Chinese herbal medicine represents only one part of Traditional Chinese.
Medicine, which also ... Over a 40 year period he compiled his book. Bencao
Gangmu ...
Baran Group Meeting
Molecules of Traditional Chinese Medicine
Will Gutekunst
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).
Molecules of Traditional Chinese Medicine
Baran Group Meeting
A sampling of the molecules found in Traditional Chinese Medicine that are not covered in this presentation
Will Gutekunst
HO
O
HO
N O
O O
N
HO O HO
O
N
O
Me
O
HO
O
O
Camptothecin See camptothecin group meeting
N Me
O H
MeO
O
morphine See morphine/codeine group meeting
Ph
O Ph
N H
O
O
Me
OH
Me
H
O
H BzO AcO
HO
taxol
OH MeO
N
H
OMe Me
N
MeO
vinblastine See vindoline group meeting
See dendrobine group meeting
OH O
MeO
OH
berberine See Isoquinoline Alkaloids group meeting
MeO
phorbol See Tigliane, Daphnane, Ingenane, Lathyrane Diterpene group meeting
N
podophyllotoxin
See Stegane Natural Products group meeting
See Lignan Synthesis group meeting
CO2Me O
OH
MeO
O
O AcO MeO2C
H
O
OH
H
MeO O
OH
azadiractin
H
NHAc
MeO
O
strychnine
H
O
H H
gomisin A
O
H
O
OMe OMe
OH OH
H O
OMe
H
O HO OMe
H
OH
O OH
N
O
H
MeO
H
MeO
N
O
OMe
chasmanine
O
OH H
O
MeO
H
OAc HO CO2Me
See vetivane sequiterpene group meeting
O
HO N Me
quadrone See quadrone group meeting
H
HO
MeO
O
O
huperzine A
O
N N H MeO2C
O
!-vetivone
stenine See stemona alkaloid group meeting
Me
O
H2N
O
H
O
Me H N
Me
N
OH
See ajmaline and sarpagine alkaloid group meeting
Me
Me
O
ajmaline
Me
O AcO
OH
H
HO
cephalotaxine See cepharamine and related alkaloids group meeting
gelsemine
ginkgolide B
N
N Me H
N
H
OMe
H
O HO
O
O
H
H N
O
C5H11
OMe
colchicine
tetrahydrocannabinol
Baran Group Meeting
Molecules of Traditional Chinese Medicine
OH OH HO
O
H O
OH
Atractylodin
O OH
OH
O
OH O
OH O
epigallocatechin-3-gallate (EGCG)
O
O
O
O
O
O OH O
O
evodinone (s)SugarO
OH
O
OH
AcO
OAc OAc OAc
BzO OH OH
O
OAc
O HO
AcO O
OH
O
OH
hypericin
N O
wilforine
Will Gutekunst
Molecules of Traditional Chinese Medicine
Baran Group Meeting H
O
Me
H
O O
Me
O
O HO
H
Me
H
3M H2SO4
O
TMSO HOOC
Me
Will Gutekunst O O
Me
O HO
35%
H
O
Semi-Synthesis Lansbury et al. Tet. Lett. 1992, 33, 1029-1032.
