Step-economical synthesis of taxol-like tricycles through a palladium-catalyzed domino reaction

Article abstract of DOI:10.1002/anie.201007751

A quick and easy way to produce tricycles related to the core structure of taxanes has been achieved using a palladium-catalyzed domino reaction (see scheme, Bz=benzoyl). These studies have been performed with function-oriented synthesis in mind. An effic

Full text of DOI:10.1002/anie.201007751

DOI: 10.1002/anie.201007751
Synthetic Methods
Step-Economical Synthesis of Taxol-like Tricycles through a Palladium-
Catalyzed Domino Reaction**
Julien Petrignet, Aicha Boudhar, Gaꢀlle Blond, and Jean Suffert*
The world of natural bioactive products offers a large variety
of structurally complex molecules.[1] Two main factors slow
their study and clinical advancement: 1) the scarcity and
variability of the natural sources and 2) their availability by
synthesis which often requires many steps and therefore time
and effort. In contrast, knowledge of how a natural product
functions could allow for the design of simpler, more
synthetically accessible, and more effective agents. Several
studies on this function-oriented synthesis (FOS) concept[2]
have been published, and have resulted in affording simplified
active drug leads inspired by the more complex natural
products.[3] A key to success in an FOS approach is the design
of a step-economical route to the core scaffold. Typically,
cascade or domino reactions[4] offer efficient ways to quickly
achieve scaffold complexity. Herein, we describe a facile
route to the taxane tricyclic core that is part of a larger
program to ultimately produce simplified agents exhibiting
superior functional activity.
cyclocarbo-palladation and subsequent Stille cross-coupling
and/or intramolecular Heck reaction. Completion of the
domino process with a 8p and/or 6p electrocyclization, leads
to three new rings overall and multiple stereogenic centers on
a densely functionalized framework.[9]
Herein, we describe a new, rapid, and efficient strategy for
accessing the highly functionalized taxane ring system 3 in
two key steps (Scheme 1). With this strategy, the tricyclic
skeleton of taxol (1) was expected to be derived by a
regioselective oxidative cleavage of the most strained double
bond of the diene 4. Based on our method, this racemic
tetracyclic structure would be obtained in a two-step process
through a palladium-catalyzed domino sequence reaction
using propargylic alcohol 5 and subsequent oxidation of the
hydroxy group.
The aim of this work is not to access the natural product
but a core scaffold which could be decorated to achieve
activity comparable or superior to taxol. Since its discovery in
1971 by Wani, Wall, and co-workers, taxol (1; see Scheme 1
for structure) has generated great research interest and
significant therapeutic benefit.[5] The inherent chemical com-
plexity of this polycyclic compound has also stimulated much
synthetic interest, and has led to six total syntheses of taxol
reported to date.[6] Notwithstanding the value of 1 and
taxotere (2) for the treatment of various cancers, develop-
ment of cellular resistance to these agents is a major cause of
failure in therapy. Recent investigations have focused on the
development of new taxanes or taxane modifications that
would overcome this resistance.[7] Step-economical access to
new taxanes, particularly those that would overcome resist-
ance, is thus a goal of great clinical importance.[8] In recent
years, our research group has developed efficient cascade
reactions that provide rapid access to new polycyclic com-
pounds. These processes are initiated through a 4-exo-dig
Scheme 1. General strategy: a) oxidative cleavage; b) 1. 4-exo-dig/6-exo-
trig/6p electrocyclization palladium-catalyzed cascade; 2. oxidation.
Bz=benzoyl.
[*] Dr. J. Petrignet, A. Boudhar, Dr. G. Blond, Dr. J. Suffert
Facultꢀ de Pharmacie, Universitꢀ de Strasbourg
UMR 7200 CNRS/UDS, 74 Route du Rhin, Strasbourg (France)
Fax: (+33)3-6885-4310
E-mail: jean.suffert@pharma.u-strasbg.fr
Homepage: http://www-chimie.u-strasbg.fr/~lsb/
[**] We thank the CNRS and the ANR for financial support to J.P.,
Prof. Paul A. Wender and Prof. Marc L. Snapper for stimulating
discussions, as well as Dr. Lydia Brelot (Service de Cristallographie,
Institut de Chimie de Strasbourg) for the X-ray analysis.
Significantly, polycycle 3 is potentially available in only
eight steps from 2-bromocyclohexenone through this strategy.
In exploring our plan, a range of propargylic alcohols 5 with
various R groups and different alkene geometries (Z or E)
were prepared in one step from alkyne 6, which in turn was
