3-tert-butoxycarbonylamino-4-oxohexahydropyrrolo[2,1-b][1,3]oxazine-6-carboxylic acid methyl ester | 174709-52-5

• 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: 3-tert-butoxycarbonylamino-4-oxohexahydropyrrolo[2,1-b][1,3]oxazine-6-carboxylic acid methyl ester
• 英文别名: (3S,6S,9S)-1-aza-3-tert-butoxycarbonylamino-9-methoxycarbonyl-5-oxa-2-oxobicyclo[4.3.0]nonane；methyl (3S,6S,8aS)-3-[(2-methylpropan-2-yl)oxycarbonylamino]-4-oxo-2,3,6,7,8,8a-hexahydropyrrolo[2,1-b][1,3]oxazine-6-carboxylate
• CAS: 174709-52-5
• 化学式: C₁₄H₂₂N₂O₆
• 分子量: 314.338
• InChiKey: PWQLJURBQZDRCE-GUBZILKMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  22
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.79
• 拓扑面积：
  94.2
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  3-tert-butoxycarbonylamino-4-oxohexahydropyrrolo[2,1-b][1,3]oxazine-6-carboxylic acid methyl ester 在 sodium hydroxide 作用下， 以 甲醇 为溶剂， 反应 1.0h， 以30%的产率得到Boc-(R)-Ser-(S-ec)-(S)-Pro-OH
  参考文献：
  名称：

  Electrochemical Cyclization of Dipeptides To Form Novel Bicyclic, Reverse-Turn Peptidomimetics. 2. Synthesis and Conformational Analysis of 6,5-Bicyclic Systems

  摘要：

  Novel, highly constrained, 6,5-bicyclic dipeptides (1-aza-5-oxa-2-oxoibicyclo[4.3.0]nonane ring skeletons, 2) have been synthesized by a one-step electrochemical cyclization from the dipeptides Boc-(S)-serine-(S)-proline-OMe (Boc-(S)-Ser-(S)-Pro-OMe, 3) and Boc-(R,S)-alpha-methylserine-(S)-proline-OMe (Boc-(R,S)-alpha-MeS-(S)-Pro-OMe, 12) in yields of 10-25% and 41%, respectively. The one-pot reaction uses selective anodic amide oxidation to generate an N-acyliminium cation which is trapped by an intramolecular hydroxyl group. The cyclization of Boc-(S)-Ser-(S)-Pro-OMe (3) to the 6,5-bicyclic skeleton 4 was highly diastereoselective, generating a new chiral center with an S configuration. This bicyclic compound was sufficiently stable to trifluoroacetic acid and anhydrous hydrofluoric acid for use in standard solid phase peptide synthesis methodologies. Oxidation of Boc-(R,S)-MeS-(S)-Pro-OMe (12) gave different results for each diastereoisomer. Cyclization only occurred for the S,S-diastereoisomer with very low stereoselectivity (6:4 ratio of diastereomers) at the newly-formed ring fusion. In terms of conformation, the 6,5-bicyclic system restricts two (psi(2) and phi(3)) Of the four torsion angles that characterize a reverse turn. Conformational analyses of tetrapeptides containing the 6,5-bicyclic system were performed using Monte Carlo conformational searches and molecular dynamics simulations. AU of the eight possible diastereomers arising from the three stereogenic centers (Ser C alpha, Pro C alpha, and newly formed bridgehead) were considered. These studies revealed that the 3S,7S,10S and 3R,7R,10R configurations are effective turn inducers although the torsion angles of the backbone do not exactly mimic those of classical beta-turns. Other diastereomers were found to stabilize the peptide backbone in an extended conformation.

  DOI：

  10.1021/jo950898o
• 作为产物：
  描述：

  1-(2-tert-butoxycarbonylamino-3-hydroxypropionyl)-5-methoxypyrrolidine-2-carboxylic acid methyl ester 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 1.5h， 以81%的产率得到3-tert-butoxycarbonylamino-4-oxohexahydropyrrolo[2,1-b][1,3]oxazine-6-carboxylic acid methyl ester
  参考文献：
  名称：

  Building Functionalized Peptidomimetics:  Use of Electroauxiliaries for Introducing N-Acyliminium Ions into Peptides

  摘要：

  A series of silyl-substituted amino acids have been synthesized, inserted into peptides, and then employed as precursors for oxidatively generating reactive N-acyliminium ions. Both electrochemical and chemical oxidation procedures have been employed. N-Acyliminium ion generation in a solid-phase substrate as well as application to a small library of functionalized dipeptides has been demonstrated. Limitations in terms of how electron-rich the silyl groups can be as well as the compatibility of multiple silyl groups within a longer peptide are defined.

