Abstract
In this work, three possible reaction pathways (Path 1, Path 2 and Path 3) for the generation process of cyclic dipeptide from amino acid have been investigated in detail using density functional theory. Path 1 and Path 2 are the intramolecular reaction processes, while Path 3 involves the intermolecular reaction process that assisted with water molecule. Our calculated results indicate that Path 3 is more energy favorable than Path 1 and Path 2. There are four steps in Path 3 proceed from the amino acid to cyclic dipeptide. The first step is two adjacent amino acids to form precursor of dipeptide, the second step is the removal of water molecule of precursor of dipeptide for the formation of the linear dipeptide, the third step is generation of precursor of cyclic dipeptide associated with other hydrogen atom transfer, and the last step is another dehydration process to generate the final product of cyclic dipeptide. Moreover, the obtained results indicate that the generation mechanisms of different cyclic dipeptides are similar, and the energy barrier of the rate-determined step influenced somewhat by the hydrophilic or hydrophobic group linked to the Cα atom. Additionally, the potential energy profiles suggest that the generation reactions of the studied nine cyclic dipeptides are exothermic processes. The detailed mechanisms should be helpful for people to understanding the title reaction at the molecular level, and the proposed novel intermolecular process might provide valuable insights on rational improve reaction condition for this type of reaction.
Similar content being viewed by others
References
Wipf P (1995) Synthetic studies of biologically active marine cyclopeptides. Chem Rev 95:2115–2134
Dinsmore CJ, Beshore DC (2002) Recent advances in the synthesis of diketopiperazines. Tetrahedron Lett 58:3297–3312
Martins MB, Carvalho I (2007) Diketopiperazines: biological activity and synthesis. Tetrahedron Lett 63:9923–9932
Borthwick AD (2012) 2,5-Diketopiperazines: synthesis, reactions, medicinal chemistry, and bioactive natural products. Chem Rev 112:3641–3716
Li P, Roller PP, Xu J (2002) Current synthetic approaches to peptide and peptidomimetic cyclization. Curr Org Chem 6:411–440
Davies JSJ (2003) The cyclization of peptides and depsipeptides. Peptide Sci 9:471–501
Kanoh K, Kohno S, Katada J, Takahashi J, Uno I (1999) (−)-Phenylahistin arrests cells in mitosis by inhibiting tubulin polymerization. J Antibiot 52:134–141
Nicholson B, Lloyd GK, Miller BR, Palladino MA, Kiso Y, Hayashi Y, Neuteboom STC (2006) NPI-2358 is a tubulin-depolymerizing agent: in vitro evidence for activity as a tumor vascular-disrupting agent. Anticancer Drugs 17:25–31
Evd Merwe, Huang D, Peterson D, Kilian G, Milne PJ, Venter MVD, Frost C (2008) The synthesis and anticancer activity of selected diketopiperazines. Peptides 29:1305–1311
Sinha S, Srivastava R, Clercq ED, Singh RK (2004) Synthesis and antiviral properties of arabino and ribonucleosides of 1,3-dideazaadenine, 4-nitro-1,3-dideazapurine and diketopiperazine. Nucleosides, Nucleotides Nucleic Acids 23:1815–1824
Houston DR, Synstad B, Eijsink VGH, Stark MJR, Eggleston IM, van Aalten DMF (2004) Structure-based exploration of cyclic dipeptide chitinase inhibitors. J Med Chem 47:5713–5720
Abraham WR (2005) Controlling pathogenic Gram-negative bacteria by interfering with their biofilm formation. Drug Des Rev 2:13–33
Gaunitz F, Hipkiss AR (2012) Carnosine and cancer: a perspective. Amino Acids 43:135–142
Deepa I, Kumar SN, Sreerag RS, Nath VS, Mohandas C (2015) Purification and synergistic antibacterial activity of arginine derived cyclic dipeptides, from Achromobacter sp. associated with a rhabditid entomopathogenic nematode against major clinically relevant biofilm forming wound bacteria. Front Microbiol 6:876
Giessen TW, Marahiel MA (2015) Rational and combinatorial tailoring of bioactive cyclic dipeptides. Front Microbiol 6:785
