Total and semisynthesis and in vitro studies of both enantiomers of 20-fluorocamptothecin

Article abstract of DOI:10.1016/j.bmcl.2005.07.074

Both enantiomers of 20-fluorocamptothecin and the racemate have been prepared by total synthesis. The (R)-enantiomer is essentially inactive in a topoisomerase-I/DNA assay, while the (S)-enantiomer is much less active than (20S)-camptothecin. The lactone ring of 20-fluorocamptothecin hydrolyzes more rapidly than that of camptothecin in PBS. The results provide insight into the role of the 20-hydroxy group in the binding of camptothecin to topoisomerase-I and DNA.

Full text of DOI:10.1016/j.bmcl.2005.07.074

Bioorganic & Medicinal Chemistry Letters 15 (2005) 4736–4740
Total and semisynthesis and in vitro studies of both
enantiomers of 20-fluorocamptothecin
Raghuram S. Tangirala,a Rachel Dixon,a Danzhou Yang,b,c Attila Ambrus,b
Smitha Antony,d Keli Agama,d Yves Pommierd and Dennis P. Currana,*
aDepartment of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA
bCollege of Pharmacy, University of Arizona, 1703 E. Mabel St, Tucson, AZ 85721, USA
cArizona Cancer Center, 1515 N. Campbell Avenue, Tucson, AZ 85724, USA
dLaboratory of Molecular Pharmacology, Center for Cancer Research, NCI, Bethesda, MD 20892, USA
Received 15 June 2005; revised 21 July 2005; accepted 25 July 2005
Available online 2 September 2005
Dedicated to Professor Bernd Giese on the occasion of his 65th birthday.
Abstract—Both enantiomers of 20-fluorocamptothecin and the racemate have been prepared by total synthesis. The (R)-enantiomer
is essentially inactive in a topoisomerase-I/DNA assay, while the (S)-enantiomer is much less active than (20S)-camptothecin. The
lactone ring of 20-fluorocamptothecin hydrolyzes more rapidly than that of camptothecin in PBS. The results provide insight into
the role of the 20-hydroxy group in the binding of camptothecin to topoisomerase-I and DNA.
Ó 2005 Elsevier Ltd. All rights reserved.
Members of the camptothecin family are among the
most important current and prospective drugs for clini-
cal treatment of solid tumors.1 Structure/activity studies
on (S)-camptothecin 1 (Fig. 1) and congeners have iden-
tified the hydroxy lactone E-ring as important for func-
tion,2 and several suggestions have been made about
how the crucial 20-hydroxy group interacts in the topo-
isomerase/DNA cleavable complex that is responsible
for the anticancer activity.
conditions.6 The 20-hydroxy group can activate the lac-
tone carbonyl group towards attack by water inductive-
ly and by intramolecular hydrogen bonding.
O
O
A
B
N
C
N
D
N
N
E
O
O
OH
–
CO
Et
Et
2
20
H
O
OH
A crystal structure of a ternary complex of topoisomer-
ase I/DNA and the drug topotecan (present in both
closed lactone and open hydroxy acid forms) shows a
lone hydrogen bond between the 20-OH and Asp533.3
A similar interaction was found for camptothecin lac-
tone.4 Other models propose different H-bonding inter-
actions,1a,5 but again the 20-OH is a key group that
interacts with topo-I. This hydroxy group is also pro-
posed to be an important factor in the pharmacodynam-
ics of camptothecin, which suffers rapid lactone opening
to an inactive hydroxy acid form 2 under physiological
1, (S)-camptothecin
closed lactone form
2, lactone-opened
(hydroxy acid) form
the 20-hydroxy group is suggested to:
bind to asp 533 in the topo I/DNA complex
facilitate lactone opened in vivo by
(a) H-bonding and (b) induction
O
O
N
N
N
N
O
O
O
Et
Et
O
F
OH
Keywords: Camptothecin; Topoisomerase I; Isonitrile radical
annulation.
