Short Lit. 5/16/2011. John M. Roberts

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1 Short Lit. 5/16/2011 Masahiko Seki Highly Efficient Catalytic System for C H Activation: A Practical Approach to Angiotensin II Receptor Blockers ACS Catal., 2011, 1, Xin Jia, Yi Xu, and Zhi Li Regio- and Stereoselective Concurrent xidations with Whole Cell Biocatalyst: Simple and Green Syntheses of Enantiopure 1,2-Diols via xidative Kinetic Resolution ACS Catal., 2011, 1, John M. Roberts

2 ACS Catalysis Editor In Chief ewest ACS Journal Dedicated to heterogeneous, homogeneous, and bio-catalysis Will feature experimental and theoretical work Publishes Letters, Articles, Reviews, Perspectives, and Viewpoints Christopher W. Jones Professor and Pirkle Fellow, School of Chemical & Biomolecular Engineering School of Chemistry and Biochemistry Georgia Institute of Technology The journal seeks to acquire content in the areas of new reactions and new approaches to synthesis involving known catalysts, discovery of or modification of new catalysts, novel mechanistic and investigatory studies on catalysis, practical enhancements of known processes, and conceptual advances.

3 ACS Catalysis--Editors Associate Editors: T. Brent Gunnoe Huimin Zhao ther Editors of note: Wenbin Lin Shengming Ma Scott Miller lanie Sanford Matthew Sigman

4 Masahiko Seki Highly Efficient Catalytic System for C H Activation: A Practical Approach to Angiotensin II Receptor Blockers ACS Catal., 2011, 1,

5 API Corporation Seemingly a consolidation of Mitsubishi Chemical Corporation and the fine chemicals division of Yoshitomi Pharmaceuticals Specializes in Azidation, Asymmetric synthesis, Cyanation, xidation, Reduction, Resolution, rganometallic reaction, Cryogenic reactions ( 80 C on 5000L scale, dedicated tank for nbuli!!), bio-catalyzed asymmetric reduction C H Activation Pros and Cons Pros: Direct functionalization Better atom economy Catalytic, no stoiciometric transition metals (sometimes) Cons: Requires directing groups High catalyst loading ften requires stoiciometric oxidants Can over functionalize

6 Angiotensin II Receptor Blockers (ARBs) Cl C 2 H K H Losartan Potassium Valsartan High blood pressure and congestive heart failure medication US sales of Valsartan = $6.0 Billion Previous process routes towards ARBs require organometallics such as Grignards and boronic acids to generate the biphenyl triazole Cl H PhCCl, Et 3 CPh 3 1. BuLi 2. B(-iPr) 3 3. Acid CPh 3 B() 2 + Cl Br Pd(Ac) 2, PPh 3 K Larsen, R. D.; King, A..; Chen, C. Y.; Corley, E. G.; Foster, B. S.; Roberts, F. E.; Yang, C.; Lieberman, D. R.; Reamer, R. A.; Tschaen, D. M.; Verhoeven, T. R.; Reider, P. J.; Lo, Y. S.; Rossano, L. T.; Brookes, S.; loni, D.; Moore, J. R.; Arnett, J. F. J. rg. Chem. 1994, 59, 6391

7 Synthesis Plan and Catalyst ptimization Retrosynthetic Analysis: R H Alkylation and Deprotection X PG C H Activation and displacement PG + Br Ac Catalyst ptimization: PG + Br Ac Ru cat., Ligand K 2 C 3, MP, 140 C 12 h Ac PG Ru Cat. Ligand PG % Yield [RuCl2(Benzene)]2, 10 mol % PPh3, 20 mol % PMB 48 [RuCl2(CD)]n, 10 mol% PPh3, 20 mol % PMB 63 RuCl3 xh2, 1.3 mol% PPh3, 1.3 mol % MB 65 RuCl3 xh2, 1.3 mol% PPh3, 2.34 mol % MB 81

8 Catalyst ptimization Part 2 ptimized Conditions: MB + Br Ac RuCl3 xh 2 (1.3 mol %) PPh 3 (2.34 mol %) K 2 C 3, MP, 140 C 12 h Ac MB 81% A literature report inspired these conditions; unstable catalysts are expected to provide higher rate accelertion (decreasing the activation energy by increasing the ground state energy) Triphenylphosphine is important; too little (0 mol%) or too much (4 mol %) results in poor conversion Large protecting groups also result in poor conversion Water plays a crucial role: anhydrous RuCl3 nor anhydrous RuCl3 and an equal amount of water resulted in good conversion Triphenylphosphine was the best (and cheapest!) phosphine ligand rder of addition matters, pre-forming the catalyst results in lower conversion This catalyst loading is the lowest reported so far for o-arylation! Wassenaar, J.; Jansen, E.; van Zeist, W.-J.; Bickelhaupt, F. M.; Siegler, M. A.; Spek, A. L.; Reek, J.. H. ature Chem. 2010, 2, 417

