A formal synthesis of (±)-roseophilin is described. Scandium(III)-catalyzed Nazarov cyclization of 2,5-disubstituted N-tosylpyrrole 19 gives a 5,5'-fused ketopyrrole, and ansa-bridge formation via π-allyl palladium macrocyclization gives 21.Roseophilin (1), isolated from Streptomyces griseoviridis, was identified as a potent cytotoxic agent against K562 human erythroid leukemia cells (chronic myeloid leukemia model; IC 50 , 0.34 μM) and KB human epidermoid carcinoma cells (nasopharyngeal carcinoma model; IC 50 , 0.88 μM). 1 Unexpectedly, the unnatural enantiomer of 1, ent-roseophilin, was shown to possess 2-10 fold greater potency than the naturally occuring enantiomer. 2The structure of 1 contains an ansa-bridged macrocycle that is connected to a pyrrolylfuran moiety via an azafulvene subunit. Its unique chemical structure coupled with its poorly understood mechanism of cytotoxicity 3 has led to the development of several synthetic approaches targeting 1. 2,4 Herein, we disclose our approach to the formal synthesis of 1 via macrotricycle 2, using a strategy involving the catalytic Nazarov cyclization of polarized aryl vinyl ketones. 5,6Our retrosynthetic analysis of macrotricycle 2 is shown in Scheme 1. Execution of a late-stage macrocyclization to close the strained 13-membered ansa bridge was planned with some trepidation. In most of the published approaches toward this target, the final stages involved closure of either the cyclopentenyl ring or the pyrrole ring within an existing macrocyclic scaffold. In the few cases when a late-stage macrocyclization was performed on the fused 5,5'-fused ring system, bulky substituents on the side chain were needed to conformationally induce ring closure. 4d,4h With greater confidence, we planned to prepare macrocyclization precursor 3 from Nazarov cyclization of pyrrolylvinyl ketone 4 ,6 which could in turn be assembled via [3+2] cycloaddition/chelotropic extrusion of the alkynyl ester 5, a sequence discovered by Padwa 7 and investigated further in our laboratory. 8The synthesis began with ozonolytic desymmetrization 9 of cyclohexene followed by Jones oxidation of the intermediate aldehyde to provide carboxylic acid 6 in excellent yield (Scheme 2). Under refluxing conditions in the presence of trifluoroacetic anhydride and carboxylic acid 6, N-tosylpyrrole was acylated selectively at the 2 position. 10 Subsequently, the ketopyrrole formed was reductively deoxygenated under mild conditions using zinc iodide and sodium frontier@chem.rochester.edu.
NIH Public Access Author ManuscriptOrg Lett. Author manuscript; available in PMC 2010 January 1. Vilsmeier-Haack formylation 13 of 9 provided pyrrolylcarboxaldehyde 10 which was subjected to the first step of the Corey-Fuchs transformation 14 to arrive at gem-dibromoalkene 11 (Scheme 3). Reduction of the α,β-unsaturated ester moiety of 11 with DIBAL-H and subsequent silyl protection of the alcohol 12 yields gem-dibromoalkene 13. The rearrangement step of the Corey-Fuchs sequence provided alkyne 14 in good yield. Selective...
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