Total synthesis of enhygrolide A and analogs

Article abstract of DOI:10.1016/j.tetlet.2020.151786

The total synthesis of enhygrolide A, a γ-alkylidene butenolide natural product which exhibits antibacterial activities, is reported. The synthetic route features several key transformations, including a copper mediated Sonogashira/oxacyclization 5-exo-dig process to generate the alkylidene butenolide system and a Suzuki cross-coupling to introduce the benzylic unit. The methodology employed for this total synthesis represents a sufficiently flexible route to allow the synthesis of numerous analogs of these enhygrolides.

Full text of DOI:10.1016/j.tetlet.2020.151786

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Total Synthesis of Enhygrolide A and analogs
Douha Sghairi, Moufida Romdhani-Younes, Vincent Guilloteau, Julien
Petrignet, Jérôme Thibonnet
PII:
S0040-4039(20)30218-5
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.151786
TETL 151786
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Tetrahedron Letters
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1 February 2020
20 February 2020
25 February 2020
Please cite this article as: Sghairi, D., Romdhani-Younes, M., Guilloteau, V., Petrignet, J., Thibonnet, J., Total
Synthesis of Enhygrolide A and analogs, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.
2020.151786
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Total Synthesis of Enhygrolide A and analogs
Douha Sghairi,a,b Moufida Romdhani-Younes,b Vincent Guilloteau,a Julien Petrignet,*a Jérôme
Thibonnet*a
a
Laboratoire Synthèse et Isolement de Molécules BioActives (SIMBA, EA 7502), Université de
Tours, Faculté des Sciences et Techniques, Parc de Grandmont, 32 Avenue Monge, 37200 Tours,
France.
b
Université de Tunis ElManar, Faculté des Sciences de Tunis, Département de chimie,
Laboratoire de Chimie (Bio)Organique, Structurale et de Polymères (LR99ES14), Campus
Universitaire, 2092 El Manar, Tunisie.
Corresponding author: julien.petrignet@univ-tours.fr
Keywords: alkylidene butenolides, natural product, cross-coupling, total synthesis
Abstract: The total synthesis of enhygrolide A, a -alkylidene butenolide natural product which
exhibits antibacterial activities, is reported. The synthetic route features several key
transformations, including a copper mediated Sonogashira/oxacyclization 5-exo-dig process to
generate the alkylidene butenolide system and a Suzuki cross-coupling to introduce the benzylic
unit. The methodology employed for this total synthesis represents a sufficiently flexible route to
allow the synthesis of numerous analogs of these enhygrolides.
1

Introduction
Based on the literature of the last thirty years, -alkylidene butenolides are important structures
in the areas of heterocyclic chemistry and natural lactones.1 Because this planar oxygenated
heterocycle constitutes the skeleton of many natural products, various strategies have been
developed to prepare these -lactones with wide diversity on the ,  and  positions.2
Representative examples of natural compounds include aspergon isolated from a marine sponge,3
aruncin B extracted from a variety of the plant Aruncuns dioicus,4 maculalactone B and the
nostoclides identified as metabolites of two different cyanobacteria (Fig. 1).5,6
EtO
OH
OH
O
O
O
O
OH
Aruncin B
Aspergon


O

O
O
O
O
O
Nostoclides
(R=Cl, H)
Maculalactone B
Cl
R
HO
Figure 1. Selected natural compounds containing the -alkylidene butenolide core.
Among them, enhygrolide A 1a, a structure close to the nostoclides, was found to inhibit the
growth of the Gram-positive bacterium Arthobacter crystallopoietes with an MIC of 4 µg/mL.
This metabolite was isolated by König and co-workers from the marine myxobacterium
Enhygromyxa salina in 2013.7 Four years later, Boukouvalas and co-workers published the first
synthesis of 1a using tetronic acid as the starting material.8 In this elegant five-step sequence, the
2

,  and  substituents of the lactone ring were respectively introduced via a reductive alkylation
of an aldehyde, an iron-catalyzed cross-coupling reaction with a Grignard reagent, and a
vinylogous aldol condensation with another aldehyde. To the best of our knowledge, no other
synthesis of 1a has been reported in the literature until now. In the current context of bacteria
resistance to antibiotics, new antibacterial compounds such as 1a have a potential interest in this
field of research.9 Herein, we report a five step-synthesis of enhydrolide A 1a and analogs on the
 and  position of the lactone, using 4-methylpent-1-yne 2 as the starting material. This approach
relies on a strategy previously developed in our group, based on a regioselective domino
Sonogashira/oxacyclization 5-exo-dig process2i, 10 followed by a Suzuki-Miyaura cross-coupling,
which has already been used as a key-step for the total synthesis of the nostoclides (Scheme 1).2j
Previous work (Boukouvalas and co-workers, 2017):
Formation of three C-C bonds
cross-coupling
PhCHO
i-BuMgBr
4-MeOPhCHO
OH
HO
Reductive alkylation
O
O
O
O
5 steps
Vinylogous aldol condensation
1a
Enhygrolide A
This work :
Formation of two C-C bonds + one C-O bond
Ph
Ar
Suzuki
ArCH2BF3K
O
O
Domino Sonogashira/oxacyclization
5 steps
Enhygrolide A
+ analogs
Scheme 1. Approaches for the preparation of enhygrolide A 1a.
3

