Skip to main content
SpringerLink
Log in

Highly stable atropisomers by electrophilic amination of a chiral γ-lactam within the synthesis of an elusive conformationally restricted analogue of α-methylhomoserine

  • Original Article
  • Published:
Amino Acids Aims and scope Submit manuscript

Abstract

Starting from chiral-protected 4-hydroxymethyl pyrrolidin-2-ones, the otherwise elusive 3,4-trans-3,3,4-trisubstituted isosteres of α-methyl homoserine, tethered on a γ-lactam ring, were prepared exploiting stereoselective electrophilic aminations. These reactions led to the isolation and characterization of a novel type of atropisomers, exceedingly stable at room temperature, that were directly converted to the desired products by a novel non-reductive N–N bond cleavage reaction.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Scheme 1
Fig. 2
Scheme 2
Scheme 3
Fig. 3
Fig. 4
Scheme 4
Fig. 5
Scheme 5

Similar content being viewed by others

References

  • Ahn JA, Boyle NA, MacDonald MT, Janda KD (2002) Peptidomimetics and peptide backbone modifications. Mini Rev Med Chem 2:463–473

    Article  CAS  PubMed  Google Scholar 

  • Alkorta I, Elguero J, Roussel C, Vanthuyne N, Piras P (2012) Atropisomerism and axial chirality in heteroaromatic compounds. Advan Heterocycl Chem 105:1–188

    Article  CAS  Google Scholar 

  • Al-Obeidi FA, Hruby VJ, Sawyer TK (1998) Peptide and peptidomimetic libraries: molecular diversity and drug design. Mol Biotechnol 9:205–223

    Article  CAS  PubMed  Google Scholar 

  • Alonso F, Radivoy G, Yus M (2000) Reduction of hydrazine, azo and azoxy compounds, and amine N-oxides with the NiCl2·2H2O-Li-DTBB (cat.) combination. Tetrahedron 56:8673–8678

    Article  CAS  Google Scholar 

  • Arthur RJ, Coogan MP, Casadesus M, Haigh R, Headspith DA, Francesconi MG, Laye RH (2009) Stereostructural behaviour of N-N atropisomers: two conglomerate crystallisations and a crystallisation-induced deracemisation. Cryst Eng Comm 11:610–619

    Article  CAS  Google Scholar 

  • Avan I, Hall CD, Katritzky AR (2014) Peptidomimetics via modifications of amino acids and peptide bonds. Chem Soc Rev 43:3575–3594

    Article  CAS  PubMed  Google Scholar 

  • Becke AD (1993) Density-functional thermochemistry. III. The role of exact exchange. J Chem Phys 98:5648–5652

    Article  CAS  Google Scholar 

  • Boy KM, Guernon JM, Shi J, Toyn JH, Meredith JE, Barten DM, Burton CR, Albright CF, Marcinkeviciene J, Good AC, Tebben AJ, Muckelbauer JK, Camac DM, Lentz KA, Bronson JJ, Olson RE, Macor JE, Thompson LA III (2011) Monosubstituted γ-lactam and conformationally constrained 1,3-diaminopropan-2-ol transition-state isostere inhibitors of β-secretase (BACE). Bioorg Med Chem Lett 21:6916–6924

    Article  CAS  PubMed  Google Scholar 

  • Brimble MA, Heathcock CH (1993) Allylic amination by the lewis-acid-mediated ene reaction of diethyl azodicarboxylate with alkenes. J Org Chem 58:5261–5263

    Article  CAS  Google Scholar 

  • Broadrup RL, Wang B, Malachowski WP (2005) A general strategy for the synthesis of azapeptidomimetic lactams. Tetrahedron 61:10277–10284

    Article  CAS  Google Scholar 

  • Bryskier A (2005) γ-Lactams and derivatives. Antimicrobial Agents 447–452

  • Bursavich MG, Rich DH (2002) Designing non-peptide peptidomimetics in the 21st century: inhibitors targeting conformational ensembles. J Med Chem 31:541–558

    Article  Google Scholar 

  • Chandrasekhar S, Reddy CR, Rao RJ (2001) Unprecedented Direct Conversion of N–N and N=N bonds to N-(tert-Butyloxy)-carbamates. Synlett 10:1561–1562

