Pd-Catalyzed Synthesis of γ-Keto Esters as Key Intermediates for the Synthesis of γ-Hydroxybutenolides

Article abstract of DOI:10.1002/ejoc.201900023

We herein report a robust and safe palladium catalyzed domino-carbonylation/Suzuki–Miyaura cross-coupling reaction of vinyltosylates with arylboronic acids using Mo(CO)₆ as CO-source. The derived γ-keto ester were subsequently cyclized under acidic conditions to obtain γ-hydroxybutenolides, an important structural motif, which occurs in biologically active natural products.

Full text of DOI:10.1002/ejoc.201900023

A Journal of
Accepted Article
Title: Pd-catalyzed Synthesis of γ-Ketoester as Key Intermediates for
the Synthesis of γ-Hydroxybutenolides
Authors: Mathias Schacht, Djawid Mohammadi, and Nina
Schützenmeister
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900023
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900023
Supported by

10.1002/ejoc.201900023
European Journal of Organic Chemistry
COMMUNICATION
Pd-catalyzed Synthesis of γ-Ketoester as Key Intermediates for
the Synthesis of γ-Hydroxybutenolides
Mathias Schacht,[a] Djawid Mohammadi,[a] Nina Schützenmeister*[a]
oxo-Pauson Khand reaction[8] or BF3-catalyzed intermolecular
Abstract: We herein report a robust and safe palladium catalyzed
annulation[9] (scheme 1).
domino-carbonylation/Suzuki-Miyaura cross coupling reaction of
vinyltosylates with arylboronic acids using Mo(CO)6 as CO-source.
The derived γ-ketoester were subsequently cyclized under acidic
conditions to obtain γ-hydroxybutenolides, an important structural
motif, which occurs in biologically active natural products.
Introduction
The structural motif of γ-hydroxybutenolides occurs frequently in
natural products, which exhibit a broad range of biological
activities (figure 1). Terpenoid γ-hydroxybutenolides isolated from
marine sponges such as Manoalide 1[1] Cacospongionolide 2[2]
and Dysidiolide 3[3] demonstrated significant antibiotic, anti-
inflammatory and antitumor activity, while Allantofuranone 4[4] and
Sinularone I 5[5] showed decent antifungal and antifouling
activities. Furthermore, synthetic derivatives such as PD156707 6
by Doherty et. al gained interest as effective endothelin receptor
type A antagonist.[6]
Scheme 1. Synthetic preparation of γ-hydroxybutenolides.[7-9]
Herein, we report a short and robust method for the synthesis of
disubstituted γ-hydroxybutenolides via γ-ketoesters as key
Figure 1. Biologically active γ-hydroxybutenolides 1-6.[1-6]
intermediates obtained by
a
domino-carbonylation/Suzuki-
Miyaura cross coupling of vinyltosylates 17a-c[10] and boronic
acids 18a-e using Mo(CO)6 19 as CO-source to avoid the use of
toxic CO-gas 12. While vinyltosylates have been used in Suzuki-
Due to the plethora of biological activities, several synthetic
approaches of trisubstituted γ-hydroxybutenolides were
established either via an Indium mediated barbier type reaction
with subsequent lactonization/aerobic oxidation[7], intramolecular
Miyaura
cross
coupling
reactions[10]
,
a
domino-
carbonylation/Suzuki-Miyaura cross coupling variant of this
reaction has not been reported to date. Our approach provides a
safe and robust protocol with a broad tolerance of functional
groups making this method attractive for lab-scale chemistry.
[a]
Prof. Dr. Nina Schützenmeister, Mathias Schacht, M.Sc., Djawid
Mohammadi, B.Sc., Department of Chemistry, Institute of
Pharmacy, Universität Hamburg, Bundesstrasse 45, 20146
Hamburg, Germany
Results and Discussion
E-mail: nina.schuetzenmeister@chemie.uni-hamburg.de
https://www.chemie.uni-hamburg.de/pha/schuetzenmeister/
Firstly, we investigated the palladium catalyzed domino-
Supporting information for this article is given via a link at the end of
the document.
carbonylation/Suzuki-Miyaura cross coupling of phenylboronic
acid 18a
and
vinyltosylate 17b[10d]
.
The
domino-
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900023
European Journal of Organic Chemistry
COMMUNICATION
carbonylation/Suzuki-Miyaura of 21b in presence of Pd(TFA)2 and
PPh3 worked in 12% yield (table 1, entry 1), while the use of SIPr
(table 1, entry 2) lead to an increase of 21b. Finally, PCy3 (table
1, entry 3) as ligand proved to be most effective in forming 21b as
major product in 53% yield. In addition, a solvent screening was
performed (table 1, entries 4-7), which showed that aromatic
solvents were the most suitable solvents (entry 3-5) for the
domino-carbonylation/Suzuki-Miyaura cross coupling reaction.
