X HXighlights from the Top Three Chinese Research Labs ! A dramatic rise in the quantity and quality of papers from China In 2000, China ranked 5th (7.9%) in the number of SCI (Science Citation Index) papers on organic synthesis and catalysis. In 2008, China ranked 1st (21.6%), followed by USA (19.2%), Germany (8.5%), and Japan (8.3%). In 2010, papers from Chinese researchers increased to 23.8%. Total scientific research papers - 20,000 papers to 130,000 papers per year (2000 to 2010, respectively) The number of papers from China published in Nature research journals has risen from six in 2000 to 149 in 2010. Similarly, a comparable rise is seen in other high impact journals - Science, Cell, The Lancet, and NEJM - from three papers in 2000 to 27 in 2010. "That China in such a short time has been able to increase the amount of quality science done is truly spectacular." -- Dr. John Richmond, editor of Advanced Synthesis & Catalysis Nature Press Release, Grace Baynes, May 11th, 2011 Zhou, Q. Adv. Synth. Catal. ASAP X X X Delineations, Limitations, and Restrictions ! Geography only research labs located in China, Hong Kong, or Taiwan ! Chemistry only research labs strongly centered in organic chemistry ! Diversity research labs with a varying and diverse set of interests ! Subjectivity this is not comprehensive! X X X C-O Activation via Nickel Catalysis ! Attractive features X lack of toxicity OR [Ni], L + abundance of phenols, carboxylates, heat esters, etc. orthogonal reactivity ! C-O activation is not a new concept MgBr OMe 10 mol% Ni(PPh3)2Cl2 + 71% benzene, reflux, 72 hr Wenkert, E.; Michelotti, E. L.; Swindell, C. S. J. Am. Chem. Soc. 1978, 101, 2246-2247. Roughley, S. D.; Jordan, A. M. J. Med. Chem. ASAP X X X C-O Activation via Nickel Catalysis ! Attractive features X lack of toxicity OR [Ni], L + abundance of phenols, carboxylates, heat esters, etc. orthogonal reactivity ! C-O activation is not a new concept MgBr OMe 10 mol% Ni(PPh3)2Cl2 + benzene, reflux, 72 hr 77% Wenkert, E.; Michelotti, E. L.; Swindell, C. S. J. Am. Chem. Soc. 1978, 101, 2246-2247. Roughley, S. D.; Jordan, A. M. J. Med. Chem. ASAP X X X C-O Activation via Nickel Catalysis ! Direct benzylic alkylation 2 mol % NiCl2(dppf) OMe 2 mol % dppf + MeMgBr Me toluene, RT to 110o C 99% ! Substrate scope Me Et Me Me Me 99% 99% 45% 85% Et Bu 96% 51% 20% 22% Guan, B.; Xiang, S.; Wang, B.; Sun, Z.; Wang, Y.; Zhao, K.; Shi, Z. J. Am. Chem. Soc. 2008, 130, 3268-3269. X X X C-O Activation via Nickel Catalysis 3 2 ! Chemoselective C-O activation of sp and sp ethers OMe 2 mol % NiCl2(dppf) OMe 2 mol % dppf MeO MeMgX Me toluene, rt 99% sp3 activation 5 mol % NiCl2(PCy3)2 5 mol % PCy3 MeMgX or PhMgX toluene, 70o C 74% sp2 activation 7 mol % Ni(acac)2 2 mol % dppf, 10 mol % PCy3 R MeMgX Me toluene, 70o C 93% sp3 activation and sp2 activation R = Me or Ph Stereospecific approach: Taylor, B.; Swift, E.; Waetzig, E. Jarvo, R. J. Am. Chem. Soc. 