1. Practical Asymmetric Catalytic Hydrogenation Examples of Green Chemistry Professor Xumu Zhang Rutgers University xumu@rutgers.edu

2. B.S. Wuhan University 1978-1982 M.S. Chinese Academy of Sciences 1982-1985, Under Professor Jixi Lu (former president of Chinese Academy of Sciences, Former Postdoctoral Fellow of Professor Linus Pauling) Ph. D. Stanford University. 1987-1992, under Professor James P. Collman （ former postdoctoral advisor of Barry Sharpless and Bob Grubbs ） Sabbatical, 1999-2000 in Professor Grubbs, Sharpless and Nicolau’s Lab Professor of Chemistry, Penn State Univ. 1994-2006. Distinguished Professor of Chemistry, Rutgers University, 2007-  Xumu Zhang has received the 2002 ACS Arthur C. Cope Scholar Award ， as the first person from mainland China.  Name reaction: Zhang Enyne Cycloisomerization, in a Name reaction book  Published >220 papers in Science; J. Am. Chem. Soc.; Angew. Chem. >50 Patents  Citation >10000, H index > 61 。

3. Acknowledgement Postdoc fellows: Dr. Guoxin Zhu Dr. Zhaoguo Zhang Dr. Yonggui Zhou Dr. Aiwen Lei Dr. Chunjiang Wang Dr. Guohua Hou Dr. Jian Liao Dr. Shichao Yu Visiting scholars: Dr. Le Zhou Dr. Qin Yang Dr. Jian Chen Dr. Huiling Geng Dr. Zhenghui Guan Dr. Farong Guo Mr. Tanglin Liu Financial support: NIH, NSF Merck and Dow Chiral Quest Wuhan University Graduate students: Dr. Wenjun Tang (TangPhos) Dr. Duan Liu (DuanPhos) Dr. Yongjun Yan (YanPhos) Dr. Qian Dai Dr. Xianfeng Sun Dr. Gao Shang Dr. Weicheng Zhang Dr. Wei Li Dr. Xiaowei Zhang (ZhangPhos) Mr. Kexuan Huang Mr. Bonan Cao Ms. Tian Sun Mr. Mingxin Chang Ms. Xin Zheng Mr. Shaodong Liu Mr. Shengkun Li Mr. Jialin Wen Graduate students in WHU Ms. Qingli Wang Mr. Caiyou Chen Mr. Xuefeng Tan Mr. Ming Zhou Mr. Hailong Yang Ms. Ming Gao Mr. Biao Wei Mr. Weilong Wu Mr. Jianjian Ji Mr. Jun Jiang Mr. Jianfei Yu Mr. Zhichao Xiong Mr. Cai You Ms. Xiuxiu Li Ms. Ningning Huo Mr. Pan Li Mr. Liyang Shi Mr. Fangyuan Wang Dr. JingJing Meng Associated Professor Hui Lv Xiuqin Dong

4. Catalysis: A Key Technology for the 21th Century Photo -Catalysis Homogeneous Catalysis Bio -Catalysis Heterogeneous Catalysis Electro -Catalysis C ATALYSIS Key Technology 3 Food Health OilRefinery PolymerSynthesis BasicChemicals EnvironmentalTechnology Energy MolecularBiology NewMaterials FineChemicals

5. Asymmetric Catalysis (45 year history) ： Nobel Prize in 2001 From Lab to Industry (1984) L-Menthol, 2000 t/y

6. 6 Asymmetric Catalysis and Green Chemistry electivityffeciency Basic Chemistry Understanding Mechanism Found out key control Factors For activity and selectivity Developing New Ligands and catalysts Key Issues No Universal Ligands, Ligand Diversity, Electronic and Steric Factors Some Catalysts are not practical (e.g. TON = 100-1000) Increasing Turnovers (e.g. TON = 10000,100,000 to 1,000,000)

