Selective deoxygenation of leurosine: Concise access to anhydrovinblastine

Article abstract of DOI:10.1021/jo0202942

Straightforward access to anhydrovinblastine starting from the parent alkaloid leurosine is reported. The key deoxygenation step was first optimized on a model substrate. However, applied to leurosine, only the low-valent CP₂TiCl gave satisfactory results.

Full text of DOI:10.1021/jo0202942

SCHEME 1
Selective Deoxygen a tion of Leu r osin e:
Con cise Access to An h yd r ovin bla stin e
Christophe Hardouin, Eric Doris,*
Bernard Rousseau, and Charles Mioskowski
CEA/ Saclay, Service de Marquage Mole´culaire et de Chimie
Bioorganique, Baˆt. 547, De´partement de Biologie
J oliot-Curie, 91191 Gif sur Yvette Cedex, France
eric.doris@cea.fr
Received April 26, 2002
Abstr a ct: Straightforward access to anhydrovinblastine
starting from the parent alkaloid leurosine is reported. The
key deoxygenation step was first optimized on a model
substrate. However, applied to leurosine, only the low-valent
Cp2TiCl gave satisfactory results.
SCHEME 2
Leurosine 1 is one of the most abundant bisindole
alkaloids isolated from the leaves of the Madagascan
Periwinkle Catharanthus roseus. It was initially classi-
fied in the family of Vinca alkaloids, which included
vinblastine 2, vincristine 3, and anhydrovinblastine 4
(Scheme 1).1
Together with vinorelbine 5 (Navelbine), a semisyn-
thetic derivative currently on the market, these dimeric
alkaloids inhibit mitosis by binding to tubuline, thus
allowing a broad spectrum of activity in the treatment
of various carcinomas.2 The synthesis of Navelbine 5
requires two steps: the biomimetic coupling of two
monomers (catharanthine 6 and vindoline 7) to afford
anhydrovinblastine 43, followed by contraction of the
latter’s C′ ring (Scheme 2).4
Anhydrovinblastine is thus the key intermediate in the
synthesis of the anticancer drug Navelbine. Since the
alkaloids 1 and 4 differ only by the presence of an epoxide
on the “northern” portion of leurosine, the selective
deoxygenation of the cyclic ether should thus provide
direct access to anhydrovinblastine as previously dem-
onstrated by Atta-ur-Rahman using TMSCl/Zn dust
(Scheme 3).5
SCHEME 3
In the present article we report a detailed account of
our investigations for the synthesis of anhydrovinblastine
4 starting from the parent alkaloid leurosine 1.
(1) The Alkaloids. Antitumor Bisindole Alkaloids from Catharanthus
Roseus (L.). Brossi, A., Suffness, M. Eds.; Academic Press: San Diego,
1990; Vol. 37.
(2) Zavala, F.; Gue´nard, D.; Potier, P. Experientia 1978, 34, 1497-
1499. Gue´ritte, F.; Pouilhe`s, A.; Mangeney, P.; Andriamialisoa, R. Z.;
Langlois, N.; Langlois, Y.; Potier, P. Eur. J . Med. Chem.-Chim. Ther.
1983, 18, 419-424. Lobert, S.; Vulevic, B.; Correia, J . J . Biochemistry
1996, 35, 6806-6814. Lobert, S.; Fahy, J .; Hill, B. T.; Duflos, A.;
Etievant, C.; Correia, J . J . Biochemistry 2000, 39, 12053-12062.
(3) Potier, P.; Langlois, N.; Langlois, Y.; Gue´ritte, F. J . Chem. Soc.,
Chem. Commun. 1975, 670-671. Langlois, N.; Gue´ritte, F.; Langlois,
Y.; Potier, P. J . Am. Chem. Soc. 1976, 98, 7017-7024.
The structure of leurosine was established in 1969 by
spectroscopic comparison with related alkaloids6 and
(4) Mangeney, P.; Andriamialisoa, R. Z.; Lallemand, J . Y.; Langlois,
N.; Langlois, Y.; Potier, P. Tetrahedron 1979, 35, 2175-2179. Andri-
amialisoa, R. Z.; Langlois, N.; Langlois, Y.; Potier, P. Tetrahedron 1980,
36, 3053-3060.
