(2S,4RS,8S)-di-tert-butyl 4-carbomethoxy-5-oxo-2,8-bisazelate | 185121-26-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 芴
• 英文名称: (2S,4RS,8S)-di-tert-butyl 4-carbomethoxy-5-oxo-2,8-bisazelate
• 英文别名: 1-O,7-O-ditert-butyl 3-O-methyl (1S,7S)-4-oxo-1,7-bis[(9-phenylfluoren-9-yl)amino]heptane-1,3,7-tricarboxylate
• CAS: 185121-26-0
• 化学式: C₅₇H₅₈N₂O₇
• 分子量: 883.097
• InChiKey: LFQWPMCYGXRZCM-WZSDMLEESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  10.4
• 重原子数：
  66
• 可旋转键数：
  20
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  120
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  (2S,4RS,8S)-di-tert-butyl 4-carbomethoxy-5-oxo-2,8-bisazelate 在 sodium hydroxide 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 1.0h， 以99%的产率得到(2S,8S)-di-tert-butyl 5-oxo-2,8-di-[N-(9-(9-phenylfluorenyl))amino]azelate
  参考文献：
  名称：

  Rigid Dipeptide Mimetics:  Efficient Synthesis of Enantiopure Indolizidinone Amino Acids

  摘要：

  An effective means to synthesize indolizidinone amino acids has been developed and furnishes all possible stereoisomers of these conformationally rigid mimetics of peptide secondary structures. Inexpensive glutamic acid was employed as chiral educt in a Claisen condensation/reductive amination/lactam cyclization sequence that furnished stereoselectively azabicyclo[3.4.0]alkane amino acid 1. Enantiopure (3S,6S,9S)- and (3R,6R,9R)-2-oxo-3-N-(BOC)amino-1-azabicyclo[4.3.0]nonane-9-carboxylic acids ((3S,6S,9S)- and (3R,6R,9R)-1) were respectively synthesized from L- and D-N-(PhF)glutamates 2 (PhF = 9-(9-phenylfluorenyl)). Slow addition of sodium bis(trimethylsilyl)amide to 2 provided good to excellent yields of beta-keto esters 3, which were subsequently hydrolyzed and decarboxylated to give symmetric alpha,omega-bis[N-(PhF)amino]azelate delta-ketones 5. Augmentation of hydrogen pressure increased diastereoselectivity in reductive aminations with 5 and afforded 5-alkylprolines 8 and 10. Lactam formation on exposure of 10 to triethylamine and N-protection with di-tert-butyl dicarbonate gave methyl 2-oxo-3-[N-(BOC)amino]-1-azabicyclo[4.3.0]nonane-9-carboxylate (12) which on C-terminal ester hydrolysis with hydroxide ion gave enantiopure [N-(BOC)amino]indolizidinone acid 1. Alternatively, hydride addition to ketone 5a gave symmetric alpha,omega-bis[N-(PhF)amino]azelate delta-alcohol 7a, which upon mesylation, and intramolecular S(N)2 displacement by the PhF amine gave specifically cis-5-alkylproline 15 that was similarly converted to (3S,6S,9S)-1. In addition, epimerization of the C-9 stereocenter of (3S,6S,9S)-[N-(BOC)amino]-indolizidinone methyl ester 12 with NaN(SiMe(3))(2) and ester hydrolysis gave (3S,6S,9R)-indolizidinone amino acid (3S,6S,9R)-1. By providing efficient methodology for synthesizing all of the possible stereoisomers of enantiopure indolizidinone amino acid 1, our route is specifically designed to enhance the general use of these peptide mimetics in the exploration of conformation-activity relationships of various biologically active peptides.

