Next generation organofluorine containing blockbuster drugs

Fried, 1953, Synthesis of 17α-hydroxycorticosterone and its 9α-halo derivatives from 11-epi-17α-hydroxycorticosterone, J. Am. Chem. Soc., 75, 2273, 10.1021/ja01105a527 Fried, 1954, 9α-Fluoro derivatives of cortisone and hydrocortisone, J. Am. Chem. Soc., 76, 1455, 10.1021/ja01634a101 Fujiwara, 2014, Successful fluorine-containing herbicide agrochemicals, J. Fluorine Chem, 167, 16, 10.1016/j.jfluchem.2014.06.014 Han, 2011, Biomimetic transamination – a metal-free alternative to the reductive amination. Application for generalized preparation of fluorine-containing amines and amino acids, Curr. Org. Synth., 8, 281, 10.2174/157017911794697277 Zhu, 2018, Modern approaches for asymmetric construction of carbon–fluorine quaternary stereogenic centers: synthetic challenges and pharmaceutical needs, Chem. Rev., 118, 3887, 10.1021/acs.chemrev.7b00778 Ogawa, 2020, Current contributions of organofluorine compounds to the agrochemical industry, ISCIENCE, 23, 10.1016/j.isci.2020.101467 Wang, 2014, Fluorine in pharmaceutical industry: fluorine-containing drugs introduced to the market in the last decade (2001–2011), Chem. Rev., 114, 2432, 10.1021/cr4002879 Zhou, 2016, Next generation of fluorine-containing pharmaceuticals, compounds currently in phase II–III clinical trials of major pharmaceutical companies: new structural trends and therapeutic areas, Chem. Rev., 116, 422, 10.1021/acs.chemrev.5b00392 Zhu, 2014, Recent advances in the trifluoromethylation methodology and new CF3-containing drugs, J. Fluorine Chem., 167, 37, 10.1016/j.jfluchem.2014.06.026 Mei, 2020, Applications of fluorine-containing amino acids for drug design, Eur. J. Med. Chem., 186, 10.1016/j.ejmech.2019.111826 Meanwell, 2018, Fluorine and fluorinated motifs in the design and application of bioisosteres for drug design, J. Med. Chem., 61, 5822, 10.1021/acs.jmedchem.7b01788 Mei, 2020, Tailor-made amino acids and fluorinated motifs as prominent traits in the modern pharmaceuticals, Chem. Eur. J., 26, 11349, 10.1002/chem.202000617 Mei, 2020, Fluorine-containing drugs approved by the FDA in 2019, Chin. Chem. Lett., 10.1016/j.cclet.2020.03.050 Yin, 2020, Tailor-made amino acid-derived pharmaceuticals approved by the FDA in 2019, Amino Acids, 10.1007/s00726-020-02887-4 Mei, 2019, Fluorine-containing drugs approved by the FDA in 2018, Chem. Eur. J., 25, 11797, 10.1002/chem.201901840 O’Hagan, 2010, Fluorine in health care: organofluorine containing blockbuster drugs, J. Fluorine Chem., 131, 1071, 10.1016/j.jfluchem.2010.03.003 Fox, 1999, Mechanism of action for leflunomide in rheumatoid arthritis, Clin. Immunol., 93, 198, 10.1006/clim.1999.4777 Bartlett, 1991, Leflunomide (HWA 486), a novel immunomodulating compound for the treatment of autoimmune disorders and reactions leading to transplantation rejection, Agents Actions, 32, 10, 10.1007/BF01983301 Zhang, 2002, Application of LC/MS/MS in the quantitation of SU101 and SU0020 uptake by 3T3/PDGFr cells, J. Pharm. Biomed. Anal., 28, 701, 10.1016/S0731-7085(01)00654-9 Alexander, 2006, The active form of leflunomide, HMR1726, facilitates TNF-α and IL-17 induced MMP-1 and MMP-3 expression, Cell. Physiol. Biochem., 17, 69, 10.1159/000091465 Cao, 1995, Mechanism of the antiproliferative action of leflunomide. A77 1726, the active metabolite of Leflunomide, does not block T-cell receptor-mediated signal transduction but its