(6) Abraham, D. J .; Farnsworth, N. R. J . Pharm. Sci. 1969, 58, 694-
698.
(5) Atta-ur-Rahman; Perveen, S. J . Nat. Prod. 1988, 51, 1271-1272.
10.1021/jo0202942 CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/30/2002
J . Org. Chem. 2002, 67, 6571-6574
6571

TABLE 1. Deoxygen a tion Attem p ts on Mod el Su bstr a te
11
SCHEME 4
entry
conditions
solvent
CH3CN
THF/CH3CN
THF
yield (%)
1
2
3
TMSCl/NaI
(CF3CO)2O/NaI
Cp2TiCl2/Zn
81
56
43
later confirmed by oxidation of anhydrovinblastine.7
Since no X-ray data were available at this time, we
initiated a study to elucidate the solid-state conformation
of leurosine. Treatment of leurosine 1 with excess
iodomethane furnished leurosine-methiodide 8 (mono-
alkylated at N6′). Suitable colorless crystals were ob-
tained by slow evaporation of a MeOH/H2O/THF solution.
The X-ray structure of leurosine-methiodide8 (see Sup-
porting Information) shows that the central and adjacent
six-membered rings of vindoline are in boat and sofa
conformations, respectively. The piperidine ring of the
upper part of the alkaloid adopts a sofa conformation,
while the seven-membered ring incorporating the oxirane
is in a boat conformation. The stereochemistry of the
epoxide was found to be in agreement with the one
previously determined by NMR experiments.9
SCHEME 5
or the low-valent Cp2TiCl16 (entry 3) permitted the
smooth conversion of 11 into deoxygenated derivative 10.
With these results in hands, we attempted the deoxy-
genation of leurosine 1 using the aforementioned meth-
ods. Unfortunately, the reactions involving NaI combined
with either TMSCl or trifluoroacetic anhydride did not
allow conversion of 1 into anhydrovinblastine 4. Leuro-
sine 1 was ultimately treated with Cp2TiCl for 15 min
at room temperature in THF. The low-valent titanium-
(III) complex was readily prepared by the in situ reduc-
tion of 2.5 equiv of Cp2TiCl2 with 5 equiv of powdered
zinc for 45 min.17 The reaction produced anhydrovinblas-
tine 4 cleanly in 70% yield. Compound 4 was unambigu-
ously identified by spectroscopic and chromatographic
comparison with an authentic sample. Our strategy
involving the utilization of a low-valent titanium species
for the key deoxygenation step was inspired by the work
of Nugent and RajanBabu, who reported that Cp2TiCl
efficiently promotes the conversion of epoxides to the
corresponding olefins under mild conditions.18
A postulated reaction mechanism is illustrated in
Scheme 5. In the first step, the sequential single-electron
transfer from Cp2TiCl to the oxirane and homolysis of
the C-O bond generate a â-alkoxy radical 12. The
relative stability of the carbon-centered radical interme-
diate (for example, tertiary > secondary > primary)
governs the regiochemistry of the ring opening. Upon
reaction with a second equivalent of Cp2TiCl, a â-alkoxy
carbanion 13 results, followed by subsequent elimination
of a titanium-oxo byproduct to provide deoxygenated
anhydrovinblastine 4.
Deoxygenation was first attempted on a model sub-
strate 11, which incorporates the main structural fea-
tures of the northern portion of leurosine, including the
key epoxide (Scheme 4). Our synthesis of the model
substrate started from catharanthine 6, which was
converted to 18-carboxymethoxycleavamine 9 (as a 3/1
mixture of epimers) by a ring-opening/reduction se-
quence.10 The indole nitrogen atom was then protected
as the methyl carbamate using KH as a base.11 It should
be noted that the center bearing the ester moiety fully
epimerized during the basic process. Finally, the oxirane
was introduced in 59% yield by tert-butyl peroxide
epoxidation of the double bond leading to 11.12
Among the various deoxygenation conditions tested,13
three procedures gave satisfactory results on the model
substrate 11 (Table 1). The utilization of either TMSCl/
NaI14 (entry 1), trifluoroacetic anhydride/NaI15 (entry 2),
(7) Langlois, N.; Potier, P. J . Chem. Soc., Chem. Commun. 1979,
582-584.
