CYP27B1 can hydroxylate 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 associated with phospholipid membranes with the highest activity yet reported for the enzyme. The expressed enzyme has low activity at higher concentrations of 25-hydroxyvitamin D in membranes, revealing that substrate inhibition may contribute to the regulation of the activity of this enzyme.
- Tang, Edith K.Y.,Voo, Kimberley J.Q.,Nguyen, Minh N.,Tuckey, Robert C.
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experimental part
p. 171 - 179
(2011/02/23)
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- Structural evidence for enhancement of sequential vitamin D3 hydroxylation activities by directed evolution of cytochrome P450 vitamin D 3 hydroxylase
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Vitamin D3 hydroxylase (Vdh) isolated from actinomycete Pseudonocardia autotrophica is a cytochrome P450 (CYP) responsible for the biocatalytic conversion of vitamin D3 (VD3) to 1α,25-dihydroxyvitamin D3 (1α,25(OH)2VD 3) by P. autotrophica. Although its biological function is unclear, Vdh is capable of catalyzing the two-step hydroxylation of VD3, i.e. the conversion of VD3 to 25-hydroxyvitamin D3 (25(OH)VD3) and then of 25(OH)VD3 to 1α,25(OH) 2VD3, a hormonal form of VD3. Here we describe the crystal structures of wild-type Vdh (Vdh-WT) in the substrate-free form and of the highly active quadruple mutant (Vdh-K1) generated by directed evolution in the substrate-free, VD3-bound, and 25(OH)VD3-bound forms. Vdh-WT exhibits an open conformation with the distal heme pocket exposed to the solvent both in the presence and absence of a substrate, whereas Vdh-K1 exhibits a closed conformation in both the substrate-free and substrate-bound forms. The results suggest that the conformational equilibrium was largely shifted toward the closed conformation by four amino acid substitutions scattered throughout the molecule. The substratebound structure of Vdh-K1 accommodates both VD3 and 25(OH)VD3 but in an anti-parallel orientation. The occurrence of the two secosteroid binding modes accounts for the regioselective sequential VD3 hydroxylation activities. Moreover, these structures determined before and after directed evolution, together with biochemical and spectroscopic data, provide insights into how directed evolution has worked for significant enhancement of both the VD3 25-hydroxylase and 25(OH)VD3 1α-hydroxylase activities.
- Yasutake, Yoshiaki,Fujii, Yoshikazu,Nishioka, Taiki,Cheon, Woo-Kwang,Arisawa, Akira,Tamura, Tomohiro
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experimental part
p. 31193 - 31201
(2011/12/14)
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- An expeditious route to 1α,25-dihydroxyvitamin D3 and its analogues by an aqueous tandem palladium-catalyzed a-ring closure and suzuki coupling to the C/D unit
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Chemical equation presented Daily vitamins: A mild, general, and highly stereoselective Pd0-catalyzed cascade to the triene system of the hoi mone 1α,25-dihydroxyvitamin D3 and six representative analogues is reported. The intramolecular cyclization of an enol-triflate (lower fragment) followed in situ by Suzuki Miyaura coupling with an alkenyl boronic ester (upper fragment, also efficiently prepared by Pd0-catalyzed coupling) in equimolar amounts under protic conditions is ideal for the preparation of small amounts of new vitamin D analogues for biological testing (see scheme).
- Gogoi, Pranjal,Sigueeiro, Rita,Eduardo, Silvina,Mourino, Antonio
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supporting information; experimental part
p. 1432 - 1435
(2010/06/15)
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- Isolation and identification of 2α,25-dihydroxyvitamin D3, a new metabolite from Pseudonocardia autotrophica 100U-19 cells incubated with Vitamin D3
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Pseudonocardia autotrophica converted Vitamin D3 to 25-hydroxyvitamin D3 and 1α,25-dihydroxyvitamin D3. The hydroxylation of Vitamin D3 with P. autotrophica was enhanced by the addition of cyclodextrin. In this microbial hydroxylation, a new Vitamin D3 metabolite was observed in the reaction mixture of P. autotrophica and Vitamin D3, and was isolated in a pure form by several steps of chromatography. The structure of the new metabolite was determined to be 2α,25-dihydroxyvitamin D3 by UV, NMR and mass spectroscopic analyses. Biological evaluation of the new metabolite was conducted by means of several experiments.
