Cascade Metathesis Reactions for the Synthesis of Taxane and Isotaxane Derivatives

Article abstract of DOI:10.1002/chem.201600592

Tricyclic isotaxane and taxane derivatives have been synthesized by a very efficient cascade ring-closing dienyne metathesis (RCDEYM) reaction, which formed the A and B rings in one operation. When the alkyne is present at C13 (with no neighboring gem-dimethyl group), the RCEDYM reaction leads to 14,15-isotaxanes 16 a,b and 18 b with the gem-dimethyl group on the A ring. If the alkyne is at the C11 position (and thus flanked by a gem-dimethyl group), RCEDYM reaction only proceeds in the presence of a trisubstituted olefin at C13, which disfavors the competing diene ring-closing metathesis reaction, to give the tricyclic core of Taxol 44.

Full text of DOI:10.1002/chem.201600592

DOI: 10.1002/chem.201600592
Full Paper
&
Synthesis Design
Cascade Metathesis Reactions for the Synthesis of Taxane and
Isotaxane Derivatives
Cong Ma,[b] AurØlien Letort,[a] RØmi Aouzal,[b] Antonia Wilkes,[a] Gourhari Maiti,[b]
Louis J. Farrugia,[a] Louis Ricard,[c] and Jolle Prunet*[a]
Abstract: Tricyclic isotaxane and taxane derivatives have
been synthesized by a very efficient cascade ring-closing di-
enyne metathesis (RCDEYM) reaction, which formed the A
and B rings in one operation. When the alkyne is present at
C13 (with no neighboring gem-dimethyl group), the
RCEDYM reaction leads to 14,15-isotaxanes 16a,b and 18b
with the gem-dimethyl group on the A ring. If the alkyne is
at the C11 position (and thus flanked by a gem-dimethyl
group), RCEDYM reaction only proceeds in the presence of
a trisubstituted olefin at C13, which disfavors the competing
diene ring-closing metathesis reaction, to give the tricyclic
core of Taxol 44.
Introduction
Taxolꢀ (paclitaxel), together with its derivatives Taxotereꢀ (doce-
taxel) and Jevtanaꢀ (cabazitaxel) are the largest selling anti-
cancer drugs of all time, with sales of over three billion USD
per year for Taxotere alone in 2010.[1] Originally indicated for
the treatment of ovarian and breast cancers, they are now
widely prescribed to treat a broad range of malignancies.[2] The
structures of these three compounds only differ in terms of
the functionalization of the amine on the side chain and the
hydroxyl groups at C10 and C7 (Scheme 1). Taxol is currently
being manufactured through plant-cell fermentation by
Phyton Biotech, LLC, a DFB Pharmaceuticals Company for Bris-
tol–Myers Squibb, whilst Taxotere and Jevtana are produced
by semisynthesis from 10-deacetylbaccatin III by Sanofi, which
still requires an expensive extraction process of natural resour-
ces. There have been six total syntheses of Taxol by the groups
of Holton,[3] Nicolaou,[4] Danishefsky,[5] Wender,[6] Mukaiyama[7]
and Kuwajima,[8] as well as three formal syntheses by the
groups of Takahashi,[9] Nakada[10] as well as Sato and Chida,[11]
but they all comprise at least 37 steps.[12] An efficient synthesis
[a] A. Letort, A. Wilkes, Dr. L. J. Farrugia, Dr. J. Prunet
WestCHEM, School of Chemistry, University of Glasgow
Joseph Black Building, University Avenue, Glasgow G12 8QQ (UK)
E-mail: joelle.prunet@glasgow.ac.uk
Scheme 1. Taxol and derivatives; retrosynthesis of the ABC tricycle of Taxol
featuring a ring-closing metathesis (RCM).
[b] C. Ma, R. Aouzal, Dr. G. Maiti
Laboratoire de Synth›se Organique, CNRS UMR 7652
Ecole Polytechnique, DCSO, 91128 Palaiseau (France)
of active taxoid analogues has yet to be achieved, because of
the sterically hindered, complex and highly functionalized
structure of these compounds.
[c] Dr. L. Ricard
Laboratoire de Chimie MolØculaire, CNRS UMR 9168
Ecole Polytechnique, LCM, 91128 Palaiseau (France)
A rapid synthesis of the tricyclic core of Taxol where all of
the functional groups required for activity are present or in
a latent form would facilitate access to a diverse array of novel
taxoids with potential anticancer activity. We report here a syn-
thetic strategy featuring a cascade ring-closing dienyne meta-
thesis (RCDEYM) reaction that allows access to the ABC tricyclic
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201600592.
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
This is an open access article under the terms of the Creative Commons At-
tribution License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited.