(8) Hardouin, C.; Doris, E.; Rousseau, B.; Mioskowski, C.; Nierlich,
M. Acta Crystallogr. 2000, C56, 225-226.
(9) De Bruyn, A.; De Taeye, L.; Simonds, R.; De Pauw, C. Bull. Soc.
Chim. Belg. 1981, 90, 185-189.
(10) Ratremaniaina, Z.; Langlois, N.; Langlois, Y. Heterocycles 1981,
15, 245-250.
(11) Kutney, J . P.; Balsevich, J .; Bokelman, G. H.; Hibino, T.; Honda,
T.; Itoh, I.; Ratcliffe, A. H.; Worth, B. R. Can. J . Chem. 1978, 56, 62-
70.
(12) Kutney, J . P.; Balsevich, J .; Worth, B. R. Can. J . Chem. 1979,
57, 1682-1690.
(14) Caputo, R.; Mangoni, L.; Neri, O.; Palumbo, G. Tetrahedron Lett.
1981, 22, 3551-3552.
(13) For example, see: Cornforth, J . W.; Cornforth, R. H.; Mathew,
K. K. J . Chem. Soc. 1959, 112-127 (NaI/Zn). Suzuki, H.; Fuchita, T.;
Iwasa, A.; Mishina, T. Synthesis 1978, 905-908 (P2I4/pyridine). Martin,
M. G.; Ganem, B. Tetrahedron Lett. 1984, 25, 251-254 (dimethyl
diazomalonate/Rh2(OAc)4). Paryzek, Z.; Wydra, R. Tetrahedron Lett.
1984, 25, 2601-2604 (PPh3I2). Yamada, K.; Goto, S.; Nagase, H.;
Kyotani, Y.; Hirata, Y. J . Org. Chem. 1978, 43, 2076-2077 (MTPI/
BF3‚OEt2). Paulsen, H.; Heiker, F. R.; Feldmann, J .; Heyns, K.
Synthesis 1980, 636-638 (3-methyl-2-selenoxo-1,3-benzothiazol/CF3-
CO2H).
(15) Sonnet, P. E. J . Org. Chem. 1978, 43, 1841-1842.
(16) Gold, H. J . Synlett 1999, 159. Gansa¨uer, A.; Bluhm, H. Chem.
Rev. 2000, 100, 2771-2788. Li, J . J . Tetrahedron 2001, 57, 1-24.
(17) Hardouin, C.; Chevallier, F.; Rousseau, B.; Doris, E. J . Org.
Chem. 2001, 66, 1046-1048. Moisan, L.; Hardouin, C.; Rousseau, B.;
Doris, E. Tetrahedron Lett. 2002, 43, 2013-2015. See also ref 18.
(18) RajanBabu, T. V.; Nugent, W. A.; Beattie, M. S. J . Am. Chem.
Soc. 1990, 112, 6408-6409. RajanBabu, T. V.; Nugent, W. A. J . Am.
Chem. Soc. 1994, 116, 986-997. See also: Schobert, R. Angew. Chem.,
Int. Ed. Engl. 1988, 27, 855-856.
