Skip to main content

Advertisement

SpringerLink
Log in

A refined synthesis of enantiomerically pure 2-aminocyclobutanecarboxylic acids

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

Abstract

The synthesis of enantiomerically pure 2-aminocyclobutanecarboxylic acids has been refined to improve both the efficiency and the simplicity. These improvements provide a shorter and easier access to the racemic cis-cyclobutane β-amino acid core. Derivatization of this material with a chiral non-racemic oxazolidin-2-one allows easy diastereoisomeric separation and presents the advantage of allowing the non-destructive cleavage of the chiral auxiliary either by hydrolysis or by ammonolysis, thus providing an efficacious access to N-protected derivatives of all four stereoisomers of Boc-2-aminocyclobutanecarboxylic acid.

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

Scheme 1
Scheme 2
Scheme 3
Scheme 4

Similar content being viewed by others

References

  • Ager DJ, Prakash I, Schaad DR (1996) 1, 2-Amino alcohols and their heterocyclic derivatives as chiral auxiliaries in asymmetric synthesis. Chem Rev 96(2):835–875

    Article  PubMed  CAS  Google Scholar 

  • Ahmed S, Adat S, Murrells A, Owen CP, Amanuel Y (2002) Design, synthesis, and evaluation of 4-(4′-aminobenzyl)-2-oxazolidinones as novel inhibitors of the cytochrome P-450 enzyme aromatase. Bioorg Chem 30(5):315–331

    Article  PubMed  CAS  Google Scholar 

  • Aitken DJ, Gauzy C, Pereira E (2002) A short synthesis of the cis-cyclobutane β-amino acid skeleton using a [2 + 2] cycloaddition strategy. Tetrahedron Lett 43(35):6177–6179

    Article  CAS  Google Scholar 

  • Aitken DJ, Gauzy C, Pereira E (2004) Studies on the stability of the cyclobutane β-amino acid skeleton: a cautionary tale. Tetrahedron Lett 45(11):2359–2361

    Article  CAS  Google Scholar 

  • Appella DH, Christianson LA, Klein DA, Powell DR, Huang X, Barchi JJ Jr., Gellman SH (1997) Residue-based control of helix shape in β-peptide oligomers. Nature 387(6631):381–384

    Google Scholar 

  • Appella DH, Christianson LA, Karle IL, Powell DR, Gellman SH (1999a) Synthesis and characterization of trans-2-aminocyclohexanecarboxylic acid oligomers: an unnatural helical secondary structure and implications for β-peptide tertiary structure. J Am Chem Soc 121(26):6206–6212

    Article  CAS  Google Scholar 

  • Appella DH, Christianson LA, Klein DA, Richards MR, Powell DR, Gellman SH (1999b) Synthesis and structural characterization of helix-forming β-peptides: trans-2-aminocyclopentanecarboxylic acid oligomers. J Am Chem Soc 121(33):7574–7581

    Article  CAS  Google Scholar 

  • Bégis G, Cladingboel DE, Jerome L, Motherwell WB, Sheppard TD (2009) Asymmetric synthesis of aminocyclopropanes and N-cyclopropylamino alcohols through direct amidocyclopropanation of alkenes using chiral organozinc carbenoids. Eur J Org Chem 10:1532–1548

    Article  Google Scholar 

  • Boger DL, Ramsey TM, Cai H, Hoehn ST, Kozarich JW, Stubbe J (1998) Assessment of the role of the bleomycin A2 pyrimidoblamic acid C4 amino group. J Am Chem Soc 120(1):53–65

    Article  CAS  Google Scholar 

  • Bolm C, Schiffers I, Atodiresei I, Hackenberger CPR (2003) An alkaloid-mediated desymmetrization of meso-anhydrides via a nucleophilic ring opening with benzyl alcohol and its application in the synthesis of highly enantiomerically enriched β-amino acids. Tetrahedron Asymmetr 14(22):3455–3467

    Article  CAS  Google Scholar 

  • Chakraborty P, Diederichsen U (2005) Three-dimensional organization of helices: design principles for nucleobase-functionalized β-peptides. Chem Eur J 11(11):3207–3216

    Article  CAS  Google Scholar 

  • Chandrasekhar S, Babu BN, Prabhakar A, Sudhakar A, Reddy MS, Kiran MU, Jagadeesh B (2006) Oligomers of cis-β-norbornene amino acid: formation of β-strand mimetics. Chem Commun 14:1548–1550