Chem. Eur. J. 2016, 22, 6891 – 6898
6891 ꢁ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
ring system of taxanes as well as taxane analogues that pos-
sess a novel skeleton and cannot be prepared by semi-synthe-
sis.[13]
the corresponding known ketone,[22] was submitted to tBuLi
for the Shapiro coupling, only degradation was observed.[23]
We surmised that this was due to the deprotonation at the al-
lylic position, and thus the alkene was masked as a protected
primary alcohol. Enantiopure hydrazone 13[15b] was treated
with aldehyde (Æ)-9 using conditions we had developed pre-
viously.[15b] To our surprise, the reaction only proceeded in 20%
yield. Several additives were screened. Addition of MgBr2 and
ZnCl2 did not lead to any of the desired product, but we ob-
served a dramatic increase in yield when dry CeCl3 was stirred
for 30 min with the vinyllithium reagent derived from hydra-
zone 13 before addition of aldehyde (Æ)-9, and diols 14a,b
were obtained in 85% combined yield after hydrolysis of the
TMS ether. The reason for this difference in reactivity between
the model aldehyde (butyl side chain at C1) and (Æ)-9(2-butyn-
yl side chain at C1) is unclear.[15b] As had been observed previ-
ously for the model aldehydes, this reaction was highly diaste-
reoselective, giving the trans diol compounds[24] 14a and 14b
after hydrolysis of the trimethylsilyl ether. The stereochemistry
of 14a and 14b was assigned by comparing their proton NMR
spectra with those of the corresponding model Shapiro ad-
ducts possessing a butyl side chain at C1.[25] Diols 14a and
14b were then submitted separately to trityl ether hydrolysis,
elimination of the resulting primary alcohol using the Grieco
protocol[26] and protection of the C1-C2 diol as the cyclic car-
bonate ester to furnish the metathesis precursors 15a and
15b in 75% and 65% overall yields for the four steps, respec-
tively. No intermediate purification was required for these
transformations.
Results and Discussion
Our initial retrosynthesis is outlined in Scheme 1. We aimed for
a formal synthesis of Taxol, so we chose the intermediate 4 de-
scribed by Holton during his synthesis of this natural product
as our primary target.[3] The A ring would be closed by a pina-
col coupling between the ketones at C11 and C12 in com-
pound 5, as previously described by Mukaiyama on a similar
substrate.[7] The ketone at C12 would be installed by hydration
of alkyne 6. The eight-membered B ring would be formed by
a ring-closing metathesis (RCM) reaction[14] between the al-
kenes at C10 and C11 in compound 7. This key step was suc-
cessful in our synthesis of model BC bicyclic systems of Taxol
(with no hydroxyl group at C7 and a butyl side chain at C1).[15]
Finally, the metathesis precursor 7 would be assembled by
a Shapiro reaction between hydrazone 8 and aldehyde 9. This
coupling reaction has proved to be very diastereoselective on
similar substrates during our previous approaches to taxoids.[16]
Our synthesis commenced with the preparation of aldehyde
9 (Scheme 2). Commercially available 3-pentyn-1-ol was oxi-
dized with the Dess–Martin periodinane[17] (DMP) and the re-
sulting aldehyde was subjected to a Barbier reaction with
prenyl bromide under the Luche conditions[18] to furnish alco-
hol 10 in excellent yield. Oxidation of alcohol 10 gave the cor-
responding ketone 11, which was submitted to trimethylsilyl
cyanide in the presence of a the tertiary amine 1,4-diazabicy-
clo[2.2.2]octane (DABCO) as a catalyst. The resulting cyanohy-
drin was reduced to the intermediate imine, which was hydro-
lyzed to give the racemic aldehyde (Æ)-9 by exposure to silica
gel. Optically active aldehyde 9 was also prepared in 99% ee in
a similar fashion[19] using a chiral amine base for the cyanation
reaction,[20] but we chose to pursue the synthesis of the meta-
thesis precursors with the racemic aldehyde to widen the array
of taxoids generated, and to study the influence of the stereo-
chemistry of the precursor on the RCM reaction outcome.
Scheme 3. Synthesis of metathesis precursors 15a,b. a) tBuLi, CeCl3, THF,
À788C; b) 1 N aq. HCl, 14a 45% (over 2 steps), 14b 40% (over 2 steps);
c) Amberlyst H-15, MeOH; d) o-NO2C6H4SeCN, PBu3, THF; e) Im2CO, toluene,
110 8C; f) (NH4)6Mo7O24·4H2O, H2O2, H2O, 15a, 75% (over 4 steps), 15b 65%
(over 4 steps). THF=tetrahydrofuran, Im=imidazolyl.
