English version Ukrainian version
Last issue Archive Editorial board Instructions to authors Contact us

This site supported by

Ukr. Bioorg. Acta 2020, Vol. 15, N1, 26-33.

Three-component cyclization as an approach to a combinatorial library of 2H-spiro-[chromeno[2,3-c]pyrrole-1,3'-indoline]-2',3,9-triones

Roman N. Vydzhak 1, Maryna V. Kachaeva 1, Stepan G. Pilyo 1, Viktoriia S. Moskvina 1,2, Olga V. Shablykina 1,2, Andriy V. Kozytskiy 3,4 and Volodymyr S. Brovarets 1

1 V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine
2 Taras Shevchenko National University of Kyiv, 60 Volodymyrska St., Kyiv, 01601, Ukraine
tel.: +380-44-239-3342; e-mail: b.moskvina@gmail.com
3 L. V. Pisarzhevskii Institute of Physical Chemistry of the NAS of Ukraine, 31 Nauky Ave., Kyiv, 03028, Ukraine
4 Enamine Ltd. (www.enamine.net), 78 Chervonotkatska St., Kyiv, 02094, Ukraine

A versatile and efficient three-component cyclization of methyl 4-(o-hydroxyphenyl)-2,4-dioxobutanoates 1, N-substituted isatins 2, and primary amines 3 was explored to synthesize of 2H-spiro[chromeno[2,3-c]pyrrole-1,3'-indoline]-2',3,9-triones. We obtained a library of 122 derivatives with an indolin-2-one motif as an important structural fragment in natural alkaloids. This method is practical and useful strategy for constructing dihydrochromeno[2,3-c]pyrrole-3,9-diones. Most of the obtained products also have functional groups for easy and further diversification by classical reactions.

isatin, multicomponent reactions, chromenes, combinatorial library.

1. Welsch, M. E.; Snyder, S. A.; Stockwell, B. R. Privileged scaffolds for library design and drug discovery. Curr. Opin. Chem. Biol. 2010, 14, 347-361.
2. Rodrigues, T.; Reker, D.; Schneider, P. Schneider, G. Counting on natural products for drug design. Nature Chem. 2016, 8, 531-541.
3. Davison, E. K.; Brimble, M. A. Natural product derived privileged scaffolds in drug discovery. Curr. Opin. Chem. Biol. 2019, 52, 1-8.
4. James, M. J.; O'Brien, P.; Taylor, R. J. K.; Unsworth, W. P. Synthesis of Spirocyclic Indolenines. Chem. Eur. J. 2016, 22, 2856-2881.

5. Jossang, A.; Jossang, P.; Hadi, H. A.; Sevenet, T.; Bodo, B. Horsfiline, an oxindole alkaloid from Horsfieldia superba. J. Org. Chem. 1991, 56, 6527-6530.
6. Anderton, N.; Cockrum, P. A.; Colegate, S. M.; Edgar, J. A.; Flower, K.; Vit, I.; Willing, R. I. Oxindoles from Phalaris coerulescens. Phytochemistry 1998, 48, 437-439.

