JoVE Journal > Chemistry
Summary
Abstract
Introduction
Protocol
Results
Discussion
Disclosures
Acknowledgements
Materials
References
자동 번역
Please note that all translations are automatically generated. Click here for the English version.
화학

[4.4] 刺环氧基的固相合成

Published: February 06, 2019
doi:
10.3791/58508
, ,
1Department of Biology and Chemistry,Azusa Pacific University

Summary

在这里, 我们提出了一个协议, 以证明一种有效的方法, 合成螺旋体杂环。五步过程采用固相合成和再生迈克尔链接器策略。通常很难合成, 我们提出了一个可定制的方法, 合成螺旋体环分子, 否则无法进入其他现代方法。

Abstract

由于螺旋体杂环在生物系统中的潜在应用, 一种方便的杂环合成路线备受追捧。通过固相合成、再生 michael (rem) 链接器策略和 1, 3-偶极环加法, 可以构建一个结构相似的杂环库, 无论是否有螺旋体中心。固支撑合成的主要优点如下: 第一, 每个反应步骤都可以使用大量过量的试剂驱动完成, 从而产生较高的产量;其次, 利用市售的原料和试剂, 将成本保持在较低水平;最后,反应步骤易于通过简单的过滤进行净化。快速眼动链接器策略具有吸引力, 因为它具有可回收性和无迹性。反应方案完成后, 链接器可以重复使用多次。在典型的固相合成中, 产品包含部分或整个链接器, 这可能被证明是不可取的。rem 链接器是 “无痕” 的, 产品与聚合物之间的连接点是无法区分的。分子内1、3-偶极环加成的高亚光选择性是有据可查的。受固体支撑的不溶解性的限制, 反应进展只能通过红外 (ir) 光谱学对官能团 (如果有的话) 的变化进行监测。因此, 中间体的结构识别不能用常规核磁共振 (nmr) 光谱来表征。这种方法的其他局限性来自于聚合物链剂与所需化学反应方案的兼容性。在此, 我们报告了一个协议, 允许方便生产螺旋体杂环, 只需简单的修改, 就可以通过高通量技术实现自动化。

Introduction

尽管最近发现在许多生物系统1中使用高度功能化的螺旋体杂环, 但一个方便的途径仍然是易于制造所必需的。这些杂环的系统和用途包括: mdm2 抑制和其他抗癌活性2,3,4,5, 酶抑制6,7,8, 抗生素活性9,10, 荧光标记10,11, 12, 对映体选择性结合的 dna 探针13,14, 15和 rna 针对16, 以及许多潜在的应用于治疗 17,18,19。随着对这些杂环的需求不断增加, 目前的文献对于哪种合成途径是最好的仍存在分歧。现代合成方法的这个问题使用异锡和异锡衍生物作为起始材料为各种杂环20,21, 复杂分子内重组22,23 ,24,25, lewis 酸1,26,27或过渡金属催化 17,28,29, 30, 或不对称进程31。虽然这些程序成功地生产了功能有限的特定螺旋体血氧基, 但研究了一种合成策略, 以产生具有高环氧选择性的分子库, 相对较少32。

这里介绍的技术表明, 这些感兴趣的分子可以使用一些很好理解的合成技术同时生成。从使用快速眼动链接器和分子内西丽基硝酸-烯烃环加 (isoc) 在固体载体上合成分子开始, 提出的路径展开了一条非线性路径, 其特征是在三环系统中切断了键, 从而留下高度功能化的杂环。快速眼动链接器以其便利性和可回收性而闻名, 它利用坚实的支撑来合成三胺33。由于通过简单过滤可轻松地将其认证为 rem 链接器, 这种固相合成技术为科学家提供了一种可回收且无示的链接器, 并已在此处使用。反应完成后, rem 链接器将被重新生成, 并可多次重复使用。rem 链接器也是无痕量的, 因为与许多固相链接器不同, 产品与聚合物之间的连接点无法区分 34,35。此外, 对 isoc 反应也有很好的研究和了解, 该反应在合成吡咯烷酮类氧基 36,37中非常有用。这些反应也许被更好地称为 1, 3-偶极极环加成, 形成了许多具有高副选择性的杂环 38,39, 40,41, 42,43,44,45. 利用改进的 rem-耦合-isoc 技术合成螺旋体循环分子, 产生了一种高度不相关的选择性产物。在此, 我们报告了螺旋体血氧的有效生产使用一种新的合成方法, 结合了两种众所周知的途径和现成的起始材料。