- Takeda, Koji,Kominato, Kaichiro,Sugita, Atsuko,Iwasaki, Yukiko,Shimazaki, Mika,Shimizu, Masato
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p. 736 - 744
(2007/10/03)
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- Treatment of inflammatory bowel disease with vitamin D compounds
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A method of treating inflammatory bowel disease, particularly ulcerative colitis and Crohn's disease, is disclosed. The method involves administering a vitamin D compound in an amount effective to treat the disease. The administration of a vitamin D compound also prevents the development of or delays the onset of inflammatory bowel disease in susceptible individuals.
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- Pd-catalyzed carbocyclization-negishi cross-coupling cascade: A novel approach to 1α,25-dihydroxyvitamin D3 and analogues
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(Chemical Equation Presented) A mild palladium-catalyzed cascade has been used for the synthesis of the hormone 1α,25-dihydroxyvitamin D3 (calcitriol, 1a) and its analogues 1b and 1c. This one-pot process involves two consecutive transformations at room temperature: An initial palladium-catalyzed 6-exo-cyclocarbopalladation of vinyl triflates followed by a Negishi cross-coupling reaction with an alkenyl zinc. This novel strategy opens new possibilities for the preparation of a variety of new vitamin D analogues of therapeutic potential, particularly with modifications at the triene and/or ring-A.
- Gomez-Reino, Clara,Vitale, Cristian,Maestro, Miguel,Mourino, Antonio
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p. 5885 - 5887
(2007/10/03)
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- Selective capture of 1α,25-(OH)2-previtamin D3 utilizing polymer-supported trialkylsilyl triflate in the synthesis of 1α,25-(OH)2-vitamin D3
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Catch and release method utilizing polymer-support was investigated in the separation of 1α,25-(OH)2 pre- and provitamin D3. Polymer-supported alkyldiisopropylsilyl triflate selectively captured the previtamin D3 from a 26:74 mixture of pre- and provitamin D 3 produced by photoisomerization of provitamin D3.
- Doi, Takayuki,Yoshida, Masahito,Hijikuro, Ichiro,Takahashi, Takashi
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p. 5727 - 5729
(2007/10/03)
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- Efficient convergent synthesis of 1alpha,25-dihydroxyvitamin D3 and its analogues by Suzuki-Miyaura coupling.
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[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).
- Hanazawa, Takeshi,Koyama, Akiko,Wada, Takeshi,Morishige, Eiko,Okamoto, Sentaro,Sato, Fumie
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p. 523 - 525
(2007/10/03)
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- New Convergent Synthesis of 1α,25-Dihydroxyvitamin D3 and Its Analogues by Suzuki-Miyaura Coupling between A-Ring and C,D-Ring Parts
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A new convergent method for the synthesis of 1α,25 -dihydroxyvitamin D3 and its analogues has been developed that involves efficient preparation of the A-ring part 1a, (Z)-(3S,5R)-1-bromom-ethylene-3,5-bis(tert-butyldimethylsilyloxy) -2-methylenecyclohexane, starting from epichlorohydrin (4) and its Suzuki-Miyaura coupling reaction with the C,D-ring part 12. Thus, (R)-4 was converted to (3S,5R)-5-(tert-butyldimethylsilyloxy)-8-(trimethylsilyl)-oct-l-en-7-yn-3-ol (3a) through a ten-step reaction sequence in 49% overall yield. Compound 3a thus obtained was treated with a Ti(O-i-Pr)4/2 i-PrMgCl reagent and then with NBS to afford (Z)-(1S,2S,5R)-2-bromomethyl-3-[bromo-(trimethylsilyl)methylene] -5-(tert-butyldimethylsilyloxy)cyclohexanol (10a) in 51% yield, from which la was obtained in 87% yield by sequential treatment with TBSCl/imidazole, DBU, and Cs2CO3. The resulting A-ring intermediate 1a was reacted with alkenylboronate 12 in the presence of a PdCl2(dppf) catalyst to furnish 1α,25 -dihydroxyvitamin D3 in 82% yield after protodesilylation. Similarly, all of the other three possible stereoisomers of A-ring parts 1b, 1c, and 1d were prepared, from which 1-epi-, 3-epi-, and 1,3-di-epi-1α,25-dihydroxyvitamin D3 were synthesized by coupling with 12 in excellent yield, respectively. Starting from 1a and 1c, des-C,D-1α,25-dihydroxyvitamin D3 analogues, retiferol 13 and its 3-epi derivative, were also prepared, respectively.