Whereby carrying out the reaction in toluene (table 1, entry 4)
afforded the desired product in a good yield of 66%. By increasing
the equivalents of Mo(CO)6 19 a higher yield of 72% with a
significant reduction of the formation of the undesired Suzuki-
Miyaura cross coupling product was obtained (table 1, entry 8).
Substitution of K2CO3 with Na2CO3, Cs2CO3 and CsF (table 1,
entry 9 – 11) or KF and K3PO4 (table 1, entry 10 and 13) did not
improve the yield of the domino-carbonylation/Suzuki-Miyaura
cross coupling reaction.
Table 2. Scope of the Pd-catalyzed domino-carbonylation/Suzuki-
Miyaura cross coupling with Mo(CO)619 as solid CO surrogate. [a]
Table 1. Optimization of reaction conditions.[a]
entry
ligand
Mo(CO)6 19
base
solvent
Yield[a]
PPh3
1.0 equiv.
K2CO3
anisole
12%
1
2
SIPr
PCy3
PCy3
1.0 equiv.
1.0 equiv.
1.0 equiv.
K2CO3
K2CO3
K2CO3
anisole
anisole
toluene
27%
53%
66%
3
4
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
1.0 equiv.
1.0 equiv.
1.0 equiv.
2.0 equiv.
2.0 equiv.
2.0 equiv.
2.0 equiv.
2.0 equiv.
2.0 equiv.
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Cs2CO3
CsF
xylene
58%
12%
7%
5
6
1,4-
dioxane
THF
7
toluene
toluene
toluene
toluene
toluene
toluene
72%
11%
traces
-.
8
9
10
11
12
13
KF
50%
45%
K3PO4
[a] The reported yields are isolated yields.
Based on the optimized reaction conditions, we investigated the
scope of the domino-carbonylation/Suzuki-Miyaura cross
coupling. Herein, tosylates 17a-c and boronic acids 18a-g were
employed bearing either electron donating or electron
withdrawing groups. As shown in table 2, electron-donating and
electron-withdrawing functionalities on tosylates 17a-c and
boronic acids 18a-g were coupled in moderate to good yields.
Further optimization was carried out using microwave irradiation
affording higher yields for 21d-f and 21p-u.
[a] The reported yields are isolated yields. [b] 1 h reaction time,
microwave irradiation (M.W.).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900023
European Journal of Organic Chemistry
COMMUNICATION
In case of the o-substituted phenyl boronic acid 18g microwave
irradiation was crucial for the domino-carbonylation/Suzuki-
Miyaura cross coupling. Unfortunately, the aliphatic n-
butylboronic acid 18h did not afford the desired domino
products 21v-x.
Table 3. Scope of the one-pot saponification-cyclization reaction of γ-
ketoester 21a-o.[a]
The structure of 21j was unambiguously determined by single-
crystal X-ray crystallography showing the successful synthesis
of the carbonyl compound (figure 2).[11]
Figure 2. X-ray single-crystal structure of 21j. Thermal ellipsoids are shown at
50% probability level. Hydrogen atoms are omitted for clarity.
The domino-carbonylation/Suzuki-Miyaura cross coupling of
vinyltosylates 17 and boronic acids 18 may proceed similar to
earlier proposed mechanisms for carbonylative cross couplings of
aryls.[12] Oxidative addition of Pd0-complex I to vinyltosylates 17
(X-R1) may deliver Pd(II)-complex II. Coordination of carbon
monoxide 19, which is released from Mo(CO)6 19, and insertion
into the R1-Pd-bond may form complex IV. Possible ligand
exchange[13] and subsequent transmetalation between complex V
and activated boronic acid VI may lead to complex VIII. Reductive
elimination releases the carbonylated product 21 under
reproduction of the Pd(0)-species I. The observed by-products of
the reported domino-carbonylation/Suzuki-Miyaura reaction are
products of the competing Suzuki-Miyaura cross coupling, which
are formed in case of a fast transmetallation and a slow formation
of Pd(II)-complex IV (figure 3).
[a] The reported yields are isolated yields.
In solution the hydroxybutenolides 20a-o revealed a dynamic
equilibrium between the cyclized butenolide 22 and the open
chained tautomer 23 (scheme 2). While the characteristic signal
for the hemiketal was not detected 13C-NMR at ~298 °K, low
temperature experiments at ~225 °K in acetone-d6 (see
supporting information) clearly showed at ~106 ppm the signal for
the hemi ketal tautomer.
