Advertisement

Amino Acids

pp 1–9 | Cite as

Synthesis of α/β dipeptides containing linear or cyclic α-dehydro-β-amino acids as scaffolds for bioactive compounds

  • Lucia FerrazzanoEmail author
  • Dario Corbisiero
  • Roberto Greco
  • Eleonora Potenza
  • Giulia De Seriis
  • Andrea Garelli
  • Alessandra Tolomelli
Original Article
  • 28 Downloads

Abstract

The synthesis of α/β dipeptides containing linear or cyclic α-dehydro-β-amino acids has been performed starting from alkylidene acetacetamides, which were obtained from α-amino esters via Ir-catalyzed allylic amination. Differently hindered carbonates were synthesized via a protocol involving chemoselective Luche’s reduction, acylation, and allylic amination. Depending on the nature of the selected α-amino acid, we observed strong influence on the product regiochemistry due to the carbonate size and the amino-acid side chain. In particular, complete regioselectivity was observed in the aminic allylation of carbonates deriving from amino acids possessing a methylene unit in β-position. On the contrary, methyl carbonates deriving from β-branched amino acid afforded different results depending on the hindrance of the carbonate. Moreover, spontaneous cyclization was observed for carbamate-containing intermediates, allowing to obtain peptidomimetic polyfunctionalized dihydropyrimidine-2,4-dione. Finally, by inverting the order of reduction/acylation steps on the starting alkylidene acetoacetamides, the formation of polyfunctionalized 1,3-oxazinane-2,4-dione was obtained demonstrating the wide applications of these substrates for the preparation of bioactive peptidomimetics.

Keywords

α/β dipeptides Allylic amination Steric hindrance Alkylidene acetacetamides Cyclic scaffolds 

Notes

Acknowledgements

This study has been carried out with the fundamental contribution of MIUR (PRIN project 2015) and University of Bologna.

Compliance with ethical standards

Conflict of interest

There are no conflicts to declare. Any research involving human participants and/or animals has been reported in this work, so any informed consent was required.

Supplementary material

726_2019_2782_MOESM1_ESM.docx (40 kb)
Supplementary material 1 (DOCX 39 kb)