- Hanazawa, Takeshi,Koyama, Akiko,Nakata, Kunio,Okamoto, Sentaro,Sato, Fumie
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p. 9767 - 9772
(2007/10/03)
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- VITAMIN D DERIVATIVES AND PROCESS FOR PRODUCING THE SAME
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A process for producing hydroxyvitamin D derivatives, characterized by converting a hydrogen atom or atoms at the 2-position, 24-position, 25-position and/or 26-position of a vitamin D into a hydroxyl group or groups in a solution containing a microorganism that belongs to the genus Nocardia, Streptomyces,Sphingomonas or Amycolata which has an ability to hydroxylate vitamin Ds or an enzyme produced by that microorganism, and optionally under the coexistence of a cyclodextrin; and novel vitamin D3 derivatives obtained by that process.
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- 26,27-homologated-20-EPI-2-alkylidene-19-nor-vitamin D compounds
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This invention provides a novel class of vitamin D related compounds, namely, the 2-alkylidene-19-nor-vitamin D derivatives, as well as a general method for their chemical synthesis. The compounds have the formula: where Y1and Y2, which may be the same or different, are each selected from the group consisting of hydrogen and a hydroxy-protecting group, R6and R8, which may be the same or different, are each selected from hydrogen, alkyl, hydroxyalkyl and fluoroalkyl, or when taken together represent the group —(CH2)x— where x is an integer from 2 to 5, and where the group R represents any of the typical side chains known for vitamin D type compounds. These 2-substituted compounds are characterized by relatively high intestinal calcium transport activity and relatively high bone calcium mobilization activity resulting in novel therapeutic agents for the treatment of diseases where bone formation is desired, particularly low bone turnover osteoporosis. These compounds also exhibit pronounced activity in arresting the proliferation of undifferentiated cells and inducing their differentiation to the monocyte thus evidencing use as anti-cancer agents and for the treatment of diseases such as psoriasis.
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Page column 16; 31-32
(2008/06/13)
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- Parallel synthesis of a vitamin D3 library in the solid-phase
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A highly efficient synthesis of the vitamin D3 system on solid support is described. Two synthetic strategies for the solid-phase synthesis of vitamin D3 were developed. One is for 11-hydroxy analogues, and the other is for most other synthetic analogues. In the latter strategy, the sulfonate-linked CD-ring 58 was initially immobilized on PS-DES resin to give solid-supported CD-ring 63 (Scheme 10). Similarly, solid-supported CD-ring 63 was prepared by attachment of the CD-ring 10 to the chlorosulfonate resin 64. The vitamin D3 system was synthesized by Horner-Wadsworth-Emmons reaction of the A-ring phosphine oxide to a solid-supported CD-ring, followed by simultaneous introduction of the side chain and cleavage from resin with a Cu1-catalyzed Grignard reagent. Parallel synthesis of the vitamin D3 analogues was accomplished by a split and pool methodology utilizing radio frequency encoded combinatorial chemistry, and a manual parallel synthesizer for side chain diversification and deprotection. Additionally, we demonstrated the synthesis of various A-rings in a similar protocol for efficient preparation of building blocks.
- Hijikuro,Doi,Takahashi
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p. 3716 - 3722
(2007/10/03)
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- Efficient synthesis and biological evaluation of all A-ring diastereomers of 1α,25-dihydroxyvitamin D3 and its 20-epimer
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An improved synthesis of the diastereomers of 1α,25-dihydroxyvitamin D3 (1) was accomplished utilizing our practical route to the A-ring synthon. We applied this procedure to synthesize for the first time all possible A- ring diastereomers of 20-epi-1α,25-dihydroxyvitamin D3 (2). Ten-step conversion of 1-(4-methoxyphenoxy)but-3-ene (6), including enantiomeric introduction of the C-3 hydroxyl group to the olefin by the Sharpless asymmetric dihydroxylation, provided all four possible stereoisomers of A- ring enynes (3), i.e., (3R,5R)-, (3R,5S)-, (3S,5R)- and (3S,5S)-bis[(tert- butyldimethylsilyl)oxy]oct-1-en-7-yne, in good overall yield. Palladium- catalyzed cross-coupling of the A-ring synthon with the 20-epi CD-ring portion (5), (E)-(20S)-de-A,B-8-(bromomethylene)cholestan-25-ol, followed by deprotection, afforded the requisite diastereomers of 20-epi-1α,25- dihydroxyvitamin D3 (2). The biological profiles of the synthesized stereoisomers were assessed in terms of affinities for vitamin D receptor (VDR) and vitamin D binding protein (DBP), HL-60 cell differentiation- inducing activity and in vivo calcium-regulating potency in comparison with the natural hormone. (C) 2000 Elsevier Science Ltd.
