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Home , Antonine Plague, Black Death, Great Plague of London, Hong Kong flu, Manchurian plague, Pandemic severity index

Baran Group Meeting Dongmin Xu and 04/27/20

Timeline of some major epidemics/pandemics in history Quick facts: • From wikipedia: • An is the rapid spread of a to a large number of ~ 400 BC of Athens (Greece, possibly ) people in a given population within a short period of time. 165-180 (, possibly ) • A is a serious epidemic that has spread over a large region and/or affects a substantial number of people. 250-266 (, possibly smallpox) • The most fatal pandemic in was the Black , which resulted in an estimated 75-200 million deaths (1/3 of European population) 541-542 (Europe, plague) • Major that were responsible for outbreaks: • Medication available: plague, tuberculosis, , malaria, cholera, 735-737 Japanese smallpox epidemic (, smallpox) , AIDS/HIV • Only vaccines: , smallpox, typhus, yellow , 1300s (Europe, plague) • No treatments available: coronavirus (SARS, MERS, COVID-19) 1600s Italian plague (, plague) Compartment model in : • The simplest model for a is the SIR model, where: Great plague of (, plague) • S = number of Susceptibles • I = number of Infected Great plague of Vienna (Austria, plague) • R = number of Recovered (or deceased) S, I and R are all functions with respect to time t susceptible Great plague of (, plague) recovered 1700s • Rates of change for S, I, and R: Persian plague (Persia, plague) (β = avg. number of social encounters, I/N = avg. prob. of encoutering a patient) 1800s Ottoman plague epidemic (, plague) infected (γ = the rate at which patients recover/die) 1st, 2nd and 3rd cholera pandemic (worldwide, cholera) http://jsxgraph.uni-bayreuth.de/wiki/ 1889-1890 flu pandemic (worldwide, influenza) index.php/Epidemiology:_The_SIR_model 1900s (, ) • Controlling the infected curve is crucial to pandemic management https://en.wikipedia.org/ (worldwide, influenza) wiki/Pandemic

Asian flu (worldwide, influenza) • Containment • Mitigation (worldwide, influenza) • Suppression HIV/AIDS pandemic (worldwide, HIV/AIDS) 2000s 2004-04 SARS outbreak (worldwide, SARS) • The basic reproduction number (R0): the expected number of cases generated by one case in a population where all individuals are still susceptible. 2009 flu pandemic (worldwide, influenza) • Not to be confused with the effective reproduction number (R) Measles 12-18 • When R > 1, the disease spreads 2012 MERS outbreak (worldwide, MERS) Chickenpox 10-12 • When R < 1, the outbreak is under controll and will die out Rubella 5-7 • Importance of vaccination: decrease R (herd ) Ebola virus epidemic (west , Ebola) Smallpox 3.5-6 This GM covers: Zika virus epidemic (worldwide, Zika virus) COVID-19 1.4-5.7 • Basic information of epidemics/pandemics HIV/AIDS 2-5 • Several viral epidemics (influenza, HIV, coronavirus) present 2019-20 coronavirus pandemic (worldwide, COVID-19) Common cold 2-3 • Associated antiviral drugs and their synthesis Influenza (1918) 1.4-2.8 = over 100,000 deaths Not covered: Seasonal flu 0.9-2.1 • Bacterial or parasitic diseases = over 1 million deaths • Baran Group Meeting Dongmin Xu Epidemics and Pandemics 04/27/20