Scheme 2. Synthesis of aldehyde (Æ)-9. a) DMP, CH2Cl2; b) Zn, NH4Cl, prenyl
bromide, 99% (over 2 steps); c) a) DMP, CH2Cl2, 95%; d) TMSCN, DABCO,
CH2Cl2; e) DIBAL-H, CH2Cl2; SiO2 (58% over 2 steps). DMP=Dess–Martin peri-
odinane, TMS=trimethylsilyl, DABCO=1,4-diazabicyclo[2.2.2]octane, DIBAL-
H=diisobutylaluminium hydride.
We first tried out the key RCM reaction on carbonate 15a,
which possesses the opposite configuration at C1 and C2 com-
pared to Taxol. Treatment of this compound with 10 mol% of
the second-generation Grubbs precatalyst in toluene at reflux
for 24 h did not lead to the desired cyclooctene, but gave tri-
cyclic derivative 16a instead (Scheme 4). This product resulted
from an enyne metathesis reaction between the alkene at C10
and the alkyne at C13, furnishing the intermediate bicycle
In order to test the key metathesis reaction, we decided to
use a 7-deoxy C ring as a coupling partner in the Shapiro reac-
tion. It is worth noting that removal of the functional group at
C7 in Taxol did not result in a significant loss of bioactivity.[21]
When hydrazone 12 (Scheme 3), prepared in 76% yield from
Chem. Eur. J. 2016, 22, 6891 – 6898
www.chemeurj.org
6892 ꢁ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
16a’, which further cyclized by a diene metathesis to give 16a
in good yield. This intermediate 16a’ could be isolated as a 1:1
mixture with 16a if only 5 mol% of the precatalyst was used
for the reaction. The first enyne metathesis reaction was not
unexpected;[27] what was more surprising to us was the ease of
formation of the strained tricyclic system in compound 16a.
This 14,15-isotaxane has an unprecedented skeleton, which is
very similar to that of taxane derivatives, except that the C14
and C15 carbons have swapped positions, which places the
gem-dimethyl group in the A-ring alone. In addition, the C2
stereogenic center possesses the undesired configuration for
Taxol.
Figure 1. ORTEP (50% probability) representation of compound 16b.
and C2 on the outcome of the metathesis reactions.[15b] These
isotaxanes possess the undesired configuration at C1. Isotax-
ane 16b was crystalline, and its X-ray crystallographic analy-
sis[28] (Figure 1) established its tricyclic structure and confirmed
the configuration of the carbonate-bearing stereocenters at C1
and C2.
The isotaxanes 16a, 16b and 18b represent a novel class of
Taxol analogues, and could be transformed into potentially
active compounds. Indeed, taxanes such as tasumatrols E, F
and G (Figure 2), isolated from Taxus sumatrana, do not pos-
sess the classical ABC 6,8,6-tricyclic system of Taxol; however,
they exhibit more potent activity than Taxol in vitro against
four human cancer cell lines.[29]
Figure 2. Structures of tasumatrols E, F and G.
Scheme 4. Attempts at metathesis and synthesis of isotaxanes. a) 5 mol%
Grubbs 2, toluene, 110 8C, 48 h, 1:1 16a/16a’ 30%; b) 10 mol% Grubbs 2,
toluene, 110 8C, 24 h, 16a 62%; c) PhLi, THF, À788C, 17a 54%, 17b 70%;
d) 5 mol% Grubbs 2, toluene, 808C, 2 h, 91%; e) 5 mol% Grubbs 2, toluene,
110 8C, 1 h, 57%. For the structure of Grubbs 2, see Table 1.
An easy way to circumvent the unwanted dienyne metathe-
sis cascade is to perform the alkyne hydration before the RCM
step, and this has been achieved in excellent yield (Scheme 5).
Diol 19 was prepared in three steps from the Shapiro adduct
14b in 68% overall yield. Treatment of alkyne 19 with the
Gagosz catalyst[30] in the presence of water did not give the
corresponding ketone but hemiketal 20.[31] Fortunately, com-
pound 20 underwent ring-closing metathesis in 98% yield to
form the BC ring system of Taxol 21. Work is in progress for
the completion of the synthesis of the tricyclic core of Taxol ac-
cording to the retrosynthesis shown in Scheme 1.
In an effort to assess the influence of the nature of the diol
protecting group on the outcome of the metathesis reaction,
which was shown to be crucial for model compounds,[15b] the
benzoate 17a was prepared by addition of phenyllithium to
the carbonate 15a (Scheme 4). Unfortunately, benzoate 17a
did not undergo metathesis when treated with the Grubbs 2
precatalyst, but slowly decomposed.