Artemisinin (Qinghaosu)
H
H
Me
O
O
2) m-CPBA - 78 ºC 94%
O SOPh
1) TsNHNH2 2) 4 eq BuLi TMEDA, then DMF 60% two steps
O
O
H
TMS H
Me
3 eq LDEA -78ºC ! 50ºC, then 2 eq LDA MeI 61%
O O
H
H
O
2 eq. sodium naphthalenide,
O
TMSOTf 94% 2 steps
H
O O
82%
H
O
H
Me
1) 2 eq LDA, HMPT 2) Al(Hg) Amalgam wet THF 37-50% two steps
MOMO
H
88%
O
O
H
Me
O3/O2, -78ºC, then SiO2;
HOOC
Me
Me
O O O HO
30-35% OMOM
H Me O
Acton et al. J. Org. Chem. 1992, 57, 3610-3614 Me H
Me
H
1O 2
Me
H HO2C
3O 2
Me HOO
H H
H HO2C
Me
"simple sugar"
engineered S. cerevisiae
H
trace H2O 17-32%
O O
H
H Me O
H
Me Me
H HO2C
Me
O HO
Keasling et al. Nature 2006, 440, 940-943
TMS H
Me
then CSA
O
(TMS)3Al•Et2O, then Ac2O, DMAP
OHC
O2, Rose Bengal
H
O
H O
then MOMCl
H
O O
dihydroartemisinic acid
O
O
TMSO
H
Br
H
O
H
1) NaSPh O
O
arteannuin
H O
H
O
O
Me
NaOH
O
O3
O
Me
2) WCl6, 2 eq nBuLi 60%
H
O
OTMS
Avery et al. J. Am. Chem. Soc. 1992, 114, 974-979
O
H
artemisinic acid
- 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.
Me
1) Wilkinson's
2) CrO3 3,5-dimethylpyrrole
HO2C
O
H2O2 74%
H
H
1) [H]
From Artemisia annua; other common names include Sweet Wormwood, Sweet Annie and Sweet Sagewort. Chinese: Qinghao
O
H Me
Me
O
O
Me
H
Me
O O O HO
H Me O
Molecules of Traditional Chinese Medicine
Baran Group Meeting
6,9-Desmethylartemisinin Avery et al. J. Org. Chem. 1989, 54, 1792-1795
N
Cl
O
Cl
O
TMS
PhSH, O2
1) KOH 2) Oxalic Acid, SiO2
TMS
O
O O
Me
O HO
3) O3 4) Amberlyst 15 50% CO2Me
5 eq (CF3CO)2O
PhS O
H
O HO
O
yingzhaosu A
50% 55:45 dr
O
10 eq 2,6-lutidine
O
F3CO2
O O O H
90 %
- 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.
O
TMSO O
HO
O
yingzhaosu A
CHO
1) m-CPBA
O2, h! Methylene Blue
1) MeMgBr
O
2) POCl3, py ca 15% 4 steps
O O
O
OMe O
3) HC(OMe)3 p-TsOH 4) POCl3
1) PtO2, H2
O
80%
OH
OH O
O O
HO
yingzhaosu A
O O
O
2) p-TsOH, H2O
OH
p-TsOH 55% 1:1 dr
O
OMe
1) LiBH4 2) O3
2) m-CPBA
O
87%
O
O H O O
O
Ph3As OH
Then LiBH4 62% 3:2 dr
O O H
43% two steps
O
O
H
O TMSO
TiCl4, then 21 eq py 70%
O
71%, 9:1 dr
O
O
OH
R-CBS, BH3
Xu et al. Tet. Lett., 1991, 32, 5785-5788
2) BF3•OEt
PhS
OTMS
then 2% HF in MeOH
O
1) 4.3 eq SOCl2 11 eq py
morpholine MeOH/DCM
PhS O
H2, 0.15 eq PtO2 -11ºC to -12ºC OH
O
OH
Ph3P
PhS
AIBN, hv
2) Ac2O, Et3N 64%
OH
H
OMe
58%
CO2Me
O
1) O3, NaHCO3 TMS MeOH
78%
Ph P Ph MeO Li
OHC
Bachi et al. J. Org. Chem. 2005, 70, 3618-3632
LiCH(TMS)2
40%
Will Gutekunst
OH
Isolated from extracts of Tripterygium wilfordii Hook F Common names include lei gong teng and Thunder God Vine.
triptolide Traditionally used to dispel wind and dampness, it is used to 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 potential treatment for rheumatoid arthritis, leukemia, hepatitis, nephritis, and various skin disorders. More recently triptolide and related structures have been tested for their antifertility properties to be one day used as a male contraceptive.
