artemisinin o me a little about the chemistry of peroxides · a little about the chemistry of...
TRANSCRIPT
A Little About the Chemistry of Peroxides
(which can fight malaria, by the way)
Ramil BaiazitovNovember 4, 2003
O
OMe
Me
HMe
O
O
O
Artemisinin
Me
Me
O
O
HO OH
MeMe
Yingzhaosu A
Natural Peroxy Compounds
O O
n-C16H33
MeO
CO2Me
chondrilline
Fatty acid peroxyketals 1,2-dioxane or dioxolane carboxylates
H
O
O
H
CO2H
mycaperoxide A
Mono- and sesquiterpenes
OOH
isolyratylhydroperoxide A
O
OOH
OH O
OO
CHO
HO
O
O
OO
HOH
HO
HO
OO
OH O
OH
O
O
OH
OHC
H
Facts about Malaria1. 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 EBOLA 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. *Other 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 HIV) but still not recognised in developed countries as a disaster like AIDS or EBOLA.
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.
http://www.malaria.org
Plasmodium falciparum
Anopheles - see how shesits! falciparum: sporozoites
falciparum: exo-erythrocytic schizont
falciparum: merozoitesbud from exo-erythrocytic schizonts
http://www.anaesthetist.com/icu/infect/malpix.htmInternational Journal of Parasitology, 2002, 32, 1537
The infection is caused by a blood-dwelling apicomplexan parasitebelonging to the genus Plasmodium (Plasmodium falciparum,Plasmodium vivax, Plasmodium ovale and Plasmodium malariae causehuman infections). The parasites are transmitted by blood-sucking femaleanopheline mosquitoes (more than 50 species are known vectors).
Malaria chemotherapy have been directed at killing the parasite when it hasinfected human erythrocytes. Starving the malaria parasite by blocking itsdigestion of human haemoglobin (e.g. using protease inhibitors) and poisoningthe malaria parasite by blocking aggregation of toxic haeme into innocuoushaemozoin are two areas of active research.Also, killing the malaria schizonts in human erythrocytes has been achievedeffectively with iron-activated peroxide drugs related to the natural herb-derived antimalarial peroxide artemisinin.
Posner G. H et al, International Journal of Parasitology, 2002, 32, 1661
Some Antimalarial Drugs
WW2 Vietnam War
1000 years ago + Vietnam War
1,2,4-Trioxane-Type Antimalarial AgentsArtemisinin 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
O
O
H
O
O
O
Artemisinin
O
O
H
O
O
OR
R=H, Me, Et,
COCH2CH2CO2Na,
CH2C6H4CO2Na
Oil or water solubility
1,2,4-Trioxane-Type Antimalarial AgentsArtemisinin 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
O
O
H
O
O
O
Artemisinin
O
O
H
O
O
OR
R=H, Me, Et,
COCH2CH2CO2Na,
CH2C6H4CO2Na
Oil or water solubility
-C-O-O-C-O-C-O-C=O moiety may be responsible for the activity
The interest in cyclic peroxides increased
Ways to Generate Peroxides.
Photo oxidation
http://www.chem.vt.edu/chem-ed/quantum/jablonsk.html
Sens+ hv-------->1Sens1Sens -------->3Sens3Sens+3O2---->Sens+1O21O2+A--->AO2
Ground state 3!g-
First excited 1"g
Second excited1!g+ +37 kcal
+22 kcal
Sentisizer electronic states Oxygen electronic states
O O
Ways to Generate Peroxides.Still Photo Oxidation
Rose Bengal Tetraphenylporphine (TPP)
O
Benzophenone
Sens+ hv-------->1Sens1Sens -------->3Sens3Sens+3O2---->Sens+1O21O2+A--->AO2
Sens+ hv-------->1Sens1Sens -------->3Sens3Sens+3O2---->Sens*O2Sens*O2+A--->AO2
Reactions of Singlet Oxygen
H
+ 1O2
OOH
H
O
O
1. Ene-reaction
2. 1,4-cycloaddition
+ 1O2
O
OO
O
H
H
O
O
1. 1O2
2. LAH
H
H
O
O
OH
CrO3
H
H
O
O
O
64%
Ireland, R.E. et al, JACS, 1970, 92, 5743White, J.D. et al, JACS, 1976, 98, 634Motoyoshiya, J., J. Org. Chem. 1999, 64, 493
1O2OH
OH
OBn
OH
OH
OBn
OO52%
1. Ac2O
2. ! 50%
O
O
OBn
OAc
OAc
crotepoxide
MeAr
Me
Ar
O O
Ar MeO2, TPP
PhH, hv
O O
Ar MeX
Me
Ar
NaClO+H2O2------>NaCl+H2O+1O2
Reactions of Singlet Oxygen 2.Chiral Auxiliary.