    Article  Google Scholar 

  • Chibale K, Warren S (1995) Asymmetric aldol reactions of achiral 2-phenylsulfanyl aldehydes with small- and medium-sized carbocyclic rings: The synthesis of homochiral spirocyclic lactones, pyrrolidines and tetrahydrofurans. J Chem Soc Perkin Trans 1 19:2411–2418

    Article  Google Scholar 

  • Commerçon A, Paris JM (1991) Enantioselective synthesis of girolline. Tetrahedron Lett 32(37):4905–4906

    Article  Google Scholar 

  • D’Elia V, Zwicknagl H, Reiser O (2008) Short α/β-peptides as catalysts for intra- and intermolecular aldol reactions. J Org Chem 73(8):3262–3265

    Article  PubMed  Google Scholar 

  • De Pol S, Zorn C, Klein CD, Zerbe O, Reiser O (2004) Surprisingly stable helical conformations in α/β-peptides by incorporation of cis-β-aminocyclopropane carboxylic acids. Angew Chem Int Ed 43(4):511–514

    Article  Google Scholar 

  • Dutot L, Gaucher A, Elkassimi K, Drapeau J, Wakselman M, Mazaleyrat J-P, Peggion C, Formaggio F, Toniolo C (2008) Synthesis and characterization of helical β-peptide architectures that contain (S)-β3-HDOPA (crown ether) derivatives. Chem Eur J 14(10):3154–3163

    Article  CAS  Google Scholar 

  • English EP, Chumanov RS, Gellman SH, Compton T (2006) Rational development of β-peptide inhibitors of human cytomegalovirus entry. J Biol Chem 281(5):2661–2667

    Article  PubMed  CAS  Google Scholar 

  • Fernandes C, Gauzy C, Yang Y, Roy O, Pereira E, Faure S, Aitken DJ (2007) [2 + 2] Photocycloadditions with chiral uracil derivatives: access to all four stereoisomers of 2-aminocyclobutanecarboxylic acid. Synthesis 14:2222–2232

    Google Scholar 

  • Fernandes C, Pereira E, Faure S, Aitken DJ (2009) Expedient preparation of all isomers of 2-aminocyclobutanecarboxylic acid in enantiomerically pure form. J Org Chem 74(8):3217–3220

    Article  PubMed  CAS  Google Scholar 

  • Fernandes C, Faure S, Pereira E, Théry V, Declerck V, Guillot R, Aitken DJ (2010) 12-Helix folding of cyclobutane β-amino acid oligomers. Org Lett 12(16):3606–3609

    Article  PubMed  CAS  Google Scholar 

  • Fülöp F (2001) The chemistry of 2-aminocycloalkanecarboxylic acids. Chem Rev 101(7):2181–2204

    Article  PubMed  Google Scholar 

  • Fülöp F, Martinek TA, Tóth GK (2006) Application of alicyclic β-amino acids in peptide chemistry. Chem Soc Rev 35(4):323–334

    Article  PubMed  Google Scholar 

  • Gauzy C, Pereira E, Faure S, Aitken DJ (2004) Synthesis of (+)-(1S,2R)- and (−)-(1R,2S)-2-aminocyclobutane-1-carboxylic acids. Tetrahedron Lett 45(38):7095–7097

    Article  CAS  Google Scholar 

  • Gauzy C, Saby B, Pereira E, Faure S, Aitken DJ (2006) The [2 + 2] photocycloaddition of uracil derivatives with ethylene as a general route to cis-cyclobutane β-amino acids. Synlett 9:1394–1398

    Google Scholar 

  • Gnad F, Reiser O (2003) Synthesis and applications of β-aminocarboxylic acids containing a cyclopropane ring. Chem Rev 103(4):1603–1623

    Article  PubMed  CAS  Google Scholar 

  • Godier-Marc E, Aitken DJ, Husson H-P (1997) Synthesis of peptides containing 2, 3-methanoaspartic acid. Tetrahedron Lett 38(23):4065–4068

    Article  CAS  Google Scholar 

  • Hetényi A, Mándity IM, Martinek TA, Tóth GK, Fülöp F (2005) Chain-length-dependent helical motifs and self-association of β-peptides with constrained side chains. J Am Chem Soc 127(2):547–553

