A Little About the Chemistry of Peroxides

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1 A Little About the Chemistry of Peroxides (which can fight malaria, by the way) Artemisinin Yingzhaosu A Ramil Baiazitov November 4, 2003

2 Natural Peroxy Compounds Fatty acid peroxyketals n-c C 2 chondrilline 1,2-dioxane or dioxolane carboxylates C 2 Mono- and sesquiterpenes isolyratylhydroperoxide A mycaperoxide A C C

3 Facts about Malaria 1. Scale *Around 2.5 billion people (at least 40% of the world s population) are at risk in over 90 countries *Malaria causes or contributes to 3 million deaths and up to 500 million acute clinical cases each year. In other words: almost as many deaths per annum as the AIDS death total in the last 15 years *20 times more deaths each day than deaths from the 1995 EBLA epidemic in Zaire (~250). *Cause of more military casualties than bullets in every 20th century war in malarious regions *The majority of deaths are children. In other words children are dying at a rate of 4 per minute, 5,000 a day and 35,000 a week. *ther high risk groups include pregnant women, refugees, migrant workers, and non-immune travellers - over 20 million Western tourists at risk annually. *The main areas affected are Africa, South East Asia, India and South America but surveillance and records are too poor to know the real distribution and case numbers. *Malaria is one of leading causes of morbidity and mortality in the developing world (along with TB, acute respiratory syndrome, diarrhoea and IV) but still not recognised in developed countries as a disaster like AIDS or EBLA. 2. Resistance *Drug resistance is increasing rapidly, largely due to widespread uncontrolled and unregulated drug distribution. *Drugs have been used until resistance has rendered them ineffective, after which closely related drugs that are introduced show reduced efficacy and severely compromised life spans. *Today, there are few effective anti-malarial drugs - most tropical countries still rely on chloroquine (which is increasingly ineffective) primarily due to cost and the limitation of alternatives. *The vicious circle of new drug resistance limits research and rollout options and increases the cost of R&D - it is hard to establish whether to use new options widely, risking resistance, or keep them in reserve until resistance to existing drugs such as chloroquine or quinine becomes widespread. *Another underlying factor contributing to the development of resistance is the improper usage of the drugs; for example, subcurative doses - people feel better, so stop taking their medicine, and some resistant parasites may be given the chance to survive and be transmitted by mosquitoes. *There is insufficient research into novel drug targets. Current new options are based on the same three families of compounds (the quinolines, antifolates, and artemesinin derivatives) all of which have records of resistance and/or ineffectiveness. Insecticide programmes have also been hampered by the emergence of resistance to DDT and other insecticides.

4 Plasmodium falciparum Anopheles - see how she sits! falciparum: sporozoites falciparum: exo-erythrocytic schizont falciparum: merozoites bud from exoerythrocytic schizonts The infection is caused by a blood-dwelling apicomplexan parasite belonging to the genus Plasmodium (Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale and Plasmodium malariae cause human infections). The parasites are transmitted by blood-sucking female anopheline mosquitoes (more than 50 species are known vectors). Malaria chemotherapy have been directed at killing the parasite when it has infected human erythrocytes. Starving the malaria parasite by blocking its digestion of human haemoglobin (e.g. using protease inhibitors) and poisoning the malaria parasite by blocking aggregation of toxic haeme into innocuous haemozoin are two areas of active research. Also, killing the malaria schizonts in human erythrocytes has been achieved effectively with iron-activated peroxide drugs related to the natural herbderived antimalarial peroxide artemisinin. International Journal of Parasitology, 2002, 32, 1537 Posner G. et al, International Journal of Parasitology, 2002, 32, 1661

5 Some Antimalarial Drugs WW2 Vietnam War 1000 years ago + Vietnam War

6 1,2,4-Trioxane-Type Antimalarial Agents Artemisinin Artemisinin was isolated as a new antimalarial drug in 1972 in China Artemisia annua contains <0.1% (under special agricultural conditions) Poor oil or water solubility Short plasma half-life Poor oral activity R R=,, Et, CC 2 C 2 C 2 Na, C 2 C 6 4 C 2 Na il or water solubility

7 1,2,4-Trioxane-Type Antimalarial Agents Artemisinin Artemisinin was isolated as a new antimalarial drug in 1972 in China Artemisia annua contains <0.1% (under special agricultural conditions) Poor oil or water solubility Short plasma half-life Poor oral activity R -C---C--C--C= moiety may be responsible for the activity The interest in cyclic peroxides increased R=,, Et, CC 2 C 2 C 2 Na, C 2 C 6 4 C 2 Na il or water solubility