On the other hand, we also wanted to take advantage of
this very efficient metathesis cascade to synthesize the ABC tri-
cycle of Taxol, and our revised retrosynthesis is shown in
Scheme 6. The 2-ene-1,4-diol unit of compound 4 would be in-
stalled by a TiIII radical-mediated opening of the corresponding
1,3-diepoxide, which can be generated from the 1,3-diene
moiety at C10-C13 of compound 22.[12b] A hydroboration/oxi-
A similar cascade dienyne metathesis reaction was observed
with stereoisomer 15b, but the reaction proceeded under
milder conditions and gave tricycle 16b in 91% yield
(Scheme 4). This time, RCM of benzoate 17b, obtained by phe-
nyllithium addition to 15b, furnished isotaxane 18b in 57%
yield, underscoring the influence of the configuration at C1
Chem. Eur. J. 2016, 22, 6891 – 6898
www.chemeurj.org
6893 ꢁ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
crotylmagnesium chloride to the corresponding Weinreb
amide (compound 41, see Scheme 9 for structure) furnished
a complex mixture of products, so we next turned to the croty-
lation of aldehyde 29. Treatment of this aldehyde with crotyl
magnesium chloride in the presence of aluminum trichloride[33]
led to a 1:1.5 mixture of a and g crotylation products. Fortu-
nately, allyl transfer from 2,3-dimethyl-4-penten-2-ol catalyzed
by tin(II) triflate[34] gave the desired alcohol 30 (as an inconse-
quential 3:1 mixture of E/Z isomers) in 76% yield after 2 days.
Oxidation of 30 with 2-iodoxybenzoic acid (IBX) followed by
homologation of the resulting ketone 31 furnished aldehyde
(Æ)-24[35] in good overall yield.
Scheme 5. Alkyne hydration followed by RCM. a) Amberlyst H-15, MeOH,
98%; b) PPh3, imidazole, I2, 82%; c) NaH, DMF, 84%; d) Ph3PAuNTf2, THF, H2O,
80%; e) 5 mol% Grubbs 2, CH2Cl2, reflux, 1.5 h, 98%. DMF=dimethylforma-
mide, Tf=trifluroromethanesulfonyl.
dation sequence of the C3-C4 olefin would lead to the ketone
at C4.[5] Tricycle 22 would be formed by a metathesis cascade
reaction from dienyne 23, where the alkyne at C11 and the
alkene at C13 have swapped positions compared to those in
compound 15b. In order to direct the metathesis cascade re-
action so it starts with the olefin at C10 and not with the one
at C13, we elected to have a disubstituted olefin at C13, which
would react more slowly with the metathesis precatalysts. It is
important to note that this extra methyl group will not be
present in the metathesis product 22, but will be part of the
propene released after the diene metathesis reaction. Discon-
nection of dienyne 23 through the C2ÀC3 bond reveals the
two precursors aldehyde 24 and hydrazone 25.
Scheme 7. Synthesis of aldehyde (Æ)-24. a) KOH, H2O, MeOH, 93%; b) tBuOK,
DMSO, 758C, 94%; c) LiAlH4, THF; d) (COCl)2, DMSO, Et3N, CH2Cl2, 76% (over
2 steps); e) 2,3-dimethyl-4-penten-2-ol, Sn(OTf)2, CH2Cl2, 76%; f) IBX, DMSO,
THF, 93%; g) TMSCN, ZnI2, CH2Cl2, reflux; g) DIBAL-H, hexane; SiO2 (62% over
2 steps). DMSO=dimethyl sulfoxide, IBX=2-iodoxybenzoic acid.
The dienynes 32a,b and 34a,b were prepared using a similar
reaction sequence to the one used for compounds 15a,b and
17a,b, as described in the preliminary account of our work.[13]
Metathesis reactions of carbonates 32a,b and benzoates 34a,b
with Grubbs 2 precatalyst did not produce tricyclic com-
pounds, but led to the bicycles 33a,b and 35a,b, respectively,
resulting from a simple diene RCM between the olefins at C10
and C13 (Scheme 8).[13]
Compound 33a was crystalline, and its X-ray crystallographic
analysis[36] (Figure 3) confirmed the configuration at C1 and C2
of the metathesis precursors 32a and 34a.
We had assumed that in the case of compounds 15 and 17
(Scheme 4), the initial enyne methathesis (between C10 and
C13) would be favored compared to the alternative diene
metathesis (between C10 and C11) because it would lead to
a more stable tricyclic product after subsequent diene meta-
thesis, but it seems that in all cases the first RCM takes place
with the less hindered unsaturated functional group having no
neighboring gem-dimethyl group. Since this gem-dimethyl
group is part of the Taxol skeleton, it is not possible to relieve
the steric hindrance at the propargylic position in compounds
32 and 34, but another option is to increase the steric hin-
drance of the alkene at C13, so the undesired diene RCM is dis-
favored. We thus embarked on the synthesis of metathesis pre-
cursors bearing a trisubstituted olefin at C13. The synthesis of
Scheme 6. Novel retrosynthesis of taxol featuring a cascade ring-closing di-
enyne metathesis (RCDEYM).
