(3R,4R,5S)-3,5-bis[(tert-butyldimethylsilyl)oxy]-4-[3-{(tert-butyldimethylsilyl)oxy}propyl]oct-1-en-7-yne | 288380-89-2

• 分子结构分类: 有机化合物 - 有机金属化合物 - 有机类金属化合物
• 英文名称: (3R,4R,5S)-3,5-bis[(tert-butyldimethylsilyl)oxy]-4-[3-{(tert-butyldimethylsilyl)oxy}propyl]oct-1-en-7-yne
• 英文别名: (3R,4S,5R)-3,5-bis(tert-butyldimethylsilanyloxy)-4-[3-(tert-butyldimethylsilanyloxy)propyl]oct-1-en-7-yne；tert-butyl-[(4S,5R)-5-[tert-butyl(dimethyl)silyl]oxy-4-[(1R)-1-[tert-butyl(dimethyl)silyl]oxyprop-2-enyl]oct-7-ynoxy]-dimethylsilane
• CAS: 288380-89-2
• 化学式: C₂₉H₆₀O₃Si₃
• 分子量: 541.05
• InChiKey: UANSYTKAJWYCJS-TWJOJJKGSA-N

物化性质

• 沸点：
  490.2±45.0 °C(Predicted)
• 密度：
  0.881±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  9.39
• 重原子数：
  35
• 可旋转键数：
  16
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.86
• 拓扑面积：
  27.7
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (3R,4R,5S)-3,5-bis[(tert-butyldimethylsilyl)oxy]-4-[3-{(tert-butyldimethylsilyl)oxy}propyl]oct-1-en-7-yne 在 四(三苯基膦)钯 氢氟酸 、 三乙胺 作用下， 以 甲苯 、 乙腈 为溶剂， 反应 4.0h， 生成 2α-(3-hydroxypropyl)-20(R)-(tetrahydro-3-methylene-2-furanone-4(R)-ethyl-5(S)-yl)methyl-9,10-secopregna-5(Z),7(E),10(19)-triene-1α,3β-diol
  参考文献：
  名称：

  基于25-脱氢-1α-羟基维生素D（3）-26,23-内酯的C24-烷基化和C2α-官能化的维生素D激素拮抗剂的进一步合成和生物学研究。

  摘要：

  高效合成和生物学评估80种新型25-脱氢-1α-羟基维生素D3-26,23S-内酯2（TEI-9647）及其23R差向异构体（3），其中内酯环通过引入描述了在C24位的C1至C4伯烷基（5组4个非对映异构体），以及它们的C2α-甲基，3-羟丙基和3-羟基丙氧基取代的衍生物。维生素D3的三烯结构是通过A环前体烯炔的钯催化烯基环化和侧链上具有C24烷基化内酯部分的CD环对应的溴烯烃而构建的。具有23,24-顺式内酯的CD环前体是通过使用铬介导的顺-选择性烯丙基化-内酯化工艺制备的，然后将23,24-顺式内酯 通过反式的C23立体化学从中衍生出24反式内酯衍生物。生物学评估表明，对鸡维生素D激素受体的结合亲和力和拮抗活性（抑制维生素D激素诱导的HL-60细胞分化）均受内酯环上伯烷基的取向和链长的影响。此外，C24烷基化的维生素D3内酯的C2alpha官能化大大增强了它们的生物学活性。最有效的化合

  DOI：

  10.1021/jm060797q
• 作为产物：
  描述：

  benzyl 5-O-pivaloyl-2-O-methoxymethyl-3-deoxy-3-C-hydroxymethyl-α-D-lyxo-pentofuranose 在 palladium dihydroxide 吡啶 、 咪唑 、 2,6-二甲基吡啶 、 甲醇 、 4-二甲氨基吡啶 、 sodium tetrahydroborate 、 正丁基锂 、 三氟化硼乙醚 、 四丁基氟化铵 、 氢气 、 4-甲基苯磺酸吡啶 、 二异丁基氢化铝 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 二甲基亚砜 、 N,N-二甲基甲酰胺 、 叔丁醇 为溶剂， 生成 (3R,4R,5S)-3,5-bis[(tert-butyldimethylsilyl)oxy]-4-[3-{(tert-butyldimethylsilyl)oxy}propyl]oct-1-en-7-yne
  参考文献：
  名称：

  Syntheses and biological evaluation of novel 2α-substituted 1α,25-dihydroxyvitamin D3 analogues