    Article  Google Scholar 

  • Civitavecchia A, Martelli G, Orena M, Rinaldi S (2014) Synthesis of a cyclic isostere of α-methyl homoserine by a stereoselective acylation-alkylation sequence of a chiral γ-lactam. Amino Acids 46:1097–1103

    Article  CAS  PubMed  Google Scholar 

  • Coogan MP, Passey SC (2000) Tetraacyl hydrazines and 3,3′-biquinazoline-4,4′-diones; synthesis, studies of rotational barriers and deracemisation. J Chem Soc Perkin Trans 2:2060–2066

    Article  Google Scholar 

  • Coogan MP, Hibbs DE, Smart E (1999) Asymmetric transformation (deracemisation) of an atropisomeric bisheterocyclic amine. Chem Commun 1991–1992

  • Craik DJ, Simonsen S, Daly NL (2002) The cyclotides: novel macrocyclic peptides as scaffolds in drug design. Curr Opin Drug Discov Develop 5:251–260

    CAS  Google Scholar 

  • Crucianelli E, Martelli G, Orena M, Rinaldi S, Sgolastra F (2009) New isosteres of (R)-2-methylhomoserine and (R)-2-methylaspartic acid by alkylation of a chiral imine leading stereoselectively to a quaternary stereogenic center. Tetrahedron Asymmetry 20:1824–1827

    Article  CAS  Google Scholar 

  • Crucianelli E, Galeazzi R, Martelli G, Orena M, Rinaldi S, Sabatino P (2010) A novel conformationally restricted analogue of 3-methylaspartic acid via stereoselective methylation of chiral pyrrolidin-2-ones. Tetrahedron 66:400–405

    Article  CAS  Google Scholar 

  • Ding H, Friestad GK (2004) Trifluoroacetyl-activated nitrogen-nitrogen bond cleavage of hydrazines by samarium(II) iodide. Org Lett 6:637–640

    Article  CAS  PubMed  Google Scholar 

  • Dolbeare K, Pontoriero GF, Gupta SK, Mishra RK, Johnson RL (2003) Synthesis and dopamine receptor modulating activity of 3-substituted γ-lactam peptidomimetics of L-prolyl-L-leucylglycinamide. J Med Chem 46:727–733

    Article  CAS  PubMed  Google Scholar 

  • Eguchi M, Kahn M (2002) Design, synthesis, and application of peptide secondary structure mimetics. Mini Rev Med Chem 2:447–462

    Article  CAS  PubMed  Google Scholar 

  • Evans DA, Britton TC, Dorow RL, Dellaria JF (1986) Stereoselective amination of chiral enolates. A new approach to the asymmetric synthesis of α-hydrazino and α -amino acid derivatives. J Am Chem Soc 108:6395–6397

    Article  CAS  Google Scholar 

  • Eyring H (1935) The Activated Complex in Chemical Reactions. J Chem Phys 3:107–115

    Article  CAS  Google Scholar 

  • Fava C, Galeazzi R, Mobbili G, Orena M (1999) New chiral 3-naphthylaminomethyl-pyrrolidines: an unexpected epimerisation reaction. Heterocycles 51:2463–2470

    Article  CAS  Google Scholar 

  • Feuer H, Brown F Jr (1970) Chemistry of hydrazides. X. The reduction of cyclic and acyclic hydrazides with diborane. J Org Chem 35:1468–1471

    Article  CAS  Google Scholar 

  • Freidinger RM (2003) Design and synthesis of novel bioactive peptides and peptidomimetics. J Med Chem 46:5553–5566

    Article  CAS  PubMed  Google Scholar 

  • Furuta H, Hase M, Noyori R, Mori Y (2005) Synthesis of the ABCD ring of Gambierol. Org Lett 7:4061–4064

    Article  CAS  PubMed  Google Scholar 

  • Furuta H, Hasegawa Y, Hase M, Mori Y (2010) Total synthesis of gambierol by using oxiranyl anions. Chem Eur J 16:7586–7595

    Article  CAS  PubMed  Google Scholar 

  • Galaud F, Lubell WD (2005) Homoserine-derived cyclic sulfamidate as chiral educt for the diversity-oriented synthesis of lactam-bridged dipeptides. Biopolymers 80:665–674

