βUnsaturated acyl cyanides as new bis-electrophiles for enantioselective organocatalyzed formal [3+3]spiroannulation

Article abstract of DOI:10.1002/chem.201303613

α,β-Unsaturated acyl cyanides are key bis-electrophile substrates for successful domino enantioselective organocatalyzed Michael-intramolecular acylation domino sequences. This new reactivity has been applied to the synthesis of enantioenriched azaspiro[4

Full text of DOI:10.1002/chem.201303613

DOI: 10.1002/chem.201303613
Communication
&
Organic Synthesis
a,b-Unsaturated Acyl Cyanides as New Bis-Electrophiles for
Enantioselective Organocatalyzed Formal [3+3]Spiroannulation
Sꢀbastien Goudedranche, Xavier Bugaut, Thierry Constantieux, Damien Bonne,* and
Jean Rodriguez*[a]
Abstract: a,b-Unsaturated acyl cyanides are key bis-elec-
trophile substrates for successful domino enantioselective
organocatalyzed Michael-intramolecular acylation domino
sequences. This new reactivity has been applied to the
synthesis of enantioenriched azaspiro[4,5]decanone ring
systems by a formal [3+3]spiroannulation, constituting
a rare example of synthesis of glutarimides in an optically
active form.
Enantioselective organocatalysis is a fast-growing area of re-
search in organic chemistry and many elegant synthetic path-
Scheme 1. Organocatalytic strategies for formal [3+3]cyclizations.
ways have been developed in their organocatalyzed versions.[1]
Among them, enantioselective Michael addition-initiated multi-
ple bond-forming transformations[2] leading to complex struc-
when reacted with a judiciously selected 1,3-dinucleophile
tures from simple substrates have received a special enthusi-
asm becoming a central element in modern organic synthetic
chemistry.[3] One of the main requirements is the availability of
substrates exhibiting at least two complementary reactive cen-
ters in combination with a sharp control of the selectivity of
each individual bond-forming event. In this respect, simple
enals 1 have been exploited as 1,3-bis-electrophiles with se-
lected 1,3-bis-nucleophiles 2 in Michael acylation organocata-
lyzed enantioselective formal [3+3]cyclization sequences upon
oxidation of the transient cyclic hemiacetals[4] or hemiaminals
3[5] (Scheme 1a) to afford scaffolds 4. In sharp contrast, use of
the corresponding less reactive unsaturated carboxylic acid de-
rivatives avoiding the oxidation step remains a challenging
task and the quest for new unsaturated ester surrogates that
could be activated in an organocatalytic transformation is still
an active field of research with high synthetic potential.[6]
In this respect, we surmised that acyl cyanides 5 that are un-
familiar Michael acceptors,[7] should also constitute a good
acylating agent resulting in a formal [3+3]cyclization process
(Scheme 1b).
Herein, we report our preliminary investigations on the
design of a new spirocyclization leading to functionalized
azaspiro[4,5]decanones of high synthetic value (Scheme 2).
This spirocyclic substructure is found in several natural prod-
ucts, such as meloscandonine[8] and lycoflexine[9] alkaloids, and
could therefore be of particular interest in synthetic ap-
proaches to these families of natural products. It may also be
noted that the corresponding product contains an original spi-
roimide function,[10] that may confer high synthetic potentiali-
ties. To the best of our knowledge, there is no report of direct
enantioselective synthesis of glutarimide derivatives,[11] which
is an important structural motif found in many natural prod-
ucts.[12] Moreover, the domino sequence involves the dual reac-
tivity of acyl cyanides as new C/C bis-electrophiles allowing
a one-pot enantioselective organocatalytic Michael addition-in-
tramolecular acylation with simple b-ketoamides as C/N bis-nu-
cleophiles. The overall cascade forms one CÀC and one CÀN
bond,[13] and produces ring systems bearing two adjacent ste-
reogenic centers including a tetrasubstituted one.[14]
Based on our experience in enantioselective domino trans-
formations,[15] we started our investigations using b-ketoamide
6a as the bis-nucleophilic partner, which was reacted with cin-
namoyl cyanide (5a) under hydrogen-bonding catalysis
(Table 1).[16] Hence, when the reaction was conducted in tolu-
ene at 08C with Takemoto’s thiourea catalyst I,[17,18] we were
pleased to find that the domino-Michael-intramolecular nucle-
ophilic substitution was efficient and the spiroimide 7a was
produced in 90% yield albeit in low stereoselectivity (Table 1,
entry 1). We have identified the crucial role of the amide
[a] S. Goudedranche, Dr. X. Bugaut, Prof. T. Constantieux, Dr. D. Bonne,
Prof. J. Rodriguez
Aix-Marseille Universitꢀ, Centrale Marseille
CNRS, iSm2 UMR 7313
13397, Marseille (France)
Fax: (+33)491 289 187
E-mail: damien.bonne@univ-amu.fr
jean.rodriguez@univ-amu.fr
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201303613. It contains experimental proce-
dures, complete characterization for all new compounds, VCD analysis, X-
1
ray diffraction analysis, chiral HPLC analysis, and H and 13C NMR spectra.