https://www.cdc.gov/flu/about/index.html Influenza Virus: https://micro.magnet.fsu.edu/cells/ Influenza viruses/influenzavirus.html • An infectious respiratory disease caused by the influenza virus • Belongs to , a family • Common symptoms include high fever, runny nose, sore throat, muscle and joint pain, of RNA viruses • Four distinct genera: A, B, C, and D headache, coughing, and fatigue • Some structural charateristrics: • Shares many symptoms with common cold. However, common cold is mostly caused • Lipid envelop by human rhinovirus and its symptoms are usually milder. (why rubbing alcohol disinfects) • A yearly outbreak pattern: October to May considered in the US • Nucleoprotein: 8 pieces of single- • 300k - 650k deaths annually; over 3 million cases of severe illness stranded RNA packed with proteins • On average, about 8% of the U.S. population gets flu every season • Hemagglutinin (HA) and • (PSI): a level 1 to 5 scale for severity of influenza pandemics (NA): important surface glycoproteins for based on the . Level 5 has the highest case fatality rate of >2.0%. cell recognition and viral replication. Also the major antigens to trigger immune responses. Pandemic History: J. Appl. Microbiol. 2001, 91, 572–579 Serotypes: • First confirmed record of an influenza epidemic dates back to 1500s • : mutations and of viral strains can lead to structural • Responsible for several major outbreaks since the 20th century changes in HA and NA, resulting in different antigenic properties. Case Pandemic • Only observed in influenza A viruses Name Date Deaths fatality rate severity index • Influenza A serotypes are denoted as HxNy • x and y are arbitrary numbers denoting the types of HA and NA 1918 flu pandemic • A total of 18 different types of HA and 11 different types of NA were identified (Spanish flu) 1918-1919 17-50 million 2-3% 5 • Out of the 198 possible permutations, 131 serotypes were found in Asian Flu 1957-1958 1-1.5 million 0.13% 2 • Trivia: match the influenza serotype with the corresponding epidemics/pandemics Hong Kong Flu 1968-1969 0.75-1 million <0.1% 2 2009 swine flu H1N1 2009 flu pandemic 2004 avian flu/bird flu (swine flu) 2009-2010 100k - 400k 0.03% N/A H2N2 1968 Hong Kong flu H3N2 The 1918 Flu Pandemic: Emerg Infect Dis. 2006, 12, 15–22. • Origin was disputed; hypotheses include Kansas or European troops in WWI 1957 Asian flu H5N1 • Around 500 million people were infected globally, around 1/3 of the world’s population 1918 Spanish Flu H7N9 • A unique (and not explained) feature is the high mortality rate among young adults • Public places were closed and were enforced; “” Mechanism of Action: Front. Immunol. 2018, 9, 1581 • Mutation of the virus was observed between the “waves” • usually occurs through aerosols (coughs, sneezes, etc.), less commonly of outbreaks through saliva, bodily fluids and feces. • Massive troop movements during WWI likely accelerated • Step 1: Viral HA binds to the epithelial cell, causing the the pandemic and selected for more virulent strains. virus being imported by endocytosis • Died out quickly in early 1919 • Step 2: Viral RNA and RNA polymerases are • Genetic mapping of the virus made possible after Johan released into the cytoplasm and relocate Hultin’s discovery of body samples stored in the permafrost to the nucleus. near Brevig Mission, a remote Alaskan • Step 3: RNA replication in the nucleus (https://www.cdc.gov/flu/pandemic-resources/reconstruction-1918-virus.html) • Step 4: Viral mRNA re-enters the cyto- plasm and is translated by ribosomes • Step 5: Viral proteins are transported to the cell membrane (HA and NA) or stay the cytoplasm for inhibition of normal cell activity • Step 6: Viral RNA and proteins aggregates near the cell membrane and forms a protusion • Step 7: The new virus detaches (facilitated by NA) by exocytosis, usually followed by death of host cell (https://en.wikipedia.org/ wiki/Orthomyxoviridae) Baran Group Meeting Dongmin Xu Epidemics and Pandemics 04/27/20 OH O O Clin. Microbiol Rev. 2016, 29, 695–747 All Approved Antiviral Drugs for Influenza: For a useful review of viral NA inhibitors, see: O O Molecules 2016, 21, 1513 HO OH Me OEt

