- Furan approach to vitamin D analogues. Synthesis of the A-ring of calcitriol and 1α-hydroxy-3-deoxyvitamin D3
-
The A-rings of calcitriol (1α,25-dihydroxyvitamin D3) and 1α-hydroxy-3-deoxyvitamin D3 were synthesized using the furan approach. The critical steps in the synthesis of the A-ring of calcitriol involved an asymmetric carbonyl-ene reaction of 3-methylene-2,3-dihydrofuran with 3-(tert-butyldimethylsiloxy)propanal, a diastereoselective Friedel-Crafts hydroxyalkylation, an oxidation of the 2,3-disubstituted furan to give a γ-hydroxybutenolide, and a Peterson olefination. The A-ring (Z)-dienol of calcitriol was synthesized in 12 steps from 3-(tert-butyldimethylsiloxy)propanal in 17% yield.
- Miles, William H.,Connell, Katelyn B.,Ulas, Goezde,Tuson, Hannah H.,Dethoff, Elizabeth A.,Mehta, Varun,Thrall, April J.
-
experimental part
p. 6820 - 6829
(2010/12/18)
-
- Efficient synthesis of the A-ring phosphine oxide building block useful for 1α,25-dihydroxy vitamin D3 and analogues
-
The 1α-hydroxy A-ring phosphine oxide 1, a useful building block for vitamin D analogues, was synthesized from (S)-carvone in nine synthetic operations and a single chromatographic purification in 25% overall yield. The synthesis features two novel efficient synthetic transformations: the Criegee rearrangement of α-methoxy hydroperoxyacetate 10 in methanol to obtain directly the desired secondary 3β-alcohol 11 and the highly chemo- and stereoselective isomerization of dieneoxide ester (E)-7 to the 1α-allylic alcohol with an exocyclic double bond (E)-8. Further insight into the selectivity control of the latter rearrangement was obtained from the reactions of (Z)epimeric substrates. The new synthetic approach leading to the 1α-hydroxy epimers complements our previously reported synthesis of the corresponding 1β-epimers, thus producing all stereoisomers of these versatile building blocks efficiently from carvone.
- Daniewski, Andrzej R.,Garofalo, Lisa M.,Hutchings, Stanley D.,Kabat, Marek M.,Liu, Wen,Okabe, Masami,Radinov, Roumen,Yiannikouros, George P.
-
p. 1580 - 1587
(2007/10/03)
-
- Parallel synthesis of a vitamin D3 library in the solid-phase
-
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
-
p. 3716 - 3722
(2007/10/03)
-
- Synthesis and evaluation of A-ring diastereomers of 1α,25-dihydroxy-22-oxavitamin D3 (OCT)
-
A-ring diastereomers of 1α,25-dihydroxy-22-oxavitamin D3 (OCT) (2), 3-epi-1α,25-dihydroxy-22-oxavitamin D3 (3-epiOCT) (3) and 1,3-diepi-1α,25-dihydroxy-22-oxavitamin D3 (1,3-diepiOCT) (4) were synthesized by the convergent method. In vitro binding affinity for rat vitamin D binding protein and calf-thymus vitamin D receptor, differentiation-inducing activity on HL-60 cells, and transcriptional activity of 3-epiOCT (3) and 1,3-diepiOCT (4) were evaluated in comparison with OCT (2), 1-epi-1α,25-dihydroxy-22-oxavitamin D3 (1-epiOCT) (5) and 1α,25-dihydroxyvitamin D3 (1).
- Hatakeyama, Susumi,Okano, Toshio,Maeyama, Junji,Esumi, Tomoyuki,Hiyamizu, Hiroko,Iwabuchi, Yoshiharu,Nakagawa, Kimie,Ozono, Keiichi,Kawase, Akira,Kubodera, Noboru
-
p. 403 - 415
(2007/10/03)
-
- Efficient and versatile synthesis of A-ring precursors of 1α,25-dihydroxyvitamin D3 and analogues. Application to the synthesis of Lythgoe-Roche phosphine oxide
-
An efficient, versatile synthesis of Lythgoe-Phosphine Oxide has been developed starting from l-carvene. The key steps are rupture of protected epoxide 7 to give dicarbonyl compound 8, preparation of vinylic triflate 2, and palladium-catalysed cyclization-carbonylation of vinylic triflate 2.
- Mourino, Antonio,Torneiro, Mercedes,Vitale, Cristian,Fernandez, Sara,Perez-Sestelo, Jose,Anne, Sofia,Gregorio, Carlos
-
p. 4713 - 4716
(2007/10/03)
-
- Synthesis of Retiferol RAD1 and RAD2, the Lead Representatives of a New Class of des-CD Analogs of Cholecalciferol
-
The design and total convergent synthesis are described for the leading representatives of the new class of analogs of cholecalciferol with the CD-ring system replaced with a two-carbon aliphatic spacer.The leading representatives of C21 retiferols (RAD1
- Kutner, A.,Zhao, H.,Fitak, H.,Wilson, S. R.
-
-
- An efficient route to a key A-ring synthon for 1α,25-dihydroxyvitamin D3 and its analogs
-
An efficient and highly stereoselective route to the Roche's A-ring synthon of 1α,25-dihydroxyvitamin D3 from R-(-)-epichlorohydrin has been developed utilizing double propargylation of R-(-)-epichlorohydrin and palladium(0) catalyzed intramole
- Hatakeyama, Susumi,Irie, Hiroshi,Shintani, Takashi,Noguchi, Yohko,Yamada, Hidetoshi,Nishizawa, Mugio
-
p. 13369 - 13376
(2007/10/02)
-
- Asymmetric Synthesis of a Key 1α,25-Dihydroxy-Vitamin D3 Ring A Synthon
-
An efficient and highly stereoselective synthesis of the A-ring synthon 4 of 1,25(OH)2-vitamin D3 (1) is deascribed.The aldehyde 12, which was used for an intramolecular ene reaction to form the main framework 18, was obtained by two different asymmetric
- Kabat, Marek M.,Lange, Meinolf,Wovkulich, Peter M.,Uskokovic, Milan R.
-
p. 7701 - 7704
(2007/10/02)
-
- Chemical conversion of vitamin D3 to its 1,25-dihydroxy metabolite
-
Vitamin D3 (6) has been converted to the 1,25-dihydroxy vitamin D3 metabolite (1) and the 1α-fluoro derivative 2 via a new process. The strategy involved the cleavage of the ring A portion from the CD portion in vitamin D3
- Kiegiel,Wovkulich,Uskokovic
-
p. 6057 - 6060
(2007/10/02)
-
- Efficient Enantiospecific Synthesis of Key A-Ring Synthons for the Preparation of 1α,25-Dihydroxyvitamin D3 Using a Chromium((II)-Mediated Reaction
-
Key A-ring synthons for the synthesis of 1α,25-dihydroxyvitamin D3 have been prepared efficiently from (R)-(-)-carvone by use of diastereoselective chromium(II)-mediated addition of an allylic halide to an aldehyde as a key step.
- Hatakeyama, Susumi,Numata, Hirotoshi,Osanai, Ken,Takano, Seiichi
-
p. 3515 - 3517
(2007/10/02)
-
- Stereocontrolled Total Synthesis of 1α,25-Dihydroxycholecalciferol and 1α,25-Dihydroxyergocalciferol
-
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.
-
p. 3098 - 3108
(2007/10/02)
-