molecules of traditional chinese medicine
TRANSCRIPT
Will GutekunstBaran Group Meeting Molecules of Traditional Chinese Medicine
Traditional Chinese Medicine (TCM)- Chinese herbal medicine represents only one part of Traditional Chinese Medicine, which also encompasses acupuncture, cupping theory, meditation and other methods.- All methods deeply based in Taoist and Buddhist thought.
Chinese Herbal Medicine- Currently 12,807 Chinese medicines officially documented of which there are 11,146 plants, 1,581 animal species and 80 minerals.- Of these, roughly 500 are still commonly used.
History- The first records of the use of Chinese medicine date back to hieroglyphics during the Shang dynasty in the eleventh century BC.- The first formal manual on pharmacology was the Shennong Bencao Jing which lists 365 medicines and dates to roughly the 1st century in the Han dynasty.- The next major and still most influencial text was written during the Ming dynasty by Li Shizhen in 1596. Over a 40 year period he compiled his book Bencao Gangmu (Compendium of Materia Medica) which contains more than 1,800 drugs with 1,100 illustrations and 11,000 prescriptions.
-Treatment with TCM is highly personalized, based on a patient's current state of yin and yang (The Four Natures), the Five Tastes and the Meridians. Unlike in western medicine, many times the efficacy of the treatment is believed to be based upon the balance and interaction of the combined ingredients, rather than on specific constituent being the cure.- In the Four Natures, each herb has a quality of hot or cold (yin/yang) associated with it, in which it can be used to balance out a person's own yin/yang state.- The Five Tastes consist of sweet, sour, bitter, salty and pungent, each of which has its own set of features and effects. - The Meridians involve which organs the herbs effect, which in turn have their own set of elemental qualities associated with them (wood, fire, earth, water and metal).
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A sampling of the molecules found in Traditional Chinese Medicine that are not covered in this presentation
N
N
O
O
O
HO
Camptothecin
O
O
O
HO
H
OO
MeHO
OH
HO
O
ginkgolide B
OHOAcO
HOBzO
H O
AcO
ONH
O
OH
Ph
Ph
O
taxol
N
NH
NMe
N
CO2Me
OAc
HO
MeO2C
OH
MeO
vinblastine
HN
NMe
O
O
gelsemine
N
O
H
H
O
stenine
HMeO
OMeHO
HMeO
NMe
OMe
HO
H
chasmanine
N
O
O
MeO
OMe
berberine
OH
H
HO
OH
OH
O
H
OH
phorbol
O
HO
HN
HO
morphine
O
O
N
H
MeOOMe
cephalotaxine
NMe
N
HO
H
OHH
ajmaline
Me
Me
MeMe
O
!-vetivone
See vetivane sequiterpenegroup meeting
See cepharamine and relatedalkaloids group meeting
See morphine/codeinegroup meeting
