A cooperative participation of the amido group in the organocatalytic construction of all-carbon quaternary stereocenters by Michael addition with β-ketoamides

Article abstract of DOI:10.1021/ol200924e

The secondary amido group of α-substituted β-ketoamides plays a crucial role in the control of the reactivity and spatial arrangement (selectivity) in the organocatalyzed Michael addition to unsaturated carbonyls. This results in an unprecedented activati

Full text of DOI:10.1021/ol200924e

ORGANIC
LETTERS
2011
Vol. 13, No. 13
3296–3299
A Cooperative Participation of the Amido
Group in the Organocatalytic Construction
of All-Carbon Quaternary Stereocenters by
Michael Addition with β-Ketoamides
†
†
†
ꢀ †
Maria del Mar Sanchez Duque, Olivier Basle, Nicolas Isambert, Anouk Gaudel-Siri,
ꢀ
‡
‡
,†
Yves Genisson, Jean-Christophe Plaquevent, Jean Rodriguez,* and
Thierry Constantieux*,†
ꢀ
Aix-Marseille Universite, iSm2, UMR CNRS 6263, Centre St Jerome, service 531,
13397 Marseille Cedex 20, France, and Universite Paul Sabatier Toulouse III,
ꢀ ^
ꢀ
LSPCMIB, UMR CNRS 5068, 31062 Toulouse 9, France
thierry.constantieux@univ-cezanne.fr; jean.rodriguez@univ-cezanne.fr
Received April 8, 2011
ABSTRACT
The secondary amido group of R-substituted β-ketoamides plays a crucial role in the control of the reactivity and spatial arrangement (selectivity)
in the organocatalyzed Michael addition to unsaturated carbonyls. This results in an unprecedented activation mode of substrates through
H-bonding interactions allowing the construction of enantiomerically enriched functionalized all-carbon quaternary centers and spiroaminals of
high synthetic potential.
The enantioselective construction of quaternary centers
is one of the most demanding key steps in the stereocon-
trolled synthesis of complex natural and/or pharmaceuti-
cals products.1 In this context, the asymmetric conjugate
addition represents a powerful tool for the elaboration of
these particular stereocenters. Despite well-established
transition-metal-based catalytic methods,2 the generation
of all-carbon quaternary stereocenters via Michael addi-
tion still constitutes a formidable challenge owing to
additional steric hindrance considerations.3 In the past
decade, extensive studies have been devoted to the devel-
opment of organocatalytic systems performing with
excellent enantioselectivities,4 employing simple sub-
strates. In this way, a wide variety of R-substituted-1,3-
dicarbonyls or synthetic equivalents such as β-diketones, β-
ketoesters5 or R-cyanoesters and ketones6 have been exten-
sively and successfully used. On the other hand, asymmetric
conjugate addition with simple β-ketoamides, of broad
€
(4) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701. Erkkila, A.;
Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107, 5416. Dondoni, A.;
Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638. Melchiorre, P.; Marigo,
M.; Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138. Palomo,
ꢀ
C.; Oiarbide, M.; Lopez, R. Chem. Soc. Rev. 2009, 38, 632. Bertelsen, S.;
Jorgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178. Gruttadauria, M.;
Giacalone, F.; Noto, R. Adv. Synth. Catal. 2009, 351, 33. Bella, M.;
Gasperi, T. Synthesis 2009, 1583. For a recent example, see: Zhu, Q.; Lu,
Y. Angew. Chem., Int. Ed. 2010, 49, 7753.
(5) Capuzzi, M.; Perdicchia, D.; Jorgensen, K. A. Chem.;Eur. J.
2008, 14, 128. Rigby, C. L.; Dixon, D. J. Chem. Commun. 2008, 3798. Yu,
Z.; Liu, X.; Zhou, L.; Lin, L.; Feng, X. Angew. Chem., Int. Ed. 2009, 48,
5195. Akiyama, T.; Katoh, T.; Mori, K. Angew. Chem., Int. Ed. 2009, 48,
4226. Boddaert, T.; Coquerel, Y.; Rodriguez, J. Adv. Synth. Catal. 2009,
351, 1744. Yang, J.; Li, W.; Jin, Z.; Liang, X.; Ye, J. Org. Lett. 2010, 12,
5218.
†
ꢀ
Aix-Marseille Universite.
‡
ꢀ
Universite Paul Sabatier Toulouse III.
(1) Steven, A.; Overman, L. E. Angew. Chem., Int. Ed. 2007, 46, 5488.