- Fujishima, Toshie,Konno, Katsuhiro,Nakagawa, Kimie,Kurobe, Mayuko,Okano, Toshio,Takayama, Hiroaki
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p. 123 - 134
(2007/10/03)
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- Vitamin D3 derivatives and production process thereof
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A vitamin D3 derivative represented by the following formula: STR1 wherein, R is, independently, a hydrogen atom, tri(C1 to C7 hydrocarbon)silyl group, C2 to C8 acyl group, or group forming an acetal bond together with an oxygen atom of a hydroxyl group, A is STR2 where, R1 is a methyl group or methylene group, and when R1 is a methylene group, the bond between the R1 and the 3-position of the lactone ring is a double bond, R2 is a hydrogen atom or C1 to C3 alkyl group, R3 is a hydrogen atom, or R2 and R3 together indicate a substitutable single methylene group.
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- Antiproliferative vitamin D3 hybrids
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Vitamin D3 analogues of formula STR1 wherein R represents a 1-hydroxyalkyl group or 1-fluoroalkyl group in a trans- configuration with a 3-hydroxyl group on the A ring and R2 represents the substituents completing a vitamin D3 analogue. These novel compounds are potent anti-proliferative substances with activities comparable to that of calcitriol but with vitamin D3 receptor binding ratings of less than 10-3 compared to that of calcitriol.
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- An effective procedure for the synthesis of 1α,25-dihydroxy-cholecalciferol (calcitriol) starting with 1α,3β, 25-trihydroxy-cholesta-5,7-diene (pro-calcitriol)
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In order to develop an effective synthesis of the important vitamin D metabolite 1α,25-(OH)2-cholecalciferol (calcitriol) 5a starting with pro-calcitriol 1a the influence of reaction temperature and degree of turnover of 1a to the compositions of the photoproducts at irradiation in a 500 ml photoreactor were investigated. The combination of the highly photostable filter solution consisting of 2,7-dimethyl-3,6-diaza-cyclohepta-1,6-diene-tetrafluoroborate and biphenyl in ethanol realizes the double wavelength irradiation in the range of 290 to 300 nm and>330 nm resulting in a highly amount of the desired pre-calcitriol 2a. The reversible photoisomers of pre-calcitriol 2a 1α,25-(OH)2-lumisterol3 4a and 1α,25-(OH)2-tachysterol3 3a were isolated from an irradiation mixture in pure form by means of an appropriate combination of flash-chromatography, MPLC and preparative HPLC, respectively. The isomers 2a, 3a and 4a were characterized chromatographically and spectroscopically. Photoisomerization of 1a at -45°C using the filter solution mentioned above and recycling all reversible photoisomers resulted in highly pure 5a after thermally induced isomerization of 2a isolated from the irradiation mixture by means of flash-chromatography on Ag+-impregnated silica with a yield of 68%. Johann Ambrosius Barth 1996.
- Reichenbaecher,Gliesing,Lange,Gonschior,Schoenecker
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p. 634 - 641
(2007/10/03)
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- Convergent synthesis of vitamin D3 metabolites. Control of the stereoselectivity in samarium-induced cyclopropanations of cyclopentenes
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The 25-hydroxy and 1α,25-dihydroxy vitamin D3 metabolites are obtained by solvolytic rearrangements of the 1-desoxy and 1α-hydroxy cyclopropyl vinylogous alcohols 31 and 29, respectively, with simultaneous formation of the vitamin D structural triene and the 3-hydroxy function. Two complementary methods have been employed to direct the stereoselectivity of the samarium induced olefin cyclopropanations which ultimately lead to key chiral ring A precursors. One protocol uses the two stereogenic centers of the (R,R)-2,3-butanediol ketal moiety of 8, while the other method uses the allylic hydroxyl group of (R)-16.