See ajmaline and sarpaginealkaloid group meeting
See camptothecin group meeting
See stemona alkaloidgroup meeting
See vindoline group meeting See dendrobine group meeting
See Isoquinoline Alkaloids group meeting
See Tigliane, Daphnane, Ingenane,Lathyrane Diterpene group meeting
Me
MeH2N
HN O
huperzine A
MeMe
OO O
quadrone
See quadronegroup meeting
H
OH
MeO
MeO
MeO
OMe
O
O
gomisin A
See Stegane Natural Products group meeting
O
HOH
OMe
OMe
MeO
O
O
OH
podophyllotoxin
See Lignan Synthesisgroup meeting
N
N
OOH
HH
H
strychnine
O
AcO OH
O
MeO2C
O
OHO
CO2Me
O
O
OH
O
H
azadiractin
O
NHAc
HMeO
MeO
MeO
OMe
colchicine
Molecules of Traditional Chinese Medicine
O
OH
H
H
C5H11
tetrahydrocannabinol
Will GutekunstBaran Group Meeting Molecules of Traditional Chinese Medicine
O
O
OH
OH
OH
H
OOH
OH
OH
HO
OH
epigallocatechin-3-gallate (EGCG)
O
Atractylodin
O
O
(s)SugarO
O
O
O
O
OH
O
O
O
O
evodinone
AcO
BzO
OAcOAc
HO
O
OAc
OAc
AcO
O
O
O
N
wilforine
O OHOH
OH
OH O OH
OH
hypericin
Will GutekunstBaran Group MeetingMolecules of Traditional Chinese Medicine
Artemisinin(Qinghaosu)
3)
O
O
Me
MeH
H
OO
H
Me
O
Avery et al. J. Am. Chem. Soc. 1992, 114, 974-979
O
Me
O
Me
OO
Me
SOPh
O
MeOO H
OHC
MeOO H
MeOO H
TMS
O
O
H
MeOO H
TMS
HOOC Me
MeH
TMSOHOOC Me
O
OO
H
HO
O
Me
MeH
H
OO
H
Me
O
NaOH
H2O274%
1) NaSPh
2) m-CPBA - 78 ºC 94%
1) 2 eq LDA, HMPT2) Al(Hg) Amalgam wet THF
OO
Br
1) TsNHNH2
2) 4 eq BuLi
TMEDA, then DMF
(TMS)3Al•Et2O,
then Ac2O, DMAP
3 eq LDEA -78ºC ! 50ºC,
then 2 eq LDA MeI
O3/O2, -78ºC, then SiO2;
3M H2SO4
37-50% two steps
60% two steps 88%
61%
35%
Semi-Synthesis Lansbury et al. Tet. Lett. 1992, 33, 1029-1032.
HO2C
H
H H
H
HO
O
H
HO
O
O
1) [H]
2) CrO3 3,5-dimethylpyrrole
1) Wilkinson's
2) WCl6, 2 eq nBuLi
artemisinic acidarteannuinO3
H
HO
O
O
O
H
OTMSTMSO
TMSOTf
94% 2 steps
60%
H
HO
O
O
H
OO
2 eq. sodium naphthalenide,
then MOMCl
82%
H
H
OMOM
O
H
OO
MOMO
O2, Rose Bengal
then CSA
30-35% O
O
Me
MeH
H
OO
H
Me
O
Keasling et al. Nature 2006, 440, 940-943
"simple sugar"
engineeredS. cerevisiae
HO2C
MeH
H H O
O
Me
MeH
H
OO
H
Me
O
Acton et al. J. Org. Chem. 1992, 57, 3610-3614
Me
HO2C
MeH
H H
dihydroartemisinic acid
H
1O2
Me
HO2C
MeH
H
H
HOO
3O2
O
O
Me
MeH
H
OO
H
Me
O
trace H2O
17-32%
- Qinghao has been used in traditional chinese medicine for centuries, prepared as a tea for treating fever. Popularized in 1970 when the reemergence of Chinese Handbook of Prescriptions for Emergency Treatments from 340AD was rediscovered.- Qinghaosu (Artemisinin) was first isolated in China in 1972 as a potent antimalarial agent.- It continues to be a highly important drug in the pharmaceutical arena with its analog Artemether being marketed by Novartis in the drug Co-artem.