McCleland K, Milne PJ, Lucieto FR, Frost C, Brauns SC, Venter MVD, Plessis JD, Dyason K (2004) An investigation into the biological activity of the selected histidine-containing diketopiperazines cyclo(His-Phe) and cyclo(His-Tyr). J Pharm Pharmacol 56:1143–1153
Kwak MK, Liu R, Kwon JO, Kim MK, Kim AH, Kang SO (2013) Cyclic dipeptides from lactic acid bacteria inhibit proliferation of the influenza A virus. J Microbiol 51:836–843
Song MK, Hwang IK, Rosenthal MJ, Harris DM, Yamaguchi DT, Yip I, Go VLW (2003) Anti-hyperglycemic activity of zinc plus cyclo (His-Pro) in genetically diabetic Goto-Kakizaki and aged rats. Exp Biol Med 228:1338–1345
Balraju V, Iqbal J (2006) Synthesis of cyclic peptides constrained with biarylamine linkers using Buchwald–Hartwig C–N coupling. J Org Chem 71:8954–8956
Peng L, Roller PP (2002) Cyclization strategies in peptide derived drug design. Curr Top Med Chem 2:325–341
Lim HJ, Gallucci JC, RajanBabu TV (2010) Annulated diketopiperazines from dipeptides or schollkopf reagents via tandem cyclization-intramolecular N-arylation. Org Lett 12:2162–2165
Alfonso IM, Burguete I, Luis SV (2006) A hydrogen-bonding-modulated molecular rotor: environmental effect in the conformational stability of peptidomimetic macrocyclic cyclophanes. J Org Chem 71:2242–2250
Billing JF, Nilsson UJ (2005) C-2-symmetric macrocyclic carbohydrate/amino acid hybrids through copper(I)-catalyzed formation of 1,2,3-triazoles. J Org Chem 70:4847–4850
Punna S, Kuzelka J, Wang Q, Finn MG (2005) Head-to-tail peptide cyclodimerization by copper-catalyzed azide-alkyne cycloaddition. Angew Chem Int Ed 44:2215–2220
Fernández-López S, Kim HS, Choi EC, Delgado M, Granja JR, Khasanov A, Kraehenbuehl K, Long G, Weinberger DA, Wilcoxen KM, Ghadiri MR (2001) Antibacterial agents based on the cyclic D, l-alpha-peptide architecture. Nature 412:452–455
Loughlin WA, Tyndall JDA, Glenn MP, Fairlie DP (2004) Beta-strand mimetics. Chem Rev 104:6085–6117
Singh Y, Stoermer MJ, Lucke AJ, Guthrie T, Fairlie DP (2005) Structural mimicry of two cytochrome b(562) interhelical loops using macrocycles constrained by oxazoles and thiazoles. J Am Chem Soc 127:6563–6572
Heinrichs G, Kubic S, Lacour J, Vial L (2005) Matched/mismatched interaction of a cyclic hexapeptide with ion pairs containing chiral cations and chiral anions. J Org Chem 70:4498–4501
Thajudeen H, Park K, Moon S-S, Hong IS (2010) An efficient green synthesis of proline-based cyclic dipeptides under water-mediated catalyst-free conditions. Tetrahedron Lett 51:1303–1305
Tullberg M, Grøtli M, Luthman K (2006) Efficient synthesis of 2,5-diketopiperazines using microwave assisted heating. Tetrahedron Lett 62:7484–7491
Wang G, Li C, Li J, Jia X (2009) Catalyst-free water-mediated N-Boc deprotection. Tetrahedron Lett 50:1438–1440
Carlsson AC, Jam F, Tullberg M, Pilotti Å, Ioannidis P, Luthman K, Grøtli M (2006) Microwave-assisted synthesis of the schöllkopf chiral auxiliaries: (3S)- and (3R)-3,6-dihydro-2,5-diethoxy-3-isopropyl-pyrazine. Tetrahedron Lett 47:5199–5201
Glass RS, Hug GL, Schöneich C, Wilson GS, Kuznetsova L, Lee TM, Ammam M, Lorance E, Nauser T, Nichol GS, Yamamoto T (2009) Neighboring amide Participation in thioether oxidation: relevance to biological oxidation. J Am Chem Soc 131:13791–13805
Xia P, Wang C, Qi C (2013) Theoretical study on the cyclization mechanism of dipeptides. Chinese J Chem 31:813–818
Zhu YY, Tang MS, Shi XY, Zhao YF (2007) Quantum chemical study of cyclic dipeptides. Int J Quantum Chem 107:745–753
Zhu YY, Zhao HG, Liu CM, Wei DH, Li X, Li SJ, Tang MS (2013) DFT studies on inclusion complexes of 1-phenyl-1-propanol enantiomers with modified cyclic decapeptides. Struct Chem 25:699–705
Zhao H, Zhu Y, Tong M, He J, Liu C, Tang M (2012) Density functional theory studies on the inclusion complexes of cyclic decapeptide with 1-phenyl-1-propanol enantiomers. J Mol Model 18:851–858
Wei DH, Tang MS (2009) DFT study on the mechanisms of stereoselective C(2)-vinylation of 1-substituted imidazoles with 3-phenyl-2-propynenitrile. J Phys Chem A 113:11035–11041