- Kabat,Kiegiel,Cohen,Toth,Wovkulich,Uskokovic
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p. 118 - 124
(2007/10/03)
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- Nickel-Mediated Conjugate Addition. Elaboration of Calcitriol from Ergocalciferol
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A convenient method for introduction the side chain of the hormone calcitriol (3) was achieved by coupling the nickel(0) complex derived from ethyl acrylate with the C-22 iodides 15, 16, 27, and 30 to give the corresponding esters 18, 21, 28, and 23 in yields of 73-82percent.Iodide 15 was also coupled with the Ni(0) complex derived from methyl vinyl ketone.The C-22 iodides 15 and 27 were obtained from ergocalciferol (6) and the 1(S),3(R)-bis-(5E,7E)-ergocalciferol derivative 24, respectively, by selective ozonolysis of their SO2 adducts, followed by in situ reduction of the ozonides with NaBH4 and iodination of the derived alcohols 14 and 26 with I2/PPh3/imidazole.The triene iodide 16 was prepared by extrusion of SO2 from 15, while 30 was obtained from the corresponding alcohol 29.Extrusion of SO2 from 21 and 28 gave the 5(E),7(E)-trienes 18 and 23, respectively.The latter was also made from the former by C-1 hydroxylation with selenium dioxide followed by silylation with tert-butyldimethylsilyl chloride and chromatographic separation.Completion of the synthesis of 3 was accomplished by treating 23 with methylmagnesium bromide to give 31, followed by desilylation with n-Bu4NF and triplet-sensitized photoisomerization.Alternatively, 31 was photoisomerized to 33, desilylation of which gave 3.Alcohol 33 was also prepared by the reaction of the 5Z,7E-triene ester 34, which was obtained by the photoisomerization of 23, with methylmagnesium bromide.
- Manchand, Percy S.,Yinnikouros, George P.,Belica, Peter S.,Madan, Pradeep
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p. 6574 - 6581
(2007/10/03)
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- Palladium catalyzed akylative cyclization useful in syntheses of Vitamin D and analogues
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An alkylative cycloaddition method is provided that is particularly useful for the synthesis of many of the Vitamin D analogues with differing side chains. Thus, a preferred synthesis is of Vitamin D analogues having a side chain R1 where a first precursor having the structure STR1 with X being a halide or a pseudo halide, and a second precursor are provided, the second precursor being a 1,7 enyne. These precursors are reacted in the presence of a palladium catalyst to form compounds having the structure STR2 where R2 is hydrogen, hydroxyl, lower alkoxy, fluorine, or a protecting group, and R3 is hydrogen, hydroxyl, lower alkoxy, fluorine, or a protecting group.
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- Vitamin D compound, method of preparing this compound and intermediate thereof
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The invention relates to a new vitamin D compound, substituted in the 18-position with an alkyl group, a hydroxy group, an alkoxy group, an alkenyl group, an alkynyl group, a fluorinated alkyl group or a fluorinated alkenyl group. The invention also relates to a method of preparing said vitamin D compound and to a lactone and a hydrindane intermediate. The vitamin D compound is of the general formula STR1
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- Convenient synthesis of 1α,25-dihydroxyvitamin D3 from vitamin D2
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(1S,6R)-1-Acetoxy-6-(1,3-benzodithiol-2-yloxy)-3,5-cyclovitamin D2 (7) was synthesized from vitamin D2 by five steps. The new compound 7 was ozonized regioselectively and subsequently reduced, leading to (7E)-(1S,3S,5R,6R)-1-acetoxy-6-(1,3-benzodithiol-2-yloxy)-3,5-cyclo-9, 10-seco-23,24-dinor-7,10(19)-choladien-22-ol (11). The alcohol 11 obtained as a key intermediate was tosylated, iodinated, and coupled with 2-methyl-4-phenylsulfonyl-2-(tetrahydropyranyloxy)butane to give (1S,6R)-1-hydroxy-6-(1,3-benzodithiol-2-yloxy)-23-phenylsulfonyl-25-te trahydropyranyloxy-3,5-cyclovitamin D3 (16). By desulfonylation and hydrolysis of the compound 16 1α,25-dihydroxyvitamin D3 was obtained selectively.
