Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone?

Journal of Medicinal Chemistry

Volumn 59, Issue 10, 2016, Pages 4443-4458

  Brown, Dean G ^a   Boström, Jonas ^b  

^a ASTRAZENECA   (United Kingdom)

^b ASTRAZENECA R AND D   (Sweden)

Author keywords

[No Author keywords available]

Indexed keywords

BIPHENYL DERIVATIVE; NATURAL PRODUCT; NEW DRUG; REAGENT; BIOLOGICAL PRODUCT; DRUG;

ARTICLE; BUCHWALD HARTWIG REACTION; CHEMICAL REACTION; DECARBOXYLATION; DRUG SELECTIVITY; DRUG SYNTHESIS; FRIEDEL CRAFTS REACTION; MEDICINAL CHEMISTRY; METHODOLOGY; SUZUKI REACTION; CHEMISTRY; DRUG DEVELOPMENT; SYNTHESIS;

BIOLOGICAL PRODUCTS; CHEMISTRY, PHARMACEUTICAL; DRUG DISCOVERY; PHARMACEUTICAL PREPARATIONS;

EID: 84969617464     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.5b01409     Document Type: Article

References (88)

1. Brown, D. G.; Gagnon, M. M.; Boström, J. Understanding our love affair with p-chlorophenyl: present day implications from historical biases of reagent selection J. Med. Chem. 2015, 58, 2390-2405 10.1021/jm501894t
2. Lajiness, M. S.; Maggiora, G. M.; Shanmugasundaram, V. Assessment of consistency of medicinal chemists in reviewing sets of compounds J. Med. Chem. 2004, 47, 4891-4896 10.1021/jm049740z
3. Sternbach, L. H. The benzodiazepine story J. Med. Chem. 1979, 22, 1-6 10.1021/jm00187a001
4. Patridge, E.; Gareiss, P.; Kinch, M. S.; Hoyer, D. An analysis of FDA-approved drugs: natural products and their derivatives. Drug Discovery Today 2015, DOI: 10.1016/j.drudis.2015.01.009.
5. Lombardino, J. G.; Lowe, J. A., III. The role of the medicinal chemist in drug discovery-then and now Nat. Rev. Drug Discovery 2004, 3, 853-862 10.1038/nrd1523
6. Roughley, S. D.; Jordan, A. M. The medicinal chemist's toolbox: an analysis of reactions used in the pursuit of drug candidates J. Med. Chem. 2011, 54, 3451-3479 10.1021/jm200187y
7. Sauer, W. H. B.; Schwarz, M. K. Molecular shape diversity of combinatorial libraries: a prerequisite for broad diversity J. Chem. Inf. Model. 2003, 43, 987-1003 10.1021/ci025599w
8. OEChem Toolkits. http://www.eyesopen.com/oechem-tk (accessed Sep 9, 2015).
9. Paul, F.; Patt, J.; Hartwig, J. F. Palladium-catalyzed formation of carbon-nitrogen bonds. Reaction intermediates and catalyst improvements in the hetero cross-coupling of aryl halides and tin amides J. Am. Chem. Soc. 1994, 116, 5969-5970 10.1021/ja00092a058
10. Guram, A. S.; Buchwald, S. L. Palladium-catalyzed aromatic aminations with in situ generated aminostannanes J. Am. Chem. Soc. 1994, 116, 7901-7902 10.1021/ja00096a059
11. Guram, A. S.; Rennels, R. A.; Buchwald, S. L. A simple catalytic method for the conversion of aryl bromides to arylamines Angew. Chem., Int. Ed. Engl. 1995, 34, 1348-1350 10.1002/anie.199513481
12. Suzuki, A. Cross-coupling reactions of organoboranes: An easy way to construct C-C bonds (Nobel Lecture) Angew. Chem., Int. Ed. 2011, 50, 6722-6737 10.1002/anie.201101379