The synthesis of aldehyde 24 in its racemic form was not as
straightforward as the synthesis of the corresponding aldehyde
9. It started with ester 26,[32] obtained by propargylation of
ethyl isobutyrate (Scheme 7). Attempts to isomerize the termi-
nal alkyne of 26 into the internal one with potassium tert-but-
oxide only resulted in degradation products. Fortunately, this
isomerization reaction was successful on the corresponding
acid 27, and acid 28 was obtained in 94% yield. Addition of
Chem. Eur. J. 2016, 22, 6891 – 6898
www.chemeurj.org
6894 ꢁ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
from acid 28 (Scheme 7) was also attempted. To our surprise,
this reaction was very clean and afforded ketone 38 in 95%
yield. In this fashion, aldehyde (Æ)-36[37] was obtained after ho-
mologation of 38 in 7 steps and 66% overall yield from ethyl
isobutyrate.
Scheme 9. Synthesis of aldehyde (Æ)-36. a) 2,3,3-Trimethyl-4-penten-2-ol,
Sn(OTf)2, CH2Cl2, 15–61%; b) IBX, DMSO, THF, 85%; c) TMSCN, ZnI2, CH2Cl2;
d) DIBAL-H, hexane; SiO2 (83% over 2 steps); e) 1,2-ethanedithiol; BF3·OEt2,
CH2Cl2, 75%; f) BuLi, prenyl bromide, THF, À788C, 99%; g) MeI, CaCO3,
MeCN, H2O, 83%; h) Mg, THF, prenyl chloride, 95%.
Compounds 42a,b and 43a,b bearing a trisubstituted olefin
at C13 were synthesized in the same way as compounds 32a,b
and 34a,b as previously described, then subjected to the
Grubbs 2 precatalyst in toluene at reflux (Scheme 10).[13] We
were disappointed to find out that carbonate 42a and ben-
zoate 43a, possessing the undesired configurations at C1 and
C2, furnished the bicyclic compounds 33a and 35a that we
had already observed for the metathesis reactions of 32a and
34a (Scheme 8). Taxol-like benzoate 43b also underwent diene
RCM to produce 35b. However, Taxol-like carbonate 42b fur-
nished compound 44 after RCDEYM, which corresponds to the
tricyclic core of Taxol, along with the undesired bicyclic com-
pound 33b.[13]
Scheme 8. Attempts at metathesis cascade. a) 10 mol% Grubbs 2, toluene,
110 8C, 12 h, 33a 63%, 35a 78%, 33b 68%, 35b 86%.
In order to confirm the structure of the highly strained tricy-
clic product 44, we converted it to the crystalline p-nitroben-
zoate derivative 45 by hydrolysis of the carbonate and acyla-
tion of the resulting secondary alcohol (Scheme 11). X-ray crys-
tallographic analysis of 45[38] not only confirmed the tricyclic
structure, but also established without ambiguity the configu-
rations at C1 and C2 for the Taxol-like series of compounds.
We then set to optimize the yield of the desired tricyclic
compound 44. The 44/33b ratio was the same under different
concentrations ranging from 3”10À3 to 15”10À3 m,[13] so all
metathesis reactions were performed at 5”10À3 m. Toluene at
reflux proved to be a better choice than 1,2-dichloroethane at
reflux (808C) or xylene at reflux (1408C).[13] Various precatalysts
were then screened (Table 1). No reaction was observed with
the less reactive Grubbs 1 precatalyst, so we tested second-
generation ruthenium complexes. The Hoveyda–Grubbs preca-
talyst HG2 gave an improved yield of the desired compound
44 compared to the Grubbs 2 precatalyst (69 vs. 45%), and so
did the Grela complex, which possesses a nitro substituent on
the benzylidene ligand. Pleasingly, the HG2 derivative Zhan-1B,
which possesses a N,N-dimethylsulfonamido group gave the
Figure 3. ORTEP (50% probability) representation of compound 33a.
the aldehyde (Æ)-36 required for their preparation is shown in
Scheme 9. Prenyl transfer to aldehyde 29 from 2,3,3-trimethyl-
4-penten-2-ol was unreliable, with yields of 37 ranging from 15
to 61%. Ketone 38 was then obtained by IBX oxidation. An
umpolung synthesis of 38 was also achieved. Prenylation of di-
thiane 39, prepared from aldehyde 29, furnished 40 in excel-
lent yield. Hydrolysis of the dithiane moiety gave ketone 38.
However, this route was not very convenient on large scale, so
as a last resort prenylation of the Weinreb amide 41 derived
Chem. Eur. J. 2016, 22, 6891 – 6898
www.chemeurj.org
6895 ꢁ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Table 1. Optimization of the formation of 44.[a]
Precatalyst
Yield of 44 [%]
Yield of 33b [%]
Grubbs 1
Grubbs 2
Hoveyda–Grubbs 2
Grela
Zhan-1B
0[b]
45
59
55
0
45
38
45
20
70
[a] Reaction conditions: a) 10 mol% precatalyst, toluene, 5”10À3 m,
110 8C. [b] No reaction was observed.