8 steps 7.3% overall yield
O
O
Molecules of Traditional Chinese Medicine
Baran Group Meeting
Will Gutekunst
Berchtold et al. J. Am. Chem. Soc. 1980, 102, 1200-1201 O
I
1) NaH, DMF OMe
2) Me2NH
OMe
O
1) CrO3•py
OTBS
1) MeI, NaI 2) MeLi 3) MsCl, TEA
OH
then MeOH-HCl 86-93% from butenolide
H
Me2N
CO2Me OMe
2) neutral alumina 83%
O
94%
O
O
O
O
OH
4) Li/NH3 65-70%
H
MeO OMe
OMe
1) p-TsOH, benzene reflux 2) NaBH4
OMe
Me2N OH
O OHC
O
OMe H
H
NMe2
xylene reflux 80%
56%
3) aq HCl workup 88%
Me2N
H
5 steps OMe
OMe O NMe2
H
HO
CHO
O
1) NaOMe, MeOH 2) CrO3, HOAc-H2O
OMe
3) BBr3, DCM 4) NaBH4
O O
NaIO4, aq MeOH
OH
O
H
O
13% over 4 steps
O
steps OMe
then 1M HCl 80%
74%
OH
1) m-CPBA 2) LiHMDS,
O O
O
H
O
O
OH
triptolide
van Tamelen et al. J. Am. Chem. Soc. 1982, 104, 1785-1786 O
1) m-CPBA 2) H2O2, NaOH O O
O
3) NaBH4
O
25% (1:3 dr)
H
O
O
O
OMe
H
O
O
1) Ba(OH)2, heat
NaH, THF
O
OH
OMe
OMe
99%
O
Br
2) LAH 92%
CO2Me
triptolide
O
van Tamelen et al. J. Am. Chem. Soc. 1982, 104, 867-869
O
LiBr, PBr3, O
O
OMe
Li/NH3, t-BuOH then,
O
O
O O
EtO
P Cl OEt
1) 3M H2SO4 2) CS2, then MeI
O
H
then 1:6 6M HCl-MeOH H
84%
LiH 90%
Br
H OMe O
LDA, HMPA TBSCl
H
then ZnBr2 70%
O
SMe SMe
O
O HO
THF t-BuOH 90-92%
S
t-Bu
Li t-Bu
(EtO)2OPO
O
Li, EtNH2
OEt OMe
1) SnCl4 2) MsCl, Et2NH
EtO2C O
OMe EtO2C
1) m-CPBA 2) n-BuLi
H
51% over 4 steps
Molecules of Traditional Chinese Medicine
Baran Group Meeting
O
Corey et al. J. Am. Chem. Soc. 1993, 115, 8871-8872 and Classics in Total Synthesis I pg 633-640.
O
O O
O
steps
OMe
O O
H
20 eq NC
Me
OH
Me
triptolide
H
KOAc, MeCN 48%
OTIPS
O
5 steps
OTIPS
NC
I
OH BnO
H
OMe
OH
H
O O
HO
5 steps
Me
OTIPS
Pd 86%
H
O
BnO BnO
O O
BzO HO
Me
93%
O
O
NC
slow addn. SmI2 (7 eq)
H
SnBu3 O
61%
OTIPS O
NC
Sheburn et al. Chem. Comm. 2008, 1226-1228 I
O
H Cl
O O
O
Me
OH
4 eq Mn3O(OAc)7
H
O
Will Gutekunst
OP(OMe)2
OBn
ZnCl2, AgClO4 4A MS 18%
OTIPS
O
O O
MeO
H
1) NaBH4 2) Ag2O, MeI
H O O
19 kbar, DCM 50%
H
O H
99% 2 steps
O
H
O
44%
O
BnO BnO
Tf2O
H
O
3) H2O2
O
O
OTIPS
Me
HO HO
Me
OH OH
Paeoniflorin
CHO
83%
OH
TMS PivO
75%
TBSO PivO
CO2Me
1) 1M NaOH 2) CH2N2 Me
O
CO2Me
3) Swern 86% BzO
1) TMSCN KCN 18-crown-6
Me
Me CN
3)
hexane 64% O OH Me
BzO
2) 0.1M HCl
1) conc HCl 2) (COCl)2
O O
CO2Me
Me
O
N
CN O O
BzO
OH S
MeO2C
h! O
resolution
BzO
OTBS
Me MeO
TMSOTf
O
O
5 steps
Me
5 steps
O Me
O
Traditionally used for regulating the blood and Ying, paeoniflorin has displayed anticoagulant, sedative, antiinflamatory, and neuromuscular activities.
