α-伊米诺γ-乳胶酮和阿基地利酮吡唑酮有机催化环加花法高效构建药物样双环脚手架
Summary
通过简单的有机催化 1, 3-偶极极环加成反应, 不对称地合成了富聚物的双吡咯烷酮—-吡咯烷酮] 骨架。
Abstract
双环支架是许多自然产品中重要的结构子单元之一, 具有多样化和吸引力的生物活性。最近, 我们开发了一种高效的有机催化策略, 为人们提供了一种简便的富对映体双吡咯烷酮 [γ-丁基-吡咯烷酮-4, 4 ‘-吡唑酮] 骨骼。本文通过有机催化剂 1, 3-偶极环加成反应, 证明了用两个螺旋体环碳中心不对称合成类似药物的双环化合物的详细协议。首先制备了α-氨基γ-内酯和烷基化物吡唑酮, 然后在双功能四酰胺有机催化剂的存在下进行环加成反应, 以提供所需的双硫磷高产量和出色的立体选择性。采用手性高效液相色谱法 (hplc) 测定产物的对映体纯度, 用质子核磁共振 (1h nmr) 检测其 d. r. 值。产品的绝对结构是根据 x 射线晶体学分析分配的。这种合成策略使科学家能够在高产量和优良的非对映体和对映性中制备多种双环支架。
Introduction
在天然产物中发现的手性螺旋体化合物, 手性配体和有机金属配合物由于其结构复杂性和生物活性1,2, 已成为有吸引力的合成靶点。 (三)有什么问题吗？具体而言, 双环支架是许多具有重要生物活性4、5的天然产物中的结构子单元, 由三个环和两个刚性尖塔组成。因此, 在过去几十年中, 具有立体控制、光学纯双环骨架的化合物的构建引起了极大的关注。通过有机金属方法和有机催化方法成功合成了大量的螺旋体环化合物及其衍生物, 例如 1, 3-偶极极环加和狄勒-阿尔德等不对称环加。反应6,7,8。然而, 这些分子大多是单旋循环结构, 而双环结构的报道较少, 仅限于建立基于作物醇的双环。
为了获得结构更加多样化的双环化合物, 探讨了环加成合成子在螺旋体环中心不对称构造中的多功能性。特别是双功能的四酰胺有机催化剂, 偶氮胺 ylide12,13,14, 如α-两乙酮-内酯, 和双极体, 如烷基脂酰胺吡唑酮15,16 ,17, 能够经历一个简单的 1, 3-偶极环加成, 以构建具有多个立体中心的双吡咯环骨骼, 使它们成为完美的螺旋体环化合成子 (图 1)。经过有机催化剂和反应溶剂结构的优化, 该循环加成工艺有效地为所需产品提供了较高的产率和优良的对映体和环氧选择性。此外, 这种反应表现出相对较高的结构耐受性, 在广泛的环加成合成子与不同的功能群18。这种新方法通过简单的有机催化环加成, 在结构多样性导向中的应用, 为各种具有两个第四纪螺旋体的高功能化类似药物的化合物提供了有效的访问合成了这一类有趣的化合物。
Protocol
注意: 使用前请查阅所有相关材料安全数据表 (msds)。所使用的化学品和溶剂都是试剂级的, 使用时没有进一步的净化。所有涉及空气或对水分敏感的试剂或中间体的反应都是在氩气氛下进行的。 1. α-芳基吡唑酮的制备 准备工作吡唑酮 在室温下从刻度缸中加入40毫升的冰醋酸, 加入250毫升的圆底烧瓶。在加入联氨 (1 当量, 1.58 摩尔) 和乙?…
Representative Results
在25°c 时, 在二氯甲烷 (dcm) 有机催化剂的存在下, 对各种氢键供体双功能有机催化剂进行了检测 (表 1)。具有代表性的有机催化剂合成过程如图 1所示。通过对不同有机催化剂的筛选 (表 1, 第1-6 项), c5 具有优异的立体选择性 (94% ee, & gt;20:1 d. r., 第5个条目) 和最佳产率 (85% 收率)。溶剂的进一步优化 (表 1, 条目 7-11) ?…
Discussion
双吡咯 [γ-丁基吡咯烷酮-4, 4 ‘-吡唑酮] 骨架的成功制备取决于许多因素。
这种一步不对称环加成工艺的关键步骤是双功能四酰胺催化剂对α-芳基吡唑酮1a 和环咪诺酯2a 的协同作用。它是通过催化剂作为氢键供体和两个反应基板之间形成多个分子间氢键来实现的。因此, 在大量的位阻下, c5 在所有的氢键供体双功能有机催化剂中表现出最佳的立体选择性…
Disclosures
The authors have nothing to disclose.
Acknowledgements
作者非常感谢国家自然科学基金 (第21708051至 x. c. 号) 的资助。
Materials
| Acetonitrile, anhydrous, 99.9% | Innochem (China) | A0080 | |
| α-amino-γ-butyrolactone hydrobromide, 98% | Alfa Aesar | B23148 | |
| 3,5-bis(trifluoromethyl)aniline, 98+% | Adamas | 48611B | |
| Dichloromethane, 99.5% | Greagent | G81014H | |
| 3,4-dimethoxycyclobut-3-ene-1,2-dione, 98+% | Leyan (China) | 1062550 | |
| Ethanol, 99.5% | Greagent | G73537B | |
| Ethyl acetate, 99.5% | Greagent | G23272L | |
| Ethyl ether,anhydrous,99.5% | Greagent | G69159B | |
| Ethyl 3-oxobutanoate, 98% | TCI | A0649 | |
| 4-fluorobenzaldehyde, 98% | Innochem (China) | A24295 | |
| Glacial acetic acid, 99.5% | Greagent | G73562B | |
| Magnesium oxide, 99+% | Alfa Aesar | 44733 | |
| Magnesium sulfate, 98% | Greagent | G80872C | |
| Methanol, 99.5% | Greagent | G75851A | |
| Petroleum ether | Greagent | G84208D | |
| Phenylhydrazine, 98% | Innochem (China) | A57671 | |
| (S)-(6-methoxyquinolin-4-yl)((1S,2R,4S,5R)-5-vinylquinuclidin-2-yl)methanamine | DAICEL Group | 111240 | |
| Sodium sulfate,anhydrous,99% | Greagent | G82667A | |
| Thiophene-2-carbaldehyde, 98% | J & K scientific (China) | 124605 | |
| Triethylamine, 99% | J & k scientific (China) | 432915 |
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Tags
Keyword Extraction:Drug-like Bispirocyclic ScaffoldsOrganocatalytic Cycloadditionsα-imino γ-lactonesAlkylidene PyrazolonesBipolar CycloadditionBispirocyclic CompoundsNatural ProductsBiological ActivitiesChiral Spiral CentersHigh YieldsStereoselectivityPyrazoloneHydrazineEthyl Acetoacetateα-arylidiene PyrazolinoneBenzaldehydeMagnesium OxideAcetonitrile
Cite This Article
Zhou, Y., Chen, N., Cheng, Y., Cai, X. Efficient Construction of Drug-like Bispirocyclic Scaffolds Via Organocatalytic Cycloadditions of α-Imino γ-Lactones and Alkylidene Pyrazolones. J. Vis. Exp. (144), e59155, doi:10.3791/59155 (2019).