1. Baran Group Meeting Reviewing Camptothecin Ke Chen
9/ 26/ 2007
In Fig 1, normally, topoisomerases I introduces a nick in the DNA
backbone allowing the rotation of one strand around another. This
O releases the torsional strain which otherwise accumulates in front of
N
the advancing replication fork (the large arrow). The DNA break is
extremely transient and is religated as it release the other strand.
N
O
OH O
Name Camptothecin
IUPAC name 4-ethyl-4-hydroxy-1H-pyrano[3',4':6,7]
indolizino[1,2-b]quinoline-3,14-(4H,12H)-dione
CAS number 7689-03-4
Formula C20H16N2O4
Mol. mass 348.352 g/mol
This quinoline based alkaloid was found in the bark of the Chinese
camptotheca tree.
Camptotheca goes by many names in China, including "happy tree", Fig 1 Fig 2
"dragon tree" and "fine tree".
Chinese have used the "happy tree" in traditional medicine for thousands In Fig 2, when camptothecin is present(black oval with C), it binds to the
of years. It has been used for psoriasis, leukemia and diseases of liver, topoisomerase I-nicked DNA complex. This prevents the religation of the
gallbladder, spleen, and stomach. nicked strand and the release of the enzyme. Eventually, the replication
fork collides with the complex, causing the formation of a double-strand
During the last half century, scientists have discovered its potential as a break.
selective anticancer drug.
The unique mode of action for this potent cytotoxic compound was found to Hsiang, Y.H. Cancer Res. 1989, 49, 5077.
act via inhibition of an enzyme known as DNA topoisomerase I.
1

2. Baran Group Meeting Discovering Camptothecin Ke Chen
9/ 26/ 2007
Monroe E. Wall (1916–2002) Timeline of Camptothecin:
Born in 1916 in Newark, NJ, Dr. Wall received 1960-1966 Isolation of active compound from amptotheca acuminata;
his B.S., M.S., and Ph.D. degrees from determination of structure of camptothecin
Rutgers
University. In 1941, he joined the United States
Department of Agriculture. From 1941 to 1960, O O
Dr. Wall gained national recognition as a N N
OH
government scientist in steroid chemistry. In N N
1960, Dr. Wall joined the Research Triangle Na+
Institute (RTI) to start a chemistry research O O
group. He became RTI Vice President of
Chemistry and Life Sciences in 1971. Among
OH O OH O
numerous contributions to the field of natural
product research, he is best known for the
discovery and development of taxol and low solubility in water water-soluable but inactive
camptothecin. In 1981 He retired from
administration and devoted his time to research Clinical trials started in the 1960s but were abandoned shortly thereafter.
until two weeks before his death at 85.
1985 Determination of mechanism of action of camptothecin
Monroe Doctrine: "Get good people, support them with good facilities,
do good science, work hard, and keep doing it." After Camptothecin returned, like " the phoenix from the ashes", it rekindled
interest in developing analogs of camptothecin that were both water soluble
and retained anticancer activity
Mansukh C. Wani 1996 FDA approval of two analogs of camptothecin for treatment
Born in Nandurbar, India, Dr. Wani received of ovarian, lung, breast and colon cancer.
his B.S. and M.S. degrees from the University
of Bombay. He came to the United States and
finished his Ph.D in chemistry at Indiana Some numbers and facts...
University under the instruction of Professor
Ernest Campaign. After a postdoctoral 11729 publications regarding "camptothecin".
fellowship at the University of Wisconsin-
Madison, he accepted a position at RTI from 114 publications involving total or formal synthese of camptothecin and its
Dr. Wall in 1962. Together they developed two derivatives.
of the most promising anticancer
agents, taxol and camptothecin., which are By 2001, the analogs developed included Pharmacia’s Camptosar and
benefiting millions of people all over the GlaxoSmithKline’s Hycamtin, collectively reporting worldwide sales
world. Dr. Wani is still active at RTI, approaching $ 800 million.
supervising junior researchers.
Synthetic chemists embrace practility and perfection.
2