7. James, M. N. G.; Williams, G. J. B. The Molecular and Crystal Structure of an Oxindole Alkaloid (6-Hydroxy-2-(2-methylpropyl)-3,3-spirotetrahydropyrrolidino-oxindole). Can. J. Chem. 1972, 50, 2407-2412.
8. Edmondson, S.; Danishefsky, S. J.; Sepp-Lorenzino, L.; Rosen, N. Total Synthesis of Spirotryprostatin A, Leading to the Discovery of Some Biologically Promising Analogues. J. Am. Chem. Soc. 1999, 121, 2147-2155.
9. Ohiri, F. C.; Verpoorte, R.; Svendsen, A. B. The African Strychnos Species and Their Alkaloids: A Review. J. Ethnopharmacol. 1983, 9, 167-223.
10. Natural Compounds: Alkaloids. Plant Sources, Structure and Properties, Azimova, S. S.; Yunusov, M. S., Eds., Springer Science & Business Media: New York, NY, USA, 2013.
11. Gonzales, G.; Valerio, L. Medicinal Plants from Peru: A Review of Plants as Potential Agents Against Cancer. Anti-Cancer Agents Med. Chem. 2006, 6, 429-444.
12. Krishnaiah, D.; Sarbatly, R.; Nithyanandam, R. A review of the antioxidant potential of medicinal plant species. Food Bioprod. Process. 2011, 89, 217-233.
13. Paniagua-Perez, R.; Madrigal-Bujaidar, E.; Molina-Jasso, D.; Reyes-Cadena, S.; Alvarez-Gonzalez, I.; Sanchez-Chapul, L.; Perez-Gallaga. Antigenotoxic, Antioxidant and Lymphocyte Induction Effects Produced by Pteropodine. J. BasicClin. Pharmacol. Toxicol. 2009, 104, 222-227.
14. Rojas-Duran, R.; Gonzalez-Aspajo, G.; Ruiz-Martel, C.; Bourdy, G.; Doroteo-Ortega, V. H.; Alban-Castillo, J.; Robert, G.; Auberger, P.; Deharo, E. Anti-inflammatory activity of Mitraphylline isolated from Uncaria tomentosa bark. J. Ethnopharmacol. 2012, 143, 801-804.
15. Joshi, K. C.; Jain, R.; Sharma, K.; Bhattacharya, S. K.; Goel, R. Studies in Spiro-Heterocycles. Part 12. Synthesis of Some Fluorine Containing Spiro (3H-indole-3, 4
(4H)-pyrano (2, 3-d) pyrimidine)-2, 5, 7(1H)-triones as CNS Agents. J. Indian Chem. Soc. 1988, 65, 202-204.
16. Nandakumar, A.; Thirumurugan, P.; Perumal, P. T.; Vembu, P.; Ponnuswamy, M. N.; Ramesh, P. One-pot multicomponent synthesis and anti-microbial evaluation of 2
-(indol-3-yl)-2-oxospiro(indoline-3,4-pyran) derivatives. Bioorg. Med. Chem. Lett. 2010, 20, 4252-4258.
17. Joshi, K. C.; Jain, R.; Arora, S. Spiro Heterocycles. Part 8. Synthesis, Herbicidal, and Fungicidal Activities of Some New Fluorine?Containing Spiro (3H-indole-3, 4
(1 H)-pyrano (2, 3-c) pyrazole)-5-carbonitriles/carboxylic Acid Ethyl Esters. J. Indian Chem. Soc. 1988, 65, 277-279.
18. Xu, J.; Shao, L.-D.; Shi, X.; Ren, J.; Xia, C.; Zhao, Q.-S. Collective formal synthesis of (±)-rhynchophylline and homologues. RSC Adv. 2016, 6, 63131-63135.
19. Vydzhak, R. N.; Panchishin, S. Ya.; Bezuglaya, E. M.; Chernega, A. N. A convenient approach to the synthesis of 1H-pyrrolo[3,4-b]chromene-3,9-dione derivatives Zh. Org. Farm. Khim. 2005, 3, 58-63. (In Rus.)
20. Vydzhak, R. N.; Panchishin, S. Ya. Simple synthesis of 1,2-diaryl-1,2-dihydrochromeno[2,3-c]pyrrole-3,9-diones. Russ. J. General. Chem. 2006, 76, 1681-1682.
21. Vydzhak, R. N.; Panchishin, S. Ya. Synthesis of 2-alkyl-1-aryl-1,2-dihydrochromeno[2,3-c]pyrrole-3,9-dione derivatives. Russ. J. General. Chem. 2008, 78, 2391-2397.
22. Vydzhak, R. N.; Panchishin, S. Ya. Synthesis of 2-phenyl-5,6-dihydropyrano[2,3-c]pyrrole-4,7-dione derivatives. Russ. J. General. Chem. 2008, 78, 1641-1642.
23. Vydzhak, R. N.; Panchishin, S. Ya. Synthesis of 1-aryl-2-[2-(dimethylamino)ethyl]-1,2-dihydrochromeno[2,3-c]pyrrole-3,9-diones and their analogs. Russ. J. General. Chem. 2010, 80, 323-329.
24. Vydzhak, R. N.; Panchishin, S. Ya. Synthesis of 1,2-dihydro-chromeno[2,3-c]pyrrole-3,9-diones spiro derivatives Russ. J. General. Chem. 2011, 81, 617-619.

Full-text in PDF