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One-pot synthesis of densely functionalized cyclic \(\beta \)-aminoesters containing four stereocenters, based on a \(\hbox {Et}_{3}\)N-promoted pseudo five-component reaction

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Abstract

An effective and practical method has been developed for the diversity-oriented synthesis of fully substituted cyclohexene \(\beta \)-aminoester via a pseudo five-component reaction between nitromethane, aromatic aldehydes, and substituted cyanoacetate for the generation of a wide range of structurally relevant and highly functionalized compounds. The attractive range and features of the method, which enables the facile preparation of highly substituted cyclohexenes, are its simple and straightforward procedure, mild reaction conditions, and ideal yields. The mechanism involves a double Michael addition reaction followed by intramolecular ring closure. The fully substituted cyclohexene \(\beta \)-aminoesters with potential bioactivities could be of impact in medical chemistry.

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References

  1. Yestrepsky BD, Xu Y, Breen ME, Li X, Rajeswaran WG, Ryu JG, Sorenson RJ, Tsume Y, Wilson MW, Zhang W, Sun D, Sun H, Larsen SD (2013) Novel inhibitors of bacterial virulence: development of 5,6-dihydrobenzo[h]quinazolin- 4(3H)-ones for the inhibition of group A streptococcal streptokinase expression. Bioorg Med Chem 21:1880–1897. doi:10.1016/j.bmc.2013.01.046

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Markosyan AI, Akopyan KhS, Arsenyan FG, Sukasyan RS, Garibdzhanyan BT (2006) Synthesis, antineoplastic and antimonoamineoxidase activity of 3-allyl-4-oxo-2-thioxo-1,2,3,4,5,6-hexahydrospiro(benzo[h]quinazoline-5,1’-cyclohexanes). Pharm Chem J 40:480–484. doi:10.1007/s11094-006-0159-7

    Article  CAS  Google Scholar 

  3. Markosyan AI, Akalyan KS, Arsenyan FG, Sukasyan RS, Garibdzhanyan BT (2008) Synthesis and biological properties of 3-phenyl-and 3-phenethyl-5-methyl-5-ethyl-4-oxo-3,4,5,6-tetrahydrobenzo[h]quinazolines. Pharm Chem J 42:313–318. doi:10.1007/s11094-008-0115-9

    Article  CAS  Google Scholar 

  4. Markosyan AI, Gabrielyan SA, Arsenyan FG, Sukasyan RS (2010) Synthesis, antineoplastic and antimonoamineoxidase activity of 3-allyl-4-oxo-2-thioxo-1,2,3,4,5,6-hexahydrospiro(benzo[h]quinazoline-5,1’-cyclohexanes). Pharm Chem J 44:405–408. doi:10.1007/s11094-010-0477-7

    Article  CAS  Google Scholar 

  5. Ginsburg DR, Sun H, Larsen S (2010) Methods and compositions for treating bacterial infection. WO 2010090860

  6. Motin VL, Chauhan S, Gilbertson SR, Agarkov A, Lory P (2009) Substrates and inhibitors of plague plasminogen activator and their use in detecting and controlling Yersinia pestis infections. US 20090069248

  7. Christensen ISB, Bender PE, Forster CJ, Gleason JG (1995) 4-Phenylcyclohexene derivatives and anti-inflammatory compositions and methods thereof. US 5449687

  8. Jourdan JP, Rochais C, Legay R, Dallemagne P (2013) An unusual boron tribromide-mediated, one-pot bromination/cyclization reaction. Application to the synthesis of a highly strained cyclopenta[1,3]cyclopropa[1,2-b] pyrrolizin-8-one. Tetrahedron Lett 54:1133–1136. doi:10.1016/j.tetlet.2012.12.056

    Article  CAS  Google Scholar 

  9. Cagir A, Jones SH, Eisenhauer BM, Gao R, Hecht SM (2004) Synthesis and biochemical properties of E-ring modified luotonin A derivatives. Bioorg Med Chem Lett 14:2051–2054. doi:10.1016/j.bmcl.2004.02.069

  10. Koert U (1997) \(\upbeta \)-Peptides: novel secondary structures take shape. Angew Chem Int Ed Engl 36:1836–1837. doi: 10.1002/anie.199718361