  摘要：

  Novel 2 alpha-substituted 1 alpha,25-dihydroxyvitamin D-3 analogues were efficiently synthesized and their biological activities were evaluated. 2 alpha-Methyl-1 alpha,25-dihydroxyvitamin D-3 (2), whose unique biological activities were previously reported, was modified to 2 alpha-alkyl (ethyl and propyl) and 2 alpha-hydroxyalkyl (hydroxymethyl, hydroxyethyl, and hydroxypropyl) analogues 3-7 by elongation of the alkyl chain and/or introduction of a terminal hydroxyl group. 2 alpha-Hydroxypropyl-1 alpha,25-dihydroxyvitamin D-3 (7) exhibited an exceptionally potent calcium-regulating effect and a unique activity profile. (C) 2000 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(00)00189-x

文献信息

• Remarkable effect of 2α-modification on the VDR antagonistic activity of 1α-hydroxyvitamin D₃-26,23-lactones
  作者：Nozomi Saito、Toshihiro Matsunaga、Toshie Fujishima、Miyuki Anzai、Hiroshi Saito、Kazuya Takenouchi、Daishiro Miura、Seiichi Ishizuka、Hiroaki Takayama、Atsushi Kittaka

  DOI：10.1039/b311107e

  日期：——

  Novel 2α-methyl-, 2α-(3-hydroxypropyl)- and 2α-(3-hydroxypropoxy)-substituted 25-dehydro-1α-hydroxyvitamin D3-26,23-lactone derivatives were efficiently synthesized via Reformatsky type allylation and palladium-catalyzed alkenylative cyclization processes, and their biological activities were evaluated. Introducing functional groups into the 2α-position of the vitamin D3-26,23-lactones resulted in remarkable enhancement of their antagonistic activity on vitamin D receptor (VDR).

  新型2α-甲基、2Îα-(3-羟基丙基)和2Îα-(3-羟基丙氧基)取代的25-脱氢-1Îα-羟基维生素D3-26,23-内酯衍生物通过Reformatsky型烯丙基化和钯催化的烯烃化环化过程被高效合成，并对其生物活性进行了评估。向维生素D3-26,23-内酯的2Îα位引入功能团显著提高了它们对维生素D受体(VDR)的拮抗活性。
• Synthesis of 2α- and 2β-substituted-14-epi-previtamin D3 and their genomic activity
  作者：Daisuke Sawada、Tomoyuki Katayama、Yuya Tsukuda、Nozomi Saito、Hiroshi Saito、Ken-ichiro Takagi、Eiji Ochiai、Seiichi Ishizuka、Kazuya Takenouchi、Atsushi Kittaka

  DOI：10.1016/j.tet.2010.05.028

  日期：2010.7

  and 2β-Substituted analogs of 14-epi-previtamin D3 were synthesized and isolated after thermal isomerization of 14-epi-vitamin D3 triene at 80 °C. The VDR binding affinity and transactivation activity of osteocalcin promoter in HOS cells were tested, and the 2α-methyl-substituted analog was found to have greater genomic activity than 14-epi-previtamin D3. We found that modification at the C2 position

  14-表位-维生素D 3三烯在80°C下热异构化后，合成并分离了14-表位-维生素D 3的2α和2β取代类似物。在HOS细胞骨钙蛋白启动子的VDR结合亲和力和反式激活活性进行了测试，并且2α甲基取代的类似物被发现具有更大的基因组活性比14-外延-previtamin d 3。我们发现，在修改的C2位置塞科-steroidal骨架提供了对前维生素d形式的生物基因组活动以及天然维生素d形式有趣的效果。
• Synthesis of 24,24-Ethanovitamin D₃ Lactones Using Ruthenium-Catalyzed Intermolecular Enyne Metathesis: Potent Vitamin D Receptor Antagonists
  作者：Atsushi Kittaka、Nozomi Saito、Manami Masuda、Hiroshi Saito、Kazuya Takenouchi、Seiichi Ishizuka、Jun-ichi Namekawa、Midori Takimoto-Kamimura

  DOI：10.1055/s-2005-872075

  日期：——

  Novel vitamin D receptor antagonists, 24,24-ethanovitamin D3-26,23-lactones 6 and 7 and their 2α-functionalized analogues 6a-c and 7a-c were synthesized and their biological activities were evaluated. The triene structure of vitamin D3 was constructed using Pd-catalyzed alkenylative cyclization of A-ring precursor enynes 12 and 12a-c with the CD-ring bromo-olefin counterpart having 24,24-ethano-α-methylene-γ-lactone on the side chain (21 or 22). The CD-ring precursors 21 and 22 were efficiently synthesized via Ru-catalyzed intermolecular enyne metathesis of 15 with ethylene to give dienone 17 followed by cyclopropanation. The VDR antagonistic activity of the newly designed vitamin D3 lactones 6 and 7 increased to 2.8 times that of TEI-9647 (2) in a HL-60 cell differentiation evaluating system. Moreover, introduction of three substituents, that is, a methyl (6a and 7a), a 3-hydroxypropyl (6b and 7b), or a 3-hydroxypropoxyl group (6c and 7c) into the C2α position of 6 and 7, resulted in marked enhancement, up to 19 times, of the antagonistic activity toward VDR.