13. Miyaura, N.; Yanagi, T.; Suzuki, A. The palladium-catalyzed cross-coupling reaction of phenylboronic acid with haloarenes in the presence of bases Synth. Commun. 1981, 11, 513-519 10.1080/00397918108063618
14. Sonogashira, K.; Tohda, Y.; Hagihara, N. A convenient synthesis of acetylenes: catalytic substitutions of acetylenic hydrogen with bromoalkenes, iodoarenes and bromopyridines Tetrahedron Lett. 1975, 16, 4467-4470 10.1016/S0040-4039(00)91094-3
15. Grignard, V. Sur quelques nouvelles combinaisons organométaliques du magnésium et leur application à des synthèses d'alcools et d'hydrocabures Compt. Rend. 1900, 130, 1322-1325
16. Wittig, G.; Schöllkopf, U. Über triphenyl-phosphin-methylene als olefinbildende reagenzien I Chem. Ber. 1954, 87, 1318 10.1002/cber.19540870919
17. Horner, L.; Hoffmann, H.; Wippel, H. G. Phosphine oxides as reagents for the olefin formation Chem. Ber. 1958, 91, 61-63 10.1002/cber.19580910113
18. Wadsworth, W. S., Jr.; Emmons, W. D. The utility of phosphonate carbanions in olefin synthesis J. Am. Chem. Soc. 1961, 83, 1733-1738 10.1021/ja01468a042
19. Moroder, L.; Hallett, A.; Wünsch, E.; Keller, O.; Wersin, G. Di tert. butyl dicarbonate, a useful tert. butyloxycabonylating reagent Hoppe-Seyler's Z. Physiol. Chem. 1976, 357, 1651-1653 10.1515/bchm2.1976.357.2.1651
20. Sigma-Aldrich Catalog of Fine Chemicals, 1979-1980 ed.; Sigma-Aldrich: St. Louis, MO.
21. Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Fluorine in medicinal chemistry Chem. Soc. Rev. 2008, 37, 320-330 10.1039/B610213C
22. Campbell, M. G.; Ritter, T. Late-stage fluorination: From fundamentals to application Org. Process Res. Dev. 2014, 18, 474-480 10.1021/op400349g
23. Mo, F.; Dong, G.; Zhang, Y.; Wang, J. Recent applications of arene diazonium salts in organic synthesis Org. Biomol. Chem. 2013, 11, 1582-1593 10.1039/c3ob27366k
24. Kalyani, D.; McMurtrey, K. B.; Neufeldt, S. R.; Sanford, M. S. Room-temperature C-H arylation: merger of Pd-catalyzed C-H functionalization and visible-light photocatalysis J. Am. Chem. Soc. 2011, 133, 18566-18569 10.1021/ja208068w
25. Csanády, G. A.; Laib, R. J.; Filser, J. G. Metabolic transformation of halogenated and other alkeneî - ątheoretical approach. Estimation of metabolic reactivities for in vivo conditions Toxicol. Lett. 1995, 75, 217-223 10.1016/0378-4274(94)03174-6
26. Kumar, N.; Windisch, W.; Ammon, H. L. Photoinstability of some tyrphostin drugs: chemical consequences of crystallinity Pharm. Res. 1995, 12, 1708-1715 10.1023/A:1016213721861
27. Armaly, A. M.; DePorre, Y. C.; Groso, E. J.; Riehl, P. S.; Schindler, C. S. Discovery of novel synthetic methodologies and reagents during natural product synthesis in the post-palytoxin era Chem. Rev. 2015, 115, 9232-9276 10.1021/acs.chemrev.5b00034
28. Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Analysis of the reactions used for the preparation of drug candidate molecules Org. Biomol. Chem. 2006, 4, 2337-2347 10.1039/b602413k
29. Vasilevich, N. I.; Kombarov, R. V.; Genis, D. V.; Kirpichenok, M. A. Lessons from natural products can offer novel approaches for synthetic chemistry in drug discovery J. Med. Chem. 2012, 55, 7003-7009 10.1021/jm300344v
