methyl (1S,5S,7R)-3-benzyl-6,8-dioxa-3-azabicyclo[3.2.1]octane-7-exo-carboxylate | 250137-88-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: methyl (1S,5S,7R)-3-benzyl-6,8-dioxa-3-azabicyclo[3.2.1]octane-7-exo-carboxylate
• 英文别名: methyl (1S,5S,7R)-3-benzyl-6,8-dioxa-3-azabicyclo[3.2.1]octane-7-carboxylate
• CAS: 250137-88-3
• 化学式: C₁₄H₁₇NO₄
• 分子量: 263.293
• InChiKey: VCIUSTQAFLLEKV-RWMBFGLXSA-N

物化性质

• 沸点：
  343.5±42.0 °C(Predicted)
• 密度：
  1.241±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  19
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  48
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  methyl (1S,5S,7R)-3-benzyl-6,8-dioxa-3-azabicyclo[3.2.1]octane-7-exo-carboxylate 在 palladium on activated charcoal ammonium formate 作用下， 以 甲醇 为溶剂， 反应 14.0h， 生成 (1S,5S,7R)-3-aza-6,8-dioxabicyclo[3.2.1]octane-7-carboxylic acid ((biphenyl-4-yl)methyl)amide
  参考文献：
  名称：

  Synthesis of bicyclic molecular scaffolds (BTAa): An investigation towards new selective MMP-12 inhibitors

  摘要：

  Starting from 3-aza-6,8-dioxa-bicyclo[3.2.1]octane scaffold (BTAa) a virtual library of molecules was generated and screened in silico against the crystal structure of the Human Macrophage Metalloelastase (MMP-12). The molecules obtaining high score were synthesized and the affinity for the catalytic domain of MMP-12 was experimentally proved by NMR experiments. A BTAa scaffold 20 having a N-hydroxyurea group in position 3 and a p-phenylbenzylcarboxy amide in position 7 showed a fair inhibition potency (IC50 = 149 microM) for MMP-12 and some selectivity towards five different MMPs. These results, taken together with the X-ray structure of the adduct between MMP-12, the inhibitor 20 and the acetohydroxamic acid (AHA), suggest that bicyclic scaffold derivatives may be exploited for the design of new selective matrix metalloproteinase inhibitors (MMPIs).

  DOI：

  10.1016/j.bmc.2006.07.028
• 作为产物：
  描述：

  methyl (1R,5S,7R)-3-benzyl-2-oxo-6,8-dioxa-3-azabicyclo[3.2.1]octane-7-exo-carboxylate 在 dimethyl sulfide borane 、 sodium hydroxide 、 水 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 反应 18.0h， 生成 methyl (1S,5S,7R)-3-benzyl-6,8-dioxa-3-azabicyclo[3.2.1]octane-7-exo-carboxylate
  参考文献：
  名称：

  [EN] PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF DISEASES RELATED TO NEUROTROPHINES
  [FR] COMPOSITIONS PHARMACEUTIQUES POUR LE TRAITEMENT DE MALADIES ASSOCIEES AUX NEUROTROPHINES

  摘要：

  本发明涉及包含作为活性化合物的3-aza-bicyclo[3.2.1]辛烷衍生物的药物制剂，其通用式为(I)，以及其通用式为(II)和(III)的二聚体，作为人类神经营养因子的激动剂。因此，通式(I)、(II)和(III)的这些化合物对于治疗神经营养因子功能缺陷相关的疾病非常有用，尤其是神经生长因子（NGF）缺陷，例如中枢神经系统（CNS）的神经退行性疾病、由于NGF生物可用性降低而导致的获得性免疫缺陷，或者在其中新生血管生成过程的刺激是方便的病态条件。

  公开号：

  WO2004000324A1

文献信息

• Stereoselective Meisenheimer rearrangement using BTAa's as chiral auxiliaries
  作者：Antonio Guarna、Ernesto G Occhiato、Mirco Pizzetti、Dina Scarpi、Sauro Sisi、Matthijs van Sterkenburg

  DOI：10.1016/s0957-4166(00)00402-x

  日期：2000.10

  highly diastereoselective, the asymmetric induction in the rearrangement was generally low. However, the interaction between the 4-endo group on the BTAa and a 2′-substituent on the allylic moiety allowed a more efficient chirality transfer in the [2,3]-sigmatropic process, affording d.e. values as high as 65% in the best case. The cleavage of the NO bond in the rearrangement products was possible by using

  迈森海默重排涉及将烯丙基叔胺-N-氧化物[2,3]σ重排为O-烯丙基羟胺。各种BTAa（衍生自酒石酸和α-氨基酸的自行车）被用作手性助剂，用于通过BTAa's与肉桂基溴化物和（E）-2-甲基-n偶联而获得的N-烯丙胺的N-氧化物的Meisenheimer重排。乙酸2-戊烯酯。尽管N-氧化物的形成具有非对映选择性，但重排中的不对称诱导通常较低。然而，4-内在之间的相互作用BTAa上的基团和烯丙基部分上的2'-取代基可在[2,3]-σ过程中实现更有效的手性转移，在最佳情况下，de值高达65％。通过使用具有良好的醇和手性助剂回收率的Mo（CO）6，可以在重排产物中裂解N = O键。
• [EN] PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF DISEASES RELATED TO NEUROTROPHINES<br/>[FR] COMPOSITIONS PHARMACEUTIQUES POUR LE TRAITEMENT DE MALADIES ASSOCIEES AUX NEUROTROPHINES
  申请人：GUARNA ANTONIO

  公开号：WO2004000324A1

  公开（公告）日：2003-12-31

  The present invention refers to pharmaceutical preparations including as active compounds 3-aza-bicyclo[3.2.1]octane derivatives of general formula (I) and/or their dimers of general formula (II) and (III) acting as agonists of human neurotrophines. Therefore, such compounds of formula (I), (II) and (III) are useful for treatment of diseases in which the neurotrophine functions are involved in defect, particularly of Nerve Growth Factor (NGF), such as neurodegenerative diseases of central nervous system (CNS), acquired immundeficiency due to a reduced NGF biodisponibility, or morbous conditions in which the stimulus of neoangiogenesis process is convenient.

