A catalytic versus stoichiometric photoinduced electron transfer promoted selective C16-C21 bond cleavage of catharanthine

Article abstract of DOI:10.1016/S0040-4039(00)02117-1

A clean and efficient access to the cleavamine skeleton is described through the selective oxidative C₁₆-C₂₁ bond cleavage of catharanthine. The best result is obtained by the use of catalytic quantities of β-lapachone as photosensitizer, which permits the successful control of competition between the back electron transfer, the deprotonation and the fragmentation pathway.

Full text of DOI:10.1016/S0040-4039(00)02117-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 839–841
A catalytic versus stoichiometric photoinduced electron transfer
promoted selective C ꢀC bond cleavage of catharanthine
1
6
21
†
Guillaume Cocquet, Patrice Rool and Clotilde Ferroud*
Laboratoire de Chimie Organique associ e´ au CNRS, ESA 7084, Conservatoire National des Arts et M e´ tiers,
292, rue Saint Martin, F-75141 Paris Cedex 03, France
Received 2 June 2000; accepted 16 November 2000
Abstract—A clean and efficient access to the cleavamine skeleton is described through the selective oxidative C ꢀC bond
16
21
cleavage of catharanthine. The best result is obtained by the use of catalytic quantities of b-lapachone as photosensitizer, which
permits the successful control of competition between the back electron transfer, the deprotonation and the fragmentation
pathway. © 2001 Elsevier Science Ltd. All rights reserved.
The field of green chemistry requires a significant
rethinking of the ways in which chemists design organic
reactions, of particular importance are the subset of
reactions that employ toxic reagents in stoichiometric
the favourable thermodynamically back electron trans-
fer (BET) gives the starting material. Secondly, a depro-
tonation reaction of the radical cation by the
−
’
semi-reduced form S can occur to give an a-amino-
1
’
quantities and their replacement by catalysts. Some of
radical 1 , which after oxidation can finally lead to the
3
the most important unsolved technological problems in
both selectivity and green chemistry involve oxidation.
Among the candidates as reagents for benign oxidation
chemistry are the photochemical transformations
involving photoinduced electron transfer. In this com-
munication, we applied this methodology to a selective
transformation in the alkaloid series.
3b-cyanocatharanthine 2. We have already described
photochemical conditions allowing such a selective evo-
4
lution. Lastly a previously observed C ꢀC bond
16
21
fragmentation can occur leading to the cleavamine
5
skeleton.
In this paper we report new photooxidative conditions
with catalytic quantities of photosensitizer resulting in a
selective decay of the radical ion pair via this third
pathway.
Vinblastine (VLB) and vincristine (VCR), vinca alka-
loids isolated from the Madagascan periwinkle Catha-
ranthus roseus, are well-known useful anticancer
2
agents. One of the most interesting pathways to these
dimeric compounds involves an oxidative fragmenta-
tion of catharanthine 1 followed by the coupling with
3
the vindoline moiety. Our ongoing interest in photoox-
idation by visible light prompted us to try to realize
photochemically such a cleavage by SET. Oxidation of
catharanthine 1 achieved by irradiation with visible
light in the presence of a photosensitizer (S) leads to a
+
’
−
’
radical ion pair (1 , S ). Once formed, the radical ion
pair can decay via three pathways (Scheme 1). Firstly,
Keywords: oxygen; singlet; photochemistry; oxidation; alkaloids;
cleavage reactions.
*
Corresponding author. E-mail: ferroud@cnam.fr
Present address: Roowin S.A., 37, rue Louise Weiss, 75013 Paris,
France.
†
Scheme 1.
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02117-1

