(1S)-(+)-methylenecyclopropaneacetic acid | 125873-65-6

• 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)-(+)-methylenecyclopropaneacetic acid
• 英文别名: Cyclopropaneacetic acid, 2-methylene-, (S)-；2-[(1S)-2-methylidenecyclopropyl]acetic acid
• CAS: 125873-65-6
• 化学式: C₆H₈O₂
• 分子量: 112.128
• InChiKey: QJBXAEKEXKLLLZ-YFKPBYRVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.3
• 重原子数：
  8
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  37.3
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (1S)-(+)-methylenecyclopropaneacetic acid 在 sodium hydroxide 、 三乙胺 作用下， 以 水 为溶剂， 反应 1.34h， 生成 (S)-(2-methylenecyclopropyl)acetyl-CoA
  参考文献：
  名称：

  Mechanistic study on the inactivation of general acyl-CoA dehydrogenase by a metabolite of hypoglycin A

  摘要：

  General acyl-CoA dehydrogenase (GAD) is a flavin-dependent (FAD) enzyme that catalyzes the oxidation of a fatty acyl-CoA to the corresponding alpha,beta-enolyl-CoA. When GAD is exposed to (methylenecyclopropyl)acetyl-CoA (MCPA-CoA), a metabolite of hypoglycin A that is the causative agent of Jamaican vomiting sickness, time-dependent inhibition occurs with concomitant bleaching of the active-site FAD. The inactivation mechanism is generally believed to be initiated by C-alpha anion formation followed by ring fragmentation and the covalent modification of FAD. However, formation of a cyclopropyl radical intermediate through one-electron oxidation followed by ring opening and then radical recombination to yield a modified FAD is an appealing alternative. As described herein, studies of the inactivation of GAD by (1S)- and (1R)-MCPA-CoA bearing a stereospecific tritium label at C-alpha have provided direct evidence suggesting that C-alpha proton abstraction occurs during inactivation and the two diastereomers of MCPA-CoA bind to the same locus in the active site of GAD. Despite the fact that the inactivations mediated by (1R)- and (1S)-MCPA-CoA proceed at different rates, the observed partition ratios are almost identical. Using [alpha,alpha-H-2(2)]MCPA-CoA as inhibitors, we have found that the sluggish inactivation observed for (1S)-MCPA-CoA is not due to mechanistic rerouting, but is instead a result of the retardation of the initial deprotonation step. Thus, the equivalent partition ratios found in these studies clearly indicate that inactivation by either (1R)- or (1S)-MCPA-CoA follows the same chemical course. Such a lack of stereospecificity for the bond rupture at C-beta of MCPA-CoA in the enzyme active site suggests that the ring-opening step leading to inactivation is likely a spontaneous event. Since the rearrangement of alpha-cyclopropyl radicals to ring-opened alkyl radicals is extremely rapid, the ring cleavage induced by an alpha-cyclopropyl radical may bypass the chiral discrimination normally imposed by the enzyme. Thus, the mechanistic insights deduced from this study support our early notion that inactivation of GAD by MCPA-CoA is likely to proceed through a radical mechanism.

  DOI：

  10.1021/ja00019a040
• 作为产物：
  描述：

  亚甲基环丙烷-2-羧酸 在 chromium(VI) oxide 、 lithium aluminium tetrahydride 、 15-冠醚-5 、 硫酸 、 二异丁基氢化铝 、 三乙胺 作用下， 以 四氢呋喃 、 乙醚 、 正己烷 、 二甲基亚砜 、 丙酮 、 苯 为溶剂， 反应 12.67h， 生成 (1S)-(+)-methylenecyclopropaneacetic acid
  参考文献：
  名称：

  Mechanistic study on the inactivation of general acyl-CoA dehydrogenase by a metabolite of hypoglycin A

  摘要：

  General acyl-CoA dehydrogenase (GAD) is a flavin-dependent (FAD) enzyme that catalyzes the oxidation of a fatty acyl-CoA to the corresponding alpha,beta-enolyl-CoA. When GAD is exposed to (methylenecyclopropyl)acetyl-CoA (MCPA-CoA), a metabolite of hypoglycin A that is the causative agent of Jamaican vomiting sickness, time-dependent inhibition occurs with concomitant bleaching of the active-site FAD. The inactivation mechanism is generally believed to be initiated by C-alpha anion formation followed by ring fragmentation and the covalent modification of FAD. However, formation of a cyclopropyl radical intermediate through one-electron oxidation followed by ring opening and then radical recombination to yield a modified FAD is an appealing alternative. As described herein, studies of the inactivation of GAD by (1S)- and (1R)-MCPA-CoA bearing a stereospecific tritium label at C-alpha have provided direct evidence suggesting that C-alpha proton abstraction occurs during inactivation and the two diastereomers of MCPA-CoA bind to the same locus in the active site of GAD. Despite the fact that the inactivations mediated by (1R)- and (1S)-MCPA-CoA proceed at different rates, the observed partition ratios are almost identical. Using [alpha,alpha-H-2(2)]MCPA-CoA as inhibitors, we have found that the sluggish inactivation observed for (1S)-MCPA-CoA is not due to mechanistic rerouting, but is instead a result of the retardation of the initial deprotonation step. Thus, the equivalent partition ratios found in these studies clearly indicate that inactivation by either (1R)- or (1S)-MCPA-CoA follows the same chemical course. Such a lack of stereospecificity for the bond rupture at C-beta of MCPA-CoA in the enzyme active site suggests that the ring-opening step leading to inactivation is likely a spontaneous event. Since the rearrangement of alpha-cyclopropyl radicals to ring-opened alkyl radicals is extremely rapid, the ring cleavage induced by an alpha-cyclopropyl radical may bypass the chiral discrimination normally imposed by the enzyme. Thus, the mechanistic insights deduced from this study support our early notion that inactivation of GAD by MCPA-CoA is likely to proceed through a radical mechanism.