    Article  CAS  Google Scholar 

  11. Porter EA, Wang X, Lee HS, Weisblum B, Gellman SH (2000) Antibiotics: non-haemolytic \(\upbeta \)-amino-acid oligomers. Nature 404:565–567. doi: 10.1038/35007145

    Article  CAS  PubMed  Google Scholar 

  12. Raguse TL, Jonathan R, Leplae PR, Gellman SH (2001) Toward \(\upbeta \)-peptide tertiary structure: self-association of an amphiphilic 14-helix in aqueous solution. Org Lett 3:3963–3966. doi: 10.1021/ol016868r

    Article  CAS  PubMed  Google Scholar 

  13. Ding FX, Shen HC, Wilsie LC, Krsmanovic ML, Taggart AK, Ren N, Cai TQ, Wang J, Tong X, Holt TG, Chen Q, Waters MG, Hammond ML, Tata JR, Colletti SL (2010) Discovery of pyrazolyl propionyl cyclohexenamide derivatives as full agonists for the high affinity niacin receptor GPR109A. Bioorg Med Chem Lett 20:3372–3375. doi:10.1016/j.bmcl.2010.04.013

    Article  CAS  PubMed  Google Scholar 

  14. Shen HC, Ding FX, Raghavan S, Deng Q, Luell S, Forrest MJ, Carballo-Jane E, Wilsie LC, Krsmanovic ML, Taggart AK, Wu KK, Wu TJ, Cheng K, Ren N, Cai TQ, Chen Q, Wang J, Wolff MS, Tong X, Holt TG, Waters MG, Hammond ML, Tata JR, Colletti SL (2010) Discovery of a biaryl cyclohexene carboxylic acid (MK-6892): a potent and selective high affinity niacin receptor full agonist with reduced flushing profiles in animals as a preclinical candidate. J Med Chem 53:2666–2670. doi:10.1021/jm100022r

    Article  CAS  PubMed  Google Scholar 

  15. Imbriglio JE, DiRocco D, Bodner R, Raghavan S, Chen W, Marley D, Esser C, Holt TG, Wolff MS, Taggart AKP, Waters MG, Tata JR, Colletti SL (2011) The discovery of high affinity agonists of GPR109a with reduced serum shift and improved ADME properties. Bioorg Med Chem Lett 21:2721–2724. doi:10.1016/j.bmcl.2010.11.116

    Article  CAS  PubMed  Google Scholar 

  16. Allwein SP, Roemmele RC, Haley JJ Jr, Mowrey DR, Petrillo DE, Reif JJ, Gingrich DE, Bakale RP (2012) Development and sale-up of an optimized route to the ALK inhibitor CEP-28122. Org Process Res Devel 16:148–155. doi:10.1021/op200313v

    Article  CAS  Google Scholar 

  17. Kiss L, Fülöp F (2014) Synthesis of carbocyclic and heterocyclic \(\upbeta \)-aminocarboxylic acids. Chem Rev 114:1116–1169. doi: 10.1021/cr300454h

    Article  CAS  PubMed  Google Scholar 

  18. Gomes PB, Nett M, Dahse HM, Hertweck C (2010) Pitucamycin: structural merger of a phenoxazinone with an epoxyquinone antibiotic. J Nat Prod 73:1461–1464. doi:10.1021/np100344u

    Article  CAS  PubMed  Google Scholar 

  19. Schmidt D, Smenton A, Raghavan S, Shen H, Ding FX, Carballo-Jane E, Luell S, Ciecko T, Holt TG, Wolff M, Taggart A, Wilsie L, Krsmanovic M, Ren N, Blom D, Cheng K, McCann PE, Waters MG, Tata J, Colletti SL (2010) Anthranilic acid replacements in a niacin receptor agonist. Bioorg Med Chem Lett 20:3426–3430. doi:10.1016/j.bmcl.2010.04.001

    Article  CAS  PubMed  Google Scholar 

  20. Martinek TA, Fülöp F (2012) Peptidic foldamers: ramping up diversity. Chem Soc Rev 41:687–702. doi:10.1039/C1CS15097A