(2) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 5363. Trost, B. M.; Jiang, C. Synthesis 2006, 369. Alexakis, A.;
Vuagnoux d’Augustin, M.; Martin, D.; Kehrli, S.; Palais, L.; Henon, H.;
Hawner, C. Chimia 2008, 62, 461.
(3) Hamashima, Y.; Hotta, D.; Sodeoka, M. J. Am. Chem. Soc. 2002,
124, 11240. Christoffers, J.; Baro, A. Angew. Chem., Int. Ed. 2003, 42,
1688. Ogawa, C.; Kizu, K.; Shimizu, H.; Takeuchi, M.; Kobayashi, S.
Chem.;Asian J. 2006, 1ꢀ2, 121.
(6) Jautze, S.; Peters, R. Synthesis 2010, 365 and references cited
therein. See also: Kawato, Y.; Takahashi, N.; Kumagai, N.; Shibasaki,
M. Org. Lett. 2010, 12, 1484.
r
10.1021/ol200924e
Published on Web 06/06/2011
2011 American Chemical Society

synthetic value by post-transformations involving the amido
functionality,7,8 remained unsolved. This limitation is due to
the lack of efficient activation modes of these peculiar sub-
strates. According to mechanistic studies on proton exchange
in amides and related compounds,9 β-ketoamides are better
represented under their imidic acid form that could constitute
a new activation mode of these unexplored potential pronu-
cleophiles in Michael addition (Scheme 1).
Table 1. Screening of Catalysts for the Organocatalytic Con-
jugate Addition of β-Ketoamide 1a to Methylvinylketone (2a)a
Scheme 1. Equilibrium between Amide and Acid Imidic Forms
time
(h)
temp
conversionb
(%)
ee
entry
catalyst
(°C)
(%)c
Moreover, based on the seminal works from Miller’s
group,10 the presence of the amido moiety will result in a
favorable cooperative effect in the organization of the
transition state for efficient enantiocontrol of the reaction.
Based on our precedent developments in ketoamide
reactivity11 and organocatalytic conjugate additions,12
we present these unprecedented achievements under
thiourea-based bifunctional catalysis,13 for the enantiose-
lective construction of functionalized all-carbon qua-
ternary stereocenters from R-substituted β-ketoamides as
pronucleophiles.14 Also, the synthetic advantage of the
additionalamide functionisillustratedthrough anefficient
enantioselective domino Michael/spirolactamization se-
quence leading to chiral scaffolds of high synthetic interest.
To initiate our study, we selected the conjugate addition
of β-ketoamide 1a to methylvinylketone (2a) in the pre-
sence of 10 mol % of various organocatalysts 3aꢀh, as a
test experiment (Table 1).
1
3ad
3bd
3c
3d
3e
3f
96
144
20
20
20
20
20
20
20
0
20e
0
ꢀ
2
No reaction
100
3
35
73
32
87
83
79
75
80
4
24
100
5
168
48
100
6
7
100
3f
48
100
8
3f
48
ꢀ20
20
20
100
9
3g
3h
48
100
10
48
100
a A solution of 1a (1 equiv), 2a (2 equiv), and catalyst 3 (10 mol %) in
toluene (0.05 M) was stirred until full conversion. b Determined by TLC
analysis. c Determined by HPLC on a chiral stationary phase. d Catalyst
loading 20 mol %. e Determined by 1H NMR.
Efficient in the case of R-unsubstituted β-amidoesters,8
the (S)-proline derivatives 3a and 3b either gave a very low
conversion with no enantioselection or failed in producing
the desired Michael adduct (entries 1 and 2), ruling out a
possible mechanism involving enamine or iminium inter-
mediates.15 On the contrary, H-bonding activation with
bifunctional catalysts 3cꢀh led to complete conversion and
moderate to good ee’s (entries 3ꢀ10). The Takemoto
ThioUrea Catalyst16 (TUC, 3f) proved to be the most
promising, giving the adduct with 87% ee after 48 h at rt
(entry 6). It is noteworthy that the presence of a tertiary
amine inthe structureofthe catalystiscrucial, since 3ewith
a less basic appended primary amine provided the desired
product with decreased efficiency and selectivity (entry 5).
Unfortunately, lowering the temperature to 0 or ꢀ20 °C
did not improve the enantioselectivity of the reaction
(entries 7 and 8), and cinchona alkaloids 3c and 3d or their
more elaborated thiourea derivatives17 3g and 3h revealed
to be less efficient than the TUC 3f (entries 3, 4, 9, and 10).
(7) Pilling, A. W.; Boehmer, J.; Dixon, D. J. Angew. Chem., Int. Ed.
