Synthesis of C-15 vindoline analogues by palladium-catalyzed cross-coupling reactions

Article abstract of DOI:10.1021/jo061243y

(Chemical Equation Presented) Described are general protocols for the rapid construction of various C-15-substituted analogues of vindoline using palladium-catalyzed cross-coupling reactions. The required bromo-and iodovindolines were prepared in high yie

Full text of DOI:10.1021/jo061243y

Synthesis of C-15 Vindoline Analogues by
Palladium-Catalyzed Cross-Coupling Reactions
Peter D. Johnson, Jeong-Hun Sohn, and Viresh H. Rawal*
Department of Chemistry, UniVersity of Chicago,
5735 South Ellis AVenue, Chicago, Illinois 60637
Vrawal@uchicago.edu
ReceiVed June 16, 2006
Described are general protocols for the rapid construction of
various C-15-substituted analogues of vindoline using palladi-
um-catalyzed cross-coupling reactions. The required bromo-
and iodovindolines were prepared in high yield by the reac-
tion of vindoline with N-bromosuccinimide or N-iodosuccini-
mide, respectively. The study not only led to the preparation
of a number of structurally novel vindoline analogues but
also opens the door to new strategies for the synthesis of
vinblastine, vincristine, and related anticancer agents. Also
described is the conversion of ent-tabersonine to ent-
vindoline.
FIGURE 1. Clinically efficacious bisindole alkaloids and derivatives.
more naturally abundant vindoline and catharanthine by connec-
tion between C-15 at the former and C-18′ at the latter.6 The
coupling of these compounds has been accomplished several
times and inevitably takes advantage of the nucleophilicity of
vindoline at C-15.7 Recent efforts by Fahy have also made use
of this reactivity to elaborate the vindoline skeleton by addition
to glycolates.8 Our interest in the total synthesis of vinblastine
drew our attention to the possibility of installing a halogen at
C-15 of vindoline, which would allow for further elaboration at
this position by utilizing the broad spectrum of cross-coupling
reactions.9 These reactions are typically performed under mild
conditionsandprovideahighdegreeoffunctionalgrouptolerance.
The implementation of this chemistry would allow introduction
of novel substituents at C-15, in addition to providing a versatile
scaffold from which further synthetic elaborations could provide
a new synthesis of vinblastine, vincristine, and related compounds.
Initial concerns about the electron-rich nature of the aryl ring,
which slows down oxidative addition of Pd, prompted us to first
investigate the feasibility of cross-coupling of such systems using
a model compound. Thus a substituted carbazole containing the
essential features of 15-bromovindoline was first synthesized to
Vinblastine (1) and vincristine (2) are two bisindole alkaloid
natural products isolated from the Madagascar periwinkle, Catha-
ranthus roseus G. Don (Figure 1).1 Both possess considerable
antimitotic activity and thus have found use in treatment for
various carcinomas, particularly childhood leukemia and Hodg-
kin’s disease.2 The low natural availability and cytotoxic proper-
ties of these molecules have meant that considerable synthetic
efforts have been expended to find efficacious analogues. In the
40 years since the isolation of vinblastine, two such compounds,
vindesine (3, Eldesine, Lilly)3 and vinorelbine (4, Navelbine,
Pierre-Fabre),4 have found use in clinical treatment. A third,
vinflunine (5, Javlor, Pierre-Fabre/Bristol-Myers-Squibb), is cur-
rently in phase III clinical trials.5 The suggestion that these latter
two compounds have similar, but different, modes of action to
the natural compounds is encouraging for the prospect of further
analogues to tackle cross-resistance.
(6) (a) For a review on synthetic studies, see: Antitumor Bisindole
Alkaloids from Catharanthus roseus (L.). The Alkaloids; Brossi, A.,
Suffness, M., Eds.; Academic Press, Inc.; San Diego, 1990; Vol. 37, Chapter
2, pp 77-131. (b) Mangeney, P.; Andriamialisoa, R. Z.; Langlois, N.;
Langlois, Y.; Potier, P. J. Am. Chem. Soc. 1979, 101, 2243. (c) Kutney, J.
P.; Choi, L. S. L.; Nakano, J.; Tsukamoto, H.; McHugh, M.; Boulet, C. A.
