Asymmetric organocatalytic 1,6-conjugate addition of aldehydes to dienic sulfones

Article abstract of DOI:10.1002/anie.201100804

An unprecedented 1,6-enamine conjugate addition exploiting the charge delocalization in 1,3-bis(sulfonyl) butadienes has been developed. By appropriately designing a Michael acceptor, unique reactivities were obtained for the formation of highly valuable

Full text of DOI:10.1002/anie.201100804

DOI: 10.1002/anie.201100804
Asymmetric Catalysis
Asymmetric Organocatalytic 1,6-Conjugate Addition of Aldehydes to
Dienic Sulfones**
John J. Murphy, Adrien Quintard, Patrick McArdle, Alexandre Alexakis,* and John C. Stephens*
Building enantiopure complex molecules simply, in a mini-
mum number of operations, and in an environmentally
friendly approach is one of the greatest challenges for
synthetic chemistry, and particularly, for chemical industry.[1]
Taking into account the requirements for the industrial
application of an laboratory-scale reaction (functional
group/H2O tolerance, simple procedures, no extreme temper-
atures), enamine catalysis has recently appeared as a method
of choice to fulfil this ideal goal of reaction efficiency.[2,3]
In this field, the asymmetric conjugate addition to
activated alkenes has been extensively studied, as evidenced
by the large number of publications on the subject.[4] In
contrast, the analogous asymmetric 1,6-addition to extended
conjugated systems remains underdeveloped.[5,6] Several
groups reported the 1,4-addition to activated dienes in
enamine catalysis without any traces of vinylogous 1,6-
addition.[7] This higher reactivity of the b position compared
to the d position seems to be a general trend difficult to
overcome (Scheme 1). It probably arises from the poor
propagation of the electronic effect through the conjugated
system. This problem of charge delocalization is in contrast to
the principle of vinylogy where the reactivity is in theory
extended through the p–p system.[8] In our continuing efforts
toward the development of new approaches for the stereo-
selective construction of enantiopure synthetically useful
buildings blocks, we thought about expanding the scope of
enamine Michael reactions to 1,6-addition.
Scheme 1. Proposal for the organocatalytic vinylogous 1,6-addition
reaction. En=enamine catalysis.
We hypothesized that
a suitably designed Michael
acceptor would be able to promote exclusively the 1,6-
addition. To this purpose, we have focused our attention on
unsaturated sulfones. The sulfonyl group is known for its
electron-withdrawing ability together with high synthetic
versatility.[9] It has been shown that a vinyl sulfone with a
single activating sulfone group was not sufficiently reactive to
promote intermolecular enamine attack and generate a 1,4-
conjugate addition. Instead a second sulfone was required to
generate the Michael-type addition.[10] As a result, 1,3-bis-
(sulfonyl) butadiene (Scheme 1), should be able to promote
exclusively the 1,6-addition by the insertion of an appropri-
ately placed second electron-withdrawing group.[11] This
butadiene should serve as an exciting application of the
exceptional potential of charge delocalization in vinylogous
reactions. The sulfone in the a position would not sufficiently
activate the b-carbon atom toward enamine addition but
would be expected to sufficiently delocalize the charge of the
d-carbon atom thanks to the cooperative effect of the second
sulfonyl group, thus promoting the single 1,6-addition
(Scheme 1). Herein, we present our results on this unprece-
dented asymmetric 1,6-addition that leads, in operationally
simple conditions, to exceptional levels of diastereo- and
enantioselectivities for the formation of highly attractive
chiral dienes.
[*] J. J. Murphy, Dr. J. C. Stephens
Department of Chemistry, National University of Ireland Maynooth
Co. Kildare (Ireland)
Fax: (+353)1-7083815
E-mail: john.stephens@nuim.ie
Prof. P. McArdle
Department of Chemistry, National University of Ireland Galway
Co. Galway (Ireland)
A. Quintard, Prof. Dr. A. Alexakis
Department de chimie organique, Universite de Geneve
30 quai Ernest Ansermet, 1211 Geneve 4 (Switzerland)
Fax: (+41)223-793-215
E-mail: Alexander.alexakis@unige.ch
[**] We thank the Irish Research Council for Science, Engineering &
Technology (IRCSET) and NUI Maynooth for funding. We also thank
Dr. Padraig McLoughlin of Teagasc and the Ashtown Food Research
Centre, Dublin for some NMR analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201100804.