Figure 3. Proposed reaction mechanism for the domino carbonylation/Suzuki-
Miyaura cross coupling
With γ-ketoesters 21a-o as key intermediates, the last step of the
γ-hydroxybutenolide synthesis was conducted by a one pot
saponification/cyclization sequence yielding the desired γ-
hydroxybutenolides 20a-o in satisfying yields ranging between
54% and 98% (table 3).
Scheme 2. Tautomerization of γ-hydroxybutenolide 22 and 23.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900023
European Journal of Organic Chemistry
COMMUNICATION
Lett. 1999, 9, 2537-2538; M. Takahashi, K. Dodo, Y. Sugimoto, Y. Aoyagi,
Y. Yamada, Y. Hashimoto, R. Shirai, Bioorg. Med. Chem. Lett. 2000, 10,
2571–2574.
Furthermore, the structure of 23d was unambiguously determined
by single-crystal X-ray crystallography (figure 4).[14]
[4]
[5]
a) A. Schüffler, D. Kautz, J. C. Liermann, T. Opatz, T. Anke, J. Antibiot.
2009, 62, 119–121; b) A. Schüffler, J. C. Liermann, T. Opatz, T. Anke,
ChemBioChem 2011, 12, 148–154 c) A. Schüffler, T. Anke, Nat. Prod.
Rep. 2014, 31, 1425–1448.
a) H. Shi, S. Yu, D. Liu, L. van Ofwegen, P. Proksch, W. Lin, Mar. Drugs
2012, 10, 1331–1344; b) G. Chen, H.-F. Wang, Y.-H. Pei, J. Asian Nat.
Prod. Res. 2014, 16, 105–122; c) W. Yuan, S. Cheng, W. Fu, M. Zhao.
X. Li, Y. Cai, J. Dong, K. Huang, K. R. Gustafson, P. Yan, J. Nat. Prod.
2016, 79, 1124–1131.
[6]
a) A. M. Doherty, W. C. Patt, J. J. Edmunds, K. A. Berryman, B. R.
Reisdorph, M. S. Plummer, A. Shahripour, C. Lee, X.-M. Cheng, D. M.
Walker, S. J. Haleen, J. A. Keiser, M. A. Flynn, K. M. Welch, H. Hallak,
D.G. Taylor, E. E: Reynolds, J. Med. Chem. 1995, 38, 1259–1263; b) W.
C. Patt, J. J. Edmunds, J. T. Repine, K. A. Berryman, B. R. Reisdorph,
C. Lee, M. S. Plummer, A. Shahripour, S. J. Haleen, J. A. Keiser, M. A.
Flynn, K. M. Welch, E. E. Reynolds, R. Rubin, B Tobias, H. Hallak, A. M.
Doherty, J. Med. Chem. 1997, 40, 1063–1074.
Figure 4. X-ray single-crystal structure of 23d. Thermal ellipsoids are shown at
50% probability level. Hydrogen atoms are omitted for clarity.
[7]
a) K. H. Kim., H. S. Lee, S. H. Kim, K. Y. Lee, J-E. Lee, J. N. Kim, Bull.
Korean Chem. Soc. 2009, 30, 1012–1020; b) J. W. Lim, K. H. Kim, S. H.
Kim, J. N. Nyoung, Bull. Korean Chem. Soc. 2012, 33, 1781–1784.
H. Miura, K. Takeuchi, T. Shishido, Angew. Chem. Int. Ed. 2016, 55,
278–282; Angew. Chem. 2016, 128, 286–290.
Conclusions
In conclusion, a robust and safe Pd-catalyzed reaction has been
developed for the first described domino-carbonylation/Suzuki-
Miyaura cross coupling of vinyltosylates 17a-c with aryl boronic
acids 18a-g with Mo(CO)6 19 as solid carbon monoxide source.
By avoiding CO gas, this method provides a modular, very robust
and safe protocol for the preparation of varieties of γ-
ketoesters 21a-o. Moreover, application of easily accessible and
stable vinyltosylates 17a-c instead of triflates[15] made this
substrate simpler to handle for carbonylative cross couplings.
These were further applied as key intermediates for the synthesis
[8]
[9]
W. Mao, C. Zhu, Chem. Commun. 2016, 52, 5269–5272.
[10] a) H. Nakatsuji, H. Nishikado, K. Ueno, Y. Tanabe, Org. Lett. 2009, 11,
4258–4261; b) H. Nishikado, H. Nakatsuji, K. Ueno, R. Nagase, Y.
Tanabe, Synlett 2010, 14, 2087–2092; c) Y. Ashida, Y. Sato, T. Suzuki,
K. Ueno. K.-I. Kai, H. Nakatsuji, Y. Tanabe, Chem. Eur. J. 2015, 21,
5934–5945; e) Y. Ashida, A. Honda, Y. Sato, H. Nakatsuji, Y. Tanabe,
ChemistryOpen 2017, 6, 73–89; d) Y. Sato, Y. Ashida, D. Yoshitake, M.