3, (R)-homocamptothecin
4, (S)-20-fluorocamptothecin
(20-deoxy-20-fluorocamptothecin)
*
Corresponding author. Tel.: +1 412 624 8240; fax: +1 412 624
9861; e-mail: curran@pitt.edu
Figure 1. Structures of (20S)-camptothecin and analogs.
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.07.074

R. S. Tangirala et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4736–4740
4737
Hecht and others have prepared an assortment of E-ring
analogs of camptothecin, including 20-amino-, thio-,
chloro-, bromo-, and 20-deoxycamptothecin.7 Most of
these analogs are not very active either against isolated
topoisomerase I/DNA complex or in cells, and for some
time the a-hydroxy lactone functionality was thought to
be indispensable. More recently, homocamptothecin 3
has been shown to be highly active,8 and other non-lac-
tone analogs have also shown some activity.9,10 Both
homocamptothecins and the non-lactone analogs bear
a 20-hydroxy group.
one- and two-bond couplings to 19F in the broadband
13
decoupled C NMR spectrum18 (see Supplementary
data for details). The ee of the sample was 89%, as mea-
sured by chiral HPLC, and 92%, as measured by optical
rotation; the absolute configuration was assigned as R
by the assays described below. This assignment is consis-
tent with both HPLC and optical rotation data of Shi-
bata, Toru, and co-workers15 who tentatively assigned
absolute configuration by the CD lactone sector rule.
Thus, the absolute configuration of 20-fluorocamptothe-
cin is confirmed, and the fluorination occurs with pre-
dominant inversion.
Conspicuously missing from the list of camptothecin
analogs until very recently was 20-fluorocamptothecin
4.11 From the activity standpoint, this is a crucial com-
pound to test since fluorine is generally considered to be
the closest substituent to hydroxy with respect to size
and electronic effects, but has very different hydrogen
bonding properties.12
7
7
R
R
10
10
R
R
O
S
O
N
N
DAST
CH Cl
N
N
2
2
O
O
O
O
R
˚
–78 C
Et
HO
F
Et
7
10
S-1 R = R = H
R-4, 61% yield, 89% ee
R-6, 61% yield, ee not known
7
t
10
Sporadic recent reports of 20-fluorocamptothecin pro-
vide conflicting information. In their 2002 review,
Ulukan and Swaan state that 20-fluorocamptothecin
is inactive, but they do not provide a supporting ref-
erence.13 In another 2002 review, Zunino and cowork-
ers state that the compound is active and cite
unpublished results.14 As this work was being com-
pleted, Shibata, Toru, and co-workers reported a syn-
thesis of enantioenriched (S)-20-fluorocamptothecin by
asymmetric fluorination of (rac)-20-deoxycamptothe-
cin.15 They resorted to fluorination of the deoxy com-
pound after attempts to directly deoxyfluorinate
camptothecin itself failed. They also speculated that
the 20-fluoro substituent would deactivate the E-ring
toward opening relative to camptothecin, and stated
in a footnote that the compound was less active than
camptothecin.
S-5 R = Si( Bu)Me , R = OH
2
ð1Þ
The important camptothecin analog DB-6719 S-5 was
also fluorinated under the same conditions to provide
20-fluoroDB-67 R-6 in 61% yield. The enantiomeric ex-
cess of this sample was not determined, but we presume
that it is predominantly the R-enantiomer.
Although not surprising, the inversion result is not
favorable since the 20S enantiomer of fluorocampto-
thecin is the more interesting one. Thus, we decided to
prepare both the S and R enantiomers and the racemate
by total synthesis.
