MAGNETIC RESONANCE IN CHEMISTRY Magn. Reson. Chem. 2004; 42: 973–976 Published online 6 September 2004 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/mrc.1479 Note Conformational insights into furo- and thieno[2,3-b]indolines derived from coupling constants and molecular modeling Martha S. Morales-R ´ ıos, ∗ Norma F. Santos-S ´ anchez, Nadia A. P ´ erez-Rojas and Pedro Joseph-Nathan Departamento de Qu´ ımica, Centro de Investigaci ´ on y de Estudios Avanzados del Instituto Polit ´ ecnico Nacional, Apartado 14-740, M ´ exico D.F., 07000 Mexico Received 15 May 2004; Revised 9 July 2004; Accepted 12 July 2004 The extent to which conformational preferences of fused heterocyclic five-membered rings change with the nature of the heteroatom (O and S) was investigated in furo- (1, 2) and thieno[2,3-b]indolines (3, 4) by the combined use of 1 H NMR spectroscopy and density functional theory (DFT) calculations. In contrast to the behavior observed for pyrroloindolines, the furo- and thienoindolines exist in solution in only one conformer, with structures in the 2 E– 2 T 3 (1,2) and 2 T 3 –E (3,4) North/West region of the pseudorotational wheel, and with pseudorotation phase angles (P) of 315.8, 311.6, 337.2 and 331.6 ◦ , respectively. Copyright  2004 John Wiley & Sons, Ltd. KEYWORDS: NMR; 1 H NMR; pyrrolo[2,3-b]indolines; furo[2,3-b]indolines; thieno[2,3-b]indolines; conformation; molecular modeling INTRODUCTION Furobenzofurans and pyrroloindolines are an important class of natural products with both toxic and therapeutic properties (for reviews, see Ref. 1). With the advances being made in their binding to protein receptors, there is significant interest, from the drug-design perspective, in establishing the conformational preferences of these compounds. Recent the- oretical studies lead to only one minimum energy conforma- tion for furobenzofurans, 2 whereas pyrroloindolines, namely the alkaloids physostigmine and debromoflustramine B, are characterized by two minimum energy conformations for the considerably constrained pyrrolidine C-ring. 3 Hence, these two alkaloids exist in solution in a dynamic conformational equilibrium between two extreme low-energy structures labeled North/West and South/East conformations, while a fixed South/East conformation is found for physostigmine hydrochloride. It was shown that the umbrella inversion through N-1 in the free base appears to be a major factor in determining the pseudorotation 4 in the pyrrolidine ring. In this work, we extended these studies to examine the extent to which conformational preferences in solution of fused five-membered indolines change with the nature of L Correspondence to: Martha S. Morales-R´ ıos, Departamento de Qu´ ımica, Centro de Investigaci ´ on y de Estudios Avanzados del Instituto Polit´ ecnico Nacional, Apartado 14-740, M´ exico D.F., 07000 Mexico. E-mail: smorales@mail.cinvestav.mx Contract/grant sponsor: CONACYT; Contract/grant number: 34405-N; G-32631-N. the heteroatom (O and S) in ring C. For this purpose, the furoindolines 1 and 2 and the thienoindolines 3 and 4 were prepared from the methiodide derivative of the corresponding pyrroloindoline. The solution conformation of indolines 1 – 4 in CDCl 3 was assessed with the aid of 1D and 2D NMR (COSY, HETCOR, gHMBC, NOESY) techniques, DFT calculations and subsequent determination of pseudorotational parameters. The results reveal that replacement of the N-1 nitrogen atom by oxygen or sulfur results in drastic changes in the conformational preferences of these tricyclic compounds. These studies are in line with our interest in defining the molecular conformation in solution of natural products. 5 RESULTS AND DISCUSSION Furo- and thienoindolines 1 – 4 were obtained by reaction of the methiodide of the corresponding pyrroloindolines 5 and 6 with NaOH or NaSH, respectively (Scheme 1), by using published procedures. 6 Although the tricyclic sys- tems possessed a certain amount of flexibility, the presence of a heteroatom in rings B and C could predispose these molecules to a preferred conformation, which may be ascer- tained by NMR studies. In all cases, the expected cis B/C ring junction stereochemistry was deduced by the NOESY correlation between H-8a and the alkyl protons at C-3a. Con- formation A (Fig. 1) was established by a detailed analysis of the 1 H NMR spectra. For example, the methylene protons Copyright  2004 John Wiley & Sons, Ltd.