antiproliferative effects are antagonized by pyrimidine nucleosides, J. Heart Lung Transplant., 14, 1016 Xu, 1996, Two activities of the immunosuppressive metabolite of leflunomide, A77 1726. Inhibition of pyrimidine nucleotide synthesis and protein tyrosine phosphorylation, Biochem. Pharmacol., 52, 527, 10.1016/0006-2952(96)00303-6 Manna, 1999, Immunosuppressive leflunomide metabolite (A77 1726) blocks TNF-dependent nuclear factor-κB activation and gene expression, J. Immunol., 162, 2095, 10.4049/jimmunol.162.4.2095 Hamilton, 1999, A771726, the active metabolite of leflunomide, directly inhibits the activity of cyclo-oxygenase-2 in vitro and in vivo in a substrate-sensitive manner, Br. J. Pharmacol., 127, 1589, 10.1038/sj.bjp.0702708 G. McMahon, P.C. Tang, L.K. Shawver, K.P. Hirth, WO 1998052944A1 (1998). Tan, 2008, Prevention of acetaminophen (APAP)-induced hepatotoxicity by leflunomide via inhibition of APAP biotransformation to N-acetyl-p-benzoquinone imine, Toxicol. Lett., 180, 174, 10.1016/j.toxlet.2008.06.001 Warnke, 2009, Review of teriflunomide and its potential in the treatment of multiple sclerosis, Neuropsychiatr. Dis. Treat., 5, 333 Papageorgiou, 1997, Leflunomide’s bioactive metabolite has the minimal structural requirements for the efficient inhibition of human dihydroorotate dehydrogenase, Bioorg. Chem., 25, 233, 10.1006/bioo.1997.1072 Ren, 1998, Dihydroorotate dehydrogenase inhibitors: quantitative structure-activity relationship analysis, Pharm. Res., 15, 286, 10.1023/A:1011978904905 Liu, 2000, Structures of human dihydroorotate dehydrogenase in complex with antiproliferative agents, Structure, 8, 25, 10.1016/S0969-2126(00)00077-0 Jöckel, 1998, Structural and functional comparison of agents interfering with dihydroorotate, Succinate and NADH oxidation of rat liver mitochondria, Biochem. Pharmacol., 56, 1053, 10.1016/S0006-2952(98)00131-2 Prakash, 1999, Leflunomide. A review of its use in active rheumatoid arthritis, Drugs, 58, 1137, 10.2165/00003495-199958060-00010 Garnock-Jones, 2013, Teriflunomide: a review of its use in relapsing multiple sclerosis, CNS Drugs, 27, 1103, 10.1007/s40263-013-0118-2 Weber-Schoendorfer, 2017, Leflunomide - A human teratogen? A still not answered question. An evaluation of the German Embryotox pharmacovigilance database, Reprod. Toxicol., 71, 101, 10.1016/j.reprotox.2017.04.007 Andersen, 2018, Pregnancy Outcomes in Men and Women Treated With Teriflunomide. A Population-Based Nationwide Danish Register Study, Front. Immunol., 9, 2706, 10.3389/fimmu.2018.02706 Baumann, 2009, Dihydroorotate dehydrogenase inhibitor A771726 (leflunomide) induces apoptosis and diminishes proliferation of multiple myeloma cells, Mol. Cancer Ther., 8, 366, 10.1158/1535-7163.MCT-08-0664 Huang, 2015, Teriflunomide, an immunomodulatory drug, exerts anticancer activity in triple negative breast cancer cells, Exp. Biol. Med. (Maywood), 240, 426, 10.1177/1535370214554881 Qiao, 2015, A77 1726, the active metabolite of leflunomide, attenuates lupus nephritis by promoting the development of regulatory T cells and inhibiting IL-17-producing double negative T cells, Clin. Immunol., 157, 166, 10.1016/j.clim.2015.01.006 S. Kota, V. Tellapaneni, S. Duddu, K.S.B.R. Adibhatla, V.C. Nannapaneni, WO 2017103942A1 (2017). K.P. Hirth, D.P. Schwartz, E. Mann, L.K. Shawver, G. Kéri, I. Székely, T. Bajor, K. Haimichael, L. Őrfi, A. Levitzki, A. Gazit, A. Ullrich, R. Lammers, F.F. Kabbinavar, D.J. Slamon, C.P. Tang, WO 