Total Synthesis of the Antitumor Antibiotic (±)-Streptonigrin: First- and Second-Generation Routes for de Novo Pyridine Formation Using Ring-Closing Metathesis

Timothy J Donohoe,Luiz C A Barbosa,Louise J Walport,David B Baker,Christopher R Jones,Akshat H Rathi,Matthew R Tatton,Michael O’Hagan,Anne F Kornahrens

doi:10.1021/jo402388f

Timothy J Donohoe, Luiz C A Barbosa + Show 7 more

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https://doi.org/10.1021/jo402388f

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Abstract

The total synthesis of (±)-streptonigrin, a potent tetracyclic aminoquinoline-5,8-dione antitumor antibiotic that reached phase II clinical trials in the 1970s, is described. Two routes to construct a key pentasubstituted pyridine fragment are depicted, both relying on ring-closing metathesis but differing in the substitution and complexity of the precursor to cyclization. Both routes are short and high yielding, with the second-generation approach ultimately furnishing (±)-streptonigrin in 14 linear steps and 11% overall yield from inexpensive ethyl glyoxalate. This synthesis will allow for the design and creation of druglike late-stage natural product analogues to address pharmacological limitations. Furthermore, assessment of a number of chiral ligands in a challenging asymmetric Suzuki–Miyaura cross-coupling reaction has enabled enantioenriched (up to 42% ee) synthetic streptonigrin intermediates to be prepared for the first time.

Highlights

Ever since its isolation from Streptomyces f locculus in 1959 by Rao and Cullen, the chemistry of streptonigrin (1) (Figure 1)has received considerable interest from both the synthetic organic and biochemical communities.[1,2] Rao, Biemann, and Woodward established the structure of the metabolite four years later through a series of elegant spectroscopic and chemical degradation studies, and the connectivity was confirmed in 1975 by Chiu and Lipscomb via X-ray crystallographic analysis.[3,4]The broad-spectrum anticancer activity displayed by streptonigrin has made it extremely attractive for medical application, reaching phase II clinical trials in the late 1970s.5 allied to this activity was an unavoidably high degree of toxicity that caused the cessation of these trials
Streptonigrin has been shown to be a potent and selective protein arginine deiminase (PAD 4) inhibitor.[15]. Another important structural feature of streptonigrin is the configurationally stable C−D ring axis, which accounts for the observed optical activity of the natural product; circular dichroism studies determined the absolute stereochemistry as M.16
The key ring closing metathesis (RCM) step was effected extremely efficiently using Hoveyda−Grubbs second-generation catalyst (3.0 mol % catalyst loading), which afforded dihydropyridone 11 in 97% yield. This reaction has been carried out on a 3.5 g (14.5 mmol) scale, and the catalyst loading can be lowered to 1.0 mol % without a drop in yield, reducing the amount of catalyst resulted in an increase in reaction time

Summary

Introduction

Ever since its isolation from Streptomyces f locculus in 1959 by Rao and Cullen, the chemistry of streptonigrin (1) (Figure 1)has received considerable interest from both the synthetic organic and biochemical communities.[1,2] Rao, Biemann, and Woodward established the structure of the metabolite four years later through a series of elegant spectroscopic and chemical degradation studies, and the connectivity was confirmed in 1975 by Chiu and Lipscomb via X-ray crystallographic analysis.[3,4]The broad-spectrum anticancer activity displayed by streptonigrin has made it extremely attractive for medical application, reaching phase II clinical trials in the late 1970s.5 allied to this activity was an unavoidably high degree of toxicity that caused the cessation of these trials. Subsequent structure−activity investigations involving 1 and a series of truncated analogs, as well as recent genome scanning studies, have led to a proposed biosynthesis and established the cytotoxic mode of action.[6−14] Mechanistically, it is believed that streptonigrin binds irreversibly to DNA in the presence of certain metal cations (e.g., Zn, Cu, Fe, Mn, Cd, Au) and is activated via a one- or two-electron reductase, with NAD(P)H as a cofactor, to form a semiquinone or hydroquinone intermediate Both of these species can react with in situ oxygen, through a Fenton-type reaction catalyzed by the metal, to regenerate streptonigrin and produce hydroxyl radicals that are responsible for DNA strand cleavage. Another important structural feature of streptonigrin is the configurationally stable C−D ring axis, which accounts for the observed optical activity of the natural product; circular dichroism studies determined the absolute stereochemistry as M.16

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Conclusion