  本发明涉及包含作为活性化合物的3-aza-bicyclo[3.2.1]辛烷衍生物的药物制剂，其通用式为(I)，以及其通用式为(II)和(III)的二聚体，作为人类神经营养因子的激动剂。因此，通式(I)、(II)和(III)的这些化合物对于治疗神经营养因子功能缺陷相关的疾病非常有用，尤其是神经生长因子（NGF）缺陷，例如中枢神经系统（CNS）的神经退行性疾病、由于NGF生物可用性降低而导致的获得性免疫缺陷，或者在其中新生血管生成过程的刺激是方便的病态条件。
• Synthesis and Reactivity of Bicycles Derived from Tartaric Acid and α-Amino Acids:  A Novel Class of Conformationally Constrained Dipeptide Isosteres Based upon Enantiopure 3-Aza-6,8-dioxabicyclo[3.2.1]octane-7-carboxylic Acid
  作者：Antonio Guarna、Antonio Guidi、Fabrizio Machetti、Gloria Menchi、Ernesto G. Occhiato、Dina Scarpi、Sauro Sisi、Andrea Trabocchi

  DOI：10.1021/jo9904967

  日期：1999.10.1

  3-Aza-6,8-dioxabicyclo[3.2.1]octane-7-carboxylic acids (named BTAa) derived from (R,R), (S,S)-, or meso-tartaric acid and natural (L), unnatural (D), or unusual alpha-amino acids are described as conformationally constrained dipeptide isosteres. The general strategy developed for their preparation has required the transformation of the amino acids into the corresponding N-benzylamino alcohols, followed by the PyBroP-promoted condensation with the monomethyl ester of the suitable 2,3-di-O-isopropylidenetartaric acid. Oxidation of the hydroxy group to aldheyde and subsequent acid-catalyzed trans-acetalization with the two hydroxy groups of the tartaric acid moiety provided 3-aza-2-oxo-6,8-dioxabicyclo [3.2.1] octane-7-carboxylic acid methyl esters [named BTAa(O)] in good yield and, in most cases, as single enantiopure diastereoisomers. This strategy has been applied to the preparation of BTAa(O) starting from (R,R)-, (S,S)-, or meso-tartaric acid and glycine, L- and D-phenylalanine, L- and D-alanine, and (+/-)-phenylglycine. In the cases of glycine, L- and D-phenylalanine, and L- and D-alanine, the selective reduction by BH3. DMS of the amide group succeeding to the cyclization step, or the reduction of both amide and ester functions followed by reoxidation of the hydroxy to carboxylic group, provided in good yield the 3-aza-3-benzyl-6,8-dioxabicyclo[3.2.1]-octane-7-carboxylic acids (or their methyl ester) BTAa, having the side chain of the amino acid precursors at position 4. The stability and rigidity of the bicyclic skeleton, the complete control of all the stereocenters, the possibility of introducing the side chains of L- or D-amino acids, and the demonstrated compatibility with the conditions required for solid-phase peptide synthesis make the BTAa compounds potential dipeptide isosteres useful for the synthesis of modified peptides.
• Synthesis of bicyclic molecular scaffolds (BTAa): An investigation towards new selective MMP-12 inhibitors
  作者：Claudia Mannino、Marco Nievo、Fabrizio Machetti、Athanasios Papakyriakou、Vito Calderone、Marco Fragai、Antonio Guarna

  DOI：10.1016/j.bmc.2006.07.028

  日期：2006.11

  Starting from 3-aza-6,8-dioxa-bicyclo[3.2.1]octane scaffold (BTAa) a virtual library of molecules was generated and screened in silico against the crystal structure of the Human Macrophage Metalloelastase (MMP-12). The molecules obtaining high score were synthesized and the affinity for the catalytic domain of MMP-12 was experimentally proved by NMR experiments. A BTAa scaffold 20 having a N-hydroxyurea group in position 3 and a p-phenylbenzylcarboxy amide in position 7 showed a fair inhibition potency (IC50 = 149 microM) for MMP-12 and some selectivity towards five different MMPs. These results, taken together with the X-ray structure of the adduct between MMP-12, the inhibitor 20 and the acetohydroxamic acid (AHA), suggest that bicyclic scaffold derivatives may be exploited for the design of new selective matrix metalloproteinase inhibitors (MMPIs).
• Oligomers of Enantiopure Bicyclic γ/δ-Amino Acids (BTAa). 1. Synthesis and Conformational Analysis of 3-Aza-6,8-dioxabicyclo[3.2.1]octane-7-carboxylic Acid Oligomers (PolyBTG)
  作者：Fabrizio Machetti、Alessandro Ferrali、Gloria Menchi、Ernesto G. Occhiato、Antonio Guarna

  DOI：10.1021/ol006548s

  日期：2000.12.1

  A series of dimeric through pentameric oligomers of a bicyclic gamma/delta -amino acid (BTG) were synthesized using peptide coupling methods in solution with PyBroP or HATU. The analysis of H-1 NMR and Co spectra suggests that these oligomers could have a partially ordered structure in alcohol solutions.