1995019169A2 (1995). S. Patel, S. Dhol, V. Ray, WO 2014177978A2 (2014). J. Hachtel, B. Neises, W. Schwab, R. Utz, M. Zahn, US 20040186173A1 (2004). K. Deo, S. Patel, S. Dhol, S. Sanghani, V. Ray, WO 2009147624A2 (2009). R.R. Bartlett, K.U. Weithmann, E.S. Kurtz, US 5504084 (1996). S. T. Rajan, S. Eswaraiah, WO 2015029063A2 (2015). Métro, 2015, Comprehensive study of the organic-solvent-Free CDI-Mediated acylation of various nucleophiles by mechanochemistry, Chem. Eur. J., 21, 12787, 10.1002/chem.201501325 Métro, 2012, Mechanosynthesis of amides in the total absence of organic solvent from reaction to product recovery, Chem. Commun., 48, 11781, 10.1039/c2cc36352f Kim, 2005, (2R)-4-Oxo-4-[3-(Trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine: a potent, orally ActiveDipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes, J. Med. Chem., 48, 141, 10.1021/jm0493156 Dhillon, 2010, Sitagliptin, Drugs, 70, 489, 10.2165/11203790-000000000-00000 Hansen, 2005, First generation process for the preparation of the DPP-IV inhibitor sitagliptin, Org. Process Res. Dev., 9, 634, 10.1021/op0500786 Zhou, 2014, Chemical kinetic resolution of unprotected β-Substituted-β-Amino acids using recyclable chiral ligands, Angew. Chem. Int. Ed., 53, 7883, 10.1002/anie.201403556 Zhou, 2018, Configurationally stable (S)- and (R)-a-Methylproline-Derived ligands for the direct chemical resolution of free unprotected β3-Amino acids, Eur. J. Org. Chem., 2018, 1821, 10.1002/ejoc.201800120 Soloshonok, 2017, A question of policy: should tests for the self-disproportionation of enantiomers (SDE) be mandatory for reports involving scalemates?, Tetrahedron: Asymmetry, 28, 1430, 10.1016/j.tetasy.2017.08.020 Sorochinsky, 2013, Self-disproportionation of enantiomers of chiral, non-racemic fluoroorganic compounds: role of fluorine as enabling element, Synthesis, 45, 141 Keating, 2014, Sofosbuvir: first global approval, Drugs, 74, 273, 10.1007/s40265-014-0179-7 Parrish, 2013, Evaluation of 2’-α-fluorine modified nucleoside phosphonates as potential inhibitors of HCV polymerase, Bioorg. Med. Chem. Lett., 23, 3354, 10.1016/j.bmcl.2013.03.095 Keating, 2015, Ledipasvir/sofosbuvir: a review of its use in chronic hepatitis C, Drugs, 75, 675, 10.1007/s40265-015-0381-2 Greig, 2016, Sofosbuvir/velpatasvir: a review in chronic hepatitis C, Drugs, 76, 1567, 10.1007/s40265-016-0648-2 P. Chen, S. Peng, Y. Li, D. Li, X. Dong, Process for preparation of lactone derivatives and intermediates thereof, (2018) WO2018032356. Cini, 2018, Stereoselective synthesis of Sofosbuvir through nucleoside phosphorylation controlled by kinetic resolution, Eur. J. Org. Chem., 2018, 2622, 10.1002/ejoc.201800158 Citrome, 2007, Paliperidone: quo vadis?, Int. J. Clin. Pract., 61, 653, 10.1111/j.1742-1241.2007.01321.x M.K.J. François, R.C.A. Embrechts, H.K. Borghijs, J. Monbaliu, WO 1997044039A1 (1997). Spina, 2007, The pharmacology and safety of paliperidone extended-release in the treatment of schizophrenia, Expert Opin. Drug Saf., 6, 651, 10.1517/14740338.6.6.651 Samtani, 2009, Population pharmacokinetics of intramuscular paliperidone palmitate in patients with schizophrenia. A novel once-monthly, long-acting formulation of an atypical antipsychotic, Clin. Pharmacokinet., 48, 585, 10.2165/11316870-000000000-00000 M.K.J. François, W.M.A.C. Dries, E.D.G. Basstanie, WO 199925354A2 (1999). B. Dolitzky, WO 