Formal Asymmetric (4+1) Annulation Reaction between Sulfur Ylides and 1,3-Dienes

Article abstract of DOI:10.1002/chem.201502579

A highly enantioselective synthesis of functionalized cyclopentanoids by a formal asymmetric (4+1) annulation strategy was developed. The methodology consists of a stereoselective cyclopropanation reaction between chiral sulfur ylides and 1,3-dienes follo

Full text of DOI:10.1002/chem.201502579

DOI: 10.1002/chem.201502579
Communication
&
Asymmetric Synthesis
Formal Asymmetric (4+1) Annulation Reaction between Sulfur
Ylides and 1,3-Dienes
Olivier Rousseau, Thierry Delaunay, Geoffroy Dequirez, Tran Trieu-Van, Koen Robeyns, and
Raphal Robiette*[a]
Sulfur ylides are versatile reagents which have been report-
Abstract: A highly enantioselective synthesis of function-
alized cyclopentanoids by a formal asymmetric (4+1) an-
ed to be efficient alternatives to (metal) carbenes in different
(2+1) annulations, such as epoxydation, aziridination, and cy-
nulation strategy was developed. The methodology con-
clopropanation reactions.[13] They have the advantage over car-
sists of a stereoselective cyclopropanation reaction be-
benes of being easy to generate and handle, and of tolerating
tween chiral sulfur ylides and 1,3-dienes followed by a, in
a wide range of functional groups. Another important aspect is
situ, stereospecific MgI2-catalyzed rearrangement of vinyl-
that, in all these methods, the use of chiral sulfur ylides al-
cyclopropanes. This method is distinguished by a remark-
lowed the resulting products to be obtained with a high enan-
able compatibility with functional groups and a high ste-
tiocontrol.[13a–d]
reocontrol.
We envisioned that the addition of sulfur ylides onto elec-
tron-poor 1,3-dienes would lead to zwitterionic intermediates
such as 1 that could undergo a ring-closing reaction to form
cyclopentenes (Scheme 1).[14] Another possibility is to ring
Cycloaddition reactions occupy a central role in organic
chemistry as they allow the construction of complex molecular
architectures in a single convergent step.[1] The usually high
stereocontrol of the newly formed stereogenic centers in these
transformations has also contributed to their prominence.
Given the ubiquity of five-membered carbocyclic motifs in bio-
logically active compounds,[2] several strategies have been dis-
closed to develop a (4+1) cycloaddition methodology.[3] Most
reported (4+1) cycloaddition strategies toward five-membered
carbocycles involve addition of carbenes onto 1,3-dienes or vi-
nylketenes.[4] The high reactivity of carbenes is, however, re-
Scheme 1. Reaction of electron-poor 1,3-dienes and sulfur ylides.
sponsible for a low functional-group tolerance. Alternatives to
carbenes have thus been explored by using carbenoid re-
agents, such as isocyanides,[5] carbon monoxide (and transi-
tion-metal catalysis),[6] ylides,[7] a-benzotriazolyl lithium com-
pounds[8] or palladium catalysis.[9] Other four-carbon units have
also been considered, such as w-halogeno-alkenes[10] or 2-(ace-
toxymethyl)-buta-2,3-dienoate.[11] Intensive efforts are thus un-
derway in order to develop an efficient (4+1) strategy; with
the main actual challenges being the chemoselectivity and the
lack of asymmetric variants.[12] Herein, we report the enantiose-
lective synthesis of functionalized cyclopentanoids by a formal
asymmetric (4+1) annulation strategy using 1,3-dienes and
sulfur ylides.
close 1 to a three-membered ring.[15] However, in this latter
case, one could consider the, in situ, rearrangement of the
formed vinylcyclopropane into its corresponding cyclopentene.
Indeed, Danheiser,[4m,p] Hudilicky,[4n,o,q] Lambert,[9b] and Le-
gault[4b] have showed that cyclopropanation of 1,3-dienes fol-
lowed by a vinylcyclopropane rearrangement could constitute
an efficient alternative strategy for the direct (4+1) annulation
in the synthesis of cyclopentenes.[16]
We began our investigation with the model reaction of 1,3-
diene 2a (1 equiv) with the ylide formed by deprotonation of
3a (1.1 equiv) (Scheme 2). Stirring these two reagents at
À788C for 1 h and then at room temperature for 16 h led to
vinylcyclopropane 4aa with a total trans selectivity and no
trace of corresponding cyclopentene.[17] All our attempts to ob-
serve direct formation of cyclopentene 5aa by modifying the
reaction conditions failed. Accordingly, we decided to find re-
action conditions under which 4aa could rearrange into the
more stable cyclopentene 5aa. In the event, we found that
MgI2 catalyzes the rearrangement of 4aa under very mild con-
ditions (20 mol% MgI2, RT, 16 h) to give the desired cyclopen-
tene 5aa in 50% yield.[18,19]
[a] O. Rousseau, Dr. T. Delaunay, Dr. G. Dequirez, T. Trieu-Van, Dr. K. Robeyns,
Prof. R. Robiette
Institute of Condensed Matter and Nanosciences
UniversitØ catholique de Louvain
Place Louis Pasteur 1 box L4.01.02 (Belgium)
Fax: (+32)010474168
E-mail: raphael.robiette@uclouvain.be
Homepage: http://www.uclouvain.be/raphael.robiette
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201502579.
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Communication
Table 1. Substrate scope of the formal (4+1) annulation.
Entry Diene (2)
R1
Product
Yield [%][a]
65
1
Ph
2
3
4
5
p-FPh
57
55
50
58
Scheme 2. Investigation of the model reaction.
After having showed the potential of sulfur ylides in the de-
velopment of a (4+1) annulation strategy, we searched for suit-