2011, 133, 389. Guan, B.; Xiang, S.; Wang, B.; Sun, Z.; Wang, Y.; Zhao, K.; Shi, Z. J. Am. Chem. Soc. 2008, 130, 3268. X X X C-O Activation via Nickel Catalysis ! Nickel-catalyzed cross-coupling with aryl Grignard reagents OH [Ni], L + Ph-MgX 120 oC Yu, D.; Li, B.; Zheng, S.; Guan, B.; Wang, B.; Shi, Z. Angew. Chem. Int. Ed. 2010, 49, 4566-4570. X X X C-O Activation via Nickel Catalysis ! Nickel-catalyzed cross-coupling with aryl Grignard reagents 10 mol % NiF OH 2 40 mol % PCy3 + Ph-MgX 120 mol % MeMgBr 200 mol % ArMgBr toluene, 120 oC Me Me NMe2 Me 89% 67% 73% OTBS TMS N 86% 89% 67% Yu, D.; Li, B.; Zheng, S.; Guan, B.; Wang, B.; Shi, Z. Angew. Chem. Int. Ed. 2010, 49, 4566-4570. X X X C-O Activation via Nickel Catalysis ! Nickel-catalyzed cross-coupling with aryl Grignard reagents 10 mol % NiF OH 2 40 mol % PCy3 + Ph-MgX 120 mol % MeMgBr 200 mol % ArMgBr toluene, 120 oC What is the active intermediate in C-O activation chemistry of esters? 106 kcal/mol 80 kcal/mol O O Yu, D.; Li, B.; Zheng, S.; Guan, B.; Wang, B.; Shi, Z. Angew. Chem. Int. Ed. 2010, 49, 4566-4570. X X X C-O Activation via Nickel Catalysis NiF2 + PCy3 ArOH + MeMgBr active catalyst formation Ar R Ni(PCy3)n Ar O Mg 2 S Br phenoxide generation reductive elimination L R Ni O catalytic cycle oxidative addition Ni Ar Mg 2 Ar Ln S Br R-MgX Mg salt Ln Ar Ni O R Mg 2 Mg X Br S transmetalation X X X C-O Activation via Nickel Catalysis ! Biaryl construction via Ni-catalyzed C-O activation of phenolic carboxylates Ar O R 20 mol % Ni(PCy3)2Cl2 B K PO , H O + O O 3 4 2 O B B dioxane, 110 oC Ar O Ar ! Substrate scope MeO HO 73% O 70% 42% Me O O H H H O Me OMe Me 72% 78% 62% Guan, B.; Wang, Y.; Li, B.; Yu, D.; Shi, Z. J. Am. Chem. Soc. 2008, 130, 14468-14470. X X X C-O Activation via Nickel Catalysis 3 2 ! Cross-coupling of sp /sp centers via Fe-catalyzed C-O activation 1 mol % FeCl2 2 mol % N N OPiv Cl- hexyl CO Et CO2Et 2 + nhexylMgX THF, 0 oC, 1 hr 93% ! Substrate scope hexyl hexyl hexyl CO2Et CO2Et 93% 78% 90% O O * O hexyl hexyl hexyl 65% 71% 80% * double bond isomerization, E:Z - 2:1 Li, B.; Xu, L.; Guan, B.; Sun, C.; Wang, B.; Shi, Z. J. Am. Chem. Soc. 2009, 131, 14656-14657. X X X C-O Activation via Iron Catalysis ! Highly reduced iron-magnesium clusters FeCl2 + 4 RMgX [Fe(MgX)2] "...speculated that highly reduced iron-magnesium clusters of the formal composition [Fe(MgX)2]n generated in situ may play a decisive role in the catalytic cycle." alkylBr [Fe(MgX)2] alkyl-Ar oxidative addition reductive elimination catalytic cycle [alkyl-Fe(MgX)] + MgX2 ArMgX Ar alkyl Fe(MgX)2 transmetalation Martin, R.; Furstner, A. Angew. Chem. Int. Ed. 2004, 43, 3955-3957. X X X Transition-Metal Free Biaryl Cross-Coupling ! Organocatalytic method for biaryl construction 40 mol% N N R Y 3.0 equiv. KOt-Bu R Y X + H 110 oC 32 examples ! Substrate scope Me N F MeO NC N MeO Me F 77% 72% 72% 81% N NC Me N Me F Me 65% 52% 26% 