(2S,3R)-3-((S)-1-(叔丁氧基羰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酸 | 133164-08-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 中文名称: (2S,3R)-3-((S)-1-(叔丁氧基羰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酸
• 英文名称: <2S-<2R*,α(R*),β(S*)>>-1-<(1,1-Dimethylethoxy)carbonyl>-β-methoxy-α-methyl-2-pyrrolidinepropanoic acid
• 英文别名: (2S,3R)-3-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-3-meth-oxy-2-methylpropanoic acid；(2S,3R,4S)-3-(N-tert-butoxycarbonyl-2'-pyrrolidinyl)-3-methoxy-2-methylpropanoic acid；N-(tert-Butoxycarbonyl)-(2S,3R,2'S)-dolaproine；N-Boc-(2S)-iso-dolaproine；(2S,3R)-3-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanoic acid；(2S,3R)-3-methoxy-2-methyl-3-[(2S)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidin-2-yl]propanoic acid
• CAS: 133164-08-6
• 化学式: C₁₄H₂₅NO₅
• 分子量: 287.356
• InChiKey: LNEHHTWYEBGHBY-GARJFASQSA-N

物化性质

• 沸点：
  397.8±17.0 °C(Predicted)
• 密度：
  1.133±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  20
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.86
• 拓扑面积：
  76.1
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (2S,3R)-3-((S)-1-(叔丁氧基羰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酸 在 盐酸 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 、 乙腈 为溶剂， 反应 4.0h， 生成 (2S,3R)-3-methoxy-2-methyl-N-((S)-2-phenyl-1-(thiazol-2-yl)ethyl)-3-((S)-pyrrolidin-2-yl)propanamide
  参考文献：
  名称：

  新型dolastatin 10类似物的合成和抗肿瘤活性。

  摘要：

  Dolastatin 10（1）是有效的抗肿瘤五肽。合成了各自在组成氨基酸衍生物之一上修饰的新型dolastatin 10类似物，并评估了其对小鼠中P388白血病的抗肿瘤活性。讨论了抗肿瘤活性的结构要求。一些类似物31c，35c，38b和50c在体内显示出出色的活性。选择没有噻唑基团1的高活性50c作为抗肿瘤剂进行进一步开发。

  DOI：

  10.1248/cpb.43.1706
• 作为产物：
  描述：

  ethyl (2S,3R,4S)-3-(N-tert-butoxycarbonyl-2'-pyrrolidinyl)-3-methoxy-2-methyl-propanoate 在 sodium hydroxide 作用下， 以 乙醇 为溶剂， 反应 14.5h， 以80%的产率得到(2S,3R)-3-((S)-1-(叔丁氧基羰基)吡咯烷-2-基)-3-甲氧基-2-甲基丙酸
  参考文献：
  名称：

  Stereoselective Synthesis of iso-Dolaproine via Dynamic Kinetic Resolution

  摘要：

  [GRAPHCIS]An efficient multigram-scale synthesis of optically pure Boc-(2S,3R,4S)-iso-dolaproine is reported using dynamic kinetic resolution (DKR), The catalytic asymmetric hydrogenation of ethyl (4S)-3-(2 ' -pyrrolidinyl)-3-oxo-2-methyl propanoate hydrochloride using in situ generated Ru[(S)MeO-BIPHEP]Br-2 catalyst affords the anti beta -hydroxy alpha -methyl ester quantitatively, The two new stereogenic centers are simultaneously controlled with high diastereoselectivity.

  DOI：

  10.1021/ol015955g

文献信息

• Synthesis and biological activity evaluation of dolastatin 10 analogues with N-terminal modifications
  作者：Xin Wang、Suzhen Dong、Dengke Feng、Yazhou Chen、Mingliang Ma、Wenhao Hu

  DOI：10.1016/j.tet.2017.03.006

  日期：2017.4

  We have described the synthesis of the two complex units (2R,3R,4S)-dolaproine (Dap) and (3R,4S,5S)-dolaisoleuine (Dil) of dolastatin 10 from natural amino acids. The stereoselective syntheses of N-Boc-Dap (4a) and N-Boc-(2S)-iso-Dap (4b) were performed by employing crotylation of N-Boc-l-prolinal as a key step. Barbier-type allylation of N-Boc-l-isoleucinal provided a mild and convenient approach