Heterocycles 1988, 27, 1845. (d) Kuehne, M. E.; Matson, P. A.; Bornmann,
W. G. J. Org. Chem. 1991, 56, 513. (e) Magnus, P.; Mendoza, J. S.;
Stamford, A.; Ladlow, M.; Willis, P. J. Am. Chem. Soc. 1992, 114, 10232.
(f) Yokoshima, S.; Ueda, T.; Kobayashi, S.; Ayato, S.; Kuboyama, T.;
Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 2137.
(7) (a) Harley-Mason, J.; Atta-Ur-Rahman. Tetrahedron 1980, 36, 1057.
(b) Kutney, J. P.; Beck, J.; Bylsma, F.; Cretney, W. J. J. Am. Chem. Soc.
1968, 90, 4504. (c) Magnus, P.; Mendoza, J. S.; Stamford, A., Ladlow,
M.; Willis, P. J. Am. Chem. Soc. 1992, 114, 10232. (d) Langlois, N.;
Gueritte, F.; Langlois, Y., Potier, P. J. Am. Chem. Soc. 1976, 98, 7017. (e)
Vukovic, J.; Goodbody, A. E.; Kutney, J. P.; Misawa, M. Tetrahedron 1988,
44, 325. (f) Misawa, M.; Endo, T.; Goodbody, A.; Vukovic, J.; Chapple,
C.; Choi, L.; Kutney, J. P. Phytochemistry 1988, 27, 1355. Tabakovic, T.;
Gunic, E.; Juranic, I. J. Org. Chem. 1997, 62, 947.
In addition, there have been a number of efforts to synthesize
vinblastine, both de novo and semisynthetically, from the much
(1) (a) Noble, R. L.; Beer, C. T.; Cutts, J. H. Ann. N.Y. Acad. Sci. 1958,
76, 882. (b) Svoboda, G. H.; Neuss, N.; Gorman, M. J. Am. Pharm. Assoc.
Sci. Ed. 1959, 48, 659.
(2) For a review of the medicinal chemistry of vinblastine, see: Antitumor
Bisindole Alkaloids from Catharanthus roseus (L.). The Alkaloids; Brossi,
A., Suffness, M., Eds.; Academic Press, Inc.; San Diego, 1990; Vol. 37,
Chapters 3 and 4, pp 133-204.
(3) (a) Barnett, C. J.; Cullinan, G. J.; Gerzon, K.; Hoying, R. C.; Jones,
W. E.; Newlon, W. M.; Poore, G. A.; Robison, R. L.; Sweeney, M. J.;
Todd, G. C.; Dyke, R. W.; Nelson, R. L. J. Med. Chem. 1978, 21, 88. (b)
Gokbuget, N.; Hoelzer, D. Leuk. Lymphoma 1997, 26, 497.
(4) (a) Potier, P. Semin. Oncol. 1989, 16, 2. (b) Gregory, R. K.; Smith,
I. E. Br. J. Cancer 2000, 82, 1907.
(5) (a) Fahy, J.; Duflos, A.; Ribet, J. P.; Jacquesy, J. C.; Berrier, C.;
Jouannetaud, M. P.; Zunino, F. J. Am. Chem. Soc. 1997, 119, 8576. (b)
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(8) Fahy, J.; du Boullay, V. T.; Bigg, D. C. H. Bioorg. Med. Chem. Lett.
2002, 12, 505.
(9) During the preparation of this manuscript, a communication describing
some similar transformations was published: Fekete, M.; Kalonits, P.; Novak,
L. Heterocycles 2005, 65, 165. This communication reports the slow nature
of the Suzuki coupling of 15-bromovindoline, in contrast to our findings.
10.1021/jo061243y CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/07/2006
J. Org. Chem. 2006, 71, 7899-7902
7899

TABLE 1. Heck Couplings of Aryl Bromide 11a
SCHEME 1. Synthesis of Model Compound 11
SCHEME 2. Suzuki Reaction of 11 with Phenylboronic
Acid
serve as a platform for the development of optimum protocols for
the cross-coupling reactions.
