Stereocontrolled total synthesis of (±)-catharanthine via radical-mediated indole formation

Article abstract of DOI:10.1021/ol990749i

(matrix presented) A stereocontrolled total synthesis of (±)-catharanthine, 1, has been completed. The key step involves the radical-mediated cyclization of a highly functionalized intermediate to furnish the corresponding indole. The cyclization utilizes

Full text of DOI:10.1021/ol990749i

ORGANIC
LETTERS
1999
Vol. 1, No. 7
973-976
Stereocontrolled Total Synthesis of
(±)-Catharanthine via Radical-Mediated
Indole Formation
Matthew T. Reding† and Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo,
CREST, The Japan Science and Technology Corporation (JST),
7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
fukuyama@mol.f.u-tokyo.ac.jp
Received June 21, 1999
ABSTRACT
A stereocontrolled total synthesis of (±)-catharanthine, 1, has been completed. The key step involves the radical-mediated cyclization of a
highly functionalized intermediate to furnish the corresponding indole. The cyclization utilizes a simple phosphorus-based radical-reducing
agent. This synthesis provides a potential route for the production of analogues of catharanthine and is more convergent and experimentally
less complex than previous syntheses of 1.
Catharanthine, 1, is an important member of the Iboga class
of alkaloids.1 It is a chemical and presumed biological
precursor of the antitumor alkaloids vinblastine and vin-
cristine, two venerable yet effective anticancer agents used
in the treatment of a number of human cancers.2 The dense,
pentacyclic skeleton of 1 contains a tryptamine fragment
substituted at the 2-position by a quaternary sp3 carbon, and
thereby represents an attractive challenge to our recently
disclosed methodology for the synthesis of 2,3-disubstituted
indoles.3 The successful completion of this synthesis dem-
onstrates the utility of this radical-based methodology for
the construction of complex indole-containing natural prod-
ucts.
(()-Catharanthine has been the target of numerous suc-
cessful total and formal total syntheses.4-6 However, all of
the previously reported routes to 1 have made use of
preexisting indolyl frameworks,7 and as such offer little hope
for the facile construction of analogues of 1 substituted on
the aromatic carbocyle. Controlled access to such compounds
is essential for the rational examination of structure and
activity relationships of the derived drugs. Furthermore,
recent syntheses of 1 have relied on nonstereocontrolled
(4) Total syntheses: (a) Bu¨chi, G.; Kulsa, P.; Ogasawara, K.; Rosati, R.
L. J. Am. Chem. Soc. 1970, 92, 999. (b) Kutney, J. P.; Bylsma, F. HelV.
Chim. Acta 1975, 58, 1672. (c) Andriamialisoa, R. Z.; Langlois, N.; Langlois,
Y. Heterocycles 1980, 14, 1457. (d) Marazano, C.; LeGoff, M.; Fourrey,
J.; Das, B. C. J. Chem. Soc., Chem. Commun. 1981, 389. (e) Raucher, S.;
Bray, B. L. J. Org. Chem. 1985, 50, 3236. (f) Kuehne, M. E.; Bornmann,
W. G.; Earley, W. G.; Marko, I. J. Org. Chem. 1986, 51, 2913. (g) Raucher,
S.; Bray, B. L.; Lawrence, R. F. J. Am. Chem. Soc. 1987, 109, 442. (h)
Sza´ntay, C.; Bo¨lcskei, H.; Ga´cs-Baitz, E. Tetrahedron 1990, 46, 1711.
(5) Formal syntheses: (a) Trost, B. M.; Godleski, S. A.; Belletire, J. L.
J. Org. Chem. 1979, 44, 2052. (b) Imanishi, T.; Shin, H.; Yagi, N.; Hanaoka,
M. Tetrahedron Lett. 1980, 21, 3285. (c) Imanishi, T.; Yagi, N.; Shin, H.;
Hanaoka, M. Chem. Pharm. Bull. 1982, 30, 4052.
† Current Address: Department of Structural, Analytical & Medicinal
Chemistry, Pharmacia & Upjohn, Kalamazoo, MI 49001.
(1) (a) Gorman, M.; Neuss, N.; Svoboda, G. H.; Barnes, A. J.; Cone, N.
J. J. Am. Pharm. Assoc. (Sci. Ed.) 1959, 48, 256. (b) Svoboda, G. H.; Neuss,
N.; Gorman, M. J. Am. Pharm. Assoc. (Sci. Ed.) 1959, 48, 659. (c) Neuss,
N.; Gorman, M. Tetrahedron Lett. 1961, 206. (d) Gorman, M.; Neuss, N.;
Cone, N. J. J. Am. Chem. Soc. 1965, 87, 93. (e) Bu¨chi, G.; Coffen, D. L.;
Kocsis, K.; Sonnet, P. E.; Ziegler, F. E. J. Am. Chem. Soc. 1966, 88, 3099.
(2) The Alkaloids. Antitumor Bisindole Alkaloids from Catharanthus
roseus (L.); Brossi, A., Suffness, M., Eds.; Academic Press: San Diego,
1990; Vol. 37.
(6) Only one account of a nonracemic synthesis of 1, via resolution, has
been published (see ref 4h).
(7) All of the syntheses listed in refs 4 and 5 utilize 2-indoleacetic acid
or tryptamine as their indole source, except ref 4d, which begins with
thioxindole.
(3) Tokuyama, H.; Yamashita, T.; Reding, M. T.; Kaburagi, Y.;
Fukuyama, T. J. Am. Chem. Soc. 1999, 121, 3791.
10.1021/ol990749i CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/08/1999

