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DOI: 10.1055/a-2413-6896
Practical Multigram Approach to Conformationally Constrained α-Proline-Based Building Blocks with γ-Spiro Conjunction
The research was funded by internal Enamine grant, the Ministry of Education and Science of Ukraine (grant number 0123U102102), and the National Academy of Sciences of Ukraine (grant number 0120U104905).
Dedicated to all the brave defenders of Ukraine, whose sacrifice made this publication possible.
Abstract
Unusual amino acids have arisen as an indispensable instrument at the disposal of modern medicinal chemistry. While extensively exploited as building blocks in the search for new pharmaceuticals, their application goes far beyond. They are currently involved in explorations of the structure and conformational mobility of peptides, modification and amplification of peptidomimetic activity, and others. Herein, we report an effective synthetic approach to nonplanar, conformationally restricted, sp3-enriched spirocyclic α-prolines. The protocol employs readily available nitrile-based starting materials and conventional experimental procedures. The synthetic sequence is concise and includes three principal stages (one of them a four-step telescopic process). The reactions proceed on a multigram scale affording the target prolines in overall good yields. The possibility of chiral separation of the synthesized racemic spiro prolines to both pure enantiomers is shown. The building blocks synthesized in the study are expected to have practical uses in the field of medicinal chemistry.
Key words
amino acids - proline - spiro compounds - multigram - building blocks - medicinal chemistry - conformational rigiditySupporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/a-2413-6896.
- Supporting Information
Publication History
Received: 06 May 2024
Accepted after revision: 11 September 2024
Accepted Manuscript online:
11 September 2024
Article published online:
10 October 2024
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References
- 1 Hessler G, Baringhaus K.-H. Drug Discovery Today: Technol. 2010; 7: e263
- 2 Lovering F, Bikker J, Humblet C. J. Med. Chem. 2009; 52: 6752
- 3 Fang Z, Song Y, Zhan P, Zhang Q, Liu X. Future Med. Chem. 2014; 6: 885
- 4 de Sena M, Pinheiro P, Rodrigues AD, do Couto Maia R, Thota S, Fraga AM. C. Curr. Top. Med. Chem. 2019; 19: 1712
- 5 Prosser KE, Stokes RW, Cohen SM. ACS Med. Chem. Lett. 2020; 11: 1292
- 6 Meyers J, Carter M, Mok NY, Brown N. Future Med. Chem. 2016; 8: 1753
- 7 Zheng Y, Tice CM, Singh SB. Bioorg. Med. Chem. Lett. 2014; 24: 3673
- 8 Hiesinger K, Dar’in D, Proschak E, Krasavin M. J. Med. Chem. 2021; 64: 150
- 9 Batista VF, Pinto D, Silva AM. S. Expert Opin. Drug Discovery 2022; 17: 603
- 10 Derkach N, Levchenko K, Iermolenko I, Ostapchuk E, Lega D, Makhankova V, Rozhenko A, Volochnyuk D, Ryabukhin S. ChemRxiv 2024; preprint
- 11 Müller-Kuhrt L. Nat. Biotechnol. 2003; 21: 602
- 12 Newman DJ, Cragg GM. J. Nat. Prod. 2012; 75: 311
- 13 Xu Q, Deng H, Li X, Quan Z.-S. Front. Chem. 2021; 9: 650569
- 14 Gomari MM, Abkhiz S, Pour TG, Lotfi E, Rostami N, Monfared FN, Ghobari B, Mosavi M, Alipour B, Dokholyan NV. Mol. Med. 2022; 28: 146
- 15 Ding D, Xu S, da Silva-Júnior EF, Liu X, Zhan P. Drug Discovery Today 2023; 28: 103468
- 16 Zabolotna Y, Volochnyuk DM, Ryabukhin SV, Horvath D, Gavrilenko KS, Marcou G, Moroz YS, Oksiuta O, Varnek A. J. Chem. Inf. Model. 2022; 62: 2171
