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Synlett 2014; 25(4): 574-578
DOI: 10.1055/s-0033-1340622
letter
© Georg Thieme Verlag Stuttgart · New York

From Diketopiperazines to Hydantoins: An Unprecedented Rearrangement

Guilhem Chaubet
Institut des Biomolécules Max Mousseron IBMM UMR 5247 CNRS-Université Montpellier I-Université Montpellier II, Pl. E. Bataillon, 34095 Montpellier Cedex 5, France   Fax: (+33)467144866   Email: isabelle.parrot@um2.fr
,
Guillaume Cazals
Institut des Biomolécules Max Mousseron IBMM UMR 5247 CNRS-Université Montpellier I-Université Montpellier II, Pl. E. Bataillon, 34095 Montpellier Cedex 5, France   Fax: (+33)467144866   Email: isabelle.parrot@um2.fr
,
Aurélien Lebrun
Institut des Biomolécules Max Mousseron IBMM UMR 5247 CNRS-Université Montpellier I-Université Montpellier II, Pl. E. Bataillon, 34095 Montpellier Cedex 5, France   Fax: (+33)467144866   Email: isabelle.parrot@um2.fr
,
Jean Martinez
Institut des Biomolécules Max Mousseron IBMM UMR 5247 CNRS-Université Montpellier I-Université Montpellier II, Pl. E. Bataillon, 34095 Montpellier Cedex 5, France   Fax: (+33)467144866   Email: isabelle.parrot@um2.fr
,
Isabelle Parrot*
Institut des Biomolécules Max Mousseron IBMM UMR 5247 CNRS-Université Montpellier I-Université Montpellier II, Pl. E. Bataillon, 34095 Montpellier Cedex 5, France   Fax: (+33)467144866   Email: isabelle.parrot@um2.fr
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Further Information

Publication History

Received: 08 November 2013

Accepted after revision: 15 December 2013

Publication Date:
29 January 2014 (online)

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Abstract

Bis-Boc-activated 2,5-diketopiperazines on reaction with potassium hydroxide or sodium methoxide in dry tetrahydrofuran led to Boc-protected hydantoins through an unprecedented ring contraction. This rearrangement was applied to several monosubstituted 2,5-diketopiperazines with good yields and regioselectivity.

Key words

ring contraction - rearrangement - heterocycles - lactams - amino acids

Supporting Information

    for this article is available online at http://www.thieme-connect.com/ejournals/toc/synlett.
  • Supporting Information
 

