<1S-<1α(4R*,5R*),3α,4β,5α,6α(2E,4R*,6R*),7β>>-1-<4-(acetyloxy)-5-methyl-3-methylene-6-phenylhexyl>4,6,7-trihydroxy-2,8-dioxabicyclo<3.2.1>octane-3,4,5-tricarboxylic acid, 6-(4,6-dimethyl-2-octenoate), 3,4,5-tris(1,1-dimethylethyl) ester | 144358-24-7

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: <1S-<1α(4R*,5R*),3α,4β,5α,6α(2E,4R*,6R*),7β>>-1-<4-(acetyloxy)-5-methyl-3-methylene-6-phenylhexyl>4,6,7-trihydroxy-2,8-dioxabicyclo<3.2.1>octane-3,4,5-tricarboxylic acid, 6-(4,6-dimethyl-2-octenoate), 3,4,5-tris(1,1-dimethylethyl) ester
• 英文别名: <1S-<1α(4S,5R),3α,4β,5α,6α(2E,4S,6S),7β>>-1-<4-acetyloxy-5-methyl-3-methylene-6-phenylhexyl>-6-(4,6-dimethyl-2-octenoyl)-4,6,7-trihydroxy-2,8-dioxabicyclo<3.2.1>octane-3,4,5-tricarboxylic acid 3,4,5-tris(1,1-dimethylethyl) ester；<1S-<1α(4R*,5S*),3α,4β,5α,6α(2E,4R*,6R*),7β>>-1-<4-(acetyloxy)-5-methyl-3-methylene-6-phenylhexyl>-4,6,7-trihydroxy-2,8-dioxabicyclo<3.2.1>octane-3,4,5-tricarboxylic acid, 6-(4,6-dimethyl-2-octenoate) 3,4,5-tris(1,1-dimethylethyl) ester；tritert-butyl (1S,3S,4S,5R,6R,7R)-1-[(4S,5R)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-6-[(E,4S,6S)-4,6-dimethyloct-2-enoyl]oxy-4,7-dihydroxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylate
• CAS: 144358-24-7
• 化学式: C₄₇H₇₀O₁₄
• 分子量: 859.064
• InChiKey: VKMQWPAGWWMBPE-ITXJLCPSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.8
• 重原子数：
  61
• 可旋转键数：
  25
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.68
• 拓扑面积：
  190
• 氢给体数：
  2
• 氢受体数：
  14

反应信息

• 作为反应物：
  描述：

  <1S-<1α(4R*,5R*),3α,4β,5α,6α(2E,4R*,6R*),7β>>-1-<4-(acetyloxy)-5-methyl-3-methylene-6-phenylhexyl>4,6,7-trihydroxy-2,8-dioxabicyclo<3.2.1>octane-3,4,5-tricarboxylic acid, 6-(4,6-dimethyl-2-octenoate), 3,4,5-tris(1,1-dimethylethyl) ester 在 cerium(III) chloride 、 乙基氯化镁 、 4-甲基苯磺酸吡啶 、 臭氧 作用下， 以 四氢呋喃 、 吡啶 、 二氯甲烷 为溶剂， 反应 5.83h， 生成 (1S,3S,4S,5R,6R,7R)-6-((E)-(4S,6S)-4,6-Dimethyl-oct-2-enoyloxy)-4-hydroxy-1-((4S,5R)-4-hydroxy-5-methyl-3-oxo-6-phenyl-hexyl)-7-(1-methoxy-1-methyl-ethoxy)-2,8-dioxa-bicyclo[3.2.1]octane-3,4,5-tricarboxylic acid tri-tert-butyl ester
  参考文献：
  名称：