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We began our study by synthesizing 1,3-bis(sulfonyl)
branched aldehydes isovaleraldehyde 2d and citronellal 2e
reacted efficiently even though longer reaction times where
required to reach completion (40 h and 144 h respectively;
Table 1, entries 5 and 6). This lower reactivity is consistent
with the higher steric hindrance of the substrates. Again we
were happy to see that the expected compounds were still
formed with perfect stereocontrol even though they required
a longer reaction time (compound 4d and 4e were isolated as
single stereoisomers). Furthermore, this protocol could also
be applied for unsaturated phenylacetaldehyde 2 f, that
underwent a high-yielding reaction with excellent diastereo-
selectivity and enantioselectivity (Table 1, entry 7). This
attractive synthon should lead to an enantiomerically pure
C2 symmetric diene by sulfone removal.
butadiene substrates 1 by a high-yielding, four-step reaction
sequence.[12] To evaluate the feasibility of the asymmetric 1,6-
addition, we subjected the sulfonyl diene 1 to the addition of
butanal 2a using 30 mol% of the organocatalyst (R)-diphe-
nylprolinol silyl ether 3. Chloroform was chosen as it easily
solubilized the 1,3-bis(sulfonyl) butadiene. As we expected
from our proposal (Scheme 1), only the 1,6-addition product
was obtained in an excellent yield of 91% using only
2 equivalents of aldehyde (Table 1, entry 1). The observed
Table 1: Scope of aldehydes for the 1,6-addition.
To fully explore this remarkable transformation, we then
continued to investigate the scope of the reaction by testing
the 1,6-conjugate addition of valeraldehyde 2b to a family of
1,3-bis(phenylsulfonyl)butadienes 1a–e in the presence of
30 mol% of organocatalyst in chloroform (Table 2). Avariety
Entry Cat.
t [h]
R
Yield
[%][a]
d.r.
ee
(syn/anti)[b] [%][c]
Table 2: Scope of the bis(arylsulfonyl) butadienes.
1
2
3
4
5
6
7
(R)-3
(R)-3
(S)-3
(R)-3
(R)-3
24 Et
91 (4a)
98 (4b)
98 (4b)
92 (4c)
95 (4d)
1:99
1:99
1:99
1:99
1:99
99
99
24 nPr
24 nPr
24 allyl
40 iPr
(À) 99[d]
99
99
–
(R)-3 144 (S)-citronellal 89[e] (4e) 1:99
(R)-3
24 Ph
96 (4 f)
1:99
99
[a] Yield of isolated product. [b] Determined by 1H NMR spectroscopy
and HPLC analysis. [c] Determined by HPLC on a chiral stationary phase
for the anti products. [d] Opposite S,S enantiomer of the product
formed. [e] Isolated as a single diastereoisomer as determined by
1H NMR spectroscopy. TMS=trimethylsilyl.
Entry
t [h]
X
Yield [%][a]
d.r. (syn/anti)[b]
ee [%][c]
1
2
3
4
5
6
24
24
24
20
20
4
OMe
H
F
Cl
Br
75 (5b)
98 (4b)
81 (5c)
81 (5d)
70 (5e)
75 (5 f)
1:99
1:99
1:99
1:99
1:99
1:99
99
99
99
99
99
99
high reactivity and regioselectivity is in total agreement with
our preliminary hypothesis of charge delocalization. The
intermediate linear product was not observed and sponta-
neously cyclized to form the conjugated diene 4. It must be
pointed out here that the cyclized product could be isolated
from the crude reaction mixture by a very simple procedure.
After evaporation of the solvent, the solid was only triturated
with ice-cold methanol to directly obtain the pure compound.
More remarkably, an exceptional diastereo- and enantiocon-
trol was observed in this reaction to furnish the 1,6-adduct in
an astonishingly high 99% ee and 99:1 d.r. while performing
the reaction at room temperature. Decreasing the catalyst
loading to 10 mol% led to the same excellent stereoselectiv-
ities (99% ee, 99:1 d.r.) but as expected, a prolonged reaction
time was needed to obtain 100% conversion (120 h vs. 24 h,
result not shown).
We explored the scope and limitations of this reaction by
testing 1,3-bis(phenylsulfonyl)butadiene 1a with a variety of
different sterically demanding aldehydes 2a–f (Table 1).
Gratifyingly, all reactions gave the 1,6-addition product
exclusively with no trace of the 1,4-adduct. Furthermore,
the products were all isolated as virtually pure stereoisomers.
The unbranched aldehydes 2a–c underwent a fast 1,6-
addition in excellent yields, diastereoselectivities, and enan-
tioselectivities (Table 1, entries 1–3). Perhaps most notable,
NO2
[a] Yield of isolated product. [b] Determined by 1H NMR spectroscopy
and HPLC analysis. [c] Determined by HPLC on a chiral stationary phase
for the anti products.
of different aryl substituents with a range of electronic
properties could be used without affecting the overall
selectivity of the reaction. All reactions gave greater than
1
99% conversion by H NMR spectroscopy. The yields of the
isolated 1,6-addition products were slightly lower in all cases
(71 to 81% yield vs. 98% for the phenyl). This outcome
probably arises from an increase in the solubility of the final
compounds and results in product loss during workup. When
the electron-withdrawing properties of the substituents were
increased from F, Cl, to Br the reactions were slightly
accelerated. The lower electron density of the acceptor 5 f
containing a nitro substituent resulted in an impressive
increase in reactivity (4 h vs. 24 h to obtain a full conversion;
Table 2, entry 6 vs. entry 2). This result is in agreement with a
Michael 1,6-addition mechanism and should indicate that the
À
C C bond formation and not the cyclization is the rate-
determining step. This finding is consistent with the fact that
no traces of the noncyclized product could be observed when
monitoring the reaction by 1H NMR spectroscopy.
