Synthesis, structural characterization and conformational aspects of nostoclide analogues R.R. Teixeira a,b , L.C.A. Barbosa a, * , J.W.de M. Carneiro c , R.S. Corrêa d , J. Ellena d , A.C. Doriguetto e a Department of Chemistry, Federal University of Viçosa, Avenida P.H. Rolfs, CEP 36570-000, Viçosa, MG, Brazil b Chemistry Department, Federal University of Minas Gerais, Avenida Antônio Carlos, 6627, CEP 31270-9001, Belo Horizonte, MG, Brazil c Inorganic Chemistry Department, Fluminense Federal University, Outeiro de São João Batista, s/n, Centro, CEP 24020-141, Niterói, RJ, Brazil d São Carlos Physics Institute – USP, Cx. postal 369, CEP 13560-970, São Carlos, SP, Brazil e Department of Exact Science, Federal University of Alfenas, Rua Gabriel Monteiro da Silva, 700, CEP 37130-000, Alfenas, MG, Brazil article info Article history: Received 26 April 2008 Received in revised form 18 June 2008 Accepted 20 June 2008 Available online 26 June 2008 Keywords: Nostoclide analogues c-Alkylidenebutenolides DFT calculation X-ray analysis Herbicides abstract The synthesis and structural analysis of a set of nostoclide analogues with potential herbicide activity is described. The influence of intra- and intermolecular hydrogen bonding, as well as other interactions on the conformation and packing of the compounds is thoroughly described using DFT calculations and sin- gle crystal X-ray diffraction analyses. All lactones exhibited the Z configuration as confirmed by NOESY experiments and by single crystal X-ray diffraction measurements. Ó 2008 Elsevier B.V. All rights reserved. 1. Introduction Marine organisms are capable of producing a myriad of structur- ally diverse secondary metabolites [1]. More than 17,000 com- pounds have been described from marine sources [2] including compounds from polar habitats [3]. Alongside exploring the diver- sity found among the marine natural products for drug development [4], these metabolites can also be explored either as herbicides or no- vel lead structures towards the development of weed controllers [5]. The metabolites known as nostoclides (1)(Fig. 1) were first iso- lated in 1993 by Yang and co-workers. They are produced by a cya- nobacterium (or blue-green algae; Nostoc sp.), which can live free or in symbiosis, for instance, in the lichen Peltigera canina [6], and belong to a family of compounds know as c-alkylidenebuteno- lides [7]. The nostoclides (1) resemble the substance cyanobacterin (2)(Fig. 1), a lactone that is capable of inhibiting the photosyn- thetic electron transport in isolated chloroplasts [8]. Because of the structural similarity between the nostoclides (1) and cyanobacterin (2), we have considered the former as a poten- tial new lead for herbicide development. As a consequence, a vari- ety of nostoclide analogues [general structures (3) and (4), Fig. 1] have been synthesized. Their biological activities were evaluated in vitro as the ability to interfere with light-driven reduction of fer- ricyanide by isolated spinach chloroplasts [9]. Several compounds exhibited inhibitory properties in the micromolar range against the basal electron flow from water to K 3 [Fe(CN) 6 ]. Moreover, sev- eral of the synthesized analogues were submitted to in vitro eval- uation against different cancer cell lines using the MTT assay. Some of the evaluated compounds exhibited moderate cytotoxicity against at least one of the cell lines [10]. In addition to biological property studies, we have also been interested in the molecular properties of the nostoclide analogues. In a previous paper [11], a combined study using XRD techniques and DFT calculations was carried out to characterize two nostoclide analogues [compounds (5) and (6), Fig. 1] namely 5(Z)-3-benzyl-5- (1,3-dioxalanebenzylidene)furan-2(5H)-one (5) and 5(E)-3-benzyl- 5-(2,4,6-trimethoxybenzylidene)furan-2(5H)-one (6). In order to get further insight into the molecular properties of this type of lac- tone, we conducted an investigation on a series of nostoclide ana- logues employing a combination of NMR analyses, DFT calculations and XRD techniques. Herein we describe the results of this investigation. 2. Experimental 2.1. Materials and methods All reactions were carried out under a protective atmosphere of dry nitrogen. Dichloromethane, tetrahydrofuran (THF), diethyl 0022-2860/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.molstruc.2008.06.019 * Corresponding author. Tel.: +55 31 3899 3068; fax: +55 31 3899 3065. E-mail address: lcab@ufv.br (L.C.A. Barbosa). Journal of Molecular Structure 917 (2009) 1–9 Contents lists available at ScienceDirect Journal of Molecular Structure journal homepage: www.elsevier.com/locate/molstruc