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).
Baran Group Meeting Molecules of Traditional Chinese Medicine Will Gutekunst

A sampling of the molecules found in Traditional Chinese Medicine

that are not covered in this presentation HO
O
N HO
O
O O
H N
O HO H N OH
N N N Me H
O O HO O O MeO H
N OMe H
H HO
O cephalotaxine morphine ajmaline
Me O
HO N See cepharamine and related See morphine/codeine See ajmaline and sarpagine
Me O
HO O
O H alkaloids group meeting group meeting alkaloid group meeting
O
Camptothecin
gelsemine Me
See camptothecin group meeting ginkgolide B Me
Me Me Me

O H
AcO O Me Me N O
Ph O OH H
O O Me O O
H2N
O
Ph N O
H N O huperzine A quadrone
OH H
H O
HO !-vetivone See quadrone
BzO AcO group meeting
taxol See vetivane sequiterpene
stenine group meeting
See stemona alkaloid
group meeting
O OH
OH H
O O N
MeO H
N H
O
O H
HO OMe MeO H H O
N MeO N
N Me H H
H N OH
MeO2C HO O O
MeO MeO OMe H
MeO N OAc H
OMe OMe
Me MeO
HO CO2Me OMe
gomisin A podophyllotoxin strychnine
vinblastine chasmanine
See Stegane Natural See Lignan Synthesis
See vindoline group meeting See dendrobine group meeting Products group meeting group meeting

O OH
O CO2Me
O OH MeO
O OH H
O OH
H O H
NHAc
MeO
H O O
OH MeO H
N
MeO O HO OH O C5H11
AcO OH O
OMe OH MeO2C H
O OMe
berberine phorbol colchicine tetrahydrocannabinol
azadiractin
See Isoquinoline Alkaloids See Tigliane, Daphnane, Ingenane,
group meeting Lathyrane Diterpene group meeting
Baran Group Meeting Molecules of Traditional Chinese Medicine Will Gutekunst

OH
OH
H
HO O
OH O

O
Atractylodin
OH OH
O

OH
OH O

epigallocatechin-3-gallate (EGCG) O

O O

O
O O
O
OH
O O

evodinone

(s)SugarO

OH O OH OAc OAc
AcO
BzO OAc

OH OAc
O O
OH HO
AcO

O
OH O OH N
O
hypericin
wilforine
 Baran Group Meeting Molecules of Traditional Chinese Medicine Will Gutekunst
O Me Me
Me H H
H
O 3M H2SO4 Me O O
Me O O O
O
O H 35% H
H TMSO HO
HO
HOOC Me Me
Me
O
O
Artemisinin Semi-Synthesis Lansbury et al. Tet. Lett. 1992, 33, 1029-1032.
(Qinghaosu)
H H H

From Artemisia annua; 1) [H] 1) Wilkinson's

other common names
include Sweet Wormwood, H H 2) CrO3 H 2) WCl6, 2 eq nBuLi O O H
O
Sweet Annie and Sweet 3,5-dimethylpyrrole 60%
HO2C
Sagewort.
Chinese: Qinghao O O
artemisinic acid
O3 arteannuin
O
H O O H
- Qinghao has been used in traditional chinese medicine for centuries, prepared as a tea for treating
OTMS
fever. Popularized in 1970 when the reemergence of Chinese Handbook of Prescriptions for Emergency 2 eq. sodium naphthalenide,
O TMSO O
Treatments from 340AD was rediscovered.
- Qinghaosu (Artemisinin) was first isolated in China in 1972 as a potent antimalarial agent. O H TMSOTf O H then MOMCl
- It continues to be a highly important drug in the pharmaceutical arena with its analog Artemether being H H
94% 2 steps 82%
marketed by Novartis in the drug Co-artem.
O O