Scheme 10. Attempts at metathesis cascade and synthesis of the ABC tricy-
cle of taxol. a) 10 mol% Grubbs 2, toluene, 110 8C, 24 h, 33a 79%, 35a 80%,
44 45% and 33b 45%, 35b 90%.
The different ratios observed with the Hoveyda–Grubbs-type
precatalysts cannot be easily rationalized. Indeed, metathesis
of substrate 42b with any precatalyst will result in the same
carbene (Scheme 12). This intermediate should then lead to
the same ratios of 44 and 33b after cyclization, releasing the
same isopropylidene catalyst. The only difference between the
reactions is the ligand released after the first catalytic cycle,
which could recombine with the isopropylidene catalyst to
reform the precatalyst. To probe the influence of the ligand,
a metathesis experiment was run with 10 mol% of the Hovey-
da–Grubbs 2 precatalyst and 300 mol% of the corresponding
ligand, but the observed ratio of 44 and 33b was very similar
to the one observed without any added ligand.
Attempts to convert bicyclic product 33b to the desired tri-
cycle 44 by heating it in toluene at reflux in the presence of
the Grubbs 2 or Zhan-1B precatalyst were unsuccessful, even
Scheme 11. Synthesis and ORTEP (50% probability) representation of p-ni-
trobenzoate 45. a) 2 N aq. NaOH, 1,4-dioxane, 80%; b) p-nitrobenzoyl chlo-
ride, DMAP, Et3N, CH2Cl2, 80%.
best yield (70%) of compound 44. It seems that RCDYEM is fa-
vored with precatalysts possessing high initiation rates.
Scheme 12. Metathesis scheme. Conditions: toluene, reflux.
Chem. Eur. J. 2016, 22, 6891 – 6898
www.chemeurj.org
6896 ꢁ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
under microwave conditions. When 10 mol% of precatalyst
was used, only 33b was recovered, and with 100 mol% of pre-
catalyst decomposition occurred. Ring opening of 33b in the
presence of ethylene was not considered, because it would
lead to a carbene unsubstituted at C13, carbene’ (Scheme 13),
which would undergo diene metathesis preferentially. In an
effort to regenerate the carbene with a trisubstituted olefin at
C13, bicycle 33b was submitted to the above conditions in the
presence of 2-methyl-2-butene, the reagent which Grubbs and
co-workers have employed for the synthesis of trisubstituted
olefins from their terminal homologues by cross metathesis,[39]
but to no avail (Scheme 13). These results seem to indicate
that the formation of compound 33b is not reversible, and
that the metathesis reactions leading to 33b and 44 are under
kinetic control.
Experimental Section
All experimental details can be found in the Supporting Informa-
tion. The material includes compound characterization, crystal
structures of 16b and 33a, and copies of spectra for all new com-
pounds.
Acknowledgements
Financial support for this work was provided by the CNRS, the
Ecole Polytechnique, the University of Glasgow and the BBSRC
(Doctoral Training Allocation BB/D526310/1 for A.W.). We
thank Dr. Brian Millward for a generous donation.
Keywords: cyclooctenes · enyne · metathesis · synthesis
design · taxanes
[1] D. Yvon, Paclitaxel Ranks First Among World’s Anticancer Drugs. Market-
ing Articles [Online], February 28, 2012: http://www.articlesfactory.com/
articles/marketing/paclitaxel-ranks-first-among-worlds-anti-cancer-
drugs.html (accessed 11 June, 2015).
[2] J. A. Yared, K. H. R. Thaczuk, Drug Des. Dev. Ther. 2012, 371–384.
[3] a) R. A. Holton, C. Somoza, H. B. Kim, F. Liang, R. J. Biediger, P. D. Boat-
man, M. Shindo, C. C. Smith, S. Kim, J. Am. Chem. Soc. 1994, 116, 1597–
1598; b) R. A. Holton, H. B. Kim, C. Somoza, F. Liang, R. J. Biediger, P. D.
Boatman, M. Shindo, C. C. Smith, S. Kim, J. Am. Chem. Soc. 1994, 116,
1599–1600.
[4] K. C. Nicolaou, Z. Yang, J. J. Liu, H. Ueno, P. G. Nantermet, R. K. Guy, C. F.
Claiborne, J. Renaud, E. A. Couladouros, K. Paulvannan, E. J. Sorensen,
Nature 1994, 367, 630–634.
[5] J. J. Masters, J. T. Link, L. B. Snyder, W. B. Young, S. J. Danishefsky, Angew.