7. Very Few Asymmetric Catalytic Hydrogenations Have Been Applied in Industry Statistics for the industrial application of enantioselective catalytic reactions Transformation Production Pilot Bench scale >5 t/y 50 k <50 kg Hydrogenation of enamides 1 1 2 64 Hydrogenation of C=C-COOR 1 0 3 46 and C=C-CH-OH Hydrogenation of other C=C 1 0 1 22 Hydrogenation of α - and 2 2 3 64 β -functionalized C=O Hydrogenation/reduction 0 0 0 14 of other C=O Hydrogenation of C=N 1 0 1 00 Dihydroxylation of C=C 0 1 0 04 Epoxidation of C=C and 2 1 2 02 oxidation of sulfide Isomerization etc. 2 0 3 01 M. Thommen, H.-U. Blaser in Phosphorus Ligands in Asymmetric Catalysis, ed. A. Börner, Wiley-VCH, 2008

8. Despite the importance, yet only few active academic groups are working in asymmetric hydrogenation area in US during the last 40 years. Top Research groups: Ryoji Noyori, Andreas Pfaltz, Johannes De Vries, Jean Pierre Genet, Felix Spinder, Ben Feringa, Mark Burk, etc.

9. Processes of Asymmetric Hydrogenation in Industry Asymmetric catalytic hydrogenation is the most popular chiral technology, 70% asymmetric processes used in industry are asymmetric hydrogenation Takasago Process for 4AA (intermediate for antibiotic carbapenems) Syngenta Process of (S)-Metolachlor

10. Asymmetric Catalytic Hydrogenations Used by Chiral Quest Inc. Statistics for the industrial application of enantioselective catalytic reactions Transformation Production Pilot >5 t/y 50 k Hydrogenation of enamides 3 3 10 Hydrogenation of C=C-COOR 0 0 0 Hydrogenation of other C=C 0 0 0 Hydrogenation of α - and 1 1 5 β -functionalized C=O Hydrogenation/reduction 1 1 0 of other C=O Hydrogenation of C=N 0 0 1 Dihydroxylation of C=C 0 0 0 Epoxidation of C=C and 0 0 0 oxidation of sulfide Total Chiral Quest 5 5 16 Chiral Quest, > 5 Commercial Products, > 5 Phase III, > 20 Phase II

11. Dr. James Wu, CEO, Dr. Ian Lennon, SVP of Business ， Professor Xumu Zhang, Founder of Chiral Quest

12. Chiral Quest Suzhou – Headquarter Headquarters – Chiral Quest has its HQ on the Suzhou Industrial Park – The new R&D center and HQ houses 40 employees – Business offices in Princeton US, Cambridge UK, India –Chiral Quest employs 14 PhD and 23 MS level chemists –Chiral Quest was founded in 2000 by Xumu Zhang at Penn State University with one Postdoctoral fellow and now has a total of 220 employees

13. Chiral Quest’s Commercial Manufacturing Facility  This new facility is located in Jiangxi Province, P.R. China.  Chiral Quest’s faculty has >180 employees

15. 15 Making Impacts, providing intermediates to global pharmaceutical and generic companies Pre-Clinical Exclusive Synthesis to Global Pharmaceutical Companies Phase IPhase IIPhase IIILaunch Generic Intermediate & API Generic Development Paragraph IV Stage 1 Stage 2 Stage 2: Generic Intermediate and API –With significant pricing advantage, focus on generic opportunities for drugs that will come off patent within the next 2-3 years –Given unique technology and assets, manufacturing capacity On-patent Off-patent Generic Market  Stage 1: Exclusive Synthesis Strategic Intermediate  Provide stable and consistent revenue through immediate exclusive synthesis opportunities  Grow along with drugs as they move through development, focusing on larger Phase III and launched drug opportunities  Sell Catalysts to major pharma 5 > 5 commercial processes 20 >100 Chiral Quest (>200 People, R&D to Manufacturing): Making Kg to 10’s tons of chiral pharmaceutical Intermediates through advanced chiral technology such as asymmetric hydrogenation

