1. 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

2. Structure of Plectosphaeroic acid B * * * * * * * 1

3. 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

4. Structures of the family and related metabolites sulfide bridges 3

5. Structures of the family and related metabolites ETP 生物鹼 結構 :diketopiperazine sulfide bridges sulfide bridges 4

6. Past synthesis of (+)-gliocladin C Org.Lett. 2007, 9, 339 –341 Larry E. Overman* Mukaiyama aldol reaction 5

7. Boc-d-tryptophan methyl ester Past synthesis of (+)-gliocladin C Angew. Chem. Int. Ed. 2011, 50, 9655 –9659 Corey R. J. Stephenson* 6

8. Retrosynthetic analysis C-N cross coupling then sulfenylation 7

9. Retrosynthetic analysis 8

10. Synthesis of the derivative 16 of (+)-gliocladin C *reference: J. Am. Chem. Soc. 2011, 133, 6549-6552 9

11. Synthesis of the derivative 16 of (+)-gliocladin C *reference: J. Am. Chem. Soc. 2011, 133, 6549-6552 10

12. Synthesis of intermediates 20 *reference: (a) J. Am. Chem. Soc. 2013, 135, 4117-4128 (b) J. Am. Chem. Soc. 2011, 133, 6549-6552 11

13. Synthesis of Plectosphaeroic acid B Synthesis of epimers 21a,21b Synthesis of epimers 21a,21b 12

14. Synthesis of Plectosphaeroic acid B 13

15. Preparation of Phenoxazinone Iodides 18 and S8 14

16. The critical C−N bond-forming step Key step 15

17. Buchwald-Hartwig copper catalyzed amidation reaction Buchwald-Hartwig 16 Mechanism:

18. The critical C−N bond-forming step 8% yield of 19 0~20% yield of 19 17 Other Cu(I) salts and ligand combinations

19. 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

20. 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

21. 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

22. Synthesis of Plectosphaeroic acid B Synthesis of di(methylthio)ethers 24 Synthesis of di(methylthio)ethers 24 80~90% 21

23. Completion of Synthesis of Plectosphaeroic acid B 22

24. 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

25. 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

26. Thanks for your attention