首页   按字顺浏览 期刊浏览 卷期浏览 Rapid Synthesis of (±)-(E)- and(±)-(Z)-1-Amino-1-aminomethyl-2-(hydroxyme...
Rapid Synthesis of (±)-(E)- and(±)-(Z)-1-Amino-1-aminomethyl-2-(hydroxymethyl)cyclopropanes, Preparation of their Dichloroplatinum(II)Complexes, and Crystal Structure of a Derivative of the(±)-(E) Isomer

 

作者: Fabrice Vergne,  

 

期刊: Journal of Chemical Research, Synopses  (RSC Available online 1997)
卷期: Volume 0, issue 4  

页码: 124-125

 

ISSN:0308-2342

 

年代: 1997

 

DOI:10.1039/a606840e

 

出版商: RSC

 

数据来源: RSC

 

摘要:

124 J. CHEM. RESEARCH (S), 1997 J. Chem. Research (S), 1997, 124–125 J. Chem. Research (M), 1997, 0773–0794 Rapid Synthesis of (�)-(E)- and (�)-(Z)-1-Amino- 1-aminomethyl-2-(hydroxymethyl)cyclopropanes, Preparation of their Dichloroplatinum(II) Complexes, and Crystal Structure of a Derivative of the (�)-(E) Isomer Fabrice Vergne,a David J. Aitken,*a Ang`ele Chiaroni,b Claude Richeb and Henri-Philippe Hussona aLaboratoire de Chimie Th�erapeutique associ�e au CNRS, Facult�e des Sciences Pharmaceutiques et Biologiques, Universit�e Ren�e Descartes (Paris V), 4 Avenue de l’Observatoire, 75270 Paris cedex 06, France bLaboratoire de Cristallochimie, Institut de Chimie des Substances Naturelles du CNRS, Avenue de la Terrasse, 99198 Gif-sur-Yvette cedex, France An efficient four-step synthesis of racemic Z and E forms of 1-amino-1-aminomethyl-2-(hydroxymethyl)cyclopropane is described, along with the preparation and cell-growth inhibition evaluation of the corresponding dichloroplatinum(II) complexes; the crystal structure of the synthetic intermediate (E)-1-[(benzyloxycarbonyl)aminomethyl]-1-dibenzylamino- 2-(hydroxymethyl)cyclopropane has been determined. Cyclopropane compounds continue to attract interest on account of their varied chemical and biological properties.1,2 As part of our research programme dealing with the preparation of polyfunctional cyclopropanes, particularly those containing diamine functions,15,26 we were interested in the synthesis of both diastereoisomers of the trifunctional molecule (�) - 1 - amino - 1 - aminomethyl - 2 - (hydroxymethyl)cyclopropane 2.In the search for new analogues of the anticancer drug cisplatin,16,17 the dichloroplatinum(II) complexes of 2 appeared attractive targets, since the presence of a peripheral non-metal-bound hydroxy group might be expected to improve the aqueous solubility and induce different biological activity profiles.23,24 The title compounds were prepared conveniently as shown in the Scheme.Double alkylation of N,N-dibenzylaminoacetonitrile with epibromohydrin gave cyclopropane 510 as a mixture of diastereoisomers (60 : 40), which was reduced with an excesss of borane.THF to give the diamine 6. It is noteworthy that no other products, such as those that might conceivably arise from decyanation25 or rearrangement processes, 26 were observed. Treatment of 6 with benzyl *To receive any correspondence. Scheme Fig. 1 X-Ray structure of compound (E)-7J. CHEM. RESEARCH (S), 1997 125 chloroformate led to the carbamate 7 whose low polarity facilitated separation of Z and E diastereoisomeric forms by flash chromatography. Each isomer of 7 was completely deprotected by hydrogenolysis to give the title compounds as hygroscopic oils. Each of the four steps in this sequence proceeded in high yield. Surprisingly, several attempts to transform the hydroxy group of (Z)-7 or (E)-7 into a halide or phosphate ester function met with failure, although it was