Total synthesis of 20-fluorocamptothecin. The total syn-
thesis approach employs the cascade radical annulation
of isonitriles and N-propargyl iodopyridones that has
been so useful in preparing diverse analogs of campto-
thecin and homocamptothecin.20 The synthesis of the
key radical precursor, iodopyridone 10, is shown in
Eq. 2. Enol ether 7 was subjected to dihydroxylation fol-
lowed by oxidation with NIS to provide the pivotal hy-
droxy lactone 8. The usual use of (DHQD)2PYR in the
Sharpless asymmetric dihydroxylation21 reaction pro-
vided S-8 in 75% yield and 96% ee, while the use of
(DHQ)2PYR provided R-8 in 76% yield and 91% ee.
The ee analysis was conducted by chiral hplc. The race-
mate of 8 was prepared in 76% yield by dihydroxylation
with DABCO.22
We report here the synthesis of both enantiomers and
the racemate of 20-fluorocamptothecin. In contrast to
Shibata and Toruꢀs observations, we find that it is pos-
sible to directly fluorinate camptothecin and analogs,
but these reactions occur primarily with inversion to
give the 20R enantiomer. The racemate and both enan-
tiomers are accessed by total synthesis. The 20S enantio-
mer is only weakly active in a standard topo I/DNA
assay, but the fluorine atom is found to activate the lac-
tone toward opening relative to camptothecin. These re-
sults help to clarify further the key role of the 20-
hydroxy group in the camptothecin family of natural
products.
Semisynthesis of 20-fluorocamptothecin. The preparation
of 20-fluorocamptothecin by direct deoxyfluorination of
camptothecin is shown in Eq. 1. Diethylaminosulfur tri-
fluoride (DAST)16,17 was added dropwise to a suspen-
sion of (S)-camptothecin S-1 in dichloromethane at
ꢀ78 °C. After 3 h, the reaction mixture was warmed to
room temperature, quenched, and worked up, and the
crude product was purified by flash chromatography
to give (R)-20-fluorocamptothecin R-4 as a yellow solid
in 61% yield. The structure was assigned by a detailed
spectroscopic analysis. Especially diagnostic were the
Fluorinations of each of the subsequent intermediates in
the synthesis were attempted with DAST,16,17 and the
best results in terms of yields, ees, and ease of analysis
were obtained in the fluorination of 8.18 Fluorination of
8 with deoxofluor23 was also possible, but DAST was
superior. Fluorination of R-8 with DAST at ꢀ78 °C, as
above, provided a clean crude product S-9 in 84% yield
and 91% ee, while fluorination of S-8 provided R-9 in
89% yield and 84% ee. As before, predominant but not
complete inversion of configuration was observed. The
racemate of 8 was also fluorinated to give rac-9.

4738
R. S. Tangirala et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4736–4740
OMe
OMe
O
O
S
1) AD
DAST
CH Cl
C H NC
N
O
N
O
6
5
N
N
O
R
2) NIS,
Bu NI
4
TMS
TMS
O
2
2
N
S
Me SnSnMe
3
3
I
O
HO Et
cmd
–78 ˚C
Et
hν, C H
O
O
6
6
Et
F
AD rgt
yld ee
7
Et
(DHQ) PYR R-8
76% 91%
75% 96%
F
2
(DHQD) PYR S-8
2
prec prod
yld ee
S-10
rac-8
–
76%
DABCO
S-10 S-4
R-10 R-4
rac-10 rac-4
53% 69%
48% 79%
ð2Þ
OMe
Et
O
1) ICl, 10-40%
2) TMSCl, NaI, 71-76%
–
29%
N
O
F
N
O
S
S
TMS
O
I
O
3) NaH, LiBr,
Et
F
BrCH CCH, 66-73%
2
from R-10 and 3,4-methylenedioxy isonitrile, 1/2.5 ratio
prec prod
yld ee
S-10, shown
also, R-10, rac-10
O
O
R-8
S-8
S-9
R-9
84% 91%
89% 84%
O
O
O
O
rac-8 rac-9
–
92%
N
N
N
N
O
O
O
O
Iododesilylation of 9 with ICl was problematic, and the
best results were obtained in runs of 1 h with 5 equiv ICl
where about 40% conversion was observed along with
recovered starting material (which was reused). In other
runs with different times and amounts of ICl, as low as
10% conversion to the iodide was observed. The purified
iodides from the various runs were pooled and taken
forward through demethylation and N-propargylation
to give 10 as both enantiomers and the racemate.