30. Varkonyi, O.; Hoppe, C.; Muresan, S. IBEXî - ąccess and exploit SAR data from patents and journals. Presented at ChemAxon EUGM, Budapest, Hungary, June 7-8, 2008; http://www.chemaxon.com/forum/viewpost16936.html#16936.
31. Dictionary of Natural Products, Taylor & Francis Group. http://dnp.chemnetbase.com/dictionary-search.do?method=view&id=11256630&si= (accessed Mar 20, 2015).
32. Over, B.; Wetzel, S.; Grütter, C.; Nakai, Y.; Renner, S.; Rauh, D.; Waldmann, H. Natural-product-derived fragments for fragment-based ligand discovery Nat. Chem. 2013, 5, 21-28 10.1038/nchem.1506
33. Occam's razor. https://en.wikipedia.org/wiki/Occam%27s-razor (accessed Sep 7, 2015).
34. Larsen, R. D.; King, A. O.; 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.; Meloni, D.; Moore, J. R.; Arnett, J. F. Efficient synthesis of Losartan, a nonpeptide angiotensin II receptor antagonist J. Org. Chem. 1994, 59, 6391-6394 10.1021/jo00100a048
35. Link, J. O.; Taylor, J. G.; Xu, L.; Mitchell, M.; Guo, H.; Liu, H.; Kato, D.; Kirschberg, T.; Sun, J.; Squires, N.; Parrish, J.; Keller, T.; Yang, Z.-Y.; Yang, C.; Matles, M.; Wang, Y.; Cheng, G.; Tian, Y.; Mogalian, E.; Mondou, E.; Cornpropst, M.; Perry, J.; Desai, M. C. Discovery of ledipasvir (GS-5885): a potent, once-daily oral NS5A inhibitor for the treatment of hepatitis C virus infection J. Med. Chem. 2014, 57, 2033-2046 10.1021/jm401499g
36. Gaulton, A.; Bellis, L. J.; Bento, A. P.; Chambers, J.; Davies, M.; Hersey, A.; Light, Y.; McGlinchey, S.; Michalovich, D.; Al-Lazikani, B.; Overington, J. P. ChEMBL: A large-scale bioactivity database for drug discovery Nucleic Acids Res. 2012, 40, D1100-D1107 10.1093/nar/gkr777
37. Haigh, J. A.; Pickup, B. T.; Grant, J. A.; Nicholls, A. Small molecule shape-fingerprints J. Chem. Inf. Model. 2005, 45, 673-684 10.1021/ci049651v
38. Kaitin, K. Deconstructing the drug development process: the new face of innovation Clin. Pharmacol. Ther. 2010, 87, 356-361 10.1038/clpt.2009.293
39. Pihan, E.; Colliandre, L.; Guichou, J.-F.; Douguet, D. e-Drug3D: 3D structure collections dedicated to drug repurposing and fragment-based drug design Bioinformatics 2012, 28, 1540-1 10.1093/bioinformatics/bts186
40. DOI: 10.1093/bioinformatics/bts186. http://chemoinfo.ipmc.cnrs.fr/MOLDB/index.html.
41. Data were generated using SciFinder from CAS, A Division of the American Chemical Society. http://www.cas.org/products/scifinder (accessed May 29, 2015).
42. Coste, J.; Le-Nguyen, D.; Castro, B. PyBOP: A new peptide coupling reagent devoid of toxic by-product Tetrahedron Lett. 1990, 31, 205-208 10.1016/S0040-4039(00)94371-5
43. Carpino, L. A. 1-Hydroxy-7-azabenzotriazole. An efficient peptide coupling additive J. Am. Chem. Soc. 1993, 115, 4397-4398 10.1021/ja00063a082
44. El-Faham, A.; Subirós-Funosas, R.; Prohens, R.; Albericio, F. COMU: a safer and more effective replacement for benzotriazole-based uronium coupling reagents Chem.î -Eur. J. 2009, 15, 9404 10.1002/chem.200900615
