Abstract
Chiral (R)-1-phenylethylamine was successfully employed in a tandem aza-Henry addition–reduction reaction to give chiral β-nitro α-trifluoromethyl amines. A subsequent coupling reaction with N-Boc-protected amino acids leads to obtain optically pure CF3-modified dipeptides carrying two different N-protecting groups. These peptidomimetic units are characterized by the presence of the [CH(CF3)NH] group as mimetic of the natural [CONH] peptidic bond and can be used for the synthesis of more complex CF3-modified peptides after selective deprotection of one of the two amine functions. 2D NMR spectral analyses were employed to determine the absolute configurations of all newly synthesized chiral compounds.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Acena JL, Simon-Fuentes A, Fustero S (2010) Recent developments in the synthesis of fluorinated β-amino acids. Curr Org Chem 14:928–949. doi:10.2174/138527210791111777
Aliev AE, Mia ZA, Busson MJM, Fitzmaurice RJ, Caddick S (2012) Diastereomer configurations from joint experimental–computational analysis. J Org Chem 77:6290–6295. doi:10.1021/jo301119h
Aresu E, Fioravanti S, Gasbarri S, Pellacani L, Ramadori F (2013a) Synthesis of gem-diamino acid derivatives by a Hofmann rearrangement. Amino Acids 44:977–982. doi:10.1007/s00726-012-1428-2
Aresu E, Fioravanti S, Gasbarri S, Pellacani L, Sciubba F (2013b) Stereoselective synthesis of short benzyl malonyl peptides. RSC Adv 3:13470–13476. doi:10.1039/c3ra41852a
Aresu E, Fioravanti S, Pellacani L, Sciubba F, Trulli L (2013c) Water-controlled chiral inversion of a nitrogen atom during the synthesis of diaziridines from α-branched N,N′-dialkyl α-diimines. New J Chem 37:4125–4129. doi:10.1039/c3nj00780d
Bégué JP, Bonnet-Delpon D, Crousse B, Legros J (2005) The chemistry of trifluoromethyl imines and related acetals derived from fluoral. Chem Soc Rev 34:562–572. doi:10.1039/B401707M
Buer BC, Marsh ENG (2012) Fluorine: a new element in protein design. Protein Sci 21:453–462. doi:10.1002/pro.2030
Buer BC, Levin BJ, Marsh ENG (2012) Influence of fluorination on the thermodynamics of protein folding. J Am Chem Soc 134:13027–13034. doi:10.1021/ja303521h
Cahard D, Bizet V (2014) The influence of fluorine in asymmetric catalysis. Chem Soc Rev 43:135–147. doi:10.1039/c3cs60193e
Carroccia L, Fioravanti S, Pellacani L, Tardella PA (2010) Solvent-free stereoselective synthesis of (E)-trifluoromethyl imines and hydrazones synthesis. Synthesis: 4096–4100. doi:10.1055/s-0030-1258280
Carroccia L, Fioravanti S, Pellacani L, Sadun C, Tardella PA (2011) Synthesis of optically active trifluoromethyl substituted diaziridines and oxaziridines. Tetrahedron 67:5375–5381. doi:10.1016/j.tet.2011.05.097
Carroccia L, Delfini M, Fioravanti S, Pellacani L, Sciubba F (2012) Stereoselective synthesis and ROESY 1H NMR study of bidiaziridines. J Org Chem 77:2069–2073. doi:10.1021/jo202618u
Cho J-I, Nishizono N, Iwahashi N, Saigo K, Ishida Y (2013) Stereo-regulated synthesis of peptides containing a β-trifluoromethyl-β-amino acid. Tetrahedron 69:9252–9260. doi:10.1016/j.tet.2013.08.051
Claridge TDW (2009) High-resolution NMR techniques in organic chemistry, 2nd edn. Elsevier, Amsterdam
Couve-Bonnaire S, Cahard D, Pannecoucke X (2007) Chiral dipeptide mimics possessing a fluoroolefin moiety: a relevant tool for conformational and medicinal studies. Org Biomol Chem 5:1151–1157. doi:10.1039/b701559c