A. Cross-Couplings of Model Compound. The required mo-
del compound (11) was synthesized by a five-step sequence as
shown in Scheme 1. Boc-hydrazine 6, a single regioisomer, was
prepared in 76-83% yield following the known procedure.10
Treatment of this hydrazine with tosic acid and cyclohexanone
in refluxing ethanol promoted in situ removal of the carbamate
followed by the Fischer-indole reaction.11 Two regioisomeric
indoles were formed, due to the substitution pattern of the hydra-
zine, and these were separated by column chromatography to
give pure indoles 712 and 813 in 41-43% and 16-21% yields,
respectively. Indole 7 was reduced using NaBH3CN in the pres-
ence of AcOH to give 9 as a single diastereomer, which was
protected directly as the pivalate (10) in good yield. Early explor-
ation of the bromination of this system had shown that attenu-
ation of the reactivity of the nitrogen lone pair was necessary
to provide highly selective halogenation para to the amine,
without competing dihalogenation. The desired bromination was
achieved by simple treatment of the aniline with NBS in MeCN
at room temperature to afford 11 in 86% yield (Scheme 1).
Compound 11 was evaluated as a partner in various pallad-
ium-catalyzed cross-coupling processes. Among these, the Suzu-
ki reaction is arguably the most robust, so it was investigated
first. The Suzuki coupling of 11 and phenylboronic acid proceed-
ed smoothly under standard conditions to give the expected biaryl
(12) in 68% yield (Scheme 2). We next examined the Heck
reaction of 11 with a number of coupling partners. Considerable
effort was put into optimizing the conditions for this coupling,
since it was expected to prove useful in other endeavors, such
as the synthesis of vinblastine and analogues. Table 1 shows the
various conditions employed in the Heck coupling of 11 and
methyl acrylate. It is clear that although the Heck reactions
worked well, the yields, even under optimized conditions, barely
a Reactions were conducted using 5 equiv of alkene and 25 mol % of
PdCl2[P(o-tol)3]2 at 100 °C until the reaction was judged complete by TLC.
b Isolated yield. Yields in parentheses are based on recovered starting mater-
ial. c Product contaminated with amine. d Reaction time was 24 h.
e Pd(OAc)2[P(o-tol)3]2 was used as catalyst.
rivaled those of the Suzuki reaction. Best results were obtained
using either N,N-dimethylformamide (DMF) or N,N-dimethylacet-
amide (DMA) as solvents and a large excess of a tertiary amine
base. The yields were lower when the base was employed in
stoichiometric amounts (entry 1 vs 4 and entry 2 vs 5). In most
cases, the recovered starting material was contaminated with
varying amounts of the corresponding dehalogenated compound.
As reported in the literature,14 the use of 1 equiv of MeNCy2 as
the base reduced the extent of dehalogenation, but at the price
of a lower isolated yield (entry 6). Of the palladium catalysts
examined, PdCl2[P(o-tol)3]2 gave the best results in terms of
turnover and yield. The optimized Heck protocol also allowed
the coupling of bromide 11 with methyl vinyl ketone (entry 11),
methyl cinnamate (entry 12), and dimethyl maleate (entry 13).
The coupling reactions of bromide 11 with ester enolates were
also investigated.15 Such reactions are of particular interest because
of their direct applicability to the synthesis of vinblastine and
analogues. Even from this brief study (Table 2) it is clear that
a variety of enolates can participate in the arylation. Of particular
interest is the result shown in entry 2, since it demonstrates the
coupling with an arylacetic ester, as would be required for the
synthesis of vinblastine.
B. Cross-Coupling with Vindoline. Having confirmed the
feasibility of various cross-coupling methods on model compound
(10) Wolter, M.; Klapars, A.; Buchwald, S. L. Org. Lett. 2001, 3, 3803.
(11) Lim, Y.-K.; Cho, C.-G. Tetrahedron Lett. 2004, 45, 1857.
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(13) Kawase, M.; Miyake, Y.; Kikugawa, Y. J. Chem. Soc., Perkin Trans.
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Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234 and references
therein. (c) Rawal, V. H.; Iwama, T. Abstracts of Papers, 222nd ACS
National Meeting, Chicago, IL, August 26-30, 2001. ORGN-606 (CAS:
AN 2001:640969).
