Synthesis of New Structural Analogues of Natural Integrastatins with a Basic Epoxybenzo[7,8]oxocine Skeleton: Combined Experimental and Computational Study

Alena L. Stalinskaya; Semyon Y. Chikunov; Irina A. Pustolaikina; Yuri V. Gatilov; Ivan V. Kulakov

doi:10.1055/s-0042-1751521

Synthesis, Table of Contents

Synthesis 2024; 56(02): 329-345
DOI: 10.1055/s-0042-1751521

paper

Synthesis of New Structural Analogues of Natural Integrastatins with a Basic Epoxybenzo[7,8]oxocine Skeleton: Combined Experimental and Computational Study

Alena L. Stalinskaya

^aInstitute of Chemistry, Tyumen State University, 15a Perekopskaya St., Tyumen 625003, Russian Federation

,

Semyon Y. Chikunov

^aInstitute of Chemistry, Tyumen State University, 15a Perekopskaya St., Tyumen 625003, Russian Federation

,

Irina A. Pustolaikina

^bKaragandy University of the Name of Academician E. A. Buketov, Karaganda, 100024 Kazakhstan, Kazakhstan

,

Yuri V. Gatilov

^сN. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Science, 9 Akademika Lavrientieva Ave., Novosibirsk 630090, Russian Federation

,

Ivan V. Kulakov ∗

^aInstitute of Chemistry, Tyumen State University, 15a Perekopskaya St., Tyumen 625003, Russian Federation

› Author Affiliations

Abstract

All articles of this category

Abstract

In this work, the cyclization reactivity of various 3-acetyl-2-methylpyridines (including 3-acetyl-2-methylquinoline) containing both electron donor and acceptor substituents with salicylaldehyde into epoxybenzooxocino[4,3-b]pyridine derivatives was studied. The reactions were carried out in mild (under room temperature or reflux in 2-propanol) and harsh (in a sealed glass ampoule) conditions. It was shown that 3-acetyl-2-methylpyridines with an aryl substituent in the 4-position do not react with salicylaldehyde either under normal convection heating conditions or under more severe conditions. This effect was explained by the steric hindrance of the substituents using quantum chemical calculations. It was found that electron donor substituents in 3-acetyl-2-methylpyridines significantly facilitate cyclization in epoxybenzooxocino[4,3-b]pyridines. The presence of electron acceptor substituents (NO₂ group for example) in the 5-position of pyridine prevents cyclization under normal conditions, but gives a rather high conversion to oxocinopyridines under more specific conditions. This effect is quantum-chemically explained by the decrease in the basicity of pyridine. Pyridines with two pairs of methyl groups in ortho-positions to the acetyl group are capable to form mixtures of regioisomeric epoxybenzooxocinopyridines. Further, epoxybenzooxocinopyridines with methyl and acetyl groups can form a mixture of diastereomeric bisoxocins under more specific conditions. All 17 initial pyridines were studied quantum-chemically in order to understand what features of their structure and properties affect the success of the cyclization reaction and the yield of the target product. The pyridine molecules were calculated by the DFT RB3LYP/6-311++G(d,p) method taking into account the alcohol solvent within the CPCM model using Gaussian-2016 program. It was shown that the absence of steric hindrances in the form of bulky substituents in 4-position of pyridines is the main factor affecting the success of the cyclization reaction. Also, the yield of the target product is affected by the CH-acidity of the methyl group in 2-position, which, in turn, is affected by electron-donating and electron-withdrawing substituents in the 5- and 6-positions.

Key words

integrastatins A,B - intramolecular cyclization - tetracyclic epoxybenzooxocine - 3-acetyl-2-methylpyridine - computational study