16. Homogeneous Asymmetric Hydrogenations Offer Access to a Wide Variety of Chiral Products or APIs (2011 sale) C=N C=C C=O H2H2 Duloxetine 4748.6M 82,094 kg 3 Sitagliptin 5280.7M, 199,479kg

17. Important industrial processes – Hydrogenation – Hydroformylation – Polymerization – C-C bond formation – Epoxidation and more Remarkable Features – Mild reaction conditions – High activity & stereoselectivity – Atomic economy – Cost efficiency – Operational simplicity Development of New Ligands is the Key, Especially Phoshine Ligands Goal: Efficient routes for the synthesis of clinical, launched, generic pharmaceutical compounds and commodity chemical products A powerful strategy leading to important Chemicals catalytic system

18. Research Strategies in Catalytic Asymmetric Reactions - 2

19. Important strategies for ligand development Increase conformational rigidity Create new ligand motifs Build ligands from readily available materials Fine-tuning the conformational, steric, and electronic properties of ligands

20. Historic View: Important Ligands for Asymmetric Hydrogenation Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029. Shang, G.; Li, W.; Zhang, X. in Catalytic Asymmetric Synthesis, 3 rd Ed; Ojima, I. Ed.; Wiley: Hoboken, 2010. 0

21. Ligand ‘Toolbox’ Developed by Zhang Group Zhang, W.; Chi, Y; Zhang, X. Acc. Chem. Res. 2007, 40, 1278. Li, W.; Hou, G.; Sun, X.; Shang, G.; Zhang, W. Zhang, X. Pure Appl. Chem. 2010, 82, 1429. 0 2

22. Five commercial chiral catalysts (Available from ChiralQuest, Strem, Aldrich)

24. Large Scale Processes (10’s tons)

25. Large Scale of Asymmetric Hydrogenation in China Hydrogenation reactors with high pressure capability (100 L to 1000 L)  2 x 1000 L and 1 x 500 L stainless steel hydrogenation reactors (100 atm)  1 x 1000 L and 1 x 100 L glass lined hydrogenation reactor (10 atm)  2 x 2000 L, 2 x 1000 L and 1 x 500 L stainless steel reactors  Our own proprietary catalysts

26. New generation of asymmetric hydrogenation catalysts High Activity: – High Substrate / Catalyst Ratio (S/C >10,000) High Selectivity: > 99% ee Low Pressure: < 150 psi Broad Substrate applicability Resistant to Substrate impurities (Robust) Practical Ligand Synthesis (both enantiomers) Use Friendly Model by Customers From PPh 3 to P t Bu 3, Buchwald and Fu

27. 1970’s-1980’s First Generation – BINAP (triaryl phosphine) is not efficient for Rh-catalyzed hydrogenation – Ru-BINAP chemistry 1990’s Second Generation – DuPhos (dialkyl phosphine) – Rh chemistry 2000’s Third Generation – Trialkyl phosphine bearing at least one tert-butyl group – TangPhos, BINAPINE, DuanPhos, Trichickenfootphos – Highly electron-donating – Highly enantioselective and active catalysts New Generation of Ligands

28. Electron-donating Rigid Bisphosphines Accelerating oxidative addition of hydrogen Strong trans effect, reducing substrate and product inhibition and thus increase turnovers and turnover Frequency Conformational rigidity provides super high enantioselectivity 28

29. Previous P-Chiral bisphosphines

30. Increase conformational rigidity with a ring structure

31. Enantioselective step in Rh-catalyzed hydrogenation (7 Kcal/mol; 99.999%ee ?!) For a related ligand system, see Imamoto, T. etc. J. Am. Chem. Soc. 2000, 122, 7183 “6.9 Kcal/mol difference in energy, R/S = 100000 : 1 = 99.999% ee, perfect”