possible to obtain the corresponding acetates by reaction with acetic anhydride.There was no obvious reason for the unusual lack of reactivity of the primary alcohol, but it was interesting to observe the existence of an intramolecular hydrogen bond between the carbamate hydrogen atom and the hydroxy group oxygen atom in the crystal structure of (E)-7 (Fig. 1), a phenomenon which could conceivably diminish the reactivity of the alcohol function.The dichloroplatinum(II) complexes 9 and 10 were prepared by reaction of the appropriate isomer of 2 with potassium tetrachloroplatinate. The expected cis-N2Cl2 squareplanar platinum ligand set was confirmed by the 195Pt NMR resonances at around µ2200 ppm,27 thus confirming that the hydroxy function was not metal-bound. The in vitro cellgrowth inhibition activities of 9 and 10 were evaluated as IC50 values on L1210 (murine leukaemia) cells, and were found to be 32 mM and a50 mM respectively. Both compounds were thus at least an order of magnitude less potent than cisplatin (IC50=1.6 mM).Crystal Data for (E)-7.·C27H30N2O3, Mr=430.55, orthorhombic, space group Pbca, Z=8, a=8.383(6), b=13.146(9), c=44.094(20) Å, V=4859.3 Å3, dc=1.18 g cmµ3, F(000)=1840, l(CuKa)=1.5418 Å, m=0.57 mmµ1. Experimental data were collected on a Nonius CAD-4 diffractometer using graphite-monochromated CuKa radiation. The structure was solved by direct methods and the final R value was 0.065 (Rw=0.079).Estimated standard deviations for geometrical parameters involving non-hydrogen atoms lie within the following ranges: bond lengths, 0.007–0.021 Å; bond angles, 0.4–1.3°. We thank Dr F. Libot (CNRS URA 1310) for recording mass spectra and Dr F. Siret (CNRS URA 400) for recording 195Pt NMR spectra. We are grateful to the Experimental Cancerology Laboratory of Institut de Recherches Servier for carrying out the biological tests, to the Comptoir Lyon Alemand Louyot for the gift of potassium tetrachloroplatinate, and to the Ligue Nationale Contre le Cancer for a fellowship to F.V.References: 30 Schemes: 2 Tables 1–5: Fractional atomic coordinates for non-H atoms, fractional atomic coordinates for H atoms, anisotropic thermal parameters, bond lengths and angles and selected torsion angles Received, 7th October 1996; Accepted, 2nd January 1997 Paper E/6/06840E References cited in this synopsis 1 The Chemistry of the Cyclopropyl Group, ed.Z. Rappoport, Wiley, New York, 1987. 2 J. Sala�un and M. S. Baird, Curr. Med. Chem., 1995, 2, 545; C. J. Suckling, Angew. Chem., Int. Ed. Engl., 1988, 27, 537. 10 D. Guillaume, D. J. Aitken and H.-P. Husson, Synlett, 1991, 747; D. J. Aitken, F. Vergne, A. S. Phimmanao, D. Guillaume and H.-P. Husson, Synlett, 1993, 599. 15 F. Vergne, D. J. Aitken and H.-P. Husson, J. Org. Chem., 1992, 57, 6071. 16 Platinum and Other Metal Complexes in Cancer Chemotherapy, ed. M. Nicolini, Martinus Nijhoff, Boston, 1988. 17 N. Farrell, Transition Metal Complexes as Drugs and Chemotherapeutic Agents, Kluwer Academic Press, Dordrecht, 1989. 23 S. Hanessian and J. Wang, Can. J. Chem., 1993, 71, 2102. 24 P. Mailliet, E. Segal-Bendirdjian, J. Kozelka, M. Barreau, B. Baudoin, M.-C. Bissery, S. Gontier, A. Laoui, F. Lavelle, J. B. Le Pecq and J.-C. Chottard, Anti-Cancer Drug Design, 1995, 10, 51. 25 K. Ogura, Y. Shimamura and M. Fujita, J. Org. Chem., 1991, 56, 2920. 26 F. Vergne, K. Partogyan, D. J. Aitken and H.-P. Husson, Tetrahedron, 1996, 52, 2421. 27 P. S. Pregosin, Annu. Rep. NMR Spectr

 



返 回