70% (8:5:1) Sun, C.; Li, H.; Yu, D.; Yu, M.; Zhou, X.; Lu, X.; Huang, K.; Zheng, S.; Li, B.; Shi, Z. Nature Chemistry 2010, 2, 1044-1049. X X X Transition-Metal Free Biaryl Cross-Coupling ! Control experiments plasma atomic emission spectroscopy (ICP-AES) and inductively coupled plasma mass spectroscopy (ICP- MS) were used to detect 1 ppb-10 ppm of Pd, Cu, Fe, and other metal species in the base and the ligand ! a zero-order dependence in metal catalysts was discovered ! in most cases, metal additives retarded the reaction ! repeated the reactions in new glassware ! other labs retested the reaction for reliability Sun, C.; Li, H.; Yu, D.; Yu, M.; Zhou, X.; Lu, X.; Huang, K.; Zheng, S.; Li, B.; Shi, Z. Nature Chemistry 2010, 2, 1044-1049. X X X Transition-Metal Free Biaryl Cross-Coupling ! Mechanistic insights? Shi - ! TEMPO impedes the reaction ! radical quenching studies seem to indicate a radical intermediate ! Postulated mechanism - Hayashi - Ar I I- + Ar SET N N tBuONa catalytic cycle tBuONa N N aryl radical addition deprotonation SET H H Sun, C.; Li, H.; Yu, D.; Yu, M.; Zhou, X.; Lu, X.; Huang, K.; Zheng, S.; Li, B.; Shi, Z. Nature Chemistry 2010, 2, 1044-1049. X X X Transition-Metal Free Biaryl Cross-Coupling ! Postulated mechanism - Curran ! Hayashi's mechanisms involves the interaction of two transient, radical intermediates. ! Initial reduction is very endothermic, can be viewed more attractively as an initiation step. radical addition H + deprotonation H K+ + KOtBu + HOtBu I electron transfer + + KI propagation Studer, A.; Curran, D. P. Angew. Chem. Int. Ed. 2011, 50, 2-7. X X X Complex Depsipeptide Synthesis Me ! Depsipeptides have a range of valuable Me biological properties Me cytotoxic, anti-HIV, anti-inflammatory, OH O OH H anti-fungal, anti-tumor N papuamide B N Me H HO Me O HN O Ma's recent depsipeptide syntheses: H2N O Me O Microsclerodermin E - Zhu, J.; Ma, D. Angew. Chem. Me HN Int. Ed. 2003, 42, 5348-5351. NH2 Halipeptin A - Yu, S.; Pan, X.; Lin, X.; Ma, D. Angew. Chem. Me Int. Ed. 2005, 44, 135-138. HN O O O Papuamide B - Xie, W.; Ding, D.; Zi, W.; Li, G.; Ma, D. Angew. N OMe Chem. Int. Ed. 2008, 47, 2844-2848. NH iPr O MeO O Salinamide A - Tan, L.; Ma, D. Angew. Chem. Int. Ed. 2008, O NH 47, 3614-3617. O NH O OH H Piperazimycin A - Li, W.; Gan, J.; Ma, D. Angew. Chem. Int. N Me Ed. 2009, 48, 8891-8895. N H O Me OH X X X Total Synthesis of (-)-Englerin A ! Englerin A O Me ! (-)-Englerin A is a guaiane sesquiterpene that was isolated from Ph Me Phyllanthus engleri, a plant growing in East Africa O ! has the ability to inhibit renal cancer cells well and selectively 9 H O O (GI50 = 1 - 87 nM) Me ! the activity of englerin A is highly dependent on the substitution O OH at the C9 position H ! Retrosynthesis O Me Me Me Ph Me O O H O O OR Me Me O OH Me H H gold-catalyzed cyclization Me OR O Me Me Me Simultaneous publication of Englerin A - Molawi, K.; Delpont, N.; Echavarren, A.