32. Highly enantioselective hydrogenation of dehydroamino acids

33. Manufacture of (R)-N-Boc-3,5-Difluorophenylalanine (100 kgs made) Erlenmeyer chemistry is scaleable, cost effective and provides pure substrates, suitable for asymmetric hydrogenation Conditions for the Rh-DuanPhos hydrogenation are mild and scaleable Chiral Quest has made many protected phenyl alanine products on a 10’s – 1000’s kg scale, using this approach

34. Clinical Candidates that use (S)-2,6-Dimethyltyrosine

35. Chiral Quest Manufacture of (R)-2,6-Dimethyltyrosine Substrate was made using a Heck coupling in good yield The substrate was readily purified and was clean enough for the asymmetric hydrogenation step A good catalyst loading was achieved using Rh-TangPhos on this sterically hindered substrate Both (S)- and (R)-2,6-Dimethyltyrosine have been made on a 10-50 kg scale

36. New Route to N-Boc-(S)-2,6-Dimethyltyrosine The Erlenmeyer route does not work for the sterically hindered aldehyde We have produced the Horner-Emmons reagent on a 3 MT scale This reagent is now routinely used for  -amino acid manufacture

37. Clinical Candidates that use (S)-2,6-Dimethyltyrosine Phase III

38. 38 Eluxadoline Approved by FDA (US) on May 27, 2015 100 mg twice a day, IBS-D, The ton scales of key chiral intermediate has been provided by chiral quest using asymmetric hydrogenation for Phase I, II, III and now launched stage

39. Practical Asymmetric Hydrogenation Large scale industrial synthesis of chiral Phosphine ligands (10kgs) BINAP (1980-1996), 16 years Ni-catalyzed coupling reactions by Merck process group DuPhos (1990-1998), 8 years Photochemistry, LiAlH 4 reduction and enzyme chemistry and expensive intermediates DuanPhos (2005-2009), 4 years 40 Kg of a DuanPhos intermediate produced in one batch! Practical Ligands for many applications 100L 500L 1000L -78 o C 15 M 3 Liquid N 2

40. New Approach to the Key Intermediate of Duloxetine  Process transferred to Jiang Xi Long Life and is in routine production.  >15,000 kg of MMAA has been manufactured, >99% ee, >99% purity Chiral Quest has filed a US DMF for the MMAA process – Ref. Number 26862 REACH Registration completed – Registration No. 01-2120053179-54-0000

41. Commercial Manufacture of MMAA 2200 kg of MAK.HCl has been made at CQS Repeatable: 16 x 1000 L asymmetric hydrogenation reactions have been successfully completed at a S/C = 9,000 1250 kg of MMAA has been obtained as a yellow solid, >99.5% ee Typical concentration for asymmetric hydrogenation is 104 kg in a 1000 L vessel 132 kg of white crystalline MMAA is in stock, 99.9% pure, >99.5% ee 20,000kgs be produced 41

42. Typical Synthesis in China (two less than 50% steps) Five steps, tedious resolution and modification 度洛西汀案例（ DMAA Route) <50% Low yield

43. Comparision of Two Processes of Duloxetine $ = 6.6 Rmb6.61000 Kg API 名 Duloxetine New ProcessOld Process CQ Process Advantage 1000 Kgs1000 Starting material ¥374,085.89 ¥ 2,353,887.18 ¥ 1,979,801.2984% People Cost ¥ 92,000.00 ¥ 148,000.00 ¥ 56,000.0038% Energy ¥184,000.00 ¥ 296,000.00 ¥ 112,000.0038% Pollution ¥ 10,105.36 ¥ 55,820.14 ¥ 45,714.7882% QC/QA Cost ¥ 9,500.00 ¥ 16,000.00 ¥ 6,500.0041% Management ¥ 66,969.12 ¥ 286,970.73 ¥ 220,001.6177% Other Cost ¥138,000.00 ¥ 166,000.00 ¥ 28,000.0017% Total Cost ¥874,660.37 ¥ 3,322,678.05 ¥ 2,448,017.6874% Material Cost:RMB/ Kg ¥ 374.09 ¥ 2,353.89 ¥ 1,979.8084% RMB/ Kg ¥ 874.66 ¥ 3,322.68 ¥ 2,448.0274% API $/ Kg $ 132.52 $ 503.44 ¥ 370.9174%