- Takahashi,Sakakibara
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p. 2494 - 2499
(2007/10/02)
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- 7,8-Cis geometric isomers of the steroid hormone 1α,25-dihydroxyvitamin D3
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The syntheses of the previously unknown, sterically hindered geometric isomers 3 and 4 of the steroid hormone 1α,25-dihydroxyvitamin D3(1,1,25) have been achieved for the first time. The stereoselective synthesis of the vinylallene precursor 23a was achieved by the Inanaga method, Pd(0)-Sm(II)-iPrOH reduction of propargyl benzoate 33. The latter observation reveals that the Inanaga propargyl ester to allene transformation is in fact stereoselective (～10:1), involving a formal anti-SN2′ displacement of benzoate by hydrogen. Highly stereoselective (50:1, 85% yield) (1,5)-hydrogen shift of vinylallene 23a to the sterically hindered 7,8-cis isomer of the hormone 1, namely, 3, was achieved by the Shibasaki method using (naphthalene)tricarbonylchromium (22, (np)(CO)3Cr). By examining this chromium-(0)-mediated isomerization on all four diastereomeric vinylallene analogue systems 6a,b and 7a,b, all of which resulted highly selectively (50:1) in hindered 7,8-cis geometric isomers, new stereomechanistic information concerning the Shibasaki type 1,5-shift has also emerged. By cheleotropic addition-extrusion of sulfur dioxide on 3, there was obtained the final unknown geometric isomer of 1, 5,6-trans-7,8-cis-1,25 4; this result parallels the known transformation of 1 to 2. Although the vinylallene 23a can be thermally rearranged via a [1,5]-sigmatropic hydrogen shift to the natural hormone 1, the yield and selectivity are modest. By contrast, one-way triplet photosensitized isomerism of the now readily available 7,8-cis-isomer 3 results primarily in the natural hormone 1 in good yield and selectivity. Taken collectively, these observations reveal that the synthesis of all four geometric isomers 1-4 can be achieved from a single precursor, the vinylallene 23a. Comparative biochemical evaluation, in vitro, of the four geometric isomers in terms of their ability to bind to the chick intestinal receptor reveals that 7,8-cis isomerism (3 and 4) significantly suppresses their ability to bind receptor (2% each versus 100% for the hormone 1,25).
- VanAlstyne, Ellen M.,Norman, Anthony W.,Okamura, William H.
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p. 6207 - 6216
(2007/10/02)
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- Palladium catalyzed alkylative cyclization useful in synthesis of vitamin D and analogues
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An alkylative cycloaddition method is provided that is particularly useful for the synthesis of many of the Vitamin D analogues with differing side chains. Thus, a preferred synthesis is of Vitamin D analogues having a side chain R1 where a substantially geometrically pure first precursor having the structure STR1 and a second precursor are provided, the second precursor being a 1,7 enyne. These precursors are reacted in the presence of a palladium catalyst to form compounds having the structure STR2 where R2 hydrogen, hydroxyl, lower alkoxy, fluorine, or a protecting group, and R3 is hydrogen, hydroxyl, lower alkoxy, fluorine, or a protecting group.
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- Ultrasonically Induced Conjugate Addition of Iodides to Electron-Deficient Olefins and Its Application to the Synthesis of Side-Chain Analogs of the Hormone 1α,25-Dihydroxyvitamin D3
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A versatile method for the rapid construction of fragments related to the upper part of vitamin D3 from the Lythgoe-Inhoffen diol is described.The key feature of the strategy is a new zinc-copper-induced conjugate addition of iodo triflate 10a to electron-deficient olefins under sonochemical aqueous conditions.These fragments are rapidly and efficiently transformed via the dienyne convergent approach to several derivatives of the hormone 1α,25-(OH)2-D3 modified at C-25.
- Sestelo, Jose Perez,Mascarenas, Jose L.,Castedo, Luis,Murino, Antonio
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p. 118 - 123
(2007/10/02)
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- Studies on the A-Ring Diastereomers of 1α,25-Dihydroxyvitamin D3
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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.