Protocol

注意: 使用前请查阅所有相关材料安全数据表 (msds)。这些合成中使用的几种化学物质具有剧毒性和致癌性。在进行以下反应时, 请使用所有适当的安全惯例, 包括使用工程控制 (通风罩、红外和 nmr 光谱仪) 和个人防护设备 (安全护目镜、手套、实验室外套、全长裤子和闭脚鞋)。 1. 在快速眼动器中添加呋喃胺 注: 此步骤的持续时间为设置的25分钟和24小时的反?…

Representative Results

如上述过程所述, 螺旋体血氧的合成路线 (见图 1) 始于迈克尔在化合物1(rem 链接器) 中添加呋喃胺, 以承受2。随后的迈克尔加法和 1, 3-偶极环加成的支持2使用各种β-硝基苯衍生物产生三环化合物3, n-水杨质异恶唑嗪具有四个独特的立体原代中心。3与 tbaf 的脱硅产生螺旋体氧基 4, 仍…

Discussion

在典型的 rem linker 固相合成策略中, 在固体支撑释放胺之前, 形成季铵盐至关重要, 如协议39第4节所述。由于三环系统和笨重的 r2基团 (苯基和辛卤化物) 的位阻, 在这一反应中只能使用小的烷基化试剂 (甲基和烯丙基卤化物)。通过简单的改性, 允许添加和使用较大的甾体试剂, 通过打开前32的异烷基化步骤, 降低了三环结构的刚性。…

Disclosures

The authors have nothing to disclose.

Acknowledgements

这项工作的资金来自教师研究委员会向黄克萨 (美国阿祖萨太平洋大学) 提供的赠款。c. r. 德里斯科是约翰·施陶弗奖学金和根卡雷拉本科生研究补助金的获得者。格里芬获得了生物和化学系的 s2s 本科生研究奖学金。

Image 1

作者 (从左到右) 科迪·德里斯科、凯文·黄博士和西拉斯·格里芬进行了实验并准备了手稿。科迪·德里斯科是约翰·斯陶弗研究员, 也是根卡雷拉研究资助金的获得者。塞拉斯是 azusa 太平洋大学的 s2s 研究员。黄博士提供研究指导, 是阿祖萨太平洋大学教师研究委员会资助的获得者。

Materials

Chemicals
REM Resin Nova Biochem 8551010005 Solid Polymer Support; 1.1 mmol/g loading
Furfurylamine Acros Organics 119800050 Reagent
Dimethylformamide (DMF) Sigma-Aldrich 227056 Solvent
Dichloromethane (DCM) Sigma-Aldrich 270997 Solvent
Methanol Sigma-Aldrich 34860 Solvent
trans-4-bromo-β-nitrostyrene Sigma-Aldrich 400017 Nitro-olefin solid
trans-3,4-dimethoxy-β-nitrostyrene Sigma-Aldrich S752215 Nitro-olefin solid
trans-2,4-dichloro-β-nitrostyrene Sigma-Aldrich 642169 Nitro-olefin solid
trans-β-nitrostyrene Sigma-Aldrich N26806 Nitro-olefin solid
Triethylamine (TEA) Sigma-Aldrich T0886 Solvent
Trimethylsilyl chloride (TMSCl) Sigma-Aldrich 386529 Reagent; CAUTION – highly volatile; creates HCl gas
Tetra-n-butylammonium fluoride (TBAF) in Tetrahydrofuran (THF) Sigma-Aldrich 216143 Reagent
Tetrahydrofuran (THF) Sigma-Aldrich 401757 Reagent
1-Bromooctane Sigma-Aldrich 152951 Alkyl-halide
Iodomethane Sigma-Aldrich 289566 Alkyl-halide
Allylbromide Sigma-Aldrich 337528 Alkyl-halide
Benzylbromide Sigma-Aldrich B17905 Alkyl-halide
Glassware/Instrumentation
25 mL solid-phase reaction vessel Chemglass CG-1861-02 Glassware with filter
Thermo Scientific Nicole iS5 Thermo Scientific IQLAADGAAGFAHDMAZA Instrument
AVANCE III NMR Spectrometer Bruker N/A Instrument; 300 MHz; Solvents: CDCl3 and CD3OH
Wrist-Action Shaker Model 75 Burrell Scientific 757950819 Instrument
DOWNLOAD MATERIALS LIST

