Dehydrogenative Coupling to Enable the Enantioselective Total Synthesis of (−)‐Simaomicin α

Abstract

Simaomicin a (1) is a polycyclic xanthone natural product with remarkable biological properties. It was isolated by scientists from American Cyanamid Company from the culture broth of an actinomycete, and its structure and relative stereochemistry were established by NMR spectroscopy and X-ray crystallography. [1] Simaomicin a originally garnered attention for its ability to prevent coccidiosis infection in chickens that were fed meal containing 1 mg drug/kg feed. The isolation group noted that it was "the most potent natural-occurring anticoccidial agent reported". [2] Fifteen years after its structure and anti-parasitic activity was reported, Tomoda and co-workers revealed that simaomicin a had little effect on Jurkat cells as a single agent at low concentration (0.6 nm), but that it synergized with the DNAdamaging agent bleomycin. Thus, while bleomycin caused G2-arrest, the combination of bleomycin and simaomicin a was cytotoxic against this T-lymphocyte cell line. Provocatively, even much higher concentrations of simaomicin a (500 nm) had little effect on a normal HUVEC cell line. The molecular underpinnings for these effects are unknown, but the checkpoint regulators Chk1, Chk2, ATM, ATR, and Wee1 are not inhibited. [3] The natural product was found to suppress phosphorylation of retinoblastoma protein, [4] but a molecular target has not been identified. The therapeutic implication of these observations is that co-administration of a DNAdamaging agent with a cell-cycle inhibitor could be more efficacious than treatment with a single agent.Given the potent biological activity and unique structure of simaomicin a, we targeted it for total synthesis. [5] Our work builds on the discoveries from the Kelly group, which reported the first synthesis of a polycyclic xanthone natural product, cervinomycin A 2 . [6] Subsequently the Suzuki group disclosed a synthesis of the FD-594 aglycon, [7] and Porco and co-workers [8] and our group [9] independently synthesized kibdelone C (Scheme 1, top). The latter studies were the first to target members of this class that feature a tetrahydroxanthone ring system with its attendant stereogenic centers. In all of these syntheses, formation of the B-D biaryl bond was a critical synthetic step that allowed assembly of the polycyclic ring system from simpler precursors. Early approaches relied on low-yielding photocyclizations of a diaryl olefin, while more recent work has focused on transition metal-promoted couplings. For example, Pd-mediated couplings of an aryl iodide with an aryl CÀH bond was successful for both kibdelone C [9] and FD-594 aglycon, [7] whereas the Porco synthesis introduced a novel Pt-catalyzed addition of a phenol to a quinone monoacetal. [8] Herein we present an advance in the synthesis of polycyclic xanthone natural products that involves a Pd-mediated direct dehydrogenative coupling of two unfunctionalized aryl rings to forge the key B-D biaryl linkage. This transformation enabled the enantioselective synthesis of simaomicin a and the assignment of its absol...