Avery et al. J. Am. Chem. Soc. 1992, 114, 974-979

O O H Me
Me Me H
Me
O O H O2, Rose Bengal O O
NaOH 1) NaSPh Me
Br H then CSA O
O MOMO
H2O2 O 2) m-CPBA O HO H
O
74% O 1) 2 eq LDA, HMPT 30-35%
- 78 ºC SOPh Me
94% 2) Al(Hg) Amalgam OMOM
wet THF O
37-50% two steps Acton et al. J. Org. Chem. 1992, 57, 3610-3614
1) TsNHNH2 Me
H Me Me
2) 4 eq BuLi H H
Me Me (TMS)3Al•Et2O, 1O 3O
O O H O O H 2 2 O O
TMEDA, Me
then DMF then Ac2O, DMAP Me Me
H H O
HOO H
trace H2O H
O
60% two steps 88% HO
OHC HO2C
H HO2C 17-32% Me
H
dihydroartemisinic acid O

Me 3 eq LDEA Me Keasling et al. Nature 2006, 440, 940-943

O O H O O H O3/O2, -78ºC, Me
-78ºC ! 50ºC, then SiO2; Me H
H
TMS TMS engineered Me O O
then 2 eq LDA S. cerevisiae
H MeI H "simple sugar" O
O HO H
61% HOOC Me H H
Me
O HO2C
O
 Baran Group Meeting Molecules of Traditional Chinese Medicine Will Gutekunst

6,9-Desmethylartemisinin Avery et al. J. Org. Chem. 1989, 54, 1792-1795

Bachi et al. J. Org. Chem. 2005, 70, 3618-3632
OH
O OH 1) 4.3 eq SOCl2
Cl Cl O 1) O3, NaHCO3 Ph3P
N LiCH(TMS)2 TMS MeOH PhSH, O2 11 eq py
PhS PhS
AIBN, hv O 50% O
40% 78% 2) Ac2O, Et3N O 55:45 dr 2) m-CPBA
O
64% 87%
O H
OMe
1) KOH
OHC Ph P O O O morpholine
Ph 2) Oxalic Acid, SiO2 Me 5 eq (CF3CO)2O PhS MeOH/DCM O
MeO Li PhS
TMS O O O
TMS O O
3) O3 HO H
O 10 eq 2,6-lutidine F3CO2
O
43% two steps H
58% 4) Amberlyst 15
CO2Me 50%
CO2Me O OTMS
H2, 0.15 eq PtO2 O O
-11ºC to -12ºC TMSO
O TMSO O
O TiCl4, then O
OH 90 % H
- Isolated from the Chinese medicine Yingzhao (Artabotrys uncinatus) 21 eq py
O
O - Another antimalarial agent from TCM, but has not received as much 70%
HO attention as its peroxide cousin artemisinin, primarily due lack of
available compound.
yingzhaosu A OH
R-CBS, BH3 O 8 steps
O 7.3% overall yield
then 2% HF in MeOH HO

Xu et al. Tet. Lett., 1991, 32, 5785-5788 71%, 9:1 dr

yingzhaosu A
CHO
O2, h!
1) m-CPBA 1) MeMgBr Methylene Blue
O
2) BF3•OEt 2) POCl3, py p-TsOH
O O O O Isolated from extracts of
ca 15% 4 steps 55% 1:1 dr
OH Tripterygium wilfordii Hook F
O
OMe O O Common names include
O
1) LiBH4 Ph3As H lei gong teng and Thunder
2) O3 OMe H O God Vine.
O 1) PtO2, H2 OH
O O triptolide
3) HC(OMe)3 2) p-TsOH, H2O Then LiBH4
O O p-TsOH 62% 3:2 dr
4) POCl3 O 80% O Traditionally used to dispel wind and dampness, it is used
to treat people who have swollen joints, difficulty moving,
OH fever, chills, edema, and carbuncle. Also known as "qi bu si"
which means "sevens steps to death" as a result of its
OH potential toxicity.
OH
O Lei gong teng has been clinically evaluated as a potential
O
O HO treatment for rheumatoid arthritis, leukemia, hepatitis,
nephritis, and various skin disorders. More recently triptolide
yingzhaosu A and related structures have been tested for their antifertility
O properties to be one day used as a male contraceptive.
 Baran Group Meeting Molecules of Traditional Chinese Medicine Will Gutekunst
Berchtold et al. J. Am. Chem. Soc. 1980, 102, 1200-1201