References

  1. Agenet N, Amatore C, Gamez S, Gérardin H, Jutand A, Meyer G, Orthwein C (2002) Effect of the leaving group and the allylic structure on the kinetics and thermodynamics of the reaction of allylic carboxylates with palladium (0) complexes. Arkivoc 92:101Google Scholar
  2. Avan I, Hall CD, Katritzky AR (2014) Peptidomimetics via modifications of amino acids and peptide bonds. Chem Soc Rev 4:3575CrossRefGoogle Scholar
  3. Benfatti F, Cardillo G, Gentilucci L, Mosconi E, Tolomelli A (2008) Synthesis of dehydro-β-amino esters via highly regioselective amination of allylic carbonates. Org Lett 10:2425CrossRefGoogle Scholar
  4. Butts CP, Filali E, Lloyd-Jones GC, Norrby PO, Sale DA, Schramm Y (2009) Structure-based rationale for selectivity in the asymmetric allylic alkylation of cycloalkenyl esters employing the trost ‘standard ligand’ (TSL): isolation, analysis and alkylation of the monomeric form of the cationic η3-cyclohexenyl complex [(η3-c-C6H9)Pd(TSL)]+. J Am Chem Soc 131:9945CrossRefGoogle Scholar
  5. Cabrele C, Martinek TA, Reiser O, Berlicki L (2014) Peptides containing β-amino acid patterns: challenges and successes in medicinal chemistry. J Med Chem 57:9718CrossRefGoogle Scholar
  6. Checco JW, Lee EF, Evangelista M, Sleebs NJ, Rogers K, Pettikiriarachchi A, Kershaw NJ, Eddinger GA, Belair DG, Wilson JL, Eller CH, Raines RT, Murphy WL, Smith BJ, Gellmann SH, Fairlie WD (2015) α/β-peptide foldamers targeting intracellular protein-protein interactions with activity in living cells. J Am Chem Soc 137:11365CrossRefGoogle Scholar
  7. Chen M, Hartwig JF (2016) Iridium-catalyzed regio- and enantioselective allylic substitution of trisubstituted allylic electrophiles. Angew Chem Int Ed 55:11651CrossRefGoogle Scholar
  8. Cheng RP, Gellmann SH, DeGrado WF (2001) β-peptides: from structure to function. Chem Rev 101:3219CrossRefGoogle Scholar
  9. Cheng Q, Tu HF, Zheng C, Qu JP, Helmchen G, You SL (2019) Iridium-catalyzed asymmetric allylic substitution reactions. Chem Rev 119:1855CrossRefGoogle Scholar
  10. De Marco R, Tolomelli A, Juaristi E, Gentilucci L (2016) Integrin ligands with α/β-hybrid peptide structure: design, bioactivity, stability, and conformational aspects. Med Res Rev 36:389CrossRefGoogle Scholar
  11. Dong G, Wang S, Miao Z, Yao J, Zhang Y, Guo Z, Zhang W, Sheng C (2012) New tricks for an old natural product: discovery of highly potent evodiamine derivatives as novel antitumor agents by systemic structure–activity relationship analysis and biological evaluations. J Med Chem 55:7593CrossRefGoogle Scholar
  12. Galeazzi R, Martelli G, Marcucci E, Orena M, Rinaldi S, Lattanzi R, Negri L (2010) Analogues of both Leu- and Met-enkephalin containing a constrained dipeptide isostere prepared from a Baylis-Hillman adduct. Amino Acids 38:1057CrossRefGoogle Scholar
  13. Jianping Q, Helmchen G (2017) Applications of iridium-catalyzed asymmetric allylic substitution reactions in target-oriented synthesis. Acc Chem Res 50:2539CrossRefGoogle Scholar
  14. Kuwano R (2011) Usage of the carboxylate leaving group in transition-metal-catalyzed cross─coupling and related reactions. J Synth Org Chem Jpn 69:1263CrossRefGoogle Scholar
  15. Luche JL (1978) Lanthanides in organic chemistry. 1. Selective 1,2 reductions of conjugated ketones. J Am Chem Soc 100:2226–2227CrossRefGoogle Scholar
  16. Madrahimov ST, Li Q, Sharma A, Hartwig JF (2015) Origins of regioselectivity in Iridium catalyzed allylic substitution. J Am Chem Soc 137:14968CrossRefGoogle Scholar
  17. Martinek TA, Fulop F (2003) Side-chain control of β-peptide secondary structures. Eur J Biochem 270:3657CrossRefGoogle Scholar
  18. Mu F, Lee DJ, Pryor DE, Hamel E, Cushman E (2002) Synthesis and investigation of conformationally restricted analogues of lavendustin A as cytotoxic inhibitors of tubulin polymerization. J Med Chem 45:4774CrossRefGoogle Scholar
  19. Norman MH, Navas F III, Thompson JB, Rigdon GC (1996) Structure–activity relationships of a series of substituted benzamides: potent D2/5-HT2 antagonists and 5-HT1a agonists as neuroleptic agents. J Med Chem 39:4692CrossRefGoogle Scholar
  20. North M (2000) Incorporation of conformationally constrained β-amino acids into peptides. J Pept Sci 6:301CrossRefGoogle Scholar
  21. Rajesh S, Srivastava J, Banerji B, Iqbal J (2001) α-dehydro-β-amino acid derivatives as turn inducer: synthesis of potential HIV protease inhibitors based on structural mimicry. Ind J Chem 40B:1029Google Scholar
  22. Raskatov JA, Spiess S, Gnamm C, Brödner K, Rominger F, Helmchen G (2010) Ir-catalysed asymmetric allylic substitutions with cyclometalated (phosphoramidite)Ir complexes—resting states, catalytically active (π-Allyl)Ir complexes and computational exploration. Chem Eur J 16:6601CrossRefGoogle Scholar
  23. Seebach D, Matthews JL (1997) β-Peptides: a surprise at every turn. Chem Commun 1997:2015–2022CrossRefGoogle Scholar
  24. Shu C, Leitner A, Hartwig JF (2004) Enantioselective allylation of aromatic amines after in situ generation of an activated cyclometalated iridium catalyst. Angew Chem Int Ed 43:4797–4800CrossRefGoogle Scholar
  25. Tolomelli A, Gentilucci L, Mosconi E, Viola A, Dattoli SD, Baiula M, Spampinato S, Belvisi L, Civera M (2011a) Development of isoxazoline-containing peptidomimetics as dual αvβ3- and α5β1 integrin ligands. ChemMedChem 6:2264–2272CrossRefGoogle Scholar
  26. Tolomelli A, Gentilucci L, Mosconi E, Viola A, Paradisi E (2011b) A straightforward route to enantiopure 2-substituted-3,4-dehydro-β-proline via ring closing metathesis. Amino Acids 41:575CrossRefGoogle Scholar
  27. Tolomelli A, Baiula M, Belvisi L, Viola A, Gentilucci L, Troisi S, Dattoli SD, Spampinato S, Civera M, Juaristi E, Escudero M (2013) Modulation of αvβ3- and α5β1-integrin-mediated adhesion by dehydro-beta-amino acids containing peptidomimetics. Eur J Med Chem 66:258CrossRefGoogle Scholar
  28. Tolomelli A, Baiula M, Viola A, Ferrazzano L, Gentilucci L, Dattoli SD, Spampinato S, Juaristi E, Escudero M (2015) Dehydro-β-proline containing peptidomimetics as selective α4β1 integrin antagonists: a stereochemical recognition in ligand-receptor interaction”. ACS Med Chem Lett 6:701CrossRefGoogle Scholar
  29. Trost BM, Crawley ML (2003) Asymmetric transition-metal catalyzed allylic alkylations: applications in total synthesis. Chem Rev 103:2921CrossRefGoogle Scholar
  30. Trost BM, Fandrick DR (2007) Aldrichimica Acta 40:59Google Scholar
  31. Viola A, Ferrazzano L, Greco R, Cerisoli L, Caldi J, Tolomelli A (2016) One-pot two-step microwave-assisted synthesis of alkylidene acetoacetamido esters, useful intermediates for β-dehydropeptides. Eur J Org Chem 19:3217CrossRefGoogle Scholar
  32. Weix DJ, Markovic D, Ueda M, Hartwig JF (2009) Direct, intramolecular, enantioselelctive, Iridium-catalyzed allylation of carbamates to form carbamate-protected, branched allylic amines. Org Lett 11:2944CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Chemistry “G. Ciamician”University of BolognaBolognaItaly

Personalised recommendations