Chem. Eur. J. 2014, 20, 410 – 415
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ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
proton of ketoamides in earlier
studies on enantioselective Mi-
chael additions, and we clearly
observed that increasing its acid-
ity resulted in increased enantio-
selectivities.[5a]
Consequently,
more electron-withdrawing sub-
stituents on the nitrogen atom
of ketoamides 6 were screened
(entries 2–4). As expected, lower-
ing the pKa of the amide proton
had a beneficial impact on ste-
reoselectivities and this was par-
ticularly the case for enantiose-
lectivities (entries 2 and 3). When
ketoamide 6c (R=4-nosyl) was
employed we observed the for-
Scheme 2. New approach to the azaspiro[4,5]decanone ring system.
Table 1. Optimization of the reaction conditions.[a]
mation of 7c in good yield
(83%) and with an excellent
enantiomeric ratio of 96:4 for its major diastereomer (in this
case diastereomeric ratio (d.r.)=3:1). Other organocatalysts
were investigated and catalyst II bearing a piperidine ring in-
stead of the dimetylamine moiety of I was not efficient and
the product 7c was obtained in less than 10% yield (entry 4).
Catalyst III allowed the formation of the desired product 7c
with equivalent stereoselectivity albeit a lower yield was ob-
tained (35%, entry 5). Chiral cinchona alkaloid-derived thiourea
catalysts IV[19] and V[20] were used in the present transformation
but were not as efficient as the Takemoto catalyst I especially
in term of yields (entries 6 and 7). The temperature was then
lowered to À108C (entry 8) and we observed similar stereose-
lectivity and a slight decrease in the yield that could be due to
lower solubility of the starting materials. The use of more polar
solvents such as ethyl acetate, acetonitrile, or dichloromethane
resulted in lower enantioselectivities (entries 9–11) with similar
yields. When the reaction was conducted in diethyl ether
(entry 12) the yield as well as the stereoselectivity were compa-
rable to the ones obtained in toluene (entry 3). When the reac-
tion was conducted in m-xylene a slight increase in the diaste-
reoselectivity was observed (6:1, entry 13) and these last reac-
tion conditions were chosen for subsequent substrate scope
evaluations.
Entry Cat. Solvent T [8C]
6
Product Yield [%][b] d.r.[c] e.r. [%][d,e]
1
2
3
4
5
6
7
8
I
I
I
II
III
toluene
toluene
toluene
toluene
toluene
0
0
0
0
0
0
0
6a 7a
6b 7b
6c 7c
6c 7c
6c 7c
6c 7c
6c 7c
90
83
87
67:33 75:25
83:17 90:10
75:25 96:4
To demonstrate the specificity of acyl cyanides, the reaction
was conducted by using other potential bis-electrophiles.
Hence, replacing 5a by cinnamaldehyde (1a), under identical
reaction conditions (Scheme 3), proved unproductive, possibly
due to retro-Michael addition. Therefore, the use of acyl cya-
nides 5 answers to a limitation in permitting the introduction
of a substituent alpha to the quaternary carbon in the final spi-
rocyclic structure 7, which was not possible using the corre-
sponding enals.[5a] Similarly, the corresponding cinnamoyl chlo-
ride 8 did not react under these reaction conditions possibly
due to catalyst inhibition.[21] In addition, the reaction was also
conducted using 4-nitrophenyl cinnamate (9),[22] which could
in theory behave as an efficient bis-electropile for this transfor-
mation but here also, no reaction occurred. These experiments
show the specificity of unsaturated acyl cyanides for this trans-
<10
35
61
41
73
89
61
83
87
n.d.
n.d.
