Diastereoselective Synthesis of an Advanced Intermediate of Thapsigargin and Other 6,12-Guaianolides Using a RCEYM Strategy

Article abstract of DOI:10.1021/acs.orglett.8b00456

A new and flexible approach toward the synthesis of 6,12-guaianolide anticancer drugs such as trilobolides or thapsigargin has been developed that could be applied to the preparation of analogues with a modified ring system. The synthesis starts from commercial 2-methylcyclopentane-1,3-dione, only relying on diastereoselective reactions for the construction of the stereogenic centers at C1, C3, C6, and C10 and features a high-yielding ring-closing enyne metathesis (RCEYM) step for the formation of the [5,7] bicyclic core.

Full text of DOI:10.1021/acs.orglett.8b00456

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Diastereoselective Synthesis of an Advanced Intermediate of
Thapsigargin and Other 6,12-Guaianolides Using a RCEYM Strategy
Morgan Jouanneau,†,⊥ Karunakar Reddy Bonepally,†,# Alan Jeuken,‡ Aurelien Tap,§,⊗ Regis Guillot,∥
́
́
Janick Ardisson,§ Jean-Pierre Ferezou,*,† and Joelle Prunet*,‡
́
́
̈
†Met
Batiment 410, F-91405 Orsay, France
‡WestCHEM, School of Chemistry, University of Glasgow, Joseph Black Building, University Avenue, Glasgow G12 8QQ, U.K.
§Faculte
de Pharmacie (CNRS UMR 8638), Universite Paris Descartes, 4 avenue de l’Observatoire, F-75270 Paris 06, France
∥Institut de Chimie Molec
ulaire et des Materiaux d’Orsay (CNRS UMR 8182), Universite Paris-Sud, Universite Paris-Saclay,
Batiment 420, F-91405 Orsay, France
́
hodologie, Synthes
̀
e et Molec
́
ules Ther
́
apeutiques, ICMMO (CNRS UMR 8182), Universite
́
́
Paris-Sud, Universite Paris-Saclay,
̂
́
́
́
́
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́
̂
S
* Supporting Information
ABSTRACT: A new and flexible approach toward the synthesis of 6,12-guaianolide anticancer drugs such as trilobolides or
thapsigargin has been developed that could be applied to the preparation of analogues with a modified ring system. The synthesis
starts from commercial 2-methylcyclopentane-1,3-dione, only relying on diastereoselective reactions for the construction of the
stereogenic centers at C1, C3, C6, and C10 and features a high-yielding ring-closing enyne metathesis (RCEYM) step for the
formation of the [5,7] bicyclic core.
ancer is still a major health issue, and solutions for all
facets of this problem include the continuous search for
To date, three total syntheses of this class of guaianolides
have been reported, with more than a 13-year gap between the
first synthesis and the two most recent ones. The pioneering
work of Ley’s group in 2003 was based on a Favorskii
rearrangement of a carvone-derived cyclohexanone precursor
for the elaboration of the polyhydroazulene scaffold of the
molecule, followed by extensive functional transformations.7
Two additional total syntheses appeared very recently.8
Baran’s group published a concise route featuring a classical
photochemical rearrangement of a santonin-type intermediate
obtained from dihydrocarvone. Subsequent adequate function-
alizations led to 1a.8a Evans and co-workers assembled the
bicylic core of thapsigargin in a very efficient fashion using an
intramolecular pinacol coupling.8b Other partial approaches of
the polyhydroazulene skeleton of these molecules have been
also published.9
C
new active molecules. Among them, thapsigargin 1a (Tg,
Figure 1)1 emerged during the past decade as a highly
Figure 1. Thapsigargin and trilobolides.
In our laboratories, due to the high pharmacological potential
of thapsigargin and the continuing scientific impetus to
understand more fully and/or modulate the interaction of
this family of molecules with therapeutically significant SERCA
targets, it was decided that we would develop synthetic
strategies able to deliver “upon request” the natural molecules
as well as unnatural skeleton-modified analogues. To be
promising anticancer lead compound, and prodrug derivatives
of 1a are currently in phase II clinical trials directed toward a
variety of cancers such as prostate cancer or hepatocellular
carcinoma, as well as neovascular tissues in a broad range of
other cancer cells.2 This plant secondary metabolite, as well as
its structurally closely related 2-deoxy natural congeners
trilobolides 1b,c3 or thapsivillosin F 1d (not shown),4 belong
to the class of the 6,12-guaianolide sesquiterpenes5 known for
their prominent endo/sarcoplasmic calcium ATPase (SERCA)
inhibitor activities.6
Received: February 7, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00456
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Letter
practical, the developed routes have to require only incremental
modifications from the initially developed synthetic route.