6572 J . Org. Chem., Vol. 67, No. 18, 2002

18-Ca r boxym eth oxyclea va m in e (9).10 A solution of catha-
ranthine sulfate (20.16 g, 46.4 mmol, 1 equiv) in 120 mL of CF3-
CO2H was stirred at room temperature for 36 h. NaBH4 (4.5 g,
2.5 equiv) in 40 mL of THF was then cautiously added dropwise,
at 0 °C, over a period of 10 min. The reaction mixture was
further stirred for 30 min, and the reaction was quenched with
saturated NaHCO3. The aqueous layer was extracted three times
with CH2Cl2. The combined organic layers were dried over Na2-
SO4, filtered, and concentrated under reduced pressure. After
chromatography on silica (5:1 hexane/EtOAc), 18(S)- and 18(R)-
carboxymethoxycleavamine were obtained in a 3:1 ratio (12.9
g, 83% combined yield). 18(S)-Carboxymethoxycleavamine (Rf
) 0.55 (4:1 hexane/EtOAc), white solid): 1H NMR (CDCl3) δ 1.07
(t, J ) 7.4 Hz, 3H), 2.06 (m, 3H), 2.18 (m, 1H), 2.29-2.41 (m,
4H), 2.72 (m, 1H), 2.86 (m, 2H), 3.12 (m, 2H), 3.66 (s, 3H), 5.17
(d, J ) 10 Hz, 1H), 5.29 (d, J ) 3.4 Hz, 1H), 7.06-7.17 (m, 2H),
7.33 (d, J ) 7.8 Hz, 1H), 7.51 (d, J ) 7.6 Hz, 1H), 8.59 (brs, 1H);
13C NMR (CDCl3) δ 12.6, 26.3, 27.6, 34.7, 38.2, 38.6, 52.0, 53.1,
53.7, 55.2, 110.5, 111.6, 118.2, 118.9, 121.5, 121.8, 127.9, 134.6,
135.7, 141.5, 175.7; MS (ESI) 338 (M+, 100); IR (KBr) 3381, 2960,
2921, 1718, 1461, 1159, 741; HRMS calcd for C21H26N2O2 (M)+
338.1994, found 338.1987. 18(R)-Carboxymethoxycleavamine (Rf
) 0.35 (4:1 hexane/EtOAc), white solid): 1H NMR (CDCl3) δ 0.88
(t, J ) 7.3 Hz, 3H), 1.82 (q, J ) 7.3 Hz, 2H), 1.91-2.11 (m, 2H),
2.25 (m, 2H), 2.56 (m, 2H), 2.79 (d, J ) 15.9 Hz, 1H), 2.91-3.12
(m, 3H), 3.62 (d, J ) 12.2 Hz, 1H), 3.76 (s, 3H), 4.08 (dd, J ) 2
and 4.9 Hz, 1H), 5.51 (d, J ) 4.3 Hz, 1H), 7.09-7.21 (m, 2H),
7.37 (d, J ) 7.3 Hz, 1H), 7.58 (d, J ) 7.3 Hz, 1H), 9.08 (brs, 1H);
13C NMR (CDCl3) δ 12.2, 21.7, 27.2, 34.1, 39.1, 39.3, 47.0, 51.2,
52.2, 57.5, 109.6, 110.7, 117.6, 118.8, 121.0, 124.2, 128.0, 135.0,
135.2, 138.7, 176.1.
16,18(S)-Dica r boxym eth oxyclea va m in e (10).11 At 0 °C, to
a solution of a 3:1 mixture of epimers of 18-carboxymethoxy-
cleavamine (1.4 g, 4.14 mmol, 1 equiv) in 40 mL of THF was
added, over a period of 10 min, KH (2 g of a 35% dispersion in
oil, 4.2 equiv). The reaction was stirred 30 min at 0 °C, and
methyl chloroformate (1.5 mL, 4.9 equiv) was added dropwise
at this temperature. The reaction was further stirred for 90 min
at room temperature and quenched, at 0 °C, with saturated
NaHCO3. The aqueous layer was extracted once with Et2O and
twice with CH2Cl2. The combined organic layers were washed
with brine, dried over Na2SO4, filtered, and concentrated under
reduced pressure. After chromatography on silica (9:1 hexane/
EtOAc), 16,18(S)-dicarboxymethoxycleavamine was obtained as
a pale yellow oil (1.16 g, 71%): 1H NMR (CDCl3) δ 1.04 (t, J )
7.4 Hz, 3H), 1.90 (m, 1H), 2.02 (q, J ) 7.4 Hz, 2H), 2.13 (m,
1H), 2.38 (d, J ) 11.6 Hz, 1H), 2.44-2.58 (m, 2H), 2.75-2.86
(m, 4H), 3.06 (s, 2H), 3.58 (s, 3H), 3.94 (s, 3H), 5.41 (d, J ) 4.3
Hz, 1H), 5.82 (d, J ) 6.7 Hz, 1H), 7.22-7.32 (m, 2H), 7.46 (d, J
) 8.2 Hz, 1H), 8.14 (d, J ) 9 Hz, 1H); 13C NMR (CDCl3) δ 12.6,
26.8, 27.6, 34.7, 35.8, 38.6, 51.8, 52.4, 53.1, 54.3, 54.5, 115.7,
118.1, 119.5, 122.1, 127.7, 124.3, 129.8, 136.0, 137.7, 141.1, 151.9,
173.7; MS (CI/NH3) 397 ((M + H)+, 100); IR (neat) 2955, 1735,
1459, 1328, 1233, 732.