    Article  CAS  PubMed  Google Scholar 

  • Galeazzi R, Martelli G, Mobbili G, Orena M, Panagiotaki M (2003) A stereoselective approach to both 3,4-trans-disubstituted pyrrolidin-2-ones and pyrrolidines. A convenient synthesis of (3R,4R)-4-benzyl-3-pyrrolidinecarboxylic acid. Heterocycles 60:2485–2498

    Article  CAS  Google Scholar 

  • Galeazzi R, Martelli G, Natali D, Orena M, Rinaldi S (2005a) Chiral 3-hydroxypyrrolidin-2-ones. Part 2: Stereodivergent synthesis of conformationally restricted analogues of β-homoserine. Tetrahedron Asymmetry 16:1779–1787

    Article  CAS  Google Scholar 

  • Galeazzi R, Martelli G, Orena M, Rinaldi S, Sabatino P (2005b) Conformationally restricted analogues of both (S)-β-homoserine and (S)-aspartic acid from chiral 3-acylamino pyrrolidin-2-ones. Tetrahedron 61:5465–5473

    Article  CAS  Google Scholar 

  • Galeazzi R, Martelli G, Marcucci E, Mobbili G, Natali D, Orena M, Rinaldi S (2007) A new conformationally restricted mimetic of dipeptide EG-synthesis of an analogue of FEG. Eur J Org Chem 4402–4407

  • Galeazzi R, Marcucci E, Martelli G, Natali D, Orena M, Rinaldi S (2008) Synthesis of a versatile constrained analogue of dipeptide DG (Asp-Gly). Amino Acids 34:333–336

    Article  CAS  PubMed  Google Scholar 

  • Galeazzi R, Martelli G, Mazzanti A, Orena M, Rinaldi S (2011) Quaternary centres as a tool for modulating foldamer conformation. Chem Eur J 17:12564–12568

    Article  CAS  PubMed  Google Scholar 

  • Gaussian 09, Revision E.01, 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, Montgomery JA Jr, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas Ö, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ, Gaussian, Inc., Wallingford CT, 2009

  • Grauer A, Konig B (2009) Peptidomimetics-A versatile route to biologically active compounds. Eur J Org Chem 5099–5113

  • Gulder TAM, Moore BS (2010) Salinosporamide natural products: potent 20S proteasome inhibitors as promising cancer chemotherapeutics. Angew Chem Int Ed 49:9346–9367

    Article  CAS  Google Scholar 

  • Hruby VJ (2002) Designing peptide receptor agonists and antagonists. Nat Rev Drug Discov 1:847–858

    Article  CAS  PubMed  Google Scholar 

  • Hruby VJ, Balse PM (2000) Conformational and Topographical Considerations in Designing Agonist Peptidomimetics from Peptide Leads. Curr Med Chem 7:945–970

    Article  CAS  PubMed  Google Scholar 

  • Hruby VJ, Cai M (2013) Design of peptide and peptidomimetic ligands with novel pharmacological activity profiles. Annu Rev Pharmacol Toxicol 53:557–580

    Article  CAS  PubMed  Google Scholar 

  • Jacobi PA, Martinelli MJ, Polanc S (1984) Total synthesis of (±)-saxitoxin. J Am Chem Soc 106:5594–5598

    Article  CAS  Google Scholar 

  • Jamieson AG, Boutard N, Beauregard K, Bodas Mandar S, Ong H, Quiniou C, Chemtob S, Lubell WD (2009) Positional scanning for peptide secondary structure by systematic solid-phase synthesis of amino lactam peptides. J Am Chem Soc 131:7917–7927

    Article  CAS  PubMed  Google Scholar 

  • Lee C, Yang W, Parr RG (1988) Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Phys Rev B 37:785–789

    Article  CAS  Google Scholar 

  • Lesma G, Landoni N, Pilati T, Sacchetti A, Silvani A (2009) Tetrahydroisoquinoline-based spirocyclic lactam as a type II’ β-turn inducing peptide mimetic. J Org Chem 74:8098–8105