In an integrated program devoted to the synthesis of the
thapsigargin family 1 itself as well as targeted analogues
possessing a modified framework, an allene−yne Pauson−
Khand double-annulation reaction was employed for an
asymmetric synthesis of a complex system related to
thapsigargin.10 More recently, application of this approach for
the synthesis of functionalized guaiane-type skeletons as well as
several heterobicyclo[5.3.0] frameworks has been reported.11
A second synthetic approach is also currently being
developed in our laboratories, where the functionalized
octahydroazulene precursor of thapsigargin is designed to be
built from a conveniently ramified cyclopentenol precursor of
type 4 (n1 = 1) using a ring-closing enyne metathesis
(RCEYM) as the key step12 to form bicycle 3, according to
the strategy depicted in Scheme 1.13 Besides synthesizing Tg-
on a Michael/Wittig one-pot sequence for the construction of
the required disubstituted cyclopentene precursor 10, as
summarized in Scheme 2.18 Although large scale one-pot
Scheme 2. Previous Michael−Wittig Approach18
condensation of di-tert-butyl acetylenedicarboxylate 8 and 2,3-
butanedione (large excess) led to di-tert-butyl ester 9 in 63%
after optimization, we were nevertheless unable to obtain the
disubstituted cyclopentenol ketoester 10 required for con-
tinuation of the synthesis in an acceptable yield.
Our first objective was the synthesis of the ( )-cis hydroxy
methyl ketone 5 from commercial diketone 7 (Scheme 3).
Scheme 1. Retrosynthesis for Tg Family of Guaianolides and
Analogues
Scheme 3. Synthesis of Methyl Ketone 5
Condensation of Mander’s reagent on the extended enolate
derived from enol ether 11 using LiHMDS yielded 6 in 71%
yield; this yield could be improved to 86% by using methyl
chloroformate. No O-acylation was observed with the latter
reagent, presumably due to the hard nature of the enolate.
Compound 6 was subsequently submitted to the conjugate
addition of cyanide using the Nagata reagent.
The resulting ketone 12 was reduced with sodium
borohydride at −78 °C, giving a 4:1 inseparable mixture of
1,3-cis/1,3-trans alcohols 13.14 Further transformation into
Weinreb amide 1418 gave, after chromatography, the required
pure 1,3-cis isomer, which was converted into 1,3-cis methyl
ketone 5 upon addition of MeMgBr. This ketone was prone to
epimerization in contact with silica gel, so it was carried on to
the next step without purification.
With this ketone in hand, we next addressed the two
important stereoselective addition reactions to set up the
stereogenic centers at C6 and C10. For the allylation of methyl
ketone 5,19 we hypothesized that a bridge chelate between the
secondary hydroxyl and the methyl ketone would promote a
stereoselective addition at C10 (Scheme 4).20 A preliminary
study for this step was carried out using the methyl ester 10
synthesized in the previous approach. First attempts with 2
equiv of allylmagnesium bromide led to a complex mixture of
compounds, so we turned to milder nucleophiles. After some
type guaianolides with the natural 5−7−5 core, this project will
also involve access to homologated analogues 2 characterized
by 5−8−5, 5−7−6, or even 5−8−6 modified frameworks. It is
interesting to note that, for access to these analogues, the
RCEYM synthetic route described in the present paper and the
previously described allene−yne Pauson−Khand reaction are
quite complementary. For example, in the RCEYM case, 5−8−
5 tricyclic analogues could be directly accessible using the
homologated enyne 4 (n1 = 2) as a precursor.
As a key strategic sequence for the viability of the approach
in the case of thapsigargin and other guaianolides, two
successive diastereoselective additions, an allylation at C1014
and then an alkynylation reaction at C6, are envisioned to
prepare 4 (n1 = 1) from the cyanocyclopentenyl methyl ketone
5. For the construction of the latter, we planned a sequence
similar to that used by Ciufolini et al. for the synthesis of
sordarin,15 i.e., sequential condensation of Mander’s cyano-
formate16 for the carboxylation of 2-methyl-1,3-cyclopentane-
dione 7, and cyanation with Nagata’s diethylaluminum
cyanide17 to obtain 5. We report here the results of our efforts
for this project.
It is worth noting that the choice of the above route to 4 was
dictated by the low overall yield of the preceding route based
B
DOI: 10.1021/acs.orglett.8b00456
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Scheme 4. Stereoselective Allylation Reactions
Scheme 5. Synthesis of the Precursors of RCEYM
efforts, the best result was obtained by adding a large excess of
allylzinc chloride formed in situ by adding a stoichiometric
amount of dry ZnCl2 to a solution of allylmagnesium bromide.
Under these conditions, a single adduct was formed in good
yield, and X-ray analysis of the derived p-nitrobenzoate showed
that it was the desired diastereomer 15 (Scheme 4). This result
is in agreement with a remote chelate TS, as depicted.
Unfortunately, when these conditions were applied to the
corresponding cyanomethyl ketone 5, an almost 1:1 ratio of
isomers was obtained. When the allylation reaction was
performed at room temperature, the ratio increased to 80:20.
This trend could reflect temperature-dependent aggregation
forms of the mixed magnesium−zinc metal reacting species that
can interact with the cyano-containing substrate21a or could be
due to the reversibility of the addition of allylzinc reagent to
ketones.21b However, the best result was obtained with the
corresponding allylcerium derivative, and alcohol 16 was
obtained in 85:15 dr and 87% yield (over two steps) from
Weinreb amide 14.