From Artemisia annua;other common names include Sweet Wormwood,Sweet Annie and SweetSagewort.Chinese: Qinghao
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6,9-Desmethylartemisinin Avery et al. J. Org. Chem. 1989, 54, 1792-1795
NClCl O
LiCH(TMS)2 TMS1) O3, NaHCO3 MeOH
2) Ac2O, Et3N
TMS
CO2Me
OMe
OHC
TMS
CO2Me
P
O
PhPh
MeO Li
1) KOH2) Oxalic Acid, SiO2
3) O34) Amberlyst 15 O
O
Me
H
H
OO
H
O
OO
HO
OH
yingzhaosu A
O
1) m-CPBA
2) BF3•OEt
CHO
O O
1) MeMgBr
2) POCl3, py
ca 15% 4 steps
O2, h!Methylene Blue
p-TsOH
55% 1:1 dr
O O
O
1) LiBH42) O3
3) HC(OMe)3 p-TsOH4) POCl3
O
O
OMe
OMe 1) PtO2, H2
2) p-TsOH, H2O
O
O
O
HPh3As
O
OH
Then LiBH4
O
O
OH
OH
OO
HO
OH
yingzhaosu A
62% 3:2 dr
Xu et al. Tet. Lett., 1991, 32, 5785-5788
Bachi et al. J. Org. Chem. 2005, 70, 3618-3632
PhSH, O2
AIBN, hv OO
Ph3P
50%55:45 dr
OOH
PhS
OO
OH
PhS
1) 4.3 eq SOCl2 11 eq py
2) m-CPBA
OO
PhS
87%
5 eq (CF3CO)2O
10 eq 2,6-lutidineO
O
PhSO
F3CO2
morpholineMeOH/DCM
OO
O
H43% two steps
H2, 0.15 eq PtO2
-11ºC to -12ºC
90 %
OO
O
H
OO
TMSO
OTMS
TiCl4, then 21 eq py
70%
OTMSO
R-CBS, BH3
then 2% HF in MeOH
71%, 9:1 dr
OO
HO
OH
yingzhaosu A
O
O
O
O
O
OH
H
triptolide
40% 78%
64%
58%50%
- Isolated from the Chinese medicine Yingzhao (Artabotrys uncinatus)- Another antimalarial agent from TCM, but has not received as much attention as its peroxide cousin artemisinin, primarily due lack of available compound.
Isolated from extracts ofTripterygium wilfordii Hook F
Common names include lei gong teng and Thunder God Vine.
Traditionally used to dispel wind and dampness, it is usedto treat people who have swollen joints, difficulty moving, fever, chills, edema, and carbuncle. Also known as "qi bu si"which means "sevens steps to death" as a result of its potential toxicity.
Lei gong teng has been clinically evaluated as a potentialtreatment for rheumatoid arthritis, leukemia, hepatitis, nephritis, and various skin disorders. More recently triptolideand related structures have been tested for their antifertility properties to be one day used as a male contraceptive.
Molecules of Traditional Chinese Medicine
80%
8 steps7.3% overall yield
Will GutekunstBaran Group Meeting
O
I
O
O
OMe
O
OMe
O
Me2NOH
OMe
OHCO
Me2N
OMe
CHOO
Me2N
OH
OMe
O
O
OH
O
OH
OH
O
O
OH
OOH
O
OH
O
O
O
Berchtold et al. J. Am. Chem. Soc. 1980, 102, 1200-1201
1) NaH, DMF
2) Me2NH
94%
1) CrO3•py
2) neutral alumina
1) p-TsOH, benzene reflux2) NaBH4
3) aq HCl workup
1) NaOMe, MeOH2) CrO3, HOAc-H2O
