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Enantioselective Total Synthesis of Plectosphaeroic acid B J. Am. Chem. Soc. 2013, 133, 6549−6552 Salman Y. Jabri and Larry E. Overman* Speaker: 古宜加
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Structure of Plectosphaeroic acid B * * * * * * * 1
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Introduction Isolation In 2009, Mauk, Andersen, and co-workers reported the isolation of plectosphaeroic acids A−C (1−3) from cultured extracts of the fungus Plectosphaerella cucumerina collected. Biological activity They were equipotent (IC50 = 2 μM) against indoleamine 2,3-dioxygenase (IDO) Antimicrobial, antiviral, antifungal, immunosuppressive, and anticancer activities. Indoleamine 2,3-dioxygenase (IDO) 2
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Structures of the family and related metabolites sulfide bridges 3
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Structures of the family and related metabolites ETP 生物鹼 結構 :diketopiperazine sulfide bridges sulfide bridges 4
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Past synthesis of (+)-gliocladin C Org.Lett. 2007, 9, 339 –341 Larry E. Overman* Mukaiyama aldol reaction 5
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Boc-d-tryptophan methyl ester Past synthesis of (+)-gliocladin C Angew. Chem. Int. Ed. 2011, 50, 9655 –9659 Corey R. J. Stephenson* 6
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Retrosynthetic analysis C-N cross coupling then sulfenylation 7
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Retrosynthetic analysis 8
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Synthesis of the derivative 16 of (+)-gliocladin C *reference: J. Am. Chem. Soc. 2011, 133, 6549-6552 9
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Synthesis of the derivative 16 of (+)-gliocladin C *reference: J. Am. Chem. Soc. 2011, 133, 6549-6552 10
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Synthesis of intermediates 20 *reference: (a) J. Am. Chem. Soc. 2013, 135, 4117-4128 (b) J. Am. Chem. Soc. 2011, 133, 6549-6552 11
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Synthesis of Plectosphaeroic acid B Synthesis of epimers 21a,21b Synthesis of epimers 21a,21b 12
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Synthesis of Plectosphaeroic acid B 13
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Preparation of Phenoxazinone Iodides 18 and S8 14
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The critical C−N bond-forming step Key step 15
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Buchwald-Hartwig copper catalyzed amidation reaction Buchwald-Hartwig 16 Mechanism:
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The critical C−N bond-forming step 8% yield of 19 0~20% yield of 19 17 Other Cu(I) salts and ligand combinations
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Synthesis of Plectosphaeroic acid B Synthesis of C−N cross-coupling reaction 22a Synthesis of C−N cross-coupling reaction 22a 10−30% yields 18
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Synthesis of Plectosphaeroic acid B Synthesis of C−N cross-coupling reaction 22a, 22b Synthesis of C−N cross-coupling reaction 22a, 22b 50~58% yield 19
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Synthesis of Plectosphaeroic acid B Synthesis of di(methylthio)ethers 24 Synthesis of di(methylthio)ethers 24 79~92%, 1.3: 1.0 dr 20
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Synthesis of Plectosphaeroic acid B Synthesis of di(methylthio)ethers 24 Synthesis of di(methylthio)ethers 24 80~90% 21
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Completion of Synthesis of Plectosphaeroic acid B 22
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Conclusion The first total synthesis of (+)-plectosphaeroic acid B. Seven steps from the known intermediates 20a and 20b, 9.4% overall yield. The key step: 1.C−N cross-coupling 2. Stereoselective introduction of the two methylthio substituents. The optical rotation of synthetic 2, [α] D 23 +228 (c 0.08, MeOH), was considerably higher than the value reported for the natural sample, [α] D 23 +69.8 (c 0.27, MeOH). 23
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JournalNatural products stepsyieldKey step Org.Lett. 2007, 9, 339 –341 Larry E. Overman* (+)-Gliocladin C 21~4% Mukaiyama aldol reaction Angew. Chem. Int. Ed. 2011, 50, 9655 –9659 Corey R. J. Stephenson* (+)-Gliocladin C 1030% Ru(II) & blue LEDs J. Am. Chem. Soc. 2011, 133, 6549-6552 Larry E. Overman* (+)-Gliocladin C (+)-gliocladine C 10 6 11% 29% Fu’s catalyst AD-Mix- oxidant J. Am. Chem. Soc. 2013, 133, 6549−6552 Larry E. Overman * (+)-plectosphaeroic acid B 79.4% C−N cross-coupling Summary 24
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