  • References and Notes

  • 1 Borthwick AD. Chem. Rev. 2012; 112: 3641
    CrossrefPubMed
  • 2 González JF, Ortín I, de la Cuesta E, Menéndez JC. Chem. Soc. Rev. 2012; 41: 6902
    Crossref
  • 3 Ware E. Chem. Rev. 1950; 46: 403
    CrossrefPubMed
  • 4 Schafmeister CE, Brown ZZ, Gupta S. Acc. Chem. Res. 2008; 41: 1387
    Crossref
  • 5 Liu X, Walsh CT. Biochemistry (Moscow) 2009; 48: 11032
    Crossref
  • 6 López-Rodríguez ML, Morcillo MJ, Fernández E, Benhamú B, Tejada I, Ayala D, Viso A, Campillo M, Pardo L, Delgado M, Manzanares J, Fuentes JA. J. Med. Chem. 2005; 48: 2548
    CrossrefPubMed
  • 7 Royo M, Van Den Nest W, del Fresno M, Frieden A, Yahalom D, Rosenblatt M, Chorev M, Albericio F. Tetrahedron Lett. 2001; 42: 7387
    Crossref
  • 8 Welsch ME, Snyder SA, Stockwell BR. Curr. Opin. Chem. Biol. 2010; 14: 347
    Crossref
  • 9 Mendgen T, Steuer C, Klein CD. J. Med. Chem. 2012; 55: 743
    CrossrefPubMed
  • 10 Wamhoff H, Kleimann W. J. Chem. Soc., Chem. Commun. 1981; 743
  • 11 Kaneti J, Kirby AJ, Koedjikov AH, Pojarlieff IG. Org. Biomol. Chem. 2004; 2: 1098
    Crossref
  • 12 Meusel M, Ambrożak A, Hecker TK, Gütschow M. J. Org. Chem. 2003; 68: 4684
    Crossref
  • 13 Farran D, Parrot I, Martinez J, Dewynter G. Angew. Chem. Int. Ed. 2007; 46: 7488
    Crossref
  • 14 Coursindel T, Restouin A, Dewynter G, Martinez J, Collette Y, Parrot I. Bioorg. Chem. 2010; 38: 210
    Crossref
  • 15 Farran D, Parrot I, Toupet L, Martinez J, Dewynter G. Org. Biomol. Chem. 2008; 6: 3989
    Crossref
  • 16 Coursindel T, Martinez J, Parrot I. Eur. J. Org. Chem. 2011; 4519
  • 17 Chaubet G, Coursindel T, Morelli X, Betzi S, Roche P, Guari Y, Lebrun A, Toupet L, Collette Y, Parrot I, Martinez J. Org. Biomol. Chem. 2013; 11: 4719
    Crossref
  • 18 Farran D, Echalier D, Martinez J, Dewynter G. J. Pept. Sci. 2009; 15: 474
    Crossref
  • 19 Satoh N, Akiba T, Yokoshima S, Fukuyama T. Angew. Chem. Int. Ed. 2007; 46: 5734
    CrossrefPubMed
  • 20 Yeung Hong S, Corey EJ. J. Am. Chem. Soc. 2006; 128: 6310
    Crossref
  • 21 Flynn DL, Zelle RE, Grieco PA. J. Org. Chem. 1983; 48: 2424
    Crossref
  • 22 Burk MJ, Allen JG. J. Org. Chem. 1997; 62: 7054
    Crossref
  • 23 General Experimental Procedure for the Synthesis of Hydantoins To a solution of Boc-activated DKP (1.0 equiv) in anhydrous THF (c 0.4 mol L–1) under argon atmosphere was added KOH or MeONa powder (1.6 equiv) at –15 °C. The reaction mixture was stirred for 1 h at –15 °C and then 5 h at 25 °C. The suspension was then diluted with EtOAc and acidified with 1.0 M HCl solution. The organic layer was then washed with sat. NaHCO3 solution allowing the recovery of the starting DKP. The aqueous layer was acidified using 1.0 M HCl solution and then extracted three times with EtOAc. After drying over Na2SO4 and filtration, the solvent was removed under vacuum. The crude material was then purified according to the method described for each compound. All reactions were performed on a 0.2 mmol scale. Scaling up to 5.6 mmol, in each case, gave reproducible results.