3) BBr3, DCM4) NaBH4
83%
88%
13% over 4 steps
NaIO4, aq MeOH
74%
1) m-CPBA2) H2O2, NaOH
3) NaBH4
25% (1:3 dr)
van Tamelen et al. J. Am. Chem. Soc. 1982, 104, 867-869
O
OOLi/NH3, t-BuOHthen,
EtOP
O
OEt
Cl(EtO)2OPO
OO OOLi, EtNH2
THF t-BuOH
90-92%
1) 3M H2SO42) CS2, then MeI
t-Bu
t-Bu
O
Li
O SMe
SMeS
then 1:6 6M HCl-MeOH
O
O LDA, HMPA
TBSCl
84%
O
OTBS
O
OMe
then MeOH-HCl
OH
CO2Me
86-93% from butenolide
1) MeI, NaI2) MeLi3) MsCl, TEA
4) Li/NH3
OMe
H H
HH
H H
H
65-70%
5 steps
56%
OMe
H
HO
OMe
H
O
NMe2
H NMe2
OMeMeO
xylenereflux
80%
1) m-CPBA2) LiHMDS,
then 1M HCl
80%
OMe
O
O
OH
O
OH
O
O
O
van Tamelen et al. J. Am. Chem. Soc. 1982, 104, 1785-1786
OMe
Br
O
O
OMe
NaH, THF
99%
OMe
O
CO2Me
1) Ba(OH)2, heat
2) LAH
92%
OMe
HO
LiBr, PBr3,
then ZnBr2
70%
OMe
Br
O O
OEt
LiH
OMe
EtO2C
O
90%
1) SnCl4
2) MsCl, Et2NH
OMe
HEtO2C
1) m-CPBA
2) n-BuLi
51% over 4 steps
steps
triptolide
triptolide
Molecules of Traditional Chinese Medicine
Will GutekunstBaran Group Meeting
OMe
HO
O
steps OH
O
OH
O
O
O
triptolide
Sheburn et al. Chem. Comm. 2008, 1226-1228
I
OH
O
OMe
I
O
H
H O61%
SnBu3
O
H
H O
Pd
O
O
19 kbar, DCMO
H
H O
H
H
O
O
50%
O
H
H O
H
H
MeO
O
1) NaBH42) Ag2O, MeI
99% 2 stepsTf2O
N tButBu
O
H
H O
MeO
O
O
H
H
H
17%44%
1) TIPSOTf, Et3N2) PhSeCl
3) H2O2 O
O
MeO
72%
O
O
Me
BzOO
OH
OHO
HOHO OH
Paeoniflorin
Corey et al. J. Am. Chem. Soc. 1993, 115, 8871-8872 and Classics in Total Synthesis I pg 633-640.
Me
OTIPS
Me
O
O
H OTIPS
NC
4 eq Mn3O(OAc)7
KOAc, MeCN
NC
O
OH20 eq
5 steps
Me
O
OH
H OTIPS
O
O
NC
Cl
slow addn.SmI2 (7 eq)
93%
48%
O
O
Me
NC
HO
OTIPS
5 steps O
O
Me
BzO
HO
OTIPS
O
BnO
BnOBnO
OBn
OP(OMe)2
ZnCl2, AgClO44A MS18%
O
O
Me
BzO
O
OTIPS
OBnO
BnOBnO OBn
O
O
Me
BzO
O
OH
OHO
HOHO OH
Paeoniflorin
1) H2, Pd(OH)2/C2) HF-MeCN
92%
Hatakeyama et al. 1994, 166, 4081-4082
Me
OOCHO
TBSO OTBS
OH
Me
O
O
TBSO
TBSO
Li
5 steps
OCO2Me
PivO
Me
MeO83% 75%
TMS
Me
TMSOTf
OCO2Me
PivO
Me
Me
OCO2Me
O
Me
Me
1) 1M NaOH2) CH2N2
3) Swern
86%
h!
hexane
O
Me
MeO2C
O64%
5 steps
resolution
O
Me
O
BzO 1) TMSCN KCN 18-crown-6
2) 0.1M HCl
OH
O
Me
BzO
CN
PhI(OAc)2I2, h!
92% 2 steps
O
O
Me
BzO
CN
1) conc HCl2) (COCl)2
3) N
S
OH
O
O
Me
BzO
O O N
S
Toluene, O2
80º C, then (MeO)3P
Isolated from the roots of Chinese peony (Paeonialactiflora). In TCM it is known as shao yao or bai shao yao.
Traditionally used for regulating the blood and Ying, paeoniflorin has displayed anticoagulant, sedative, antiinflamatory, and neuromuscularactivities.
