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

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 
• 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 
• 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
• 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 
• 4b Isobe T. Fukuda K. Yamaguchi K. Seki H. Tokunaga T. Ishikawa T. J. Org. Chem.  2000,  65:  7779 
• 4c Matosiuk D. Fidecka S. Antkiewicz-Michaluk L. Dybala I. Koziol AE. Eur. J. Med. Chem.  2001,  36:  783 
• 4d Dennis M. Hall LM. Murphy PJ. Thornhill AJ. Nash R. Winters AL. Hursthouse MB. Light ME. Horton P. Tetrahedron Lett.  2003,  44:  3075 
• 4e Abou-Jneid R. Ghoulami S. Martin M.-T. Dau ETH. Travert N. Al-Mourabit A. Org. Lett.  2004,  6:  3933 
• 4f Sanière L. Leman L. Bourguignon J.-J. Dauban P. Dodd RH. Tetrahedron  2004,  60:  5889 
• 4g Kim M. Mulcahy JV. Espino CG. Du Bois J. Org. Lett.  2006,  8:  1073 
• 5 For a review, see: Bräse S. Gil C. Knepper K. Zimmermann V. Angew. Chem. Int. Ed.  2005,  44:  5188 
• 6a Molina P. Conesa C. Velasco D. Synthesis  1996,  1459 
• 6b See also: Palacios F. Alonso C. Aparicio D. Rubiales G. de los Santos JM. Tetrahedron  2007,  63:  523 
• 7 Cooper RG. Etheridge CJ. Stewart L. Marshall J. Rudginsky S. Cheng SH. Miller AD. Chem. Eur. J.  1998,  4:  137 ; and references therein
• 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 
• 13 For example, see: Hodgkinson TJ. Shipman M. Synthesis  1998,  1141 ; and references cited therein

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.