Direct asymmetric vinylogous Michael addition of cyclic enones to nitroalkenes via dienamine catalysis

Article abstract of DOI:10.1073/pnas.1001150107

In spite of the many catalytic methodologies available for the asymmetric functionalization of carbonyl compounds at their a and β positions, little progress has been achieved in the enantioselective carbon-carbon bond formation ? to a carbonyl group. Her

Full text of DOI:10.1073/pnas.1001150107

Corrections
BIOCHEMISTRY
CHEMISTRY
Correction for “Confinement of caspase-12 proteolytic activity to
autoprocessing,” by Sophie Roy, Jeffrey R. Sharom, Caroline
Houde, Thomas P. Loisel, John P. Vaillancourt, Wei Shao, Maya
Saleh, and Donald W. Nicholson, which appeared in issue 11,
March 18, 2008, of Proc Natl Acad Sci USA (105:4133–4138; first
published March 10, 2008; 10.1073/pnas.0706658105).
The authors note that Fig. 6 appeared incorrectly. There was
an error in the alignment of the molecular mass markers, and
minor adjustments have been made to the assignment of caspase-
12 bands. The authors also note that the source of the anti-
caspase-12 antibody for Fig. 6 was Sigma (clone 14F7). This
error does not affect the conclusions of the article. The corrected
figure and its corresponding legend appear below.
Correction for “Direct asymmetric vinylogous Michael addition
of cyclic enones to nitroalkenes via dienamine catalysis,” by
Giorgio Bencivenni, Patrizia Galzerano, Andrea Mazzanti,
Giuseppe Bartoli, and Paolo Melchiorre, which appeared in issue
48, November 30, 2010, of Proc Natl Acad Sci USA (107:20642–
20647; first published June 21, 2010; 10.1073/pnas.1001150107).
The authors note that they incorrectly assigned the structure
of the reaction product reported in Scheme 4. The published
structure represents the γ-aminated adduct 8, when it should
instead be the α-analogue arising from an α-site selective path-
way. As a result of this, Scheme 4 and its related comments
should be removed from the article.
On page 20642, left column, within the Abstract, lines 16–18,
“Finally, we describe the extension of the dienamine catalysis-
induced vinylogous nucleophilicity to the asymmetric γ-amination
of cyclohexene carbaldehyde” should be removed from the article.
On page 20645, right column, third full paragraph, lines 1–8,
to page 20646, left column, first paragraph, lines 1–2, “Finally, to
explore the potential of the chiral primary amine-induced vi-
nylogous nucleophilicity, we wondered whether this unique re-
activity concept may be translated to an aldehyde derivative
adorned with a six-membered ring scaffold, reminiscent of the
β-substituted cyclohexanone framework. Although the vinylogous
Michael addition of 1-cyclohexene-1-carboxaldehyde 7 to ni-
trostyrene 2a did not proceed at all, the combination with tert-
butylazodicarboxylate under the catalysis of A furnished the
γ-amination product 8 with perfect regio- and enantioselectivity
(Scheme 4)” should be removed from the article.
kDa
150
IP: Anti-Flag-caspase-1
Western: Anti-Csp-12
100
75
proCaspase-12
50
*
37
Auto-processing products
These errors do not affect the conclusions of the article of the
vinylogous Michael addition of cyclic enones to nitroalkenes. The
ability of primary amine catalysis to address the synthetic issue
connected with the enantioselective carbon–carbon bond forma-
tion gamma to a carbonyl group, promoting vinylogous nucleo-
philicity upon selective activation of unmodified cyclic unsaturated
ketones, is fully supported by the separated results presented in
Tables 1, 2, and 3, and Schemes 2 and 3.
25
20
IgG light chain
15
1
2
3
4
5
Total
IP
www.pnas.org/cgi/doi/10.1073/pnas.1302980110
Fig. 6. Procaspase-12 forms a complex with caspase-1 and is partially au-
toprocessed in the complex. HEK293T cells were cotransfected with expres-
sion vectors harboring Flag-tagged procaspase-1 (all lanes) plus either
procaspase-12 (lanes 1 and 4) or the catalytically incapacitated C299A mutant
(lanes 2 and 5). After 24 h, cells were harvested and lysed. One tenth of the
lysate was directly applied to SDS/PAGE (lanes 1 and 2), and the remainder
was immunoharvested with antibodies directed against the caspase-1 Flag
epitope tag (lanes 4 and 5; lane 3 was processed in the same way, except that
only lysis buffer was used). Immunoblotting for the large subunit (p20) of
caspase-12 revealed that procaspase-12 and the resulting autocleavage
product were both immunoharvested with caspase-1. The asterisk indicates
a band of unknown identity that is detected by prebleed control serum.