    Article  CAS  PubMed  Google Scholar 

  21. Kim JH, Shin H, Lee S (2012) Chemoselective intramolecular alkylation of the blaise reaction intermediates: tandem one-pot synthesis of exo-cyclic enaminoesters and their applications toward the synthesis of N-heterocyclic compounds. J Org Chem 77:1560–1565. doi:10.1021/jo201964a

    Article  CAS  PubMed  Google Scholar 

  22. Miura T, Harumashi T, Murakami M (2007) Cyclization reaction of cyano-substituted unsaturated esters prompted by conjugate addition of organoborons. Org Lett 9:741–743. doi:10.1021/ol062882y

    Article  CAS  PubMed  Google Scholar 

  23. Sass DC, de Lucca Jr EC, Barbosa Jda S (2011) Tandem reduction cyclization of ortho-substituted cinnamic esters. Tetrahedron Lett 52:5371–5374. doi:10.1016/j.tetlet.2011.08.039

    Article  CAS  Google Scholar 

  24. Nakamura S, Sugimoto H, Ohwada T (2008) Superacid-catalyzed intramolecular cyclization reaction of arylcyanopropionate: geminal substitution effect on superelectrophilicity. J Org Chem 73:4219–4224. doi:10.1021/jo800674h

    Article  CAS  PubMed  Google Scholar 

  25. Ruijter E, Scheffelaar R, Orru RVA (2011) Multicomponent reaction design in the quest for molecular complexity and diversity. Angew Chem Int Ed 50:6234–6246. doi:10.1002/anie.201006515

    Article  CAS  Google Scholar 

  26. Tejedor D, Garcia-Tellado F (2007) Chemo-differentiating ABB\(^{\prime }\) multicomponent reactions. Privileged building blocks. Chem Soc Rev 36:484–491. doi: 10.1039/B608164A

    Article  CAS  PubMed  Google Scholar 

  27. Zhu J, Bienayme H (eds) (2005) Multicomponent reactions. Wiley-VCH, Weinheim

    Google Scholar 

  28. Domling A (2006) Recent developments in isocyanide based multicomponent reactions in applied chemistry. Chem Rev 106:17–89. doi:10.1021/cr0505728

    Article  PubMed  Google Scholar 

  29. Michaud D, Ayoubi SAE, Dozias MJ, Toupet L, Texier-Boullet F, Hamelin J (1997) New route to functionalized cyclohexenes from nitromethane and electrophilic alkenes without solvent under focused microwave irradiation. Chem Commun 1613–1614: doi:10.1039/A704241H

  30. Michaud D, Hamelin J, Texier-Boullet F (2003) Michael monoadditions of nitromethane or nitroethane with electrophilic gem-disubstituted alkenes over alumina under microwave irradiation. Tetrahedron 59:3323–3331. doi:10.1016/S0040-4020(03)00419-8

    Article  CAS  Google Scholar 

  31. Sridharan V, Menendez JC (2008) Two-step stereocontrolled synthesis of densely functionalized cyclic \(\upbeta \)-aminoesters containing four stereocenters, based on a new cerium(IV) ammonium nitrate catalyzed sequential three-component reaction. Org Lett 10:4303–4306. doi: 10.1021/ol801738d

    Article  CAS  PubMed  Google Scholar 

  32. Fustero S, de la Torre GM, Jofre V, Carlon RP, Navarro A, Fuentes AS, Carrio JS (1998) Synthesis and reactivity of new \(\upbeta \)-enamino acid derivatives: a simple and general approach to \(\upbeta \)-enamino esters and thioesters. J Org Chem 63:8825–8836. doi: 10.1021/jo9809480

    Article  CAS  Google Scholar 

  33. Ono N (2001) The nitro group in organic synthesis. Wiley-VCH, Weinheim

    Book  Google Scholar 

  34. Altug C, Burnett AK, Caner E, Durust Y, Elliott MC, Glanville RPJ, Guy C, Westwell A (2011) An efficient one-pot multicomponent approach to 5-amino-7-aryl-8-nitrothiazolo[3,2-\(a\)]pyridines. Tetrahedron 67:9522–9528. doi:10.1016/j.tet.2011.10.005

  35. Kshirsagar SW, Patil NR, Samant SD (2010) One-pot synthesis of 2-amino-5-nitro-4,6-diarylcyclohex-1-ene-1,3,3-tricarbonitriles by condensation of aldehyde, malononitrile, and nitromethane in the presence of Mg-Al HT under solvent-free condition. Tetrahedron Lett 51:2924–2927. doi:10.1016/j.tetlet.2010.03.112