  DOI：

  10.1021/ja064737l

文献信息

• Highly Efficient Synthesis of Azabicyclo[<i>x</i>.<i>y</i>.0]alkane Amino Acids and Congeners by Means of Rh-Catalyzed Cyclohydrocarbonylation
  作者：Wen-Hua Chiou、Nobihiro Mizutani、Iwao Ojima

  DOI：10.1021/jo061692y

  日期：2007.3.1

  A highly efficient method for the synthesis of 1-azabicyclo[x.y.0]alkane amino acid derivatives and their congeners by means of extremely regioselective cyclohydrocarbonylation (CHC) is described. The CHC reactions are catalyzed by Rh-BIPHEPHOS complex under mild conditions. These CHC reaction processes involve (i) an extremely linear-selective hydroformylation of the terminal alkene moiety of a dehydrodipeptide

  合成1-氮杂双环[ x的高效方法。ÿ 0.0]烷烃氨基酸衍生物和由极区域选择性cyclohydrocarbonylation（CHC）的装置及其同类物进行说明。在温和条件下，Rh-BIPHEPHOS络合物催化CHC反应。这些CHC反应过程涉及（i）脱氢二肽底物的末端烯烃部分的极线性选择性加氢甲酰基化;（ii）分子内缩合形成环状N-酰亚胺关键中间体;和（iii）通过分子内亲核加成第二次环化环状N-酰基亚氨基部分的杂原子亲核基团得到相应的1-氮杂双环[ x]。ÿ.0]系统。在大多数情况下，此连续的双环化过程以极高的非对映选择性进行。此方法已成功应用于1-azabicyclo [4.4.0]，-[5.4.0]和-[4.3.0]系统的合成。介绍了反应的机理和观察到的极高非对映选择性的原理。这种Rh催化的CHC方法将用作合成各种构象受限的二肽，拟肽，生物碱和其他具有生物活性的天然或非天然产物的高效且通用的方法。
• Building Functionalized Peptidomimetics:  Use of Electroauxiliaries for Introducing <i>N</i>-Acyliminium Ions into Peptides
  作者：Haizhou Sun、Connor Martin、David Kesselring、Rebecca Keller、Kevin D. Moeller

  DOI：10.1021/ja064737l

  日期：2006.10.1

  A series of silyl-substituted amino acids have been synthesized, inserted into peptides, and then employed as precursors for oxidatively generating reactive N-acyliminium ions. Both electrochemical and chemical oxidation procedures have been employed. N-Acyliminium ion generation in a solid-phase substrate as well as application to a small library of functionalized dipeptides has been demonstrated. Limitations in terms of how electron-rich the silyl groups can be as well as the compatibility of multiple silyl groups within a longer peptide are defined.
• Electrochemical Cyclization of Dipeptides To Form Novel Bicyclic, Reverse-Turn Peptidomimetics. 2. Synthesis and Conformational Analysis of 6,5-Bicyclic Systems
  作者：Urszula Slomczynska、David K. Chalmers、Fabrice Cornille、Mark L. Smythe、Denise D. Beusen、Kevin D. Moeller、Garland R. Marshall

  DOI：10.1021/jo950898o

  日期：1996.1.1

  Novel, highly constrained, 6,5-bicyclic dipeptides (1-aza-5-oxa-2-oxoibicyclo[4.3.0]nonane ring skeletons, 2) have been synthesized by a one-step electrochemical cyclization from the dipeptides Boc-(S)-serine-(S)-proline-OMe (Boc-(S)-Ser-(S)-Pro-OMe, 3) and Boc-(R,S)-alpha-methylserine-(S)-proline-OMe (Boc-(R,S)-alpha-MeS-(S)-Pro-OMe, 12) in yields of 10-25% and 41%, respectively. The one-pot reaction uses selective anodic amide oxidation to generate an N-acyliminium cation which is trapped by an intramolecular hydroxyl group. The cyclization of Boc-(S)-Ser-(S)-Pro-OMe (3) to the 6,5-bicyclic skeleton 4 was highly diastereoselective, generating a new chiral center with an S configuration. This bicyclic compound was sufficiently stable to trifluoroacetic acid and anhydrous hydrofluoric acid for use in standard solid phase peptide synthesis methodologies. Oxidation of Boc-(R,S)-MeS-(S)-Pro-OMe (12) gave different results for each diastereoisomer. Cyclization only occurred for the S,S-diastereoisomer with very low stereoselectivity (6:4 ratio of diastereomers) at the newly-formed ring fusion. In terms of conformation, the 6,5-bicyclic system restricts two (psi(2) and phi(3)) Of the four torsion angles that characterize a reverse turn. Conformational analyses of tetrapeptides containing the 6,5-bicyclic system were performed using Monte Carlo conformational searches and molecular dynamics simulations. AU of the eight possible diastereomers arising from the three stereogenic centers (Ser C alpha, Pro C alpha, and newly formed bridgehead) were considered. These studies revealed that the 3S,7S,10S and 3R,7R,10R configurations are effective turn inducers although the torsion angles of the backbone do not exactly mimic those of classical beta-turns. Other diastereomers were found to stabilize the peptide backbone in an extended conformation.