SCHEME 6
The intermediacy of a radical species similar to 12
prompted us to trap this transient by either a hydrogen-
atom donor19 or ethyl acrylate.20 Such radical capture
would produce vinblastine-type alkaloids analogous to 14
and 15, respectively, by selective reduction of the epoxide
(Scheme 6). To corroborate this hypothesis, a solution of
Cp2TiCl in THF was added dropwise to a mixture of
leurosine 1 and a 10-fold excess of 2-methyl-2-pro-
panethiol. Changing the order of addition of the titanium
reagent to the epoxide was required to minimize the
competing deoxygenation to anhydrovinblastine. This
furnished an alkaloid derivative to which we tentatively
assign the structure of the bisindole 14.21 It should be
noted that we obtained this product only in modest yield
(11%) and as a single diastereomer, albeit with unknown
stereochemistry of the ethyl group. The same comments
hold true for the synthesis of 15 (8% yield) where ethyl
acrylate was used as radical trap instead of t-BuSH.
In conclusion, we have shown that the low-valent Cp2-
TiCl efficiently deoxygenates leurosine to anhydrovin-
blastine.22 This procedure was also applied to the syn-
thesis of vinblastine-type alkaloids (e.g., 14 and 15) by
tandem selective reduction of the epoxide moiety of
leurosine/trapping of the resulting radical intermediate.
Exp er im en ta l Section
Gen er a l Meth od s. 1H and 13C NMR spectra were recorded
at 300 and 75 MHz using residual CHCl3 (7.25 ppm) and CDCl3
(77 ppm) as internal standards, respectively. Flash column
chromatography was performed on silica gel (60 Å, 230-400
mesh). All reactions were performed under Ar. THF was distilled
over Na/benzophenone. HRMS was recorded at the “Centre
Re´gional de Mesures Physiques de l’Ouest” (Rennes, France).
Leu r osin e-m eth iod id e (8).8 Leurosine (0.5 g) was added
portionwise to 5 mL of CH3I. The solution was stirred for 1 h at
room temperature, and excess CH3I was removed under reduced
pressure. Suitable colorless crystals for X-ray analysis were
obtained by slow evaporation of a MeOH/H2O/THF solution.
16,18(S)-Dica r boxym eth oxy-3(R),4(S)-ep oxyd ih yd r ocle-
a va m in e (11).12 To a solution of 16,18(S)-dicarboxymethoxy-
cleavamine (1.1 g, 2.77 mmol, 1 equiv) in 60 mL of THF was
added a 1% solution of CF3CO2H in H2O (6 mL, 0.3 equiv) and
TBHP (5.5 mL of a 70% solution in H2O, 15 equiv). The reaction
mixture was stirred for 24 h at room temperature, and the
reaction was quenched with saturated NaHCO3. The aqueous
layer was extracted three times with EtOAc. The combined
organic layers were washed with 5% NaOH, H2O, and brine,
dried over Na2SO4, filtered, and concentrated under reduced
pressure. After chromatography on silica (4:1 hexane/EtOAc),
16,18(S)-dicarboxymethoxy-3(R),4(S)-epoxydihydrocleavamine was
obtained as a pale yellow powder (mp 133 °C, 0.68 g, 59%): 1H
NMR (CDCl3) δ 1.03 (t, J ) 7.3 Hz, 3H), 1.47-1.59 (m, 1H),
1.63-1.77 (m, 1H), 2.01-2.16 (m, 3H), 2.40 (m, 1H), 2.59 (m,
1H), 2.71 (m, 1H), 2.79 (m, 2H), 2.95 (m, 3H), 3.11 (d, J ) 12.8
Hz, 1H), 3.62 (s, 3H), 3.97 (s, 3H), 5.88 (d, J ) 6.7 Hz, 1H), 7.22-
7.32 (m, 2H), 7.45 (d, J ) 7.3 Hz, 1H), 8.12 (d, J ) 7.3 Hz, 1H);
13C NMR (CDCl3) δ 8.9, 26.2, 29.9, 33.4, 33.5, 39.3, 50.4, 51.9,
52.6, 53.3, 60.6, 62.7, 115.8, 118.1, 119.4, 122.8, 124.4, 129.6,
(19) Gansa¨uer, A.; Bluhm, H.; Pierobon, M. J . Am. Chem. Soc. 1998,
120, 12849-12859. Gansa¨uer, A. Synlett 1998, 801-809.