2007, 46, 5428. Yang, T.; Campbell, L.; Dixon, D. J. J. Am. Chem. Soc.
€
2007, 129, 12070. Pilling, A. W.; Bohmer, J.; Dixon, D. J. Chem.
Commun. 2008, 832.
(8) Very recently, R-unsubstituted β-amidoesters have been proposed
as pronucleophiles leading to the creation of a tertiary stereogenic
ꢀ
center: Franzen, J.; Fisher, A. Angew. Chem., Int. Ed. 2009, 48, 787.
ꢀ
Zhang, W.; Franzen, J. Adv. Synth. Catal. 2010, 352, 499. Valero, G.;
Schimer, J.; Cisarova, I.; Vesely, J.; Moyano, A.; Rios, R. Tetrahedron
Lett. 2009, 50, 1943. Jin, Z.; Wang, X.; Huang, H.; Liang, X.; Ye, J. Org.
Lett. 2011, 13, 564.
(9) Perrin, C. L.; Dwyer, T. M.; Rebek, J., Jr.; Duff, R. J. J. Am.
Chem. Soc. 1990, 112, 3122 and references therein.
(10) Horstmann, T. E.; Guerin, D. J.; Miller, S. J. Angew. Chem., Int.
Ed. 2000, 39, 3635. Vasbinder, M. M.; Jarvo, E. R.; Miller, S. J. Angew.
Chem., Int. Ed. 2001, 40, 2824. Jakobsche, C. E.; Peris, G.; Miller, S. J.
Angew. Chem., Int. Ed. 2008, 47, 6707.
(11) Sanchez Duque, M. M.; Allais, C.; Isambert, N.; Constantieux,
T.; Rodriguez, J. Top. Heterocycl. Chem. 2010, 23, 227 and references
cited there in.
ꢁ
(12) Bonne, D.; Salat, L.; Dulcere, J.-P.; Rodriguez, J. Org. Lett.
ꢁ
2008, 10, 5409. Raimondi, W.; Lettieri, G.; Dulcere, J.-P.; Bonne, D.;
Rodriguez, J. Chem. Commun. 2010, 46, 7247.
(15) Bartoli, G.; Melchiore, P. Synlett 2008, 1759.
(16) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y.
(13) Connon, S. J. Chem. Commun. 2008, 2499. Zhang, Z.; Schreiner,
P. R. Chem. Soc. Rev. 2009, 38, 1187. Connon, S. J. Synlett 2009, 354.
(14) For isolated examples of enantioselective addition of an
R-substituted-β-amidoester to a nitroolefin, see: Jakubec, P.; Helliwell,
M.; Dixon, D. J. Org. Lett. 2008, 10, 4267. Jakubec, P.; Cockfield, D. M.;
Dixon, D. J. J. Am. Chem. Soc. 2009, 131, 16632.
ꢀ
J. Am. Chem. Soc. 2005, 127, 119. Hamza, A.; Schubert, G.; Soos, T.;
ꢀ
Papai, I. J. Am. Chem. Soc. 2006, 128, 13151.
(17) Cinchona Alkaloids in Synthesis and Catalysis; Song, C. E., Ed.;
Wiley-VCH: Weinheim, 2009. Marcelli, T.; Hiemstra, H. Synthesis 2010,
1229.
Org. Lett., Vol. 13, No. 13, 2011
3297

Finally, several solvents have been investigated in combi-
nation with 3f, and toluene was selected as the best one.
We next decided to explore the effect of the amide func-
tionality on reactivity and selectivity and try to identify its role
in the activation process. We postulated that simple mod-
ification of the secondary amide substituent would impact its
H-bonding character and potentially increase the reaction
selectivity. Thus, various cyclic aromatic β-ketoamides 1bꢀg
were reacted with methylvinylketone (2a) under the opti-
mized conditions to afford the corresponding Michael ad-
ducts with good to high yields and high ee values (Table 2).
of a proton on the amide function, we ran additional
experiments with various substrates under the standard
conditions.20 First, we were pleased to note that neither
aliphatic 1h nor aromatic tertiary amides 1i showed any
significant reactivity even after a long reaction time. Also,
the sterically crowded and electron-rich aliphatic second-
ary β-ketoamide 1j (R = t-Bu), with a less acidic amide
proton, remained totally unreactive, highlighting the cru-
cial role of the proton in the activation of the substrate.21
To lend further credence to the hypothesis of a proposed
correlation between ee and the acidity of the NꢀH proton, we
performed theoretical calculations,20 to determine the NꢀH
pKa values of ketoamides 1a, 1d, 1g, and 1j. As depicted in
Figure 1, a direct correlation has been evidenced, clearly
indicating that the ee increased with the acidity of the amide
proton. This theoretical study also revealed that the NꢀH
pKa value of the amide 1j bearing a tert-butyl substituent is
much higher than that of aromatic amides, preventing its
participation in activating H-bonding interactions.
Table 2. Effect of the Amide Nature on the Enantioselectivitya
entry
R
4
time (h) yield (%)b ee (%)c
1
2
3
4
5
6
7
1-naphthyl (1b)
(ꢀ)-4b
48
96
72
40
48
72
72
90
98
62
98
64
88
90
91
90
97
83
83
98
99d
1-anthracenyl (1c) (ꢀ)-4c
p-NO2C6H4 (1d)
p-MeOC6H4 (1e)
m-MeOC6H4 (1f)
Tosyl (1g)
(ꢀ)-4d
(ꢀ)-4e
(ꢀ)-4f
(ꢀ)-4 g
(þ)-4 g
Tosyl (1g)
a A solution of 1 (1 equiv), 2a (2 equiv), and catalyst (R,R)-3f (10mol%)
in toluene (0.05 M) was stirred until full conversion. b Isolated yield after
purification by column chromatography on silica gel. c Determined by
HPLC on a chiral stationary phase. d In this case, catalyst (S,S)-3f was
used, vide infra.
Figure 1. Correlation between ee and pKa (NH).
As expected, the modifications that operated on the
amide function had a significant impact on the reaction
selectivity. Indeed, substrates with polyaromatic substitu-
ents 1b (entry 1) and 1c (entry 2) or electron-withdrawing
group-substituted aniline 1d (entry 3) led to high ee’s,
whereas aniline derivatives 1e (entry 4) and 1f (entry 5)
bearing an electron-donating substituent on the aromatic
ring were revealed to be less efficient.
From these experimental data, we surmised that the
observed ee’s might be correlated to the acidity of the
proton of the amide function. Although this is a simplistic
hypothesis,18 we intended to verify it with substrate 1g
derived from tosylamide.19 To our delight, the TUC-3f
catalyst efficiently activated this substrate providing the
desired Michael adduct 4g with the highest ee (Table 2,
entry 6). Then, to confirm the importance of the presence
To understand the enantioselective outcome of this trans-
formation, it was of main interest to assess the absolute
configuration of the newly created stereogenic center. This
was made possible by single crystal X-ray analysis of adduct
4d.20,22 In addition, the (þ)-(S)-enantiomer of 4g has been
also obtained with a very high ee, using catalyst S,S-3f
(Table 1, entry 7). The absolute configurations of the stereo-
genic centers of both enantiomers of adduct 4g were deter-
mined by comparison of experimental and calculated
Vibrational Circular Dichroism (VCD) spectra.20
At this early stage of the study, the mode of action of the
catalyst is not known with certitude, but the stereochemical
data combined with our experimental observations concern-
ing the decisive role of the amide NꢀH moiety prompted us
to propose a transition-state model (Scheme 2). In the
presence of the bifunctional catalyst, the activated acid imidic
form would favor the base-catalyzed abstraction of the
(18) For a complete study on the pKa slide rule, see: Gilli, P.; Pretto,
L.; Bertolasi, V.; Gilli, G. Acc. Chem. Res. 2009, 42, 33.
(19) Presset, M.; Coquerel, Y.; Rodriguez, J. J. Org. Chem. 2009, 74,
415.
(20) See Supporting Information for experimental details. Unreac-
tive substrates 1hꢀj.
(21) We observed a similar effect with R-ketoamides in organocata-
ꢀ
lyzed conjugate addition to nitroolefins: Basle, O.; Raimondi, W.;
Sanchez Duque, M. M.; Bonne, D.; Constantieux, T.; Rodriguez, J.
Org. Lett. 2010, 12, 5246.
(22) CCDC 798318 contains the supplementary crystallographic
data for this paper which can be obtained free of charge from The
Cambridge Crystallographic Data Centre (www.ccdc.cam.uk/data_re-
quest/cif).
3298
Org. Lett., Vol. 13, No. 13, 2011

Scheme 2. Transition-State Model for the Michael Addition of
β-Ketoamides
Scheme 3. Synthesis and Oxidation of Hemi-aminal 5
between β-ketoamide 1g and acrolein, in toluene at ꢀ40 °C,
produced the spiro-hemiaminal 5 as a 3/2 mixture of two
diastereomers according to a domino Michael additionꢀ
spiro-hemiacetalization sequence.23 Oxidation of 5 afforded
the corresponding spiroimide 6 isolated with an excellent
ee of 98%. This methodology opens the way to a general
access to various aza-spiro compounds24 under an optically
active form,25 which is of prime importance since biologi-
cal activities are frequently associated with the asymmetric
spiro-carbon atom.26
In summary, we have developed the first organocatalytic
enantioselective conjugate addition of R-substituted β-ketoa-
mides to unsaturated carbonyls by bifunctional catalysts,
involving anunprecedentedcooperativeeffectofthe amide
function in the activation of these pronucleophiles. The
corresponding adducts containing a highly functionalized
all-carbon quaternary stereocenter are obtained in good
yields and high to excellent ee’s. The synthetic potential of
the products bearing the extra amide function was high-
lighted using acrolein through a new domino spiroannula-
tion leading to a synthetically valuable intermediate
precursor of highly enantioenriched spiro-heterocycles of
biological and synthetic interest.
exposed methine proton to generate a reactive enolate inter-
mediate stabilized by the thiourea function. Subsequently, the
resulting protonated tertiary amine would coordinate the
basic oxygen atom of the tautomeric amide form, resulting in
the formation of an ion pair complex in which only the re face
of the enolate is accessible. As a consequence, the acidic
amide NꢀH would be free to activate the carbonyl of the
acceptor, according to Miller’s model.10 This proposed dou-
ble activation of both the substrate and acceptor by the (R,
R)-TUC catalyst may account for the observed R absolute
configuration and highlights the crucial cooperative role of
the NꢀH proton in the activation.
Acknowledgment. This work was supported by the
Agence Nationale de la Recherche (ANR-07-CP2D-06),
ꢀ
ꢀ
the Universite Paul Cezanne, the CNRS, and the Centre
ꢀ
ꢀ
ꢀ
ꢀ
Regional de Competences en Modelisation Moleculaire de
Marseille (CR-CMM). Dr. Nicolas Vanthuyne (ee mesure-
ments), Dr. J.-V. Naubron (VCD analysis), and Dr. M.
Giorgi (X-ray analysis) are gratefully acknowledged.
Figure 2. Scope of the enantioselective Michael addition.
The next step was the investigation of the scope of the
process compiled in Figure 2. Various cyclic substrates
were reacted with either methyl- or ethylvinylketone to
afford the corresponding adducts 4jꢀr in good yields and
high ee’s up to 99%. This methodology works well with
five- and six-membered cyclic compounds, and tosyl and
naphthyl derivatives generally give the best results. Sub-
stituted indanones and tetralones proved also to be suita-
ble substrates, allowing this methodology to generate
complex structure diversity 4o,p,r without altering the
enantioselective potential of the process.
Supporting Information Available. Experimental pro-
cedures, NMR spectra, chiral HPLC chromatograms,
and cif file of 4d. This material is available free of charge
via the Internet at http://pubs.acs.org.
(24) Zhou, C.-Y.; Che, C.-M. J. Am. Chem. Soc. 2007, 129, 5828.
Adam, A. W.; Boehmer, J.; Dixon, D. J. Angew. Chem., Int. Ed. 2007, 46,
5428. Habib-Zahmani, H.; Viala, J.; Hacini, S.; Rodriguez, J. Synlett
2007, 1037. Boddaert, T.; Coquerel, Y.; Rodriguez, J. Adv. Synth. Catal.
2009, 351, 1744. Li, M.; Dixon, D. J. Org. Lett. 2010, 12, 3784. Presset,
M.; Coquerel, Y.; Rodriguez, J. Org. Lett. 2010, 12, 4212.
(25) To our knowledge, there is only one isolated example of an
optically pure spirolactam of this type reported in the literature: Hilmey,
D. G.; Paquette, L. A. Org. Lett. 2005, 7, 2067.
(26) Meng, X.; Maggs, J. L.; Pryde, D. C.; Planken, S.; Jenkins, R. E.;
Peakman, T. M.; Beaumont, K.; Kohl, C.; Park, B. K.; Stachulski, A. V.
J. Med. Chem. 2007, 50, 6165. Nakagawa, A.; Uno, S.; Makishima, M.;
Miyachi, H.; Hashimoto, Y. Bioorg. Med. Chem. 2008, 16, 7046.
We then investigated the use of enals in place of enones
(Scheme 3). To our delight, the (R,R)-3f-catalyzed reaction
(23) The ee of 5 was not determined because of its instability under
chiral HPLC analysis conditions.
Org. Lett., Vol. 13, No. 13, 2011
3299