A Route to 1,4-Disubstituted Aromatics and Its Application to the Synthesis of the Antibiotic Culpin Rajesh Sunasee and Derrick L. J. Clive* Chemistry Department, UniVersity of Alberta, Edmonton, Alberta T6G 2G2, Canada derrick.cliVe@ualberta.ca ReceiVed July 10, 2008 A method is described for converting tert-butyl benzoates or tert-butyl 1-naphthoates into derivatives having an alkyl or substituted alkyl group in a 1,4-relationship to an alkyl, aryl, alkenyl, or alkynyl group. Key steps in the sequence are (i) addition of an organometallic species to a cross-conjugated cyclohexadienone obtained by Birch alkylation of a tert-butyl benzoate or a tert-butyl 1-naphthoate, followed by allylic oxidation, and (ii) treatment with BiCl 3 · H 2 O, which results in removal of the tert- butyl group and spontaneous decarboxylative aromatization. The method was applied to the synthesis of the antimicrobial fungal metabolite culpin. Introduction Although many approaches are available for the synthesis of substituted aromatics, 1 the general importance of such com- pounds leaves considerable room for the development of new synthetic procedures, and we report a method that starts with tert-butyl benzoates or tert-butyl 1-naphthoates and allows the introduction of two substituents in a 1,4-relationship. Results and Discussion Numerous cross-conjugated dienones of type 3 have been prepared in this laboratory by alkylative Birch reduction (1 f 2), followed by allylic oxidation (2 f 3) (Scheme 1). 2 Some of these dienones were then elaborated into the alcohols 4, which underwent aromatization (4 f 5) on heating (70-80 °C) with BiCl 3 · H 2 O, a reagent known 3 to be useful for deprotection of tert-butyl carbamates but which we had found to be equally effective for deprotection of tert-butyl esters. 2 This earlier work was aimed specifically at the preparation of benzo-fused carbocycles (such as 5), but the facility of the decarboxylative aromatization step (4 f 5) suggested that monocyclic com- pounds of type 6, which would be readily available from the cross-conjugated dienones 3 by Grignard or organolithium addition, might likewise be aromatized to afford para-disubsti- (1) (a) Modern Arene Chemistry; Astruc, D., Ed.; Wiley-VCH: Weinheim, 2002. (b) Snieckus, V. Chem. ReV. 1990, 90, 879–933. (c) Donohoe, T. J.; Orr, A. J.; Bingham, M. Angew. Chem., Int. Ed. 2006, 45, 2–9. (2) (a) Clive, D. L. J.; Sunasee, R. Org. Lett. 2007, 9, 2677–2680. (b) Clive, D. L. J.; Sunasee, R.; Chen, Z. Org. Biomol. Chem. 2008, 2434–2441. (c) Beckwith, A. L. J.; Roberts, D. H. J. Am. Chem. Soc. 1986, 108, 5893–5901. (d) Schultz, A. G.; Lavieri, F. P.; Macielag, M.; Plummer, M. J. Am. Chem. Soc. 1987, 109, 3991–4000. (e) Schultz, A. G.; Taveras, A. G.; Harrington, R. E. Tetrahedron Lett. 1988, 29, 3907–3910. SCHEME 1. Principle of the Method 10.1021/jo8015192 CCC: $40.75  2008 American Chemical Society 8016 J. Org. Chem. 2008, 73, 8016–8020 Published on Web 09/25/2008