Synthesis of (-)-viriditoxin: a 6,6'-binaphthopyran-2-one that targets the bacterial cell division protein FtsZ.
Synthesis of (-)-viriditoxin: a 6,6'-binaphthopyran-2-one that targets the bacterial cell division protein FtsZ.
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DOI：
10.1002/anie.201007298
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发表时间：
2011-04-11
影响因子：
16.6
通讯作者：
Shaw, Jared T.
中科院分区：
文献类型：
--
作者：
Park, Young Sam;Grove, Charles I.;Gonzalez-Lopez, Marcos;Urgaonkar, Sameer;Fettinger, James C.;Shaw, Jared T.
The inhibition of bacterial cell division offers a new approach to controlling resistant bacterial infections.[1, 2] FtsZ is a protein of central importance to cell division that is often described as the prokaryotic homolog of tubulin because of the structural similarity of these two proteins, in spite of low sequence homology.[3–5] Both proteins undergo GTP-driven oligomerization and the active sites of both proteins are similar. Tubulin forms microtubules in the bipolar spindle assembly, which mediates chromosome separation in eukaryotes. FtsZ oligomerizes at midcell during bacterial cell division to form the Z-ring, which constricts to induce septation. Inhibition of FtsZ has been validated as a potential new therapeutic strategy for fighting resistant infections, including methicillin-resistant Staphylococcus aureus (MRSA).[6–8] In stark contrast to tubulin, few FtsZ-targeting natural products are known and no information regarding the molecular basis of their inhibition of FtsZ has been documented.[9–12] The development of efficient syntheses for FtsZ-targeting natural products will enable elucidation of their mechanisms of inhibition and enable further development of this target. Here, we describe the synthesis of viriditoxin, one the most potent FtsZ-targeting natural products and the first 6, 6’-binaphthopyranone to be synthesized.[13] Viriditoxin was discovered as an FtsZ inhibitor by researchers at Merck in a high-throughput biochemical screen.[14] The 6, 6’-binaphthopyranone structure, previously isolated from Aspergillus viridinutans (Scheme 1) was originally misassigned as having 8–8’linkage like that of vioxanthin (6a, Scheme 1).[15–17] 6, 6’-Binaphthopyran-2-ones are uncommon natural products and so far only four others have been reported.[18–20] A small number of the biosynthetically related binaphthopyran-4-ones, such as cephalochromin (6b, Scheme 1), have also been reported.[21–25] Although the absolute configuration at C3 of semiviriditoxin was recently confirmed by synthesis,[26] the axial configuration of viriditoxin was not known unequivocally at the outset of our studies.The key bond construction in viriditoxin is the stereoselective formation of the 6–6’biaryl linkage. Strategies for achieving atropselectivity in the construction of complex molecules have been recently reviewed.[27, 28] Subsequent recent examples for asymmetric biaryl construction often employ auxillary-and catalyst-controlled oxidative homocoupling [29–31] and cross-coupling reactions.[32–35] In two complementary approaches, atropselectivity can also be realized by the asymmetric de novo assembly of aromatic rings in cycloadditions [36–41] and by dynamic kinetic resolution polycyclic lactones through aminolysis [42] or reduction.[43] Most of these strategies rely on either the influence of chiral catalysts
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