(20) RajanBabu, T. V.; Nugent, W. A. J . Am. Chem. Soc. 1989, 111,
4525-4527.
(21) Compound 14 has already been reported by Kutney et al.; see:
Kutney, J . P.; Honda, T.; Kazmaier, P. M.; Lewis, N. J .; Worth, B. R.
Helv. Chim. Acta 1980, 63, 366-374.
(22) Hardouin, C.; Doris, E.; Rousseau, B.; Mioskowski, C. Org. Lett.
2002, 4, 1151-1153.
J . Org. Chem, Vol. 67, No. 18, 2002 6573

135.8, 136.8, 151.9, 173.4; MS (CI/NH3) 413 ((M + H)+, 100); IR
94.2, 110.4, 117.3, 118.3, 118.8, 121.2, 122.2, 122.8, 123.5, 123.8,
124.5, 129.4, 130.0, 131.0, 134.9, 140.0, 152.7, 158.0, 170.8, 171.6,
174.6.
25
(KBr) 2955, 1734, 1461, 1364, 1196, 913, 732; [R]D + 92 (c 0.5,
CH2Cl2). HRMS calcd for C23H28N2O5 (M)+ 412.1998, found
412.1981.
P r oced u r e for th e Syn th esis of Bisin d ole Alk a loid (14)
fr om Leu r osin e (1). To a solution of leurosine 1 (0.19 g, 0.24
mmol, 1 equiv) and 2-methyl-2-propanethiol (0.26 mL, 10 equiv)
in 4 mL of THF was added dropwise, over a period of 10 min,
2.3 mL of a solution of Cp2TiCl (2.5 equiv) in THF (supernatant)
prepared as described above. After 45 min, the reaction was
quenched with 1 N HCl. The solution was basified to pH 8 with
saturated NaHCO3. The precipitate was filtered through a fritted
glass funnel, and the aqueous layer was extracted three times
with Et2O. The combined organic layers were dried over Na2-
SO4, filtered, and concentrated under reduced pressure. The
crude product was purified by chromatography over silica (97:3
CH2Cl2/MeOH) to afford 1421 in 11% yield (0.021 g, amorphous
powder): 1H NMR δ 0.78 (t, J ) 7.3 Hz, 3H), 0.96 (t, J ) 7.3
Hz, 3H), 1.20-1.34 (m, 3H), 1.72-1.88 (m, 3H), 2.08 (s, 3H),
2.05-2.25 (m, 1H), 2.39-2.47 (m, 2H), 2.62 (brs, 2H), 2.71 (s,
3H), 2.79 (d, J ) 16.5 Hz, 1H), 2.96-3.42 (m, 10H), 3.61 (s, 3H),
3.64-3.72 (m, 3H), 3.78 (s, 3H), 3.79 (s, 3H), 5.28 (d, 1H, J )
4.9 Hz, 1H), 5.43 (s, 1H), 5.83 (dd, J ) 4.3 and 10.4 Hz, 1H),
6.07 (s, 1H), 6.50 (s, 1H), 7.07-7.19 (m, 3H), 7.45 (d, J ) 7.3
Hz, 1H), 8.01 (brs, 1H), 9.83 (brs, 1H); 13C NMR δ 8.3, 11.0, 21.1,
22.7, 25.5, 30.7, 30.8, 32.2, 35.9, 36.2, 38.1, 41.4, 42.6, 44.5, 52.1,
52.6, 53.2, 54.9, 55.7, 57.0, 65.5, 67.8, 71.5, 76.3, 79.6, 83.1, 94.1,
110.5, 115.3, 118.0, 119.4, 119.6, 122.8, 123.1, 123.2, 124.6, 128.5,
129.8, 130.3, 134.9, 153.1, 157.9, 170.9, 171.6, 174.3; MS (CI/
NH3) 811 ((M + H)+, 100); IR (KBr) 3464, 1738, 1615, 1502, 1460,
1233, 1039, 733; HRMS (FAB) calcd for C46H59N4O9 (M + H)+
811.4282, found 811.4280.
