FULL PAPER DOI: 10.1002/ejoc.201101343 Iodolactonization: Synthesis, Stereocontrol, and Compatibility Studies Martins S. Oderinde, [a] Howard N. Hunter, [a] Stacy W. Bremner, [a] and Michael G. Organ* [a] Keywords: Synthetic methods / Diastereoselectivity / Lactones / Natural products / Iodolactonization Generalized iodolactonization conditions have been devel- oped for the formation of both cis- and trans-γ-lactones from 3-pentenoic acid derivatives containing various protected alcohol moieties. Kinetic control of the reaction using iodine Introduction Iodolactonization of olefin-containing carboxylic acids and amides with high stereochemical fidelity continues to attract interest in organic synthesis, particularly in the total synthesis of bioactive compounds. [1] More specifically, γ- olefinic carboxylic acids and their derivatives can be trans- formed readily into primary iodo-γ-lactones. [2] γ-Lactone moieties exist in the structure of natural products, in both the trans and cis forms; thus, their diastereoselective synthe- ses are of general interest (see Figure 1 for examples). [3–6] Figure 1. Representatives of natural products possessing cis and trans-γ-lactone cores. As the iodolactonization of β-substituted γ-olefinic carb- oxylic acids can be thermodynamically or kinetically con- trolled to provide either the trans- or cis-iodo-γ-lactone with moderate to good selectivity, the iodolactonization of γ-olefinic esters and amides gives mainly the trans-iodo-γ- [a] Department of Chemistry, York University, 4700 Keele Street, Toronto, ON, M3J 1P3, Canada Fax: +1-416-736-5936 E-mail: organ@yorku.ca Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ejoc.201101343. Eur. J. Org. Chem. 2012, 175–182 © 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 175 and base at 0 °C for 6 h provided the cis-lactone with good selectivity (75:25), and thermodynamic control at room tem- perature for 24 h provided the trans-lactone with excellent selectivity (98:2). lactone with moderate selectivity. [1] Iodolactonization con- ditions cannot be generalized, because the diastereoselectiv- ity and reactivity are sensitive to functional groups, steric hindrance, and electronic effects. [7,8] For instance, the dia- stereochemical outcome of the iodolactonization of γ-ole- finic carboxylic acids 5a and 5b, having either a β-phenyl or β-methyl group, respectively, varies slightly under thermodynamic control but significantly under kinetic con- trol [Scheme 1 (A)]. [7] Scheme 1. Thermodynamically and kinetically controlled iodo- lactonization of β-substituted γ-olefinic carboxylic acids and amides. Reagents and conditions: [7,8] (a) I 2 , aqueous NaHCO 3 , CHCl 3 , 0 °C, 6 h; (b) I 2 , MeCN, 0 °C to room temp., 24 h; (c) I 2 , MeCN/H 2 O, reflux, 24 h. Similarly, the stereocontrol in the iodolactonization of γ-olefinic amides 8a and 8b is strongly affected by steric hindrance and electronic effects [Scheme 1 (B)]. [8] The reac- tion proceeded with dimethylamide 8a, whereas it failed to proceed with diisopropylamide 8b . The diastereochemical outcome of the iodolactonization of 8a was also solvent- dependent, rationalized as a consequence of the dipolar character of the transition states in the conformational equilibrium. [8] As iodolactonization conditions are either