稳定笼 Aziridinium 离子的制备及其开环 Azaheterocycles 的合成
Summary
笼 aziridinium 离子, 如 1-azoniabicyclo [4.1. 0] 庚烷磺酸盐是由 2-[4-tolenesulfonyloxybutyl] 氮丙啶, 用于制备替代的 piperidines 和 azepanes 通过地-和立体环形膨胀与各种亲核试剂。这一高效的协议允许我们准备各种 azaheterocycles, 包括自然产品, 如 fagomine, febrifugine 模拟和 balanol。
Abstract
笼 aziridinium 离子是通过在氮丙啶环中的氮原子的内部亲核攻击去除适当的离开群而产生的。笼 aziridinium 离子的效用, 特别是 1-azoniabicyclo [3.1. 0] 己烷和 1-azoniabicyclo [4.1. 0] 庚烷磺酸盐突出在氮丙啶环开口由亲核试剂与释放环应变产生相应的环扩张 azaheterocycles, 如吡咯烷, 哌啶和 azepane 与不同的取代基在环上的范围-和立体方式。在此, 我们报告了一个简单和方便的方法, 以制备稳定的 1-杂双环 [4.1. 0] 庚烷磺酸盐后, 选择性环开口通过亲核攻击无论是在桥梁或在桥头碳产生哌啶和 azepane环, 分别。这一综合策略使我们能够高效地制备含有哌啶和 azepane 的生物活性天然产物, 包括 sedamine、allosedamine、fagomine 和 balanol。
Introduction
在三元循环化合物中, 氮丙啶具有类似的环应变能, 如丙烷和环氧乙烷, 可通过环形开口1、2、3来承受各种含氮循环和非环状化合物。然而, 氮丙啶的特性和反应性取决于环氮的取代基。氮丙啶与一个电子撤退的小组在圆环氮气4, 被叫 “激活的氮丙啶”, 被激活与接踵而来的亲核试剂反应, 不用任何另外的活化试剂。另一方面, “非活化氮丙啶” 与电子捐赠取代基在氮气是相当稳定和惰性的亲核试剂, 除非它被激活作为一个 aziridinium 离子作为Ia (图 1a)5,6,7. 非活化氮丙啶环的开启取决于各种因素, 如 C2 的取代基和氮丙啶的 C3 碳、亲电性激活氮丙啶环和传入的亲核试剂。由于亲核试剂对开环反应的高反应性, aziridinium 离子的分离和表征是不可能的, 但它的形成和特征 spectroscopically 与非亲核反负离子5,8,9,10. aziridinium 离子的立体环开放反应由适当的亲核试剂产生含氮非循环有价值分子 (pi和pii)5, 6,7,8,9,10。
同样, 笼 aziridinium 离子 (Ib) 可能是通过去除组内的氮丙啶环氮的亲核攻击而产生的 (图 1b)。然后, 该中间体通过环应变的释放与传入亲核试剂进行环形扩展。笼 aziridinium 离子的形成和稳定性取决于许多因素, 如取代基、环的大小和溶剂介质9。氮丙啶环扩展的立体选择性是其综合效用的一个关键方面, 它依赖于起始基板的取代性和应用亲核试剂的特性。
在我们早期的研究中, 我们成功地准备了 1-azoniabicyclo [3.1. 0] 己烷磺酸盐Ib (n = 1), 其随后的环扩张导致了吡咯烷和哌啶的形成 (piii和piv, n= 1,图 1)8。作为我们继续研究笼 aziridinium 离子化学的一部分, 我们在这里描述了 1-azoniabicyclo [4.1. 0] 庚烷磺酸盐Ib (n = 2) 的形成, 作为一个代表性的例子。这是由 2-(4-toluensulfonyloxybutyl) 氮丙啶和它的圆环扩展被触发由亲核试剂负担得起价值的哌啶和 azepane (pi和pii, n = 2,图 1) 以各种各样的取代在圆环11附近。enantiopure 氮丙啶 4-[(r)-1 (r)-1-苯) aziridin 2 基] 氨基正丁-1-ol (1) 的扩环导致取代 azaheterocycles 的不对称合成, 适用于生物具有哌啶和 azepane 骨架的活性分子。该合成协议已应用于各种化合物, 从简单的 2-cyanomethylpiperidine 5f, 2-acetyloxymethylpiperidine 5h和 3-hydroxyazepane 6j到更复杂的分子, 包括自然产品如 fagomine (9), febrifugine 模拟 (12) 和 balanol (15) 在光学纯净的形式11。
Protocol
Representative Results
Discussion
哌啶和 azepane 是 azaheterocycles 许多救生药物和抗生素中最丰富的两种, 包括各种生物活性天然产物16。为了获得 enantiopure 哌啶 (5) 和 azepane (6) 与不同的取代基, 我们得以一个有效的合成方法通过形成 1-azoniabicyclo [4.1. 0] 庚烷磺酸盐从 entiopure 2-(4-丁基)aziridne 其次是 regiospecific 亲核攻击在桥梁或在桥头碳。在乙腈中溶解相应的 2-(4-tosyloxybutyl) 氮丙啶, 容易制备…
Divulgazioni
The authors have nothing to disclose.