F
F
Et
Et
R-11a
R-11b
from R-10 and 4-fluoroisonitrile
F
O
N
N
O
F
The results of the cascade radical annulation reactions
with 10 and several isonitriles are shown in Figure 2.
The reaction of phenyl isonitrile with S-10 provided
(S)-20-fluorocamptothecin S-4 and the reaction with
rac-10 provided the racemate of 4. Likewise, the reac-
tion of R-10 with phenyl isonitrile, 4-fluorophenylisonit-
rile, and 3,4-methylene-dioxyphenylisonitrile provided
(R)-20-fluorocamptothecin R-4 and the corresponding
analogs R-11a,b and R-12 in the indicated yields. The
crude product of the reaction with methylene-dioxyphe-
nylisonitrile was a 1/2.5 mixture of regioisomers 11a and
11b, which were isolated in pure form by chromatography.
O
Et
R-12
Figure 2. Radical annulations to make 20-fluorocamptothecin and
analogs.
The results of the topoisomerase assay of the 20-fluoro-
camptothecins are shown in Figure 3. Lanes 1 and 2 are
controls with no drug, while lanes 3–5 are the campto-
thecin standard at 1, 10, and 100 lm. Lanes 6–11 are
the three samples at 10 and 100 lM. None of the 20-flu-
orocamptothecin samples shows much activity at
10 lM, but there is a clear trend at 100 lM with S-4
showing significant activity, rac-4 showing moderate
activity, and R-4 showing a trace of activity. These
results form the basis of the enantiomer assignment.
Analysis of the ees of pure samples of (R)- and (S)-20-flu-
orocamptothecin by chiral HPLC and optical rotation
provided somewhat differing results, with rotation pro-
viding a higher value. The (S)-enantiomer was 69% ee
by HPLC but 84% ee by rotation, while the (R)-enantio-
mer was 79% ee by chiral HPLC and 98% ee by rotation.
We presume that the HPLC numbers are more accurate,
and in that case there has been a slight decrease in ee over
the course of synthesis from 8. The source of that de-
crease is not clear. The ees of the derivatives 11a,b and
12 could not be determined because they did not resolve
under the chiral HPLC conditions and the rotations of
enantiopure samples are not known. However, based
on the results above, we presume that they are (R)-enan-
tiomers with at least 70% ee, possibly higher.
The analogs 6, 11a,b, and 12 of camptothecin are all (R)-
enantiomers and are therefore not expected to be very
active. This was confirmed by topoisomerase assays
(not shown); none of the samples showed activity at
10 lM, while a few showed slight activity at 100 lM. Be-
cause the samples are not enantiopure, the low activity
might be due to the residual (S)-enantiomer.
From these results, we conclude that the (R)-enantiomer
of 20-fluorocamptothecin is essentially inactive, while
the (S)-enantiomer is at least 100–1000 times less potent
than the natural product. Clearly, the seemingly small
substitution of hydroxy by fluoro has a significant detri-
mental effect on interactions of the drug with the topo1/
DNA complex.
Topoisomerase I assays. The detailed procedures for the
topoisomerase I assays are contained in the supplementa-
ry data. Briefly, labeled DNA was incubated with recom-
binant topo I with and without drug. After 20 min, the
reaction was stopped and the samples were denatured
and analyzed for cleavage on a polyacrylamide gel.
Kinetics of lactone ring opening. The stability and hydro-
lysis reaction of (S)-20-fluorocamptothecin S-4 were

R. S. Tangirala et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4736–4740
4739
20-Fluoro-CPT
the fluorine substituent accelerates the hydrolysis.
