Modified Julia Olefination on Anhydrides: Extension and Limitations. Application to the Synthesis of Maculalactone B

Article abstract of DOI:10.1021/acs.orglett.6b02160

The preparation of exo-enol esters from cyclic anhydrides is reported using a modified Julia olefination. The reaction is highly stereoselective. The Smiles rearrangement can be performed in a one-pot process, giving a straightforward access to exo-enol lactones. Furthermore, the reaction was extended to semistabilized sulfones, and this methodology was applied to the synthesis of maculalactone B.

Full text of DOI:10.1021/acs.orglett.6b02160

Letter
pubs.acs.org/OrgLett
Modified Julia Olefination on Anhydrides: Extension and Limitations.
Application to the Synthesis of Maculalactone B
Nicolas Dussart, Huu Vinh Trinh, and David Gueyrard*
́ ́
Universite de Lyon, ICBMS, UMR 5246 - CNRS, Bat. 308 - Curien (CPE Lyon), Universite Claude Bernard Lyon 1, 43 Bd du 11
Novembre 1918, F-69622 Villeurbanne, France
S
* Supporting Information
ABSTRACT: The preparation of exo-enol esters from cyclic anhydrides is reported using a modified Julia olefination. The
reaction is highly stereoselective. The Smiles rearrangement can be performed in a one-pot process, giving a straightforward
access to exo-enol lactones. Furthermore, the reaction was extended to semistabilized sulfones, and this methodology was applied
to the synthesis of maculalactone B.
exo-Enol esters are esters having an exocyclic carbon−carbon
double bond at the α position to the oxygen. Benzalphthalides,
exo-enol lactones structurally related to phthalic anhydride, have
shown anxiolytic effects.1 More recently, some exo-enol ester
butenolides have been identified as antioxidants.2 Many natural
products contain these structures such as freelingyne3 extracted
from Eremophila freelingii, the antibiotic tetrenolin4 isolated
from Micropolyspora, some tetronic acids5 from sponges, and
natural alkylidene phthalides6 extracted from celery (Figure 1).
Halo-enol lactones are also structurally similar and could act as
inhibitors of α-chymotrypsin.7 exo-Enol esters can also be used
as key intermediates in total synthesis.8
Our goal has been to extend the modified Julia reaction to
unsaturated and saturated cyclic anhydrides and a variety of
heteroaryl sulfones in order to show the functional group
tolerance of our method and allow access to many butenolides
and exo-enol esters inaccessible by other methods (Scheme 1).
Scheme 1. Modified Julia Olefination on Anhydrides
Initially developed on aldehydes and ketones,15 the modified
Julia reaction has been extended to carboxylic acid derivatives
such as lactones, Boc-protected lactams, and imides by our
group, providing access to di-, tri-, and tetrasubstitued exo-
glycals,16 mono- and difluoro exo-glycals,17 exo-enamides,18 and
bicyclic lactam enamides.19
We first started our study by finding the optimal conditions
for this reaction. We chose the commercially available, UV-vis
phthalic anhydride 1 as the initial substrate. The n-
propylphenyltetrazolyl sulfone 2 was prepared from inexpensive
and odorless mercaptophenyltetrazole through a two-step
process involving S-alkylation and S-oxidation.
Figure 1. Natural products or biologically active compounds containing
exo-enol esters.
Our previous studies on the modified Julia reaction have
shown that the addition of sulfone to the carbonyl derivative
should generally be performed at −78 °C in THF in the
presence of an excess of BF3·Et2O and LiHMDS (2 equiv).
These conditions were applied to phthalic anhydride and n-
Many methods have been developed to obtain exo-enol esters
from anhydrides, such as Wittig reactions9 or Gabriel10 and
Knoevenagel11 type condensations, but they are limited to
stabilized nucleophiles. The use of Grignard,12 organolithium,13
or Tebbe14 reagents provides access to alkyl exo-enol esters, but
only for the introduction of simple alkyl chains.
