methyl (1S,4S,5S,7R)-4-exo-benzyl-6,8-dioxa-3-azabicyclo[3.2.1]octane-7-exo-carboxylate | 250137-95-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 氧氮杂卓类
• 英文名称: methyl (1S,4S,5S,7R)-4-exo-benzyl-6,8-dioxa-3-azabicyclo[3.2.1]octane-7-exo-carboxylate
• 英文别名: methyl (1S,4S,5S,7R)-4-benzyl-6,8-dioxa-3-azabicyclo[3.2.1]octane-7-carboxylate
• CAS: 250137-95-2
• 化学式: C₁₄H₁₇NO₄
• 分子量: 263.293
• InChiKey: GSAYHKCTAQKSRZ-FMSGJZPZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 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：
  56.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  methyl (1S,4S,5S,7R)-4-exo-benzyl-6,8-dioxa-3-azabicyclo[3.2.1]octane-7-exo-carboxylate 在 盐酸 作用下， 以 二氯甲烷 为溶剂， 反应 72.0h， 生成 (1S,4S,5S,7R)-3-(9-fluorenylmethoxycarbonyl)-4-exo-benzyl-6,8-dioxa-3-azabicyclo[3.2.1]octane-7-exo-carboxylic acid
  参考文献：
  名称：

  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

  摘要：

  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.

  DOI：

  10.1021/jo9904967
• 作为产物：
  描述：

  (4R,5R)-5-(methoxycarbonyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid 在 palladium dihydroxide 草酰氯 、 dimethyl sulfide borane 、 硫酸 、 氢气 、 二甲基亚砜 、 N,N-二异丙基乙胺 、 bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 甲苯 为溶剂， 反应 25.08h， 生成 methyl (1S,4S,5S,7R)-4-exo-benzyl-6,8-dioxa-3-azabicyclo[3.2.1]octane-7-exo-carboxylate
  参考文献：
  名称：

  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

  摘要：

  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.

  DOI：

  10.1021/jo9904967

文献信息

• [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.