  DOI：

  10.1021/jo961872f
• 作为产物：
  描述：

  L-α-tert-butyl γ-methyl N-(9-(9-phenylfluorenyl))glutamate 在 sodium hexamethyldisilazane 作用下， 以 四氢呋喃 为溶剂， 反应 1.5h， 以74%的产率得到(2S,4RS,8S)-di-tert-butyl 4-carbomethoxy-5-oxo-2,8-bisazelate
  参考文献：
  名称：

  Rigid Dipeptide Mimetics:  Efficient Synthesis of Enantiopure Indolizidinone Amino Acids

  摘要：

  An effective means to synthesize indolizidinone amino acids has been developed and furnishes all possible stereoisomers of these conformationally rigid mimetics of peptide secondary structures. Inexpensive glutamic acid was employed as chiral educt in a Claisen condensation/reductive amination/lactam cyclization sequence that furnished stereoselectively azabicyclo[3.4.0]alkane amino acid 1. Enantiopure (3S,6S,9S)- and (3R,6R,9R)-2-oxo-3-N-(BOC)amino-1-azabicyclo[4.3.0]nonane-9-carboxylic acids ((3S,6S,9S)- and (3R,6R,9R)-1) were respectively synthesized from L- and D-N-(PhF)glutamates 2 (PhF = 9-(9-phenylfluorenyl)). Slow addition of sodium bis(trimethylsilyl)amide to 2 provided good to excellent yields of beta-keto esters 3, which were subsequently hydrolyzed and decarboxylated to give symmetric alpha,omega-bis[N-(PhF)amino]azelate delta-ketones 5. Augmentation of hydrogen pressure increased diastereoselectivity in reductive aminations with 5 and afforded 5-alkylprolines 8 and 10. Lactam formation on exposure of 10 to triethylamine and N-protection with di-tert-butyl dicarbonate gave methyl 2-oxo-3-[N-(BOC)amino]-1-azabicyclo[4.3.0]nonane-9-carboxylate (12) which on C-terminal ester hydrolysis with hydroxide ion gave enantiopure [N-(BOC)amino]indolizidinone acid 1. Alternatively, hydride addition to ketone 5a gave symmetric alpha,omega-bis[N-(PhF)amino]azelate delta-alcohol 7a, which upon mesylation, and intramolecular S(N)2 displacement by the PhF amine gave specifically cis-5-alkylproline 15 that was similarly converted to (3S,6S,9S)-1. In addition, epimerization of the C-9 stereocenter of (3S,6S,9S)-[N-(BOC)amino]-indolizidinone methyl ester 12 with NaN(SiMe(3))(2) and ester hydrolysis gave (3S,6S,9R)-indolizidinone amino acid (3S,6S,9R)-1. By providing efficient methodology for synthesizing all of the possible stereoisomers of enantiopure indolizidinone amino acid 1, our route is specifically designed to enhance the general use of these peptide mimetics in the exploration of conformation-activity relationships of various biologically active peptides.

  DOI：

  10.1021/jo961872f

文献信息

• Mimicry of Peptide Backbone Geometry and Heteroatomic Side-Chain Functionality:  Synthesis of Enantiopure Indolizidin-2-one Amino Acids Possessing Alcohol, Acid, and Azide Functional Groups
  作者：Felix Polyak、William D. Lubell

  DOI：10.1021/jo001251t

  日期：2001.2.1

  and 8, and indolizidin-2-one amino dicarboxylate 9. Both 5- and 7-hydroxymethylindolizidinone amino acids 5 and 6 were obtained from sequences commencing with the Claisen condensation of alpha-tert-butyl gamma-methyl l-N-(PhF)-L-glutamate to furnish di-tert-butyl 4-carbomethoxy-5-oxo-2,8-di-[N-(PhF)amino]azelate 10 (PhF = 9-(9-phenylfluorenyl)). Subsequent hydride reduction of 10 to an isomeric mixture