Received: July 22, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02160
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Letter
propylphenyltetrazolylsulfone by varying the number of
equivalents of each reagent (Table 1).
the stereoselectivity according to the nature of the hetero-
aromatic group is described in Table 2.
Table 1. Optimization
Table 2. Influence of the Heterocycle on the Stereoselectivity
anhydride
(equiv)
sulfone
(equiv)
BF3·Et2O
(equiv)
LiHMDS
(equiv)
yield
(%)
entry
1
2
3
4
5
6
7
2
1
2
2
2
2
2
0
2
2
2
2
2
2
2
1
90
85
83
78
71
64
7
1.2
1
1
1
1
1.2
1.5
1
1
1.2
1.2
a
Second step: microwaves (toluene, 2 h, 140 °C).
1
In the initial procedure,16 the second step (Smiles rearrange-
ment and elimination) was performed with 3 equiv of DBU.
This procedure only gave traces of product in this case. So,
instead of using DBU for the elimination step, we found that the
Smiles rearrangement could occur by concentration over silica
gel following treatment with acetic acid in a one-pot process.
Thereby, we avoid an aqueous treatment and the second step
using this procedure.
No inversion of selectivity was observed, and we only saw a
decrease of the E/Z ratio and the yield in all cases compared to
entry 1. The elimination step over silica gel is more difficult in
the case of benzothiazolylsulfone 4 (entry 2) and requires
heating of the solution before concentration. In the case of the
pyridinyl sulfone (entry 3), the second step was performed
under microwave irradiation according to our previous
studies.17c
Then we extended this reaction to a range of sulfones to show
the chemical functional group tolerance of our modified Julia
procedure. Using the procedure described above, we prepared
sulfones bearing functionalized groups on the R chain such as
terminal alkene, nitrile, amine, and different ethers. These
sulfones were engaged in modified Julia reactions to give the
phthalide derivatives from phthalic anhydride (Scheme 2).
Alkyl phthalides 3, 7, and 11 were obtained in good yields.
Sulfones bearing the terminal alkene also give the corresponding
compound 8 in high yield. The methylene compound 9 was
obtained in small quantities, as purification by chromatography
seems to be a problem in that case. Using sulfones bearing a
protected alcohol, the desired product was isolated in good
yields (compounds 12 and 14) except for compound 13, which
is difficult to purify. The cyclopropyl phthalide 10 was obtained
from the bromo sulfone through a multistep process via the
cyclopropyl sulfone formed in situ. For compound 16, the poor
yield could be explained by the presence of the cyano group
which can act as an electrophile during the addition step. The
product 15 containing a morpholine moiety was isolated in
good yield. Lastly, we studied the specific situation of the
semistabilized sulfone 18 (Scheme 3). While no reactivity was
previously observed between benzothiazolyl-semistabilized
sulfones and lactones, we were surprised to observe the
formation of the compound 17 in moderate yield as the E
isomer. In order to increase the yield and modify the selectivity,
we concentrated our efforts on the use of pyridinyl sulfones.
Thus, we recently showed that in the particular case of less
reactive sulfone such as α-difluorinated sulfone the use of the
pyridinyl moiety was necessary.17c This observation was
confirmed by our results. From sulfone 19, compound 17 was
prepared in 43% yield with the Z isomer as the major product
(3/7 E/Z mixture).
We found that an excess of anhydride gave better yields, while
an excess of sulfone lowering the yields and leading to difficult
purifications (see entries 1 and 2 vs 4 and 5, Table 1).
We next tried to vary experimental conditions such as the
presence of the activating agent (BF3·Et2O) or number of
equivalents of LiHMDS, but no improvement of yield was
observed (entries 6 and 7, Table 1). The carbonyl groups of an
anhydride are expected to be electrophilic enough to permit the
addition of a lithiated sulfone, yet the presence of an activating
agent such as BF3·Et2O gives better yields (entry 2 vs 6, Table
1). An excess of LiHMDS is necessary during the addition step
(entry 2 vs 7).