Acknowledgements
这项工作得到韩国国家研究基金会 (NRF-2012M3A7B4049645 和 HUFS 研究基金 (2018) 的支持。
Materials
| Thin Layer Chromatography (TLC) | Merck | 100390 | |
| UV light | Sigma-Aldrich | Z169625-1EA | |
| Bruker AVANCE III HD (400 MHz) spectrometer | Bruker | NA | |
| JASCO P-2000 | JASCO | P-2000 | For optical rotation |
| High resolution mass spectra/ MALDI-TOF/TOF Mass Spectrometry | AB SCIEX | 4800 Plus | High resolution mass spectra |
| (2R)-1-[(1R)-1-Phenylethyl]-2-aziridinecarboxylic acid (–)-menthol ester, 98% | Sigma-Aldrich | 57,054-0 | |
| (2S)-1-[(1R)-1-Phenylethyl]-2-aziridinecarboxylic acid (–)-menthol ester | Sigma-Aldrich | 57,051-6 | |
| Triethylethylamine | DAEJUNG | 8556-4400-1L | CAS No: 121-44-8 |
| Dichloromethane | SAMCHUN | M0822-18L | CAS No: 75-09-2 |
| p-Toluenesulfonic anhydride | Sigma-Aldrich | 259764-25G | CAS No: 4124-41-8 |
| n-Hexane | SAMCHUN | H0114-18L | CAS No: 110-54-3 |
| Ethyl acetate | SAMCHUN | E0191-18L | CAS No: 141-78-6 |
| Sodium sulfate | SAMCHUN | S1011-1kg | CAS No: 7757-82-6 |
| Acetonitrile-d3 | Cambridge Isotope Laboratories, Inc | 15G-744-25g | CAS No: 2206-26-0 |
| Acetonitrile | SAMCHUN | A0127-18L | CAS No: 75-05-8 |
| 1,4-Dioxane | SAMCHUN | D0654-1kg | CAS No: 123-91-1 |
| Sodium hydroxide | DUKSAN | A31226-1kg | CAS No: 1310-73-2 |
| Sodium acetate | Alfa Aesar | 11554-250g | CAS No: 127-09-3 |
| Lithium aluminum hydride | TCI | L0203-100g | CAS No: 16853-85-3 |
| Tetrahydrofuran | SAMCHUN | T0148-18L | CAS No: 109-99-9 |
| Sodium azide | D.S.P | 703301-500g | CAS No: 26628-22-8 |
| Cesium fluoride | aldrich | 18951-0250-25g | CAS No: 13400-13-0 |
| Tetrabutylammonium bromide | aldrich | 426288-25g | CAS No: 1643-19-2 |
| Sodium iodide | aldrich | 383112-100g | CAS No: 7681-82-5 |
| Sodium cyanide | Acros Organics | 424301000-100g | CAS No: 143-33-9 |
| Sodium thiocyanate | aldrich | 467871-250g | CAS No: 540-72-7 |
| Sodium methoxide | aldrich | 156256-1L | CAS No: 124-41-4 |
| Benzylamine | Alfa Aesar | A10997-1000g | CAS No: 100-46-9 |
| Phenol | TCI | P1610-500g | CAS No: 108-95-2 |
| Sodium benzoate | Alfa Aesar | A15946-250g | CAS No: 532-32-1 |
| Chloroform-d | Cambridge Isotope Laboratories, Inc | DLM-7TB-100S/16H-239, 100g | CAS No: 865-49-6 |
| Dimethyl sulfoxide-d6 | Cambridge Isotope Laboratories, Inc | DLM-10-25, 25g | CAS No: 2206-27-1 |
| Methanol | SAMCHUN | M0585-18L | CAS No: 67-56-1 |
| Ninhydrin | Alfa Aesar | A10409-250g | CAS No: 485-47-2 |
| Phosphomolybdic acid hydrate | TCI | P1910-100g | CAS No: 51429-74-4 |
| p-Anisaldehyde | aldrich | A88107-5g | CAS No: 123-11-5 |
Riferimenti
- Singh, G. S., D’hooghe, M., De Kimpe, N. Synthesis and Reactivity of C-Heteroatom-Substituted Aziridines. Chem. Rev. 107, 2080-2135 (2007).
