Synthesis of novel allocolchicine analogues with a pyridine c-ring through intermolecular vollhardt diyne-nitrile cyclotrimerization

Article abstract of DOI:10.1055/s-0030-1258512

A short synthesis of new allocolchicinoids with a pyridine C-ring and an oxa-B-ring was developed exploiting a cobalt-catalyzed intermolecular [2+2+2] cycloaddition (diyne-nitrile cyclotrimerization). Starting from readily accessible 3,4,5-trimethoxybenza

Full text of DOI:10.1055/s-0030-1258512

LETTER
2071
Synthesis of Novel Allocolchicine Analogues with a Pyridine C-Ring through
Intermolecular Vollhardt Diyne–Nitrile Cyclotrimerization
New
A
llocolchicin
o
e
A
nalogues
r
w
ith a
P
m
yridine C-Ring an Nicolaus, Hans-Günther Schmalz*
Department für Chemie, Universität zu Köln, Greinstr. 4, 50939 Köln, Germany
Fax +49(221)4703064; E-mail: schmalz@uni-koeln.de
Received 20 May 2010
In addition, it was known that modification of ring B by
Abstract: A short synthesis of new allocolchicinoids with a pyri-
dine C-ring and an oxa-B-ring was developed exploiting a cobalt-
catalyzed intermolecular [2+2+2] cycloaddition (diyne–nitrile cy-
clotrimerization). Starting from readily accessible 3,4,5-
introduction of a 6-oxa-bridge is tolerated in terms of the
basic structure–activity relationships of colchicinoids.2h,5
As a polar functionality at ring C is a required structural
trimethoxybenzaldehyde or 3,4,5-trimethoxyacetophenone, the (ra- feature, pyridines of type 3 also represent potentially ac-
cemic) target compounds were regioselectively obtained in 15–20%
tive compounds. To the best of our knowledge such mol-
overall yield (five steps).
ecules have not yet been described.
Key words: heterocycles, cycloaddition, regioselectivity, micro-
Our retrosynthetic analysis of compounds of type 3 is out-
wave, transition metal catalysis, natural product analogues
lined in Scheme 1. The target molecules would result
from an intermolecular [2+2+2] cycloaddition of a diyne
of type 4 and a nitrile (5) according to the cobalt-catalyzed
The natural product colchicine (1) and its natural relatives
allocolchicine (2a) and N-acetyl colchinol (2b) represent
well-established lead structures in the search for new tu-
bulin-targeting small molecules as potential anticancer
drugs.1,2 In the course of our own research program con-
cerning the synthesis of colchicine3 and novel analogues4
we successfully exploited a [2+2+2]-cycloaddition strate-
gy in the synthesis of bioactive allocolchicinoids contain-
ing a 6-oxa-B-ring substructure.5
methodology introduced by Vollhardt.6 The diyne precur-
sors in turn should be accessible in a straightforward man-
ner starting from alcohols of type 6.
R1
OH
MeO
MeO
MeO
MeO
R1
O
3
R2
+
N
OMe
OMe
6
R3
In this context we became also interested in the synthesis
of related allocolchicinoids of type 3 (Figure 1). These
structures would comprise the pharmacologically essen-
tial trimethoxy substitution pattern at ring A as well as an
aromatic ring C also found in the lead structures 1 and 2.
4
5
Scheme 1 Retrosynthetic analysis of allocolchicinoids of type 3
Following this general concept, the cyclization precursors
of type 4 were prepared as shown in Scheme 2. Starting
from the commercially available ketone 7a or the alde-
hyde 7b the alcohols rac-6a and 6b, respectively, were
synthesized following the reliable three-step protocol we
described earlier.5 These two intermediates were then
converted in good yields into the diynes 4a, 4b and 4c,
through SN2-etherification with a propargylic bromide in
the presence of NaH in THF (Scheme 2).
MeO
MeO
MeO
MeO
NHAc
NHAc
OMe
OMe
O
R
OMe
1 colchicine
2a allocolchicine (R = CO2Me)
2b N-acetyl colchinol (R = OH)
R1
With the intermediates 4a–c in our hands we next focused
on the key cyclotrimerization step. At first, the reaction of
the bisterminal diyne 4a with benzonitrile was investigat-
ed. Unfortunately, under the established conditions we
had used before in [2+2+2]-alkyne cyclotrimerizations5
[20 mol% of CpCo(CO)2 in chlorobenzene under micro-
wave irradiation] the reaction failed. Despite full con-
sumption of the diyne starting material the desired product
3a was only formed in traces according to GC–MS analy-
sis (Table 1, entry 1). Also, variation of the reaction con-
ditions and catalysts [RhCl(PPh3)3 and CoCl2·6H2O–
dppe–Zn]7 did not result in any improvement. However,
much to our delight, when the methyl-substituted diyne
4b was reacted with benzonitrile under similar conditions
MeO
O
MeO
R2
OMe
N
R3
3 R1 = H, Me
R
R
2 = H, Me
3 = FG
Figure 1 Colchicine (1), allocolchicine (2a), N-acetyl colchinol
(2b) and the general structure of new analogues of type 3
SYNLETT 2010, No. 14, pp 2071–2074
Advanced online publication: 22.07.2010
DOI: 10.1055/s-0030-1258512; Art ID: G13210ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
0