Falk M, Burton IW, Hu T, Walter JA, Wright JLC (2001) Assignment of the relative stereochemistry of the spirolides, macrocyclic toxins isolated from shellfish and from the cultured dinoflagellate Alexandrium ostenfeldii. Tetrahedron 57:8659–8665. doi:10.1016/S0040-4020(01)00861-4
Filler R, Saha R (2009) Fluorine in medicinal chemistry: a century of progress and a 60-year retrospective of selected highlights. Future Med Chem 1:777–791. doi:10.4155/fmc.09.65
Fioravanti S, Gasbarri S, Morreale A, Pellacani L, Ramadori F, Tardella PA (2010a) Short malonyl dehydro peptides as potential scaffolds for peptidomimetics by an efficient Knoevenagel reaction. Amino Acids 39:461–470. doi:10.1007/s00726-009-0462-1
Fioravanti S, Gasbarri S, Pellacani L, Ramadori F, Tardella PA (2010b) Synthesis of epoxy and aziridino malonyl peptidomimetics. Tetrahedron 66:9401–9404. doi:10.1016/j.tet.2010.09.097
Fioravanti S, Pellacani L, Vergari MC (2012) Fluorinated β-nitro amines by a selective ZrCl4-catalyzed aza-Henry reaction of (E)-trifluoromethyl aldimines. Org Biomol Chem 10:8207–8210. doi:10.1039/c2ob26397a
Fustero S, Chiva G, Piera J, Sanz-Cervera JF, Volonterio A, Zanda M, Ramirez de Arellano C (2009) New fluorinated peptidomimetics through tandem aza-Michael addition to α-trifluoromethyl acrylamide acceptors: synthesis and conformational study in solid state and solution. J Org Chem 74:3122–3132. doi:10.1021/jo9001867
Gong Y, Kato K (2004) Recent applications of trifluoroacetaldehyde ethyl hemiacetal for the synthesis of trifluoromethylated compounds. Curr Org Chem 8:1659–1675. doi:10.2174/1385272043369683
Grishina GV, Luk’yanenko ER, Borisenko AA (2005) A simple diastereoselective synthesis of chiral non racemic aliphatic amines. Russ J Org Chem 41:807–810. doi:10.1007/s11178-005-0248-1
Jagodzinska M, Huguenot F, Candiani G, Zanda M (2009) Assessing the bioisosterism of the trifluoromethyl group with a protease probe. Chem Med Chem 4:49–51. doi:10.1002/cmdc.200800321
Jeener J, Meier BH, Bachmann P, Ernst RR (1979) Investigation of exchange processes by two-dimensional NMR spectroscopy. J Chem Phys 71:4546–4553. doi:10.1063/1.438208
Jones CR, Butts CP, Harvey JN (2011) Accuracy in determining interproton distances using Nuclear Overhauser Effect data from a flexible molecule. Beilstein J Org Chem 7:145–150. doi:10.3762/bjoc.7.20
Kukhar VP, Sorochinsky AE, Soloshonok VA (2009) Practical synthesis of fluorine-containing α- and β-amino acids: recipes from Kiev, Ukraine. Futur Med Chem 1:793–819. doi:10.4155/fmc.09.70
March TL, Johnston MR, Duggan PJ, Gardiner J (2012) Synthesis, structure, and biological applications of α-fluorinated β-amino acids and derivatives. Chem Biodivers 9:2410–2441. doi:10.1002/cbdv.201200307
McKinney BE, Urban JJ (2010) Fluoro olefins as peptide mimetics. 2. A computational study of the conformational ramifications of peptide bond replacement. J Phys Chem A 114:1123–1133. doi:10.1021/jp9094535
Merkel L, Budisa N (2012) Organic fluorine as a polypeptide building element: in vivo expression of fluorinated peptides, proteins and proteomes. Org Biomol Chem 10:7241–7261. doi:10.1039/c2ob06922a