methods for the formation of some of the key bonds in the
desired polycyclic framework.8
means of a high-yielding multistep sequence similar to one
used by Sza´ntay (Scheme 1).10 Pyridine 6 was benzylated
The advent of our new indole construction methodology
allowed us to envision a completely stereocontrolled route
to 1 that would culminate in the intramolecular alkylation
of a fully functionalized, highly preorganized molecule such
as 2 (Figure 1). This precursor would be available from a
Scheme 1. Diene Synthesis
in quantitative yield and then reduced to the corresponding
tetrahydropyridine. The benzyl group was replaced by a
benzyl carbamate to give 7 in 62% overall yield from the
pyridinium salt. The trisubstituted double bond was then
brominated in 97% yield to afford trans-dibromide 8. This
compound was treated with DABCO to afford the desired
diene 9 which was predictably somewhat oxygen-sensitive.11
Diene 9 was thus immediately carried on without further
purification.
Several earlier syntheses of our target have made use of
the regioselective Diels-Alder reaction of dienes such as 9
and 1,1-heterodisubstituted acrylates.4,5 This choice has
generally led to diastereomeric mixtures of cyclized products
due to imperfect exo/endo selectivity. To avoid this difficulty,
we chose to use a 1,1-homodisubstituted acrylate dienophile,
i.e., diethyl methylenemalonate. This compound, while
known, readily polymerizes even at low temperature.12 We
found that the desired dienophile could be generated in situ
from diethyl ethoxymethylmalonate, easily obtained by
hydrogenation of commercially available diethyl ethoxy-
methylenemalonate at atmospheric pressure over palladium
on carbon (10, Scheme 2). The saturated product was quite
Figure 1. Retrosynthetic analysis of catharanthine.
Scheme 2. Synthesis of the Right-Hand Side of Catharanthine
late-stage radical-mediated indole formation reaction carried
out upon a 2-alkenylthioanilide similar to 3. The left and
right halves of 3 could be joined by selective amide bond
formation between fragments 4 and 5. The cis-2-alkenyl
aniline 4 was available in a three-step sequence from
quinoline,9 while the two carboxyl groups present in 5 could
be differentiated by means of a chemoselective, reversible
halolactonization reaction. The isoquinuclidine skeleton of
5 could most easily be assembled by a regioselective Diels-
Alder reaction. The successful realization of this strategy is
disclosed herein.
Our synthesis begins with the construction of the desired
diene 9 from commercially available 3-ethylpyridine (6) by
stable at room temperature and could be stored indefinitely
at -25 °C. However, reaction with 9 at 100 °C under argon
(8) For example, see refs 4e, g, and h.
(10) See ref 4h.
(9) Aniline 4 can also be constructed by a longer (though more flexible)
route involving the use of palladium-mediated coupling reactions; see ref
3 for details.
(11) Compound 9 could be handled briefly (<1 h) in air and was stable
to neutral aqueous workup. Exposure to air over longer periods resulted in
decomposition.
974
Org. Lett., Vol. 1, No. 7, 1999