The diastereomers were successfully separated by careful
chromatography after protection of the secondary hydroxyl at
C3 by a TBS group (Scheme 5). Further protection of the
tertiary OH at C10 as a TES ether, followed by reduction of the
cyano function by DIBAL-H at −78 °C, afforded aldehyde 17,
which was then submitted to the alkynylation reaction with
methyl propiolate.22 This reaction proved to be somewhat
capricious and was first carried out using an external trap of the
generated alkoxide with an electrophile to get a good yield.
Quench with TMSCl gave the persilylated ether 18 in
quantitative yield, while the acetylated analogue 19 was
obtained in 74% yield. Direct hydrolysis of the condensation
reaction mixture failed to give the corresponding alcohol 20 in
reproducible yields. However, when this reaction was carried
out in the presence of dry CeCl3,23 the free alcohol 20 was
isolated in 81% yield. One explanation for the improvement in
the presence of CeCl3 could be the formation of a more stable
cerium alkoxide species, allowing a milder hydrolysis process
(complexation of this alkoxide with the oxygen of the C10 TES
ether is possible).24 Under all conditions tested, a single
diastereomer was obtained at C6.
Unfortunately, all attempts to obtain a crystalline derivative
failed, either at this level or after the RCEYM annelation was
performed. Since NMR experiments were also inconclusive,
even on the bicyclic adducts, we decided to prepare the epimer
of 20 at C-6 to compare the data in both series. It is worth
noting that from a synthetic point of view, the use of an epimer
of natural Tg at C-6 as an intermediate could prove useful if the
formation of the γ-lactone ring was performed by a Mitsunobu
reaction.25 Therefore, transformation of 20 into epi-21 was
carried out (Scheme 5), at first with p-NO2-benzoic acid, but
the yield was very low due to the formation of secondary
products resulting from, inter alia, SN2′ reactions at C4.
Conducting the reaction in the presence of benzoic acid in
toluene resulted in a clean reaction, giving epi-22 as a single
adduct.
The excellent diastereoselectivity observed for the alkynyla-
tion reaction is likely to result from (1) an approach of the
nucleophile from the less hindered convex face of 17 and (2) a
reacting conformation of the aldehyde being s-cis, as depicted in
Figure 2. This conformation, and not the more stable s-trans
one, is thought to be the reactive one due to a more favorable
TS for the carbonyl addition reaction in a manner similar to
that calculated from FMO calculations by Houk et al. in the
Figure 2. Chem3D minimizations (MM2) for the s-cis and s-trans
aldehyde 17.
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Letter
case of the addition of cyanide to acrolein.26 The alkynylation
reaction of 17 would therefore probably proceed in accordance
with the Curtin−Hammett principle. However, a more in-depth
study of the two possible transitions states is required to clarify
this question.
We next turned to the ring-closing enyne metathesis
reaction.27 A first set of assays established that the best
precatalyst for the annelation reaction was Grubbs II, while the
reaction was maintained under an ethylene atmosphere.28
Under these conditions at 80 °C in toluene, the protected
enynes 18 and 19 cyclized cleanly to give the desired
octahydroazulene adducts 23 and 24 in quantitative yield
(Scheme 6). These adducts correspond to the exo adducts
Experimental procedures, characterization data, and
NMR spectra (PDF)
Accession Codes
CCDC 1820695 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: jpferezou@gmail.com.
*E-mail: joelle.prunet@glasgow.ac.uk.
Scheme 6. RCEYM Annelation
ORCID
Joelle Prunet: 0000-0002-9075-971X
̈
Present Addresses
⊥(M.J.) Sygnature Discovery Limited, Biocity, Pennyfoot
Street, Nottingham NG1 1GF, UK
#(K.R.B.) Department of Chemistry, McGill University, 801
Sherbrooke Street West, Montrea
⊗(A.T.) Oncodesign, Centre de Recherches Franco
25−27 avenue du Quebec, 91140 Villebon sur Yvette, France
Notes
́
l, QC H3A 0B8, Canada.
̧
is Hyafil,
́
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support for this work was provided by the CNRS, the
■
Universite
́
Paris-Sud Orsay, the University of Glasgow, and the
French ANR (Doctoral Fellowships ANR Thaser 2010 for M.J.
and A.T., Postdoctoral fellowship for K.R.B.).
expected for a seven-membered ring formation by RCEYM.
The unprotected precursor 20 also cyclized under the same
conditions, although the reaction was not as clean, giving
variable nonidentified minor compounds in addition to the
expected adduct 25 (68% yield).
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Ye, Q.-D.; Gong, J.-X.; Meng, F. K.; You, L.; Liu, Y.-F.; Zhao, M.-Z.;
Xu, L.-M.; Shan, Z.-H.; Shi, Y.; Tang, Y.-F.; Chen, J.-H.; Yang, Z.
Angew. Chem., Int. Ed. 2011, 50, 7373−7377.
(23) (a) Imamoto, T.; Kusumoto, T.; Tawarayama, Y.; Sugiura, Y.;
Hatanaka, Y.; Yokoyama, M. J. Org. Chem. 1984, 49, 3904−3912. (b)
E
DOI: 10.1021/acs.orglett.8b00456
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