NH2 OH HN Me HN F HN NH2 NH2 Me O Me O S F NH (Tamiflu®) ® O ® (Symmetrel ) (Relenza ) Gilead, FDA Approv. 1999 FDA Approv. 1968 F N GSK, FDA Approv. 1999 O H NH2 N N O OMe O NH OH N OH Me NH O N 2 ® HO OH H N O Favipiravir (Avigan ) 2 N OH Toyama Chemical OH H MeO O O O Approv. 2014 (Japan) HN Me NH HN NH2 O Me O (Xofluza®) ® Me O Me (Flumadine ) NH Shionogi & Roche, FDA Approv. 2018 FDA Approv. 1994 (Inavir®) (Rapivab®) Daiichi Sankyo, Approv. 2010 (Japan) BioCryst, FDA Approv. 2014 M.2 protein inhibitors RNA polymerase inhibitor Neuroaminidase (NA) inhibitors Cap-dependent endonuclease inhibitor Selected Syntheses: First Synthesis by von Itzstein: OAc OH OH + O CO2Et OH O OH EtOH, H OH Ac O, AcOH AcO TMSN3, tBuOH O 80°C O 2 HO HO 80 °C O CO2H CO2Et OAc HO OH OH 93% OH 72% N 85% AcHN AcHN OH O HN OH OH OAc Me N-acetylneuraminic acid ($47/g) HN NH2 Me O O CO2Et 1) KOH OAc 1) H2, Lindlar cat. AcO NH O CO Et 2) TFA Zanamivir 2 NBoc OAc Zanamivir AcO 2) AcHN Shibasaki’s Synthesis: OAc (6 steps, 30%-50% overall) AcHN MeS NHBoc HN NBoc NO HgCl2, Et3N 2 N3 NHBoc + 85% over 2 steps Carbohydr. Res. 1994, 259, 301–305. PMBO CHO Nd5O(OiPr)13 NaHMDS OBn OTBS 1) OsO OBn OTBS CO2Me -60 °C, 71% OH 10 steps 4 2) NaIO (next page) 3% of: iPr BnO 4 BnO O H OH PMBO OTBS HO N 3) Wittig N NO 22% overall OBn NHAc OBn NHAc H O 2 F F Angew. Chem. Int. Ed. 2012, 51, 1644–1647 Baran Group Meeting Dongmin Xu Epidemics and Pandemics 04/27/20

O OAc 1) H , Pd/C OBn 2 1) Bu NF, AcOH 2) Ac O OAc Ph O CO2Et 4 2 O AcO 2) BF •OEt O CO2Me 79% over 4 steps Ac2O, AcOH 3 2 O CO2Me OAc BnO AcO Zanamivir OBn 3) PhCO2tBu N same steps as CuBr, reflux OAc AcHN AcHN O von Itzstein et al Me Me Ma’s synthesis: Me 20 mol% cat. O OMOM OMOM O CHO 1) Zn, AcOH Me acetone Me O O Me O O Me Me 2) AcCl, Et N PhCO2H 3 O2N O2N OMOM Me PhMe, relux Me O NHBoc BocHN O CuBr2, L* O 77% AcHN 72%, 98% ee O2N Cs2CO3, THF 0°C, 60% NHBoc NHBoc 1) SeO cat. = Me tBu S 2 [name and N 2) NaClO2, mechanism Bn N N NaH2PO4, H H NH OMOM of step 2?] O NH2 N OH Me H2N N Me Me O O CO H Me Ph O O CO2H + 2 Me L* = Ph OH H Zanamivir OH Me Me 88% O O N CF3 AcHN AcHN (8 steps LLS, 18% overall) NHBoc NH2 Angew. Chem. Int. Ed. 2014, 53, 13885 –13888 Rohloff synthesis (first): Et Et O Et Et 1) EtOH, SOCl2 1) TMSOTf, O HO CO2H 2) 3-pentanone O CO2Et BH Me S O CO Et Me OEt Et 3 2 2 TsOH 70% O CO2Et NaN3 Et O Me HN HO 3) MsCl, Et3N 2) KHCO3, 96% NH4Cl HO 80% over 3 steps 86% NH2 OH OMs O N Me O 3 (–)-shikimic acid Et Et Oseltamivir Et Et + 1) Ac O Et Et 2 O CO Et 2) Ra-Ni, H 2 2 O CO2Et 3) H PO NaN3 O CO Et PMe • 11 steps, 35% overall Oseltamivir 3 4 2 3 • Used for multi-ton (monophosphate salt) N3 H2N production OH N 3 HN J. Org. Chem. 1998, 63, 4545-4550 Sudalai synthesis: 1) TBSCl 1) IBX 2) (-)-DET, Ti(OiPr) O CO2Et 1) MOMCl 2) Bestmann OH 4 Br O O CO Et 2) TBAF CO Et reagent TBHP, 4Å MS CHO 2 2 (next page) 3) TEMPO Zn, NH Cl 80% 82% in 2 steps HO 4 OH RO PhI(OAc)2 TBSO 64% TBSO HO 88% over 3 steps d.r. = 4:1 (R = MOM) Baran Group Meeting Dongmin Xu Epidemics and Pandemics 04/27/20

