Formal Synthesis of (±)-Roseophilin

Abstract

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...

Catalytic Nazarov Cyclization: The State of the Art

“…Later, it was revealed that these 2-substituted furyl and benzofuryl Nazarov precursors undergo a fundamentally different reaction that involves a 1,2-hydride migration and Friedel-Crafts alkylation catalyzed by tricationic iridium(III). [13] The Nazarov cyclization of dienones containing N, O, or S heterocyclic moieties (198) was described by Occhiato and coworkers to occur most efficiently with metal triflates such as Sc(OTf) 3 or In(OTf) 3 (3-15 mol %; Scheme 39). [13] The Nazarov cyclization of dienones containing N, O, or S heterocyclic moieties (198) was described by Occhiato and coworkers to occur most efficiently with metal triflates such as Sc(OTf) 3 or In(OTf) 3 (3-15 mol %; Scheme 39).…”

“…[115] In 2009, Frontier and Bitar reported the formal synthesis of a potent cytotoxic agent, roseophilin (197), that utilizes the Sc(OTf) 3 /LiClO 4 method for the key step, a Nazarov cyclization of a 2,5-disubstituted N-tosylpyrrole intermediate (195) to give 196 in 65 % yield (Scheme 38). [13] The Nazarov cyclization of dienones containing N, O, or S heterocyclic moieties (198) was described by Occhiato and coworkers to occur most efficiently with metal triflates such as Sc(OTf) 3 or In(OTf) 3 (3-15 mol %; Scheme 39). [116,117] Copper(II) triflate had comparable activity for N-heterocyclic substrates.…”

“…[2] This transformation has received tremendous attention in the field of organic synthesis due to its ability to form synthetically versatile cyclopentenones. [3][4][5][6][7][8][9][10][11][12][13][14][15] With appropriately substituted dienones, the orbital reorganization implants new stereocenters in the oxyallyl cation (3), which are retained in the pentacyclic product (5).…”

Understanding the Fate of the Oxyallyl Cation following Nazarov Electrocyclization: Sequential Wagner−Meerwein Migrations and the Synthesis of Spirocyclic Cyclopentenones

“…1 In electronic polarization of the Nazarov substrate, one of the vinyl groups is made electrophilic and the other nucleophilic ( A in Scheme 1) so that the reaction proceeds more readily and under catalytic conditions with mild Lewis acids such as Cu(OTf) 2 3 Furthermore, the charge asymmetry that is produced in oxyallyl cation B by the electron-donating and -withdrawing groups results in regioselective elimination. Recent studies describe the use of Cu(II), 3,4 Pd(II), 5 Sc(III), 6 Ir(III), 7 V(IV), 8 Ni(II), 9 Au(I), 10 Fe(II) 11 or Co(I) 11 complexes in sub-stoichiometric amounts for catalysis of the Nazarov cyclization, including several chiral complexes furnishing cyclopentenones with modest to high enantiometric excesses. Several methodologies based on organocatalysis have also emerged to deliver Nazarov products with good enantioselectivity.…”

4‐Isoxazolines: Scaffolds for Organic Synthesis

“…The pyrrolyl vinyl ketone 160 (Scheme 37), prepared by oxidation of the 4-isoxazoline 159, underwent Nazarov cyclization to give the 5,5Ј-fused keto pyrrole 161. π-Allyl palladium macrocyclization afforded 162, which can be converted into the target molecule. [66] The proline-derived bicyclic 4-isoxazolines 163 (Scheme 38), each bearing a carboxylic substituent at C-3, afford the acyclic nitrosoalkyl-substituted α,β-unsaturated ketones 165 upon treatment with mCPBA. [67] Reduction of 4-isoxazoles can lead to β-amino ketones or β-amino alcohols.…”