Enantioselective Total Syntheses and Absolute Configuration of JBIR-02 and Mer-A2026B

Abstract

The first total syntheses of the piericidin related natural products Mer-A2026B and JBIR-02 are reported. Key features of the synthetic approach involve an Ir-catalyzed one-pot C-H activation/oxidation procedure for the preparation of the hydroxypyridine, a vinylogous Mukaiyama aldol reaction, and a final Negishi cross-coupling of an advanced pyridine derivative with an allylic side chain precursor. In addition, the absolute configuration of Mer-A2026B (9R,10R) and JBIR-02 (9R,10R) was established.

The vinylogous Mukaiyama aldol reaction (VMAR) in natural product synthesis

“…80), were synthesized by the group of Gademann. 91 They envisioned to build up the tail fragments of these molecules starting with Kobayashi's method. The rst route for the synthesis of JBIR-02 (267) starting with aldehyde 269 failed and they were not able to obtain any product.…”

The unique chemistry and biology of the piericidins

“…Lipshutz and Amorelli 44 also described a unique strategy for the key disconnection, highlighting a modified Negishi carboalumination/Ni-catalyzed cross-coupling on a polyenyne precursor. Subsequently, Gademann Piericidins from actinomycetes X Zhou and W Fenical and co-workers reported the total syntheses of the piericidin-related natural products Mer-A2026B (22) and JBIR-02 (25). 22 Central to Boger's approach is an inverse electron demand Diels-Alder reaction between an N-sulfonyl-1-aza-1,3-butadiene and tetramethoxyethene followed by Lewis acid promoted aromatization to assemble the functionalized pyridine core.…”

“…Subsequently, Gademann Piericidins from actinomycetes X Zhou and W Fenical and co-workers reported the total syntheses of the piericidin-related natural products Mer-A2026B (22) and JBIR-02 (25). 22 Central to Boger's approach is an inverse electron demand Diels-Alder reaction between an N-sulfonyl-1-aza-1,3-butadiene and tetramethoxyethene followed by Lewis acid promoted aromatization to assemble the functionalized pyridine core. Additional key elements in the convergent approach include the use of an asymmetric anti-aldol reaction to install the relative and absolute stereochemistry at C-9 and C-10, a modified Julia Olefination for formation of the C-5-C-6 trans-double bond with convergent assemblage of the side chain, and a penultimate heterobenzylic Stille cross-coupling reaction of the pyridyl core with the fully elaborated side chain ( Figure 7).…”

“…The structures of the new N-oxides were determined by NMR and highresolution MS analyses and confirmed by zinc powder reduction to yield piericidin B (3) and piericidin B5 (20). 18,19 Other piericidin aglycones that include Mer-A2026 A (21) and B (22), which lack the methoxy group at C-3′ (numbered as C-5′ in the original reference), were isolated from cultures of Streptomyces pactum Me2108. Two new piericidins, IT-143-A (23) and B (24) were isolated from the culture mycelia of Streptomyces sp.…”

“…The absolute configurations of 22 (9R,10R) and 25 (9R,10R) were subsequently established by total synthesis. 22 Piericidin C5 (26), together with piericidins C1 (10), C3 (12), D1 (14) and A3 (5), were isolated from the fermentation broth of a Streptomyces sp., whereas piericidin C6 (27), as well as piericidins C2 (11) and C4 (13) were isolated from the culture of a Nocardioides species. This is the first report of piericidins produced by a microorganism other than members of the genus Streptomyces.…”