www.pnas.org/cgi/doi/10.1073/pnas.1302753110
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www.pnas.org

MICROBIOLOGY
Correction for “Commensal bacteria play a role in mating
preference of Drosophila melanogaster,” by Gil Sharon, Daniel
Segal, John M. Ringo, Abraham Hefetz, Ilana Zilber-Rosenberg,
and Eugene Rosenberg, which appeared in issue 46, November
16, 2010, of Proc Natl Acad Sci USA (107:20051–20056; first pub-
lished November 1, 2010; 10.1073/pnas.1009906107).
The authors note the following: “The mating frequencies
reported in Table 1 of this paper did not follow a multinomial
distribution, making the statistical analysis inapplicable. This
problem was obviated by considering only the first matings
in each experimental unit and computing odds ratios. After
submitting the paper, we continued to perform experiments
identical in design to those we reported. In the table below,
we combined the results of those additional replicate experi-
ments with those already reported. From the new analysis, we
now find that experiment 4, in which flies were infected with
a mixture of Lactobacillus spp., assortative mating was not
restored. Otherwise, the conclusions of the article were not
changed by our reanalysis. We acknowledge the statistical ad-
vice of Dan Yekutieli and thank Tal Lahav for calculating the
odds ratios and their 95% confidence intervals, and for per-
forming the chi-squared tests presented in the corrected
Table 1.”
The corrected Table 1 appears below.
Table 1. The role of bacteria in diet-induced mating preference of D. melanogaster
Experiment
Fly treatment*
N†
OR‡
95% CI
P value‡
1
2
3
4
5
6
Starch-grown × CMY-grown
Experiment 1 after antibiotics
Experiment 2 after infection of starch-grown flies with homologous bacteria§
Experiment 3 with Lactobacillus spp. replacing homologous bacteria
Experiment 3 with Lactobacillus plantarum replacing homologous bacteria
Infection control (no added bacteria)
18
11
6
4
7
3.21
1.04
2.68
1.76
2.14
1.26
2.14–4.81
0.63–1.71
1.40–5.11
0.74–4.19
1.35–3.39
0.53–3.00
1.8 × 10−8
0.9888
0.0477
0.2912
0.0019
0.7712
4
*After all treatments, the flies were grown for one generation in CMY medium before performing the mating preference test.
†N is the number of replicate experiments.
‡Cochran-Mantel-Haenszel Odds Ratio and P value are from the Cochran-Mantel-Haenszel Chi-squared test (34, 35).
§Antibiotic-treated starch- and CMY-grown flies were infected with bacteria isolated from their respective growth medium (before antibiotic treatment).
34. Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22(4):719–748.
35. Cochran WD (1954) Some methods for strengthening the common χ2 tests. Biometrics 10:417–451.
www.pnas.org/cgi/doi/10.1073/pnas.1302326110
MEDICAL SCIENCES
SYSTEMS BIOLOGY
Correction for “Interaction of intracellular β amyloid peptide
with chaperone proteins,” by Virginia Fonte, Vadim Kapulkin,
Andrew Taft, Amy Fluet, David Friedman, and Christopher
D. Link, which appeared in issue 14, July 9, 2002, of Proc Natl
Acad Sci USA (99:9439–9444; first published June 27,
2002; 10.1073/pnas.152313999).
The authors note that the author name Vadim Kapulkin should
instead appear as Wadim Jan Kapulkin. The corrected author line
appears below. The online version has been corrected.
Correction for “Expanded methyl-sensitive cut counting reveals
hypomethylation as an epigenetic state that highlights functional
sequences of the genome,” by Alejandro Colaneri, Nickolas Staffa,
David C. Fargo, Yuan Gao, Tianyuan Wang, Shyamal D. Peddada,
and Lutz Birnbaumer, which appeared in issue 23, June 7, 2011,
of Proc Natl Acad Sci USA (108:9715–9720; first published
May 20, 2011; 10.1073/pnas.1105713108).
