Conformationally restricted chiral peptide nucleic acids derived from azetidines

1. Conformationally restricted chiral peptide nucleic acids derived from azetidines Lajos Kovács,a, * Miklós Hornyák,a Nicola M. Howarthb aNucleic Acids Laboratory, Department of Medicinal Chemistry, University of Szeged, H-6720 Szeged, Dóm tér 8, Hungary and bDepartment of Chemistry, Heriot-Watt University, Edinburgh, Riccarton, EH14 4AS, United Kingdom. *E-mail: kovacs@ovrisc.mdche.u-szeged.hu Introduction Aims The recent success of peptide nucleic acids (PNA) [1, 2] is shadowed by their poor cellular uptake, ability to form aggregates and limited water solubility. The advent of conformationally rigid PNA analogues derived from pyrrolidine rings [3, 4] prompted us to embark upon the synthesis of new PNA analogues with azetidine moieties. This structural unit should have similar characteristics as the pyrrolidines and has the added advantage of being cationic due to the slightly basic azetidine ring which should enhance cellular uptake. • To synthesize azetidine nucleic acid (ANA) monomers (ANA-1, ANA-2) based on 1,3-dipolar cycloaddition reaction of the appropriate nitrones and alkenes followed by ring transformations. • To reduce the formation of isomers by employing chiral auxiliaries (e.g. 3,5,6-tri-O-methyl-D-glucofuranose and 2,3:5,6-di-O-isopropylidene-a-D-mannofuranose, respectively) and/or conduct the reactions intramolecularly. The key steps of the synthesis should involve the formation of isoxazoles and their ring transformation into the corresponding azetidines as delineated in the retrosynthetic schemes. Results The synthesis of ANA-1 monomer was undertaken using the chiral auxiliary 3,5,6-tri-O-methyl-D-glucofuranose [5] available from D-glucose in simple steps. The acryloylation of this latter substance yielded different proportions of mono- and bis-acylated derivatives, depending on the amount of acylating agent applied. The transformation of the 1,2-bis-O-acryloylated derivative into the desired 2-O-acryloyl compound was attempted under a variety of conditions {(Bu3Sn)2O, toluene, D; Bu3SnOMe, ClCH2CH2Cl, D [6, 7]; (NH4)2CO3/DMF; montmorillonite K10, wet acetonitrile, D, [8]; BF3 · OEt2,wet acetonitrile, 0 °C [9]} but exclusively the 1-O-acryloyl derivative was obtained indicating an unwanted acyl migration of the acrylate group from position 2 to 1. The glycosyl halide 2-O-acryloyl-3,5,6-tri-O-methyl-D-glucofuranosyl bromide, easily available from 1,2-bis-O-acryloyl-3,5,6-tri-O-methyl-D-glucofuranose, was surprisingly stable and it did not afford the 2-O-acryloyl derivative with wet silver oxide. Direct oxime formation with hydroxylamine hydrochloride was not successful. The rationale behind the synthesis of 2-O-acryloyl-3,5,6-tri-O-methyl-D-glucofuranose was its transformation into the corresponding oxime which, in turn, with nucleobase-substituted acetaldehydes [10, 11] should give a nitrone, the intramolecular 1,3-dipolar cycloaddition of which would result in the formation of the desired isoxazole. We are currently working on these transformations. Meanwhile, two other nitrones have been prepared en route to ANA-1 and ANA-2 monomers, respectively. Thus, 3,5,6-tri-O-methyl-D-glucose oxime was allowed to react with thymin-1-ylacetaldehyde [10], while 2,3:5,6-di-O-isopropylidene-a-D-mannose oxime [12] with Fmoc-aminoacetaldehyde [13], respectively. The first nitrone, to be submitted to selective acryloylation at 2-OH, presents an alternative approach to the above detailed route through 2-O-acryloyl-3,5,6-tri-O-methyl-D-glucofuranose. The second nitrone is ready for intermolecular 1,3-dipolar cycloaddition with, e.g. N9-allyladenine [14, 15] to yield the corresponding isoxazole. References • 1. P. E. Nielsen, G. Haaima (1997) Chem. Soc. Rev.26, 73-78. • 2. P. E. Nielsen (1998) Pure Appl. Chem.70, 105-110. • 3. V. Kumar, P. S. Pallan and K. N. Ganesh (2001) Org. Lett.3, 1269-1272. • 4. T. Vilaivan, C. Suparpprom, P. Harnyuttanakorn and G. Lowe (2001) Tetrahedron Lett.42, 5533-5536. • 5. J. H. Zhang, D. L. J. Clive (1999) J. Org. Chem.64, 770-779. • 6. K. Watanabe, K. Itoh, Y. Araki and Y. Ishido (1986) Carbohydr. Res.154, 165-176. • 7. T. Moriguchi, T. Wada and M. Sekine (1996) J. Org. Chem.61, 9223-9228. • 8. J. C. Florent, C. Monneret (1987): J. Chem. Soc., Chem. Commun., 1171-1172. • 9. D. Askin, C. Angst, S. Danishefsky (1987) J. Org. Chem.52, 622-635. • 10. M. Y. Lidak, R. A. Paegle, M. G. Plata and Y. P. Shvatshkin (1971) Khim. Geterotsikl. Soedin. 530-534. • 11. A. Holy (1984) Collect. Czech. Chem. Commun.49, 2148-2166. • 12. A. Vasella (1977) Helv. Chim. Acta60, 1273-1295. • 13. Y. Sasaki, J. Abe (1997) Chem. Pharm. Bull.45, 13-17. • 14. A. Holy (1981) Collect. Czech. Chem. Commun.46, 3134-3144. • 15. J. Thibon, L. Latxague and G. Deleris (1997) J. Org. Chem.62, 4635-4642. Acknowledgement The financial support of The Wellcome Trust (grant no. 063879/Z/01/Z) is gratefully acknowledged.