44. Hydrogenation in 1000 L reactor Highly efficient asymmetric hydrogenation process, S/C = 4,000 1 kg of catalyst can produce >1,000 kg of product Chiral Quest has supplied this product on a multi-100 kg scale and can manufacture on a metric ton scale We can produce other analogues readily 1000 Kg scale Asymmetric Hydrogenation Scale-up

45. Asymmetric Hydrogenation for a HIV drug

46. Merck Process of Sitagliptin a)Strong product inhibition, low turnovers 333 with a high molecular weight of catalysts be used a)95% ee and upgrading to 99.9 results in loss of 15% of API’s

47. New Route to Sitagliptin Intermediate Highly efficient asymmetric hydrogenation process, S/C = 5,000 (2,360/1 wt / wt ) Three manufacturing campaigns completed >15,000 kg made and sold. Granted patent, US 8,278,486 B2,Oct 2 nd, 2012. Pending in Europe, China and India Chiral Quest has filed a US DMF for the Sitagliptin process – Ref. Number 27115

48. Ramipril The API went generic in 2008, but still has significant sales Ramipril sales in 2011 was $1.43 Billion and 45 MT of API was consumed Original route to intermediate is 10 steps with a late stage resolution

49. Chiral Quest’s New Process for Ramipril Intermediate  Vilsmeier-Haack reaction used to make the key aldehyde  Erlenmeyer reaction with benzoylglycine provides the hydrogenation substrate  11 g of catalyst produces 400 kg of product, S/C = 80,000 (36,235/1 wt / wt )

50. Chiral Quest’s New Process for Ramipril Intermediate Our route is 8 steps with a highly efficient asymmetric hydrogenation. This is a more environmentally friendly route to the Ramipril Intermediate >30 MT of the Ramipril intermediate has been made by this route.

51. Manufacturing Ramipril Intermediates Chiral Quest has involved for the production of Ramipril >40 MT of Hydrogenation Substrate has been produced and the asymmetric hydrogenation process has been transferred to manufacture site (2000 L vessel)

52. Asymmetric Hydrogenation of Ketones 100% ee Noyori Zhou Zhang Noyori Zhou Zhang 20% 100% ee 40% 60% 80% 20% 40% 60% 80% Zhang PennPhos Noyori BINAP Target Aliphatic Ketones Aromatic Ketones Turnovers >1,000,000

53. >20 th year’s Quest on Asymmetric Hydrogenation of Simple Ketones Using Chiral Tridentate Ligands for Asymmetric Hydrogenation of Simple Ketones was proposed by Xumu Zhang in 1994’s academic job search Job Search idea in1994 Transfer hydrogenation With Ru-Ambox reported In 1998 JACS, 1998, 120, 3817 Direct hydrogenation With a Ru-Ambox catalyst In 2010, Chem. Commun. 2010, 46, 3979. Direct Hydrogenation With an Ir-f-Amphox catalyst in 2015. Simple Ketones >99.9%ee >200,000 turnovers

54. f-Amphox: Modular, Easy to made, A Potential Powerful Ligand Family

55. Potential Applications of Asymmetric Hydrogenation of Simple Ketones Montelukast $1.196M in 2013 Ezetimibe $2.658M in 2013 Noyori’s RuCl2(diphosphine)(diamine) Does not work well for the ketone reduction of these important drugs (>$B)

56. Important industrial processes – Hydrogenation – Hydroformylation – Polymerization – C-C bond formation – Epoxidation and more Remarkable Features – Mild reaction conditions – High activity & stereoselectivity – Atomic economy – Cost efficiency – Operational simplicity Development of New Ligands is the Key Efficient routes for the synthesis of clinical, launched, generic pharmaceutical compounds and commodity chemical products A powerful strategy leading to important Chemicals catalytic system