  合成了新型维生素 D 受体拮抗剂 24,24-乙酰维生素 D3-26,23-内酯 6 和 7 及其 2δ-官能化类似物 6a-c 和 7a-c，并评估了它们的生物活性。维生素 D3 的三烯结构是通过钯催化 A 环前体烯炔烷 12 和 12a-c 与侧链上具有 24,24-乙hano-δ-亚甲基δ-δ-内酯的 CD 环溴烯烃对应物（21 或 22）发生烯基环化反应而构建的。CD 环前体 21 和 22 是通过 Ru 催化 15 与乙烯的分子间烯炔偏析生成二烯酮 17，然后进行环丙烷化反应而高效合成的。在 HL-60 细胞分化评价体系中，新设计的维生素 D3 内酯 6 和 7 的 VDR 拮抗活性是 TEI-9647 (2) 的 2.8 倍。此外，在 6 和 7 的 C2δ 位上引入三个取代基，即甲基（6a 和 7a）、3-羟基丙基（6b 和 7b）或 3-羟基丙氧基（6c 和 7c），可显著增强对 VDR 的拮抗活性，最高可达 19 倍。
• VITAMIN D3 LACTAM DERIVATIVE
  申请人：Nakamura Yuko

  公开号：US20110207944A1

  公开（公告）日：2011-08-25

  Compound represented by formula (1) or a pharmaceutically acceptable solvate thereof, useful for treating or preventing Paget's disease of bone, hypercalcaemia, osteoporosis or asthma. (1) R 1 represents a C 1 -C 6 alkyl group or C 7 -C 15 aralkyl group (the aromatic ring of which can be substituted by a C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, a hydroxyl group, a halogenatom or a trifluoromethyl group), R 2 represents a C 1 -C 6 alkyl group, and R 3 represents a C 1 -C 6 alkyl or alkoxy group, which can be substituted with a hydroxyl group.

  由以下化学式（1）表示的化合物或其药用可接受的溶剂盐，用于治疗或预防骨的帕吉特病、高钙血症、骨质疏松症或哮喘。其中，R1代表C1-C6烷基或C7-C15芳基烷基（其芳香环可以被C1-C6烷基、C1-C6甲氧基、一个羟基、一个卤原子或三氟甲基取代），R2代表C1-C6烷基，R3代表C1-C6烷基或烷氧基，可以被一个羟基取代。
• 24,24-Dimethylvitamin D3-26,23-lactones and their 2α-functionalized analogues as highly potent VDR antagonists
  作者：Nozomi Saito、Manami Masuda、Toshihiro Matsunaga、Hiroshi Saito、Miyuki Anzai、Kazuya Takenouchi、Daishiro Miura、Seiichi Ishizuka、Midori Takimoto-Kamimura、Atsushi Kittaka

  DOI：10.1016/j.tet.2004.05.113

  日期：2004.8

  Novel vitamin D receptor (VDR) antagonists, 24,24-dimethyl-1alpha-hydroxyvitamin D-3-26,23-lactones (8 and 9) and their C2alpha functionalized analogues (8a-c and 9a-c) were efficiently synthesized and their biological activities were evaluated. The construction of vitamin D-3 triene skeleton was achieved by palladium-catalyzed alkenylative cyclization of A-ring precursor enyne (22 and 22a-c) with CD-ring bromoolefin having a 24,24-dimethyl-alpha-methylene-gamma-lactone unit on the side chain (13 and 14). The CD-ring precursors 13 and 14 were prepared by using chromium-mediated allylation of the aldehyde 10 derived from vitamin D-2. On the other hand, the A-ring enyne having 2alpha-(3-hydroxypropyl) group (22b) was newly synthesized from epoxide 15 using regio- and stereoselective alkylation methodology. The potency of the antagonistic activity of the newly designed analogues (8 and 9) increased up to 12 times that of TEI-9647 (2). Furthermore, introduction of the three motifs, that is, a methyl (8a and 9a), an omega-hydroxypropyl (8b and 9b) or an omega-hydroxypropoxyl group (8c and 9c) into the C2alpha position of 8 and 9, respectively, resulted in remarkable enhancement, up to 89 times, of the antagonistic activity on VDR. (C) 2004 Elsevier Ltd. All rights reserved.