81506-25-4Relevant articles and documents
Efficient synthesis of the A-ring phosphine oxide building block useful for 1α,25-dihydroxy vitamin D3 and analogues
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)
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.
Parallel synthesis of a vitamin D3 library in the solid-phase
Hijikuro,Doi,Takahashi
, p. 3716 - 3722 (2007/10/03)
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.
Stereocontrolled Total Synthesis of 1α,25-Dihydroxycholecalciferol and 1α,25-Dihydroxyergocalciferol
Baggiolini, Enrico G.,Iacobelli, Jerome A.,Hennessy, Bernard M.,Batcho, Andrew D.,Sereno, John F.,Uskokovic, Milan R.
, p. 3098 - 3108 (2007/10/02)
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.