  • 24 Preparation of (S)-8 Compound (S)-8 was prepared according to the general procedure for the synthesis of hydantoins starting from bis-Boc cyclo[Gly-Val] 1. The crude reaction mixture was purified using method B (0% to 100% B in 25 min) yielding hydantoin 2a in 62% yield as a colorless oil. 1H NMR (600 MHz, DMSO-d 6): δ = 0.83 [d, 3 H, J = 6.9 Hz, HCH(CH3)2], 1.09 [d, 3 H, J = 7.1 Hz, HCH(CH3)2], 1.48 [s, 9 H, HC(CH3)3], 2.40 [m, 1 H, HCH(CH3)2], 4.06 [d, 1 H, J = 17.5 Hz, HNCH2COOH], 4.15 [d, 1 H, J = 17.4 Hz, HNCH2COOH], 4.45 (d, 1 H, J = 3.2 Hz, HCH*CO). 13C NMR (150 MHz, DMSO-d 6): δ = 15.7 [CCH(CH3)2], 17.8 [CCH(CH3)2], 27.5 [CC(CH3)3], 29.1 [C CH(CH3)2], 40.0 (CNCH2COOH), 63.8 (C CH*CO), 83.1 [C C(CH3)3], 148.1 (C COBoc), 151.6 (CNCON), 168.0 (CNCOCH*), 169.4 (CNCH2COOH). HPLC: t R = 1.60 min. Chiral HPLC: t R = 6.97 min. ESI-MS+: m/z = 301.1. HRMS (TOF ES MS+): m/z calcd for [C13H20N2O6 + Na+]: 323.1219; found: 323.1220. [α]D 20 +17.6 (c 1.40, MeOH).
  • 25 Ohmoto K, Yamamoto T, Okuma M, Horiuchi T, Imanishi H, Odagaki Y, Kawabata K, Sekioka T, Hirota Y, Matsuoka S, Nakai H, Toda M, Cheronis JC, Spruce LW, Gyorkos A, Wieczorek M. J. Med. Chem. 2001; 44: 1268
    Crossref
  • 26 Preparation of 9 Compound 9 was prepared according to the general procedure for the synthesis of hydantoins starting from bis-Boc cyclo[Gly-d-Val] and using freshly prepared NaOMe. The crude reaction mixture was purified using method B (0% to 100% B in 25 min), yielding 9 in 71% as a colorless oil. 1H NMR (600 MHz, CDCl3): δ = 0.94 [d, 3 H, J = 7.0 Hz, HCH(CH3)2], 1.20 [d, 3 H, J = 7.1 Hz, HCH(CH3)2], 1.54 [s, 9 H, HC(CH3)3], 2.52 [dsept, 1 H, J = 3.4, 7.1 Hz, HCH(CH3)2], 3.74 (s, 3 H, HCO2CH3), 4.22 (d, 1 H, J = 17.3 Hz, HNCH2CO2CH3), 4.26 (d, 1 H, J = 17.3 Hz, HNCH2CO2CH3), 4.38 (d, 1 H, J = 3.4 Hz, HCH*CO). 13C NMR (150 MHz, CDCl3): δ = 16.0 [CCH(CH3)2], 18.3 [CCH(CH3)2], 28.2 [CC(CH3)3], 30.2 [C CH(CH3)2], 39.5 (CNCH2CO2CH3), 53.0 (CCO2CH3), 64.7 (C CH*CO), 84.9 [C C(CH3)3], 148.8 (C COBoc), 152.1 (CNCON), 167.1 (CNCOCH*), 169.7 (C CO2CH3). HPLC: t R = 2.05 min. Chiral HPLC: t R = 17.97 min. ESI-MS+: m/z = 337.2 [M + Na]+. HRMS (TOF ES MS+): m/z calcd for [C14H22N2O6 + Na]+: 337.1376; found: 337.1375. [α]D 20 +11.8 (c 0.30, MeOH).
  • 27 Preparation of (5S)-10 Compound (5S)-10 was prepared according to the general procedure for the synthesis of hydantoins starting from bis-Boc cyclo[Gly-Ile]. The crude reaction mixture was purified using method B (30% to 75% B in 10 min) yielding hydantoin (5S)-10 in 62% yield as a colorless oil. 1H NMR (600 MHz, CDCl3): δ = 0.87 (d, 3 H, J = 6.9 Hz, HCH*CH3), 1.00 (t, 3 H, J = 7.4 Hz, HCH2CH3), 1.55 [s, 9 H, HC(CH3)3], 1.55–1.72 (m, 2 H, HCH2CH3), 2.25 (m, 1 H, HCH*CH3), 4.23 (d, 1 H, J = 17.4 Hz, HNCH2COOH), 4.30 (d, 1 H, J = 17.4 Hz, HNCH2COOH), 4.49 (d, 1 H, J = 3.0 Hz, HCH*CO), 8.41 (br s, 1 H, HNCH2COOH ). 13C NMR (150 MHz, CDCl3): δ = 12.1 (CCH2CH3), 13.2 (CCH*CH3), 25.5 (C CH2CH3), 28.1 [CC(CH3)3], 36.6 (C CH*CH3), 39.2 (CNCH2COOH), 63.2 (C CH*CO), 84.9 [C C(CH3)3], 148.7 (C COBoc), 152.1 (CNCON), 169.5 (CNCOCH*), 171.2 (CNCH2COOH). HPLC: t R = 2.03 min. Chiral HPLC: t R = 7.49 min. ESI-MS+: m/z = 337.1 [Na+ adduct]. HRMS (TOF ES MS+): m/z calcd for [C14H22N2O6 + Na+]: 337.1376; found: 337.1375. [α]D 20 +9.1 (c 3.00, MeOH).
  • 28 Allinger NL, Zalkow V. J. Org. Chem. 1960; 25: 701
    Crossref
  • 29 Liwo A, Ciarkowski J. Tetrahedron Lett. 1985; 26: 1873
    Crossref
  • 30 Kopple KD, Marr DH. J. Am. Chem. Soc. 1967; 89: 6193
    Crossref
  • 31 Watanabe H, Yoshimura T, Kawakami S, Sasamori T, Tokitoh N, Kawabata T. Chem. Commun. 2012; 48: 5346
    Crossref