Molecules of Traditional Chinese Medicine
86%
Will GutekunstBaran Group Meeting
O
O
Me
BzO
OH
1) PhCH2OCOCl2) O3, MeOH/DCM
3) p-NO2-C6H4COCl TEA, DMAP
60%
O
O
Me
BzO
HO
OCO2Bn
O
BnO
BnOBnO
BnOO
NH
CCl3
BF3•OEt2 (18 eq)
6 eq
O
O
Me
BzO
O
OCO2Bn
OBnO
BnO
BnO OBn67%
O
O
Me
BzO
O
OH
OHO
HOHO OH
Paeoniflorin
H2, Pd(OH)2
quant.
O
OH
Bermejo et al. J. Org. Chem. 2009, 74, 1798-1801
1) mCPBA2) tBuCOCl, py
48%
O
OPiv
O
cat. Cp2TiCl2Zn, THF
47%
MeOH
OPiv
OH
Me O
PivOO
OMe
OMe
Ph
H
PPTS80%
CrO3dimethyl pyrazole
63%
Me O
PivOO
Ph
H
O
1) 10 N NaOH2) H2, Pd/C
77%
Me
OH
OH
O
O
paeonisuffrone
Quassinoids
O
O
HH
H
HO
OHO
OH
O
glaucarubolone
HO
AcO
O
O
Grieco et al. J. Am. Chem. Soc. 1993, 115, 6078-6093
1) LAH2) CH2I2 Zn/Cu
HO
O
O68%
HO1) MeI, NaH2) 70% HClO4
O
MeO
O
71%
1) Li, NH32) NaH HCO2Et
3) DDQ, HOAc
H
CHO
62%
CO2H
5M LiClO4, EtOAc
73%
MeO
OH
OHC
H
CO2H
1) NaBH4
2) HCl pH 2
quant
MeO
OH
H
OH
HO
H
H
12 steps
HO
OH
H
OTBDPS
HO
H24%
HO
OH
H
OTBDPS
HOMe
H
1) DiBAL2) MeOH, HCl
AcO
OH
H
OTBDPS
HOMe
H
Ac2O
OsO4
quant
86%
HO
OH
H
OTBDPS
HOMe
H
OAc
HO1) CrO3 py2) NaOH
70%
O
OH
H
OTBDPS
HOMe
H
OH
O
1) MOMCl2) LiHMDS, HMPA then, Me2SO4
3) B2H6, NaOH, H2O2
58%
MeO
OH
H
OTBDPS
HOMe
H
OMOM
O
HO
MeO
OH
H
OTBDPS
H
H
OMOM
O
O
MeO
OH
H
OTBDPS
H
H
OMOM
O
O OH
O
1) PCC2) 10% HCl, THF3) POCl3, py
95%
1) OsO4
2)
O
I
CF3
CF3
OH
O
1) TMSCl2) PyHBr3, CSA
3) 10% HCl in THF
MeO
OH
H
OTBDPS
H
H
OMOM
O
O OH
O
HO
OH
H
OHO
O
O
O
samaderin B
The quassinoids are found in a variety of Traditional Chinese Medicines including chun bai pi(Tree of Heaven) and ya dan zi(Java Brucea). Most are known for their cooling and astringentproperties, though quassanoidshave been shown to have antimalarial, antiasthmatic andantiepileptic properties.