Full Text

References

References
1 Kulakov IV, Stalinskaya AL, Chikunov SY, Gatilov YV. New J. Chem. 2021; 45: 3559
2 Oleshchuk AL, Karbainova AA, Krivoruchko TN, Shulgau ZT, Seilkhanov TM, Kulakov IV. Chem. Heterocycl. Compd. 2019; 55: 47
3 Singh SB, Zink DL, Quamina DS, Pelaez F, Teran A, Felock P, Hazuda DJ. Tetrahedron Lett. 2002; 43: 2351
4 El Amrani M, Lai D, Debbab A, Aly AH, Siems K, Seidel C, Schnekenburger M, Gaigneaux A, Diederich M, Feger D, Lin W, Proksch P. J. Nat. Prod. 2014; 77: 49
5 Foot JS, Giblin GM, Taylor RJ. Org. Lett. 2003; 5: 4441
6 Foot JS, Giblin GM, Whitwood AC, Taylor RJ. Org. Biomol. Chem. 2005; 3: 756
7 Ramana CV, Reddy CN, Gonnade RG. Chem. Commun. 2008; 3151
8 More AA, Ramana CV. Org. Lett. 2016; 18: 612
9 More AA, Ramana CV. Org. Lett. 2016; 18: 1458
10 Tadross PM, Bugga P, Stoltz BM. Org. Biomol. Chem. 2011; 9: 5354
11 Jeong JY, Sperry J, Brimble MA. J. Org. Chem. 2019; 84: 11935
12 Yamagiwa Y, Haruna N, Kawakami H, Matsumoto K. Bull. Chem. Soc. Jpn. 2020; 93: 1036
13 Stalinskaya AL, Chikunov SY, Pustolaikina IA, Kulakov IV. Russ. J. Gen. Chem. 2022; 92: 914
14 Stalinskaya AL, Martynenko NV, Shulgau ZT, Shustov AV, Keyer VV, Kulakov IV. Molecules 2022; 27: 3701
15 Stalinskaya AL, Martynenko NV, Alkhimova LE, Dilbaryan DS, Vasilchenko AS, Dengis NA, Vlasenko VS, Kulakov IV. J. Mol. Struct. 2023; 1275: 134689
16 Memarian HR, Bagheri M, Döpp D. Monatsh. Chem. 2004; 135: 833
17 Allais C, Liéby-Muller F, Rodriguez J, Constantieux Th. Eur. J. Org. Chem. 2013; 4131
18 Memarian HR, Abdoli-Senejani M, Döpp D. Z. Naturforsch. 2006; 61b: 50
19 Memarian HR, Abdoli-Senejani M, Döpp D. J. Chin. Chem. Soc. 2007; 54: 131
20 Sagitullina GP, Garkushenko AK, Silina EO, Sagitullin RS. Chem. Heterocycl. Compd. 2009; 45: 948
21 Koveza VA, Kulakov IV, Shulgau ZT, Seilkhanov TM. Chem. Heterocycl. Compd. 2018; 54: 1127
22 Kulakov IV, Oleshchuk AL, Koveza VA, Palamarchuk IV. Synth. Commun. 2020; 50: 2432
23 Sagitullina GP, Garkushenko AK, Atavin EG, Sagitullin RS. Mendeleev Commun. 2009; 19: 155
24 Jiang H, Yang J, Tang X, Li J, Wu W. J. Org. Chem. 2015; 80: 8763
25 Rachakonda V, Alla M, Kotipallim SS, Ummani R. Eur. J. Med. Chem. 2013; 70: 536
26 Dornow A, Heinrich M. Chem. Ber. 1947; 80: 502
27 Turgunalieva DM, Stalinskaya AL, Kulakov II, Sagitullina GP, Atuchin VV, Elyshev AV, Kulakov IV. Processes 2023; 11: 576
28 CCDC 2164994–2165000 (6c, 6g, 6k, 6n, 11n, 16a, 16b) contain the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures
29 Becke AD. J. Chem. Phys. 1993; 98: 5648
30 Geerlings P, De Proft F, Langenaeker W. Chem. Rev. 2003; 103: 1793
31 Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Petersson GA, Nakatsuji H, Li X, Caricato M, Marenich AV, Bloino J, Janesko BG, Gomperts R, Mennucci B, Hratchian HP, Ortiz JV, Izmaylov AF, Sonnenberg JL, Williams-Young D, Ding F, Lipparini F, Egidi F, Goings J, Peng B, Petrone A, Henderson T, Ranasinghe D, Zakrzewski VG, Gao J, Rega N, Zheng G, Liang W, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Throssell K, Montgomery JA. Jr, Peralta JE, Ogliaro F, Bearpark MJ, Heyd JJ, Brothers EN, Kudin KN, Staroverov VN, Keith TA, Kobayashi R, Normand J, Raghavachari K, Rendell AP, Burant JC, Iyengar SS, Tomasi J, Cossi M, Millam JM, Klene M, Adamo C, Cammi R, Ochterski JW, Martin RL, Morokuma K, Farkas O, Foresman JB, Fox DJ. Gaussian 16, Revision B.01 . Gaussian, Inc; Wallingford CT: 2016
32 McLean AD, Chandler GS. J. Chem. Phys. 1980; 72: 5639
33 Krishnan R, Binkley JS, Seeger R, Pople JA. J. Chem. Phys. 1980; 72: 650
34 Tomasi J, Mennucci B, Cammi R. Chem. Rev. 2005; 105: 2999
35 Reed AE, Curtiss LA, Weinhold F. Chem. Rev. 1988; 88: 899
36 Ali A, Ashfaq M, Din ZU, Ibrahim M, Khalid M, Assiri MA, Riaz A, Tahir MN, Rodrigues-Filho E, Imran M, Kuznetsov A. ACS Omega 2022; 7: 39294
37 Ashfaq M, Tahir MN, Muhammad S, Munawar KS, Ali A, Bogdanov G, Alarfaji SS. ACS Omega 2021; 6: 31211
38 Dennington R, Keith TA, Millam JM. GaussView, Version 6 . Semichem Inc; Shawnee Mission, KS: 2016
39 ChemBioOffice 2014 version 14.0. (2014); CambridgeSoft Corporation; https://perkinelmerinformatics.com/products/research/chemdraw

Supplementary Material