References

  1. Bayat, M., Amiri, Z. Chemoselective synthesis of novel spiropyrano acenaphthylene derivatives via one-pot four-component reaction. Tetrahedron Letters. 58 (45), 4260-4263 (2017).
  2. Ding, K., et al. Structure-Based Design of Potent Non-Peptide MDM2 Inhibitors. Journal of the American Chemical Society. 127 (29), 10130-10131 (2005).
  3. D’Erasmo, M. P., et al. 7,9-Diaryl-1,6,8-trioxaspiro[4.5]dec-3-en-2-ones: Readily accessible and highly potent anticancer compounds. Bioorganic & Medicinal Chemistry Letters. 24 (16), 4035-4038 (2014).
  4. Gomez, C., et al. Phosphine-Catalyzed Synthesis of 3,3-Spirocyclopenteneoxindoles from γ-Substituted Allenoates: Systematic Studies and Targeted Applications. The Journal of Organic Chemistry. 78 (4), 1488-1496 (2013).
  5. Wu, S., et al. Novel spiropyrazolone antitumor scaffold with potent activity: Design, synthesis and structure-activity relationship. European Journal of Medicinal Chemistry. 115, 141-147 (2016).
  6. Allgardsson, A., et al. Structure of a prereaction complex between the nerve agent sarin, its biological target acetylcholinesterase, and the antidote HI-6. Proceedings of the National Academy of Sciences. 113 (20), 5514-5519 (2016).
  7. Cantín, &. #. 1. 9. 3. ;., et al. Novel Inhibitors of the Mitochondrial Respiratory Chain: Oximes and Pyrrolines Isolated from Penicillium brevicompactum and Synthetic Analogues. Journal of Agricultural and Food Chemistry. 53 (21), 8296-8301 (2005).
  8. Wu, E. S. C., et al. et al. In Vitro Muscarinic Activity of Spiromuscarones and Related Analogs. Journal of Medicinal Chemistry. 38 (9), 1558-1570 (1995).
  9. Gober, C. M., Carroll, P. J., Joullié, M. M. Triazaspirocycles: Occurrence, Synthesis, and Applications. Mini-reviews in organic chemistry. 13 (2), 126-142 (2016).
  10. Hong, C. Y., et al. Novel Fluoroquinolone Antibacterial Agents Containing Oxime-Substituted (Aminomethyl)pyrrolidines: Synthesis and Antibacterial Activity of 7-(4-(Aminomethyl)-3-(methoxyimino)pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro- 4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic Acid (LB20304),1. Journal of Medicinal Chemistry. 40 (22), 3584-3593 (1997).
  11. Ryzhakov, D., Jarret, M., Guillot, R., Kouklovsky, C., Vincent, G. Radical-Mediated Dearomatization of Indoles with Sulfinate Reagents for the Synthesis of Fluorinated Spirocyclic Indolines. Organic Letters. 19 (23), 6336-6339 (2017).
  12. Wang, L., et al. A Facile Radiolabeling of [18F]FDPA via Spirocyclic Iodonium Ylides: Preliminary PET Imaging Studies in Preclinical Models of Neuroinflammation. Journal of Medicinal Chemistry. 60 (12), 5222-5227 (2017).
  13. Lin, Y., Jones, G. B., Hwang, G. -. S., Kappen, L., Goldberg, I. H. Convenient Synthesis of NCS−Chromophore Metabolite Isosteres: Binding Agents for Bulged DNA Microenvironments. Organic Letters. 7 (1), 71-74 (2005).
  14. Kappen, L. S., Lin, Y., Jones, G. B., Goldberg, I. H. Probing DNA Bulges with Designed Helical Spirocyclic Molecules. 생화학. 46 (2), 561-567 (2007).
  15. Zhang, N., Lin, Y., Xiao, Z., Jones, G. B., Goldberg, I. H. Solution Structure of a Designed Spirocyclic Helical Ligand Binding at a Two-Base Bulge Site in DNA. 생화학. 46 (16), 4793-4803 (2007).
  16. Thomas, J. R., Hergenrother, P. J. Targeting RNA with Small Molecules. Chemical Reviews. 108 (4), 1171-1224 (2008).
  17. Jones, B., Proud, M., Sridharan, V. Synthesis of oxetane/azetidine containing spirocycles via the 1,3-dipolar cycloaddition reaction. Tetrahedron Letters. 57 (25), 2811-2813 (2016).
