NMR Conformation of (-)--D-Aristeromycin and Its 2′-Deoxy and 3′-Deoxy Counterparts in Aqueous Solution C. Thibaudeau, † A. Kumar, † S. Bekiroglu, † A. Matsuda, ‡ V. E. Marquez, § and J. Chattopadhyaya* ,† Department of Bioorganic Chemistry, Box 581, Biomedical Center, University of Uppsala, S-751 23 Uppsala, Sweden, Laboratory of Medicinal Chemistry, DPT, DCT, National Cancer Institute, NIH, Bethesda, Maryland 20892, and Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060, Japan Received February 26, 1998 The solution conformations of aristeromycin (1), 2′-deoxyaristeromycin (2), and 3′-deoxyaristeromycin (3) have been determined from an integrated analysis of X-ray (for 1 only), NMR data (i.e., 3 J HH coupling constants), and ab initio calculations. One-dimensional NOE difference experiments showed that the adenin-9-yl ring in 1 and 2 is involved in a ∼50% syn a ∼50% anti equilibrium around the C-glycosyl torsion angle, whereas an anti orientation ( )-113°) is found in the X-ray crystal structure of 1. The preferred conformation around the γ torsion angle is γ t both in solution for 1-3 and in the solid state (for 1 only). The plots of energy as a function of the phase angle of pseudorotation (Figure 2) for the structures optimized by ab initio calculations (HF/3-21G*) show that there are two major wells of low energy conformers for 1-3, supporting the two-state North- type a South/West-type equilibrium of the constituent cyclopentane rings in 1-3. The ab initio calculations suggested that the South/West-type conformers are more stable than the North-type forms for 1 [∆E (120° < P < 240°) - (330° < P < 30°) ∼10 kcal/mol], for 2 [∆E (210° < P < 240°) - (330° < P < 60°) ∼ 4 kcal/mol] and for 3 [∆E (P ) 240°) - (330° < P < 0°) ∼ 6 kcal/mol]. Newly developed A and B sets of parameters correlating the H-C-C-H torsions to the endocyclic torsions based on the ab initio optimised structures of 1-3 have been subsequently used to interpret the time-averaged 3 J HH couplings using the program PSEUROT. The discrepancy found between the X-ray crystal structure (P ) 89°, Ψ m ) 41°) of aristeromycin (1) and its structure calculated by NMR-PSEUROT conformational analysis (35° < P [ 4 3 T - 4 0 T] < 65°, 35° < Ψ m < 45°) a (128° < P [ 1 E] < 131°, 34° < Ψ m < 36°) based on observed 3 J HH couplings in aqueous solution, as well as the relatively high error in the NMR-PSEUROT analyses for 1-3 [∆J max e 1.6 Hz (i.e., maximal difference between experimental and PSEUROT-calculated 3 J HH ) and root mean square (rms) error e 0.7 Hz] prompted us to reparametrize the Karplus equation implemented in the PSEUROT program by using torsion angles derived from solid-state geometries of conformationally constrained nucleosides and their corresponding experimental 3 J HH . The precision of our reparametrized Karplus-type equation (rms error ) 0.40 Hz) became comparable to that expected for the standard Haasnoot-Altona Karplus (0.48 Hz) equation. The results of the PSEUROT analyses performed with the standard Haasnoot-Altona Karplus equation are also very comparable in terms of geometry with those based on our reparametrized equation (eq 4). Both series of PSEUROT analyses suggest that the predominant conformation of the cyclopentane ring in 1-3 is defined by 128° < P < 140° for 1, 105° < P < 116° for 2, and 118° < P < 127° for 3, with the puckering amplitude in the range from 34° to 40° for 1-3. However, PSEUROT analyses based on our Karplus equation produced a smaller rms error by e0.14 Hz and ∆J max error by e0.5 Hz than those performed with the standard Haasnoot-Altona equation. This work therefore highlights two important points: (i) the solution- and the solid-state structures of aristeromycin (1) are indeed different, and (ii) the close similarity of geometries derived from Haasnoot-Altona’s equation or from our Karplus equation suggest that the solution structures for 1-3 are correctly defined. Introduction Aristeromycin was first isolated from the culture broth of Streptomyces citricolor by Kusaka et al., 1 and shown to possess in vitro and in vivo antibiotic activity against Xanthomonas oryzae and Pyricularia oryzae. The chemi- cal and enzymatic vulnerability characteristic of the glycosyl bond of natural nucleosides has inspired the synthesis of a wide gamut of carbocyclic nucleosides 2a in which a cyclopentane ring replaces the ribose moiety. However, these more stable carbocyclic nucleosides are generally less potent 2b than their natural counterparts. This could be attributed to the more flexible nature of the cyclopentane ring where both anomeric and gauche * To whom correspondence should be addressed. Fax: +46 18 554495. E-mail: jyoti@bioorgchem.uu.se. Web site: http://bioorgchem- .boc.uu.se. † University of Uppsala. ‡ Hokkaido University. § National Cancer Institute. (1) Kusaka, T.; Yamamoto, H.; Shibata, M.; Muroi, M.; Kishi, T. and Mizuno, K. J. Antibiot. (Tokyo) 1968, 21, 255. (2) (a) Marquez, V. E.; Lim, M. I. Med. Res. Rev. 1986, 6, 1. (b) Marquez, V. E. Carbocyclic Nucleosides in Advances in Antiviral Drug Design; De Clercq, E., Ed.; JAI Press, Inc.: Greenwich, CT, 1997; Vol. 2. 5447 J. Org. Chem. 1998, 63, 5447-5462 S0022-3263(98)00364-8 CCC: $15.00 © 1998 American Chemical Society Published on Web 07/15/1998