  我们已经描述了从天然氨基酸合成dolastatin 10的两个复杂单元（2 R，3 R，4 S）-dolaproine（Dap）和（3 R，4 S，5 S）-dolaisoleuine（Dil）的合成。的立体选择性合成N-的Boc-DAP（4A）和Ñ -Boc-（2小号） -异-Dap（图4b）中采用的crotylation进行Ñ -Boc-升脯氨醛作为关键步骤。N - Boc- 1-异亮氨酸的Barbier型烯丙基化为合成N - Boc- 1-异丁香提供了温和而方便的方法Ñ -Boc-语（图5a）和Ñ -Boc-（3小号） -异-Dil（图5b）。基于已知的化合物单甲基auristatin F（MMAF，3），已经设计并合成了具有N末端修饰的十个dolastatin 10类似物。与MMAF（3）相比，其中四种化合物在体外显示出对HCT 116人结肠癌细胞的增强效力。
• Monomethylvaline Compounds Having Phenylalanine Carboxy Modifications at the C-Terminus
  申请人：Doronina Svetlana O.

  公开号：US20090111756A1

  公开（公告）日：2009-04-30

  Auristatin peptide analogs of MeVal-Val-Dil-Dap-Phe (MMAF) having a carboxylic acid equivalent at the C-terminal phenylalanine were prepared and attached to ligands through various linkers, including maleimidocaproyl-val-cit-PAB. The resulting ligand drug conjugates were active in vitro and in vivo.

  具有C-末端苯丙氨酸羧基酸等效物的MeVal-Val-Dil-Dap-Phe（MMAF）的Auristatin肽类类似物已经制备，并通过各种连接剂（包括maleimidocaproyl-val-cit-PAB）连接到配体上。 结果得到的配体药物结合物在体外和体内均具有活性。
• The Dolastatins. 17. Synthesis of Dolaproine and Related Diastereoisomers
  作者：George R. Pettit、Sheo Bux Singh、Delbert L. Herald、Paul Lloyd-Williams、Darko Kantoci、Douglas D. Burkett、Jozsef Barkoczy、Fiona Hogan、Terah R. Wardlaw

  DOI：10.1021/jo00100a034

  日期：1994.10

  A special challenge in accomplishing the total synthesis of dolastatin 10(1) entailed deducing the absolute configuration of the new beta-methoxy-gamma-amino acid component dolaproine (2) as 2S,2'R,3'R and devising a stereoselective synthesis. Synthesis of this unusual (S)-proline-derived unit as its N-tert-butoxycarbonyl derivative (9b) and three stereoisomers (9a, 9c, 9d) has been summarized. The diastereoisomers were assembled by an aldol condensation between aldehyde 5, derived from (S)-proline, with chiral propionate 6, followed by methylation and cleavage of the chiral directing ester group by hydrogenolysis to afford methyl ethers 9a-d. The absolute stereochemistry of the diastereoisomers was determined by a combination of X-ray crystallographic analyses (of 9a and lactam 11b formed from isomer 7a) and high-field (400 MHz) NMR studies. By using each of these isomers in a series of dolastatin 10 syntheses the stereochemistry of the dolaproine (2) unit of natural (-)-dolastatin 10 (1) was shown to be 2S,2'R,3'R.
• The Dolastatins. 22. Synthesis Of Boc-Dolaproinyl Dolaphenine and Four Related Chiral Isomers
  作者：George R. Pettit、Jozsef Barkoczy、Jayaram K. Srirangam、Sheo Bux Singh、Delbert L. Herald、Michael D. Williams、Darko Kantoci、Fiona Hogan、Thomas L. Groy

  DOI：10.1021/jo00090a009

  日期：1994.6

  Synthesis of the dolastatin 10 (1) dipeptide segment N-(tert-butoxycarbonyl)-dolaproinyl-dolaphenine (2, Boc-Dap-Doe) and four chiral isomers (3-5, 13) has been summarized. Formation of the amide bond was readily accomplished employing diethyl cyanophosphonate. The stereochemical assignments for Boc-Dap-Doe (2) and Boc-Dap-(6R)-Doe (3) were confirmed by X-ray crystal structure analyses.
• US8871720B2
  申请人：——

  公开号：US8871720B2

  公开（公告）日：2014-10-28