Base dependent pyrrolidine ring pucker in aep-PNA monomers: NMR and PSEUROT analysis Nagendra K. Sharma a, * , Krishna N. Ganesh b, c, y a School of Chemical Sciences, National Institute of Science Education and Research (NISER), IOP Campus, P.O. Sainik School, Bhubaneswar 751005, Orissa, India b JC Bose Fellow, Division of Organic Chemistry, National Chemical Laboratory, Pune 411008, India c Indian Institute of Science Education and Research (IISER), 900, NCL Innovation Park, Dr. Homi Bhabha Road, Pune 411008, India article info Article history: Received 21 June 2010 Received in revised form 24 September 2010 Accepted 27 September 2010 Available online 1 October 2010 Keywords: DNA, RNA and PNA A, T, G and C aep-PNA Conformational analysis Pyrrolidine ring abstract The aep-PNA is a chiral and cyclic PNA analogue, which has a stronger and base dependent binding affinity with complementary DNA. To understand the base dependent properties at monomer level, the structural studies of aep-PNA-(T/C/A) monomers have been carried out focussing on the conformational analysis of pyrrolidine ring pucker in aep-PNA by 1 H NMR and the coupling constant data fitted into PSEUROT software. The results indicate that the type of pyrrolidine pucker depends on the electronic nature of substituent, implying the effect of pyrimidine or purine substituents in determining the ring pucker in monomers. This may consequently influence the aep-PNA oligomer conformation. Since pyr- rolidine nucleic acids have emerged as an important class of PNA analogues, present results may have importance for their future development. Ó 2010 Elsevier Ltd. All rights reserved. 1. Introduction The study of relation between structure and function of bio- molecules is very important in understanding the biological functions of living systems. 1 The conformational state of active molecules is a critical factor in determining molecular structur- eefunction relationship. A conformer is not an isolable form of a compound and hence it cannot be analyzed exclusively for biological activity and many times inter-conversion of different conformers is possible. The identification and characterization of conformers depend on the rate of inter-conversion of different conformers and appropriate techniques to detect them in relevant time scale is important. 2 The molecular resolution of inter- converting conformers is favoured by lowering the temperature to lessen the rate of inter-conversion and analysis may be done by X-ray crystallography and NMR techniques. 3,4 The X-ray diffraction study provides only the structure of a stable conformer while NMR has the potential to provide information on a mixture of con- formers, including the kinetics and thermodynamics of their inter- conversion. 5 The vicinal protoneproton coupling constants (J) as determined by 1 H NMR are weighted averages of the geometry of conformers and by use of Karplus equation aids in determining the stereochemistry of organic molecules, especially the dihedral angle. 6e8 The measured J is also a function of the electronegativity of the substituent and the relationship has been extensively used to find the conformations of the puckered ring in cyclic molecules, wherein fast conformational equilibrium may exist among differ- ent puckered states. 9e11 In cyclopentane derivatives, the ring strain is relieved by puckering one atom out of plane leading to gauche relation among the vicinal substituents. 12e14 In case of furanose ring of nucleosides, Altona and Sundaraingam have developed a formalism to fit the 1 He 1 H coupling constants into Karplus equation in order to determine the relative amounts of two con- formations in furanose ring. 15,16 They have also extended their method to pyrrolidine rings found in prolines by inclusion of suitable parameters to take into account the electronegativity effects. 9a,17,18 In case of N-substituted prolines, it is found from X-ray studies that the five-membered ring prefers to adopt either of the two conformations N (North) and S (South) (Fig. 1) corre- sponding to C4-endo and C3-endo forms, respectively. 18c,19,20 However in C-substituted prolines this may significantly change depending on the electronegativity of the substituents. By applying PSEUROT programme developed by Altona et al., 16 we herein report a conformational analysis of the prolyl ring in aminoethyl prolyl (aep) peptide nucleic acid (PNA) monomers having different nucleobases A, C, G and T. aep-PNA (Fig. 2) is * Corresponding author. Tel.: þ91 674 230 4094/91 674 230 4130; fax: þ91 20 2589 9790; e-mail addresses: nagendra@niser.ac.in (N.K. Sharma), kn.ganesh@ iiserpune.ac.in (K.N. Ganesh). URLs: http://www.niser.ac.in, http://www.iiserpune.ac.in y Tel.: þ91 20 2590 8000; fax: þ91 20 2589 9790. Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2010.09.082 Tetrahedron 66 (2010) 9165e9170