2008024415A2 (2008). J.R.R. Ravi, M.P. Reddy, B.R.A.K. Satya, N.V. Chowdary, WO 2009010988A1 (2009). J. Bartl, F. Picha, WO 2009015828A1 (2009). J.R.R. Ravi, M.P. Reddy, B.R.A.K. Satya, N.V. Chowdary, WO 2009016653A1 (2009). R.N. Kankan, D.R. Rao, S.L. Pathi, WO 2009047499A2 (2009). A.A. Chavan, A.V. Joshi, M.N. Bhanu, WO 2009116071A2 (2009). U.R. Bapat, M. Jayamani, S. Ravisaravanan, V.A. Sodha, J. Valgeirsson, WO 2009118655A2 (2009). J.P. Koilpillai, P.B. Kulkarni, L.M. Kelkar, S.A. Kale, S.G. Potdar, K.B. Narwade, M.A. Khan, J.R. Thorat, WO 2009130710A2 (2009). M.S. Reddy, S. Eswaraiah, R. Satyanarayana, WO 2010004578A2 (2010). I.A. Modi, K.R. Sodagar, M. Vineet, S.H. Jain, S.N. Parikh, A.O. Sharma, U.R. Bapat, B.M. Khamar, WO 2010064134A2 (2010). M. Ružič, A. Pecavar, D. Prudic, I. Plaper, A. Klobcar, WO 2011006638A1 (2011). G. Dixit, A.S. Khile, J.L. Patel, N.S. Pradhan, WO 2011030224A2 (2011). A.A. Chavan, M.N. Bhanu, A.V. Joshi, WO 2012134445A1 (2012). Solanki, 2013, An improved and efficient process for the production of highly pure paliperidone, a psychotropic agent, via DBU catalyzed N‑alkylation, ACS Sustainable Chem. Eng., 1, 243, 10.1021/sc3000916 Riva, 2011, Selective chemical oxidation of risperidone: a straightforward and cost-effective synthesis of Paliperidone, Eur. J. Org. Chem., 2319, 10.1002/ejoc.201001618 S. Ini, Y. ShmuelyO. Porter-Kleks, K. Chen, E. Lancry, C. Singer, WO 2009089076A2 (2009). M Gharpure, D. Rane, H.M.V. Swamy, P. Patil, J. Thorat, WO 2013046225A2 (2013). K. Rajiv, K.A.P. Dharmesh, S.M. Dattaray, R.S. Praveen, P.P. Prashant, V.P. Santosh, WO 2011074017A1 (2011). D. R. Rao, R. Ponnaiah, P.K. Neela, G. Batthini, T.V. Narasimharao, K. Ravanababu, K. Sudheer, WO 2012164582A1 (2012). Lamb, 2017, Glecaprevir/Pibrentasvir: first global approval, Drugs, 77, 1797, 10.1007/s40265-017-0817-y Wagner, 2018, Highlights of the structure−activity relationships of BenzimidazoleLinked pyrrolidines leading to the discovery of the hepatitis C virus NS5A inhibitor pibrentasvir (ABT-530), J. Med. Chem., 61, 4052, 10.1021/acs.jmedchem.8b00082 Koerts, 1998, Occurrence of the NIH shift upon the cytochrome P450-Catalyzed in vivo and in vitro aromatic ring hydroxylation of Fluorobenzenes, Chem. Res. Toxicol., 11, 503, 10.1021/tx980053i Cink, 2020, Development of the enabling route for glecaprevir via ring-closing metathesis, Org. Process Res. Dev., 24, 183, 10.1021/acs.oprd.9b00469 Kawashima, 2015, Asymmetric synthesis of (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid by sequential SN2–SN2’ dialkylation of (R)-N-(benzyl)proline-derived glycine Schiff base Ni(II) complex, RSC Adv., 5, 1051, 10.1039/C4RA12658K Sato, 2016, Tailor-made α-Amino acids in pharmaceutical industry: synthetic approaches to (1R,2S)-1-Amino-2-vinylcyclopropane-1-carboxylic acid (Vinyl-ACCA), Eur. J. Org. Chem., 2016, 2757, 10.1002/ejoc.201600112 Kawashima, 2016, Advanced asymmetric synthesis of (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid by alkylation/cyclization of newly designed axially chiral Ni(II) complex of glycine Schiff base, Amino Acids, 48, 973, 10.1007/s00726-015-2138-3 Klibanov, 2009, Elvitegravir, an oral HIV integrase inhibitor, for the potential treatment of HIV infection, Curr. Opin. Investig. Drugs, 10, 190 Deeks, 2014, Elvitegravir: a review of its use in adults with HIV-1 infection, Drugs, 74, 687, 10.1007/s40265-014-0206-8 Shiomi, 2015, Pharmacokinetic