Download PDF
Synlett 2008(15): 2339-2341  
DOI: 10.1055/s-2008-1078279
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Iminophosphorane-Mediated Synthesis of Cyclic Guanidines: Application to the Synthesis of a Simplified NA22598A1 Analogue

Stefano M. Nallia, Guy J. Clarksona, Alison S. Franklinb, Graziella Bellonec, Michael Shipman*a
a Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, UK
Fax: +44(24765)24112; e-Mail: m.shipman@warwick.ac.uk;
b Department of Chemistry, University of Exeter, Stocker Road, Exeter, EX4 4QD, UK
c Department of Clinical Physiopathology, Università di Torino, Via Genova 3, 10126 Torino, Italy
Further Information

Publication History

Received 31 March 2008
Publication Date:
21 August 2008 (online)

    Permissions and Reprints All articles of this category

Abstract

Reaction of Cbz-protected β-amino azides with bis(diphenylphosphino)butane and tosyl isocyanate provides differentially substituted 2-iminoimidazolidines in good yields.

Key words

antitumor agents - azides - cyclizations - heterocycles - stereoselective synthesis

    References and Notes

  • 1a Kuwahara A. Nishikiori T. Shimada N. Nakagawa T. Fukazawa H. Mizuno S. Uehara Y. J. Antibiot.  1997,  50:  712 
    Google Scholar
  • 1b Nishikiori T, Kuwahara A, Uehara Y, Fukazawa S, and Mizuno S. inventors; Jpn. Kokai Tokkyo Koho, Jpn. Patent, JP  09048791. 
  • 2 Kawada M. Kuwahara A. Nishikiori T. Mizuno S. Uehara Y. Exp. Cell Res.  1999,  249:  240 
    CrossrefGoogle Scholar
  • 3 Recently, K01-0509 B and guadinomines A-C were isolated. These compounds all possess a carbamoylated 2-iminoimidazolidine. Moreover, guadinomine B is strikingly similar to NA22598A1, see: Tsuchiya S. Sunazuka T. Hirose T. Mori R. Tanaka T. Iwatsuki M. Omura S. Org. Lett.  2006,  8:  5577 ; and references therein
    CrossrefGoogle Scholar
  • For other recent approaches to 2-iminoimidazolidines, see:
  • 4a Dardonville C. Goya P. Rozas I. Alsasua A. Martín MI. Borrego MJ. Bioorg. Med. Chem.  2000,  8:  1567 
    Google Scholar
  • 4b Isobe T. Fukuda K. Yamaguchi K. Seki H. Tokunaga T. Ishikawa T. J. Org. Chem.  2000,  65:  7779 
    Google Scholar
  • 4c Matosiuk D. Fidecka S. Antkiewicz-Michaluk L. Dybala I. Koziol AE. Eur. J. Med. Chem.  2001,  36:  783 
    Google Scholar
  • 4d Dennis M. Hall LM. Murphy PJ. Thornhill AJ. Nash R. Winters AL. Hursthouse MB. Light ME. Horton P. Tetrahedron Lett.  2003,  44:  3075 
    Google Scholar
  • 4e Abou-Jneid R. Ghoulami S. Martin M.-T. Dau ETH. Travert N. Al-Mourabit A. Org. Lett.  2004,  6:  3933 
    Google Scholar
  • 4f Sanière L. Leman L. Bourguignon J.-J. Dauban P. Dodd RH. Tetrahedron  2004,  60:  5889 
    Google Scholar
  • 4g Kim M. Mulcahy JV. Espino CG. Du Bois J. Org. Lett.  2006,  8:  1073 
    Google Scholar
  • 5 For a review, see: Bräse S. Gil C. Knepper K. Zimmermann V. Angew. Chem. Int. Ed.  2005,  44:  5188 
    CrossrefPubMedGoogle Scholar
  • 6a Molina P. Conesa C. Velasco D. Synthesis  1996,  1459 
    Google Scholar
  • 6b See also: Palacios F. Alonso C. Aparicio D. Rubiales G. de los Santos JM. Tetrahedron  2007,  63:  523 
    Google Scholar
  • 7 Cooper RG. Etheridge CJ. Stewart L. Marshall J. Rudginsky S. Cheng SH. Miller AD. Chem. Eur. J.  1998,  4:  137 ; and references therein
    CrossrefGoogle Scholar
  • 8 Bis(diphenylphosphino)ethane has been used to address similar problems in Staudinger and Mitsunobu reactions, see: O’Neil IA. Thompson S. Murray CL. Kalindjian SB. Tetrahedron Lett.  1998,  39:  7787 
    CrossrefGoogle Scholar
  • 13 For example, see: Hodgkinson TJ. Shipman M. Synthesis  1998,  1141 ; and references cited therein
    Article in Thieme ConnectGoogle Scholar
9

Representative Procedure: To a solution of 6 (0.20 g, 0.91 mmol) in anhyd CH2Cl2 (10 mL) under nitrogen was added DPPB (0.213 g, 0.50 mmol). The reaction mixture was stirred at r.t. for 22 h, cooled to -20 ˚C and tosyl isocyanate (144 µL, 0.94 mmol) was slowly added. The reaction mixture was allowed to warm to r.t. and stirred for 22 h. Removal of the solvent in vacuo and subsequent column chromatography (8% EtOAc in CH2Cl2) gave 7 (0.24 g, 71%) as a white solid.