    Article  CAS  PubMed  Google Scholar 

  • Magnus P, Garizi N, Seibert KA, Ornholt A (2009) Synthesis of carbamates from diethoxycarbonyl hydrazine derivatives by E1cB eliminative cleavage of the N-N′-bond rather than reduction. Org Lett 11:5646–5648

    Article  CAS  PubMed  Google Scholar 

  • Martelli G, Monsignori A, Orena M, Rinaldi S, Castellucci N, Tomasini C (2012) β-Peptoids: synthesis of a novel dimer having a fully extended conformation. Amino Acids 43:2005–2014

    Article  CAS  PubMed  Google Scholar 

  • Martelli G, Orena M, Rinaldi S (2014a) Recent Advances in Chemistry of γ-Lactams: Part I. Synthesis Starting from Acyclic or Cyclic Precursors. Curr Org Chem 18:1373–1481

    Article  CAS  Google Scholar 

  • Martelli G, Monsignori A, Orena M, Rinaldi S (2014b) Recent Advances in Chemistry of γ-Lactams: Part II. Functionalization by C-C or C-Heteroatom Bond Formation. Curr Org Chem 18:1539–1585

    Article  CAS  Google Scholar 

  • Matej Z, Ziga J, Stanislav G (2009) Recent advances in the synthesis and applications of reduced amide pseudopeptides. Curr Med Chem 16:2289–2304

    Article  Google Scholar 

  • Mellor JM, Smith NM (1984) Reductive cleavage of the nitrogen-nitrogen bond in hydrazine derivatives. J Chem Soc Perkin Trans 1:2927–2931

    Article  Google Scholar 

  • Menegazzo I, Fries A, Mammi S, Galeazzi R, Martelli G, Orena M, Rinaldi S (2006) Synthesis and structural characterisation as 12-helix of the hexamer of a β-amino acid tethered to a pyrrolidin-2-one ring. Chem Comm 47:4915–4917

    Article  PubMed  Google Scholar 

  • Montaner AD, Park MK, Fischer WH, Craig AG, Chang JP, Somoza GM, Rivier JE, Sherwood NM (2001) Primary structure of a novel gonadotropin-releasing hormone in the brain of a teleost, Pejerrey. Endocrinology 142:1453–1460

    CAS  PubMed  Google Scholar 

  • Nay B, Riache N, Evanno L (2009) Chemistry and biology of non-tetramic gamma-hydroxy-gamma-lactams and gamma-alkylidene-gamma-lactams from natural sources. Nat Prod Rep 26:1044–1062

    Article  CAS  PubMed  Google Scholar 

  • Nielsen L, Brehm L, Krogsgaard-Larsen P (1990) GABA agonists and uptake inhibitors. Synthesis, absolute stereochemistry, and enantioselectivity of (R)-(-)- and (S)-(+)-homo-β-proline. J Med Chem 33:71–77

    Article  CAS  PubMed  Google Scholar 

  • Otvos F, Gembitsky DS, Murphy RF, Lovas S (2007) Synthesis and structure-activity relationship of [Nle10]Neurokinin A (4-10) analogs with constraint in the backbone and at position six. Int J Pept Res Ther 13:329–336

    Article  CAS  Google Scholar 

  • Perdih H, Kikelj D (2006) The application of Freidinger lactams and their analogs in the design of conformationally constrained peptidomimetics. Curr Med Chem 13:1525–1556

    Article  CAS  PubMed  Google Scholar 

  • Platts JA, Coogan MP (2000) Rotational barriers in tetraformylhydrazine. J Chem Soc Perkin Trans 2:1075–1079

    Article  Google Scholar 

  • Seufert W, Fleury A, Giese B (2006) Cyclizations of α-keto ester modified aspartic acids in peptides. Synlett 11:1774–1776

    Google Scholar 

  • Shibasaki M, Kanai M, Fukuda N (2007) Total synthesis of Lactacystin and Salinosporamide A. Chem Asian J 2:20–38

    Article  CAS  PubMed  Google Scholar 

  • Sinha P, Kofink CC, Knochel P (2006) Preparation of aryl-alkylamines via electrophilic amination of functionalized arylazo tosylates with alkylzinc reagents. Org Lett 8:3741–3744