Deoxygen a t ion At t em p t s on t h e Mod el Su b st r a t e 11.
Procedure A.14 To a suspension of NaI (0.25 g, 10 equiv) in 1
mL of CH3CN was added dropwise TMSCl (0.1 mL, 5 equiv).
The yellowish solution was stirred 10 min at room temperature,
and a solution of 11 (0.06 g, 0.15 mmol, 1 equiv) in CH3CN was
added dropwise. After 1 h, the reaction was quenched with a
2.5 N solution of Na2S2O3 (10 mL). The aqueous phase was
extracted three times with Et2O. The combined organic layers
were dried over Na2SO4, filtered, and concentrated under
reduced pressure. After chromatography on silica (4:1 hexane/
EtOAc), 10 was obtained in 81% yield (0.046 g). Procedure B.15
At 0 °C, to a suspension of NaI (0.2 g, 11 equiv) in 2 mL of CH3-
CN was added dropwise (CF3CO)2O (0.1 mL, 6 equiv). After 5
min, a solution of 11 (0.05 g, 0.12 mmol, 1 equiv) in 1 mL of
THF was added at 0 °C. The reaction mixture was stirred at 45
°C for 3 days, and the reaction was quenched with saturated
NaHCO3. The aqueous phase was extracted three times with
CH2Cl2. The combined organic layers were washed with a 2.5 N
solution of Na2S2O3 (10 mL) and brine, dried over Na2SO4,
filtered, and concentrated under reduced pressure. After chro-
matography on silica (4:1 hexane:EtOAc), 10 was obtained in
56% yield (0.027 g). Procedure C.22 This procedure is analogous
to the one utilized for the conversion of leurosine 1 to anhy-
drovinblastine
4 (vide infra) starting from 16,18(S)-dicar-
boxymethoxy-3(R),4(S)-epoxydihydrocleavamine 11 (0.13 g, 0.31
mmol, 1 equiv), Cp2TiCl2 (0.195 g, 2.5 equiv), and Zn (0.1 g, 5
equiv). After chromatography on silica (4:1 hexane/EtOAc), 16,-
18(S)-dicarboxymethoxycleavamine 10 was obtained in 43% yield
(0.054 g).
P r oced u r e for th e Syn th esis of Bisin d ole Alk a loid (15)
fr om Leu r osin e (1). The alkaloid 15 was prepared as described
for 14 using leurosine 1 (0.08 g, 0.1 mmol, 1 equiv), ethyl acrylate
(0.1 mL, 9 equiv), and 1 mL of a solution of Cp2TiCl (2.5 equiv)
in THF (supernatant) prepared as described above (added
dropwise over a period of 40 min). After the usual workup, the
crude product was purified by chromatography over silica (97:3
CH2Cl2/MeOH) to afford 15 in 8% yield (7.5 mg, amorphous
powder): 1H NMR δ 0.79 (t, J ) 7.3 Hz, 3H), 0.84 (t, J ) 7.1
Hz, 3H), 1.27 (t, J ) 7.2 Hz, 3H), 1.31-1.48 (m, 2H), 1.56 (m,
1H), 173-1.96 (m, 5H), 2.09 (s, 3H), 2.15 (m, 2H), 2.33-2.55
(m, 4H), 2.62 (s, 1H), 2.69 (s, 3H), 2.75 (d, J ) 10.2 Hz, 1H),
2.85 (m, 2H), 3.05 (m, 1H), 3.14-3.39 (m, 6H), 3.54 (m, 1H), 3.63
(s, 3H), 3.73 (s, 1H), 3.78 (s, 3H), 3.80 (s, 3H), 4.14 (q, J ) 7.1
Hz, 2H), 5.27 (d, J ) 7.1 Hz, 1H), 5.46 (s, 1H), 5.83 (dd, J ) 3.7
and 10.1 Hz, 1H), 6.09 (s, 1H), 6.49 (s, 1H), 7.08-7.16 (m, 3H),
7.52 (d, J ) 7.5 Hz, 1H), 7.97 (brs, 1H), 9.84 (brs, 1H); MS (ESI)
911 ((M + H)+, 100); IR (KBr) 3468, 2966, 2878, 1736, 1615,
1503, 1459, 1372, 1242, 1040, 911, 732; HRMS (FAB) calcd for
C51H66N4O11 (M + H)+ 911.4806, found 911.4798.