8 Ways to Generate Peroxides. Photo oxidation Second excited 1! g + First excited 1 " g Ground state 3! g kcal +22 kcal Sentisizer electronic states Sens+ hv > 1 Sens 1 Sens > 3 Sens xygen electronic states 3 Sens >Sens A--->A 2

(TPP) Sens+ hv--------> 1 Sens 1 Sens --------> 3 Sens 3 Sens+ 3 2

9 Ways to Generate Peroxides. Still Photo xidation Rose Bengal Benzophenone Tetraphenylporphine (TPP) Sens+ hv > 1 Sens 1 Sens > 3 Sens 3 Sens >Sens* 2 Sens* 2 +A--->A 2 Sens+ hv > 1 Sens 1 Sens > 3 Sens 3 Sens >Sens A--->A 2

10 Reactions of Singlet xygen 1. Ene-reaction LA Cr 3 64% 2. 1,4-cycloaddition Ar 2, TPP Ph, hv Ar Bn 1 2 Bn Ar 1. Ac2 Ar Bn Ac X Ar NaCl >NaCl % 2.! 50% Ac crotepoxide Ireland, R.E. et al, JACS, 1970, 92, 5743 White, J.D. et al, JACS, 1976, 98, 634 Motoyoshiya, J., J. rg. Chem. 1999, 64, 493

11 Reactions of Singlet xygen 2. Chiral Auxiliary. Wirth, T., et al. JACS, 1998, 120, 4091

12 Ways to Generate Peroxides. zonolysis R 1 R 2 T>-80C [3+2] retro R 1 R 2 [3+2] R 1 is more e-rich R 1 R 2 DCM, R 1 pentane, etc. R 2 [3+2] R 1 R 1 + R 2 Bunelle, W.. Chem. Rev. 1991, 91, 335

13 Ways to Generate Peroxides. C + Cl zonolysis Cl 3 / Cl + C 3 C 2 3 / + warm secondary products Cl 3 / Et Cl Et Et + Et 3 Et + t-buc t-bu Bunelle, W.. Chem. Rev. 1991, 91, 335

14 Ways to Generate Peroxides. ther ways Feldman, K. S. Synlett, 1995, 217 Solaja, B.A. et al, J. d. Chem., 2002, 45, 3331

15 Reactions of Peroxides 1/1 mixture Dussault, P.. et al, Tetrahedron Lett., 1995, 36, 3655 Dussault, P.. et al, Tetrahedron Lett., 1999, 40, 6553 Dussault, P.. et al, rg.lett., 1999, 1, 1391

16 Reactions of Peroxides R 2 R 1 R 2 R 1 + n 3 n= % R 2 R 1 n 3 R 2 R 1 n 1 2 n R 2 R 1 2 C n R 2 R 1 pathway 1 pathway 2 2 C R 1 R 2 1 n + PPh 3 R 1 R 2 2 n + R 2 R 1 n R 2 R 2 R 1 R 1 n n

17 Even 8- and 9-membered rings can be made Nojima, M et al J. rg. Chem. 1997, 62, 4949

18 Total Synthesis of Artemisinin 1a 2 C (-)-Isopulegol 1 1. MMCl, PhN 2, DCM 2.B 2 6, TF Qinghaosu Artemisinin MM X-Ray 80% (+epimer 10%) 1. BnCl, K 2. Cl, 3. PCC, DCM Bn 73% 1. LDA, TF, 0C 2. RI dr=6/1 3 Si Bn 62% Li 3 Si TF, Si quant 1 equiv:1/1 10 equiv:8/1 X, Y=, X Y Si3 Bn 89% 1.Li/N 3 3 Si 2. PCC, DCM 3 Si 75% 1.mCPBA, DCM 2. TFA, DCM 3 Si 72% ofheinz*, W.; Schmidt, G. JACS, 1983, 105, 624

19 Total Synthesis of Artemisinin 1b 3 Si 3 Si TBAF, TF, rt 95% TBAF, TF, rt 2 C 2 C 1 2, hv, methylene blue DCM, rt dr=5/1 cis-directing effect of in ene-reaction 2 C >60% Na 2 C 1 2, methylene blue hv,, -78C Na 2 C C 2, DCM, 0C 30% Qinghaosu Artemisinin ofheinz*, W.; Schmidt, G. JACS, 1983, 105, 624

20 Total Synthesis of Artemisinin 2a Alkaline 2 2 TF (R)-(+)-pulegone 74% NaSPh TF SPh mcpba 1. 2 LDA, MPA SPh 99% 95% S Ph 2. RBr Al(g) S Ph wet TF 37-50%, dr=9/1 for the two steps Avery, M. A. et al JACS, 1992, 114, 974