Results and Discussion
First, the -brominated butenolide 5 was prepared according to the sequence described in
Scheme 2. Briefly, the sequence started with commercially available 2 which was transformed into
the corresponding ynoic acid 3 using a stoichiometric amount of a freshly prepared solution of
EtMgBr in THF, followed by bubbling carbon dioxide into the reaction mixture. The
dibromination of 3 was performed in the presence of bromine in methanol according to a reported
method11 and afforded 4 with good yield and excellent stereoselectivity in favor of the (E)- isomer.
Finally, 5 was obtained through a domino reaction involving a regioselective copper(I) promoted
Sonogashira-like cross-coupling between 4 and phenylacetylene, followed by a 5-exo-dig
cyclization. It is noteworthy that the reaction conditions (stoichiometric amount of copper iodide
and diisopropylamine) were modified compared to those described in the original paper (catalytic
amount of copper iodide and potassium carbonate),2i in order to obtain 5 with a satisfactory yield
of 66%. With the aim of preparing analogs in the β-position, we also performed the last two steps
of this sequence starting from commercially available 2-butynoic acid 6, which afford the -
brominated butenolide 7 with an overall yield of 40% (see ESI for details).
4

Br
Br
ii)
i)
iii)
CO2H
O
Br
CO2H
O
85%
66%
70%
Ph
2
3
4
5
Br
ii) then iv)
COOH
O
O
40% overall
Ph
6
7
Scheme 2. Synthesis of 5 and 7. Reagents and conditions: i) EtMgBr in THF (1M, 1 equiv.), THF,
−10 °C to reflux, 1 h then CO2 (gas), −10 °C; ii) Br2 (2 equiv.), MeOH, −10 °C, 40 minutes; iii)
phenylacetylene (2 equiv.), CuI (1 equiv.), iPr2NH (DMF, 80 °C, overnight; iv) phenylacetylene
(2 equiv.), CuI (0.2 equiv.), K2CO3 (2 equiv.), DMF, 50 °C, overnight
We envisaged introducing the benzylic subunit on the α-position through a Suzuki-Miyaura
coupling with various potassium benzyltrifluoroborates 10a-c. Indeed, these stable and easy to
handle boronate salts were found to be better coupling partners than boronic acids.2j
Benzyltrifluoroborates 10a-b were therefore prepared through a two-step procedure starting from
the corresponding benzylic alcohols 8a-b. Classical chlorination of 8a-b in the presence of thionyl
chloride afforded the corresponding benzylic chloride 9a-b (benzyl chloride 9c is commercially
available). These benzylic chlorides were transformed into their corresponding Grignard reagents
and 10a-c were prepared according to a modified literature procedure (Scheme 3).12
5

i)
ii)
OH
Cl
BF3K
R1
R1
R1
48-55%
R2
R2
R2
1
2
8a-b
9a
9b
: 77%
: 85%
10a
10b
10c
(R = OMe, R = H): 48%
1
2
(R = H, R = OMe): 50%
1
2
(R = H, R = H): 55%
Scheme 3. Synthesis of 5 and 7. Reagents and conditions: i) SOCl2 (1.5 equiv.), CH2Cl2, 0 ° to rt.,
overnight ; ii) Mg (1 equiv.), Et2O, reflux, then B(OMe)3 (1.5 equiv.), THF, −78 °C to rt., 2 h, then
KHF2 (6 equiv.), H2O, 0 °C, 1 h.
The Suzuki-Miyaura cross-coupling reaction was performed between 5 or 7 and 10a-c, in
presence of PdCl2(dppf) as the catalyst and cesium carbonate as the base (Table 1). Compounds
8a-e were therefore obtained in average to good yields. Among them, deoxyenhygrolide A 8c, a
natural analog of enhygrolide A,13 was obtained in 66% yield.
R2
10a-c
(3 equiv.)
R3
Br
R3
R1
PdCl2(dppf), 15 mol%
O
Cs2CO3 (3 equiv.)
Toluene/water
80 °C, overnight
O
O
O
Ph
Ph
5
7
or
8a-e
Entry
α-Bromolactone
Benzyltrifluoroborate Product
Yield
6

1
7
10a
44%
OMe
O
O
Ph
Ph
8a
2
3
7
7
10b
10c
47%
66%
OMe
O
O
8b
O
O
Ph
8c
4
5
5
5
10a
10b
41%
32%
OMe
O
O
Ph
8d
OMe
O
O
Ph
8e
Table 1. Suzuki-Miyaura cross-coupling reaction between 5, 7 and 10a-c.
Demethylation of the aromatic methyl ether of compounds 8 was finally performed in the
presence of BBr3 to achieve the total synthesis of enhygrolide A 1a and three others analogs 1b-
d, in excellent to quantitative yields.
7

R2
R3
R1
BBr3 (3 equiv.)
1
CH2Cl2
0°C, 2h
O
O
Ph
8
OH
OH
O
O
O
O
Ph
Ph
1a
1b
, 95%
, 100%
OH
OH
O
O
O
O
Ph
Ph
1c
1d
, 95%
, 98%
Scheme 4. Demethylation of compounds 8.
Conclusion
In this study, we have developed a new route for the preparation of enhygrolide A 1a in five
steps starting from 4-methylpent-1-yne 2 (overall yield = 17%). This synthetic pathway was also
exploited to synthesize three new analogs 1b-d and the natural deoxyenhygrolide A 8c as new
potential antimicrobial agents.
Acknowledgements
We acknowledge Dr. Frédéric Montigny (Tours University) for mass spectra and HRMS and the
French Ministry for Research and Innovation for the financial support.
8

Appendix A: Supplementary data
Supplementary data to this article can be found online at http://
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10

Highlights




A concise total synthesis of a natural -alkylidene butenolide: the enhygrolide A.
Sonogashira/oxacyclization copper(I)-mediated reaction to generate the lactone ring.
Benzylic subunit was introduced via a Suzuki-Miyaura coupling.
Four analogs including the natural deoxyenhygrolide A were synthesized.
11

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