Me
OH
OH
TBSO
Me HO
HO HO
Paeoniflorin
Li
O
72%
Isolated from the roots of Chinese peony (Paeonia lactiflora). In TCM it is known as shao yao or bai shao yao.
O O
BzO O O
HO
92%
O
O O O
Me
OBn
TBSO
Me
BzO O O
1) H2, Pd(OH)2/C 2) HF-MeCN
Hatakeyama et al. 1994, 166, 4081-4082
O
1) TIPSOTf, Et3N 2) PhSeCl O
O O
BzO O O
BnO
MeO H
H
tBu
O H
O
H
17%
N
H
MeO
H
tBu
H
O
O Me O
PhI(OAc)2 I2, h! 92% 2 steps
Toluene, O2 Me S O N
80º C, then (MeO)3P
Molecules of Traditional Chinese Medicine
Baran Group Meeting 1) PhCH2OCOCl 2) O3, MeOH/DCM
O O
BzO
BnO O O
BzO HO
Me 3) p-NO -C H COCl 2 6 4
Me
TEA, DMAP
OH
BF3•OEt2 (18 eq)
BnO
67%
BnO BnO
BnO
6 eq
OCO2Bn
60%
Grieco et al. J. Am. Chem. Soc. 1993, 115, 6078-6093
O
BnO BnO
O
AcO
CCl3
BzO O O
NH
H2, Pd(OH)2
HO
quant.
HO HO
Me
OBn OCO2Bn
O O
BzO O O
O
1) Li, NH3 2) NaH HCO2Et
OH
MeO
48%
OMe
MeO
MeO H
H
H
H
O
H HO
OTBDPS
12 steps H
24%
O
CO2H
H
73% OH
quant
OHC
5M LiClO4, EtOAc
O
H
1) NaBH4 2) HCl pH 2
PPTS 80%
47%
OPiv
OH
OPiv OH OH
O
CO2H
CHO
3) DDQ, HOAc 62%
Me
71%
O
Me
OH
Paeoniflorin
cat. Cp2TiCl2 Zn, THF
O
68%
OMe
1) mCPBA 2) tBuCOCl, py
HO
1) MeI, NaH 2) 70% HClO4
O
Bermejo et al. J. Org. Chem. 2009, 74, 1798-1801
O
HO
1) LAH 2) CH2I2 Zn/Cu O
O O
Will Gutekunst
O
H
H
O
H
O
O PivO Me
O O
CrO3 Ph dimethyl pyrazole H
PivO Me
63%
O O
Ph H
1) 10 N NaOH 2) H2, Pd/C 77%
O
O Me
OH OH
paeonisuffrone
H H
OH
H
H
O
O
glaucarubolone O HO HO
O
O
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 astringent properties, though quassanoids have been shown to have antimalarial, antiasthmatic and antiepileptic properties.