  zaragozic acid A衍生物的C1和C6侧链的构效关系。

  摘要：

  系统地修改了一种有效的角鲨烯合酶抑制剂za​​ragozic A的C6酰基侧链，以改善其生物学活性。将C6侧链简化为辛酸酯具有有害作用。增加线性链长度可提高体外活性，直至十四烷酸酯为止。ω-苯氧基比ω-苯基更好的活性增强剂。制备了许多C6氨基甲酸酯，醚和碳酸酯，发现它们具有与C6酯相似的活性。在制备C6醚时，还分离出C4和C4,6双醚。它们的相对活性为：C6> C4> C4,6。这些C6长链衍生物是亚纳摩尔角鲨烯合酶抑制剂。然而，它们仅在抑制小鼠肝胆固醇合成中具有弱活性。C6短链衍生物在体外的活性低得多，但它们在小鼠中的口服活性均得到改善。正丁酰基类似物的C1烷基侧链（ED50为4.5 mg / kg）的修饰不能进一步提高po活性。这些C6长链衍生物中的许多也是体外有效的抗真菌剂。

  DOI：

  10.1021/jm00049a022
• 作为产物：
  描述：

  tritert-butyl (1S,3S,4S,5R,6R,7R)-6-[(E,4S,6S)-4,6-dimethyloct-2-enoyl]oxy-4-hydroxy-1-[(4S,5R)-4-[(4-methoxyphenyl)methoxymethoxy]-5-methyl-3-methylidene-6-phenylhexyl]-7-triethylsilyloxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylate 在 4-二甲氨基吡啶 、 盐酸羟胺 、 水 、 sodium acetate 、 氟化氢吡啶 、 三乙胺 、 N,N'-二环己基碳二亚胺 、 2,3-二氯-5,6-二氰基-1,4-苯醌 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 为溶剂， 反应 27.0h， 生成 <1S-<1α(4R*,5R*),3α,4β,5α,6α(2E,4R*,6R*),7β>>-1-<4-(acetyloxy)-5-methyl-3-methylene-6-phenylhexyl>4,6,7-trihydroxy-2,8-dioxabicyclo<3.2.1>octane-3,4,5-tricarboxylic acid, 6-(4,6-dimethyl-2-octenoate), 3,4,5-tris(1,1-dimethylethyl) ester
  参考文献：
  名称：

  Total Synthesis of Zaragozic Acid A (Squalestatin S1). Degradation to a Relay Compound and Reassembly of the Natural Product

  摘要：

  Zaragozic acid A (squalestatin S1) (1) was converted into the simpler derivative 2, which was reconverted into the natural product, thus establishing 2 as a viable relay compound for total synthesis of 1. The degradation (Scheme 1) consisted of formation of the tri-tert-butyl ester (3), from which the two side chains were sequentially removed to obtain 8. Aldehyde 8 was converted into dimethyl acetal 2 in standard fashion. The C6 acyl side chain 14 was prepared from (S)-2-methylbutanol (''active amyl alcohol''), and the desired 4S configuration was obtained by use of Evans asymmetric enolate methylation (Scheme 2). The C1 alkyl side chain was prepared as stannane 23a from (R)-2-methyl-3-phenylpropanol (21) as shown in Scheme 5. For conversion of 2 back into zaragozic acid A, the dimethyl acetal was first converted into the cyclic acetal 17, thus protecting the C7 hydroxyl group. The remaining hydroxyl group was then acylated with acid 14 to obtain 18, which was transformed into aldehyde 20 (Scheme 4). The C1 alkyl chain was elaborated by the addition of a chiral alpha-alkoxyorganocerium reagent, obtained from 23a, to aldehyde 20. The resulting mixture of diastereomeric secondary alcohols was converted into zaragozic acid A (1) in six steps (Scheme 6).

  DOI：

  10.1021/jo961533m

文献信息

• Chemoselective removal and replacement of the C-4′ and C-6 acyl esters of zaragozic Acid A
  作者：Robert M. Burk、Gregory D. Berger、Robert L. Bugianesi、Narindar N. Girotra、William H. Parsons、Mitree M. Ponpipom

  DOI：10.1016/s0040-4039(00)77469-7

  日期：1993.2

  An efficient chemical sequence is described for the modification of the C-4′ and C-6 positions of zaragozic acid A. Key reactions include the specific conditions devised for selective removal of either the C-4′ acetate or the C-6 acyl chain. The resultant hydroxy intermediates were then derivatized as esters, ethers, carbamates, and carbonates.