    Article  PubMed  Google Scholar 

  • Hetényi A, Szakonyi Z, Mándity IM, Szolnoki É, Tóth GK, Martinek TA, Fülöp F (2009a) Sculpting the β-peptide foldamer H12 helix via a designed side-chain shape. Chem Commun 2:177–179

    Article  Google Scholar 

  • Hetényi A, Tóth GK, Somlai C, Vass E, Martinek TA, Fülöp F (2009b) Stabilisation of peptide foldamers in an aqueous medium by incorporation of azapeptide building blocks. Chem Eur J 15(41):10736–10741

    Article  Google Scholar 

  • Horne WS, Gellman SH (2008) Foldamers with heterogeneous backbones. Acc Chem Res 41(10):1399–1408

    Article  PubMed  CAS  Google Scholar 

  • Imamura Y, Watanabe N, Umezawa N, Iwatsubo T, Kato N, Tomita T, Higuchi T (2009) Inhibition of γ-Secretase Activity by helical β-peptide foldamers. J Am Chem Soc 131(21):7353–7359

    Article  PubMed  CAS  Google Scholar 

  • Jaime-Figueroa S, Zamilpa A, Guzmán A, Morgans DJ Jr (2001) N-3-alkylation of uracil and derivatives via n-1-Boc protection. Synth Commun 31(24):3739–3746

    Article  CAS  Google Scholar 

  • Karlsson AJ, Pomerantz WC, Weisblum B, Gellman SH, Palecek SP (2006) Antifungal activity from 14-helical β-peptides. J Am Chem Soc 128(39):12630–12631

    Article  PubMed  CAS  Google Scholar 

  • Kennewell PD, Matharu SS, Taylor JB, Westwood R, Sammes PG (1982) Synthesis of γ-aminobutyric acid analogs of restricted conformation. Part 2. The 2-(aminomethyl)cycloalkanecarboxylic acids. J Chem Soc Perkin Trans 1 11:2563–2570

    Article  Google Scholar 

  • Kiss L, Forró E, Fülöp F (2009) Synthesis of carbocyclic β-amino acids. In: Hughes AB (ed) Amino acids, peptides and proteins in organic chemistry: origins and synthesis of amino acids, vol 1. Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, pp 367–409

  • Koglin N, Zorn C, Beumer R, Cabrele C, Bubert C, Sewald N, Reiser O, Beck-Sickinger AG (2003) Analogues of neuropeptides Y containing β-aminocyclopropane carboxylic acids are the shortest linear peptides that are selective for the Y1 receptor. Angew Chem Int Ed 42(2):202–205

    Article  CAS  Google Scholar 

  • Kuhl A, Hahn MG, Dumić M, Mittendorf J (2005) Alicyclic β-amino acids in medicinal chemistry. Amino Acids 29(2):89–100

    Article  PubMed  CAS  Google Scholar 

  • Lee EF, Sadowsky JD, Smith BJ, Czabotar PE, Peterson-Kaufman KJ, Colman PM, Gellman SH, Fairlie WD (2009) High-resolution structural characterization of a helical α/β-peptide foldamer bound to the anti-apoptotic protein Bcl-xL. Angew Chem Int Ed Engl 48(24):4318–4322

    Article  PubMed  CAS  Google Scholar 

  • Mándity IM, Wéber E, Martinek TA, Olajos G, Tóth GK, Vass E, Fülöp F (2009) Design of peptidic foldamer helices: a stereochemical patterning approach. Angew Chem Int Ed 48(12):2171–2175

    Article  Google Scholar 

  • Mándity IM, Fülöp L, Vass E, Tóth GK, Martinek TA, Fülöp F (2010) Building β-peptide H10/12 foldamer helices with six-membered cyclic side-chains: fine-tuning of folding and self-assembly. Org Lett 12(23):5584–5587

    Article  PubMed  Google Scholar 

  • Mangelinckx S, De Kimpe N (2003) Synthesis of racemic cis-1-alkyl- and 1-aryl-2-aminocyclopropanecarboxylic esters. Tetrahedron Lett 44(9):1771–1774

    Article  CAS  Google Scholar 

  • Martinek TA, Tóth GK, Vass E, Hollósi M, Fülöp F (2002) cis-2-Aminocyclopentanecarboxylic acid oligomers adopt a sheetlike structure: switch from helix to nonpolar strand. Angew Chem Int Ed 41(10):1718–1721