O
I CO2Me
O 1) MeI, NaI
1) NaH, DMF 1) CrO3•py OMe 2) MeLi
OMe OTBS OH 3) MsCl, TEA
OMe 2) Me2NH O 2) neutral alumina
O O 4) Li/NH3
94% 83% then MeOH-HCl
O O Me2N H H 65-70%
86-93% from butenolide
OH

MeO OMe

1) p-TsOH, benzene reflux 5 steps H NMe2

OMe
2) NaBH4 OMe OMe
OMe OMe xylene O
56% reflux
Me2N Me2N 3) aq HCl workup H
H H 80% NMe2
OH 88%
O OHC O CHO HO
O

1) m-CPBA steps O
1) NaOMe, MeOH 2) LiHMDS, OMe OH
NaIO4, aq MeOH O
2) CrO3, HOAc-H2O OH
OMe then 1M HCl O O
74% 80% H
3) BBr3, DCM O OH O O
O H
4) NaBH4 triptolide
O
O 13% over 4 steps

van Tamelen et al. J. Am. Chem. Soc. 1982, 104, 1785-1786

O
1) m-CPBA
2) H2O2, NaOH O 1) Ba(OH)2, heat
NaH, THF
O OH O OMe
O 3) NaBH4 O
OMe 99% 2) LAH
O O O OMe O
H 25% (1:3 dr) H 92%
O O Br CO2Me
triptolide
O O
van Tamelen et al. J. Am. Chem. Soc. 1982, 104, 867-869
LiBr, PBr3, OEt
Li/NH3, t-BuOH OMe OMe
O O then ZnBr2 LiH
then, O O O O Br
Li, EtNH2 HO 70% 90%
O
P Cl
THF t-BuOH
O
EtO (EtO)2OPO 90-92%
OEt H H

1) 3M H2SO4 OMe
1) SnCl4 1) m-CPBA
OMe
2) CS2, then MeI O SMe O
S EtO2C
2) MsCl, Et2NH 2) n-BuLi
t-Bu O LDA, HMPA EtO2C
SMe H 51% over 4 steps
O
TBSCl
O then 1:6 6M HCl-MeOH
H H
Li 84%
t-Bu
 Baran Group Meeting
Molecules of Traditional Chinese Medicine Will Gutekunst

O Corey et al. J. Am. Chem. Soc. 1993, 115, 8871-8872 and Classics in Total Synthesis I pg 633-640.
O O Me
O Me
OMe steps OH Me 20 eq NC
O OH
O O 4 eq Mn3O(OAc)7 5 steps O
H H H OTIPS
H OTIPS
O O O Cl
KOAc, MeCN NC O
triptolide OTIPS 48% NC
O
OH
Sheburn et al. Chem. Comm. 2008, 1226-1228 BnO
BnO O
I NC O OP(OMe)2
O H
slow addn. O BnO
I SnBu3 H O 5 steps BzO OBn
SmI2 (7 eq) O
HO Me HO Me
OMe O
OH O 93% ZnCl2, AgClO4
61% Pd OTIPS OTIPS 4A MS
H H 18%
O 86% O
O
BzO O 1) H2, Pd(OH)2/C O
O MeO BzO
H H tBu N tBu BnO O O 2) HF-MeCN HO O O
O Me O Me
1) NaBH4 BnO HO
H BnO OBn 92% HO OH
2) Ag2O, MeI H
OTIPS OH
O Paeoniflorin
H O 99% 2 steps H O
19 kbar, DCM O O Tf2O
50% H O H Hatakeyama et al. 1994, 166, 4081-4082
O