3. Baran Group Meeting Camptothecin: From Bench to Bedside Ke Chen
9/ 26/ 2007
Classical condensation O
N O
O O N
N N CO2H
Friedlander quinoline synthesis O N Ts CN
O O
CN
O O
Na2CO3, DMF, 70 oC CO2Et
OH O
CO2Et O
O 76-97 %
Br
NH2 CO2Et
aq. NaOH NTs
N CO2Et
CHO N 50 % N
O
CO2Et CO2H
O N O
N
CN
NaH, EtI, DMF O
O
steps O
O rt, 65-100 % CO2Et O
N O Et
N OH O
O NTs
N
NTol
N O
d. r. = 82 :18
NH2
Et CO2Et O
1 eq LDA Et CO2Et
Et p-TsOH, tol
O o
CO2Et reflux, 73 %
CO2Et -78 C O
CO2Et
LDA, RT 1. First asymmetric synthesis O
N
EtO2C 2. 1,4-Asymmetric induction in the diastereo-
dl-camptothecin N
Et CO2Et selective ethylation was achieved
using an N-tosyl-(R)-proline derivative O
OH 1. First synthesis reported
OH O
2. One of the key steps involves the annulation of an ester
carbonate and unsaturated lactam
Tagawa H. Tetrahedron Lett. 1989, 30, 2639-2640.
Stork G., Schultz A. G. J. Am. Chem. Soc. 1971, 36, 4074-4075.
3

4. Baran Group Meeting
9/ 26/ 2007 Camptothecin: From Bench to Bedside Ke Chen
Classical condensation CO2Me CO2Me
1. PhCHO, NaHMDS O
O O
2. O3
O 3. TMSCHN2
O 1. quinine-water
HO N O N O
2. recrystalization
Et 85 % overall
HO2C O O
CO2H CO2H OH 3. MeOCOCl, Et3N
NTol O
N
Et OCO2Me Cl Et OCO2Me NH2 1. HBr, 140 oC
1. O2, eosine N
O O dl-CPT
2. SOCl2
O O p-TsOH, tol O 2. Me NH, CuCl
MeO2C 2 2
O O reflux, 75 % O2, DMF
pyr O
O (S)-camptothecin
N
Danishefsky S. J. J. Org. Chem. 1993, 58, 611-617.
NH Danishefsky S. J. J. Am. Chem. Soc. 1971, 93, 5575.
Corey E. J. J. Org. Chem. 1975, 40, 140-2141. O O
R2 (CH2O)n/H+ R2 O
R2
Friedlander quinoline synthesis CO2Me Et
CO2Me N N O N
R1 R1 R1
H
H Et3N
N
• CO2Me O O O
CO2Me CO2Me
H MeO2C N major
92 %
O Two analogs:
CO2Me Et
+ CO2Me HO
t-BuOK/EtI (CH2O)n/H O HO
CO2Me O O
N
DME, 91 % N
N 95 % N
N O N
O
O O
O
OH O
OH O
4

5. Baran Group Meeting Camptothecin: From Bench to Bedside Ke Chen
9/ 26/ 2007
O
Modern organic chemistry Other recent applications of 1,4-addition to pyridinium salts
N
N
O Me
F N I-
CO2Me LDA PhSeBr
OH O ?
N F N
OTf
intermediate
CO2Me Me O
DCM, rt
N
CO2Me
30 min
N Br Me
H SePh
OTf
Br
N -30 oC Methylervitsine
1.5 h H
O OLi N CO2Me
LDA, THF Me
O
O O O O
-78 oC, 30 mins
Bennasar M. L.. J. Chem. Soc., Chem. Commun. 1995, 125.
then DDQ
O
O
N CO2Me Bn Bn
N O N
N N Br C6H11N=C
O N Br AcONa, MeOH, 65 oC
O NH2
O NC
OH O
71 % C6H11
O
N O
H
Bennasar M. L.. J. Chem. Soc., Chem. Commun. 2000, 2459. Lavilla R. Org. Lett 2006, 8, 5789-5792.
Bennasar M. L.. J. Org. Chem. 2002, 67, 7465.
5