2072
N. Nicolaus, H.-G. Schmalz
LETTER
R1
OH
R1
O
MeO
MeO
MeO
MeO
MeO
R1
a
3 steps
ref. 5
O
R2
MeO
OMe
OMe
OMe
7a R1 = Me
6a R1 = Me (61%)
6b R1 = H (67%)
4a R1 = Me; R2 = H (80%)
4b R1 = Me; R2 = Me (89%)
4c R1 = H; R2 = Me (85%)
7b R1 = H
Scheme 2 Synthesis of building blocks 4a–c. Reagents and conditions: (a) 3-bromo-1-propyne or 1-bromo-2-butyne, NaH, THF, 0 °C to r.t.
[20 mol% of CpCo(CO)2 in chlorobenzene under micro- metallacyclopentadiene intermediates as depicted in
wave irradiation 300 W, 150 °C, 15 min] the expected Figure 2.
pyridine product 3b was isolated in 52% yield after puri-
The fact that diyne 4a, in contrast to 4b, did not afford the
fication. Considering the fact that the formation of annu-
expected cycloaddition product (see above) may be ex-
lated seven-membered rings by intramolecular
plained with a higher tendency of terminal alkynes to un-
cycloadditions is often a difficult task,3a we were very sat-
dergo undesired side reactions such as oligomerization
isfied with this result.
through alkyne trimerization.10
Due to the intermolecular character of the reaction, the
formation of two regioisomers has to be considered.8 In
O
O
the case of 3b the isolated product (after chromatography)
proved to be the pure (desired) regioisomer as confirmed
by 2D NMR experiments. However, GC–MS analysis of
the crude reaction mixture indicated the formation of
small amounts of an isomeric product which was assigned
as the other regioisomer 3b¢ (regioisomeric ratio = 90:10).
The preferred formation of 3b is in agreement with earlier
observations.6,9 It can be explained by analyzing the steric
situation of the side-on nitrile complexes (A or B) of the
Me
Me
[Co]
R
[Co]
vs
MeO
MeO
MeO
MeO MeO
N
H
H
MeO
N
R
B
A
Figure 2 Rationalization of the regiochemical outcome of the
[2+2+2] cyclotrimerization. Intermediate A is favored because of
steric repulsion in intermediate B.
Table 1 Synthesis of Target Compounds of Type 3 through Cobalt-Catalyzed [2+2+2] Cycloaddition
R1
R1
R1
MeO
MeO
MeO
MeO
MeO
MeO
O
O
O
CpCo(CO)2 (20 mol%),
5 (2 equiv)
R2
+ R3
N
+
R2
R3
R2
µW (300 W), 150 °C,
15 min, chlorobenzene
OMe
OMe
OMe
4
5
N
N
R3
3
3'
Entry
Diyne
4a
Product
3a
R1
R2
R3
Regioisomeric ratio (3/3¢)a
Yield (%)b
<5%
52%
1
2
Me
Me
Me
Me
Me
Me
H
H
Ph
n.d.
4b
4b
4b
4b
4b
4c
3b
3c
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
90:10
n.d.
3
Me
<5%
<5%
30%
4
3d
3e
CH2CN
n.d.
5
3,4,5-(MeO)3C6H2
2-furyl
≥99:1
75:25c
≥99:1
≥99:1
98:2
6
3f
35%
7
3g
Ph
35%
8
4c
3h
3i
H
pyridin-2-yl
morpholin-1-yl
morpholin-1-yl
20%
9
4b
4c
Me
H
35%
10
3j
≥99:1
27%
a The regioisomeric ratio of the crude product was determined by GC–MS.
b Yield of isolated products after chromatography.
c In this case the regioisomeric ratio was determined by NMR, after purification.
Synlett 2010, No. 14, 2071–2074 © Thieme Stuttgart · New York