- Muralidharan, K. Raman,Lera, Angel R. de,Isaeff, Shawn D.,Norman, Anthony W.,Okamura, William H.
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p. 1895 - 1899
(2007/10/02)
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- Process for precursors to calcitriol and related compounds
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The process of the invention comprises reacting a C-22-halo-23,24-bisnorsteroid or C-22-halo-23,24-bisnor-9,10-secosteroid with a nickel complex of an electron withdrawing alkene of the formula STR1 wherein R1 is hydrogen, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyl or unsubstituted or substituted lower alkyl, and R2 is hydroxyl, lower alkoxy, or unsubstituted or substituted lower alkyl, to yield a C-25 or C-26 precursor of the formula STR2 which is appropriately functionalized for conversion into the corresponding steroid or secosteroid by treatment as hereinafter described.
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- Steroid compounds
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Steroid compounds of the following general formulas (I), (II) and (III) are provided: STR1 In the above formulas, R1 and R2 each is a hydrogen atom or a hydroxyl-protecting group, R is a group of the formula --CH2 --X (in which X is a substituent such as a hydroxyl group), a carboxyl group or a protected carboxyl group, A1 is an aryl group, a lower alkyl group or an aralkyl group, and Z1, Z2, Z3 and Z4 each is a hydrogen atom, a hydroxyl group or a protected hydroxyl group. The above steroid compounds are useful as intermediates for the synthesis of vitamin D3 derivatives having a hydroxyl group at the 1α-position.
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- New strategies for the synthesis of vitamin D metabolites via Pd-catalyzed reactions
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The invention of new palladium-catalyzed reactions offers new insights into synthetic strategies directed toward the vitamin D system. The palladium-catalyzed cycloisomerization of 1,6- and 1,7-enynes to dialkylidenecycloalkanes permits a lynchpin approach to the A ring of vitamin Ds. Using the thioacetal of formaldehyde, the proper subunits containing the olefin and the acetylene were attached. Pd(2+) effected cycloisomerization to an A ring subunit. A more effective strategy evolved from the evolution of a Pd-catalyzed alkylative cyclization of enynes. Whereas prior work established the feasibility of this process for 1,6-enynes, model studies reported herein demonstrate the feasibility of its extension to 1,7-enynes. This reaction permits the creation of a new concept for vitamin D synthesis wherein A ring formation is concomitant with its attachment to an appropriate CD fragment. An asymmetric synthesis of the requistite 1,7-enyne required six steps. Bromomethylenation of Grundmann's ketone and its side chain hydroxylated derivative proceeded with excellent geometrical selectivity (>30:1) using the Wittig reaction. A Pd catalyst generated from (dba)3Pd2·CHCl3 and triphenylphosphine stitched together these two units in a single step resulting in syntheses of alphacalcidiol and calcitriol.
- Trost, Barry M.,Dumas, Jacques,Villa, Marco
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p. 9836 - 9845
(2007/10/02)
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- Palladium-catalysed coupling of vinyl triflates with enynes and its application to the synthesis of 1α,25-dihydroxyvitamin D3
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We describe a general approach, based on the palladium-catalysed coupling of enynes with vinyl triflates, for the construction of dienynes related to vitamin D metabolites and analogues. As an application of this method, an efficient convergent synthesis of 1α,25-dihydroxyvitamin D3 starting from the Inhoffen-Lythgoe diol (6a) and natural carvones has been carried out (11 steps, 28% overall yield from 6a). This strategy allows labelling of the side chain in the final steps of the synthesis.
- Mascarenas,Sarandeses,Castedo,Mourino
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p. 3485 - 3498
(2007/10/02)
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- A new synthetic route to 1,25-dihydroxy-vitamin D3
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A synthesis of 1,25-dihydroxy-vitamin D3 using a new acetylenic Ring-A precursor is described. Ring-A synthons 4a or 4b can be prepared in homochiral form by a diastereoselective diazoester cyclization.
- Wilson, Stephen R.,Venkatesan,Augelli-Szafran,Yasmin
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p. 2339 - 2342
(2007/10/02)
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- Control of stereoselectivity in samarium metal induced cyclopropanations. Synthesis of 1,25-Dihydroxycholecalciferol
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1,25-Dihydroxycholecalciferol (23) was synthesized from A-ring precursor 18 and Windaus-Grundmann ketone 19 via cyclovitamin D 21. Key reactions include highly stereoselective (5 to 6) and stereospecific (13 to 14) cyclopropanations.