H H
O
samaderin B
H
H
O
H
O
OMe
1) CrO3 py 2) NaOH
MeO
O
OTBDPS H
70% H
O OTBDPS
HO H
3) B2H6, NaOH, H2O2 58%
H
H H
OMe
O
H O
H
OMOM
1) MOMCl 2) LiHMDS, HMPA then, Me2SO4
O
OMe
1) PCC 2) 10% HCl, THF 3) POCl3, py
OMe
OMOM MeO
O OTBDPS
O
95%
H H
H H
2)
MeO OH I
O
O OTBDPS OH
O H
H
O CF3 CF3
H
H
O
O OMOM
OMOM
1) OsO4
O
H
OMe
OTBDPS H
86%
H
OTBDPS
OH
HO HO
H H
AcO
OAc
OH
O
O
H
Ac2O quant
H
H
O
OsO4 O
OTBDPS H
Quassinoids HO HO
HO
1) DiBAL 2) MeOH, HCl
1) TMSCl 2) PyHBr3, CSA
MeO
O OTBDPS OH
O H
3) 10% HCl in THF O
H
H H
O
O
Molecules of Traditional Chinese Medicine
Baran Group Meeting OMOM O
MeO
OTBDPS OH
O H
HO HO
1) BBr3 2) TBAF
H
H
OH MgBr
O
TBSO
OTBS O
1)
NaH 4-methylbenzo[15]crown-5
OH H
H O
O
O
H
H O
H
O
78%
O
Will Gutekunst OTBS O
TBSO
Methylene Blue Toluene, 180ºC O
2) Ac2O
OH
92% 2:1 trans:cis
OAc
83%
glaucarubolone
Grieco et al. J. Am. Chem. Soc. 1994, 116, 7606-7615
TBSO
OTBS O
1) NaOH 2) Tf2O, py DMAP 3) nBu4NOAc
OTMS MeO
TMSI, HMDS TEA
OH H
H
H
O
MeO
OTMS
90%
H
OMe H
O
HO MeO
steps
H
H
OMe
O HO MeO
O
CO2Me
HO MeO
H
H
OH
H
O
O
steps
H
10 mol% Mn(OAc)3 TBHP, 3A MS O
H
90%
72%
H
O
HO
H
OTBS O
Mn(OAc)3 benzene reflux
H
O
5 steps
OH O
O H H
Shing et al. Angew. Chem. Int. Ed. 2005, 44, 7981-7984
H
O
samaderine Y 9 steps O
TBSO
OTBS O
34%
1) TFA, H2O/DCM 2) NMO, TPAP O
O
TBSO
OTBS O
78%
O O
H
TBSO AcO
O
O
OMe
OTBS O
O H
78% OMe
HO
samaderin B
H
O
H
O
OTBS O
TBSO
NaBH4, NiCl2, MeOH then conc HCl
O
H OH
O
H
TBSO
O
H
AcOOH
H
O HO HO
31%
78%
Hunig's base Cu(OAc)2 93%
O OH
TBSO
83%
1) NaBH4 2) MeOH, py, O
H
OTBS O
O
H
H O
H
65%
OMe
O
O
OAc
H
1) LDA 2) SOCl2, py O
O
MeO H
H
OAc
84%
H O
H
NIS, then TBAF
OTBS O
TBSO
O
O
O
H
OTBS O
TBSO
H
H
O
OMe
Molecules of Traditional Chinese Medicine
Baran Group Meeting
Will Gutekunst
Tanshinones Isolated from the taproot of Salvia miltiorrhiza, which has seen heavy use in Traditional Chinese Medicine. Known as dan shen, it has been used to both treat and prevent heart problems and strokes, and has been shown 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 or synergistic effects.
O O O
HO HO
OH
O
O
OH
O
O
O
H2SO4, EtOH
O
O
DDQ
O
100% tanshinone IIA
cryptotanshinone
neocryptotanshinone
Tanshindiol A Majetich et al. J. Org. Chem. 1997, 62, 6928-6951
Snyder et al. J. Org. Chem. 1992, 57, 5301-5312
OMe
1)
O
OtBu
H2N
CO2Me
O
7 steps
OCOPh
O
CO2Me
1) 5N HCl 2) Fremy's Salt O
HO
N
N
94%
O
O
tBuOK, tBuOH reflux 75%
64%
O
O
NH2NHTs NaCNBH3
99%
O
O
OMe
O
BBr3, then CAN
MeO
O
O
miltirone
MeN
H
O
O
BBr3
O
O
Me H
O
OMe H Me
Me
H
NMe
Incarvillateine
Tanshindiol A
Kibayashi et al. J. Am. Chem. Soc. 2004, 126, 16553-16558
Danheiser et al. J. Org. Chem. 1995, 60, 8341-8350 TIPSO
O OTBS
OTBS
TBAF, O2
SnBu3
Me
BuLi, Me2Zn OTBDMS
OTBDMS
OH
h!, vycor 65%
O
Isolated from the aerial parts of Incarvillae sinensis, a wild plant native to northern China. Known in TCM as jiaohao, it is traditionally used to treat rheumatism and as a pain reliever. Incarvillateine has been shown to be a potent analgesic in mice.
