A practical six-step synthesis of (S)-camptothecin

Article abstract of DOI:10.1021/ol0169271

(Matrix Presented) An asymmetric synthesis of (S)-camptothecin (1) has been accomplished in six steps starting from two commercially available heterocycles.

Full text of DOI:10.1021/ol0169271

ORGANIC
LETTERS
2
001
Vol. 3, No. 26
255-4257
A Practical Six-Step Synthesis of
S)-Camptothecin
4
(
Daniel L. Comins* and Jason M. Nolan
Department of Chemistry, North Carolina State UniVersity,
Raleigh, North Carolina 27695-8204
daniel•comins@ncsu.edu
Received October 17, 2001
ABSTRACT
An asymmetric synthesis of (S)-camptothecin (1) has been accomplished in six steps starting from two commercially available heterocycles.
(
S)-Camptothecin (CPT, 1), a pentacyclic alkaloid isolated
from Camptotheca acuminata by Wall and co-workers in
966, is an important lead compound for the preparation of
part of our research program to the development of short
syntheses of CPT and derivatives. Through this effort we
were able to achieve 10- and 9-step asymmetric syntheses
1
1,2
selective anticancer drugs. The cytotoxic activity of CPT
is attributed to a mechanism of action involving DNA and
topoisomerase I, a process causing irreversible DNA damage
3
and subsequent cell death. Two CPT analogues, topotecan
(2) and irinotecan (3), are now being used in clinical practice.
Several other analogues are in various stages of clinical
development.4
Since several syntheses of CPT and analogues have been
2
developed over the years, synthetic efforts now need to be
directed at short, practical routes that are amenable to scale-
up for drug preparation. For several years we have dedicated
(1) Wall, M. E.; Wani, M. C.; Cook, C. E.; Palmer, K. H.; McPhail, A.
T.; Sim, G. A. J. Am. Chem. Soc. 1966, 88, 3888. (b) Wall, M. E.; Wani,
M. C. J. Ethnopharmacol. 1996, 51, 239.
(
2) Recent reviews: (a) Wall, M. E.; Wani, M. C. Alkaloids 1998, 50,
5
09. (b) “The Camptothecins: from Discovery to the Patient”; Pantaziz,
P., Giovanella, B. C., Eds. Ann. N. Y. Acad. Sci. 1996, 803. (c) Camptoth-
ecins: New Anticancer Agents; Potmesil, H.; Pinedo, H., Eds.; CRC Press:
Boca Raton, FL, 1995.
(
3) Holm, C.; Covey, J. M.; Kerrigan, D.; Pommier, Y. Cancer Res. 1989,
9, 6365.
4) (a) Kim, D.-K.; Ryu, D. H.; Lee, J. Y.; Lee, N.; Kim, Y.-W.; Kim,
J.-S.; Chang, K.; Im, G.-J.; Kim, T.-K.; Choi, W.-S. J. Med. Chem. 2001,
4. 1594. (b) Dallavalle, S.; Ferrari, A.; Biasotti, B.; Merlini, L.; Penco,
4
(
4
S.; Gallo, G.; Marzi, M.; Tinti, M. O.; Martinelli, R.; Pisano, C.; Carminati,
P.; Carenini, N.; Beretta, G.; Perego, P.; De Cesare, M.; Pratesi, G.; Zunino,
F. J. Med. Chem. 2001, 44, 3264 and references therein.
1
0.1021/ol0169271 CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/22/2001