Moreover, 20-F-CPT is almost completely hydrolyzed
at pH 7.4 with an equilibrium lactone ratio of <0.5%,
while the equilibrium lactone ratio of CPT at pH 7.4
is about 20%.
CPT
RAD143 RAD131 RAD152
The important analog 20-fluorocamptothecin has been
prepared in one step by semisynthesis from camptothe-
cin, but the reaction occur with predominant inversion
to give the (R)-enantiomer. Total synthesis by the
cascade radical annulation approach provides both
enantiomers of 20-fluorocamptothecin along with the
racemate. The (R)-enantiomer is essentially inactive in
a topoisomerase-I/DNA assay, while the (S)-enantiomer
is much less active than (20S)-camptothecin. This sug-
gests that the hydrogen bonding contribution of the
20-hydroxyl group is crucial in stabilizing the ternary
complex of camptothecin, topoisomerase I, and DNA.
The lactone ring of 20-fluorocamptothecin hydrolyzes
more rapidly than that of camptothecin in PBS. This
result suggests that the inductive effect of the 20-hydrox-
yl group of camptothecin is more important than its
intramolecular hydrogen bonding effect to the lactone
carbonyl group in hydrolytic lactone ring opening.
Figure 3. Topoisomerase-I/DNA cleavage assays of S, R, and rac-20-
fluorocamptothecin. Lanes 1 and 2, controls; lanes 3–5, camptothecin
at 1, 10, and 100 lm; lanes 6–11 are the three samples at 10 and
100 lM. RAD143 is (20S)-fluorocamptothecin, S-4; RAD131 is R-4;
RAD-152 is rac-4.
investigated by reversed-phase high-performance liquid
chromatographic (HPLC) methods.6,24 Figure 4 depicts
the progress of the hydrolysis reaction of S-4 in phos-
phate-buffered saline (PBS) solution at pH 7.4 and
37 °C. The HPLC method was optimized by using a mo-
bile phase consisting of 50% acetonitrile and 50% trieth-
ylamine acetate buffer (pH 5.5, 1% in water), such that
the retention times of the carboxylate and lactone forms
were approximately 2 and 4 min, respectively. This
allows enough data points for kinetic analysis of the
hydrolysis reaction of 20-F-CPT.
Acknowledgment
We thank the NIH for partial funding of this work.
Supplementary data
Supporting information contains experimental informa-
tion and characterization data for all new compounds.
Supplementary data associated with this article can
be found in the online version at doi:10.1016/j.bmcl.
2005.07.074.
(S)-20-Fluorocamptothecin S-4 hydrolyzes with a half-
life (t1/2 value) of 7.8 min. In contrast, the t1/2 of campto-
thecin under these conditions is 30 min.25 Accordingly,
References and notes
1. (a) Recent reviews on synthesis and medicinal chemistry of
camptothecins: Thomas, C. J.; Rahier, N. J.; Hecht, S. M.
Bioorg. Med. Chem. 2004, 12, 1585; (b) Du, W. Tetrahe-
dron 2003, 59, 8649; (c) Pizzolato, J. F.; Saltz, L. B. Lancet
2003, 361, 2235; (d) Ulukan, H.; Swaan, P. W. Drugs 2002,
62, 2039; (e) Kim, D.-K.; Lee, N. Mini Rev. Med. Chem.
2002, 2, 611; (f) Lerchen, H.-G. Drugs Fut. 2002, 27, 869;
(g) Zunino, F.; Dallavalle, S.; Laccabue, D.; Beretta, G.;
Merlini, L.; Pratesi, G. Curr. Pharm. Design 2002, 8, 2505.
2. (a) Jaxel, C.; Kohn, K. W.; Wani, M. C.; Wall, M. E.;
Pommier, Y. Cancer Res. 1989, 49, 1465; (b) Hertzberg, R.