- Kabat,Kiegiel,Cohen,Toth,Wovkulich,Uskokovic
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p. 2343 - 2346
(2007/10/02)
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- Stereocontrolled Total Synthesis of 1α,25-Dihydroxycholecalciferol and 1α,25-Dihydroxyergocalciferol
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1α,25-dihydroxycholecalciferol (4) and 1α,25-dihydroxyergocalciferol (7), the hormonally active forms of vitamin D3 (1) and vitamin D2 (5), were synthesized by a Horner-Wittig reaction of the phosphine oxide 11 with the ketones 10 and 12, respectively.The synthon 11 was obtained by a sequence that involves the stereospecific opening of epoxide 15, with sodium acetate in acetic acid, followed by oxidative degradation of the isopropenyl side chain and dehydration of the intermediate 22.Photoisomerisation of the resulting 23 gave 24, which was finally converted to 11.The hydroxylated ketone 10 was obtained from the known intermediate 28.The introduction of the 25-hydroxy side chain was achieved by reaction of the lithium derivative of 30 with the tosylate 29 to give 31, which was catalytically hydrogenated to 32 and then converted to 10.The ketone 12 was prepared by a stereocontrolled route that involves as the key step, the dipolar cycloaddition of nitrone 35 with methyl 3,3-dimethylacrylate (36) to give a 1:1 mixture of isoxazolidines 37 and 38.Stereochemical control was achieved by taking advantage of the thermal reversibility of the cycloaddition, which allows the reequilibration of undesired 37.Isoxazolidine 38 was readily transformed to 43 by reduction, followed by elimination of the nitrogen function, and finally oxidation to 12.
- Baggiolini, Enrico G.,Iacobelli, Jerome A.,Hennessy, Bernard M.,Batcho, Andrew D.,Sereno, John F.,Uskokovic, Milan R.
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p. 3098 - 3108
(2007/10/02)
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- AN EFFICIENT SYNTHESIS OF 1α,25-DIHYDROXY VITAMIN D3
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An efficient synthesis of the title compound is reported based on C-1 functionalization of the triazoline Diels-Alder adduct of 25-OH previtamin D3 (2c).
- Vanmaele, L.,Clerq, P. J. de,Vandewalle, M.
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p. 141 - 144
(2007/10/02)
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- Method of treating leukemia or leukemoid diseases
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A method of leukemia or leukemoid disease treatment by administration of a vitamin D derivative with a hydroxyl group at 1α-position is disclosed. It is believed that the vitamin D derivative with a hydroxyl group at 1α-position is capable of treating cancer through redifferentiation of cancer cells and that this capability is inherent in vitamin D derivatives with a hydroxyl group at 1α-position.
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- Process for preparing 1α-hydroxylated compounds
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An improved method for the preparation of 1α-hydroxylated vitamin D compounds involving directly introducing an oxygen function at carbon 1 of the vitamin D molecule or precursors or derivatives thereof, wherein the 1α-hydroxycyclovitamin D intermediate is solvolyzed directly, without first converting the 1-hydroxy group to a 1-O-acyl function as a protective measure.
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- Fluorovitamin D compounds and processes for their preparation
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Fluorine-substituted vitamin D compounds, methods for preparation of such compounds and fluorinated intermediate compounds used in such methods are disclosed. The fluorine-substituted vitamin D compounds are characterized by vitamin D-like activity in stimulating intestinal calcium transport and bone mobilization and in promoting the calcification of rachitic bone.
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- Process for preparing 1α-hydroxylated compounds
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A method for directly introducing an oxygen function at carbon 1 of the vitamin D molecule or precursors or derivatives thereof which comprises subjecting such molecules to allylic oxidation utilizing selenium dioxide as the oxidizing agent.
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- Process for preparing 1α-hydroxylated compounds
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A method for directly introducing an oxygen function at carbon 1 of the vitamin D molecule or precursors of derivatives thereof which comprises subjecting such molecules to allylic oxidation utilizing selenium dioxide as the oxidizing agent.
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