The authors note that, within the corresponding author foot-
note on page 9715, the email address “colaneria@niehs.nih.gov”
should instead appear as “acolaneri_2000@yahoo.com.ar”.
www.pnas.org/cgi/doi/10.1073/pnas.1302473110
Virginia Fonte, Wadim Jan Kapulkin, Andrew Taft,
Amy Fluet, David Friedman, and Christopher D. Link
www.pnas.org/cgi/doi/10.1073/pnas.1302545110
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4853

Direct asymmetric vinylogous Michael addition of
cyclic enones to nitroalkenes via dienamine catalysis
Giorgio Bencivennia, Patrizia Galzeranoa, Andrea Mazzantia, Giuseppe Bartolia, and Paolo Melchiorreb,c,1
aDipartimento di Chimica Organica “A. Mangini,” Università di Bologna, Viale Risorgimento 4, 40136 Bologna, Italy; bInstitució Catalana de Recerca i
c
Estudis Avançats, Passeig Lluís Companys 23-08010 Barcelona, Spain; and Institute of Chemical Research of Catalonia, Avenida Països Catalans 16-43007
Tarragona, Spain
Edited by David W. C. MacMillan, Princeton University, Princeton, NJ, and accepted by the Editorial Board May 29, 2010 (received for review February 1, 2010)
In spite of the many catalytic methodologies available for the
asymmetric functionalization of carbonyl compounds at their α
and β positions, little progress has been achieved in the enantiose-
lective carbon–carbon bond formation γ to a carbonyl group. Here,
we show that primary amine catalysis provides an efficient way to
address this synthetic issue, promoting vinylogous nucleophilicity
upon selective activation of unmodified cyclic α,β-unsaturated
ketones. Specifically, we document the development of the unpre-
cedented direct and vinylogous Michael addition of β-substituted
cyclohexenone derivatives to nitroalkenes proceeding under die-
namine catalysis. Besides enforcing high levels of diastereo- and
enantioselectivity, chiral primary amine catalysts derived from
natural cinchona alkaloids ensure complete γ-site selectivity: The
resulting, highly functionalized vinylogous Michael adducts,
having two stereocenters at the γ and δ positions, are synthesized
with very high fidelity. Finally, we describe the extension of the
dienamine catalysis-induced vinylogous nucleophilicity to the
asymmetric γ-amination of cyclohexene carbaldehyde.
Fig. 1. Dienamine catalysis and the concept of vinylogy; Elec, electrophile.
challenge of site-selectivity onto the already present issue of
stereo-selectivity. In general, the critical regiochemical issue
can be addressed by judiciously preparing preformed, stable
dienolate equivalents. This strategy has been successfully applied
to asymmetric vinylogous aldol (17, 21), Mannich (18, 22), and
Michael reactions (19, 23). Avoiding the stoichiometric preacti-
vation of the vinylogous nucleophilic components would logically
improve this approach, particularly from the standpoint of atom
economy (24). However, examples of direct, catalytic, and asym-
metric vinylogous reactions are rare: Recently, Trost and Hitce
reported on the direct vinylogous Michael addition of 2(5H)-
furanone to nitroalkenes under dinuclear zinc catalysis (25),
whereas chiral Brønsted base catalysis proved successful to acti-
vate specific reactive alkenes, such as α,α-dicyano olefins, toward
vinylogous nucleophilicity (26).
Within this context, we wondered whether asymmetric amino-
catalysis could solve the challenge of a direct vinylogous nucleo-
philic addition of unmodified γ-enolizable carbonyl compounds.
We were inspired by a recent report by Jørgensen and coworkers
on the direct, enantioselective γ amination of α,β-unsaturated
aldehydes using azodicarboxylates as the electrophilic nitrogen
source (27). The process is based on a unique activation mode,
dienamine catalysis, which exploits the condensation of a chiral
secondary amine catalyst with β-aliphatic-substituted unsaturated
compounds. This condensation leads to the formation of the
expected electrophilic iminum ion intermediate, which is in equi-
librium with an electron-rich dienamine intermediate. The diena-
mine, exploiting its γ-nucleophilic character, actually represents
the catalytic active species. In principle, the ability to promote the
in situ formation of a dienamine from γ-enolizable carbonyl com-
pounds while enforcing γ-site selectivity during the nucleophilic
path might offer a unique and potent way to design direct viny-
logous processes (Fig. 1).
asymmetric synthesis ∣ Michael reaction ∣ organocatalysis
he stereoselective functionalization of carbonyl compounds,
Tparticularly while concomitantly forming a new carbon–
carbon bond, represents one of the more efficient and potent
chemical ways to produce valuable chiral molecules. This target
has inspired generations of synthetic chemists to design unique
chiral catalysts able to enantioselectively forge a stereocenter α
or β to a carbonyl group (1–3). In this context, intense investiga-
tions into the aldol (4, 5) and Michael reactions (6, 7) have made
them invaluable tools in modern organic chemistry. Recently, the
classical organometallic-based approach has been enriched by the
possibility of using chiral primary or secondary amines as efficient
catalysts for the asymmetric functionalization of carbonyl com-
pounds. This strategy is known as “asymmetric aminocatalysis”
(8–11). Among the many advantages of this synthetic approach
(12), one of its more attractive features is the ability to directly
generate, in situ, the catalytically active intermediates from
unmodified carbonyl compounds (13, 14).
Both metal- and organic-based approaches have achieved
levels of reliability such that synthetic chemists can now address
even the most daunting issues connected with the asymmetric cat-
alytic functionalization of carbonyl compounds at their α and β
positions. In contrast, little progress has been reported in the cor-
responding enantioselective carbon–carbon bond formation γ to
a carbonyl group (15). Among the few useful approaches devised
to date, the concept of vinylogous nucleophilicity is the most
powerful (16–19). Formulated by Fuson in 1935 as the transmis-
sion of electronic effects through a conjugated π system (20), this
principle accounts for the use of γ-enolizable α,β-unsaturated car-
bonyl compounds as precursors of nucleophilic dienolate equiva-
lents, formally inverting the usual reactivity of this compound
class. Vinylogous processes offer an efficient entry onto functio-
nalized building blocks having high level of structural complexity;
however, designing asymmetric catalytic versions is not simple.
Indeed, every approach to vinylogous reactions overlays the
Author contributions: P.M. designed research; G. Bencivenni and P.G. performed research;
G. Bartoli contributed new reagents/analytic tools; A.M. analyzed data; and P.M. wrote
the paper.
The authors declare no conflict of interest.
This article is
a PNAS Direct Submission. D.W.C.M. is a guest editor invited by the
Editorial Board.
Data deposition: The atomic coordinates have been deposited in the Cambridge Structural
Database, Cambridge Crystallographic Data Centre, Cambridge CB2 1EZ, United Kingdom
(CSD reference nos. 763174, 763175, and 763176).
1To whom correspondence should be addressed. E-mail: pmelchiorre@iciq.es.
This article contains supporting information online at www.pnas.org/lookup/suppl/
doi:10.1073/pnas.1001150107/-/DCSupplemental.
20642–20647 ∣ PNAS ∣ November 30, 2010 ∣ vol. 107 ∣ no. 48
www.pnas.org/cgi/doi/10.1073/pnas.1001150107

Scheme 1. The direct vinylogous Michael addition developed in this study.
In spite of the potential to address important synthetic issues,
such as the effective catalytic generation of a new carbon–carbon
bond and a new stereocenter γ to a carbonyl group, dienamine
catalysis has found limited application (28, 29). Accordingly, a
recently published perspective on the advent of organocatalysis
did not include dienamine catalysis among the generic modes
of activation and induction (30). This lack was probably due to
the fact that γ-amination of unsaturated aldehydes was originally
proposed to follow a [4 þ 2] cycloaddition path (27), instead of a
more generalizable nucleophilic addition manifold. Moreover,
some recent studies suggest that chiral secondary amines, such
as proline (31) and its derivatives (32, 33), can activate γ-enoliz-
able unsaturated aldehydes toward the formation of the diena-
mine intermediate, but generally promoting an α-site-selective
alkylation step via enamine catalysis in the presence of suitable
electrophiles. Nonetheless, a recent inspiring report by Christ-
mann and coworkers has highlighted the potential of dienamine
catalysis for enforcing a direct nucleophilic γ-addition path, albeit
in an intramolecular way (34).
Fig. 2. Primary amine catalysts used within this study.
Despite the increased complexity posed by β-substituted cyclic
enones, our choice was motivated by a variety of considerations.
Our experience in designing of cascade reactions (37, 38) strongly
indicated that, when reacted with acyclic, linear α,β-unsaturated
ketones, catalyst A easily facilitates the equilibrium between the
iminium ion and the nucleophilic cross-conjugated dienamine in-
termediate of type I, selectively directing the reaction manifold
toward an α′-site alkylation (path a in Fig. 3). We thus considered
using cyclohexenone derivatives to coax the regiocontrolled for-
mation of extended dienamines within a more thermodynamically
favored six-membered ring scaffold. This idea is based upon re-
lated enolization studies demonstrating that, under certain con-
ditions, the selective formation of the thermodynamic exo-cyclic
enolate of type III is strongly favored over both the endo-isomer
and the kinetic cross-conjugated dienolate (41–45). This inherent
behavior of β-substituted cyclohexenones has found a wonderful
application in the conceptually unique, direct, vinylogous aldol
reaction reported by Yamamoto and coworkers (46, 47): The
complete γ-site selectivity induced by the nonchiral, bulky alumi-
num-based catalyst has been rationalized on the basis of catalyst
steric effects (48, 49), which inhibit base deprotonation at the α′
position, whereas thermodynamic factors account for the forma-
tion of the reactive exo-dienolate isomer of the β-methyl 2-cyclo-
hexen-1-one (46). On these grounds, we considered the unique
Here, we show that dienamine catalysis, induced by chiral pri-
mary amines, can efficiently promote the direct, intermolecular
vinylogous Michael addition of unmodified β-substituted cyclo-
hexenone derivatives to nitroalkenes, imparting high levels of
diastereo- and enantioselectivity, and ensuring exclusive γ-site se-
lectivity. Notably, the two stereocenters at the γ and δ positions of
the carbonyl moiety are formed with very high fidelity (Scheme 1).
Results and Discussion
Background. Our laboratory and others, independently, have re-
cently introduced 9-amino(9-deoxy)epicinchona alkaloids
(Fig. 2), chiral primary amines easily derived from natural
sources, as general and effective catalysts for a wide variety of
asymmetric α and β functionalizations of ketones (35, 36). We
have further demonstrated the ability of catalyst A, derived from
hydroquinine, to combine orthogonal aminocatalytic modes
(iminium and enamine activations) into one mechanism, thus pro-
moting cascade reactions with α,β-unsaturated ketones (37, 38)
and even with the challenging α,β-disubstituted enals (39).
Next, we decided to investigate the behavior of this versatile
catalyst in the context of the elusive γ-site activation of unmodi-
fied enones, in order to design a dienamine-catalyzed direct,
vinylogous Michael reaction. From the outset, we were fully
aware of the inherent difficulties of our target, because the
presence of multiple potential sites of enolization has greatly
hampered the use of α,β-unsaturated ketones in even the stoi-
chiometric version of vinylogous reactions (40). We decided to
attack this problem by selecting β-substituted cyclohexenone de-
rivatives as a model substrate. At first glance, this compound class
seems highly challenging, because it further enhances the task of
regioselectivity (Fig. 3). The condensation of a chiral primary
amine catalyst with cyclic enones would lead to the formation
of the iminium ion, which could equilibrate, upon selective α′-de-
protonation or γ- and γ′-deprotonation, with the kinetic cross-
conjugated dienamine intermediate I or the thermodynamic
extended dienamines II and III, respectively. Although the for-
mer would open an avenue for α′-site alkylation (path a in Fig. 3),
the extended dienamines could be alkylated at three different
positions, namely α, γ, and even γ′, behaving as d2 or d4 reagents
(paths b, d, and c, respectively).
Fig. 3. Challenges arising from the site-selective formation of dienamines.
Bencivenni et al.
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ability of catalyst A, in combination with an acidic cocatalyst, to
perturb the iminium-dienamine equilibrium, taken together with
thermodynamic factors, that may govern the regioselective for-
mation of the exo-cyclic dienamine intermediate. We wondered
if this ability might be exploited to develop the challenging
γ-site-selective, direct stereoselective addition of β-methyl
2-cyclohexen-1-one to nitrostyrene derivatives (following the nu-
cleophilic path d in Fig. 3). Theoretical calculations accounting
for a thermodynamically driven site-selective formation of a
dienamine of type III are reported in the SI Appendix.
productively bind the two reaction partners of the vinylogous Mi-
chael addition. B has recently been introduced by Chen et al. as
an efficient bifunctional catalyst of the asymmetric 1,3-dipolar
cycloaddition of cyclic enones (51). Catalyst B greatly improved
the enantioselectivity as well as the reaction rate of the vinylogous
addition of 1 to 2a while maintaining a complete γ-selectivity
(Table 1, entry 8). The enhanced catalytic activity allowed us
to lower the catalyst loading to 10 mol % (Table 1, entry 9), de-
lineating a more practical synthetic protocol (extensive optimiza-
tion studies can be found within the SI Appendix).
The best result was obtained with the catalytic salt made by
combining B (10 mol %) and 2-fluorobenzoic acid (20 mol %)
in toluene (0.2 M). These conditions were selected to examine
the scope of the vinylogous Michael addition by evaluating a
variety of nitroalkenes (Table 2). Different substituents at the aro-
matic moiety of β-nitrostyrene derivatives were well-tolerated, re-
gardless of their electronic properties, because the corresponding
adducts 3 were obtained in good to high yield and almost perfect
stereocontrol (enantiomeric excesses ranging from 95% to 98%).
The pseudoenantiomeric catalyst C, derived from quinidine,
accounted for the possibility of accessing both antipodes of the
products (Table 2, entries 2 and 10).
As limitations of the direct vinylogous Michael reactions, ali-
phatic nitroalkenes did not react under the described conditions.
Moreover, modifying the cyclic scaffold of the nucleophilic com-
ponent (i.e., 3-methyl 2-cyclopenten-1-one) resulted in a com-
plete loss of reactivity, a result that highlights how strongly the
cyclic scaffold geometry influences (and drives) the selective for-
mation of the thermodynamic, extended dienamine intermediate.
The absolute configuration of the stereogenic center was un-
ambiguously determined to be R by anomalous dispersion X-ray
crystallographic analysis of the bromide derivative 3d. The ability
of the catalyst to communicate its inherent stereochemical infor-
mation while forging the new stereocenter at the δ position,
several atoms apart from the catalyst binding point within the
covalent dienamine intermediate, seemed noteworthy to us. It
is also intriguing to consider how primary amine catalysis can
impart unique mechanistic pathways, thus complementing and
Organocatalytic Vinylogous Michael Addition. The vinylogous
Michael addition under dienamine catalysis was first evaluated
by mixing 2 equivalents of β-methyl 2-cyclohexen-1-one 1 and ni-
trostyrene 2a in toluene (1 M, 48 h, 40 °C). In accordance with
our mechanistic postulate, the chiral primary amine A (20 mol %),
in combination with 30 mol % of 2-fluorobenzoic acid as the co-
catalyst, directed the reaction manifold toward a γ-site-selective
addition, leading to compound 3a as the unique product of the
process and with a good level of enantiocontrol (Table 1, entry 1).
Examination of the reaction media revealed that the catalytic
process was greatly influenced by polarity, with solvents with a
high dielectric constant strongly affecting both reactivity and en-
antioselectivity (Table 1, entries 1–5). The nature of the acidic
cocatalysts was also a crucial parameter, with stronger acids lead-
ing to worse results (Table 1, entries 1, 6, and 7). This evidence
suggests that fine tuning the carboxylic acid cocatalyst is essential
to modulate the perturbation of the delicate equilibrium between
iminium ion, cross-conjugated and extended dienamine inter-
mediates during the reaction.
These results further consolidate A as a general, highly versa-
tile catalyst for the activation of keto compounds, even toward
vinylogous nucleophilicity. However, we were not satisfied with
the level of stereocontrol in the present chemistry. We speculated
that using a bifunctional catalyst capable of simultaneously
activating both the electrophilic and nucleophilic components
might lead to higher catalytic activity and, more importantly,
to better stereocontrol (50). To this end, we tested the potential
of 6′-hydroxy-9-amino-9-deoxyepiquinine B to synergistically and
Table 1. Optimization studies of the vinylogous Michael addition
under dienamine catalysis
Table 2. Vinylogous Michael addition: Scope of the nitrostyrene
derivatives
ee, %†
Entry Amine
Acid
Solvent Conversion, %* ee, %†
Entry
Catalyst
R
3
Yield, %*
1
2
3
4
5
6
7
8
9
A
A
A
A
A
A
A
B
2F-C6H4CO2H
2F-C6H4CO2H
2F-C6H4CO2H
2F-C6H4CO2H
2F-C6H4CO2H
TFA
2NO2-C6H4CO2H Toluene
2F-C6H4CO2H
2F-C6H4CO2H
Toluene
CHCl3
THF
MeOH
MeCN
Toluene
>95
52
30
<5
12
82
79
82
—
—
—
80
98
98§
1
2
3
4
5
6
7
8
9
10
B
C
B
B
B
B
B
B
B
C
Ph
Ph
4-MeO-Ph
4-Me-Ph
4-Br-Ph
2-Cl-Ph
2-F-Ph
2-thiophenyl
2-OBn-Ph
2-OBn-Ph
a
a
b
c
d
e
f
g
h
h
77
55
70
70
73
84
83
68
87
68
98
95‡
97
98
97
96
97
98
97
96‡
<5
45
Toluene
Toluene
>95
B
>95 (77)‡
TFA, trifluoroacetic acid; reactions carried out using two equivalents of
Bn, benzyl; reactions carried out using two equivalents of enone 1. 1H NMR
analysis of the crude mixture indicated a highly γ-site-selective alkylation
pathway, other products arising from different reaction manifolds (e.g.,
α′-alkylation under enamine catalysis, see ref. 52) being sporadically
detected in negligible amounts.
enone 1
*Conversion determined by 1H NMR analysis of the crude mixture; only
product 3a, derived from a γ-site-selective alkylation step, has always
been detected.
†The enantiomeric excess (ee) was determined by HPLC analysis on chiral
stationary phases.
*Yield of the isolated compounds 3.
‡Number in parentheses refers to yield of the isolated compound 3a.
§Reaction performed in the presence of 10 mol % of B and 20 mol % of
2F-C6H4CO2H and using ½2ꢀ0 ¼ 0.2 M
†The enantiomeric excess (ee) was determined by HPLC analysis on chiral
stationary phases.
‡The opposite (S) enantiomer has been obtained using catalyst C.
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Bencivenni et al.

pound 5 with complete control over the relative stereochemistry
and high enantioselectivity (54).
Next, we studied the possibility of forging two contiguous
stereogenic centers at the γ and δ positions, examining the
vinylogous Michael addition of differently β-substituted cyclohex-
anones to a variety of nitrostyrene derivatives under the catalysis
of the salt made by combining 20 mol % of the chiral primary
amine B with 30 mol % of 2-fluorobenzoic acid. In line with pre-
vious observations, the nature of the carboxylic acid cocatalyst
strongly influenced both the reactivity and the stereochemical
outcome of the process: Carrying out the reaction in the presence
of 40 mol % of salicylic acid afforded higher enantiocontrol and
an increased reaction rate, albeit with slightly lower diastereos-
electivity (Table 3, entries 1 and 2). Thus, both catalyst salt com-
binations, where B is mixed with 2-fluoro- or 2-hydroxybenzoic
acids, have been evaluated. Selected results are reported in
Table 3. In general, a variety of substrate combinations can be
realized, leading to products 6, readily amenable to further func-
tionalizations, with high levels of γ-site, diastereo- and enantios-
electivity.
Crystals from bromide 6l and from compound 6i were suitable
for X-ray analysis, which established the absolute configuration of
the vinylogous reaction as well as its anti-stereochemical out-
come. Interestingly, the observed sense of relative stereoinduc-
tion is not common in the corresponding enamine-catalyzed
Michael addition of carbonyls to nitroalkenes, which generally
leads to a syn-relationship (55, 56).
Finally, to explore the potential of the chiral primary amine-
induced vinylogous nucleophilicity, we wondered whether this
unique reactivity concept may be translated to an aldehyde
derivative adorned with a six-membered ring scaffold, reminis-
cent of the β-substituted cyclohexanone framework. Although
the vinylogous Michael addition of 1-cyclohexene-1-carboxalde-
hyde 7 to nitrostyrene 2a did not proceed at all, the combination
with tert-butylazodicarboxylate under the catalysis of A furnished
Schemes 2 and 3.
enriching the established reactivity profile of secondary amine
catalysis. Within this context, a recent report has demonstrated
that a chiral secondary amine behaves in a completely different
way when exposed to the very same reagents combination, namely
β-methyl cyclohexenone and nitrostyrene, catalyzing a Diels-
Alder reaction between 1 and 2a via the selective formation of
cross-conjugated dienamine of type I (52).
Our vinylogous protocol could be successfully extended to a
β,β-disubstituted nitrostyrene, leading to the stereocontrolled
generation of compound 4 having an all-carbon quaternary
(53) stereocenter (Scheme 2). Moreover, a different class of
Michael acceptor has proven to be a viable component of the
dienamine-catalyzed direct vinylogous addition. Mixing β-methyl
2-cyclohexen-1-one with trans-α-cyanocinnamate under the cata-
lysis of A furnished the corresponding vinylogous adduct with two
stereogenic centers. As reported in Scheme 3, to avoid the
epimerization event, we designed a one-pot vinylogous Michael
addition/amination tandem sequence, directly leading to com-
Table 3. Stereoselective creation of vicinal stereocenters under dienamine catalysis
Entry
Catalyst salt combination
R1
R2
6
Yield, %*
dr
ee, %†
1
2
3
4
5
6
7
8
a
b
a
a
b
b
b
b
b
b
b
b
b
b
Me
Me
Me
Me
Me
Me
Me
Me
Bn
allyl
propyl
propyl
propyl
Ph
Ph
Ph
a
a
b
c
d
e
f
g
h
i
72
80
78
76
81
65
80
90‡
65‡
44
86‡
72
50
86‡
9∶1
6∶1
10∶1
10∶1
5∶1
3∶1
6∶1
3.3∶1
7∶1
11.5∶1
11.5∶1
13.5∶1
10∶1
2∶1
92
94§
94
92
93
95
90
94
4-MeO-Ph
4-Me-Ph
4-Br-Ph
4-NO2-Ph
2-F-Ph
2-thiophenyl
Ph
Ph
Ph
4-MeO-Ph
4-Br-Ph
Ph
9
85
10
11
12
13
14
94§
95
j
k
l
91§
94§
90§
m
Bn, benzyl; reactions carried out using two equivalents of enones 1. 1H NMR analysis of the crude mixture indicated a highly γ-site-
selective alkylation pathway, other products arising from different reaction manifolds (e.g., α′-alkylation under enamine catalysis, see
ref. 52) being sporadically detected in negligible amounts.
*Refers to the isolated single, major diastereoisomer.
†The enantiomeric excess (ee) was determined by HPLC analysis on chiral stationary phases.
‡Refers to the isolated mixture of diastereoisomers.
§Enantiomerically pure products obtained after a single crystallization.
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promote vinylogous nucleophilicity within addition reaction
manifolds. We believe this reactivity may be further extended
to a variety of vinylogous donors and acceptors as well as to
nucleophilic substitution reactions.
Methods and Materials
All the vinylogous adducts were fully characterized: Structural proofs and
spectral data for all compounds are provided in the SI Appendix.
All the reactions were carried out in undistilled solvent without any pre-
cautions to exclude moisture. To a solution of 9-amino(9-deoxy)epicinchona
alkaloids A–C (0.08 mmol) in 0.8 mL of toluene, ortho-fluorobenzoic acid
(0.16 mmol, 22.4 mg) was added at room temperature under stirring.
After 10 min, the reaction was started with the addition of β-substituted cy-
clohexenone derivative 1 (0.8 mmol, 2.0 equiv) immediately followed by the
nitroalkene 2 (0.4 mmol, 1.0 equiv), and the mixture was allowed to reach 40
°C. Stirring was continued until complete conversion of the starting material
(24–48 h, checked by thin layer chromatography). The reaction mixture was
then directly purified by flash column chromatography (SiO2, 20–30% ethyl
acetate in hexane) to yield the vinylogous adducts 3 or 6.
Scheme 4.
the γ-amination product 8 with perfect regio- and enantioselec-
tivity (Scheme 4).
Concluding Remarks
The direct, γ-site-selective addition of β-substituted cyclohexe-
none derivatives to nitroalkenes represents one of the few exam-
ples of catalytic, asymmetric vinylogous Michael reactions of
unmodified carbonyl compounds. This unprecedented chemical
transformation affords highly functionalized compounds, having
two stereocenters at the γ and δ positions, with high enantiomeric
purity. In addition to its synthetic interest, this study confirms the
ability of chiral primary amine catalysis to impart unique reactiv-
ity profiles, thus expanding the potential of asymmetric aminoca-
talysis. Specifically, dienamine catalysis has been exploited to
ACKNOWLEDGMENTS. We thank F. Pesciaioli for fruitful discussions during the
early stage of the research project. G. Bergonzini is gratefully acknowledged
for her experimental support. This work was supported by Bologna Univer-
sity, the Catalan Institution for Research and Advanced Studies, and the
Institute of Chemical Research of Catalonia Foundation.
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