OH TMS
MeO TBSO Li PivO
MeO
O 5 steps Me
1) TIPSOTf, Et3N O O TBSO
H 2) PhSeCl CHO TMSOTf
H Me 83% O Me Me
75% CO2Me
H MeO O
O O 3) H2O2 TBSO OTBS
O
44% 72% PivO O
H H O
17% O
O 1) 1M NaOH MeO2C
Me 2) CH2N2 h! O
Me
CO2Me CO2Me
O Me
3) Swern O hexane
Me 86% Me 64%
O
O Isolated from the roots of
HO BzO
O O Chinese peony (Paeonia
O Me O
HO lactiflora). In TCM it is known BzO
O 1) TMSCN KCN BzO PhI(OAc)2
HO OH 5 steps 18-crown-6 OH I2, h!
as shao yao or bai shao yao.
OH Me Me
Paeoniflorin resolution 2) 0.1M HCl 92% 2 steps
O CN

Traditionally used for regulating the blood and Ying, paeoniflorin has O 1) conc HCl O
BzO BzO Toluene, O2
displayed anticoagulant, sedative, antiinflamatory, and neuromuscular O 2) (COCl)2 O
activities. Me Me S
3) OH 80º C, then (MeO)3P
N
CN O N
O
S
 Baran Group Meeting Molecules of Traditional Chinese Medicine Will Gutekunst

1) PhCH2OCOCl BnO
BzO O 2) O3, MeOH/DCM O O
Grieco et al. J. Am. Chem. Soc. 1993, 115, 6078-6093
BzO BnO
O O
HO BnO
Me 3) p-NO -C H COCl Me BnO
2 6 4 AcO HO HO
TEA, DMAP O CCl3 1) LAH 1) MeI, NaH
OH OCO2Bn 6 eq 2) CH2I2 Zn/Cu 2) 70% HClO4
60% NH
O O
68% 71%
BzO O BzO O O
BF3•OEt2 (18 eq) BnO O H2, Pd(OH)2 HO O O O
O O
O Me O Me
BnO quant. HO
67% BnO OBn HO OH
OCO2Bn 1) Li, NH3 MeO MeO
OH OHC
Paeoniflorin 2) NaH HCO2Et CHO CO2H
CO2H
H
3) DDQ, HOAc 5M LiClO4, EtOAc
O O
Bermejo et al. J. Org. Chem. 2009, 74, 1798-1801 62% H 73% H
OMe

O OPiv OMe MeO HO

O 1) mCPBA cat. Cp2TiCl2 1) NaBH4 OH OTBDPS
Zn, THF OH 12 steps
2) tBuCOCl, py Me 2) HCl pH 2
OH H H H H
47% PPTS 24%
48% quant O O O O
OH OPiv 80% H H H H
O

1) DiBAL HO AcO
PivO PivO OTBDPS Ac2O OTBDPS
O CrO3 O
1) 10 N NaOH O 2) MeOH, HCl
Ph dimethyl pyrazole Ph Me OH
Me Me 2) H2, Pd/C OH H H quant H H
O H O H
63% 77% O OMe O OMe
O H H H H
O paeonisuffrone
OAc OH
HO O
HO 1) CrO3 py O
Quassinoids OsO4 OTBDPS 2) NaOH OTBDPS
OH 86% H H
O 70% H H
HO O OMe
HO H H O OMe
H H
O OH
The quassinoids are found in OMOM
H H 1) MOMCl OMOM
a variety of Traditional Chinese O 1) PCC
O O 2) LiHMDS, HMPA MeO 2) 10% HCl, THF O
H H Medicines including chun bai pi then, Me2SO4 OTBDPS MeO
3) POCl3, py OTBDPS
(Tree of Heaven) and ya dan zi HO
O
glaucarubolone (Java Brucea). Most are known 3) B2H6, H H
for their cooling and astringent 95% H H
NaOH, H2O2 O OMe
properties, though quassanoids H H O
O have been shown to have 58% H H
HO antimalarial, antiasthmatic and OMOM OMOM
HO O O antiepileptic properties.
O O
O 1) OsO4 MeO 1) TMSCl MeO
OTBDPS OTBDPS
H OH O 2) PyHBr3, CSA O
2) OH OH
O I O
H H H 3) 10% HCl in THF H H
O
O O O O
samaderin B CF3 H H H H
CF3
Baran Group Meeting Molecules of Traditional Chinese Medicine Will Gutekunst
OMOM OH
O OTBS OTBS
O HO O 1) NaH O
1) BBr3 MgBr TBSO TBSO
MeO HO 4-methyl- Methylene Blue
OTBDPS 2) TBAF
O O OH benzo[15]crown-5 Toluene, 180ºC
OH
H H H H O O
78% 2) Ac2O 92% 2:1 trans:cis
O O O O
H H H H OH 83% OAc