LETTER
New Allocolchicine Analogues with a Pyridine C-Ring
2073
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Using 4b as a substrate, we next explored the use of other
nitriles. While the reaction of aliphatic nitriles such as
acetonitrile and malononitrile only led to trace amounts of
the desired products (Table 1, entries 3 and 4) aromatic ni-
triles gave much better results.6b,k Thus, the reaction of 4b
with 3,4,5-trimethoxybenzonitrile and furan-2-carboni-
trile proceeded with at least acceptable yields of 30% (3e)
and 35% (3f), respectively (Table 1, entries 5 and 6). In
the case of 3e the desired regioisomer was formed exclu-
sively, while significant amounts of the second regioiso-
mer (3f¢; regioisomeric ratio = 3:1) were observed in the
reaction of the less bulky furan-2-carbonitrile. With 4c as
the cyclization precursor the reaction with benzonitrile
and 2-cyanopyridine (picolinonitrile) proceeded less effi-
ciently to afford the products 3g (35% yield) and 3h
(20%), respectively, as single regioisomers in both cases
(Table 1, entries 7 and 8). Also the reaction of both 4b and
4c with morpholine-4-carbonitrile (Table 1, entries 9 and
10) gave rise to the desired target compounds 3i and 3j, re-
spectively, with virtually perfect regioselectivity.
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In conclusion, we have developed a short synthetic entry
to a new class of allocolchicinoids (of type 3) character-
ized by a pyridine C-ring and an oxa-B-ring.11 In the key
step, we exploited a microwave-accelerated cobalt-cata-
lyzed [2+2+2] cycloaddition. This way, the tricyclic ring
system (with a seven-membered oxepin ring B) was built
up from a monocyclic diyne precursor in a single opera-
tion with excellent regioselectivity. Thus, we have paved
the way for the synthesis of novel and pharmacologically
potentially interesting colchicine-related compounds in
only five steps (15–20% overall yield) starting from readi-
ly available starting materials.
Acknowledgment
This work was supported by the Volkswagenstiftung.
References and Notes
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(10) Chopade, P. R.; Louie, J. Adv. Synth. Catal. 2006, 348, 2307.
(11) Representative Procedure for the [2+2+2]
Cycloaddition; 9,10,11-Trimethoxy-4,7-dimethyl-2-
phenyl-5,7-dihydrobenzo[5,6]oxepino[3,4-c]-pyridine
(3b): In a flame-dried microwave vessel the diyne 4b (106
mg, 370 mmol) was dissolved in anhydrous chlorobenzene
followed by addition of benzonitrile (76 mg, 740 mmol).
After degassing the solution three times, CpCo(CO)2 (7.3
mL, 73 mmol) was added via syringe. The reaction vessel
was transferred into a microwave reactor (CEM, Discover)
and the mixture was irradiated for 15 min (150 °C, 300 W).
Finally, the solvent was evaporated in vacuo (100 °C) and
the residue was purified by flash chromatography
(cyclohexane–EtOAc = 3:1, Rf 0.5) to afford compound 3b
as a yellowish solid (75 mg, 193 mmol, 52%). IR (ATR):
2927 (m), 2853 (m), 1730 (w), 1590 (s), 1541 (s), 1488 (s),
Baguley, B. C. Nat. Rev. Cancer 2005, 5, 423.
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Synlett 2010, No. 14, 2071–2074 © Thieme Stuttgart · New York

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N. Nicolaus, H.-G. Schmalz
LETTER
1463 (s), 1401 (s), 1310 (s), 1248 (m), 1194 (m), 1158 (m),
1119 (s), 1083 (s), 1054 (s), 920 (w), 835 (w), 773 (m), 694
(m). 1H NMR (300 MHz, CDCl3): d = 1.56 (d, 3J = 6.3 Hz, 3
H), 2.79 (s, 3 H, OMe), 3.71 (s, 3 H), 3.95 (s, 6 H), 3.97 (d,
2J = 11.7 Hz, 1 H), 4.16 (q, 3J = 6.3 Hz, 1 H), 4.83 (d, 2J =
11.7 Hz, 1 H), 6.85 (s, 1 H), 7.36–7.48 (m, 3 H), 7.84 (s, 1
H), 8.04 (d, 3J = 7.2 Hz, 2 H). 13C NMR (300 MHz, CDCl3):
d = 17.8 (q), 22.8 (q), 56.1 (q), 61.1 (q), 61.2 (q), 62.9 (t),
68.6 (d), 104.6 (d), 119.0 (d), 125.0 (s), 126.6 (s), 127.1 (d),
128.7 (d), 133.8 (s), 139.7 (s), 142.4 (s), 146.1 (s), 150.6 (s),
154.1 (s), 155.5 (s), 156.5 (s). HRMS (EI): m/z [M]+ calcd
for C24H25NO4: 391.1783; found: 391.178.
Synlett 2010, No. 14, 2071–2074 © Thieme Stuttgart · New York