6. Baran Group Meeting Discovering Camptothecin Ke Chen
9/ 26/ 2007
Diels-Alder Reaction:
MeO
EtO OEt O MeO
O
OMe Me3OBF4
OMe N O N
EtO N
H reflux N CN
OEt rt Ms OEt CN 82 %
NSO2Me N OEt
N N
OEt
CO2Et Revised alternative:
CO2Et OEt
OMe
OMe
O
O
86 % ee N O
Ac2O
N OEt N
N N OEt N
N H reflux N CN
OEt Modified CO2H
OEt CN
Sharpless 75 %
Dihydroxylation HO
OMe
O
OMe
OAc
O HO
1. HBr O
N O N
NaClO2 N OEt 2. K2CO3 O
N N N N CN
NaH2PO4 OEt
O O N CN
HO
OH 48 % 74 %
OH O
O
Boger, D. L.. Tetrahedron 2002, 58, 6343.
Fortunak J. Tetrahedron Lett. 1996, 37, 5679-5682.
6

7. Baran Group Meeting Camptothecin: From Bench to Bedside Ke Chen
9/ 26/ 2007
[4+1] Radical Annulation:
Curran and Shibasaki:
CO2H O
1. PCl5 O
2. HBr N OMe
HN OMe
CN 3. MeOH CO2Me
CO2Me Br 5 mol % SmLn N OTBS
CO2H Br N OTBS
Et 1.5 equiv TMSCN
CN
PhNC SMT SMT
Me3SnSnMe3 EtCN, -40 oC, 18 h Et OTMS
O
98 %, 84 % ee
OMe O
O
N 1. ICl TMSI, cat H2O
2. HCl-EtOH N O CH3CN, 87 % HN O
dl-Camptothecin N
71 % (2 steps) I O I O
CO2Me Et OH Et OH
Et
> 99 % ee after
Over 100 derivatives of camptothecin have been prepared by Dr. Curran's recryst. from MeOH-CHCl3
research group utlizing this approach.
O O
PhNC O
N N N
N
Br R R
R
O O
N N
N N
Shibasaki M.; Curran D. P. J. Am. Chem. Soc. 2001, 123, 9908-9909.
R CO2Me Shibasaki M. J. Am. Chem. Soc. 2000, 122, 7412-7413.
Et
Curran D. P. J. Am. Chem. Soc. 1992, 114, 5863-5864.
7

8. Baran Group Meeting Camptothecin: the Future Ke Chen
9/ 26/ 2007
Structure-Activity Relationships:
1. MesLi N
Li N
2. N NCHO 1. I2
2. NaBH4, H2O N
OLi O
N OMe A B C N
one pot D HO
3. n-BuLi N OMe N O
E O N
I N
I
OH O O
TMSCl, NaI 1. n-BuLi
OH O
(CH2O)n, CH3CN 2. O Hycamtin OH O
N OMe N O
CO2R*
O O N
Et Et
OR* O N O
HCl HO t-BuOK O
LiO I
N 10 additional CPT
O iPrOH N Cl DME O derivatives in various
N
stages of clinical trials
N O N O O
H
Camptosar
OH O
O O
N N
(Ph3P)2Pd(OAc)2
N N
Cl
O KOAc, CH3CN O
"Trees hold the answer to saving the planet. Scientists are discovering more
remarkable facts about trees, forests and animal interactions than ever before.
OH O OH O
The work of these scientists is immeasurably protecting humanity and all life,
now and into the future."
This remains the most efficient route reported (six steps, 12.5 % overall yield).
Scientists from GSK are utilizing this approach to synthesize analogs of CPT. Reese Halter
Comins D. L. Org. Lett 2001, 3, 4255-4257.
8