  18. Martinez, N. J., et al. A High-Throughput Screen Identifies 2,9-Diazaspiro[5.5]Undecanes as Inducers of the Endoplasmic Reticulum Stress Response with Cytotoxic Activity in 3D Glioma Cell Models. PLoS ONE. 11 (8), e0161486 (2016).
  19. Wang, Y., et al. Discovery and Optimization of Potent GPR40 Full Agonists Containing Tricyclic Spirocycles. ACS Medicinal Chemistry Letters. 4 (6), 551-555 (2013).
  20. Singh, G. S., Desta, Z. Y. Isatins As Privileged Molecules in Design and Synthesis of Spiro-Fused Cyclic Frameworks. Chemical Reviews. 112 (11), 6104-6155 (2012).
  21. Rana, S., et al. Isatin Derived Spirocyclic Analogues with α-Methylene-γ-butyrolactone as Anticancer Agents: A Structure-Activity Relationship Study. Journal of Medicinal Chemistry. 59 (10), 5121-5127 (2016).
  22. Sue, D., Kawabata, T., Sasamori, T., Tokitoh, N., Tsubaki, K. Synthesis of Spiro Compounds through Tandem Oxidative Coupling and a Framework Rearrangement Reaction. Organic Letters. 12 (2), 256-258 (2010).
  23. Perry, M. A., Hill, R. R., Rychnovsky, S. D. Trianion Synthon Approach to Spirocyclic Heterocycles. Organic Letters. 15 (9), 2226-2229 (2013).
  24. Palmer, L. I., Read de Alaniz, J. Rapid and Stereoselective Synthesis of Spirocyclic Ethers via the Intramolecular Piancatelli Rearrangement. Organic Letters. 15 (3), 476-479 (2013).
  25. Berton, J. K. E. T., Salemi, H., Pirat, J. -. L., Virieux, D., Stevens, C. V. Three-Step Synthesis of Chiral Spirocyclic Oxaphospholenes. The Journal of Organic Chemistry. 82 (23), 12439-12446 (2017).
  26. Carreira, E. M., Fessard, T. C. Four-Membered Ring-Containing Spirocycles: Synthetic Strategies and Opportunities. Chemical Reviews. 114 (16), 8257-8322 (2014).
  27. Yamazaki, S., Naito, T., Niina, M., Kakiuchi, K. Lewis Acid Catalyzed Cyclization Reactions of Ethenetricarboxylates via Intramolecular Hydride Transfer. The Journal of Organic Chemistry. 82 (13), 6748-6763 (2017).
  28. Hung, A. W., et al. Route to three-dimensional fragments using diversity-oriented synthesis. Proceedings of the National Academy of Sciences. 108 (17), 6799-6804 (2011).
  29. Wright, D. L., Schulte, J. P., Page, M. A. An Imine Addition/Ring-Closing Metathesis Approach to the Spirocyclic Core of Halichlorine and Pinnaic Acid. Organic Letters. 2 (13), 1847-1850 (2000).
  30. Qiu, B., et al. Highly Enantioselective Oxidation of Spirocyclic Hydrocarbons by Bioinspired Manganese Catalysts and Hydrogen Peroxide. ACS Catalysis. 8 (3), 2479-2487 (2018).
  31. Richmond, E., Duguet, N., Slawin, A. M. Z., Lébl, T., Smith, A. D. Asymmetric Pericyclic Cascade Approach to Spirocyclic Oxindoles. Organic Letters. 14 (11), 2762-2765 (2012).
  32. Griffin, S. A., Drisko, C. R., Huang, K. S. Tricyclic heterocycles as precursors to functionalized spirocyclic oximes. Tetrahedron Letters. , (2017).
  33. Brown, A. R., Rees, D. C., Rankovic, Z., Morphy, J. R. Synthesis of Tertiary Amines Using a Polystyrene (REM) Resin. Journal of the American Chemical Society. 119 (14), 3288-3295 (1997).
  34. Blaney, P., Grigg, R., Sridharan, V. Traceless Solid-Phase Organic Synthesis. Chemical Reviews. 102 (7), 2607-2624 (2002).
  35. Morphy, J. R., Rankovic, Z., Rees, D. C. A novel linker strategy for solid-phase synthesis. Tetrahedron Letters. 37 (18), 3209-3212 (1996).