5
of (S)-CPT and a 6-step racemic synthesis. We had hoped
that our 6-step route could be modified to afford enantiopure
Scheme 2
(S)-CPT; however, our efforts at preparing the key interme-
diate 4 in an asymmetric fashion were unsuccessful. To
accomplish our goal of a 6-step asymmetric synthesis of CPT,
we decided to explore the route depicted in Scheme 1.
Scheme 1
To limit the total number of steps to six, the AB ring
precursor 6 had to be prepared from quinoline derivative 8
in a single step. The DE ring fragment 5 would have to be
made via intermediate 7 in only three steps from com-
mercially available material. We now report the successful
development of a 6-step CPT synthesis using this strategy.
To prepare the DE ring fragment 5 in three steps, a 2-step
synthesis of intermediate 7 was required. Commercially
available 2-methoxypyridine was lithiated at C-3 with
directly to 1,3-dioxane 7 on treatment with NaI/TMSCl/
paraformaldehyde in 87% yield. Conversion of 7 to CPT
intermediate 5 was carried out in a single step. Lithium-
halogen exchange was effected with n-BuLi followed by the
5b
addition of ketoester 11 to give alkoxide 12 in situ. Addition
of HCl/i-PrOH effected protonation, acetal hydrolysis, and
lactonization to afford the desired intermediate 5. The crude
material was extracted with hot hexanes to remove and
8
recover (94%) the chiral auxiliary, (-)-TCC. The remaining
6
mesityllithium and treated with N-formyl-N,N′,N′-trimeth-
solid residue was purified by chromatography and recrys-
ylethylenediamine to give an R-amino alkoxide in situ
tallization from methanol to afford a 60% yield of DE ring
(
Scheme 2). Addition of n-BuLi effected R-amino alkoxide
intermediate 5 as white crystals: mp 222-225 °C dec;
7
23
directed lithiation at C-4 to give the dianion 9. Addition of
iodine and workup with aqueous NaBH /CeCl provided a
6% yield of alcohol 10 via a one-pot process. After
considerable effort, it was found that 10 could be converted
[R]D +117.0 (c 0.3, MeOH) (93% ee).
4
3
With the desired DE ring synthesis in hand, we explored
a 1-step preparation of AB ring fragment 6 (Scheme 3). Initial
attempts to transform commercially available 2-chloro-3-
4
quinolinecarboxaldehyde (8) into iodide 6 using a literature
(
5) (a) Comins, D. L.; Baevsky, M. F.; Hong, H. J. Am. Chem. Soc.
992, 114, 10971. (b) Comins, D. L.; Hong, H.; Jianhua, G. Tetrahedron
Lett. 1994, 35, 5331. (c) Comins, D. L.; Saha, J. K. Tetrahedron Lett. 1995,
6, 7995. (d) Comins, D. L.; Hong, H.; Saha, J. K.; Jianhua, G. J. Org.
Chem. 1994, 59, 5120.
9
2 2 3
procedure (NaI, TMSCl, (HMe Si) O, CH CN) for this type
1
of conversion were unsuccessful. Finally, it was found that
3
(
(
6) Comins, D. L.; LaMunyon, D. H. Tetrahedron Lett. 1988, 29, 773.
7) (a) Comins, D. L.; Killpack, M. O. J. Org. Chem. 1990, 55, 69. (b)
(8) TCC ) trans-2-(R-cumyl)cyclohexyl: (a) (+)- and (-)-TCC alcohols
are available from Aldrich Chemical Co. (b) Comins, D. L.; Salvador, J.
M. J. Org. Chem. 1993, 58, 4656 and references therein.
For a review of R-amino alkoxide directed lithiations, see: Comins, D. L.
Synlett 1992, 615.
(9) Aizpurua, J. M.; Palomo, C. Tetrahedron Lett. 1984, 25, 1103.
4256
Org. Lett., Vol. 3, No. 26, 2001

CN (100 °C) gave a 64% yield of (S)-camptothecin after
1
recrystallization from 1,4-dioxane: mp 264-266 °C dec (lit.
Scheme 3
2
3
2
64-267 °C dec); [R] +45 (c 0.3, CHCl
3
/MeOH 4:1)
D
1
2
(lit. +42 (c 0.51, CHCl
3
/MeOH 4:1)). Our synthetic (S)-
1
3
CPT was identical in every respect to authentic material.
In summary, the shortest asymmetric synthesis of (S)-
camptothecin to date has been achieved from two com-
mercially available heterocycles. This 6-step synthesis is
practical and should be amenable to the large-scale prepara-
tion of CPT analogues of medicinal importance.14
Acknowledgment. NMR and HRMS spectra were ob-
tained at North Carolina State University instrumentation
laboratories, which were established by grants from the North
Carolina Biotechnology Center and the National Science
Foundation (Grants CHE-9121380, CHE-9509532, and CHE-
0
078253).
Supporting Information Available: Experimental pro-
cedures for 1,5-7, 10, and 13 and characterization data for
compounds 6-7, 10, and 13. This material is available free
of charge via the Internet at http://pubs.acs.org.
a mixture of 8, Et
3
3
SiH, and TMSI in CHCl (room temp, 12
OL0169271
h) effected the desired transformation to afford iodide 6 in
10
7
9% yield. The completion of the CPT synthesis followed
(11) A 2-chloroquinoline has been used for a Heck reaction to generate
5
our earlier protocol. The two fragments, 5 and 6, were joined
on treatment with t-BuOK in DME to provide compound
a CPT analogue; see: Fang, F. G.; Bankston, D. D.; Huie, E. M.; Johnson,
M. R.; Kang, M.-C.; LeHoullier, C. S.; Lewis, G. C.; Lovelace, T. C.;
Lowery, M. W.; McDougald, D. L.; Meerholz, C. A.; Partridge, J. J.; Sharp,
M. J.; Xie, S. Tetrahedron 1997, 53, 10953.
13, which was recrystallized from MeOH to give an 81%
yield of enantiopure material (>99% ee). As before, the
C-ring was closed using a Heck reaction. Our reported
conditions were modified to address the decreased reactivity
of the quinoline C-2 halogen (Cl vs Br).11 Treatment of 13
(12) Ejima, A.; Terasawa, H.; Sugimori, M.; Tagawa, H. Tetrahedron
Lett. 1989, 30, 2639.
(
13) The structure assigned to each new compound is in accordance with
1
13
its IR, H NMR, and C NMR spectra and elemental analysis or high-
resolution mass spectra.
(14) Various substituted 2-chloroquinoline-3-carboxaldehydes are readily
3 2 2 3
with (PPh ) Pd(OAc) (15%) and KOAc (2 equiv) in CH -
available via Vilsmeier-Haack cyclization of the corresponding acetanilides;
see: (a) Meth-Cohn, O.; Narine, B.; Tarnowski, B. J. Chem. Soc., Perkin
Trans. 1 1981, 1520. (b) Ali, M. M.; Tasneem; Rajanna, K. C.; Saiprakash,
P. K. Synlett 2001, 251 and references therein.
(10) The scope of this transformation is being studied and will be reported
in due course.
Org. Lett., Vol. 3, No. 26, 2001
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