HO CO2Et 1) IBX O CO Et 1) H , Lindlar cat.RO CO2Et 1) Ph3P 2) Bestmann 2 2 RO CO2Et 95% 2) Ac2O reagent NaN3 AcHN Oseltamivir RO 2) Grubbs II 83% 3) 3-pentanol Et O 3 steps 82% in 2 steps O HO + (R = MOM) 90% 4) H (R = MOM) 53% N3 Et Org. Biomol. Chem., 2012, 10, 3988. Ma’s synthesis: O CHO NHAc Et Et EtO2C P(O)(OEt)2 then SH Et Et ArS Et Et OHC NO2 O N EtO2C O 1) TMSCl, Zn 2 cat. = Me EtO2C O Et O Oseltamivir NHAc naph Cs2CO3, 0 °C –15 °C 2) K CO naph NHAc 2 3 N NHAc H OTMS Et NO2 80%, 5:1 d.r., 96% ee NO2 Angew. Chem. Int. Ed. 2010, 49, 4656 –4660 1) NaOH F OHex 2) EDC S OH 1) n-hexyl iodide OHex O CO2Me O CO Me 90% over 2 steps F O CO H 2 O O 2 CO Me N 2) Boc-NHNH2 2 N O H O PPTS H N N H NHBoc 2 NHBoc MeO OMe N 82% N O MeO OMe (2 steps from N-Boc-L-serine) N mesityl O Me Me MeO O O O OHex O 1) MsOH, 75% OHex O CO2H 2) NaOH, 89% N O O N O d.r. = 20:1 N Me Baloxavir marboxil (Xofluza®) N O N O (p-ClC H S) , Blue LED Shionogi & Roche, FDA Approv. 2018 6 5 2 N N 92% H 1) T3P, MeSO H H 3 2) LiCl A Xofluza® O O 76% CO2H O CO H d.r = 15:1 LDA, –40 °C O O HMe Si SiMe H 2 1) PPA 2 2 HO then DMF PhSH, CSA AlCl 2) NaBH4 S OH SPh 3 SPh 81% in 3 steps 90% in 2 steps F F F F F F F F F F • Hexyl group promotes higher d.r. during final coupling step • When other PGs are used (e.g. iPr, Bn), d.r. ≤ 6:1 B

Org. Process Res. Dev. 2019, 23, 1298−1307 Baran Group Meeting Dongmin Xu Epidemics and Pandemics 04/27/20