glaucarubolone

OTBS OTBS OTBS

Grieco et al. J. Am. Chem. Soc. 1994, 116, 7606-7615 O O O
TBSO
1) NaOH TBSO TBSO
2) Tf2O, py
DMAP
O O O
O
OTMS 3) nBu4NOAc
MeO OAc OAc
OH
TMSI, HMDS H H H
TEA MeO NIS, then TBAF
OTMS 65% 31%
H H
90% H H 84%
O OMe OTBS OTBS
H H O O
O OMe TBSO
H H TBSO NaBH4, NiCl2, MeOH
1) LDA
then conc HCl
2) SOCl2, py
O O O H
O 78%
HO 83%
MeO MeO O 1) NaBH4 O O O OMe
H H H H
steps 2) MeOH, py,
H H H Hunig's base
O OMe O Cu(OAc)2 OTBS OTBS
H H H O O
93% TBSO TBSO
Mn(OAc)3 AcO
10 mol% Mn(OAc)3 benzene reflux
O TBHP, 3A MS O O
O O
HO OH HO HO H 78% H
MeO O MeO O HO O O 72%
O steps O OMe O OMe
CO2Me H H H H
O
H H H H OH
AcOOH O HO O
OH OH
H H H HO
90% samaderin B 5 steps O
H
O O
Shing et al. Angew. Chem. Int. Ed. 2005, 44, 7981-7984 H H
samaderine Y
OTBS OTBS
O O
9 steps TBSO 1) TFA, H2O/DCM TBSO
2) NMO, TPAP
O 34% O 78% O

O O
 Baran Group Meeting Molecules of Traditional Chinese Medicine Will Gutekunst
Tanshinones
O Isolated from the taproot of Salvia miltiorrhiza, which has seen heavy OH O O
O
use in Traditional Chinese Medicine. Known as dan shen, it has been O OH O O
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
O anticoagulent. Preliminary results also show dan shen has potential O H2SO4, EtOH O DDQ O
efficacy against HIV. Some studies also show that the traditional
preparation of the medicine exceeds the activity of the purified 100%
HO compounds, leading to possibly more bioactive minor metabolites or
synergistic effects. tanshinone IIA
HO neocryptotanshinone cryptotanshinone

Tanshindiol A

Majetich et al. J. Org. Chem. 1997, 62, 6928-6951

Snyder et al. J. Org. Chem. 1992, 57, 5301-5312
OMe OMe OMe
MeO MeO MeO
O 1) OtBu O BF3•Et2O O tBuOK, tBuOH O
H2N O
7 steps CCl4 reflux
CO2Me OCOPh reflux
O
CO2Me O 64% 75%
2) LDA, (PhCO)2O2 O
56%, 92% ee
O O
O OMe
1) 5N HCl O
NH2NHTs MeO BBr3, then
benzene HO 2) Fremy's Salt O
NaCNBH3 CAN
N N O
94% 99% O
O O 52% 61%
O
1) ultrasound
2) DDQ miltirone
72%, 4:1 regio
O O MeN H
Me OH
O O O Isolated from the aerial parts of Incarvillae
BBr3 sinensis, a wild plant native to northern China.
O O Me H O OMe Known in TCM as jiaohao, it is traditionally used
66% MeO O H Me to treat rheumatism and as a pain reliever.
Incarvillateine has been shown to be a potent
HO O O analgesic in mice.
HO Me
HO O H NMe