Wirth, T., et al. JACS, 1998, 120, 4091
Ways to Generate Peroxides.Ozonolysis
R1
R2
OO
O
O OO
R1 R2
T>-80C
R1
OO
O
R2
R1
OO
O
O
O
R1 R2
DCM,
pentane, etc.
MeOH
R1
OOH
OMe
R1 is more e-rich
O
R2
+
[3+2] retro[3+2]
[3+2]
Bunelle, W.H. Chem. Rev. 1991, 91, 335
Ways to Generate Peroxides.Ozonolysis
Cl
H H O
Cl OO
H H
+O3/MeOH
H H
O3/MeOH
O
O
O
Me MeO
O
H H
+
CH3OCH2OOH
CO + HCl
warmsecondary products
Cl Et
O
MeMe O3/MeOH O
Cl Et
O
MeMe
OO
O
MeO Et
O
MeMe
O OH
+MeO
EtO
Me H O
EtO OO
Me H
+t-BuCHO O
O
O
Me t-Bu
O3
Bunelle, W.H. Chem. Rev. 1991, 91, 335
Ways to Generate Peroxides.Other ways
Feldman, K. S. Synlett, 1995, 217Solaja, B.A. et al, J. Med. Chem., 2002, 45, 3331
Reactions of Peroxides
Dussault, P.H. et al, Tetrahedron Lett., 1995, 36, 3655Dussault, P.H. et al, Tetrahedron Lett., 1999, 40, 6553Dussault, P.H. et al, Org.Lett., 1999, 1, 1391
1/1 mixture
Reactions of Peroxides
R1
R2OMe
O3HO+
n
R2
O
R1
HOO
n
n=1-3 13-67%
O3
R2
O
R1
HOO
n
O
OO
O
O
OR1
R2 n
OHO
O
OR1
R2 n
OOH
1
2
21
+
PPh3
+
R2
O
R1
HOOO
OO
R2
O
R1
HOOOMe
OHO
R2
O
R1
HOO
O
n
n
n
O OMe
R1
OR2O
R2
O
R1
HOO
O
R2
O
R1
HOO
OO
H2C
O
O
H2COnn
pathway 1 pathway 2
Even 8- and 9-membered rings can be made
Nojima, M et al J. Org. Chem. 1997, 62, 4949
Total Synthesis of Artemisinin 1a
Hofheinz*, W.; Schmidt, G. JACS, 1983, 105, 624
Me
HO H
H2C Me
(-)-Isopulegol1
1. MOMCl, PhNMe2, DCM
2.B2H6, THF
Me
MOMO H
Me
HO H
80%(+epimer 10%)
Me
O H
MeOBn
H
1. BnCl, KH2. HCl, MeOH3. PCC, DCM
1. LDA, THF, 0C2. RI
Me
OH
MeBnO H
Me3Si
H
73%
dr=6/1
62%
Li
OMeMe3Si
THF, -78
Me
HO
H
MeOBn
H
Me3Si
H
X
YSiMe3
quant1 equiv:1/1 10 equiv:8/1 X, Y= OMe, H
89%
1.Li/NH3
2. PCC, DCM
O
O
O
HH
HMe
OO
H
Me
MeQinghaosuArtemisinin
Me
H
Me3Si
H
H
MeO
Me3SiO
MeO
75%
1.mCPBA, DCM
2. TFA, DCM
Me
H
OH
H
MeOMe3Si O
MeO
72%
X-Ray
Total Synthesis of Artemisinin 1bMe
H
OH
H
MeOMe3Si O
MeO
TBAF, THF, rt
Me
H
OH
H
OMe
HO2C Me
Me
H
OH
MeO
HMe3Si O
MeO
TBAF, THF, rt
Me
H
OH
H
MeO
HO2CMe
H
H
95%
1O2, hv, methylene blue
DCM, rt
MeOH
H
OMe
HO2C MeH
HOOdr=5/1
cis-directing effect of OMe in ene-reaction
>60%
Me
H
OH
H
OMe
NaO2C MeH
1O2, methylene blue