P.; Caranfa, M. J.; Holden, K. G.; Jakas, D. R.;
Gallagher, G.; Mattern, M. R.; Mong, S.-M.; OꢀLeary
Bartus, J.; Johnson, R. K.; Kingsbury, W. D. J. Med.
Chem. 1989, 32, 715.
1.2
1
0.8
0.6
0.4
0.2
0
500
1000
1500
2000
0
3. Staker, B. L.; Hjerrild, K.; Feese, M. D.; Behnke, C. A.;
Burgin, A. B., Jr.; Stewart, L. Proc. Nat. Acad. Sci. 2002,
99, 15387.
Time (s)
Figure 4. Kinetic evaluation of the rate of opening of the lactone ring
for (S)-20-fluorocamptothecin in PBS (pH 7.4 0.05) at 37 °C. Shown
are averages of at least three independent experiments with the same
time points. The standard deviation of each point is typically 5% or
4. Staker, B. L.; Feese, M. D.; Cushman, M.; Pommier, Y.;
Zembower, D.; Stewart, L.; Burgin, A. B. J. Med. Chem.
2005, 48, 2336.
5. (a) Fan, Y.; Weinstein, J. N.; Kohn, K. W.; Shi, L. M.;
Pommier, Y. J. Med. Chem. 1998, 41, 2216; (b) Stewart,
L.; Redinbo, M. R.; Qiu, X. Y.; Hol, W. G. J.; Champoux,
less. Pseudo-first-order hydrolysis rate constant is: kobs = 1.48
10ꢀ3 0.013 1/s. So the t1/2 is 7.80 0.067 min.
Æ

4740
R. S. Tangirala et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4736–4740
J. J. Science 1998, 279, 1534; (c) Kerrigan, J. E.; Pilch, D.
16. (a) Reviews: Singh, R. P.; Shreeve, J. M. Synthesis 2002,
2561; (b) Jolliffe, K. A. Aust. J. Chem. 2001, 54, 75.
17. Fluorodeoxygenations of 3°-hydroxy esters with DAST:
Takeuchi, Y.; Ogura, H.; Ishii, Y.; Koizumi, T. Chem.
Pharm. Bull. 1990, 38, 2404.
18. Tangirala, R. S., PhD Thesis, University of Pittsburgh,
2004.
19. Bom, D.; Curran, D. P.; Kruszewski, S.; Zimmer, S. G.;
Strode, J. T.; Kohlhagen, G.; Du, W.; Chavan, A. J.;
Fraley, K. A.; Bingcang, A. L.; Latus, L. J.; Pommier, Y.;
Burke, T. G. J. Med. Chem. 2000, 43, 3970.
20. (a) Curran, D. P.; Liu, H.; Josien, H.; Ko, S. B.
Tetrahedron 1996, 52, 11385; (b) Josien, H.; Ko, S. B.;
Bom, D.; Curran, D. P. Chem. Eur. J. 1998, 4, 67; (c)
Josien, H.; Bom, D.; Curran, D. P.; Zheng, Y.-H.; Chou,
T.-C. Bioorg. Med. Chem. Lett. 1997, 7, 3189; (d) Bom, D.;
Du, W.; Gabarda, A.; Curran, D. P.; Chavan, A. J.;
Kruszewski, S.; Zimmer, S. G.; Fraley, K. A.; Bingcang,
A. L.; Wallace, V. P.; Tromberg, B. J.; Burke, T. G. Clin.
Cancer Res. 1999, 5, 560; (e) Gabarda, A. E.; Curran, D.
P. J. Comb. Chem. 2003, 5, 617.
S. Biochemistry 2001, 40, 9792; (d) Laco, G. S.; Collins, J.
R.; Luke, B. T.; Kroth, H.; Sayer, J. M.; Jerina, D. M.;
Pommier, Y. Biochemistry 2002, 41, 1428.
6. (a) Burke, T. G.; Staubus, A. E.; Mishra, A. K.; Malak, H.