Jones GO, Li XC, Hayden AE, Houk KN, Danishefsky SJ (2008) The coupling of isonitriles and carboxylic acids occurring by sequential concerted rearrangement mechanisms. Org Lett 10:4093–4096
Zhang C, Zhu YY, Wei DH, Sun DZ, Zhang WJ, Tang MS (2010) Theoretical study on the reaction mechanism between 6-benzyl-6-azabicyclo[2.2.1]hept-2-ene and benzoyl isocyanate to urea and isourea. J Phys Chem A 114:2913–2919
Johnson LE, DuPre DB (2008) Topological and orbital-based mechanisms of the electronic stabilization of bis(diisopropylamino)cyclopropenylidene. J Phys Chem A 112:7448–7454
Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Keith T, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi MC, Rega JMM, Klene M, Knox JE, Cross JB, Bakken CA, Jaramillo, Gomperts R, Stratmann OY, Austin R, Cammi CP, Ochterski RLM, Morokuma VGZ, Voth GA, P Salvador JJD, Dapprich S, Daniels AD, Farkas O, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ. (2010) Gaussian 09, Revision C.01. Gaussian, Inc., Wallingford
Wang Y, Wei DH, Zhang WJ, Wang YY, Zhu YY, Jia Y, Tang M (2014) A theoretical study on the mechanisms of the reactions between 1,3-dialkynes and ammonia derivatives for the formation of five-membered N-heterocycles. Org Biomol Chem 12:7503–7514
Zhang XN, Tang MS, Li FF, Zhu YY, Liu CM, Zhang WJ, Wei DH (2015) Theoretical study on binding models of copper nucleases containing pyridyl groups to DNA. Theor Chem Acc 134:1–15
Zhao Y, Truhlar DG (2008) M06 Meta-GGA exchange-correlation functional. Here it means M06 exchange-correlation part which excludes HF exact exchange term. Theor Chem Acc 120:215–241
Sun X, Rai R, MacKerell AD, Faden AI, Xue F (2014) Facile one-step synthesis of 2,5-diketopiperazines. Tetrahedron Lett 55:1905–1908
Pereira PC, Arends IWCE, Sheldon RA (2014) Robust and straightforward chemo-enzymatic enantiopure dipeptide syntheses and diketopiperazines thereof. Tetrahedron Asymmetry 25:825–832
Barone V, Cossi M. (1998) Quantum Calculation of Molecular Energies and Energy Gradients in Solution by a Conductor Solvent Model. J Phys Chem A:1995-2001
Mennucci B, Tomasi J (1997) Continuum solvation models: a new approach to the problem of solute’s charge distribution and cavity boundaries. J Chem Phys 106:5151
Cancès E, Mennucci B, Tomasi J (1997) A new integral equation formalism for the polarizable continuum model: theoretical background and applications to isotropic and anisotropic dielectrics. J Chem Phys 107:3032
Fukui K (1981) The path of chemical reactions—the IRC approach. Acc Chem Res 14:363–368
Tullberg M, Grøtli M, Luthman K (2006) Efficient synthesis of 2,5-diketopiperazines using microwave assisted heating. Tetrahedron Lett 62
Sun DZ, Zhu YY, Wei DH, Zhang C, Zhang WJ, Tang MS (2010) Insight into the multicomponent reaction mechanisms of prop-2-en-1-amine and ethyl propiolate with alloxan derivative: a density functional theory study. Chem Phys Lett 495:33–39
Zhang WJ, Zhu YY, Wei DH, Tang MS (2012) Mechanisms of the cascade synthesis of substituted 4-amino-1,2,4-triazol-3-one from Huisgen zwitterion and aldehyde hydrazone: a DFT study. J Comput Chem 33:715–722
Alkorta I, Rozas I, Elguero J (1998) Isocyanides as hydrogen bond acceptors. Theor Chem Acc 99:116–123
Fujiwara T, Yasuda H, Nishimura Y, Nambu H, Yakura T (2015) Synthesis of 10b-fluorinated analogues of protubonine A and its 11a-epimer cia fluorocyclisation of tryptophan-containing dipeptides. RSC Adv 5:5464–5473
Acknowledgments
This work was financially supported by the National Natural Science Foundation of China (Nos. 21001095 and J120060). University Key Research Programs of Department of Education in Henan Province (Grant Nos. 15A150082 and 14A150033).
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Li, Y., Li, F., Zhu, Y. et al. DFT study on reaction mechanisms of cyclic dipeptide generation. Struct Chem 27, 1165–1173 (2016). https://doi.org/10.1007/s11224-016-0740-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11224-016-0740-y