O
HO
O
HO
TIPSO
OH
MeO
HO
N2
Me O
O
66%
O
61%
52%
1) ultrasound 2) DDQ 72%, 4:1 regio
O
MeO O
O
O
benzene
MeO O
BF3•Et2O CCl4 reflux
O
2) LDA, (PhCO)2O2 56%, 92% ee
OMe
OMe
MeO O
82-84%
then MeI, HMPA 77%
OTBDMS O
OTBDMS Me
Me
1) O3, then Me2S 2) NaBH4 68%
Molecules of Traditional Chinese Medicine
Baran Group Meeting
Will Gutekunst
I OTBDMS O
OTs
1) TsNHBoc DEAD, PPh3 2) TFA, DCM
OH
O
O
NTs H
Me
H
TBDMSO
NH
HO HO
OH
H
Me
H
TMSI, lutidine, then
TfO
N Boc N !Ts
H H Me Si
MeO
O
OMe H Me
Me
H
CO2Me
O
HO
NMe
O
1)
SnBu3
TBSO NMe
N H Ts
Aloperine
NaBH4
CO2Et
49% 2 steps PEt2
Me
O
Pseudolaric Acid
NMe
TBSO
NMe
3) HCl (aq), MeOH 90%
Me
O
NMe H
Me
steps Incarvillateine
Me
O Me
HO
N H H
N
O
Me TBSO
1) H2 (1000 psi) Pd/C MeOH 2) LAH
H
88%
HO2C O
70%
O
LAH
N
2.5% [RhCl(coe)2]2 Toluene Me2N
H
2) MeNH2, 4A MS
5.5%
C6F5OCSCl, DMAP; Bu3SnH, AIBN
N H Ts
N
63%
O
Grubbs 2nd gen
99%, 95% ee CO2Et
OH
H
OTBS EtO2C
2) TBSCl
concentrate; KF, KHCO3 H2O2
O
(S)-Binol, TFA H
N H Ts
N
Ellman et al. J. Am. Chem. Soc. 2008, 130, 6313-6317 1)
SiMe2F
H
Incarvillateine
EtO2C
HF-py, concentrate then mesitylene reflux
N N Me Si Ts Me H COHMe 2
N !Ts
Me O
Et3N
23%
OH
O Me H
N !Ts
Pd(OAc)2, K2CO3 nBu4NOTf, DMF, H2O
N
Me
CO2Me
TfOMe2Si
N Boc
O
TsO
MeN
1) DEAD, PPh3 2) Na(Hg)
OMe
MeO
NMe
Overman et al. J. Am. Chem. Soc. 1999, 121, 700-709
OTs
O
Me
2) H2, PtO2 5 atm 3) TBAF 81%
H
Me
N H H
N
1) 35% HCHO, NaCNBH3, AcOH
H
naphthalenide 70%
Isolated from Sophora alopecuroides (Ku dou zi), which is used to clear heat, dry damp, kill worms and relieve pain. Indications include dysentery stomachache, eczema, boils and intractable lichens. Aloperine in particular has shown to have antiinflamatory and inhibit allergic reactions and heart arrhythmias in rats.