hv, MeOH, -78C
Me
H
OH
MeO
OMe
NaO2C MeH
HOOHCO2H,
DCM, 0C O
O
O
HH
HMe
OO
H
Me
Me
30%QinghaosuArtemisinin
Hofheinz*, W.; Schmidt, G. JACS, 1983, 105, 624
Total Synthesis of Artemisinin 2a
Avery, M. A. et al JACS, 1992, 114, 974
Me Me
O
Me
(R)-(+)-pulegone
Alkaline H2O2
THF
Me Me
O
Me
O
74%
NaSPh
Me
Me
O
Me
O
SPh
O
Me
SPh
THF
99%
mCPBA
O
Me
SO Ph
95%
1. 2 LDA, HMPA
2. RBr
O
Me
SO Ph
OOAl(Hg)
wet THFO
MeOO
37-50%, dr=9/1for the two steps
Total Synthesis of Artemisinin 2b
Avery, M. A. et al JACS, 1992, 114, 974
O
MeOO
TsNHNH2
TsNHN
MeOO
86%
4 nBuLi/TMEDA
then DMF
MeOO
O70%
1. TMS-
2. OH->OAcyl
MeOO
O
O
Me3Si
H
Claisen
X
MeOO
O
1. Al(SiMe3)3xEt2O
2. Ac2O/DMAP
MeOO
O
Me3Si
H
O88%
2 LiNEt2
THF, -78->rt
63%
MeOO
OH
Me3Si
H
O
MeOO
O
Me3Si
H
O
Total Synthesis of Artemisinin 2c
Avery, M. A. et al JACS, 1992, 114, 974
MeOO
OH
Me3Si
O
1. 2LDA, THF, +50C
2. MeI, -78C
MeOO
OH
Me3Si
OMe
H
97%
O3,
DCM, -78C
MeOO
OH
OMe
HO
HOO
SiO2, H2SO4
O
O
O
HH
HMe
OO
H
Me
MeQinghaosuArtemisinin
MeO
OH
OMe
HO
HOO
33-39%
Total Synthesis of Artemisinin 3a
Yadav, J.S. et al ARKIVOC, 2003, 3, 125http://www.arkat-usa.org/ark/journal/2003/Sukh%20Dev/SD-616C/616C.pdf
Me
Me
Cy2BH
THF, 0C 7 days
Me
MeOH
H
CrO3/Acetone
Me
MeH82%
80%
O
HOdr=68/32
KI, I2, NaHCO3
Me
Me
HO
O
I
70%
Me
Me
HO
O
I
CH2
O
Me + AIBN, PhMe, 110C
Me
Me
HO
O
O
Me
Me
Me
HO
O10%
Bu3SnH or Ph3SnH
Me
MeH
O
HO
Ph2Se2/Br2, DCM
Me
Me
HO
O
PhSe
78%
dr=1/1
AIBN, P
hMe, 1
10C
Bu3SnH o
r Ph3
SnH
Total Synthesis of Artemisinin 3b
Yadav, J.S. et al ARKIVOC, 2003, 3, 125http://www.arkat-usa.org/ark/journal/2003/Sukh%20Dev/SD-616C/616C.pdf
Me
Me
HO
O
I
CH2
O
Me + AIBN, PhMe, 110C
Me
Me
HO
O
O
Me
Me
Me
HO
O
(Me3Si)3SiH 5%
72%
dr=4/1
O
Me Si(SiMe3)310%
Me
Me
HO
O
O
Me
Me
Me
HO
O
O
Me HS SH
BF3xEt2O
Me
Me
HO
O
Me
SS
98%
1. NaOH/MeOH (50%)
2. CH2N2, Et2O3. PCC, 89%
Me
MeO2C MeH
Me
SS
O
Total Synthesis of Artemisinin 3c
Yadav, J.S. et al ARKIVOC, 2003, 3, 125http://www.arkat-usa.org/ark/journal/2003/Sukh%20Dev/SD-616C/616C.pdf
Me
MeO2C MeH
Me
SS
O
Cl
KHMDS, THF, HMPA+50C
Me
MeO2C MeH
Me
SS
MeO
Ph3PCH2OMe HgCl2/CaCO3
45%
dr?