  通过修饰羟甲基吲哚啶酮酮氨基酸5和6，合成了在5和7位具有各种杂原子侧链的吲哚嗪酮氨基酸。用叠氮化钠置换醇5和6中的甲磺酸盐，以及氧化乙醇5 ，已经被用于提供正交保护的吲哚并丁-2-一二氨基羧酸盐7和8，以及吲哚并嗪-2-一二氨基氨基羧酸9。5-和7-羟甲基吲哚嗪酮酮氨基酸5和6均从克莱森缩合反应开始的序列中获得。 α-叔丁基γ-甲基lN-（PhF）-L-谷氨酸制备4-羧甲氧基-5-氧代-2,8-二-[N-（PhF）氨基]壬二酸二叔丁基酯10（ PhF ＝ 9-（9-苯基芴基）。随后将氢化物还原10为二醇12的异构体混合物 伯醇作为叔丁基二甲基甲硅烷基醚14的选择性保护和仲醇的氧化产生了4-叔丁基二甲基甲硅烷基氧基甲基-5-氧代-2,8-二-[N-（PhF）氨基]壬二酸酯的二叔丁基作为可分离的非对映异构体混合物。然后通过具有还原性胺化，甲磺酸盐置换和内酰胺环化的路线将直链酮15和醇14转化
• Synthesis of Enantiopure .alpha.,.omega.-Diamino Dicarboxylates and Azabicycloalkane Amino Acids by Claisen Condensation of .alpha.-[N-(Phenylfluorenyl)amino] Dicarboxylates
  作者：Henry-Georges Lombart、William D. Lubell

  DOI：10.1021/jo00100a008

  日期：1994.10

  Enantiomerically pure (3S,6S,9S)-2-oxo-3-(N-BOC-amino)-1-azabicyclo[4.3.0]nonane-9-carboxylic acid ((3S,6S,9S)-1) was prepared in 39% overall yield from alpha-tert-butyl gamma-methyl N-(9-(9-phenylfluorenyl))glutamate (5) using a Claisen condensation/reductive amination/lactam cyclization sequence.
• Rigid Dipeptide Mimetics:  Efficient Synthesis of Enantiopure Indolizidinone Amino Acids
  作者：Henry-Georges Lombart、William D. Lubell

  DOI：10.1021/jo961872f

  日期：1996.1.1

  An effective means to synthesize indolizidinone amino acids has been developed and furnishes all possible stereoisomers of these conformationally rigid mimetics of peptide secondary structures. Inexpensive glutamic acid was employed as chiral educt in a Claisen condensation/reductive amination/lactam cyclization sequence that furnished stereoselectively azabicyclo[3.4.0]alkane amino acid 1. Enantiopure (3S,6S,9S)- and (3R,6R,9R)-2-oxo-3-N-(BOC)amino-1-azabicyclo[4.3.0]nonane-9-carboxylic acids ((3S,6S,9S)- and (3R,6R,9R)-1) were respectively synthesized from L- and D-N-(PhF)glutamates 2 (PhF = 9-(9-phenylfluorenyl)). Slow addition of sodium bis(trimethylsilyl)amide to 2 provided good to excellent yields of beta-keto esters 3, which were subsequently hydrolyzed and decarboxylated to give symmetric alpha,omega-bis[N-(PhF)amino]azelate delta-ketones 5. Augmentation of hydrogen pressure increased diastereoselectivity in reductive aminations with 5 and afforded 5-alkylprolines 8 and 10. Lactam formation on exposure of 10 to triethylamine and N-protection with di-tert-butyl dicarbonate gave methyl 2-oxo-3-[N-(BOC)amino]-1-azabicyclo[4.3.0]nonane-9-carboxylate (12) which on C-terminal ester hydrolysis with hydroxide ion gave enantiopure [N-(BOC)amino]indolizidinone acid 1. Alternatively, hydride addition to ketone 5a gave symmetric alpha,omega-bis[N-(PhF)amino]azelate delta-alcohol 7a, which upon mesylation, and intramolecular S(N)2 displacement by the PhF amine gave specifically cis-5-alkylproline 15 that was similarly converted to (3S,6S,9S)-1. In addition, epimerization of the C-9 stereocenter of (3S,6S,9S)-[N-(BOC)amino]-indolizidinone methyl ester 12 with NaN(SiMe(3))(2) and ester hydrolysis gave (3S,6S,9R)-indolizidinone amino acid (3S,6S,9R)-1. By providing efficient methodology for synthesizing all of the possible stereoisomers of enantiopure indolizidinone amino acid 1, our route is specifically designed to enhance the general use of these peptide mimetics in the exploration of conformation-activity relationships of various biologically active peptides.