- Yudin, A. . Aziridines and Epoxides in Organic Synthesis. , (2006).
- Lee, W. K., Ha, H. J. Highlight of the Chemistry of Enantiomerically Pure Aziridine-2-carboxylates. Aldrichimica Acta. 36, 57-63 (2003).
- Ghorai, M. K., Bhattacharyya, A., Das, S., Chauhan, N. Ring Expansions of Activated Aziridines and Azetidines. Top. Heterocycl. Chem. 41, 49-142 (2016).
- Kim, Y., Ha, H. -. J., Yun, S. Y., Lee, W. K. The preparation of stable aziridinium ions and their ring-openings. Chem. Commun. , 4363-4365 (2008).
- D’hooghe, M., Van Speybroeck, V., Waroquier, M., De Kimpe, N. Regio- and stereospecific ring opening of 1,1-dialkyl-2-(aryloxymethyl)aziridinium salts by bromide. Chem. Commun. , 1554-1556 (2006).
- Stankovic, S., D’hooghe, M., Catak, S., Eum, H., Waroquier, M., Van Speybroeck, V., De Kimpe, N., Ha, H. J. Regioselectivity in the ring opening of non-activated aziridines. Chem. Soc. Rev. 41, 643-665 (2012).
- Ji, M. K., Hertsen, D., Yoon, D. H., Eum, H., Goossens, H., Waroquier, M., Van Speybroeck, V., D’hooghe, M., De Kimpe, N., Ha, H. J. Nucleophile-Dependent Regio- and Stereoselective Ring Opening of 1-Azoniabicyclo[3.1.0]hexane Tosylate. Chem. Asian J. 9, 1060-1067 (2014).
- Mtro, T. -. X., Duthion, B., Gomez Pardo, D., Cossy, J. Rearrangement of β-amino alcohols viaaziridiniums: a review. Chem. Soc. Rev. 39, 89-102 (2010).
- Dolfen, J., Yadav, N. N., De Kimpe, N., D’hooghe, M., Ha, H. J. Bicyclic Aziridinium Ions in Azaheterocyclic Chemistry-Preparation and Synthetic Application of 1-Azoniabicyclo[n.1.0]alkanes. Adv. Synth. Catal. 358, 3485-3511 (2016).
- Choi, J., Yadav, N. N., Ha, H. -. J. Preparation of a Stable Bicyclic Aziridinium Ion and Its Ring Expansion toward Piperidines and Azepanes. Asian J. Org. Chem. 6, 1292-1307 (2017).
- Yadav, N. N., Choi, J., Ha, H. -. J. One-pot multiple reactions: asymmetric synthesis of 2,6-cis-disubstituted piperidine alkaloids from chiral aziridine. Org. Biomol. Chem. 14, 6426-6434 (2016).
- Angoli, M., Barilli, A., Lesma, G., Passarella, D., Riva, S., Silvani, A., Danieli, B. Remote Stereocenter Discrimination in the Enzymatic Resolution of Piperidine-2-ethanol. Short Enantioselective Synthesis of Sedamine and Allosedamine. J. Org. Chem. 68, 9525-9527 (2003).
- Shaikh, T. M., Sudalai, A. Enantioselective Synthesis of (+)-α-Conhydrine and (-)-Sedamine by L-Proline-Catalysed α-Aminooxylation. Eur. J. Org. Chem. , 3437-3444 (2010).
- Miyabe, H., Torieda, M., Inoue, K., Tajiri, K., Kiguchi, T., Naito, T. Total Synthesis of (−)-Balanol. J. Org. Chem. 63, 4397-4407 (1998).
- Castillo, J. A., Calveras, J., Casas, J., Mitjans, M., Vinardell, M. P., Parella, T., Inoue, T., Sprenger, G. A., Joglar, J., Clapes, P. Fructose-6-phosphate Aldolase in Organic Synthesis: Preparation of d-Fagomine, N-Alkylated Derivatives, and Preliminary Biological Assays. Org. Lett. 8, 6067-6070 (2006).
- Kikuchi, H., Yamamoto, K., Horoiwa, S., Hirai, S., Kasahara, R., Hariguchi, N., Matsumoto, M., Oshima, Y. Exploration of a New Type of Antimalarial Compounds Based on Febrifugine. J. Med. Chem. 49, 4698-4706 (2006).