    Article  CAS  Google Scholar 

  • Martín-Vilà M, Minguillón C, Ortuño RM (1998) Stereoselective synthesis of (−)-(1R, 2S)-2-aminocyclobutane-1-carboxylic acid, a conformationally constrained β-amino acid. Tetrahedron Asymmetr 9(24):4291–4294

    Article  Google Scholar 

  • Martín-Vilà M, Muray E, Aguado GP, Álvarez-Larena Á, Branchadell V, Minguillón C, Giralt E, Ortuño RM (2000) Enantioselective synthetic approaches to cyclopropane and cyclobutane β-amino acids: synthesis and structural study of a conformationally constrained β-dipeptide. Tetrahedron Asymmetr 11(17):3569–3584

    Article  Google Scholar 

  • Moser H, Lu Q, Patten PA, Wang D, Kasar R, Kaldor S, Patterson BD (2008) Preparation of antibacterial agents. PCT Int Appl. WO 2008154642 A2

  • Pomerantz WC, Yuwono VM, Pizzey CL, Hartgerink JD, Abbott NL, Gellman SH (2008) Nanofibers and lyotropic liquid crystals from a class of self-assembling β-peptides. Angew Chem Int Ed 47(7):1241–1244

    Article  CAS  Google Scholar 

  • Raguse TL, Porter EA, Weisblum B, Gellman SH (2002) Structure-activity studies of 14-helical antimicrobial β-peptides: probing the relationship between conformational stability and antimicrobial potency. J Am Chem Soc 124(43):12774–12785

    Article  PubMed  CAS  Google Scholar 

  • Rúa F, Boussert S, Parella T, Díez-Pérez I, Branchadell V, Giralt E, Ortuño RM (2007) Self-assembly of a cyclobutane β-tetrapeptide to form nanosized structures. Org Lett 9(18):3643–3645

    Article  PubMed  Google Scholar 

  • Torres E, Gorrea E, Da Silva E, Nolis P, Branchadell V, Ortuño RM (2009) Prevalence of eight-Membered hydrogen-bonded rings in some bis(cyclobutane) β-dipeptides including residues with trans stereochemistry. Org Lett 11(11):2301–2304

    Article  PubMed  CAS  Google Scholar 

  • Torres E, Gorrea E, Burusco KK, Da Silva E, Nolis P, Rúa F, Boussert S, Díez-Pérez I, Dannenberg S, Izquierdo S, Giralt E, Jaime C, Branchadell V, Ortuño RM (2010) Folding and self-assembling with β-oligomers based on (1R,2S)-2-aminocyclobutane-1-carboxylic acid. Org Biomol Chem 8(3):564–575

    Article  PubMed  CAS  Google Scholar 

  • Tussetschläger S, Baro A, Laschat S, Frey W (2007) Synthesis of tyrosine-derived tetrahydroisoquinolines by Lewis acid catalyzed cyclization of N-(phenylsulfonyl)alkyloxazolidinones. Eur J Org Chem 33:5590–5602

    Article  Google Scholar 

  • Urman S, Gaus K, Yang Y, Strijowski U, Sewald N, De Pol S, Reiser O (2007) The Constrained amino acid β-Acc confers potency and selectivity to integrin ligands. Angew Chem Int Ed 46(21):3976–3978

    Article  CAS  Google Scholar 

  • Zou Y, Fahmi NE, Vialas C, Miller GM, Hecht SM (2002) Total synthesis of deamido bleomycin A2, the major catabolite of the antitumor agent bleomycin. J Am Chem Soc 124(32):9476–9488

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Magistère-1 (ENS Cachan) undergraduate student Ms. Charlotte Mocquard for help with some preliminary experiments.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Laboratoire de Synthèse Organique et Méthodologie, ICMMO (UMR 8182-CNRS), Université Paris-Sud 11, 15 rue Georges Clemenceau, 91405, Orsay Cedex, France

    Valérie Declerck & David J. Aitken

Authors
  1. Valérie Declerck
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David J. Aitken
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David J. Aitken.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Declerck, V., Aitken, D.J. A refined synthesis of enantiomerically pure 2-aminocyclobutanecarboxylic acids. Amino Acids 41, 587–595 (2011). https://doi.org/10.1007/s00726-011-0918-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00726-011-0918-y

Keywords

Search

Navigation