able reaction conditions that allowed cyclopentenes to be ob-
tained in one synthetic step. We found that deprotonation of
sulfonium salt 3a in the presence of diene 2a, at À788C, fol-
lowed by addition of 1.2 equivalents of MgI2 at room tempera-
ture allowed the synthesis of the corresponding cyclopentene
5aa in 65% isolated yield in one synthetic step (Table 1,
entry 1). The scope of the reaction was then evaluated under
the optimized conditions. A variety of dienes substituted at
the 2- or 3-position participated in the (4+1) annulation pro-
cess to provide the desired cyclopentenes in 32–57% yields
(entries 7–14).[20] The breadth of tolerated substituents was
broad, allowing access to cyclopentenes with a double bond
substituted by electron-rich or -poor aryl, alkyl, or additional
ester groups. The nature of the ylide can also be varied: both
electron-rich and -poor benzylic (or allylic) ylides react with
dienes 2a to provide the corresponding cyclopentenes in
moderate yields (entries 1–6).
p-CO2MePh
p-MePh
p-MeOPh
CH=CMe2
6
57
7
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
57
40
55
45
41
39
32
36[b]
8
9
The success of this formal (4+1) annulation methodology
encouraged us to develop an asymmetric variant of this pro-
cess. Aggarwal et al. have shown that high enantiocontrol in
cyclopropanation reactions could be obtained using sulfonium
salt 6a (which is readily available optically pure in two steps
from sulfur and limonene).[21] Deprotonation of 6a in the pres-
ence of diene 2a allows vinylcyclopropane 4aa to be obtained
with total diastereo- and enantiocontrol, only one stereomer
being observed by NMR spectroscopy and HPLC analysis (d.r.>
98:2 and ee> 99%; Scheme 3). Much to our surprise, the rear-
rangement of 4aa in the presence of MgI2 (20 mol%) led to
corresponding cyclopentene 5aa with no deterioration of the
10
11
12
13
14
[a] Yield of pure product after purification by flash chromatography.
[b] Determined on the crude by 1H NMR spectroscopic analysis using an
internal standard. The reaction was carried out using benzyl(diisopropyl)-
sulfonium tetrafluoroborate.
enantiomeric excess, which indicated a stereospecific rear-
rangement (vide infra). Application of this strategy using our
one-pot procedure resulted in a series of cyclopentenes in 25–
60% yield and a high enantiocontrol (90–99% ee) (Table 2).
Scheme 3. Development of an asymmetric version.
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Table 2. Asymmetric (4+1) annulation reaction.[a,b]
5aa, 47% yield,
>99% ee
5ab, 50% yield,
90% ee
5ae, 55% yield,
91% ee
5ba, 47% yield,
94% ee
5ca, 60% yield,
>99% ee
5da, 47% yield,
94% ee
Scheme 4. Transformations of 5aa.
5ea, 38% yield,
90% ee
5ia, 25% yield,[c]
>99% ee
bond was also performed, leading to acyclic compound 8 with-
out alteration of the enantiomeric excess. The double bond
can be reduced as well to introduce a new stereocenter and
produce meso-compound 9 with an excellent diastereoselectiv-
ity. Subsequent decarboxylation allows formation of 10 with
a cis–cis relative configuration.[24] Interestingly, the more stable
trans–trans isomer can be obtained by epimerization under
basic conditions.
[a] Yield of pure product after flash chromatography. Enantiomeric excess-
es were determined by chiral HPLC (see the Supporting Information).
[b] Absolute configuration of 5ia was determined by single-crystal X-ray
diffraction analysis (see the Supporting Information). Absolute configura-
tion of all other products was determined by analogy. [c] Determined
from the crude by 1H NMR spectroscopic analysis using an internal stan-
dard.
In summary, we have developed a formal asymmetric (4+1)
annulation methodology that provides facile access to func-
tionalized cyclopentenes. The strategy consists of stereoselec-
tive cyclopropanation reaction between chiral sulfur ylides and
1,3-dienes followed by, in situ, stereospecific MgI2-catalyzed re-
arrangement of vinylcyclopropanes. The reaction proceeds
under mild reaction conditions with high functional-group tol-
erance and stereocontrol. Further efforts are in progress to
expand the scope of this methodology and elucidate the exact
mechanism and factors controlling stereoselectivity.
The observed high enantioselectivity during cyclopropana-
tion is consistent with the model proposed by Aggarwal for
enantiocontrol in epoxidation in which ylide conformation and
face selectivity are controlled through nonbonded interactions
(Figure 1).[21] The stereospecific character of the vinylcyclopro-
Acknowledgements
The authors thank C. Le Duff and L. Collard for their technical
assistance in NMR and HPLC, respectively. This work was sup-
ported by the Fonds de la Recherche Scientifique-FNRS (F.R.S-
FNRS), the FRIA (fellowship to O.R.) and the FSR (fellowship to
T.D. and G.D.). R.R. is a Chercheur qualifiØ of the F.R.S.-FNRS.
Figure 1. Model for enantiocontrol.
Keywords: annulation
·
asymmetric
synthesis
·
cyclopentenes · vinylcyclopropanes · ylides
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a series of transformations
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[24] Stereochemistry was attributed assuming that the more stable diaste-
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[12] To the best of our knowledge, only a few examples of asymmetric
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[11a–b].
Received: July 2, 2015
Published online on July 31, 2015
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