Tanshindiol A Incarvillateine

Kibayashi et al. J. Am. Chem. Soc. 2004, 126, 16553-16558

Danheiser et al. J. Org. Chem. 1995, 60, 8341-8350
N2 TIPSO BuLi, Me2Zn
O OTBDMS
O OTBS 1) O3, then Me2S
OTBS TBAF, O2 SnBu3 Me OTBDMS 2) NaBH4
TIPSO O
OTBDMS
OH OTBDMS
Me Me
68%
h!, vycor 82-84% then MeI, HMPA
65% 77%
 Baran Group Meeting Molecules of Traditional Chinese Medicine Will Gutekunst
I

OTBDMS OTs Aloperine

1) TsNHBoc
DEAD, PPh3 1) K2CO3, MeCN Isolated from Sophora alopecuroides (Ku dou zi), which is used to clear
O OH O NHTs H heat, dry damp, kill worms and relieve pain. Indications include dysentery
2) TFA, DCM
stomachache, eczema, boils and intractable lichens. Aloperine in particular
2) PdCl2(MeCN)2, TEA
Me 95% Me has shown to have antiinflamatory and inhibit allergic reactions and heart
HCO2H N N
H H arrhythmias in rats.
58%
1) NaBH4 1) 35% HCHO,
H 2) TBDMSCl H
NaCNBH3, AcOH
3) sodium
O TBDMSO Overman et al. J. Am. Chem. Soc. 1999, 121, 700-709
NTs NH 2) H2, PtO2 5 atm
naphthalenide TMSI, lutidine,
H 70% H 3) TBAF
Me Me then
81% TfO
N CO2Me
OTs N TfOMe2Si
Boc
Me O Boc
H 1) DEAD, PPh3 N
!Ts Pd(OAc)2, K2CO3 N Et3N
HO OMe 2) Na(Hg) !Ts
nBu4NOTf, DMF, H2O
HO MeO OH
NMe 23%
Me H O H H
TsO HF-py, concentrate
then mesitylene reflux
MeN H N N
Me OH Me Si
O N Me Si N
Me !Ts Me H COHMe
Ts
2
Me H O OMe CO2Me
MeO O H Me

O
HO Me H NMe OH
SiMe2F concentrate; H C6F5OCSCl, DMAP;
Incarvillateine
H KF, KHCO3 Bu3SnH, AIBN
H2O2
N N 70%
N N 63% H Ts
Ellman et al. J. Am. Chem. Soc. 2008, 130, 6313-6317 H Ts
1) O
O
1) SnBu3 O
O OTBS
(S)-Binol, TFA Grubbs 2nd gen
EtO2C H EtO2C H H
2) TBSCl LAH
2) MeNH2, 4A MS
99%, 95% ee N N N N
H Ts 88% H H
O Aloperine
CO2Et 2.5% [RhCl(coe)2]2 Me
Toluene CO2Et NaBH4
TBSO TBSO O
NMe 5.5% 49% 2 steps Pseudolaric Acid O Me
Me2N PEt2 NMe O O
HO2C CO2Me
O 1) H2 (1000 psi) H
Me Me Me
Pd/C MeOH
2) LAH NMe steps
NMe The root bark of Pseudolarix kaempferi Gordon, known as tujinpi in TCM, has long been used to
TBSO HO Incarvillateine
treat fungal infections of the skin and nails. The pseudolaric acids were identified as potent
3) HCl (aq), MeOH
H antifungal agents responsible for this observed bioactivity and also have seen promise against
90% Me multidrug resistant cancer cell lines.
 Baran Group Meeting Molecules of Traditional Chinese Medicine Will Gutekunst