(Wikipedia: HIV/AIDS) HIV: https://en.wikipedia.org/wiki/HIV AIDS (Acquired Immunodeficiency Syndrome) (CDC: About HIV/AIDS) • Is a single-stranded, enveloped RNA retrovirus, • Is an immune system condition caused by the human immunodeficiency a member of the genus Lentivirus, part of the viruses (HIV). family retroviridae. • Early symtoms of HIV are usually light (“influenza-like”) to non- • Some structural charateristics: existent, followed by an incubation period of varying lengths with no • Lipid envelop: taken from the host cell, detectable symptoms. together with membrane proteins • Progressive failure of the immune system leads to AIDS and a variety of • gp120 and gp41: envelop other late-stage symptoms; most deaths are due to opportunistic glycoproteins that facilitates attachment or cancer growth at this stage. and release from the host cell • Common transmission pathways are sexual contact, body fliuds and mother-to-child. • Genome: two copies of single- • The average survival time after infection is 11 years without any treatment. stranded RNA encoding 9 genes Pandemic history: • Reverse transcriptase (RT): RNA —> DNA • HIV originated in Kinshasa, Democratic Republic of Congo around 1920 when the virus • Two subtypes: HIV-1 and HIV-2 crossed from chimpanzees to . • HIV-1 is more virulent and infectious, hence globally prevalent • First clinical cases of HIV dates back to 1981 in the US, where unusual clusters of • HIV-2 is less virulent and is only found in west Africa Pneumocystis (PCP) and Kaposi’s sarcoma (a rare skin cancer) cases were • Viral tropism: the cell types that a virus infects reported by the CDC. • M-tropic: infects macrophages through β-chemokine receptor CCR5 • In 1983, research groups led by Robert Gallo and Luc Montagnier simultaneously • T-tropic: infects CD4+ T cells through α-chemokine receptor CXCR4 discovered a retrovirus from AIDS patients, now confirmed to be HIV. • Dual-tropic: infects both macrophages and CD4+ T cells • In 2018, about 37.9 million people are carry HIV and 770,000 died from AIDS. Infection mechanism: https://www.niaid.nih.gov/diseases-conditions/hiv-replication-cycle Epidemiology: J. Clin. Invest. 2008, 118, 1244–1254 • Geographic distribution is extremely unbalanced, • Interaction between viral with sub-Saharan Africa accouting for 68% of HIV gp120 and host cell CD4 patients and 76% of all death cases. (attachment) • Caribbean is the 2nd most affected region with a • Fusion of the HIV with the overall population prevalence of 1%. host cell (endocytosis) • New HIV diagnoses by transmission category • HIV RNA and proteins (US, 2018): enters the cytoplasm • Male-to-male sexual contact: 66% • RT reverse transcribes viral • Heterosexual contact: 24% RNA back to DNA. • Injection drug use: 7% https://www.kff.org/global-health-policy/ • Integration of viral DNA into • Others: 3% fact-sheet/the-global-hivaids-epidemic/ host cell genome, facilitated Misconceptions by integrase • HIV CANNOT be transmitted through the following pathways: • Integrated viral DNA is • Kissing • Insect bites (mosquitos) • Sneezes and coughs transcribed and translated to • Hugging • Toilet seats • Sweat synthesize viral proteins • Sharing food • Bathing • Casual contact with an HIV patient • New viral RNA and proteins • In other words, not all body fluids can transmit HIV aggregate in protusions near • Those misconceptions are common causes of negative attitudes, beliefs, and discri- the cell surface (budding) mination against people living with HIV. • Release of the new virus • Maturation: viral protease Testing and Treatment: cleaves the newly- • Enzyme-linked immunosorbent assay (ELISA): detects HIV antibodies in the blood synthesized poly-protein. sample (basic principles are similar to western blots.) • If ELISA repeatedly returns positive results, confirmatory testing such as western blot, PCR, or immunofluorescence assay (IFA) are taken to complete the diagnosis. • Treatment usually includes the use of multiple antiretroviral drugs. With proper manage- * Viral RT, integrases and proteases ment, an HIV infection can be slowed and can lead to near-normal life expectancies. are common targets for antiretroviral • Precautions should be taken against opportunistic infections, e.g. proper vaccination. drugs Baran Group Meeting Dongmin Xu Epidemics and Pandemics 04/27/20

All approved anti-HIV drug molecules: Molecules 2016, 21, 1513 Class I: NRTIs O HN H H N O N O N N O N O N OH S OH S OH N N N N N N NH N Me Me 2 F 3 H N O N O N O O O O O