  DOI：

  10.1021/ja00019a040

文献信息

• Enantioselective synthesis of the methylenecyclopropane derivative related to hypoglycine, from malic acid
  作者：Barbara Achmatowicz、Marek M. Kabat、Janusz Krajewski、Jerzy Wicha

  DOI：10.1016/s0040-4020(01)89048-7

  日期：——

  Synthesis of (S)-methylenecyclopropaneacetic acid starting from L-(−)-malic acid, via (2S)-O-tert-butyldimethylsilyl-1,2-epoxybutan-4-ol and 1-O-tert-butyldiphenylsilyl-5-benzenesulfonyl-6-trimethylsilylhexane-1,3-diols as the key intermediates, is described.

  由L-（-）-苹果酸经（2S）-O-叔丁基二甲基甲硅烷基-1,2-环氧丁烷-4-醇和1-O-叔丁基二苯基甲硅烷基-5-苯甲酸合成（S）-亚甲基环丙烷乙酸描述了作为关键中间体的苯磺酰基-6-三甲基甲硅烷基己烷-1,3-二醇。
• Revision of Absolute Configuration of Enantiomeric (Methylenecyclopropyl)carbinols Obtained from (<i>R</i>)-(−)- and (<i>S</i>)-(+)-Epichlorohydrin and Methylenetriphenylphosphorane. Implications for Reaction Mechanism and Improved Synthesis of Antiviral Methylenecyclopropane Analogues of Nucleosides
  作者：Xinchao Chen、Jiri Zemlicka

  DOI：10.1021/jo010511j

  日期：2002.1.1

  reaction of (R)- and (S)-epichlorohydrin 5 with methylenetriphenylphosphorane or resolution of the corresponding oxaphospholane 6 via a salt with L-(+)-tartaric acid and subsequent Wittig transformation with formaldehyde were revised. The (-)-oxaphospholane 6 has the S,S and (-)-(methylenecyclopropyl)carbinol (4) the R configuration. The configurations of (+)-6 and (+)-4 are then R,R and S, respectively

  修订了通过（R）-和（S）-表氯醇5与亚甲基三苯基膦烷反应或通过与L-（+）-酒石酸的盐拆分相应的氧杂膦烷6并随后用甲醛进行Wittig转化而获得的对映异构体亚甲基环丙烷甲醇的绝对构型。（-）-氧杂膦烷6具有S，S和（-）-（亚甲基环丙基）甲醇（4）的R构型。那么（+）-6和（+）-4的构型分别是R，R和S。这些分配与环氧丙烷在环氧氯丙烷的环氧乙烷环上的初始攻击相符。还描述了改进的关键对映体中间体（R）-1a和（S）-1a的制备方法，对于合成核苷的抗病毒嘌呤亚甲基环丙烷类似物很重要。
• Spiropentylacetyl-CoA, A Mechanism-Based Inactivator of Acyl-CoA Dehydrogenases
  作者：Ding Li、Hui-qiang Zhou、Srikanth Dakoji、Injae Shin、Eugene Oh、Hung-wen Liu

  DOI：10.1021/ja9737634

  日期：1998.3.1

  However, recent studies of the inactivation of ACDs by a metabolite of hypoglycin A, (methylenecyclopropyl)acetyl-CoA (MCPA-CoA), led to an alternative mechanism in which the reducing equivalent is delivered from the initially formed α-anion to the bound FAD via a single electron transfer process. To further explore the observed mechanistic discrepancy, we have reexamined the inhibitory properties of

  酰基-CoA 脱氢酶 (ACD) 是 FAD 依赖性酶，可催化适当的脂肪酰基-CoA 硫酯底物转化为相应的反式-α,β-烯酰基-CoA 产物。早期研究表明，脱氢是立体有择的，是通过提取 pro-R α-H 开始的，然后将 pro-R β-H 作为氢化物等价物转移到结合的 FAD 上。然而，最近关于次甘氨酸 A 的代谢物（亚甲基环丙基）乙酰辅酶 A（MCPA-CoA）使 ACD 失活的研究导致了另一种机制，其中还原当量从最初形成的 α-阴离子传递到结合FAD 通过单电子转移过程。为了进一步探索观察到的机制差异，我们重新检查了密切相关的 MCPA-CoA 类似物的抑制特性，螺戊基乙酰辅酶A（SPA-CoA），之前报道为ACD的紧密结合抑制剂。与早期结果相反，我们的数据显示 SPA-CoA 是一种基于机制的......
• Lai, Ming-Tain; Liu, Hung-Wen, Journal of the American Chemical Society, 1990, vol. 112, # 10, p. 4034 - 4035
  作者：Lai, Ming-Tain、Liu, Hung-Wen

  DOI：——

  日期：——
• LAI, MING-TAIN;LIU, HUNG-WEN, J. AMER. CHEM. SOC., 112,(1990) N0, C. 4034-4035
  作者：LAI, MING-TAIN、LIU, HUNG-WEN

  DOI：——

  日期：——