Although the 1:1 anhydride/sulfone ratio gave a good yield,
we chose the conditions of entry 2 for the rest of the study in
order to get better yields. Under these conditions, we obtain a
partially separable 90:10 (E/Z) mixture of phthalide 3. The
isomers have been characterized by NOE experiments (Figure
2).
It is known that the nature of the heteroaromatic moiety in
the modified Julia reaction can modify the E/Z selectivity. We
therefore prepared four sulfones with different heteroaryl groups
from the corresponding mercapto−heteroaromatic compounds
following the same procedures described above. The study of
Figure 2. NOE effect on compound 3Z and 3E.
B
DOI: 10.1021/acs.orglett.6b02160
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At room temperature in dichloromethane, compound 12
leads to traces of product 21 (8%). Starting material 12 and the
THP-deprotected compound (32%) are recovered after the
reaction.
Scheme 2. Scope of the Sulfones
We then chose the isopropyl sulfone 22 to evaluate the scope
of the reaction with anhydrides and to avoid potential E/Z
isomers. The results are presented in Scheme 5.
Scheme 5. Scope of Anhydrides
Scheme 3. Extension to Semistabilized Sulfones
The desired products 7, 23, 24, and 27 were obtained in good
yields from the corresponding anhydrides. The olefination of the
norbornene anhydride was performed with a 12% yield
(compound 25). This result shows that the reaction works
with a saturated anhydride, which is a less favorable case. This
preliminary result is encouraging, and further studies could
extend the reaction to additional saturated anhydrides.
Concerning the limit of the methodology, the reaction on
maleic, succinic, and glutaric anhydride did not give the desired
product, probably due to the potential Michael addition or the
presence of acidic protons on the substrate.
In order to evaluate the regioselectivity of the reaction, the
modified Julia olefination was performed on 3- and 4-
nitrophthalic anhydride. In both cases, the sulfone reacted
preferentially on the less hindered carbonyl group. Thus, the
reaction seems to be more sensitive to steric hindrance than to
electronic effects.
The reaction between tetrahydropyran (THP)−ether−
sulfone 20 and phthalic anhydride gave the corresponding
phthalide 12. A catalytic amount of p-toluenesulfonic acid allows
the in situ deprotection of the THP and the intramolecular
cyclization of the resulting primary alcohol on the oxonium
intermediate to form the spiroketal 21 in 77% yield. By
comparison with other spiroketalization on exo-glycals,20 this
cyclization is more difficult, requiring heating at reflux of the
THF/H2O mixture over 4 days (Scheme 4).
Scheme 4. Formation of a Spiroketal Derivative
We then turned our attention to the application of our
methodology to the synthesis of maculalactone B.21 This natural
compound was isolated from marine cyanobacterium Kyrtuthrix
maculans and belongs to a larger family of derivatives based on
the tribenzylbutyrolactone skeleton, which inhibits the for-
mation of biofilms in marine systems (Figure 3).22
Starting from commercially available dichloromaleic anhy-
dride, radical substitution in toluene afforded dibenzyl maleic
anhydride.23 Then, the modified Julia olefination using pyridinyl
benzyl sulfone provided maculalactone B in 63% yield. As shown
previously in Scheme 3, the use of pyridinyl sulfone was
necessary to obtain a good yield and a total Z selectivity
C
DOI: 10.1021/acs.orglett.6b02160
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Letter
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We have extended the modified Julia reaction to anhydrides.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02160.
́
(b) Habib, S.; Larnaud, F.; Pfund, E.; Mena Barragan, T.; Lequeux, T.;
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Full experimental details, data for all new compounds, and
1H and 13C spectra (PDF)
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: david.gueyrard@univ-lyon1.fr. Homepage: http://
www.icbms.fr/co2glyco/effectif/gueyrard.
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the University Lyon 1 and the CNRS for the financial
support. We also thank the “Arc 1 Sante-
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(b) Kar, A.; Gogoi, S.; Argade, N. P. Tetrahedron 2005, 61, 5297.
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Rho
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grant (N.D.).
D
DOI: 10.1021/acs.orglett.6b02160
Org. Lett. XXXX, XXX, XXX−XXX