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The Medicinal Chemist’s Repertoire
John Gurak 8/2/18
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Roles of Medicinal Chemists
Understand biology of the target disease Be familiar with competitive therapies Frame hypothesis for new drug project Decide which existing compounds to screen Synthesis, purification, and characterization of compounds Plan SAR studies Develop in vivo activity in an appropriate animal model Lombardino, J. G.; Lowe, III, J. A. Nature Rev. Drug Discov. 2004, 3, 853.
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Comparison of Methods Carey, J. S. et al. Org. Biomol. Chem. 2006, 4, 2337.; Cooper, T. W. J. et al. Angew. Chem. Int. Ed. 2010, 49, 8082.; Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011, 54, 3451.; Brown, D. G.; Boström, J. J. Med. Chem. 2016, 59, 4443.; Schneider, N. et al. J. Med. Chem. 2016, 59, 4385.
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Results Carey, J. S. et al. Org. Biomol. Chem. 2006, 4, 2337.; Cooper, T. W. J. et al. Angew. Chem. Int. Ed. 2010, 49, 8082.; Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011, 54, 3451.; Brown, D. G.; Boström, J. J. Med. Chem. 2016, 59, 4443.; Schneider, N. et al. J. Med. Chem. 2016, 59, 4385.
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Top 10 Categories Heteroatom Alkylation & Arylation
Acylation & Related Processes Protections/Deprotections C–C Bond Forming Reactions Heterocycle Formations Reductions Functional Group Interconversions (FGI) Functional Group Addition (FGA) Oxidations Resolutions Carey, J. S. et al. Org. Biomol. Chem. 2006, 4, 2337.; Cooper, T. W. J. et al. Angew. Chem. Int. Ed. 2010, 49, 8082.; Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011, 54, 3451.; Brown, D. G.; Boström, J. J. Med. Chem. 2016, 59, 4443.; Schneider, N. et al. J. Med. Chem. 2016, 59, 4385.
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Heteroatom Alkylation & Arylation
N-Alkylation Alkyl halides Reductive aminations N-Arylation SNAr ANRORC Buchwald–Hartwig O-Alkylation Zincke Williamson ether synthesis Mitsunobu O-Arylation SNAr
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Acylation & Related Processes
N-Acylation Carboxylic acid & amine Schotten–Baumann N-Sulfonylations Sulfonic acid & amine Sulfonamide Schotten–Baumann O-Sulfonylations “Sulfonate” Schotten–Baumann Alcohols & anhydrides Alfonsi, K. et al. Green Chem. 2008, 10, 31.
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Protections/Deprotections
N-Protecting Groups Boc2O Acid Boc R’OH −OH CO2H-Protecting Groups DMAP/DCC Ester: Me, Et SOCl2/ POCl3/ (COCl)2 R’OH Base OH-Protecting Groups Silyls R3SiCl TBAF Base
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C–C Bond Forming Reactions
Suzuki-Miyaura Sonogashira Grignard Larsen, R. D. et al. J. Org. Chem. 1994, 59, 6391.; Alami, M. et al. Tetrahedron Lett. 1996, 37, 57.; Misna, R. N. et al. J. Med. Chem. 1991, 34, 2882. Nicholson, J. S. et al. US A, May 28, 1968.; Roth, B. D. US , July 21, 1987.
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C–C Bond Forming Reactions
Aldol Friedel-Crafts Wittig Larsen, R. D. et al. J. Org. Chem. 1994, 59, 6391.; Alami, M. et al. Tetrahedron Lett. 1996, 37, 57.; Misna, R. N. et al. J. Med. Chem. 1991, 34, 2882. Nicholson, J. S. et al. US A, May 28, 1968.; Roth, B. D. US , July 21, 1987.
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Heterocycle Formation
N-Heterocycles S-Heterocycles 6,5-Fused Heterocycles Pyridines Pyrimidines Pyrazines Pyrazoles Imidazoles Pyrroles (Fused) 1,2,4-Triazoles Thiophenes Thiazoles Indole Benzimidazole Benzoxazole Pyrrolo[1,2-𝛼]pyrazine O-Heterocycles Oxazoles Furans 6,6-Fused Heterocycles Quinoline Quinazoline
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Heterocycle Formation
Adapted from The Portable Chemist’s Consultant Heterocycle Formation Thiophenes Thiazoles Paal Fiesselmann Hinsberg Gewald Oxazoles Fischer Furans Paal-Knorr van Leusen Feist-Bénary Robinson-Gabriel
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Heterocycle Formation
Adapted from The Portable Chemist’s Consultant Heterocycle Formation Pyridines Pyrimidines Chichibabin Ciamician-Dennstedt Pinner Hantzsch Kröhnke Biginelli Pyrazines Bohlmann-Rahtz Guareschi-Thorpe
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Heterocycle Formation
Adapted from The Portable Chemist’s Consultant Heterocycle Formation Pyrroles Pyrazoles Paal-Knorr Piloty Knorr Knorr 1,2,4-Triazoles Barton-Zard Hantzsch Einhorn-Brunner van Leusen Pellizzari
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Heterocycle Formation
Adapted from The Portable Chemist’s Consultant Heterocycle Formation Imidazoles Indoles Fischer Debus-Radziszewski Larock Madelung Lantos-Eggleston van Leusen Batcho-Leimgruber Bartoli Hegedus Benzimidazoles Benzoxazoles Pyrrolo[1,2-𝛼]pyrazine
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Heterocycle Formation
Adapted from The Portable Chemist’s Consultant Heterocycle Formation Quinolines Meth-Cohn R = H/alkyl/aryl, R = H/alkyl/aryl R = O-alkyl/aryl, R = H/alkyl/aryl R = H/alkyl/aryl, R = O-alkyl Combes Conrad-Limpach Pfitzinger Knorr R = CO2H, R = H R = Me, R = Me Doebner Riehm Gould-Jacobs Friedländer Quinazolines Niementowski
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Heterocycles – Make or Buy?