Chem. Int. Ed. Engl. 1995, 34, 1723–1726; Angew. Chem. 1995, 107,
1886–1888.
[6] a) P. A. Wender, N. F. Badham, S. P. Conway, P. E. Floreancig, T. E. Glass, C.
Gränicher, J. B. Houze, J. Jänichen, D. Lee, D. G. Marquess, P. L. McGrane,
W. Meng, T. P. Mucciaro, M. Mühlebach, M. G. Natchus, H. Paulsen, D. B.
Rawlins, J. Satkofsky, A. J. Shuker, J. C. Sutton, R. E. Taylor, K. Tomooka, J.
Am. Chem. Soc. 1997, 119, 2755–2756; b) P. A. Wender, N. F. Badham,
S. P. Conway, P. E. Floreancig, T. E. Glass, J. B. Houze, N. E. Krauss, D. Lee,
D. G. Marquess, P. L. McGrane, W. Meng, M. G. Natchus, A. J. Shuker, J. C.
Sutton, R. E. Taylor, J. Am. Chem. Soc. 1997, 119, 2757–2758.
[7] T. Mukaiyama, I. Shiina, H. Iwadare, H. Sakoh, Y. Tani, M. Hasegawa, K.
Saitoh, Proc. Jpn. Acad. Sect. B 1997, 73, 95–100.
Scheme 13. Equilibration attempts.
Conclusions
[8] K. Morihira, R. Hara, S. Kawahara, T. Nishimori, N. Nakamura, H. Kusama,
I. Kuwajima, J. Am. Chem. Soc. 1998, 120, 12980–12981.
[9] T. Doi, S. Fuse, S. Miyamoto, K. Nakai, D. Sasuga, T. Takahashi, Chem.
Asian J. 2006, 1, 370–383.
[10] S. Hirai, M. Utsugi, M. Iwamoto, M. Nakada, Chem. Eur. J. 2015, 21, 355–
359.
In summary, we have synthesized Taxol analogues with an un-
precedented skeleton as well as the tricyclic core of Taxol in
a very efficient fashion. The key step in these syntheses is a cas-
cade ring-closing dienyne metathesis (RCDEYM) reaction, lead-
ing to either 14,15-isotaxane tricyclic ring systems or the tricyl-
ic ring system of Taxol in one operation from simple precur-
sors, by judicious choice of the position of the alkyne (C13 for
isotaxanes or C11 for taxanes). Furthermore, in the case of the
taxane synthesis, we have shown that we can direct the course
of the crucial metathesis reaction by adding a temporary
methyl substituent to the olefin at C13, which does not appear
in the structure of the tricycle. Calculations rationalizing the
different outcomes of the metathesis reactions of compounds
42a,b and 43a,b, which strongly depend on the stereochemis-
try and the protecting group of the diol at the C1 and C2 posi-
tions in the metathesis precursors, will be reported in due
course.
[11] a) K. Fukaya, Y. Tanaka, A. C. Sato, K. Kodama, H. Yamazaki, T. Ishimoto, Y.
Nozaki, Y. M. Iwaki, Y. Yuki, K. Umei, T. Sugai, Y. Yamaguchi, A. Watanabe,
T. Oishi, T. Sato, N. Chida, Org. Lett. 2015, 17, 2570–2573; b) K. Fukaya,
K. Kodama, Y. Tanaka, H. Yamazaki, T. Sugai, Y. Yamaguchi, A. Watanabe,
T. Oishi, T. Sato, N. Chida, Org. Lett. 2015, 17, 2574–2577.
[12] For recent studies on taxane synthesis, see: a) M. J. Aldegunde, L. Caste-
do, J. R. Granja, Org. Lett. 2008, 10, 3789–3792; b) M. J. Aldegunde, L.
Castedo, J. R. Granja, Chem. Eur. J. 2009, 15, 4785–4787; c) P. D. Gold-
ring, G. Pattenden, S. L. Rimmington, Tetrahedron 2009, 65, 6670–6681;
d) J. Petrignet, A. Boudhar, G. Blond, J. Suffert, Angew. Chem. Int. Ed.
2011, 50, 3285–3289; Angew. Chem. 2011, 123, 3343–3347; e) A. Men-
doza, Y. Ishihara, P. S. Baran, Nat. Chem. 2011, 4, 21–25; f) N. C. Wilde,
M. Isomura, A. Mendoza, P. S. Baran, J. Am. Chem. Soc. 2014, 136, 4909–
4912; g) R. Hanada, K. Mitachi, K. Tanino, Tetrahedron Lett. 2014, 55,
1097–1099.
[13] For a preliminary account of this work, see: A. Letort, R. Aouzal, C. Ma,
D.-L. Long, J. Prunet, Org. Lett. 2014, 16, 3300–3303.
[14] For a recent review, see: J. Prunet, Eur. J. Org. Chem. 2011, 3634–3647.