H
2) PdCl2(MeCN)2, TEA HCO2H 58%
Me
1) NaBH4 2) TBDMSCl 3) sodium
H
1) K2CO3, MeCN
NHTs
95%
Me
Aloperine
O H
CO2Me
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 potent antifungal agents responsible for this observed bioactivity and also have seen promise against multidrug resistant cancer cell lines.
Molecules of Traditional Chinese Medicine
Baran Group Meeting O
O
Me
OH
OTBS
5 steps O
I
Me
TMS
TBDPSO
58% O
N
1) CH2Br2, Zn, TiCl4 2) (sia)2BH; H2O2
N Bn H
TBSO
2) K2CO3, MeOH
3 steps OH
O
1) MePh3PBr, PhLi/LiBr then A, PhLi/LiBr then B, PhLi/LiBr; HCl, then KOtBu
A
HO
Me
CO2Me
OH
TBSO
DCE 88%
1) ClCO2Me Na2CO3 2) LAH
Me
Me
SeO2/H+
O
39%
H
HO Me
H
H
N H
H
O Me
then DBU 85%
OPMB
PMP
O H
O H
9 more steps HO2C
N
O
koumine
O
Me
O Me
CO2Me
MeN
H
O
Psuedolaric Acid
taberpsychine
koumidine E isomer
H
Bu3SnH 1,1'-Azo-bisCO2Me (cyclohexanecarbonitrile)
O
PhSe
N H
Me N
94%
O
9 steps
OH
TBAF
39%
H
CO2Me
N OTBDPS
1) DiBAL 2) Na/NH3
N Bn
H
OTBDPS
H
N
50%
B [(C8H10)Rh(COD)]+SbF6-
Will Gutekunst
O H
H O
CO2Me
Koumine
O OH
H
OH
H
OH OH
MeN
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 growth factor and a highly selective !-opiod receptor agonist.
erinacine E Nakada et al. J. Am. Chem. Soc. 2008, 130, 1150-1151
N
O
O
OH
H
MeOTf 84%
OBz
H
CO2Me NHBn
N Bn
H
NH
O
8 steps
TFA N
MeO2C
H
N Bn
80% 5.5:1 E:Z
OH
O
1) TBAF 2) TFA
OH OH H OBz
CH2OTBDPS
H OBz
OH
O
Magnus et al. J. Am. Chem. Soc. 1989, 111, 786-789
OMPM
OTES OMPM
CH2OTBDPS
H
OTES
O
PhS
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.
OMPM
O
OMPM
OBz
O
1) TESCl 2) BzCl, TEA, DMAP 3) 10% citric acid
OH
O OTES OH H OBz
Molecules of Traditional Chinese Medicine
Baran Group Meeting OBz
O
OH
O OTES
Et3N
OTES
H
OH
H H O OBz
DBU
O O
1) NaBH4 2) K2CO3, MeOH 3) IBX
OH
4) Me4NBH(OAc)3
OR
H
H
85%
O
OBz
R = TES O OH
H
OH
H
OH OH
erinacine E Absinthin
OH
H HO
H H H HH
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 tonic and anthelminthic. Absinthin has been successfully used to alleviate inflammation of gastric ulcers and regenerate the stomach wall in mice.
O
O
Zhao et al. J. Am. Chem. Soc. 2005, 127, 18-19 AcO
O H O
38.6%
AcO
H
HOAc h!, 17ºC
O H O
O O
H
1) NaBH4 2) ArSeCN PBu3 72%
H HH
H O O
R = TES
H O
H H
HO
O H
HH
H
80%
O O
O
OBz
H O OR H
KOH, MeOH H
O
OBz
O
H H
AcO
O
H
H
72%
O
93%
O
OH
neat 10 days
66%
OAc
H
H
NaIO4
O
O
Swern
AcO
OBz
O
Will Gutekunst
SeAr H O O
O
1) SOCl2, Et3N 2) OsO4, NMO 3) NaIO4 4) MeLi 69%
H HO
H
OH
H H HH
H
O
O
O O
O
Absinthin