synthesized in four steps from 2-bromocyclohexenone.
Alkyne 6 was treated with nBuLi at À788C, then with
aldehydes 7[10] to afford precursors 5 in 60–90% yield
(Scheme 2). All chiral compounds described in this study
are in racemic form.
Supporting information for this article, including detailed exper-
imental procedures and characterization data, is available on the
WWW under http://dx.doi.org/10.1002/anie.201007751.
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Communications
substituent gave, as a sole adduct, compound 8 with the
cis configuration between the R group and the bridgehead
hydrogen atom, whereas the E olefins gave exclusively
compound trans-8 (Scheme 3).
Scheme 2. Preparation of domino precursors 5. THF=tetrahydrofuran.
As summarized in Table 1, the alkenylbromides 5 were
then treated with [Pd(PPh3)4] (5 mol%) as catalyst in the
presence of diisopropylamine in benzene under microwave
heating to afford in a single process and three steps the
Table 1: Microwave-assisted domino reaction of 5.[a]
Entry
R
Configuration of 5 (Z/E) cis/trans[b] Yield [%][c]
Scheme 3. Proposed mechanism for the palladium-catalyzed domino
sequence. General reaction conditions: a) oxidative addition then
4-exo-dig; b) 6-exo-trig; c) syn dehydropalladation elimination; d) anti
dehydropalladation elimination; e) 6p electrocyclization.
1
2
3
4
5
6
7
8
H
–
10:90
100:0
40:60
0:100
100:0
–
0:100
100:0
30:70
0:100
83:17
70:30
90:10
0:100
100:0
35 (8a)
23 (8b)
65 (8c)
65 (8d)
52 (8d)
62 (8d)
63 (8e)
57 (8 f)
52 (8g)
60 (8g)
SiEt3
SiMe3
Ph
Ph
Ph
4-OMeC6H4 90:10
4-CF3C6H4
CO2Me
The excellent diastereoselectivity obtained in each of
these specific cases can be rationalized by: 1) the stereospe-
cificity of the disrotatory 6p electrocyclization according to
the Woodward–Hoffmann rules,[11] and 2) the total torquose-
lectivity determined by the cis-protected diol 9.[12] However,
one can observe that the diastereoselectivity slightly
decreased in favor of the trans adduct when R is a “Z-
aromatic” substituent (Table 1, entries 6–8). This unusual
selectivity is a possible consequence of an anti-hydride
elimination of the palladium(II) intermediate 9 prior to the
electrocyclization of 10 into 8 (Scheme 3).[13] The anti-hydride
elimination in 9 produced the compound 10b, where the
stereoelectronic interactions between the aromatic moiety
and the cyclohexene ring are minimized. The relative
stereochemistry of these compounds has been fully estab-
lished by using NMR spectroscopy. To control subsequent
chemoselectivity, we oxidized the hydroxy group present in 8
to provide enones 4. Such derivatives were easily prepared
using Dess–Martin periodinane as the oxidant (Scheme 4).
The structure of the cis-4 f derivative was confirmed by X-
ray crystallographic analysis[14] (Figure 1) and the others by
spectroscopic analogy.
100:0
0:100
100:0
9[d]
10
CO2Me
[a] Reaction conditions: [Pd(PPh3)4] (5 mol%), iPr2NH (20 equiv),
benzene, microwave 1608C, 20 min. [b] Determined by 1H NMR spec-
troscopy. [c] Yield of isolated product. [d] Reaction carried out at 1308C.
tetracyclic ring 8 as a mixture of two or four diastereoisomers.
In this domino reaction, the yields of the products varied
mainly owing to the nature of the R olefinic group. By using H
or SiEt3, 8a and 8b were obtained in modest yields (35% and
23%, respectively: Table 1, entries 1 and 2), whereas SiMe3,
CO2Me, or any aryl group afforded the corresponding
polycycles 8c–g in yields between 52% and 65% (Table 1,
entries 3–10). These quantities were sufficient to supply
structure-function studies.
It is especially noteworthy that in this one-flask operation,
three new carbon–carbon bonds, two new stereogenic centers,
and one double bond common to three rings including a four-
membered ring, are formed. These results show also that an
E configuration for the double bond in the starting material,
only slightly decreased the yields of the final polycycles
(compare Table 1, entries 5 and 6 as well as entries 9 and 10).
Furthermore and significantly, the double-bond geometry can
be used to control the relationship between the bridgehead
and pro C2 center. The Z olefins bearing a non-aromatic
It is worth noting that this oxidation did not work as well
with 8c (R = SiMe3; Table 1, entry 3). Regardless of the
oxidant used, a subsequent loss of the silyl group with an
aromatization of the central ring was observed to afford
ketone 11 in 64% yield. Thus, we tried to remove the silyl
group before oxidation to avoid this problem by using
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Angew. Chem. Int. Ed. 2011, 50, 3285 –3289