Molecules of Traditional Chinese Medicine
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MeO
OH
H
OTBDPS
H
H
OMOM
O
O OH
O
1) BBr32) TBAF
O
O
HH
H
HO
OHO
OH
O
glaucarubolone
HO
H
Grieco et al. J. Am. Chem. Soc. 1994, 116, 7606-7615
MeO
OH
OH
HOMe
H
O
TMSI, HMDSTEA
90%
MeO
OH
H
OTMS
HOMe
H
OTMS
NIS, then TBAF
84%
MeO
OH
H
HOMe
H
OO
H
stepsMeO
OH
H
OHO
O O
1) NaBH42) MeOH, py,
Hunig's base Cu(OAc)2
93%
MeO
OHH
H
OHO
O
OMeO
OHH
H
OHO
OOH
CO2Me
H
AcOOH
90%
HO
OH
H
OHO
O
Osteps
O
samaderin B
Shing et al. Angew. Chem. Int. Ed. 2005, 44, 7981-7984
O O
O
TBSO
OTBSO9 steps
34% O
O
TBSO
OTBSO
1) TFA, H2O/DCM2) NMO, TPAP
78%
MgBr
78%O
OH
TBSO
OTBSO
O
OAc
TBSO
OTBSO1) NaH
4-methyl-benzo[15]crown-5
2) Ac2O
83%
Methylene BlueToluene, 180ºC
92% 2:1 trans:cis
O
OAc
TBSO
OTBSO
H
1) NaOH2) Tf2O, py DMAP
3) nBu4NOAcO
TBSO
OTBSO
O
TBSO
OTBSO
HOAc
H
65% 31%
TBSO
OTBSO
HO O
H
1) LDA2) SOCl2, py
83%
NaBH4, NiCl2, MeOHthen conc HCl
78%
TBSO
OTBSO
HO OMe
H
H
TBSO
OTBSO
HO OMe
H
H
10 mol% Mn(OAc)3TBHP, 3A MS
72%
O
TBSO
OTBSO
HO OMe
H
H
O
78%
Mn(OAc)3benzene reflux
AcO
5 steps
HO
OHO
HO O
H
H
O
HO
samaderine Y
Molecules of Traditional Chinese Medicine
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Tanshinones
O
O
O
HO
HO
Tanshindiol A
Snyder et al. J. Org. Chem. 1992, 57, 5301-5312
O
CO2Me
1)
2) LDA, (PhCO)2O2
56%, 92% ee
H2N
O
OtBuO
CO2Me
OCOPh
O
O
O
N
O
HO
O
N O
benzene
1) 5N HCl2) Fremy's Salt
94% 99% O
O
O
1) ultrasound2) DDQ
O
O
O
O
72%, 4:1 regio
7 steps
O
O
BBr3
66%
O
O
O
HO
HO
Tanshindiol A
Danheiser et al. J. Org. Chem. 1995, 60, 8341-8350
O
N2
TIPSOOTBS
h!, vycor
65%
OH
TIPSO
OTBS
O
OH
OH
TBAF, O2
O
82-84%
neocryptotanshinone
H2SO4, EtOH
O
O
O
100%
cryptotanshinone
DDQ
O
O
O
tanshinone IIA
Majetich et al. J. Org. Chem. 1997, 62, 6928-6951
O
OMe
MeO
BF3•Et2OCCl4 reflux
O
OMe
MeO
tBuOK, tBuOH
reflux
75%64%
O
OMe
MeO
NH2NHTsNaCNBH3
52%
OMe
MeO BBr3, thenCAN
61%
O
O
miltirone
MeN
O
MeH
HMe
O
MeO
HO
OH
OMe
NMe
O
MeH
H Me
O
Incarvillateine
Kibayashi et al. J. Am. Chem. Soc. 2004, 126, 16553-16558
Me
OTBDMS
SnBu3
BuLi, Me2ZnO
OTBDMS
then MeI, HMPA
77%
O
OTBDMS
Me
OTBDMS
Me
1) O3, then Me2S2) NaBH4
68%
Isolated from the taproot of Salvia miltiorrhiza, which has seen heavyuse in Traditional Chinese Medicine. Known as dan shen, it has been used to both treat and prevent heart problems and strokes, and has beenshown from both animal and human studies that it is an effective anticoagulent. Preliminary results also show dan shen has potential efficacy against HIV. Some studies also show that the traditional preparation of the medicine exceeds the activity of the purified compounds, leading to possibly more bioactive minor metabolites orsynergistic effects.