J. Am. Chem. Soc. 1992, 114, 8318; (b) Yang, D.; Strode,
J. T.; Spielmann, H. P.; Wang, A. H. J.; Burke, T. G. J.
Am. Chem. Soc. 1998, 120, 2979.
7. (a) Wang, X.; Zhou, X.; Hecht, S. M. Biochemistry 1999, 38,
43741; (b) Rahier, N. J.; Eisenhauer, B. M.; Gao, R.;
Thomas, S. J.; Hecht, S. M. Bioorg. Med. Chem. 2005, 13,
1381.
8. (a) Lavergne, O.; Lesueur-Ginot, L.; Pla Rodas, F.;
´
Kasprzyk, P. G.; Pommier, J.; Demarquay, D.; Prevost,
G.; Ulibarri, G.; Rolland, A.; Schiano-Liberatore, A.-M.;
Harnett, J.; Pons, D.; Camara, J.; Bigg, D. C. H. J. Med.
Chem. 1998, 41, 5410; (b) Lavergne, O.; Demarquay, D.;
Bailly, C.; Lanco, C.; Rolland, A.; Huchet, M.; Coulomb,
H.; Muller, N.; Baroggi, N.; Camara, J.; Le Breton, C.;
Manginot, E.; Cazaux, J.-B.; Bigg, D. C. H. J. Med. Chem.
2000, 43, 2285.
9. (a) Du, W.; Curran, D. P.; Bevins, R. L.; Zimmer, S. G.;
Zhang, J.; Burke, T. G. Bioorg. Med. Chem. 2002, 10, 103;
(b) Laco, G. S.; Du, W.; Kohlhagen, G.; Sayer, J. M.;
Jerina, D. M.; Burke, T. G.; Curran, D. P.; Pommier, Y.
Bioorg. Med. Chem. 2004, 12, 5225.
21. (a) Kolb, H. C.; Vannieuwenhze, M. S.; Sharpless, K. B.
Chem. Rev. 1994, 94, 2483; (b) Fang, F. G.; Xie, S.;
Lowery, M. W. J. Org. Chem. 1994, 59, 6142; (c) Curran,
D. P.; Ko, S. B. J. Org. Chem. 1994, 59, 6139.
22. Do¨bler, C.; Mehltretter, G. M.; Sundermeier, U.; Beller,
M. J. Am. Chem. Soc. 2000, 122, 10289.
23. (a) Deoxofluor is (CH3OCH2CH2)2NSF3. Lal, G. S.;
Pez, G. P.; Pesaresi, R. J.; Prozonic, F. M. Chem.
Commun. 1999, 215; (b) Lal, G. S.; Pez, G. P.; Pesaresi,
R. J.; Prozonic, F. M.; Cheng, H. J. Org. Chem. 1999,
64, 7048.
24. Burke, T. G.; Mi, Z. J. Med. Chem. 1993, 36, 2580.
25. The t1/2 (30 min) and % closed form (20%) at equilibrium
for camptothecin were measured under identical condi-
tions identical to 20-fluorocamptothecin for direct com-
parison. These numbers differ somewhat from the
published values of 17 min and 13%. See Refs. 6 and 24.
`
´
´
10. Hautefaye, P.; Cimetiere, B.; Pierre, A.; Leonce, S.;
Hickman, J.; Laine, W.; Bailly, C.; Lavielle, G. Bioorg.
Med. Chem. Lett. 2003, 13, 2731.
11. The compound is more properly called 20-deoxy-20-
fluorocamptothecin.
12. (a) Smart, B. E. J. Fluorine Chem. 2001, 109, 3(b) See
special issue on ‘‘fluorine in the life sciences’’, ChemBio-
Chem. 2004, 5, 557.
13. See page 2044 of Ref. 1d.
14. See page 2508 and reference 48 of Ref. 1g.
15. Shibata, N.; Ishimaru, T.; Nakamura, M.; Toru, T.
Synlett 2004, 2509.