7900 J. Org. Chem., Vol. 71, No. 20, 2006

TABLE 2. Ester r-Arylations Using Bromide 11
SCHEME 4. Bromination of Vindoline with NBS
TABLE 3. Suzuki Couplings of Bromovindoline 20
SCHEME 3. Conversion of ent-16-Methoxytabersonine to
ent-Vindoline
11, we turned our attention to the cross-coupling reactions of
vindoline. In previous studies from this laboratory, we had de-
scribed the gram-scale enantioselective synthesis of tabersonine
and 16-methoxytabersonine.16 For the initial coupling studies,
we converted synthetic 16-methoxytabersonine, which had been
prepared in the enantiomeric form, to ent-vindoline through a
sequence of three synthetic operations, following known proce-
dures (Scheme 3).17 Since the synthetic vindoline was precious
and in the unnatural series, it was decided that all further transfor-
mations be carried out on natural vindoline. The conversion of
vindoline to 15-bromovindoline (20) proved uneventful, since
the conditions for bromination of the model system translated
directly, allowing the formation of 20 in nearly quantitative yield
(Scheme 4). The corresponding 15-iodovindoline (33, vide infra)
was prepared similarly, in 97% yield, using NIS in MeCN.
B1. Suzuki Couplings. The conditions identified as effective
for the Suzuki coupling of model compound 11 were utilized for
the corresponding cross-couplings of bromovindoline with a
broadrangeofboronicacids(Table3). Arylboronicacids, irrespec-
tive of their electronic nature, afforded biaryl products (21-26)
in good yields. Particularly encouraging is the ability to use hetero-
a All reactions were run at 90 °C, with 2 equiv of boronic acid.
b Iodovindoline 33 was used.
arylboronic acids, which allow access to a broad range of aryla-
ted vindoline analogues. The strategic introduction of function-
ality on these partners, which mimic the “upper” portion of vin-
blastine, may allow the identification of new bioactive analogues
of this important drug. Whereas arylboronic acids reacted smooth-
ly under the original conditions, vinylboronic acids were less
effective coupling partners, giving the products in moderate to
low yields (entries 7 and 11). A ligand screen revealed that the
commercially available X-PHOS ligand was highly effective
at promoting this coupling.18 The use of X-PHOS not only
allowed couplings with vinylboronic acids (entries 10, 12) but
also an alkylboronic acid (entry 13). Thus, compounds 27 and
(16) Kozmin, S. A.; Iwama, T.; Huang, Y.; Rawal, V. H. J. Am. Chem.
Soc. 2002, 124, 4628.
(17) (a) Barton, D. H. R.; Hui, R. A. H. F.; Ley, S. V.; Williams, D. J.
J. Chem. Soc., Perkin Trans. 1 1982, 1919. (b) Danieli, B.; Lesma, G.;
Palmisano, G.; Riva, R. J. Chem. Soc., Chem. Commun. 1984, 909. (c)
Kobayashi, S.; Ueda, T.; Fukuyama, T. Synlett 2000, 883.
J. Org. Chem, Vol. 71, No. 20, 2006 7901

TABLE 4. Heck Couplings of Bromovindoline 20a
yields for three different esters (Table 2), the analogous reaction
with the bromovindoline 20 proved unsuccessful. It is likely
that the reaction is complicated by the presence of the
unprotected hydroxyl as well as the methyl ester at C-3 and the
acetate at C-4. No starting material could be isolated from the
reaction, nor were any other products identified.
Given the versatility of Pd-catalyzed cross-coupling reactions,
the halovindolines could be further elaborated in many different
ways. We have examined two such transformations, the Sono-
gashira and the carbonylation reactions. Initially, the Sonogashira
coupling of phenylacetylene with bromovindoline 20 was at-
tempted, but it gave the coupled product in low yield, even at
elevated temperatures. This problem was easily circumvented
with 15-iodovindoline 33, which reacted smoothly at room tem-
perature to give the disubstituted acetylene 34 in 67% yield
(Table 5). Iodovindoline was also a superior substrate for the
carbonylation reaction. The reaction was carried out in methanol
under an atmosphere of carbon monoxide using a catalytic amount
of Pd(OAc)2 and afforded the C-15 methyl ester (35) in good
yield. The introduction of a carbonyl group at this position
provides a useful handle for further elaboration, and an extra
degree of freedom in the design of analogues of vinblastine.
We have established a number of protocols for the introduc-
tions of both aryl and aliphatic substituents at C-15 of vindoline
bypalladium-catalyzedcross-coupling,withouttheneedforprotec-
tion of the functionalized vindoline nucleus. The compounds
thus formed represent a number of structurally novel vindoline
analogues. In addition, this method should allow the introduction
of more elaborate substituents, particularly achiral aromatic
structures, which mimic the “upper” portion of vinblastine and
thus represent a new class of vinblastine analogues.
a Reactions were conducted using 5 equiv of alkene and 25 mol % of
PdCl2[P(o-tol)3]2 at 100 °C until reaction was judged complete by TLC.
b Isolated yield. Yields in parentheses are based on recovered starting
material. c Recovered starting material contaminated with vindoline. d Prod-
uct was obtained as a 4:1 mixture of diastereomers.