    Article  CAS  PubMed  Google Scholar 

  • St-Cyr DJ, Jamieson AG, Lubell WD (2010) α-Amino-β-hydroxy-γ-lactam for constraining peptide Ser and Thr residue conformation. Org Lett 12:1652–1655

    Article  CAS  PubMed  Google Scholar 

  • Stewart JJP (1989a) Optimization of Parameters for Semi-Empirical Methods I. Method. J Comp Chem 10:209–220

    Article  CAS  Google Scholar 

  • Stewart JJP (1989b) Optimization of parameters for semiempirical methods II. Applications. J Comp Chem 10:221–264

    Article  CAS  Google Scholar 

  • Szabó ZG (1969). The theory of kinetics. In: Bamford CH and Tipper CFH (ed) Comprehensive chemical kinetics. Elsevier, Amsterdam, Vol. 2, Chapter 1

  • Takao KI, Aoki SY, Tadano KI (2007) Total synthesis of structurally unique gamma-lactam natural products. J Synth Org Chem Jpn 65:460–469

    Article  CAS  Google Scholar 

  • Toniolo C, Crisma M, Formaggio F, Peggion C (2001) Control of peptide conformation by the Thorpe-Ingold effect (Cα-tetrasubstitution). Biopolymers 60:396–419

    Article  CAS  PubMed  Google Scholar 

  • Trimble LA, Vederas JC (1986) Amination of chiral enolates by dialkyl azodiformates. Synthesis of α-hydrazino acids and α-amino acids. J Am Chem Soc 108:6397–6399

    Article  CAS  Google Scholar 

  • Upadhyay SK (2006) Chemical Kinetics and Reaction Dynamics. Springer, The Netherlands

    Google Scholar 

  • Vagner J, Qu HC, Hruby VJ (2008) Peptidomimetics, a synthetic tool of drug discovery. Curr Opin Chem Biol 12:292–296

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • van der Linden JB (1994) Synthesis and reactions of sulfines derived from vinylsilanes and dithioesters. Dissertation, University of Nijmegen

  • Verma SM, Prasad R (1973) Conformational analysis by nuclear magnetic resonance spectroscopy. N’-derivatives of N-aminocamphorimides. J Org Chem 38:1004–1010

    CAS  Google Scholar 

  • Virlouvet M, Podlech J (2010) γ-Lactam-containing peptidomimetics. Tetrahedron 66:6174–6180

    Article  CAS  Google Scholar 

  • Wu YD, Gellman S (2008) Peptidomimetics. Acc Chem Res 41:1231–1232

    Article  CAS  PubMed  Google Scholar 

  • Zhao Y, Truhlar DG (2006) The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: Two new functionals and systematic testing of four M06-class functionals and 12 other functionals. J Phys Chem A 110:13126–13130

    Article  CAS  PubMed  Google Scholar 

  • Zuckermann RN, Kodadek T (2009) Peptoids as potential therapeutics. Curr Opin Mol Ther 11:299–307

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Life and Environmental Sciences, Università Politecnica delle Marche, Via Brecce Bianche, 60131, Ancona, Italy

    Paolo Amabili, Annafelicia Civitavecchia, Beatrice Maggiore, Mario Orena & Samuele Rinaldi

  2. Department of Odontostomatologic and Specialized Clinical Sciences, Università Politecnica delle Marche, Via Brecce Bianche, 60131, Ancona, Italy

    Adolfo Amici

  3. Department of Chemistry ‘‘G. Ciamician’’, Alma Mater Studiorum University of Bologna, Via Selmi 2, 40126, Bologna, Italy

    Alessandra Tolomelli

Authors
  1. Paolo Amabili
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Adolfo Amici
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Annafelicia Civitavecchia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Beatrice Maggiore
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mario Orena
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Samuele Rinaldi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Alessandra Tolomelli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Samuele Rinaldi.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Handling Editor: J. Bode.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 1404 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Amabili, P., Amici, A., Civitavecchia, A. et al. Highly stable atropisomers by electrophilic amination of a chiral γ-lactam within the synthesis of an elusive conformationally restricted analogue of α-methylhomoserine. Amino Acids 48, 461–478 (2016). https://doi.org/10.1007/s00726-015-2100-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00726-015-2100-4

Keywords

Search

Navigation