Isolated from the aerial parts of Incarvillae sinensis, a wild plant native to northern China.Known in TCM as jiaohao, it is traditionally usedto treat rheumatism and as a pain reliever.Incarvillateine has been shown to be a potentanalgesic in mice.
Molecules of Traditional Chinese Medicine
Will GutekunstBaran Group Meeting
O
OTBDMS
Me
OH
1) TsNHBoc DEAD, PPh32) TFA, DCM
95%
O
Me
NHTs
I
OTs
1) K2CO3, MeCN
2) PdCl2(MeCN)2, TEA HCO2H
58%
NTs
H
HMe
O
1) NaBH42) TBDMSCl3) sodium
naphthalenideNH
H
HMe
TBDMSO
70%
1) 35% HCHO, NaCNBH3, AcOH
2) H2, PtO2 5 atm3) TBAF
81%
NMe
H
HMe
HO
Me
MeN
O
MeH
HMe
O
MeO
HO
OH
OMe
NMe
O
Me H
H Me
O
Incarvillateine
HO
O
MeO
TsO
OTs
OMe
OH
O
1) DEAD, PPh32) Na(Hg)
23%
Ellman et al. J. Am. Chem. Soc. 2008, 130, 6313-6317
O
HEtO2C
1)
(S)-Binol, TFA
2) TBSCl
SnBu3
99%, 95% ee
OTBS
EtO2C
O
1)
Grubbs 2nd gen
2) MeNH2, 4A MS
CO2Et
NMe
TBSO
2.5% [RhCl(coe)2]2Toluene
Me2N PEt2
5.5%TBSO
Me
CO2Et
NMe
NaBH4
49% 2 steps
NMeTBSO
Me O
NMeHO
Me1) H2 (1000 psi) Pd/C MeOH2) LAH
3) HCl (aq), MeOH
90% MeH
Incarvillateinesteps
Aloperine
N NH
H
H
Overman et al. J. Am. Chem. Soc. 1999, 121, 700-709
N!Ts
TfONBoc
Pd(OAc)2, K2CO3nBu4NOTf, DMF, H2O
N!Ts
NBoc
TMSI, lutidine, then
TfOMe2SiCO2Me
Et3N
N!Ts
N
Si
CO2Me
Me
Me
NTs
N
Si
CO2MeH H
HH
Me
Me
HF-py, concentratethen mesitylene reflux
N NTs
H
H
O
SiMe2F concentrate;KF, KHCO3
H2O2
N NTs
H
H
O
OH
63%
C6F5OCSCl, DMAP;Bu3SnH, AIBN
N NTs
H
H
O
70%
88%
LAH
Aloperine
N NH
H
H
Pseudolaric Acid
CO2MeO
O
Me
O
O
HMe
HO2C
Isolated from Sophora alopecuroides (Ku dou zi), which is used to clearheat, dry damp, kill worms and relieve pain. Indications include dysenterystomachache, eczema, boils and intractable lichens. Aloperine in particularhas shown to have antiinflamatory and inhibit allergic reactions and heartarrhythmias in rats.
The root bark of Pseudolarix kaempferi Gordon, known as tujinpi in TCM, has long been used to treat fungal infections of the skin and nails. The pseudolaric acids were identified as potentantifungal agents responsible for this observed bioactivity and also have seen promise againstmultidrug resistant cancer cell lines.