80:20 9:91
75:25 96:4
83:17 33:67
87:13 92:8
88:22 87:13
89:12 79:21
80:20 87:13
80:20 92:8
87:13 98:2
IV toluene
V
I
I
I
I
I
I
toluene
toluene
EtOAc
CH3CN
CH2Cl2
Et2O
À10 6c 7c
9
0
0
0
0
0
6c 7c
6c 7c
6c 7c
6c 7c
6c 7c
10
11
12
13
m-xylene
92
[a] Reaction conditions: ketoamide
6 (1.0 equiv) and catalyst (I–V;
10 mol%) were dissolved in the solvent and stirred at 08C for 15 min.
Then, the a,b-unsaturated acyl cyanide 5a (2.0 equiv) was added and the
mixture was stirred for 40 h at 08C. [b] Yield of isolated major diastereo-
mer after flash chromatography. [c] Determined by 1H NMR spectroscopy
of the crude reaction product. [d] Determined by HPLC analysis on chiral
stationary phase. [e] Values are for the major diastereomer.
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sis, a reasonable proposal for the
assignment of the absolute con-
figuration could be obtained by
VCD analysis of compound 7c,
which indicated a (S,S) relation-
ship (see the Supporting Infor-
mation for details).[23]
Two possible activation modes
could in theory explain the ob-
served stereochemical outcome
(Scheme 4). Based on our previ-
ous studies regarding the enan-
tioselective Michael addition of
b-ketoamides to a,b-unsaturated
carbonyl compounds,[5a] the eno-
late of the ketoamide 6c is coor-
dinated to the thiourea moiety
in a perpendicular fashion in
Scheme 3. Control experiments with other potential bis-electrophiles.
formation and for an efficient access to the azaspiro-
[4,5]decanone ring system.
Table 2. Reaction scope of the formal azaspiro[4,5]annulation.
We next focused on testing our methodology by varying the
nature of the a,b-unsaturated acyl cyanide 5 using optimized
reaction conditions (Table 2). Both electron-enriched as well as
electron-impoverished aryl-substituted acyl cyanides 5 are suit-
able substrates for this transformation (7c–g) even if slightly
better enantioselectivities were noticed when an electron-do-
nating group was present on the phenyl ring (7d and 7e, 91:9
and 94:6 enantiomeric ratio (e.r.), respectively). The use of
furane-substituted acyl cyanide 5 f (R3 =2-furyl) allowed the
formation of the desired spirocyclic product 7h in good yield
and very good stereoselectivity. The reaction was also possible
with alkyl-substituted acyl cyanide 5g (R3 =Me) with good
yield (74%) though stereoselectivity was moderate in product
7i (80:20 d.r., 67:33 e.r.). The introduction of an alkenyl moiety
in the final structure 7j was successfully achieved using a,b-
unsaturated acyl cyanides 5h (R=CH=CHCH3) and the reaction
outcome was comparable to the use of aryl-substituted acyl
cyanides. Interestingly, an ester moiety could also be intro-
duced increasing the molecular complexity and functional-
group density and diversity in the final spirocyclic structure 7k.
Even if no diastereoselectivity was observed, the enantioselec-
tivity and the yield were very good (80% yield, 50:50 d.r., 93:7
e.r.). Unfortunately, the use of acryloyl cyanide (5i, R3 =H) was
not successful, and the starting ketoamide 6c was recovered.
This highlights the complementarity of the present methodolo-
gy with our previous results in which the synthesis of 7n (R1 =
H, R2 =Ts, R3 =H) is possible by a two-step procedure.[5a] Finally,
concerning the starting b-ketoamide 6, the use of another acti-
vating group on the amide (6d, R1 =H, R2 =SO2-C6H4-CF3) as
well as substitution of the cyclopentanone ring (6e, R1 =Me,
R2 =Ns) were possible and the corresponding spiroimides 7l
and 7m were obtained in good yields and very good stereo-
selectivities.
[a] Isolated yield of the major diastereomer. [b] Determined by 1H NMR
spectroscopy of the crude reaction product. In brackets is the d.r. of the
isolated product. [c] Values are for the major diastereomer. [d] Isolated
yield of the 1:1 mixture of the two diastereomers (not separable by flash
chromatography).