and bioequivalence evaluation of single-tablet and separate-tablet regimens for once-daily cobicistat-boosted elvitegravir in healthy Japanese male subjects: a randomized, two-way crossover study, Clin. Pharmacol. Drug Dev., 4, 218, 10.1002/cpdd.164 Unger, 2016, Elvitegravir for the treatment of HIV, Expert Opin. Pharmacother., 17, 2359, 10.1080/14656566.2016.1250885 Shimura, 2009, Elvitegravir: a new HIV integrase inhibitor, Antivir. Chem. Chemother., 20, 79, 10.3851/IMP1397 Shimura, 2008, Human cell proteins and human immunodeficiency virus DNA integration, J. Virol., 82, 764, 10.1128/JVI.01534-07 Turlure, 2004, Human cell proteins and human immunodeficiency virus DNA integration, Front. Biosci., 9, 3187, 10.2741/1472 Vandegraaff, 2007, Molecular mechanisms of HIV integration and therapeutic intervention, Expert Rev. Mol. Med., 9, 1, 10.1017/S1462399407000257 Yang, 1995, Recombining the structures of HIV integrase, RuvC and RNase H, Structure, 3, 131, 10.1016/S0969-2126(01)00142-3 Kawasuji, 2013, Carbamoyl pyridone HIV-1 integrase inhibitors. 2. Bi-and tricyclic derivatives result in superior antiviral and pharmacokinetic profiles, J. Med. Chem., 56, 1124, 10.1021/jm301550c Marinello, 2008, Comparison of raltegravir and elvitegravir on HIV-1 integrase catalytic reactions and on a series of drug-resistant integrase mutants, Biochemistry, 47, 9345, 10.1021/bi800791q Kawasuji, 2006, A platform for designing HIV integrase inhibitors. Part 2: a two-metal binding model as a potential mechanism of HIV integrase inhibitors, Bioorg. Med. Chem., 14, 8420, 10.1016/j.bmc.2006.08.043 Rádl, 2016, An improved synthesis of elvitegravir, J. Heterocycl. Chem., 53, 1738, 10.1002/jhet.2477 Sato, 2006, Novel HIV-1 integrase inhibitors derived from quinolone antibiotics, J. Med. Chem., 49, 1506, 10.1021/jm0600139 C.L. Sawyers, M.E. Jung, C.D. Chen, S. Ouk, D. Welsbie, C. Tran, J. Wongvipat, D. Yoo, WO2006124118A1 (2006). Flanders, 2017, Corrected net health benefit calculations for enzalutamide using ASCO value framework guidelines and NCCN evidence blocks, J. Manag. Care Spec. Pharm., 23, 1202 Nevedomskaya, 2018, Recent advances in prostate Cancer treatment and drug discovery, Int. J. Mol. Sci., 19, 1359, 10.3390/ijms19051359 Sternberg, 2019, Enzalutamide, an oral androgen receptor inhibitor for treatment of castration-resistant prostate cancer, Future Oncol., 15, 1437, 10.2217/fon-2018-0940 Vasaitis, 2010, Novel, potent anti-androgens of therapeutic potential: recent advances and promising developments, Future Med. Chem., 2, 667, 10.4155/fmc.10.14 Bohl, 2005, Structural basis for accommodation of nonsteroidal ligands in the androgen receptor, J. Biol. Chem., 280, 37747, 10.1074/jbc.M507464200 Jung, 2010, Structure−activity relationship for thiohydantoin androgen receptor antagonists for Castration-Resistant Prostate Cancer (CRPC), J. Med. Chem., 53, 2779, 10.1021/jm901488g A. Thompson, C. Lamberson, S. Greenfield, WO2011106570A1 (2011). J. Stach, O. Klecan, P. Lehnert, J. Rymes, WO2015154730A1 (2015). S. Frigoli, D. Longoni, M. Alpegiani, WO2016188996A1 (2016). Inventors: K.R. Chivukula, V.V.R. Karuturi, S. Benda, R. Anke, D. Gajula, V.R.K.M. Moturu, V.S.K. Indukuri, S.R.A. Gorantla, S. Chava, WO2016051423A2 (2016). P.H. Desai, S. Seetharaman, V.H. Nikam, K.M. Kamble, WO2019106691A1 (2019). Garvey, 2008, The naphthyridinone GSK364735 is a novel, potent human immunodeficiency virus type 