Made Made Petersen, U. et al. EP A2, March 1, 1989. Campbell, S. F. et al. US A, February 25, 1986. Bought Bought Made Szczepek, W. et al. US B2, March 9, 2010. Bought Made Bought Kohl, B. et al. J. Med. Chem. 1992, 35, 1049. Roth, B. D. US , July 21, 1987.
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Reductions Hydrogenation, Zn/AcOH, Fe/HCl LAH, DIBAL, Hydrogenation
Reductants: NaBH4 Zn/AcOH Hydrogenation LAH DIBAL Fe/HCl BH3 LAH, BH3, DIBAL NaBH4, LAH, Hydrogenation LAH, BH3, Hydrogenation NaBH4, LAH, Hydrogenation NaBH4, Hydrogenation Hydrogenation Magano, J.; Dunetz, J. R. Org. Process Res. Dev. 2012, 16, 1156.
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Kolbe Nitrile Synthesis
FGI Conditions: SOCl2 PPh3, CX4 TsCl, X− Conditions: CuCN, 𝚫 Rosenmund-von Braun Appel Conditions: PdII, [B(OR)2]2 Conditions: NaNO2, HX CuX Miyaura Borylation Sandmeyer Conditions: CN− Kolbe Nitrile Synthesis
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FGA Halogenation Nitroso Formation Masked Enamine X2, FeX3 NXS HX NXS
NaNO2, HCl RONO, Acid NOBF4 NOCl Masked Enamine DMFDMA Base Gowenlock, B. G.; Richter-Addo, G. B. Chem. Rev. 2004, 104, 3315. Abu-Shanab, F.; Sherif, S. M.; Mousa, S. A. S. J. Heterocyclic Chem. 2009, 46, 801.
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Oxidations Alfonsi, K. et al. Green Chem. 2008, 10, 31.
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Oxidations Swern Oxidation Pfitzner-Moffatt Oxidation
Parikh-Doering Oxidation Ley Oxidation Alfonsi, K. et al. Green Chem. 2008, 10, 31.
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Oxidations KMnO4, Jones Oxidation, PDC, Heyns Oxidation, RuO4, Ag2O
TEMPO, NaOCl2, H2O2, etc. H2O2/TBHP & VO(acac)2, m-CPBA, NaH2BO4, NaOCl, Oxone, etc. H2O2 & Na2WO4, m-CPBA, Oxone, etc. Alfonsi, K. et al. Green Chem. 2008, 10, 31.; Caron, S. et al. Chem. Rev. 2006, 106, 2943.
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Resolutions Salt formation Dynamic kinetic resolution (DKR)
Acid-base reaction between racemic drug and a single enantiomer compound called the resolving agent to produce diastereomers Common acid resolving agents: Cinchona alkaloids, basic amino acids, amino alcohols, etc. Common base resolving agents: Acids (camphorsulfonic acid, tartaric acid, malic acid, pyroglutamic acid, etc.) Dynamic kinetic resolution (DKR) Catalyst or enzyme preferentially reacts with one enantiomer over the other Gives full conversion of racemate to enantiopure product if conditions allow for epimerization Chromatographic HPLC with chiral stationary phase Enantiomers fit differently in chiral binding pockets of stationary phase (lock-and-key) Enzymatic Enzymes preferentially uptake and degrade one enantiomer, allowing for isolation of the other enantiomer Nguyen, L. A.; He, H.; Pham-Huy, C. Int. J. of Biomed. Science 2006, 2, 85.
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Some Unsolved Problems
Asymmetric hydrocyanation Chiral amine synthesis Asymmetric hydroamination of olefins Carbonyl + NH3 + “???” Asymmetric hydrolysis of nitriles Asymmetric hydroformylation Fluorination Oxygen nucleophiles with high reactivity ArCl + ROH to give ArOR Constable, D. J. C. et al. Green Chem. 2007, 9, 411.
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Acknowledgements Engle Lab: Keary Engle, Ph.D. Omar Apolinar
Joe Derosa Tim Gallagher De-Wei Gao, Ph.D. Yang Gao, Ph.D. Ryan Helsel Tanner Jankins Taeho Kang Malkanthi Karunananda, Ph.D. Zi-Qi Li Mingyu Liu Zhen Liu Rei Matsuura Jose Medina, Ph.D. Nhi Nguyen Lucas Oxtoby Tian-Zhang Qiao Ziyang (Nick) Qin Andrew Romine Van Tran Alena Vasquez Xin Wang Admin.: Carrie Gabaldon NMR Facilities Staff: Dee-Hua Huang, Ph.D., Laura Pasternack, Ph.D. Other labs at TSRI for support and supplies Funding: NSF GRFP, Donald and Delia Baxter Foundation
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