While the relative configuration of the two stereogenic cen-
ters was unambiguously determined by X-ray diffraction analy-
Chem. Eur. J. 2014, 20, 410 – 415
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both TSI and TSII exposing the Re face of the enolate
to the electrophile 5a. In TSI, an activation of the
a,b-unsaturated acyl cyanide 5a through hydrogen-
bonding with the ammonium part of the organocata-
lyst I is proposed. In TSII, the catalyst could form a co-
valent bond with 5a by nucleophilic displacement of
the cyanide ion.[24]
In both cases, the nucleophile would react on the
Re face of the electrophile explaining the stereoselec-
tivity. As a proof of possible formation of 9, a proton
NMR experiment of a 1:1 mixture of catalyst I and 5a
in deuterated acetonitrile clearly showed the forma-
tion of acyl ammonium 9 by creation of a covalent
bond between I and 5a (Figure 1), explaining the im-
portant shifts of the 1H NMR proton signals. These
shifts are particularly significant for vinylic protons Ha
and Hb in 5a as well as Hc, Hd and protons of the di-
methylamine moiety of catalysts I. In intermediate 9,
all these protons are close to the acyl ammonium
moiety and are the more prompt to suffer important
shifts. Moreover, its formation was followed by HRMS
(electrospray ionization in positive mode, see Sup-
porting Information). Gratifyingly, we clearly observed
the expected signal at m/z: 544.1856 corresponding
to the acyl ammonium 9 ([C26H28F6N3OS]+). More im-
portantly, when we ran similar NMR spectroscopic ex-
periments in deuterated benzene, which displays
Scheme 4. Possible transition states for the dual activation
Figure 1. 1H NMR of 5a (top), I (bottom), and the mixture of 5a and I (middle) in CD3CN.
Chem. Eur. J. 2014, 20, 410 – 415
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Communication
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similar properties to the solvent of the reaction (m-xylene), no
chemical shift was observed (see the Supporting Information),
which indicates that the formation of 9 is not probable in non-
polar solvents. These investigations led us to conclude that the
reaction was presumably going through TSI even if we cannot
completely rule out TSII and additional experiments and theo-
retical calculations are underway to shed light on this intrigu-
ing mechanism.
In conclusion, we have demonstrated the possible use of
a,b-unsaturated acyl cyanides as efficient bis-electrophiles in
enantioselective organocatalyzed formal [3+3]spiroannulations
leading to synthetically valuable azaspiro[4,5]decanones. More-
over, this method constitutes the first direct access to chiral
functionalized glutarimides in an optically active form. We are
now working to gain further insight into the present reaction
as well as extending the reactivity of this simple a,b-unsaturat-
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General procedure for the enantioselective formal [3+3]spi-
roannulation
The freshly sublimated acyl cyanide 5 (0.4 mmol, 2 equiv) was
added in one portion to a solution of ketoamide 6 (0.2 mmol,
1.0 equiv) and the thiourea catalyst I (0.02 mmol, 0.1 equiv) in m-
xylene (0.06m, 3.3 mL) at 08C. The reaction mixture was stirred
40 h at 08C and then diluted with a mixture of ethyl acetate and
petroleum ether (1:1, 10 mL) and filtrated on a short plug of silica
gel. Purification by flash column chromatography (silica gel, petro-
leum ether/EtOAc) afforded the pure product.
Typical procedure for the enantioselective formal [3+3]spi-
roannulation (on 2mmol scale)
The freshly sublimated acyl cyanide 5 (628 mg, 4 mmol, 2.0 equiv)
was added in one portion to a solution of ketoamide 6c (624 mg,
2 mmol, 1.0 equiv) and the thiourea catalyst I (82 mg, 0.2 mmol,
0.1 equiv) in m-xylene (0.06m, 33 mL) at 08C. The reaction mixture
was stirred for 40 h at 08C and then diluted with a mixture of ethyl
acetate and petroleum ether (1:1, 100 mL) and filtrated on a short
plug of silica gel. Purification by flash column chromatography
(silica gel, petroleum ether/EtOAc) afforded the pure product 7c as
a white solid (645 mg, 73%, 10:1 d.r., 96:4 e.r.).
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Acknowledgements
The Agence Nationale pour la Recherche (ANR-11-BS07-0014),
the Centre National de la Recherche Scientifique (CNRS), the
COST Action no. CM0905 Organocatalysis (ORCA), and the Aix-
Marseille Universitꢀ are gratefully acknowledged for financial
support. We also thank Dr. N. Vanthuyne and M. Jean (ee
mesurements), Dr. J.-V. Naubron (VCD analysis) and Dr. M.
Giorgi (X-ray diffraction analysis).
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Keywords: domino
glutarimides · organocatalysis · spiroannulation
reactions
·
enantioselectivity
·
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Received: September 12, 2013
[21] The reactivity of a,b-unsaturated acyl chlorides has been exploited for
the efficient generation of acyl azoliums used in enantioselective
Published online on December 4, 2013
Chem. Eur. J. 2014, 20, 410 – 415
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