1 integrase inhibitor and antiretroviral, Antimicrob. Agents Chemother., 52, 901, 10.1128/AAC.01218-07 Ziegler, 2018, 7‐Step Flow Synthesis of the HIV Integrase Inhibitor Dolutegravir, Angew. Chem. Int. Ed., 57, 7181, 10.1002/anie.201802256 Kobayashi, 2011, In vitro antiretroviral properties of S/GSK1349572, a next-generation HIV integrase inhibitor, Antimicrob. Agents Chemother., 55, 813, 10.1128/AAC.01209-10 Kandel, 2015, Dolutegravir–a review of the pharmacology, efficacy, and safety in the treatment of HIV, Drug Des. Devel. Ther., 9, 3547, 10.2147/DDDT.S84850 Cottrell, 2013, Clinical pharmacokinetic, pharmacodynamic and drug-interaction profile of the integrase inhibitor dolutegravir, Clin. Pharmacokinet., 52, 981, 10.1007/s40262-013-0093-2 Llibre, 2015, Genetic barrier to resistance for dolutegravir, AIDS Rev., 17, 56 Ballantyne, 2013, Dolutegravir: first global approval, Drugs, 73, 1627, 10.1007/s40265-013-0121-4 Greig, 2015, Abacavir/dolutegravir/lamivudine single-tablet regimen: a review of its use in HIV-1 infection, Drugs, 75, 503, 10.1007/s40265-015-0361-6 Castellino, 2013, Metabolism, excretion, and mass balance of the HIV-1 integrase inhibitor dolutegravir in humans, Antimicrob. Agents Chemother., 57, 3536, 10.1128/AAC.00292-13 Rathbun, 2014, Dolutegravir, a second-generation integrase inhibitor for the treatment of HIV-1 infection, Ann. Pharmacother., 48, 395, 10.1177/1060028013513558 Sankareswaran, 2016, Identification and control of critical process impurities: an improved process for the preparation of dolutegravir sodium, Org. Process Res. Dev., 20, 1461, 10.1021/acs.oprd.6b00156 Hughes, 2019, Review of synthetic routes and final forms of integrase inhibitors dolutegravir, cabotegravir, and bictegravir, Org. Process Res. Dev., 23, 716, 10.1021/acs.oprd.9b00031 Markham, 2018, Bictegravir: first global approval, Drugs, 78, 601, 10.1007/s40265-018-0896-4 Gallant, 2017, Bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection (GS-US-380-1489): a double-blind, multicentre, phase 3, randomised controlled non-inferiority trial, Lancet, 390, 2063, 10.1016/S0140-6736(17)32299-7 Sax, 2017, Bictegravir versus dolutegravir, each with emtricitabine and tenofovir alafenamide, for initial treatment of HIV-1 infection: a randomised, double-blind, phase 2 trial, Lancet HIV, 4, 154, 10.1016/S2352-3018(17)30016-4 Oliveira, 2018, Selective resistance profiles emerging in patient-derived clinical isolates with cabotegravir, bictegravir, dolutegravir, and elvitegravir, Retrovirology, 15, 56, 10.1186/s12977-018-0440-3 Deeks, 2018, Bictegravir/emtricitabine/tenofovir alafenamide: a review in HIV-1 infection, Drugs, 78, 1817, 10.1007/s40265-018-1010-7 Tsiang, 2016, Antiviral activity of bictegravir (GS-9883), a novel potent HIV-1 integrase strand transfer inhibitor with an improved resistance profile, Antimicrob. Agents Chemother., 60, 7086, 10.1128/AAC.01474-16 Smith, 2018, Efficacies of cabotegravir and bictegravir against drug-resistant HIV-1 integrase mutants, Retrovirology, 15, 37, 10.1186/s12977-018-0420-7 Jeong, 1993, Asymmetric synthesis and biological evaluation of β-L-(2R,5S)- and α-L-(2R,5R)-l,3-Oxathiolane-Pyrimidine and -Purine nucleosides as potential Anti-HIV agents, J. Med. Chem., 36, 181, 10.1021/jm00054a001 S. Rama, S.C.S. Gorantla, L.R. Vadali, V.B.K.S. Inupakutika, S.R. Dasari, N. Mittapelly, S.K. Singh, D. Datta, Novel process for the preparation of