9 Catalytic Cycle and Completion of Synthesis Catalytic Cycle: Ac MB Ar Br Ru II BM Ar Ru IV Br Ru IV Ar MB HBr BM Ru IV Br H Ar The active catalyst most likely has one triphenylphosphine ligand, as 0.5 equiv. is needed to reduce Ru III to Ru II Completion of Synthesis: Ac MB a MB 1. TMSBr L-ValBn pts C 2 H H 2. nbucocl, py 3. HC 2 H 4, Pd/C 90% 76% xidized egg shell Pd/C was crucial to the successful deprotection of the MB group and benzyl ester (egg shell = Pd close to surface--50 to 1050 nm vs. thick shell--250 to 500 nm from surface)

10 Summary A novel C H activation reaction has been developed specifically for the manufacture of a pharmaceutical The reaction uses low catalyst loadings and inexpensive reagents Higher activity of an unstable catalysts is invoked to explain enhanced reactivity Takes advantage of imbedded directing group in molecule

11 Xin Jia, Yi Xu, and Zhi Li Regio- and Stereoselective Concurrent xidations with Whole Cell Biocatalyst: Simple and Green Syntheses of Enantiopure 1,2-Diols via xidative Kinetic Resolution ACS Catal., 2011, 1,

12 Prof. Zhi Li BSc anjing University (1982) MEng Chinese Academy of Forestry, anjing (1984) Ph. D. University of Vienna (1991) Associate Professor at ational University of Singapore Research Interests: ew Biocatalysts for enantioselective transformations, tandem biocatalysis, recyclable magnetic nanobiocatalysts for green oxidaitons

13 Enantiopure Vicinal Diols Cl H 2 Vistide P Cl Eliprodil F 3,4 dihydro isocoumarins H Cl (+)-PS R-568 Enantiopure vicinal diols are important synthetic building blocks tal catalyzed approaches: Sharpless asymmetric dihydroxylation, asymmetric hydrogenation of hydroxy ketones, enantioselective hydrolysis of epoxides Enzymatic catalysis has not been effective; dihydroxylation of styrene with dioxygenase, reduction of hydroxy ketones with bakerʼs yeast, lipase catalyzed resolutions, and epoxide hydrolase catalyzed hydrolysis of racemic epoxides all give poor yield and/or ee The authors wondered if an oxidative kinetic resolution with whole cells would be possible

14 Cell Screening and Reaction chanism Authors screened 70 microorganisms that can grow on n-octane for oxidative resolution Strains degrading n-octane often contain oxygenase and other oxidative enzymes HX-200 (which contains monooxygenase and epoxide hydrolase activity) preformed the reaction Sphinogomonas sp. HX 200 Tris buffer, 25 C + C 2 H Proposed Reaction chanism: Time Course xidative Resolution nly 1, 5 and 6 were detected by LC MS = 6 = 5 = (S) 1 = (R) 1

15 ptimization and Substrate Scope R Sphinogomonas sp. HX 200 Tris buffer, 25 C R + R * R = C 2 H 1 3 Cl 2 4 Substrate conc. (mm) cells (g/l) activity (U/g cdw) time (h) % yield % ee Substituients at the para position increased activity of HX 200, but there was no discriminating between groups

16 ptimization and Substrate Scope Substrates 2 4 give the R enantiomer diol, time course plots show the S enantiomer reacts much faster R Sphinogomonas sp. HX 200 Tris buffer, 25 C R + R * R = C 2 H 1 3 Cl 2 4 = 2 = 3 = 4 This novel process gives the best results so far for bio-resolution of 1,2 diols

17 Summary xidative kinetic resolution gives access to useful 1,2 diols Screening of whole cells instead of enzymes led to the discovery HX 200 preforms the reaction well Higher concentrations increase yield but slightly decrease ee Using whole cells is much cheaper than using enzymes, and cell systems could be engineered to possess multiple oxidative enzymes for more efficient transformations The Heat are going up in flames!!!