Table 2: Regioselective oxidative cleavage of 4.[a]
Scheme 4. Oxidation of the allylic alcohol 8.
Entry
R
Oxidative
agents
Solvent
CH2Cl2
Yield
[%][b]
1[c]
2[d]
Ph
Ph
O3/pyridine
RuCl3/oxone/
NaHCO3
RuCl3/NaIO4
RuCl3/NaIO4
19 (3d)
AcOEt/CH3CN/H2O 42 (3d)
3[e]
4[f]
5[g]
Ph
Ph
CCl4/CH3CN/H2O
CCl4/CH3CN/H2O
AcOEt/CH3CN/H2O 40 (3e)
44 (3d)
57 (3d)
4-OMeC6H4 RuCl3/oxone/
NaHCO3
4-OMeC6H4 RuCl3/NaIO4
4-CF3C6H4
CO2Me
6[h]
7[h]
8[h]
CCl4/CH3CN/H2O
CCl4/CH3CN/H2O
CCl4/CH3CN/H2O
44 (3e)
62 (3 f)
50 (3g)
RuCl3/NaIO4
RuCl3/NaIO4
Figure 1. ORTEP drawings of 4 f and 3d with ellipsoids at 50%
probability.
[a] All reactions were carried out at 0 8C, except where noted. [b] Yield of
isolated product. [c] Reaction was carried out at À78 8C, ozone, pyridine
(20 equiv). [d] RuCl3 (3.5 mol%), oxone (4 equiv), NaHCO3 (8 equiv),
AcOEt/CH3CN/H2O (1:1:1), 1 h. [e] RuCl3 (3.5 mol%), NaIO4
(2 equiv),CCl4/CH3CN/H2O (1:1:1), 1 h. [f] RuCl3 (3.5 mol%), NaIO4
(4 equiv), CCl4/CH3CN/H2O (1:1:1), 30 min. [g] RuCl3 (3.5 mol%),
oxone (4 equiv), NaHCO3 (8 equiv), AcOEt/CH3CN/H2O (1:1:1), 1 h.
[h] RuCl3 (3.5 mol%), NaIO4 (4 equiv), CCl4/CH3CN/H2O (1:1:1),
30 min.
classical conditions for desilylation.[15] All of these conditions
afforded, with good yield, the triene 12 by vinylogous
Peterson elimination,[16] which spontaneously aromatized
into 13 (Scheme 5).
Polycycle 4 incorporates the core-ring system of taxanes
with C9 and C15 “protected” as a tetrasubstituted double
bond (Scheme 1 and 4). To remove this protection and reveal
the eight-membered B-ring in the form of 3, we investigated
the regioselective oxidative cleavage of dienes 4. Preliminary
results showed that dienes trans-4 led to complicated mixtures
of products owing to a nonselective cleavage of the double
bonds of starting material. However, in contrast, cis-4 dienes
underwent chemoselective cleavage of the desired double
bond to produce taxane 3. As summarized in Table 2, various
oxidative agents were employed to perform this reaction.[17]
While a classical ozonolysis afforded a low yield of 19% of
3d (Table 2, entry 1), ruthenium tetroxide generated in situ
with an excess amount of oxidant such as sodium periodate or
oxone was able to properly cleave the most strained
tetrasubstituted double bond to afford taxane skeleton 3.
After some optimization of the reaction conditions, taxanes
3d–g were obtained in acceptable yields (up to 62%; Table 2,
entries 3–7). Compound 3d gave crystals suitable for X-ray
crystallographic analysis,[16] thus confirming unambiguously
the structure and configuration of the newly synthesized
taxanes (Figure 1). The excellent regioselectivity of this
reaction could be explained by electronic effects: the
double bond conjugated with the ketone moiety is electron-
deficient and would thus not be expected to undergo a facile
cleavage with electrophilic oxidants.
We expected to obtain the same results with 14 as the
starting material, but were surprised to observe the exclusive
formation of the ten-membered ring polycycle 15 in 54%
yield when a less bulky protective group such as methylene
unit was used for the diol protection instead of the gem-
dimethyl (Scheme 6). Clearly, steric effects also influence the
selectivity that is achieved in this cleavage process. Com-
pound 15 represents the basic structure of brianthein A (16),
which is a novel brianane-type diterpene recently isolated
from the gorgonian Briareum excavatum.[18] Brianthein A is
known for reversing multidrug resistance in human carcinoma
cell lines.[18]
In summary, we have successfully developed a new,
concise, and efficient strategy for accessing the taxane
tricyclic scaffold. These new tricyclic structures are obtained
using two key steps: the first step involves a palladium-
catalyzed domino reaction based on methods previously
Scheme 5. Oxidation of domino product 8. Reagent and conditions:
a) pyridinium chlorochromate (2 equiv), celite, CH2Cl2, RT, 18 h;
b) TBAF (1.1 equiv), THF, À788C, 1 h; c) tBuOK (5 wt%) in DMSO,
H2O, RT, 2 h. DMSO=dimethyl sulfoxide, TBAF=tetra-n-butylammo-
nium fluoride.
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Communications
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Scheme 6. Oxidative cleavage of 14.
developed in our research group. The second step also
involves a novel process in which a regioselective oxidative
cleavage of a novel octasubstituted diene is achieved along
with the production of a diketone. This step-economical route
to highly functionalized taxane scaffolds allows for rapid
access to new analogues and more generally to other
polycycles possessing the bicyclo[5.3.1]undecane core of
taxol. In addition, the basic carbon structure of brianthein A
(16) has also been prepared by a slight modification of the
starting compound. Activity studies and application of this
method for the preparation of other polycyclic systems is
actively being pursued in our laboratory and will be reported
in due course.
Received: December 9, 2010
Published online: March 4, 2011
Keywords: analogues · domino reactions ·
.
function-oriented synthesis · palladium · taxanes
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