Mikami K, Fustero S, Sanchez-Rosello M, Acena JL, Soloshonok V, Sorochinsky A (2011) Synthesis of fluorinated β-amino acids. Synthesis: 3045–3079. doi:10.1055/s-0030-1260173
Molteni M, Volonterio A, Zanda M (2003) Stereocontrolled synthesis of ψ[CH(CF3)NH]Gly-Peptides. Org Lett 5:3887–3890. doi:10.1021/ol0354730
Molteni M, Pesenti C, Sani M, Volonterio A, Zanda M (2004) Fluorinated peptidomimetics: synthesis, conformational and biological features. J Fluor Chem 125:1735–1743. doi:10.1016/j.jfluchem.2004.09.014
Müller K, Faeh C, Diederich F (2007) Fluorine in pharmaceuticals: looking beyond intuition. Science 317:1881–1886. doi:10.1126/science.1131943
O’Hagan D (2013) Organo-fluorine chemistry III. Beilstein J Org Chem 9:2180–2181. doi:10.3762/bjoc.9.255
Purser S, Moore PR, Swallow S, Gouverneur V (2008) Fluorine in medicinal chemistry. Chem Soc Rev 37:320–330. doi:10.1039/b610213c
Qiu X-L, Qing F-L (2011) Recent advances in the synthesis of fluorinated amino acids. Eur J Org Chem 18:3261–3278. doi:10.1002/ejoc.201100032
Salwiczek M, Nyakatura EK, Gerling UIM, Ye S, Koksch B (2012) Fluorinated amino acids: compatibility with native protein structures and effects on protein–protein interactions. Chem Soc Rev 41:2135–2171. doi:10.1039/c1cs15241f
Sani M, Bruch L, Chiva G, Fustero S, Piera J, Volonterio A, Zanda M (2003) Highly stereoselective tandem aza-Michael addition–enolate protonation to form partially modified retropeptide mimetics incorporating a trifluoroalanine surrogate. Angew Chem Int Ed 42:2060–2063. doi:10.1002/anie.200250711
Silvi M, Renzi P, Rosato D, Margarita C, Vecchioni A, Bordacchini I, Morra D, Nicolosi A, Cari R, Sciubba F, Scarpino Schietroma DM, Bella M (2013) Enantioselective aza-Michael addition of imides by using an integrated strategy involving the synthesis of a family of multifunctional catalysts, usage of multiple catalysis, and rational design of experiment. Chem Eur J 19:9973–9978. doi:10.1002/chem.201301493
Volonterio A, Bellosta S, Bravo P, Canavesi M, Corradi E, Meille SV, Monetti M, Moussier N, Zanda M (2002) Solution/solid-phase synthesis of partially modified retro- and retro-inverso-ψ[NHCH(CF3)]-peptidyl hydroxamates and their evaluation as MMP-9 inhibitors. Eur J Org Chem 3:428–438. doi:10.1002/1099-0690(20022)2002:3
Zanda M (2004) Trifluoromethyl group: an effective xenobiotic function for peptide backbone modification. New J Chem 28:1401–1411. doi:10.1039/b405955g
Zhang C-P, Chen Q-Y, Guo Y, Xiao J-C, Gu Y-C (2012) Progress in fluoro alkylation of organic compounds via sulfonato dehalogenation initiation system. Chem Soc Rev 41:4536–4559. doi:10.1039/c2cs15352a
Acknowledgments
We are grateful for financial support from the Università degli Studi di Roma “La Sapienza” and the Dipartimento di Chimica of the same university.
Conflict of interest
No conflicts of interest declared by any of the authors.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
The online version of this article contains supplementary material, which is available to authorized users.
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Fioravanti, S., Pelagalli, A., Pellacani, L. et al. Trifluoromethyl-modified dipeptides by ZrCl4-promoted aza-Henry reactions. Amino Acids 46, 1961–1970 (2014). https://doi.org/10.1007/s00726-014-1749-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00726-014-1749-4