P r oced u r e for th e Syn th esis of An h yd r ovin bla stin e (4)
fr om Leu r osin e (1). To a mixture of Cp2TiCl2 (0.325 g, 2.5
equiv) and powdered Zn (0.170 g, 5.0 equiv) in a flame-dried
flask was added THF (5 mL). The solution was degassed under
vacuum and purged with nitrogen (this operation was repeated
three times). The heterogeneous solution was stirred vigorously
for 45 min at room temperature. To the green slurry of Cp2TiCl
was added dropwise leurosine 1 (0.42 g, 0.52 mmol, 1 equiv) in
10 mL of THF. The solution was degassed under vacuum and
purged with nitrogen (this operation was repeated three times).
After 15 min, the mixture was filtered over paper and the
reaction quenched with 1 N HCl. The solution was basified to
pH 8 with saturated NaHCO3. The precipitate was filtered
through a fritted glass funnel, and the aqueous layer was
extracted three times with Et2O. The combined organic layers
were dried over Na2SO4, filtered, and concentrated under
reduced pressure. The crude product was purified by chroma-
tography over silica (96:4 CH2Cl2/MeOH) to afford anhydrovin-
blastine23 4 in 70% yield (0.288 g, amorphous powder): 1H NMR
δ 0.80 (t, J ) 7.3 Hz, 3H), 0.98 (t, J ) 7.6 Hz, 3H), 1.21-1.37
(m, 2H), 1.74-1.84 (m, 2H), 1.92 (q, J ) 7.6 and 14.9 Hz, 2H),
2.10 (s, 3H), 2.08-2.15 (m, 1H), 2.36-2.47 (m, 2H), 2.55 (d, J )
13.4 Hz, 1H), 2.67 (s, 1H), 2.70 (s, 3H), 2.82 (d, J ) 16.5 Hz,
1H), 2.96-3.11 (m, 2H), 3.17-3.39 (m, 6H), 3.52 (d, J ) 16.5
Hz, 1H), 3.61 (s, 3H), 3.72 (s, 1H), 3.79 (s, 3H), 3.81 (s, 3H), 5.29
(s, 1H), 5.30 (d, J ) 6.1 Hz, 1H), 5.45 (brs, 2H), 5.84 (dd, J ) 4.0
and 10.1 Hz, 1H), 6.11 (s, 1H), 6.61 (s, 1H), 7.10-7.16 (m, 3H),
7.51 (d, J ) 7.3 Hz, 1H), 8.01 (brs, 1H), 9.86 (brs, 1H); 13C NMR
δ 8.3, 12.2, 21.1, 25.9, 27.7, 29.6, 30.7, 32.9, 34.3, 38.3, 42.6, 44.5,
45.9, 50.3, 52.1, 52.2, 53.2, 54.4, 55.5, 55.9, 65.5, 76.4, 79.6, 83.3,
Ack n ow led gm en t. This work is part of a collabora-
tion between “Pierre Fabre Me´dicament/CEA-Direction
des Sciences du Vivant”. Dr. Bryan Yeung is gratefully
acknowledged for reviewing this manuscript.
Su p p or tin g In for m a tion Ava ila ble: Reproductions of 1H
NMR spectra of compounds 1, 4, 9-11, 14, and 15 and ORTEP
of leurosine-methiodide 8. This material is available free of
charge via the Internet at http://pubs.acs.org.
(23) Sza´ntay, C., J r.; Bala´zs, M.; Bo¨lcskei, H.; Sza´ntay, C. Tetrahe-
dron 1991, 47, 1265-1274.
J O0202942
6574 J . Org. Chem., Vol. 67, No. 18, 2002