cis-nucleoside derivative, WO2011095987 (2011). Osborne, 2006, Immobilization of cholesterol esterase for use in multiple batch biotransformations to prepare (-)- FTC (Emtricitabine), Org. Process Res. Dev., 10, 670, 10.1021/op050258f Yasumoto, 2010, Self-disproportionation of enantiomers via sublimation: isopropyl 3,3,3-(Trifluoro)-Lactate, J. Fluorine Chem., 131, 535, 10.1016/j.jfluchem.2009.11.026 Nakamura, 2012, Self-disproportionation of enantiomers of non-racemic chiral amine derivatives through achiral chromatography, Tetrahedron, 68, 4013, 10.1016/j.tet.2012.03.054 S.D. Young, S.F. Britcher, L.S. Payne, L.O. Tran, W.C. Lumma Jr., WO1994003440 (1994). Grabowski, 2005, Enantiopure drug synthesis: from Methyldopa to imipenem to efavirenz, Chirality, 17, S249, 10.1002/chir.20143 Vrouenraets, 2007, Efavirenz: a review, Expert Opin. Pharmacother., 8, 851, 10.1517/14656566.8.6.851 De Clerq, 2013, The nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors,and protease inhibitors in the treatment of HIV infections (AIDS), 317, 10.1016/B978-0-12-405880-4.00009-3 Pastuch-Gawołek, 2019, Selected nucleos(t)ide-based prescribed drugs and their multi-target activity, Eur. J. Pharmacol., 865, 10.1016/j.ejphar.2019.172747 Johnson, 2019, Origins and evolutionary consequences of ancient endogenous retroviruses, Nat. Rev. Microbiol., 17, 355, 10.1038/s41579-019-0189-2 Purser, 2008, Fluorine in medicinal chemistry, Chem. Soc. Rev., 37, 320, 10.1039/B610213C Young, 1995, L-743,726 (DMP-266): a novel, highly potent nonnucleoside inhibitor of the human immunodeficiency virus type 1 reverse transcriptase, Antimicrob. Agents Chemother., 39, 2602, 10.1128/AAC.39.12.2602 Radesca, 1997, Synthesis of HIV-1 reverse transcriptase inhibitor DMP 266, Synth. Commun., 27, 4373, 10.1080/00397919708005064 Thompson, 1995, Use of an ephedrine alkoxide to mediate enantioselective addition of an acetylide to a prochiral ketone: asymmetric synthesis of the reverse transcriptase inhibitor L-743,726, Tetrahedron Lett., 36, 8937, 10.1016/0040-4039(95)01955-H Pierce, 1998, Practical asymmetric synthesis of efavirenz (DMP 266), an HIV-1 reverse transcriptase inhibitor, J. Org. Chem., 63, 8536, 10.1021/jo981170l Tan, 1999, A novel, highly enantioselective ketone alkynylation reaction mediated by chiral zinc aminoalkoxides, Angew. Chem. Int. Ed., 38, 711, 10.1002/(SICI)1521-3773(19990301)38:5<711::AID-ANIE711>3.0.CO;2-W Chinkov, 2011, Asymmetric autocatalysis enables an improved synthesis of efavirenz, Angew. Chem. Int. Ed., 50, 2957, 10.1002/anie.201006689 D. Dai, X. Long, B. Luo, A. Kulesza, J. Reichwagen, Y. Guo, WO 2012097510 (2012). Correia, 2015, A concise flow synthesis of efavirenz, Angew. Chem. Int. Ed., 54, 4945, 10.1002/anie.201411728 Okusu, 2016, Alkynyl Cinchona catalysts affect enantioselective trifluoromethylation for efavirenz under metal-free conditions, Org. Lett., 18, 5568, 10.1021/acs.orglett.6b02807 Sorochinsky, 2013, Optical purifications via Self-Disproportionation of Enantiomers by achiral chromatography; case study of a series of α-CF3-containing secondary alcohols, Chirality, 25, 365, 10.1002/chir.22180 Han, 2011, Self-disproportionation of enantiomers via sublimation; new and truly green dimension in optical purification, Curr. Org. Synth., 8, 310, 10.2174/157017911794697303 Inoue, 2020, Contribution of organofluorine compounds to pharmaceuticals, ACS Omega, 5, 10633, 10.1021/acsomega.0c00830