  36. Saruengkhanphasit, R., Collier, D., Coldham, I. Synthesis of Spirocyclic Amines by Using Dipolar Cycloadditions of Nitrones. The Journal of Organic Chemistry. 82 (12), 6489-6496 (2017).
  37. Li, F., et al. Assembly of Diverse Spirocyclic Pyrrolidines via Transient Directing Group Enabled Ortho-C(sp2)-H Alkylation of Benzaldehydes. Organic Letters. 20 (1), 146-149 (2018).
  38. Gottlieb, L., Hassner, A. Cycloadditions. 53. Stereoselective Synthesis of Functionalized Pyrrolidines via Intramolecular 1,3-Dipolar Silyl Nitronate Cycloaddition. The Journal of Organic Chemistry. 60 (12), 3759-3763 (1995).
  39. Namboothiri, I. N. N., Hassner, A., Gottlieb, H. E. A Highly Stereoselective One-Pot Tandem Consecutive 1,4-Addition−Intramolecular 1,3-Dipolar Cycloaddition Strategy for the Construction of Functionalized Five- and Six-Membered Carbocycles,1. The Journal of Organic Chemistry. 62 (3), 485-492 (1997).
  40. Dehaen, W., Hassner, A. Stereoselectivity in intramolecular 1,3-dipolar cycloadditions. Nitrile oxides versus silyl nitronates. Tetrahedron Letters. 31 (5), 743-746 (1990).
  41. Roger, P. -. Y., Durand, A. -. C., Rodriguez, J., Dulcère, J. -. P. Unprecedented in Situ Oxidative Ring Cleavage of Isoxazolidines: Diastereoselective Transformation of Nitronic Acids and Derivatives into 3-Hydroxymethyl 4-Nitro Tetrahydrofurans and Pyrrolidines. Organic Letters. 6 (12), 2027-2029 (2004).
  42. Kudoh, T., Ishikawa, T., Shimizu, Y., Saito, S. Intramolecular Cycloaddition Reactions of Silyl Nitronate Tethered to Vinylsilyl Group: 2-Nitroalkanols as Precursors for Amino Polyols. Organic Letters. 5 (21), 3875-3878 (2003).
  43. Ishikawa, T., Shimizu, Y., Kudoh, T., Saito, S. Conversion of d-Glucose to Cyclitol with Hydroxymethyl Substituent via Intramolecular Silyl Nitronate Cycloaddition Reaction: Application to Total Synthesis of (+)-Cyclophellitol. Organic Letters. 5 (21), 3879-3882 (2003).
  44. Hashimoto, T., Maruoka, K. Recent Advances of Catalytic Asymmetric 1,3-Dipolar Cycloadditions. Chemical Reviews. 115 (11), 5366-5412 (2015).
  45. Li, X., et al. Highly Enantioselective One-Pot Synthesis of Spirocyclopentaneoxindoles Containing the Oxime Group by Organocatalyzed Michael Addition/ISOC/Fragmentation Sequence. Organic Letters. 13 (23), 6160-6163 (2011).
  46. Jensen, K. H., Hanson, J. E. Synthesis and Photochemistry of Tertiary Amine Photobase Generators. Chemistry of Materials. 14 (2), 918-923 (2002).
  47. Mondal, S., Mukherjee, S., Yetra, S. R., Gonnade, R. G., Biju, A. T. Organocatalytic Enantioselective Vinylogous Michael-Aldol Cascade for the Synthesis of Spirocyclic Compounds. Organic Letters. 19 (16), 4367-4370 (2017).
  48. Ni, C., et al. Phosphine-Catalyzed Asymmetric (3 + 2) Annulations of δ-Acetoxy Allenoates with β-Carbonyl Amides: Enantioselective Synthesis of Spirocyclic β-Keto γ-Lactams. Organic Letters. 19 (13), 3668-3671 (2017).

Tags

Solid-phase SynthesisSpirocyclic OximesCombinatorial LibraryHeterocyclic CompoundsIsoxazolinesIsoxazolesREM ResinFurfurylamineBeta-nitrostyreneIsoxazoleTetrahydrofuranTetra-n-butylammonium FluorideOne-bromooctane
check_url/kr/58508?article_type=t

Play Video
PDF
DOI
DOWNLOAD MATERIALS LIST
Cite This Article
Drisko, C. R., Griffin, S. A., Huang, K. S. Solid-phase Synthesis of [4.4] Spirocyclic Oximes. J. Vis. Exp. (144), e58508, doi:10.3791/58508 (2019).
Download Citation
Reprints and Permissions

View Video

✖

To prove you're not a robot, please enter the text in the image below

CAPTCHA Image
Play CAPTCHA Audio
Refresh Image