    Article  CAS  Google Scholar 

  36. Shi D, Tu S, Yao C, Wang X, Wang Y (2002) A convenient synthesis of 2-amino-1.3.3-tri- cyano-5-nitro-4,6-diarylcyclohexenes catalyzed by KF-alumina. Synth Commun 32:3137–3142. doi:10.1081/SCC-120013724

    Article  CAS  Google Scholar 

  37. Liu H, Zhou Z, Sun Q, Li Y, Li Y, Liu J, Yan P, Wang D, Wang C (2012) Synthesis of polysubstituted 2-piperidinones via a Michael addition/nitro- Mannich/lactamization cascade. ACS Comb Sci 14:366–371. doi:10.1021/co300022f

    Article  PubMed  Google Scholar 

  38. Zhou Z, Liu H, Sun Q, Li Y, Yang J, Liu J, Yan P, Wang C (2012) Novel synthesis of trans-4,6-diaryl-5-nitropiperidin-2-ones via four-component reaction from substituted nitrostyrenes, aromatic aldehydes, dimethyl malonate, and formamide. Synlett 23:2255–2260. doi:10.1055/s-0032-1317044

    Article  CAS  Google Scholar 

  39. Liu H, Sun Q, Zhou Z, Liu J, Yang J, Wang C (2013) One-pot synthesis of polysubstituted 2-piperidinones from aromatic aldehydes, nitromethane, ammonium acetate, and dialkyl malonates. Monatsh Chem 144:1031–1041. doi:10.1007/s00706-012-0912-4

  40. Zhou Z, Liu H, Li Y, Liu J, Li Y, Liu J, Yao J, Wang C (2013) Novel synthesis of substituted furo[3,2-c]chromen-4-ones via four-component reaction from substituted nitrostyrenes, aromatic aldehydes, coumarins, and ammonium acetate. ACS Comb Sci 15:363–369. doi:10.1021/co4000419

    Article  CAS  PubMed  Google Scholar 

  41. Li Y, Liu H, Sun L, Liu J, Xue Z, Yao J, Wang C (2013) Novel synthesis of 3-aryl-4-hydroxybenzofurans via four-component reaction from substituted nitrostyrenes, aromatic aldehydes, cyclohexan-1,3-diones, and ammonium acetate. Synlett 24:1851–1855. doi:10.1055/s-0033-1339332

    Article  CAS  Google Scholar 

  42. Hogan I, Jenkins PD, Sainsbury M (1990) The chemistry of the pyrido[4,3-\(b\)]carbazoles part 15 the synthesis of unsymmetrically 1,4-disubstituted carbazoles and their use in the synthesis of 6H-Pyrido-[4,3-\(b\)]carbazoles. Tetrahedron 46:2943–2964. doi: 10.1016/S0040-4020(01)88387-3

    Article  CAS  Google Scholar 

  43. Gowrisankar S, Park DY, Kim JN (2005) Synthesis of 2,3,4-trisubstituted 2,5-dihydrofuran derivatives. Bull Korean Chem Soc 26:1826–1828. doi:10.5012/bkcs.2005.26.11.1826

    Article  CAS  Google Scholar 

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Funding

Financial support of this research by the National Natural Science Foundation of China (NNSFC 21173181) is gratefully acknowledged by authors. A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.

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Authors and Affiliations

  1. School of Chemistry and Chemical Engineering, Yangzhou University, 180 Siwangting Street, Yangzhou, 225002, Jiangsu, People’s Republic of China

    Juan Yao, Lanxiang Zhou, Chen Tan & Cunde Wang

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  1. Juan Yao
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  2. Lanxiang Zhou
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  3. Chen Tan
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  4. Cunde Wang
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Correspondence to Cunde Wang.

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Yao, J., Zhou, L., Tan, C. et al. One-pot synthesis of densely functionalized cyclic \(\beta \)-aminoesters containing four stereocenters, based on a \(\hbox {Et}_{3}\)N-promoted pseudo five-component reaction. Mol Divers 19, 43–53 (2015). https://doi.org/10.1007/s11030-014-9554-2

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