HO OH H2N N O HO HO H2N N O H2N N O Zidovudine (AZT) Didanosine Zalcitabine Stavudine Abacavir Lamivudine Emtricitabine

Class III: Protease inhibitors Class II: NNRTIs S Ph N Me NHtBu Me Me O OH O H H H Me N N N O O O Me N N S Me HN O NH2 OH HN H NH H N 2 O O N N N Me Me Ph N N H H N N O Ritonavir N N H Ph N N saquinavir Me O S O OH H Nevirapine MsHN O PhS O NHtBu N N O Me O Me O OH O O H H Delavirdine HO O N N N OMe N N Ph MeO N N H H H H Me Br H OH Amprenavir O O N O Ph O NH2 H NH2 Atazanavir O NH N N Cl Nelfinavir 2 N Me C F t HO NH BuHN O F F O Me O S O OH O H H OH N N P NC N N O Me O S O O OH H Me O N N OH H Etravirine Efavirenz Ph N N O O H Me Me Ph O O Indinavir O Darunavir O Me H O H H N Ph N N N O S N Fosamprenavir O N OH F F NC Me CN H O OH F Tipranavir F O Rilpivirine Me N O NH F Class IV: Integrase inhibitors F O O N O OH O Me O O Cl O H H OH F F O HN OH F N N N MeN H H H N F F Me MeO N N N OH bictegravir N N O H O N Me OH H O N O O Me Me O O Me Raltegravir cabotegravir Elvitegravir Dolutegravir Me F Baran Group Meeting Dongmin Xu Epidemics and Pandemics 04/27/20 Selected syntheses: [name?] Me Me BI nevirapine synthesis: Me Me O CN CN NH4OH POCl , 130°C CN + 3 1) H NH2 O O Cl + + Me 94% 88-96% 2) Br , NaOH HN H N O 2 EtO O 2 HO N O Cl N Cl H 86% in 2 steps Cl N Cl N Cl O N N N Me Cl N Pd/C, H2 HN Me HN N NH H 89% NaH Me 2 N 72% H Nevirapine in 2 steps N 84% N N N O Cl Cl N Cl O Cl N Cl J. Heterocyclic. Chem. 1995, 32, 259

Merck raltegravir synthesis: 1) Med chem route: MeO2C CO2Me O 1) NH OH 3 N O xylene, OH Me CN 2) CbzCl Me CN NH2OH DMAD N reflux HN CbzHN [structure?] CbzHN CbzHN NHCbz NH2 NH [mechanism?] Me OH Me 2 N CO2Me Me Me Me Me Me Me O O O OBz Me OBz Bz2O HN Me2SO4, LiH N H , Pd/C Me OH 2 N CbzHN 85% CbzHN 67% N CO Me N CO2Me quant. H2N 2 N CO Me amide coupling x2 Me Me Me Me 2 (+30% O-methylation) Me Me 2) Synthesis of oxadiazole fragment O O O CO Et 1) KOH OH F N 2 70 °C N N MeN N N N 2) (COCl)2, DMF N N H H Cl CO2Et – N2 NH N N Cl Me N N N 0 °C N 91% Me CO Et 91% Me O N N O 2 O Me [mechanism?] O O Me Me O Me Raltegravir 3) Optimization of methylation Me O MgX O O O Original conditions: A:B = 70:30 OH Me OH Me O MeI, base OH use Mg(OMe) N HN N + N 2 1 2 1 2 1 2 1 2 R HN NHR R HN NHR 65 °C R HN NHR R HN NHR A:B = 80:20 N N N N rxn time 4h —> 20h Me Me O Me Me O Me Me O Me Me O A B A:B = 99:1 Org. Process Res. Dev. 2011, 15, 73. Baran Group Meeting Dongmin Xu Epidemics and Pandemics 04/27/20