57. Enantioselective step in Rh-catalyzed hydrogenation (7 Kcal/mol; 99.999%ee ?!) For a related ligand system, see Imamoto, T. etc. J. Am. Chem. Soc. 2000, 122, 7183 “6.9 Kcal/mol difference in energy, R/S = 100000 : 1 = 99.999% ee, perfect”

58. Zigterman, J. L. et. al. J. Org. Chem. 2007, 72, 8870. Dong, V. M., et al. J. Am. Chem. Soc. 2009, 131, 15608 Jacobsen, E. N., et al. J. Am. Chem. Soc. 2008, 130, 12594 Bergman, R. G., et al. Chem. Commun. 2009, 3910 Yun, J., et al. Angew. Chem. Int. Ed. 2009, 48, 6062 Fu, G. C.; et al. J. Am. Chem. Soc. 2010, 132, 4568

59. TangPhos Chem. Comm. 2009, 3910 JACS, 2008, 130, 12594 JACS, 2010, 132, 4568 Angew. Chem., Int. Ed. 2009, 48, 6062 Org. Lett. 2009, 11, 3140 TL. 2005, 46, 7831 TangPhos “TangPhos has been proven to be a privileged ligand…” ——Lennon, Chemistry today THF, 135 - 175 °C Jacobsen, E. N; Bergman, R. G; Fu, G. C; Ellman; Buchwald; Zigterman, J. L.(Amgen); Dong, V. M.; etc

60. Broad applicability of asymmetric hydrogenation

61. Practical Asymmetric Hydrogenation Duloxetine 4748.6M 82,094 kg Up to 30-40 tons be made

62. Practical Asymmetric Hydrogenation Up to 20 tons be produced in six months 62

63. 63 Making Impacts, providing intermediates to global pharmaceutical and generic companies Pre-Clinical Exclusive Synthesis to Global Pharmaceutical Companies Phase IPhase IIPhase IIILaunch Generic Intermediate & API Generic Development Paragraph IV Stage 1 Stage 2 Stage 2: Generic Intermediate and API –With significant pricing advantage, focus on generic opportunities for drugs that will come off patent within the next 2-3 years –Given unique technology and assets, manufacturing capacity On-patent Off-patent Generic Market  Stage 1: Exclusive Synthesis Strategic Intermediate  Provide stable and consistent revenue through immediate exclusive synthesis opportunities  Grow along with drugs as they move through development, focusing on larger Phase III and launched drug opportunities  Sell Catalysts to major pharma 5 > 5 commercial processes 20 >100 Chiral Quest (>200 People, R&D to Manufacturing): Making Kg to 10’s tons of chiral pharmaceutical Intermediates through advanced chiral technology such as asymmetric hydrogenation

64. Chemistry That Matter Every chemist dreams about inventing a reaction that will change the world. Some did, but many of the discoveries ended up as publications that never get applied. What responsibilities of chemists for the sustainable development of humankind, i.e. What is the chemistry that matter the most to the world?

66. Green Catalysis Institute of Wuhan Univ. The Green Catalysis Institute of Wuhan University have been established by Professor Xumu Zhang in 2005. Professors Aiwen Lei and Chunjiang Wang have been two other full professors, we have recently added Drs. QH Zhou of Scripps and WB Liu of Caltech as professors in our institute. We are focusing on green chemistry, selective catalysis, and organic synthesis. The Green Catalysis Institute of Wuhan University have been established by Professor Xumu Zhang in 2005. Professors Aiwen Lei and Chunjiang Wang have been two other full professors, we have recently added Drs. QH Zhou of Scripps and WB Liu of Caltech as professors in our institute. We are focusing on green chemistry, selective catalysis, and organic synthesis. We are looking to recruit postdoctoral fellows with 200K to 300 K RMB （about $50K) payment/year under Professor Xumu Zhang (xumu@whu.edu.cn) 66