45. Lennox, A. J. J.; Lloyd-Jones, G. C. Selection of boron reagents for Suzuki-Miyaura coupling Chem. Soc. Rev. 2014, 43, 412-443 10.1039/C3CS60197H
46. Miyaura, N.; Suzuki, A. Stereoselective synthesis of arylated (E)-alkene by the reaction of alk-1-enylboranes with aryl halides in the presence of palladium catalyst J. Chem. Soc., Chem. Commun. 1979, 866-867 10.1039/c39790000866
47. Miyaura, N.; Yamada, K.; Suzuki, A. A new stereospecific cross-coupling by the palladium-catalyzed reaction of 1-alkenylboranes with 1-alkenyl or 1-alkynl halides Tetrahedron Lett. 1979, 20, 3437-3440 10.1016/S0040-4039(01)95429-2
48. Ishiyama, T.; Murata, M.; Miyaura, N. Palladium(0)-catalyzed cross-coupling reaction of alkoxydiboron with haloarenes: a direct procedure for arylboronic esters J. Org. Chem. 1995, 60, 7508-7510 10.1021/jo00128a024
49. Ishiyama, T.; Ishida, K.; Miyaura, N. Synthesis of pinacol arylboronates via cross-coupling reaction of bis(pinacolato)diboron with chlorarenes catalyzed by palladium(0)-tricyclohexylphosphine complexes Tetrahedron 2001, 57, 9813-9816 10.1016/S0040-4020(01)00998-X
50. Molander, G. A.; Sandrock, D. L. Potassium trifluoroborate salts as convenient, stable reagents for difficult alkyl transfers Curr. Opin. Drug Discovery Dev. 2009, 12, 811-823
51. Molander, G. A.; Ito, T. Cross-coupling reactions of potassium alkyltrifluoroborates with aryl and 1-alkenyl trifluoromethanesulfonates Org. Lett. 2001, 3, 393-396 10.1021/ol006896u
52. Gillis, E. P.; Burke, M. D. Iterative cross-coupling with MIDA boronates: towards a general platform for small molecule synthesis Aldrichimica Acta 2009, 42, 17-27
53. Gillis, E. P.; Burke, M. D. A simple and modular strategy for small molecule synthesis: Iterative Suzuki-Miyaura coupling of B-protected haloboronic acid building blocks J. Am. Chem. Soc. 2007, 129, 6716-6717 10.1021/ja0716204
54. Lidström, P.; Tierney, J.; Wathey, B.; Westman, J. Microwave assisted organic synthesis-a review Tetrahedron 2001, 57, 9225-9283 10.1016/S0040-4020(01)00906-1
55. McClain, R.; Streckfuss, E. High-throughput purification in support of pharmaceutical discovery Comprehensive Org. Syn (II) 2014, 9, 160-180 10.1016/B978-0-08-097742-3.00918-6
56. Sciascera, L.; Ismail, O.; Alessia, K.; Kotoni, D.; Cavazzini, A.; Botta, L.; Szczerba, T.; Kocergin, J.; Villani, C.; Gasparrini, F. Expanding the potential of chiral chromatography for high-throughput screening of large compound libraries by means of sub-2 IM Whelk-O 1 stationary phase in supercritical fluid conditions J. Chrom. A 2015, 1383, 160-168 10.1016/j.chroma.2015.01.042
57. Teijaro, C. N.; Munagala, S.; Zhao, S.; Sirisani, G.; Kokkonda, P.; Malofeeva, E. V.; Hopper-Borge, E.; Andrade, R. B. Synthesis and biological evaluation of pentacyclic Strychnos alkaloids as selective modulators of the ABCC10 (MRP7) efflux pump J. Med. Chem. 2014, 57, 10383-10390 10.1021/jm501189p
58. Ellman, J. A.; Owens, T. D.; Tang, T. P N-tert-butanesulfinyl imines: Versatile intermediates for the asymmetric synthesis of amines Acc. Chem. Res. 2002, 35, 984 10.1021/ar020066u