Molecules of Traditional Chinese Medicine
Will GutekunstBaran Group Meeting
O
O
Me
O5 steps
MeI
OTBS
TMS
HO OH
3 steps
O OTBDPS
1) MePh3PBr, PhLi/LiBr then A, PhLi/LiBr then B, PhLi/LiBr; HCl, then KOtBu
2) K2CO3, MeOH
A
B
58% H
TBSO
Me
TBDPSO
DCE
[(C8H10)Rh(COD)]+SbF6-
88%H
Me
TBSO
HOTBDPS
TBAF
HMe
HO
OH
94%
HMe
O CO2Me
O
PhSe
OPMB
9 steps
Bu3SnH1,1'-Azo-bis-
(cyclohexanecarbonitrile)
then DBU
85%
CO2MeO
PMP
O
O
HH
Me
9 more stepsPsuedolaric Acid
CO2MeO
O
Me
O
O
HMe
HO2C
N
MeN
O
H
Koumine
NBn
NHBn
HCO2Me
8 stepsNBn
N
H
MeO2C
O
H
NH
TFA
80%5.5:1 E:Z
NNBn
O
H
CO2Me
1) CH2Br2, Zn, TiCl42) (sia)2BH; H2O2 N
NBn
H
CO2Me
OH
Magnus et al. J. Am. Chem. Soc. 1989, 111, 786-789
50%
NNH
H
OH
1) DiBAL2) Na/NH3
39%
1) ClCO2Me Na2CO32) LAH N
NH
H
OMe
SeO2/H+
N
MeN
O
H
koumidine E isomer
39%
taberpsychine
koumine
OBz
H
OH
CH2OTBDPS
OOMPM
OMPM
OTESPhS
MeOTf84% OBz
H
O
CH2OTBDPS
OOMPM
OMPM
OTES
OBz
H
O
OOH
OH
OH
1) TBAF2) TFA
OH
OBz
H
O
OOBz
OTES
OH
OH
1) TESCl2) BzCl, TEA, DMAP3) 10% citric acid
H
OH
O
OH
H
OH
OH
OH
erinacine E
Nakada et al. J. Am. Chem. Soc. 2008, 130, 1150-1151
Koumine originates from the TCM gou wen (Gelsemium elegans), also known as Graceful Jessamine. Gou wen dispels wind, attacks toxins, disperses swelling and relieves pain. Koumine itself displays antitumor activity as well as potent analgesic properties.
Hou tou jun (Bearded Tooth Carpophore) is the sporocarp of the fungus Hericium erinaceum and has been used in TCM as an agent to fortify spleen, nourish stomach and quiet spirit. Erinacine E was isolated the mycelia and has shown to be a strong stimulator of nerve growthfactor and a highly selective !-opiod receptor agonist.
Molecules of Traditional Chinese Medicine
Will GutekunstBaran Group Meeting
OBz
H
O
OOBz
OTES
OH
OH
Swern
OBz
H
O
OOBz
OTES
O
O
Et3N
H
O
O
H
O
OR
H
OBz
O
R = TES
H
OH
O
OR
H
R = TES
DBU
85%
93%
OBz
OH
O
1) NaBH42) K2CO3, MeOH3) IBX
4) Me4NBH(OAc)3
H
OH
O
OH
H
OH
OH
OH
erinacine E
Absinthin
O
OH
H
OH
H
H
HO
H
H
H
O
O
O
O
O
H
HOAch!, 17ºC
38.6%O
HAcO
H
O
O 1) NaBH42) ArSeCN PBu3
O
HAcO
H
O
SeAr
72%
NaIO4
O
HAcO
H
O
66%
neat10 days
72%
O
OH
HAcO
H
H
OAc
H
H
H
O
O
KOH, MeOH
80%
O
OH
HHO
H
H
OH
H
H
H
O
O
1) SOCl2, Et3N2) OsO4, NMO3) NaIO44) MeLi
69%
Absinthin
O
OH
H
OH
H
H
HO
H
H
H
O
O
Absinthin was isolated as orange acicular crystals from Sievers Wormwood (Artemisia sieversiana) as the major guaianolide. In TCM, the plant is known as bai hao and is used as a stomach tonicand anthelminthic. Absinthin has been successfully used to alleviateinflammation of gastric ulcers and regenerate the stomach wall inmice.
Zhao et al. J. Am. Chem. Soc. 2005, 127, 18-19
Molecules of Traditional Chinese Medicine