Synthesis of the C1eC16 fragment of the ajudazols Ben A. Egan a , Michael Paradowski b , Lynne H. Thomas c , Rodolfo Marquez a, * , y a WestChem, School of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK b Pfizer Global R&D, Sandwich, Kent, CT13 9NJ, UK c Department of Chemistry, University of Bath, BA2 7AY, UK article info Article history: Received 26 July 2011 Received in revised form 26 September 2011 Accepted 10 October 2011 Available online 18 October 2011 Keywords: Ajudazol Isobenzofuran Oxidative rearrangement abstract The synthesis of the C1eC16 framework of the ajudazols has been achieved taking advantage of a highly selective isobenzofuran oxidative rearrangement and a key Stille coupling to introduce the key C14eC15 bond. Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction Myxobacteria have been widely recognized as a rich source of bioactive metabolites with significant biological activities. The myxobacterial strain Chondromyces crocatus is particularly note- worthy for having yielded extracts containing the chondramides AeD and the crocacins AeC. 1,2 Ajudazols A 1 and B 2 were isolated by Jansen and co-workers by reverse phase chromatography from the acetone extracts of the wet mass of C. crocatus. 3 Structurally, the ajudazols showcase a number of exquisite, and in some cases, unique features, such as a 4,8- dihydroxy-7-methyl-isochroman-1-one, a 3-methoxybutenoic acid methyl amide as well as an internal oxazole and a Z,Z-diene unit. Biologically, the ajudazols have been identified as inhibitors of the bacterial mitochondrial electron transport at low nanomolar concentrations (Fig. 1). 3 Biosynthetic studies by Muller have determined that the aju- dazols are assembled by a hybrid polyketide synthase (PKS) non- ribosomal peptide (NRPS) multienzyme, which efficiently puts together the ajudazol framework in a linear fashion. 4 Interestingly, the key isochromanone ring formation is promoted by a novel thioesterase domain rather than by an expected terminal cyclase. 4 The exciting combination of unique structural features com- bined with a promising therapeutic profile makes the ajudazols highly attractive targets. Rizzacasa and Taylor have published ele- gant approaches towards the total synthesis of the ajudazols; 5,6 however, there have been no reported total syntheses of either ajudazol A or B. As part of our own efforts towards the synthesis of the ajudazols, we envisioned the ajudazols as originating from the metal pro- moted coupling of vinyl halide 3 to oxazole 4 via CeH activation of the oxazole’s C2 position. Vinyl halide 3 could be formed from the alkylation of bis-alkyne 5 and the condensation of the amine functionality with methoxybutenoic acid 6. The key bis-alkyne 5 in turn was envisioned as originating from the bis-acetylene unit 7 (Scheme 1). The oxazole substituted isochroman-1-one unit 4 on the other hand, was thought of as being obtained through the coupling of the isobenzofuran anion 8 and aldehyde 9 followed by oxidative rear- rangement of the resulting a-hydroxyisobenzofuran intermediate. The isobenzofuran anion could be accessed readily through base treatment of methyl acetal 10, whilst the oxazole containing alde- hyde 9 was thought as having originated from oxazole ester 11 . N O OMe O N O OH O OH 1 Ajudazol A R 1 ,R 2 = CH 2 2 Ajudazol B R 1 = CH 3 ,R 2 =H R 1 R 2 1 8 5 10 12 15 17 19 21 23 25 27 29 Fig. 1. Ajudazol A 1 and ajudazol B 2. * Corresponding author. Tel.: þ44 141 330 5953; fax: þ44 141 330 488; e-mail address: rudi.marquez@glasgow.ac.uk (R. Marquez). y Ian Sword Reader of Organic Chemistry. Contents lists available at SciVerse ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2011.10.036 Tetrahedron 67 (2011) 9700e9707