8
40
G. Cocquet et al. / Tetrahedron Letters 42 (2001) 839–841
Scheme 2.
Irradiation of catharanthine 1 (Scheme 2) under an
argon atmosphere by visible light (u>420 nm) in the
presence of a stoichiometric amount of 9,10-dicyanoan-
As expected the photochemical process is catalytic but
we observed the presence of a small amount of the
by-product 2 which is the direct consequence of the
6
−
’
thracene (DCA) as photosensitizer, a small amount of
intrinsic basicity of the semi-reduced form FMN .
water and trimethylsilyl cyanide (TMSCN), yields 21a-
cyano-16a-(methoxycarbonyl)cleavamine
3
quantita-
In order to circumvent the decay of the radical ion pair
tively (d.e.>99%). This product is obtained in 70% yield
after crystallization.
via the deprotonation, b-lapachone (bL), an ortho-
9
quinone known to initiate photoinduced SET mainly
in the triplet excited state (Scheme 3) was chosen. Thus
the irradiation (u>430 nm) of catharanthine 1 in
methanol under anaerobic conditions in the presence of
a catalytic quantity of bL (0.03 equiv.) leads selectively
to the a-aminonitrile 3 in 88% yield (Scheme 2). In this
case the photooxidation also proceeds with a catalytic
amount of photosensitizer and the lower basicity of the
The mechanism involved under these conditions re-
quires a stoichiometric amount of DCA, a well-known
photosensitizer which initiates electron transfer in the
singlet excited state. In this case, the BET is particu-
larly rapid as this decay is an allowed spin transition
6
,7
(
Scheme 3). An efficient way to avoid this fast BET is
−
’
−
’
to quench the semi-reduced form of the photosensitizer
semi-reduced form bL compared to FMN permits
total selectivity.
−
’
(
DCA ) by protonation with trace amounts of water.
We have isolated one equivalent of reduced sensitizer
DCAH ) whose spectroscopic data are in agreement
1
0
(
We have fully characterized
the 21a-cyano-16a-
2
7
with the Farid’s data. When the irradiation is per-
formed in anhydrous solvent, no oxidation product is
formed. In this case the rate of BET is so fast that no
other decay pathway of the radical ion pair can occur.
(methoxycarbonyl)cleavamine 3. Moreover, as chemical
proof of the structure, reduction at 0°C of this com-
pound with sodium borohydride in methanol leads to
11
1
0
the expected 16a-(methoxycarbonyl)cleavamine 4 in
8
0% yield (Scheme 4).
In order to perform this reaction with a catalytic
amount of photosensitizer it is useful to slow down the
BET without consuming the semi-reduced formed S .
A sensitizer which presents a high intersystems crossing
In conclusion, we have presented photochemical condi-
−
’
tions allowing the selective oxidative C ꢀC bond
16
21
cleavage of catharanthine by SET. Moreover, our un-
derstanding of the decay of the radical ion pair allowed
us to control successfully the competition between BET
and the fragmentation pathway. As a consequence we
have found conditions which employ catalytic rather
(
ISC) mainly promotes electron transfer in the triplet
excited state. Then, the triplet radical ion pair formed
decays slower because of the forbidden spin transition
(
Scheme 3). So riboflavin 5%-phosphate sodium salt
dihydrate (FMN), a derivative from the 3-methyllumi-
flavin was chosen (phosphorescence quantum yield=
0
.55). This sensitizer was previously used in photooxida-
tion to cleave the a,b carbonꢀcarbon bond
of an aminium radical cation. The irradiation (u>400
8
nm) of catharanthine 1 is performed in methanol under
anaerobic conditions in the presence of TMSCN and a
catalytic quantity of FMN (0.10 equiv.). Two oxidation
products are obtained (Scheme 2) in 91% overall yield:
2
1a-cyano-16a-(methoxycarbonyl)cleavamine 3 result-
ing from the C ꢀC
bond cleavage and 3b-
1
6
21
cyanocatharanthine 2 resulting from the deprotonation
pathway in a 90:10 ratio, respectively.
Scheme 3.

G. Cocquet et al. / Tetrahedron Letters 42 (2001) 839–841
841
Scheme 4.
than stoichiometric amounts of photosensitizer. The
best result is observed in the case of the use of b-lapa-
chone which leads very cleanly and efficiently to the
cleavamine skeleton. A further report concerning this
C ꢀC bond cleavage mechanism will be published
10. The 21a-cyano-16a-(methoxycarbonyl)cleavamine 3 was
25
obtained as a crystalline white solid; mp 151°C; [h]
40 (c 1, CHCl ); IR (KBr): 3380, 2950, 2220, 1730 cm ;
=+
D
−
1
3
1
H NMR (300 MHz, CDCl ) l 1.11 (t, J=7.3, 3H,
3
H-18), 2.28 (m, 6H, H-14 , H-19, H-3, H-17), 2.54 (m,
a
1
6
21
1H, H-5), 2.77 (m, 1H, H-3), 2.93 (m, 3H, H-6, H-5), 3.69
shortly.
(
s, 3H, OCH ), 4.15 (s, 1H, H-21 ), 4.81 (d, J=9.1, 1H,
3
b
H-16 ), 5.56 (m, 1H, H-15), 7.13 (m, 1H, H-10), 7.20 (m,
b
1
H, H-11), 7.36 (m, 1H, H-12), 7.54 (m, 1H, H-9), 8.66
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13
(
s, 1H, N -H); C NMR (75.4 MHz, CDCl ) l 11.92
a
3
(
(
(
1
1
1
3
7
1
0
C-18), 25.67 (C-6), 26.09 (C-19), 33.57 (C-14), 37.25
C-17), 38.25 (C-16), 49.29 (C-3), 51.76 (C-5), 52.18
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3
(
(
(
(
(
(
(
(
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