  描述了一种有效的化学顺序，可用于修饰zaragozic A的C-4'和C-6位置。关键反应包括为选择性去除乙酸C-4'或C-6酰基链而设计的特定条件。 。然后将所得的羟基中间体衍生为酯，醚，氨基甲酸酯和碳酸盐。
• Structurally simplified squalestatins: A convenient route to a 67-unsubstituted derivative
  作者：Michael G. Lester、Gerard M.P. Giblin、Graham G.A. Inglis、Panayiotis A. Procopiou、Barry C. Ross、Nigel S. Watson

  DOI：10.1016/s0040-4039(00)79351-8

  日期：1993.7

  The squalestatin 1, has been converted into the 6,7-unsubstituted analogue, 3, via inversion of the alcohol at C7, selective removal of the α,β-unsaturated ester at C6 followed by a Corey-Hopkins deoxygenation of the generated 6R,7S-diol.

  squalestatin 1已通过在C7处转化醇，在C6处选择性去除α，β-不饱和酯，然后将生成的6 R进行Corey-Hopkins脱氧反应而转化为6,7-未取代的类似物3。7小号二醇。
• The Squalestatins:  Decarboxy and 4-Deoxy Analogues as Potent Squalene Synthase Inhibitors
  作者：Chuen Chan、Daniele Andreotti、Brian Cox、Brian W. Dymock、Julie L. Hutson、Suzanne E. Keeling、Alun D. McCarthy、Panayiotis A. Procopiou、Barry C. Ross、Meenu Sareen、Jan J. Scicinski、Peter J. Sharratt、Michael A. Snowden、Nigel S. Watson

  DOI：10.1021/jm9504969

  日期：1996.1.1

  group gave compounds with reduced potency, whereas decarboxylation at C-3 resulted in a dramatic loss of SQS inhibitory activity. In comparison with S1 1, C-4 deoxyS1 3 and C-3 decarboxyS1 10 have shorter in vivo durations of action on the inhibition of hepatic cholesterol biosynthesis in rats. C-4 deoxyS1 3 retains good serum cholesterol-lowering ability in marmosets, while C-3 decarboxyS1 10 showed

  制备不含有C-4处的羟基或C-3或C-4处的羧酸的Squalestatin，并评估其在体外抑制大鼠肝微粒体角鲨烯合酶（SQS）的能力。这些修饰对于在C-6（S1系列）中带有4,6-二甲基辛烯酸酯的化合物具有很好的耐受性。但是，在不含C-6酯的类似物（H1系列）中，去除C-4羟基会降低化合物的效力，而C-3处的脱羧会导致SQS抑制活性急剧下降。与S1 1相比，C-4脱氧S1 3和C-3脱羧S10 10在体内抑制大鼠肝胆固醇生物合成的作用持续时间较短。C-4脱氧S1 3在mar猴中保留了良好的降低血清胆固醇的能力，而C-3脱羧S1 10即使在高剂量下也仅显示出很小的作用。
• The Squalestatins: Novel Inhibitors of Squalene Synthase. Enzyme Inhibitory Activities and in vivo Evaluation of C1-Modified Analogs
  作者：Panayiotis A. Procopiou、Esme J. Bailey、Mark J. Bamford、Andy P. Craven、Brian W. Dymock、John G. Houston、Julie L. Hutson、Barrie E. Kirk、Alun D. McCarthy

  DOI：10.1021/jm00046a011

  日期：1994.9

  Squalestatin analogues modified in the C1 side chain were prepared and evaluated for their ability to inhibit rat liver microsomal and Candida squalene synthase (SQS) in vitro. While maintaining the 4,6-dimethyloctenoate or 4,6-dimethyloctanoate ester groups at C6, a number of modifications to the C1 side chain were well tolerated. However, in the absence of the C6 ester group, similar modifications to the C1 side chain caused substantial loss of activity. Compounds were also evaluated for their ability to inhibit cholesterol biosynthesis in vivo in rats and to reduce serum cholesterol levels in marmosets. These studies revealed that compounds with similar SQS inhibitory activities can possess different in vivo durations of action and lipid-lowering abilities.