21 Total Synthesis of Artemisinin 2b TsNN 2 TsNN 86% 4 nbuli/tmeda then DMF 70% 1. TMS >Acyl 3 Si Claisen X 1. Al(Si 3 ) 3 xet 2 2 LiNEt 2 2. Ac 2 /DMAP 3 Si 88% TF, -78->rt 3 Si 3 Si 63% Avery, M. A. et al JACS, 1992, 114, 974

22 Total Synthesis of Artemisinin 2c 1. 2LDA, TF, +50C 3, Si 2, 2 S 4 3 Si 2. I, -78C 3 Si DCM, -78C 97% 33-39% Qinghaosu Artemisinin Avery, M. A. et al JACS, 1992, 114, 974

23 Total Synthesis of Artemisinin 3a Cy 2 B TF, 0C 7 days 82% Cr 3 /Acetone 80% + AIBN, Ph, 110C C 2 Bu 3 Sn or Ph 3 Sn I PhSe Ph 2 Se 2 /Br 2, DCM 78% dr=1/1 10% AIBN, Ph, 110C KI, I 2, NaC 3 Bu 3 Sn or Ph 3 Sn 70% dr=68/32 Yadav, J.S. et al ARKIVC, 2003, 3, I

24 Total Synthesis of Artemisinin 3b I + AIBN, Ph, 110C C ( 2 3 Si) 3 Si 5% 72% dr=4/1 Si(Si 3 ) 3 10% S S BF 3 xet 2 98% S S 1. Na/ (50%) 2. C 2 N 2, Et 2 3. PCC, 89% S S 2 C Yadav, J.S. et al ARKIVC, 2003, 3, 125

25 Total Synthesis of Artemisinin 3c S S 2 C Ph 3 PC 2 Cl S S gcl 2 /CaC 3 KMDS, TF, MPA +50C 80% 45% dr? 2 C 2 C 1 2, Rose Bengal, hv, -78C 2 C Cl (dry) 2 C Cl 4 Qinghaosu Artemisinin 10% Yadav, J.S. et al ARKIVC, 2003, 3, 125

26 (+)-Yingzhaosu A Yingzhaosu A is an antimalarial constituent isolated from Yingzhao (Artabotrys uncinatus (L.) rr.) in Dioxabicyclo [3,3,1]-nonane ring system, Dihydroxy olefinic side chain. C1,C4,C6 absolute configuration was known C8 and C12 were unresolved Xu, X.-X. et al Tetrahedron Lett., 1991, 32, 5785

27 Total Synthesis of (+)-Yingzhaosu A 1a C 2 1. mcpba, DCM C 1. MgBr, Et 2, -78C 1 2, hv, methylene blue (R)-(-)-carvone 2. BF 3 xet 2, Ph 2. PCl 3, Py 15% CN, Ts 57% dr (C8)=1/1 8 LiB 4 51% separable 3, DCM, DMS 1. C() 3 2. PCl 3 Xu, X.-X. et al Tetrahedron Lett., 1991, 32, 5785

28 Total Synthesis of (+)-Yingzhaosu A 1b 1. Pt 2, 2 (1equiv), EtAc, 80% 2. Ts, acetone/water Ph 3 AsC 2 CC() 2 + Br - K 2 C 3-2, DCM LiB 4 dr=3/2 CCl 2 /Py 62% The natural product geometry By -NMR and X-Ray Xu, X.-X. et al Tetrahedron Lett., 1991, 32, 5785

29 The absolute structure of (+)-Yingzhaosu A 12b X-Ray of 12b Xu, X.-X. et al Tetrahedron Lett., 1991, 32, 5785

30 Conclusions: Peroxy compounds are not so rare in nature They can be very stable to a variety of chemical conditions Many peroxides possess useful pharmacological properties Photo oxygenation and ozonolysis are the two major ways to produce them

Malaria. Population at Risk. Infectious Disease epidemiology BMTRY 713 (Lecture 23) Epidemiology of Malaria. April 6, Selassie AW (DPHS) 1

Malaria. Population at Risk. Infectious Disease epidemiology BMTRY 713 (Lecture 23) Epidemiology of Malaria. April 6, Selassie AW (DPHS) 1 Infectious Disease Epidemiology BMTRY 713 (A. Selassie, DrPH) Lecture 23 Vector-Borne Disease (Part II) Epidemiology of Malaria Learning Objectives 1. Overview of malaria Global perspectives 2. Identify