59. Robak, M. T.; Herbage, M. A.; Ellman, J. A. Synthesis and applications of tert-butanesulfinamide Chem. Rev. 2010, 110, 3600-3740 10.1021/cr900382t
60. González-Gómez, J. C.; Medjahdi, M.; Foubelo, F.; Yus, M. Stereoselective α-aminoallylation of aldehydes with chiral tertbutanesulfinamides and allyl bromides J. Org. Chem. 2010, 75, 6308-6311 10.1021/jo101379u
61. Li, L.; Chang, K.-C.; Zhou, Y.; Shieh, B.; Ponder, J.; Abraham, A. D.; Ali, H.; Snow, A.; Petrash, J. M.; LaBarbera, D. V. Design of an amide N-glycoside derivative of β-glucogallin: A stable, potent, and specific inhibitor of aldose reductase J. Med. Chem. 2014, 57, 71-77 10.1021/jm401311d
62. Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Click chemistry: Diverse chemical function from a few good reactions Angew. Chem., Int. Ed. 2001, 40, 2004-2021 10.1002/1521-3773(20010601)40:11<2004::AID-ANIE2004>3.0.CO;2-5
63. Maltais, R.; Ayan, D.; Trottier, A.; Barbeau, X.; Lagüe, P.; Bouchard, J.-E.; Poirier, D. Discovery of a non-estrogenic irreversible inhibitor of 17β-hydroxysteroid dehydrogenase type 1 from 3-substituted-16β-(m-carbamoylbenzyl)estradiol derivatives J. Med. Chem. 2014, 57, 204-222 10.1021/jm401639v
64. Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Metathesis reactions in total synthesis Angew. Chem., Int. Ed. 2005, 44, 4490-4527 10.1002/anie.200500369
65. Blackwell, H. E.; O'Leary, D. J.; Chatterjee, A. K.; Washenfelder, R. A.; Bussmann, D. A.; Grubbs, R. H. New approaches to olefin cross-metathesis J. Am. Chem. Soc. 2000, 122, 58-71 10.1021/ja993063u
66. Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. A general model for selectivity in olefin cross metathesis J. Am. Chem. Soc. 2003, 125, 11360-11370 10.1021/ja0214882
67. Riley, A. P.; Groer, C. E.; Young, D.; Ewald, A. W.; Kivell, B. M.; Prisinzano, T. E. Synthesis and ΰ-opiod receptor activity of furan-substituted Salvinorin A analogues J. Med. Chem. 2014, 57, 10464-10475 10.1021/jm501521d
68. Nagib, D. A.; MacMillan, D. W. C. Trifluoromethylation of arenes and heteroarenes by means of photoredox catalysis Nature 2011, 480, 224-228 10.1038/nature10647
69. Asgatay, S.; Champion, C.; Marloie, G.; Drujon, T.; Senamaud-Beaufort, C.; Ceccaldi, A.; Erdmann, A.; Rajavelu, A.; Schambel, P.; Jeltsch, A.; Lequin, O.; Karoyan, P.; Arimondo, P. B.; Guianvarc'h, D. Synthesis and evaluation of analogues of N-phthaloyl-L-tryptophan (RG108) as inhibitors of DNA methyltransferase 1 J. Med. Chem. 2014, 57, 421-434 10.1021/jm401419p
70. Mothes, C.; Lavielle, S.; Karoyan, P. Amino-zinc-ene-enolate cyclization: a short access to cis-3-substituted prolino-homotryptophane derivatives J. Org. Chem. 2008, 73, 6706-6710 10.1021/jo801006a
71. O'Hara, F.; Burns, A. C.; Collins, M. R.; Dalvie, D.; Ornelas, M. A.; Vaz, A. D. N.; Fujiwara, Y.; Baran, P. S. A simple litmus test for aldehyde oxidase metabolsm of heteroarenes J. Med. Chem. 2014, 57, 1616-1620 10.1021/jm4017976