Gilead synthesis of bictegravir: O MeO C OMe 1) Med chem route: O O CO2Me 2 O O OMe H2N DMF-DMA OMe CO2Me LiOH, -2 °C O O OMe OMe MeO MeO N CO2Me OMe LiOMe 61% over OMe OMe MeO N 4 steps NMe2 H OMe OMe

O MeO OMe O HO2C OMe HO NH2 HN O CO2H MsOH, 75 °C CO2H N N CO2H N CO2Me N MeO C O MeO C O OMe 2 2 OMe OMe MeO2C O OMe OMe F F H O F O F O CO2H H H N O O N N F NH2 N N MgBr2 N H H O N N HATU, iPr2NEt O F F O F F O OMe O OMe O OH bictegravir

2) Process route: OMe F F OH O O O O O O O F OMe MeO MeO CO2H F NH 1) DMF-DMA MeO O O 2 MeO N Ar N O O O tBuCOCl H TFA H 2) MeO O O NH HN Me Me F F 2 OMe Me Me MeO

O O OMe MeO OMe O MeO H O O N Ar 1) MsOH, 75 °C H N N Ar MgBr2 N N Ar H bictegravir MeO2C N 2) N H O MeO MeO C O HO NH 2 2 O OMe OMe • Avoids the low-selectivity saponification step with LiOH OMe • The expensive aminocyclopentanol is incorporated later in the sequence

Org. Process Res. Dev. 2019, 23, 716−729 Baran Group Meeting Dongmin Xu Epidemics and Pandemics 04/27/20 Coronavirus Gilead’s synthesis of remdesivir: O O O P • …refers to the virus family Coronaviridae Me Me Cl OPh O Me • Causes respiratory tract infections ranging from mild to O Me Cl O lethal, depending on the sub-type of the virus. NH • Named due to its appearance under TEM that resembles NH3 P Me Cl Me PhO a solar corona Cl A • Structural characteristics: BnO O BnO O Ac2O, DMSO OH O B BnO BnO OBn OBn Br O N TMS TMS Me NH2 N NH2 N Me Br N 1) TMSCl N O N N N N then Na2SO3 N 2) nBuLi N N Br Li [how to make this?] NH B 2 then H+ 60% NH2 Coronavirus outbreaks: https://en.wikipedia.org/wiki/Coronavirus N BnO Case N N Disease Discovery date Cases Deaths O N TMSCN BnO fatality rate TMSOTf N CN O N SARS-CoV SARS Nov. 2002 8096 774 9.2% 85% OH MERS-CoV MERS Jun. 2012 2494 858 37% BCl3 BnO OBn SARS-CoV-2 COVID-19 Dec. 2019 2,915,368 203,534 7.0% 74% (β:α = 89:11) BnO OBn

COVID-19 drug development (as of 04/27/20): NH2 PhO NH2 • Seven drugs in late-stage clinical trials: 2 antibody drugs, 5 small molecule drugs N A O • Remdesivir: adenosine nucleotide analog; antiviral; previously Ebola drug candidate P N HO then chiral HPLC HN • Hydroxychloroquine: antiparasitic; previously used for malaria treatment N O O O N • Favipiravir: previously used as antiviral against influenza N O 21% Me N • Lopinavir/ritonavir: previously used as AIDS treatment CN • ASC-09 + ritonavir: antiviral, combination not approved O CN • Sarilumab: human monoclonal antibodies for the interleukin-6 receptor HO OH • Tocilizumab: same as above Et HO OH Et Me Et Me Ph Patent US 9724360 remdesivir OH O Me N H J. Med. Chem. 2017, 60, 1648−1661 HN OH N O N Me H “I think we’ll have to wait until it is over and we look back before we can answer that. It’s Me O O N almost like the fog of war. After the war is over, you then look back and say, “Wow, this Ph plan, as great as it was, didn’t quite work once they started throwing hand grenades at Cl N HN us.” It really is similar to that.” lopinavir hydroxychloroquine – Anthony Fauci’s comments on the cause of COVID-19 crisis