- 17 Bogen SL, Arasappan A, Bennett F, Chen K, Jao E, Liu Y.-T, Lovey RG, Venkatraman S, Pan W, Parekh T, Pike RE, Ruan S, Liu R, Baroudy B, Agrawal S, Chase R, Ingravallo P, Pichardo J, Prongay A, Brisson J.-M, Hsieh TY, Cheng K.-C, Kemp SJ, Levy OE, Lim-Wilby M, Tamura SY, Saksena AK, Girijavallabhan V, Njoroge FG. J. Med. Chem. 2006; 49: 2750
- 18 Kazmierski WM, Maynard A, Duan M, Baskaran S, Botyanszki J, Crosby R, Dickerson S, Tallant M, Grimes R, Hamatake R, Leivers M, Roberts CD, Walker J. J. Med. Chem. 2014; 57: 2058
- 19 Littler BJ, Aizenberg M, Ambhaikar NB, Blythe TA, Curran TT, Dvornikovs V, Jung YC, Jurkauskas V, Lee EC, Looker AR, Luong H, Martinot TA, Miller DB, Neubert-Langille BJ, Otten PA, Rose PJ, Ruggiero PL. Org. Process Res. Dev. 2015; 19: 270
- 20 Velázquez F, Chelliah M, Clasby M, Guo Z, Howe J, Miller R, Neelamkavil S, Shah U, Soriano A, Xia Y, Venkatraman S, Chackalamannil S, Davies IW. ACS Med. Chem. Lett. 2016; 7: 1173
- 21 Neelamkavil SF, Agrawal S, Bara T, Bennett C, Bhat S, Biswas D, Brockunier L, Buist N, Burnette D, Cartwright M, Chackalamannil S, Chase R, Chelliah M, Chen A, Clasby M, Colandrea VJ, Davies IW, Eagen K, Guo Z, Han Y, Howe J, Jayne C, Josien H, Kargman S, Marcantonio K, Miao S, Miller R, Nolting A, Pinto P, Rajagopalan M, Ruck RT, Shah U, Soriano A, Sperbeck D, Velazquez F, Wu J, Xia Y, Venkatraman S. ACS Med. Chem. Lett. 2016; 7: 111
- 22 Goldberg DR, De Lombaert S, Aiello R, Bourassa P, Barucci N, Zhang Q, Paralkar V, Stein AJ, Holt M, Valentine J, Zavadoski W. Bioorg. Med. Chem. Lett. 2017; 27: 413
- 23 Goldberg DR, De Lombaert S, Aiello R, Bourassa P, Barucci N, Zhang Q, Paralkar V, Valentine J, Zavadoski W. Bioorg. Med. Chem. Lett. 2016; 26: 1124
- 24 Smith EM, Swiss GF, Neustadt BR, McNamara P, Gold EH, Sybertz EJ, Baum T. J. Med. Chem. 1989; 32: 1600
- 25 Esch PM, Hiemstra H, de Boer RF, Speckamp WN. Tetrahedron 1992; 48: 4659
- 26 Banerjee A, Velagaleti R, Patil S, Pawar M, Yadav P, Kadam P, Qadri MM, Chakraborti S, Saini JS, Behera DB, Karanjai K, Iyer PS, Gharat LA, Das S. Bioorg. Med. Chem. Lett. 2021; 47: 128202
- 27 Conti P, Caligiuri A, Pinto A, Roda G, Tamborini L, Nielsen B, Madsen U, Frydenvang K, Colombo A, De Micheli C. Eur. J. Med. Chem. 2007; 42: 1059
- 28 Cheng W.-C, Liu Y, Wong M, Olmstead MM, Lam KS, Kurth MJ. J. Org. Chem. 2002; 67: 5673
- 29 Gao M, Li Y, Gan Y, Xu B. Angew. Chem. Int. Ed. 2015; 54: 8795
- 30 Liu T.-L, He Z.-L, Li Q.-H, Tao H.-Y, Wang C.-J. Adv. Synth. Catal. 2011; 353: 1713
- 31 Colombo L, Di Giacomo M, Vinci V, Colombo M, Manzoni L, Scolastico C. Tetrahedron 2003; 59: 4501
- 32 Gurjar MK, Ravindranadh SV, Sankar K, Karmakar S, Cherian J, Chorghade MS. Org. Biomol. Chem. 2003; 1: 1366
- 33 Kachkovskyi G, Faderl C, Reiser O. Adv. Synth. Catal. 2013; 355: 2240
- 34 Crossley MJ, Reid RC. J. Chem. Soc., Chem. Commun. 1994; 2237
- 35 Nuhrich A, Moulines J. Tetrahedron 1991; 47: 3075
- 36 Moriyama K, Izumisawa Y, Togo H. J. Org. Chem. 2012; 77: 9846
- 37 Teetz V, Gaul H. Tetrahedron Lett. 1984; 25: 4483
- 38 Candeias NR, Efimov A. In Comprehensive Heterocyclic Chemistry IV . Black DS, Cossy J, Stevens CV. Elsevier; Oxford: 2022: 512
- 39 Saito-Tarashima N, Kinoshita M, Igata Y, Kashiwabara Y, Minakawa N. RSC Med. Chem. 2021; 12: 1519
- 40 Ohtsu Y, Susaki Y, Noguchi K. Eur. J. Drug Metab. Pharmacokinet. 2018; 43: 693
- 41 Safina BS, Sweeney ZK, Li J, Chan BK, Bisconte A, Carrera D, Castanedo G, Flagella M, Heald R, Lewis C, Murray JM, Nonomiya J, Pang J, Price S, Reif K, Salphati L, Seward EM, Wei B, Sutherlin DP. Bioorg. Med. Chem. Lett. 2013; 23: 4953