72. Stout, E. P.; Choi, M. Y.; Castro, J. E.; Molinski, T. F. Potent fluorinated agelastatin analogues for chronic lymphocytic leukemia: design, synthesis and pharmacokinetic studies J. Med. Chem. 2014, 57, 5085-5093 10.1021/jm4016922
73. Umemoto, T.; Miyano, O. N-Trifluoromethyl-N-nitrosobenzensulfonamide. A new trifluoromethylating agent Tetrahedron Lett. 1982, 23, 3929-3930 10.1016/S0040-4039(00)87745-X
74. McClinton, M. A.; McClinton, D. A. Trifluoromethylations and related reactions in organic chemistry Tetrahedron 1992, 48, 6555-6666 10.1016/S0040-4020(01)80011-9
75. Michaudel, Q.; Ishihara, Y.; Baran, P. S. Academia-industry symbiosis in organic chemistry Acc. Chem. Res. 2015, 48, 712-721 10.1021/ar500424a
76. Szychowski, J.; Truchon, J.-F.; Bennani, Y. L. Natural products in medicine: transformational outcome of synthetic chemistry J. Med. Chem. 2014, 57, 9292-9308 10.1021/jm500941m
77. Walters, W. P.; Green, J.; Weiss, J. R.; Murcko, M. A. What do medicinal chemists actually make? A 50-year retrospective J. Med. Chem. 2011, 54, 6405-6416 10.1021/jm200504p
78. Schreiber, S. L. Target-oriented and diversity-oriented organic synthesis in drug discovery Science 2000, 287, 1964-1969 10.1126/science.287.5460.1964
79. Lovering, F.; Bikker, J.; Humblet, C. Escape from flatland: increasing saturation as an approach to improving clinical success J. Med. Chem. 2009, 52, 6752-6756 10.1021/jm901241e
80. Pattabiraman, V. R.; Bode, J. W. Rethinking amide bond synthesis Nature 2011, 480, 471-479 10.1038/nature10702
81. 2NH]Tpg4 ]vancomycin, and their (4-Chlorobiphenyl)methyl derivatives: synergistic binding pocket and peripheral modifications for the glycopeptide antibiotics J. Am. Chem. Soc. 2015, 137, 3693-3704 10.1021/jacs.5b01008
82. Baran, P. S.; Maimone, T. J.; Richter, J. M. Total synthesis of marine natural products without using protecting groups Nature 2007, 446, 404-408 10.1038/nature05569
83. Young, I. S.; Baran, P. S. Protecting-group-free synthesis as an opportunity for invention Nat. Chem. 2009, 1, 193-205 10.1038/nchem.216
84. Cooper, T. W. J.; Campbell, I. B.; Macdonald, S. J. F. Factors determining the selection of organic reactions by medicinal chemists and the use of these reactions in arrays (small focused libraries) Angew. Chem., Int. Ed. 2010, 49, 8082-8091 http://www.nigms.nih.gov/Research/specificareas/CMLD/centers/Pages/default.aspx 10.1002/anie.201002238
85. Nussbaumer, P. Medicinal chemists of the 21st centuryî-Who are we and where do we go? ChemMedChem 2015, 10, 1133-1139 10.1002/cmdc.201500133
86. Li, J.; Ballmer, S. G.; Gillis, E. P.; Fujii, S.; Schmidt, M. J.; Palazzolo, A. M. E.; Lehmann, J. W.; Morehouse, G. F.; Burke, M. D. Synthesis of many different types of organic small molecules using one automated process Science 2015, 347, 1221-1226 10.1126/science.aaa5414
87. Sanderson, M. March of the synthesis machines Nat. Rev. Drug Discovery 2015, 14, 299-300 10.1038/nrd4613
88. Kubinyi, H. Chance favors the prepared mindî-from serendipity to rational design J. Recept. Signal Transduction Res. 1999, 19, 15-39 10.3109/10799899909036635