Me
MeO2C MeH
Me
O
MeO80%
1O2, Rose Bengal
MeOH, hv, -78C
Me
MeO2C MeH
Me
O
MeO
OO
HCl (dry)
Me
MeO2C MeH
Me
O
O
HOO
HClO4
O
O
O
HH
HMe
OO
H
Me
MeQinghaosuArtemisinin
10%
(+)-Yingzhaosu A
Xu, X.-X. et al Tetrahedron Lett., 1991, 32, 5785
Me
O
Me
OH
MeMe
OH
O1
6
4 8
10
12
Yingzhaosu A is an antimalarial constituentisolated from Yingzhao (Artabotrys uncinatus (L.) Merr.)in 1979.
Dioxabicyclo [3,3,1]-nonane ring system,Dihydroxy olefinic side chain.
C1,C4,C6 absolute configuration was knownC8 and C12 were unresolved
Total Synthesis of (+)-Yingzhaosu A 1aMe CH2
Me
O
(R)-(-)-carvone
1. mCPBA, DCM
2. BF3xEt2O, PhH
Me CHO
Me
O
Me
Me
O
1. MeMgBr, Et2O, -78C
2. POCl3, Py
15%
1O2, hv, methylene blue
MeCN, TsOH
Me
Me
O
OOH
Me
Me
O
O
O57%dr (C8)=1/1
8
LiBH4
51%
Me
Me
HO
O
O
separable
O3, DCM, DMS
Me
Me
HO
O
O
O
Me
Me
O
O
O
Me
Me
HO
O
O
HO
1. HC(OMe)3
2. POCl3
Me
Me
OMe
O
O
MeO
Xu, X.-X. et al Tetrahedron Lett., 1991, 32, 5785
Total Synthesis of (+)-Yingzhaosu A 1b
Me
Me
OMe
O
O
MeO
1. PtO2, H2(1equiv), EtOAc, 80%
2. TsOH, acetone/water
Me
Me
O
O
O
Ph3AsCH2COC(OH)Me2+Br-
O
HO
Me
Me
O
O
OOH
K2CO3-H2O, DCM
LiBH4
Me
Me
O
O
HOOH
Me
Me
O
O
HOOH
dr=3/2
COCl2/Py
Me
Me
O
O
O O
O
Me
Me
O
O
O O
O
62%
The natural product geometryBy H-NMR and X-Ray
Xu, X.-X. et al Tetrahedron Lett., 1991, 32, 5785
The absolute structure of (+)-Yingzhaosu A
Me
Me
O
O
HOOH
MeMe
Me
Me
O
O
O O
O
12b
Xu, X.-X. et al Tetrahedron Lett., 1991, 32, 5785
X-Ray of 12b
Conclusions:
• Peroxy compounds are not so rare innature
• They can be very stable to a variety ofchemical conditions
• Many peroxides possess usefulpharmacological properties
• Photo oxygenation and ozonolysis are thetwo major ways to produce them