10

Selected Spectroscopic Data: 7: mp 152-153 ºC (from CH2Cl2-Et2O). ¹H NMR (400 MHz, CDCl3): δ = 7.81 (d, J = 8.3 Hz, 2 H, ArH), 7.71 (s, 1 H, NH), 7.29-7.37 (m, 5 H, ArH), 7.22 (d, J = 8.3 Hz, 2 H, ArH), 5.25 (s, 2 H, OCH 2Ph), 3.90-3.95 (m, 2 H), 3.60-3.65 (m, 2 H), 2.40 (s, 3 H, Me). ¹³C NMR (100.5 MHz, CDCl3): δ = 154.1 (C), 150.8 (C), 142.6 (C), 139.7 (C), 135.1 (C), 129.3 (CH), 128.6 (CH), 128.3 (CH), 128.0 (CH), 126.3 (CH), 68.5 (CH2), 43.9 (CH2), 39.9 (CH2), 21.5 (Me). IR (neat): 3315, 2919, 1753, 1621 cm-¹. MS (FAB+): m/z = 374 [M + H+], 330. HRMS (FAB+): m/z [M + H+] calcd for C18H20N3O4S: 374.1175; found: 374.1179. 16: [α]D ²4 47 (c = 1.2, EtOH). ¹H NMR (400 MHz, CDCl3): δ = 7.67-7.69 (m, 3 H, 2 × ArH, NH), 7.27-7.33 (m, 10 H, ArH), 7.21-7.25 (m, 3 H, 2 × ArH, NH), 6.54 (br s, 1 H, NH), 5.19 (d, J = 12.3 Hz, 1 H, OCHHPh), 5.11 (d, J = 12.3 Hz, 1 H, OCHHPh), 5.09 (d, J = 12.3 Hz, 1 H, OCHHPh), 5.02 (d, J = 12.3 Hz, 1 H, OCHHPh), 4.53-4.61 (m, 1 H, α-CH Ala), 4.43 (dd, J = 5.0, 8.5, Hz, 1 H, α-CH Val), 4.16-4.19 (m, 1 H, H-9), 3.56 (t, J = 9.4 Hz, 1 H, H-10), 3.22 (d, J = 10.8 Hz, 1 H, H-10′), 2.28 (s, 3 H, Me), 2.03-2.10 (m, 3 H, H-2, β-CH Val), 1.58-1.70 (m, 1 H, H-8), 1.42-1.55 (m, 3 H, H-8′, 2 × H-3), 1.25 (d, J = 7.0 Hz, 3 H, β-Me Ala), 1.05-1.20 (m, 8 H, 2 × H-4, 2 × H-5, 2 × H-6, 2 × H-7), 0.81 (d, J = 6.8 Hz, 3 H, γ-Me Val), 0.78 (d, J = 6.8 Hz, 3 H, γ-Me Val). ¹³C NMR (100.5 MHz, CDCl3): δ = 173.1 (C), 172.8 (C), 171.5 (C), 153.7 (C), 150.9 (C), 142.5 (C), 139.8 (C), 135.4 (C), 135.1 (C), 129.3 (CH), 128.6 (CH), 128.5 (CH), 128.4 (CH), 128.3 (CH), 128.0 (CH), 126.2 (CH), 68.4 (CH2), 66.9 (CH2), 57.4 (CH), 56.0 (CH), 48.6 (CH), 45.2 (CH2), 36.4 (CH2), 33.0 (CH2), 30.9 (CH), 29.1 (CH2), 29.0 (CH2), 25.5 (CH2), 24.2 (CH2), 21.5 (Me), 19.1 (Me), 18.3 (Me), 17.7 (Me). IR (neat): 3400, 3281, 3061, 2925, 2885, 1717, 1631, 1616, 1541 cm-¹. MS (FAB+): m/z = 776 [M + H+], 338. HRMS (FAB+): m/z [M + H+] calcd for C41H54N5O8S: 776.3693; found: 776.3692.

11

This data has been deposited at the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK. Deposition number: CCDC 679310.

12

The enantiomers were separated by analytical HPLC on a chiralpak OD-H column (3% IPA in n-hexanes, flow rate = 0.5 mL/min, λ = 245 nm); t R [(S)-9] = 12.5 min, t R [(R)-9] = 14.8 min.

14

Synthesised by coupling commercially available N-Boc-l-alanine with l-valine benzyl ester (EDC, HOBt, Et3N, CH2Cl2, 16 h, 90%).

15

This contamination arises from the fact that solid NH4Cl is used to quench the dissolving metal reduction and TFA is used as a co-solvent in the subsequent purification by silica gel chromatography. The effective molarity of 17 in D2O, from which the yield could be estimated, was determined by adding known quantities of 1,4-dioxane to the sample and subsequent quantification of the dioxane/17 ratio by ¹H NMR integration.