Hoshino, T. Takemoto, Y. Tanabe, Synthesis 2018, 50, 4659–4667.
[11] These data are deposited at The Cambridge Crystallographic Data
Centre and can be obtained via www.ccdc.cam.ac.uk/data_request/cif
(CCDC 1879217) contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre.
of
disubstituted
γ-hydroxybutenolides
20a-o
via
a
saponification/cyclization sequence in moderate to excellent
yields.
[12] a) L. Bartali, A. Guarna, P. Larini, R. E.OG. Occhiato, Eur. J. Org. Chem.
2007, 2152–2163; b) T. Ishiyama, H. Kizaki, T. Hayashi, A. Suzuki, N.
Miyaura, J. Org. Chem. 1998, 63, 4726–4731; c) N. Miyaura, A. Suzuki,
Chem. Rev. 1995, 95, 2457–2483; d) P. Gautam, R. Gupta, B. M.
Bhanage, Eur. J. Org. Chem. 2017, 3431–3437; e) X. Qi, L.B. Jiang, H.-
P. Li, X.-F. Wu, Chem. Eur. J. 2015, 21, 17650–17656; f) A. Pyo, A. Park,
H. M. Jung, S. Lee, Synthesis 2012, 44, 2885–2888.
Acknowledgments
We thank the Fonds der Chemischen Industrie for financial
support, and Isabelle Nevoigt and Claudia Wontorra for technical
assistance in generating the X-ray crystal structures and low
temperature NMR measurements.
[13] A. A. Thomas, S. E. Denmark, Science 2016, 352, 329–332.
[14] These data are deposited at The Cambridge Crystallographic Data
Centre and can be obtained via www.ccdc.cam.ac.uk/data_request/cif
(CCDC 1884165) contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre.
Keywords: catalysis • carbonylation • cross coupling •
vinyltosylates• boronic acids
[15]
a) T. Hayashi, J. Tang, K. Kato, Org. Lett., 1999, 1, 1487–1489; b) P.
Larini, A. Guarna, E.G. Occhiato, Org. Lett. 2006, 8, 781–784.
[1]
a) E. D. de Silva, P. J. Scheuer, Tetrahedron Lett. 1980, 21, 1611–1614;
b) B. C. M. Potts, D. J. Faulkner, R.S. Jacobs, J. Nat. Prod. 1992, 55,
1701–1717; c) A. Randazzo, C. Debitus, L. Minale, P. G. Pastor, M. J.
Alcaraz, M. Payá, L. Gomez-Paloma, J. Nat. Prod. 1998, 61, 571–575;
d) G.-X. Zhou, T. F. Molinski, J. Asian Nat. Prod. Res. 2005, 8, 15–20.
a) S. De Rosa, R. Puliti, A. Crispino, A. De Giulio, C. De Sena, C. Iodice,
C.A. Mattia, Tetrahedron 1995, 51, 10731–10736; b) S. De Rosa, A.
Crispino, A. De Giulio, C. Iodice, R. Benrezzouk, M. C. Terencio, M. L.
Ferrándiz, M. J. Alcaraz, M. Payá, J. Nat. Prod. 1998, 61, 931–935; c) S.
De Rosa, A. Crispino, A. De Giulio, C. Iodice, P. Amodeo, T. Tancredi, J.
Nat. Prod. 1999, 62, 1316–1318.
[2]
[3]
a) S. P. Gunasekera, P. J. McCarthy, M. Kelly-Borges, E. Lobkovsky, J.
Cardy, J. Am. Chem. Soc. 1996, 118, 8759–8760; b) E. Corey, B. E.
Roberts, J. Am. Chem. Soc. 1997, 119, 12425–12431; c) J. L. Blanchard,
D. M. Epstein, M. D. Boisclair, J. Rudolph, K. Pal, Bioorg. Med. Chem.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900023
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Domino Cross Coupling Reactions
Mathias Schacht, Djawid Mohammadi,
Nina Schützenmeister*
Page No. – Page No.
Pd-catalyzed Synthesis of γ-
Ketoester as Key Intermediates for
the Synthesis of γ-
A robust and safe Palladium‐catalyzed domino-carbonylation/Suzuki-Miyaura cross
coupling reaction of vinyl tosylates as coupling partners with arylboronic acids and
Mo(CO)6 as CO source was employed as key step in the synthesis of disubstituted
γ-hydroxybutenolides.
Hydroxybutenolides
This article is protected by copyright. All rights reserved.