effected elimination of ethanol followed by cycloaddition
to afford the desired diester isoquinuclidine 11 with complete
regioselectivity.13 The diester was saponified, and the result-
ing diacid was then chemoselectively iodolactonized under
kinetic conditions to give the desired endo-lactone 12 in 67%
overall yield for the four steps from dibromide 8.14
Having successfully assembled the right-hand building
block of catharanthine, we moved next to the construction
of the left-hand portion. A modified literature procedure for
the deannulation of quinoline afforded the desired cis-2-
alkenyl aniline 15 in 42% overall yield as a single diaste-
reomer (Scheme 3).15 The cis-olefin was selected in prefer-
ence to the trans isomer in light of our earlier observation
that cis olefins react more efficiently in the indole-forming
reaction.3
with Lawesson’s reagent in refluxing toluene to selectively
afford the desired radical cyclization precursor, 2-alkenyl-
thioanilide 18, in 86% yield.
We observed in earlier work that an analogue of 18 which
bore an adamantyl group in place of the isoquinuclidine
cyclized only with difficulty in the presence of triethylborane
and tributyltin hydride, and then in low (∼30%) yield.3
However, a model study indicated that the cyclization of
compound 21 (Figure 2) could successfully be carried out
Scheme 3. Synthesis of the Left-Hand 2-Alkenylaniline
Figure 2. Model radical cyclization precursor.
in moderate (∼55%) yield under these same conditions.16
Unfortunately, treatment of 18 with tributyltin hydride in the
presence of triethylborane afforded only low and variable
yields (12-22%) of the desired indole 19, even with slow,
inverse addition of the tin reagent.
Following completion of the right- and left-hand catha-
ranthine precursors, the two fragments were joined using
standard carbodiimide coupling conditions (Scheme 4). After
protection of the free primary alcohol to afford anilide
iodolactone 16 in 74% yield over two steps, iodolactonization
was reversed by treatment with zinc and acetic acid, followed
by immediate esterification of the free carboxylic acid with
diazomethane. This procedure regenerated the alkene while
also supplying the requisite methyl ester, providing com-
pound 17 in 83% yield. Anilide ester 17 was then treated
The reasons for the failure of substrate 18 to efficiently
cyclize under these conditions are not well understood. The
proposed mechanism of this reaction suggests that the rate
of initial radical attack on the thiocarbonyl, the steric bulk
of the thiocarbonyl-bearing substituent, and facile reduction
of the ultimately formed secondary radical are all contributing
factors.3 We speculate that the steric requirements of the
isoquinuclidine fragment in 18 are sufficiently different from
those in 21 to prevent efficient cyclization under “standard”
tin-hydride conditions. Especially, we note that the lacton-
Scheme 4. Total Synthesis of Catharanthine
Org. Lett., Vol. 1, No. 7, 1999
975