TABLE 5. Additional Coupling Reactions of Iodovindoline 33
Experimental Section
General Coupling Procedures. Suzuki A. A test tube was
charged with bromovindoline 20 or iodovindoline 33 (1 equiv),
K2CO3 (1.5 equiv), the arylboronic acid (2 equiv), and a magnetic stir
bar. DME and water (3:1, to 0.1 M in halovindoline) were added,
followed by Pd(PPh3)4 (10 mol %). The test tube was sealed with
a septum and the stirred solution was purged of oxygen by five
vacuum-argon cycles. The mixture was heated to 90 °C until TLC
(50% acetone-hexane) indicated the absence of starting material
(typically 2-4 h). The mixture was cooled, diluted with EtOAc,
filtered through Celite, and concentrated. The crude product was
purified by column chromatography, eluting with 25% acetone-
hexane. General Heck A, Heck B, and Suzuki B coupling procedures
and experimental details are in the Supporting Information. By the
Suzuki A procedure, bromovindoline 20 (20 mg, 0.04 mmol) and
phenylboronic acid gave the biaryl 21 (14.9 mg, 75%) as a white
solid: 1H NMR (500 MHz, CDCl3) δ 9.58 (br s, 1H), 7.41 (m,
2H), 7.36 (m, 2H), 7.26 (m, 1H), 6.94 (s, 1H), 6.17 (s, 1H), 5.86
(ddd, J ) 10.0, 5.0, 1.5 Hz, 1H), 5.49 (s, 1H), 5.25 (d, J ) 10.0 Hz,
1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.78 (s, 1H), 3.50 (ddd, J ) 16.0,
5.0, 1.0 Hz, 1H), 3.43 (m, 1H), 2.82 (br d, J ) 16.0 Hz, 1H), 2.74
(s, 3H), 2.72 (s, 1H), 2.54-2.48 (m, 1H), 2.37-2.34 (m, 2H), 2.08
(s, 3H), 1.65 (dq, J ) 15.0, 7.5 Hz, 1H), 1.20 (dq, J ) 14.5, 7.5 Hz,
1H), 0.56 (t, J ) 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 172.2,
171.2, 158.2, 153.3, 139.3, 130.7, 129.7, 128.3, 126.6, 124.7, 124.5,
122.2, 94.0, 83.9, 79.9, 76.7, 67.3, 56.0, 53.3, 52.6, 52.3, 51.4, 44.3,
43.2, 38.9, 31.2, 21.4, 8.1; mp 107-112 °C; IR(film) 1742, 1245,
1039; MS calcd for C31H37N2O6 (MH+) 533.2, found 533.1.
a Bromovindoline was used.
28 were formed in 75% and 67% yields, respectively, and
compound 29 was obtained in 52% yield. Of particular interest
is entry 14, which shows the conversion of bromovindoline to
the corresponding pinacol boronate. Ready access to this
boronate has implications on the use of Suzuki cross-couplings
for the preparation of vindoline analogues. At the present time,
the scarcity of commercially available boronic acids is perhaps
the biggest limitation of the Suzuki reaction. With the avail-
ability of vindoline boronate, it should be possible to use the
vast array of commercially available aryl and vinyl halides and
prepare innumerable analogues of vindoline.
B2. Heck Couplings. Bromovindoline (20) is also an effective
substrate for the Heck reaction. The reaction of bromide 20 with
various alkenes gave the expected coupled products in moderate
yields (Table 4). DMF was found to be more effective as solvent
than DMA in light of not only the yield but also the easier remo-
val of solvent from product. Similar yields were obtained with
15-iodovindoline 33, prepared analogously to bromide 20.
B3. Other Couplings. Although ester R-arylation reactions
with model compound 11 gave the desired products in good
Acknowledgment. Generous financial support from the Na-
tional Cancer Institute of the NIH (R01 CA101438) is gratefully
acknowledged.
Supporting Information Available: Detailed experimental
procedures and spectral data. This material is available free of
charge via the Internet at http://pubs.acs.org.
(18) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem.
Soc. 2003, 125, 13978.
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