Chem. Eur. J. 2016, 22, 6891 – 6898
www.chemeurj.org
6897 ꢁ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
[15] a) S. Schiltz, C. Ma, L. Ricard, J. Prunet, J. Organomet. Chem. 2006, 691,
5438–5443; b) C. Ma, S. Schiltz, X. F. Le Goff, J. Prunet, Chem. Eur. J.
2008, 14, 7314–7323.
[29] Y.-C. Shen, K.-C. Cheng, Y.-C. Li, Y.-B. Cheng, A. T. Khalil, J.-H. Guh, C.-T.
Chien, C.-M. Teng, Y.-T. Chang, J. Nat. Prod. 2005, 68, 90–93.
[30] N. MØzailles, L. Ricard, F. Gagosz, Org. Lett. 2005, 7, 4133–4136.
[31] Gold hydration of benzoate 17b gave an inseparable mixture of the
corresponding ketone and hemiketal in 85% yield, and hydration of
carbonate 15b was unsuccessful.
[32] Y. Yamazaki, Y. Kido, K. Hidaka, H. Yasui, Y. Kiso, F. Yakushiji, Y. Hayashi,
Bioorg. Med. Chem. 2011, 19, 595–602.
[33] Y. H. Kim, B. C. Chung, J. Org. Chem. 1983, 48, 1564–1565.
[34] J. Nokami, K. Yoshizane, H. Matsuura, S.-i. Sumida, J. Am. Chem. Soc.
1998, 120, 6609–6610.
[35] Enantioselective synthesis of aldehyde 24 was not attempted.
[36] CCDC 1405009 contains the supplementary crystallographic data for
this paper. These data are provided free of charge by The Cambridge
Crystallographic Data Centre.
[37] Optically active aldehyde 36 was prepared in 61% ee: A. Letort, PhD
Thesis, University of Glasgow, 2015.
[38] CCDC 976581 contains the supplementary crystallographic data for this
paper. These data are provided free of charge by The Cambridge Crys-
tallographic Data Centre.
[39] A. K. Chatterjee, D. P. Sanders, R. H. Grubbs, Org. Lett. 2002, 4, 1939–
1942.
[16] a) B. Muller, F. Delaloge, M. den Hartog, J.-P. FØrØzou, A. Pancrazi, J.
Prunet, J.-Y. Lallemand, A. Neuman, T. PrangØ, Tetrahedron Lett. 1996,
37, 3313–3316; b) B. Muller, J.-P. FØrØzou, J.-Y. Lallemand, A. Pancrazi, J.
Prunet, T. PrangØ, Tetrahedron Lett. 1998, 39, 279–282; c) D. Bourgeois,
J.-Y. Lallemand, A. Pancrazi, J. Prunet, Synlett 1999, 1555–1558; d) D.
Bourgeois, G. Maiti, A. Pancrazi, J. Prunet, Synlett 2000, 323–326; e) D.
Bourgeois, A. Pancrazi, L. Ricard, J. Prunet, Angew. Chem. Int. Ed. 2000,
39, 725–728; Angew. Chem. 2000, 112, 741–744; f) D. Bourgeois, J. Ma-
huteau, A. Pancrazi, S. P. Nolan, J. Prunet, Synthesis 2000, 869–882.
[17] D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155–4156.
[18] C. PØtrier, J.-L. Luche, J. Org. Chem. 1985, 50, 910–912.
[19] C. Ma, PhD Thesis, Ecole Polytechnique (Palaiseau, France), 2008.
[20] S.-K. Tian, L. Deng, J. Am. Chem. Soc. 2001, 123, 6195–6196.
[21] D. G. I. Kingston, Phytochemistry 2007, 68, 1844–1854.
[22] J. T. Mohr, D. C. Behenna, A. M. Harned, B. M. Stoltz, Angew. Chem. Int.
Ed. 2005, 44, 6924–6927; Angew. Chem. 2005, 117, 7084–7087.
[23] R. Aouzal, PhD Thesis, Ecole Polytechnique (Palaiseau, France), 2010.
[24] Diols 16a and 16b would be trans if the B ring were closed.
[25] See the Supporting Information.
[26] P. A. Grieco, S. Gilman, M. Nishizawa, J. Org. Chem. 1976, 41, 1485–
1486.
[27] S.-H. Kim, N. Bowden, R. H. Grubbs, J. Am. Chem. Soc. 1994, 116, 10801–
10802.
[28] CCDC 1427199 contains the supplementary crystallographic data for
this paper. These data are provided free of charge by The Cambridge
Crystallographic Data Centre.
Received: February 8, 2016
Published online on April 8, 2016
Chem. Eur. J. 2016, 22, 6891 – 6898
www.chemeurj.org
6898 ꢁ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim