- 13-Methyl-substituted des-C,D analogs of (20S)-1α,25-dihydroxy-2-methylene-19-norvitamin D3 (2MD): Synthesis and biological evaluation
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Analogs of (20S)-1α,25-dihydroxy-2-methylene-19-norvitamin D3 (2, 2MD), substituted at C-13 but lacking both C and D rings, were prepared in convergent syntheses, starting with the chiral ester 14 and the phosphine oxide 29. Two of the synthesized vitamins (11 and 32) were analogs in which the 13-methyl group constituted a substituent of an unsaturated fragment, that is, C(13)-C(17) double bond, whereas in the two other cases (12 and 13), the methyl group belonged to a ternary carbon stereogenic center. The aim of these studies was to further explore extensive modifications in the 'upper' part of the vitamin D skeleton in the hope of finding biologically active analogs of potential therapeutic value. The commercial (R)-(-)-methyl-3-hydroxy-2-methylpropionate (14) was converted in six steps to alcohol 18, the vitamin D side chain fragment. Its subsequent three-step transformation led to aldehyde 20 which was subjected to the Still-Gennari HWE reaction with anion derived from ester 21. The obtained α,β-unsaturated esters 22 and 23 served as convenient starting compounds to the syntheses of the corresponding chiral acyclic aldehydes, β,γ-unsaturated (28) and saturated (39 and 40), required for the final Wittig-Horner coupling with the anion of the phosphine oxide 29. After hydroxyl deprotection, the synthesized vitamin D analogs 11-13 and 32 were purified and biologically tested. Only the (13R,20S)-analog 12 retained substantial, although 30 times lower than 1α,25-(OH)2D3, binding ability to the full-length rat recombinant vitamin D receptor (VDR). This analog was also very effective in differentiation of HL-60 cells, and it exerted significant transcriptional activity (2 times and 15 times less potent, respectively, as compared to the native hormone). The in vivo tests showed that all synthesized vitamin D analogs were devoid of calcemic activity.
- Plonska-Ocypa, Katarzyna,Sicinski, Rafal R.,Plum, Lori A.,Grzywacz, Pawel,Frelek, Jadwiga,Clagett-Dame, Margaret,DeLuca, Hector F.
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experimental part
p. 1747 - 1763
(2009/08/15)
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- DES-C,D ANALOGS OF 1ALPHA,25-DIHYDROXY-19-NORVITAMIN D3
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Des-C,D 2-methylene-19-norvitamin D3 analogs are provided including compounds of formula 1, in which R1 is a straight or branched chain alkyl or alkylene group having from 8 to 27 carbons and bearing an OY3 group; and Y1, Y2 and Y3 are independently selected from H or hydroxy-protecting groups. Such compounds may be used in preparing pharmaceutical compositions and are useful in treating a variety of biological conditions. Formula(I)
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Page/Page column 19-20
(2008/06/13)
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- The first stereoselective total synthesis of lankanolide. Part 2
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The seco-acid derivative designed by conformation calculation and lactonization experiment of model seco-acids was synthesized, and subjected to macrolactonization to afford the lactone derivative. The lankanolide was synthesized via several steps after the lactonization, and the synthetic lankanolide was confirmed to have the same physical data (NMR, mass, IR and αD) as the lankanolide prepared from lankamycin according to the reported method.
- Hamada, Tatsuo,Kobayashi, Yukinari
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p. 4347 - 4350
(2007/10/03)
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- Applications of crotyldiisopinocampheylboranes in synthesis: A formal total synthesis of (+)-calyculin A
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The formal total synthesis of the marine metabolite (+)-calyculin A is reported. The key steps involve (i) the use of Brown allylboration chemistry to control the relative and absolute stereochemistry of homoallylic alcohol arrays, thus setting eight of the desired stereocenters; (ii) Stille coupling methodology in the construction of the cyano tetraene unit of the natural product; and (iii) a modified Cornforth-Meyers approach to the synthesis of the oxazole fragment.
- Anderson, Oren P.,Barrett, Anthony G.M.,Edmunds, Jeremy J.,Hachiya, Shun-Ichiro,Hendrix, James A.,Horita, Kiyoshi,Malecha, James W.,Parkinson, Christopher J.,Vansickle, Andrew
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p. 1562 - 1592
(2007/10/03)
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- Amphidinolides: Unique macrolides from marine dinoflagellates
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A series of macrolides, named amphidinolides, have been isolated from the laboratory-cultured marine dinoflagellates Amphidinium sp., which were symbionts of the Okinawan marine flatworm Amphiscolops sp. These macrolides possess unique chemical structures as well as cytotoxic activities. Here we describe our recent results on the isolation, structure elucidation, and biosynthesis of these unique macrolides.
- Ishibashi, Masami,Kobayashi, Jun'ichi
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p. 543 - 572
(2007/10/03)
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- The first total synthesis of the antitumor macrolide rhizoxin: Synthesis of the key building blocks
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The construction in optically pure form of the key building blocks, arising from our retro synthetic analysis of the antitumor macrolide rhizoxin is described.
- Nakada, Masahisa,Kobayashi, Susumu,Iwasaki, Shigeo,Ohno, Masaji
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p. 1035 - 1038
(2007/10/02)
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- Stereocontrolled Synthesis of Calyculin A: Construction of the C(15)-C(25) Spiroketal Unit
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Two concise enantioselective syntheses of the C(15)-C(25) spiroketal unit of calyculin A, using derivatives of allyldiisopinocampheylborane efficiently to control 1,2- and 1,3-diol stereochemistries, are reported.
- Barrett, Anthony G. M.,Edmunds, Jeremy J.,Horita, Kiyoshi,Parkinson, Christopher J.
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p. 1236 - 1238
(2007/10/02)
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- Synthesis of an avermectin-nemadectin hybrid
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The Wittig condensation of (2R,3R,4E)-2,6-dimethyl-3-trimethylsilyloxy-4- heptenyltriphenylphosphorylidene with aldehyde 1 produced the desired cis olefin 11 in 45% yield. Treatment of this intermediate with pyridinium tosylate in methanol effected spiroketalization and desilylation with hydrogen fluoride-pyridine in THF afforded the avermectin-nemadectin hybrid 2.
- Shih,Holmes,Mrozik,Fisher
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p. 3663 - 3666
(2007/10/02)
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- The chemistry of cyclic vinyl ethers. 6. Total synthesis of polyether ionophore antibiotics of the calcimycin (A-23187) class
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An extremely convergent (longest linear sequence, 16 steps), fully stereoselective, and potentially general synthesis of the antibiotic ionophores of the Calcimycin (A-23187) class was devised. The key steps involve a coupling reaction between the chiral nonracemic subunits dihydropyran 41 (as the α-lithio anion) and bromide 49. Subsequent acid-promoted cyclization directly produces the spirocyclic ring system found in the ionophore X-14885A (3). Alternatively, cyclopropanation of substituted vinyl ether 55 followed by acid treatment afforded the spiroketal 58 that was subsequently converted into the polyether ionophore Calcimycin (1) and also Cezomycin (2).
- Boeckman Jr., Robert K.,Charette, André B.,Asberom, Theodros,Johnston, Brian H.
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p. 5337 - 5353
(2007/10/02)
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