O OH
O OTBS
5 steps O
1) MePh3PBr, PhLi/LiBr 1) CH2Br2, Zn, TiCl4 1) DiBAL
I
Me O Me then A, PhLi/LiBr TBDPSO N 2) (sia)2BH; H2O2 N
2) Na/NH3
N N
A then B, PhLi/LiBr; Bn Bn
HCl, then KOtBu H H 39%
50%
TBSO
TMS 2) K2CO3, MeOH CO2Me CO2Me
58% Me H
3 steps
HO OH O OTBDPS OH
B 1) ClCO2Me
Na2CO3 SeO2/H+
Me N O
H N 2) LAH N
N
[(C8H10)Rh(COD)]+SbF6- OTBDPS OH H H
TBAF 39% H
TBSO HO H
DCE 94%
88% Me Me koumidine E isomer taberpsychine
H H

O
Bu3SnH
1,1'-Azo-bis- O MeN
PMP
9 steps O CO2Me (cyclohexanecarbonitrile)
PhSe O
Me O
Me OPMB then DBU CO2Me
H H O N
85% H
H
O koumine
Psuedolaric Acid O Me
9 more steps O H O
HO2C O
CO2Me O OH
H H Hou tou jun (Bearded Tooth Carpophore) is the sporocarp of the fungus
Me OH
Hericium erinaceum and has been used in TCM as an agent to fortify
spleen, nourish stomach and quiet spirit. Erinacine E was isolated
Koumine H OH the mycelia and has shown to be a strong stimulator of nerve growth
OH
factor and a highly selective !-opiod receptor agonist.
MeN
erinacine E

Nakada et al. J. Am. Chem. Soc. 2008, 130, 1150-1151 OMPM

N O
O OMPM
OH O
H O OTES
PhS OTES OMPM
Koumine originates from the TCM gou wen
(Gelsemium elegans), also known as Graceful OMPM
H CH2OTBDPS
Jessamine. Gou wen dispels wind, attacks toxins, H CH2OTBDPS
disperses swelling and relieves pain. Koumine MeOTf
OBz OBz
itself displays antitumor activity as well as potent 84%
analgesic properties.
OH OBz
O O
Magnus et al. J. Am. Chem. Soc. 1989, 111, 786-789
H 1) TESCl O OH
CO2Me O OH
H NH 1) TBAF 2) BzCl, TEA, DMAP
O OH 3) 10% citric acid OTES
NHBn 2) TFA
8 steps TFA
N OH OH
N 80% H H
N Bn
Bn MeO2C H 5.5:1 E:Z OBz
OBz
 Baran Group Meeting Molecules of Traditional Chinese Medicine Will Gutekunst

OBz AcO H OAc

OBz H
O O
neat
AcO H H
NaIO4 KOH, MeOH
O OH O O 10 days
Swern Et3N H
OTES OTES 66% H
72% 80%
H HH
O O
OH O 93%
O
H H O
O
OBz OBz O

OH 1) SOCl2, Et3N H OH
H
2) OsO4, NMO HO H
H O H O
HO H H H
3) NaIO4
O OR O 1) NaBH4
H OR 4) MeLi
OBz H 2) K2CO3, MeOH H H
DBU O
3) IBX H HH H HH
O O 69% O
H O O
85% H OH 4) Me4NBH(OAc)3 O O
O
OBz O O Absinthin
R = TES R = TES

H O
O OH
H
OH

H OH
OH

erinacine E

Absinthin
H OH
HO Absinthin was isolated as orange acicular crystals from Sievers
H H Wormwood (Artemisia sieversiana) as the major guaianolide. In
TCM, the plant is known as bai hao and is used as a stomach tonic
H and anthelminthic. Absinthin has been successfully used to alleviate
H HH inflammation of gastric ulcers and regenerate the stomach wall in
O
mice.
O
O
O

Zhao et al. J. Am. Chem. Soc. 2005, 127, 18-19

AcO AcO
O H H
HOAc O 1) NaBH4 SeAr
h!, 17ºC 2) ArSeCN
H PBu3
O H H
38.6% 72%
O O
O
O O