ized ester in 21 could reasonably be expected to be sterically
less encumbering than the untethered methyl ester in 18.
reliably afforded the desired indole 19 in 40-50% yield.
Further attempts to improve the yield of this reaction by
altering the solvent, radical initiator, temperature, and
hydrogen donor were unsuccessful. We therefore carried out
the cyclization of 18 on a 0.75 mmol scale under the
aforementioned conditions to obtain indole 19 in 50% yield.
Having completed the crucial indole cyclization, the final
steps of the synthesis proceeded smoothly. The acetate in
19 was replaced with a mesylate to give 20 in 82% yield
over two steps, and the benzyl carbamate was then removed
under mild and highly selective conditions18 to directly afford
(()-catharanthine (1) in 96% isolated yield.19 As planned,
the desired intramolecular SN2 alkylation ensued efficiently
from carbamate cleavage due to the highly rigid nature of
the surrounding molecular framework.20
An alternative set of tin-free radical cyclization conditions
were noted in our initial report, which involve the use of a
phosphorus-based hydrogen atom donor.3,17 A marked im-
provement in yield was noted when these conditions were
used with substrate 18. Cyclization initiated with stoichio-
metric AIBN in the presence of excess aqueous hypophos-
phorous acid and triethylamine in refluxing 1-propanol
(12) Feely, W.; Boekelheide, V. In Organic Syntheses, CollectiVe Volume
IV, Rabjohn, N., Ed.; Wiley: New York, 1963; p 298. The reference calls
for hydrogenation over Raney nickel at 1000 psi and 45 °C. This procedure
results in the formation of appreciable amounts (∼20%) of diethyl
methylmalonate from in situ elimination of ethanol and subsequent
hydrogenation. The milder conditions reported here afford the desired
1
compound in greater than 90% purity (by H NMR integration).
In summary, our newly disclosed radical-mediated cy-
clization reaction for the formation of indoles has been
successfully applied to a completely stereocontrolled total
synthesis of (()-catharanthine. The modular, convergent
nature of this methodology provides synthetic flexibility and
opens the door for the controlled construction of analogues
of this important drug precursor. Further application of this
methodology to related indole alkaloids is under way in our
laboratories and will be reported in due course.
(13) The other possible regioisomer was not detected in the crude reaction
mixture.
(14) Compound 11 typically retains a small amount of polymeric esters
(derived from excess starting material) after a single chromatography, while
the derived diacid is a highly viscous oil from which solvent can be
completely removed only with difficulty. These compounds were carried
forward as obtained to iodolactone 12.
(15) Hull, R. J. Chem. Soc. (C) 1968, 1777. We have found that Na2-
CO3 can be used in place of the barium salt used here. (Ueda, T.; Fukuyama,
T. Unpublished results.)
(16) Reding, M. T.; Fukuyama, T. Unpublished results.
(17) In a report published concurrently with our previous paper, Murphy
and co-workers showed that 1-ethylpiperidine hypophosphite was an
effective hydrogen atom source in a radical-mediated ring-forming reac-
tion: Graham, S. R.; Murphy, J. A.; Coates, D. Tetrahedron Lett. 1999,
40, 2415.
Acknowledgment. This work was supported in part by
the Japanese Ministry of Education, Sports and Culture.
M.T.R. gratefully acknowledges the support of a Japan
Science and Technology Corporation fellowship. We thank
Professor H. Tokuyama for insightful discussions and
suggestions.
(18) (a) Sakaitani, M. S.; Hori, K.; Ohfune, Y. Tetrahedron Lett. 1988,
29, 2983. (b) Sakaitani, M. S.; Ohfune, Y. J. Org. Chem., 1990, 55, 870.
We noted earlier that hydrogenation of compound 12 over palladium on
carbon resulted in the saturation of the olefin as well as cleavage of the
Cbz group. (Reding, M. T.; Fukuyama, T. Unpublished results.)
(19) The analytical data of the material obtained by this route was in
accord with that reported in the literature for (()-catharanthine (ref 4f).
(20) Proton NMR measurements of the indole NH chemical shift in
compounds 19 and 20 show the signal as a broad singlet at abnormally
high values (near 10 ppm downfield from TMS), indicating possible
intramolecular hydrogen bond donation to the adjacent carboxyl group. Such
a bond would be expected to enhance the desired alkylation reaction by
further predisposing the molecule to a favorable conformation. Interestingly,
the chemical shift for the analogous proton in 1 is found near 7.7 ppm, a
relatively normal value.
Supporting Information Available: Experimental details
for the synthesis of intermediates 7-9, 11, 12, 14-20, and
(()-catharanthine (1), as well as spectroscopic data for
selected compounds. This information is available free of
charge via the Internet at http://pubs.acs.org/.
OL990749I
976
Org. Lett., Vol. 1, No. 7, 1999