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In addition, the absolute and relative configuration of
both the R,R adduct and S,S adduct of 4b could be deter-
mined by X-ray crystallography (Figure 1 and the Supporting
Information).[13]
of the Michael acceptor forming 6. Previous studies have
described a similar model for the 1,4-addition of aldehydes to
vinyl sulfones,[10a,b] nitroolefins,[16] and vinyl phosphonates.[17]
Even though this classical model can rationalize the observed
stereoselectivity, several aspects still need to be addressed.
The question on whether the catalyst is involved in the
cyclization and in promoting the elimination is still not clear.
This is more plausible given the fact that no linear product is
observed, which implies that the cyclization/elimination steps
are fast with the catalyst still involved. Despite the prelimi-
nary evidence for a 1,6-addition, a possible [4+2] cycloaddi-
tion cannot be ruled out and further investigations should
shed light on these interesting problems.[11,18]
The products obtained through the 1,6-conjugate addi-
tion/condensation reaction are highly interesting building
blocks. To illustrate the synthetic utility of this method the
adduct 4a was converted into 8 in excellent 97% yield
through another conjugate addition of methyllithium
(Scheme 3).
Figure 1. ORTEP drawing of (R,R)-4b with ellipsoids at 20% probabil-
ity.
Despite the high synthetic potential of the disclosed
reaction, it is also highly interesting in terms of mechanism.
Although further experimentation is needed to have a
complete understanding of the reaction mechanism, a plau-
sible stepwise mechanism can be proposed (Scheme 2). The
absolute configuration of the products is consistent with
previous results obtained in 1,4-addition to other Michael
acceptors catalyzed by catalyst 3.[14] The acyclic synclinal
´
transition-state model, as described by Seebach and Golinski,
could be applied to the 1,6-conjugate addition of aldehydes to
1,3-bis(sulfonyl) butadienes and explains the observed high
levels of stereoselectivities.[15] Steric repulsion away from the
bulky groups of the pyrrolidine ring promotes the selective
attack of the Re face of the E-trans enamine and the Re face
Scheme 3. Addition of MeLi to 4b for the creation of four contiguous
stereogenic centers. THF=tetrahydrofuran.
Perfect regioselectivity and good levels of diasteroselec-
tivities (4:1 d.r.) were obtained for the subsequent
creation of two new stereogenic centers in this final
molecule containing four contiguous stereocenters.
After a simple recrystallization, compound 8 was
isolated as a 12:1 mixture of two diasterosiomers in
99% ee among the 16 possible stereosiomers. The
addition anti to the propyl group on the adjacent
carbon atom was confirmed using NOE studies and
1H, 13C, DEPT, and HSQC spectra. This result
highlights the great potential of the obtained dienes
for further transformations by indicating the most
electrophilic position in 4b.
In conclusion we have developed an unprece-
dented enamine 1,6-addition by exploiting the
properties of charge delocalization in 1,3-bis-
(sulfonyl) butadienes. By appropriately designing a
Michael acceptor, unique reactivities were obtained
for the formation of highly valuable dienes contain-
ing two versatile vinyl sulfones. This remarkable
reaction should find its applications in total syn-
thesis thanks to its operational simplicity and to the
exceptional levels of stereoselectivities of the final
products (typically 99% ee and 99:1 d.r.). We are
convinced that this activation principle by charge
delocalization through the addition of a second
electron-withdrawing group should serve as a key-
stone for the development of new powerful 1,6-
Scheme 2. Proposed mechanism and transition state. EWG=electron-withdrawing
group.
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Communications
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investigations employing ketones and additional 1,6-accept-
ors are currently being pursued in our laboratories and will be
published in due course.
Experimental Section
Typical procedure for the organocatalytic 1,6-addition reaction:
Diene (0.2 mmol, 1 equiv) was added to a sample vial containing
(R)-diphenylprolinol silyl ether (19,5 mg, 0.06 mmol, 0.3 equiv) dis-
solved in chloroform (0.5 mL), followed by direct addition of the
aldehyde (0.4 mmol, 2 equiv). The reaction mixture was then stirred
at RT until the reaction was complete (as evident by TLC). The
reaction mixture was concentrated under reduced pressure and
triturated with ice-cold methanol (2 ꢀ 3 mL) to yield the solid pure
product.
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Received: January 31, 2011
Revised: March 3, 2011
Published online: April 28, 2011
Keywords: asymmetric synthesis · conjugate addition · dienes ·
.
organocatalysis · sulfones
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[12] See the Supporting Information for details.
[13] CCDC 821057 ((R,R)-4b) and 821056 ((S,S)-4b) contain the
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