α-Branched Ketone Dienolates: Base-Catalysed Generation and Regio- and Enantioselective Addition Reactions

Article abstract of DOI:10.1002/chem.201901694

In this study, the unique capacity of bifunctional Br?nsted bases to generate α-branched ketone dienolates and control both site- and stereoselectivity of their addition reactions to representative classes of carbon electrophiles (i.e., vinyl sulfones, nitroolefins, formaldehyde) is documented. We demonstrate that by using selected chiral tertiary amine/squaramide catalysts, the reactions of β,γ-unsaturated cycloalkanones proceed through the dienolate Cα almost exclusively and provide all-carbon quaternary cyclic ketone adducts in good yields with very high enantioselectivities. A minor amount (<5 %) of γ-addition is observed when nitroolefins are used as electrophiles. The parent acyclic ketone dienolates proved to be less reactive under these conditions, and thus still constitute a challenging class of substrates. Quantum chemical calculations correctly predict these differences in reactivity and explain the observed site-specificity and enantioselectivity.

Full text of DOI:10.1002/chem.201901694

A Journal of
Accepted Article
Title: α-Branched Ketone Dienolates: Base-Catalyzed Generation and
Regio- and Enantioselective Addition Reactions
Authors: Iñaki Urruzuno, Odei Mugica, Giovanna Zanella, Silvia Vera,
Enrique Gómez-Bengoa, Mikel Oiarbide, and Claudio Palomo
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To be cited as: Chem. Eur. J. 10.1002/chem.201901694
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-Branched Ketone Dienolates: Base-Catalyzed Generation and
Regio- and Enantioselective Addition Reactions.
Iñaki Urruzuno, Odei Mugica, Giovanna Zanella, Silvia Vera, Enrique Gómez-Bengoa, Mikel Oiarbide,* and
Claudio Palomo*[a]
Abstract: In this study, the unique capacity of bifunctional Brønsted
bases to generate -branched ketone dienolates and control both
site- and stereoselectivity of their addition reactions to representative
classes of carbon electrophiles (i.e. vinyl sulfones, nitroolefins,
formaldehyde) is documented. We demonstrate that using selected
chiral tertiary amine/squaramide catalysts the reactions of
unsaturated cycloalkanones proceed through the dienolate C
almost exclusively and provide all-carbon quaternary cyclic ketone
adducts in good yields and very high enantioselectivities. Minor
amount (<5%) of -addition is observed when nitroolefins are used
as electrophiles. The parent acyclic ketone dienolates resulted less
reactive under these conditions, constituting a yet challenging
substrate category. Quantum calculations correctly predict these
differences in reactivity and explain the observed site- and
enantioselectivity
Introduction
Over the years the production of, and the reactions with, ketone
enolates and their equivalents have been basic operations in
organic chemistry.1 One of the most significant advances in this
field has been the development of catalytic methods to control
their generation and reactions outcomes.2 In this context, ketone
dienolates and their equivalents pose some unique challenges:
Figure 1. Divergent reaction pathways of dienolates or equivalents and the
while of great synthetic value since they lead to adducts with a
strategically positioned C=C double bond, dienolates may react
through either the  or the  nucleophilic carbon thus demanding
stringent reaction control. To date, the overwhelming majority of
catalytic methods involving dienolate or equivalent intermediates
deal with -unsubstituted ones, and proceed mainly through the
 carbon (vinylogous reactivity, Figure 1a).3 These methods
include catalyst-promoted addition reactions of preformed silyl
dienol ethers (X: OSiR’3)4 as well as direct approaches based on
metallic catalysis (X: O–M),5 dienamine activation (X: NR’2),6
and Brønsted acid7 and base8 catalysis activations. The -attack
pathway seems kinetically favourable because it involves no
disruption of the -conjugation along the reaction coordinate.
challenge to control reactions involving -branched dienolates to obtain -
quaternary products.
Exceptions to this mainstream -selectivity involve concomitant
isomerization of the C=C double bond to yield Morita-Baylis-
Hilmann type adducts (no -stereocenter is formed),9 require
restricted substrate categories10 or substrates with strong steric
bias,11 or lead to moderate enantioselectivity.12 In addition, none
of these -selective methods have been revealed useful for
enantioselective generation of -quaternary ketone (or related
carbonyl) products13, a process that would necessarily involve
as intermediates -substituted dienolates or equivalents (Figure
1b, i). Such a realization would not only require a stringent
control over the E/Z enolate geometry and the face selectivity,
but should also retain sufficient -reactivity despite the steric
congestion at C. This problem has recently been addressed by
Toste via Brønsted acid catalysis14 and as far as we know, no
other solutions have been reported. Moreover, while Brønsted
acid activation approach is well suited for -aminations,14a
apparently shows limitations with common carbon electrophiles
such as conjugated olefins, with allenamides being a notable
exception.14b Herein we report another solution to this problem
by documenting the firstcarbon-carbon bond forming reactions
[a]
Prof. C. Palomo, Prof. M. Oiarbide, Prof. E. Gómez-Bengoa, S.
Vera, I. Urruzuno, O. Mugica, G. Zanella
Departamento de Química Orgánica I
Universidad del País Vasco UPV/EHU
Manuel Lardizabal 3, 20018 San Sebastián, Spain
E-mail: claudio.palomo@ehu.es
Supporting information for this article is given via a link at the end of
the document.
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of -substituted -unsaturated ketones assisted by Brønsted
base/H-bonding catalysis. This mode of activation tolerates
several carbon electrophiles, including conjugated olefins and
formaldehyde and the reactions proceed with very high C-
siteselectivity giving access to all-carbon -quaternary ketone
products in high enantioselectivity (Figure 1b, ii).
Results and Discussion
Quite recently, we have investigated the catalytic reactions of
several in situ generated dienolate systems.15 The finding was
that chiral Brønsted base/H-bonding catalysts16 are able to
promote the smooth, enantioselective addition of -unsaturated
ketones 1 to nitroolefins 2, yielding the -addition adducts 3 as
exclusive products (Scheme 1a). It was noticed that increasing
the size of R1 in 1 the diastereoselectivity improved and the
highest selectivity was attained when using bulky
hydroxyenones (R1: Me2C(OH)) in the presence of Rawal’s17
catalyst C2. The observed reaction outcome is compatible with a
model A (R’= H) in which the catalyst acts in a bifunctional
manner, orienting both reactants correctly. While extrapolation of
model A to -branched ketone dienolates is conceivable (i.e. A,
R’≠ H), two apparent problems to overcome in this model are the
steric shielding at Cand the enolate E/Z configurational
uncertainty. With regard to the former aspect, complications may
be foreseen during both the enolate generation and the
subsequent approaching of the electrophilic reagent. In fact, with
only two specific exceptions from this and another laboratory,18
nearly all of the organocatalytic approaches for the asymmetric
-functionalization, including Michael additions, of -branched
ketones assisted by Brønsted bases are restricted to the use of
active ketones bearing an adjacent electron withdrawing group
(EWG= carbonyl, nitrile, sulfonyl or nitro).13,19 Initial attempts to
perform the reaction between nitrostyrene 2a and -branched
Scheme 1. Impact of -substitution on the reactivity of transiently formed
acyclic ketone dienolates.
These results, whilst promising, highlighted the two main
problems of catalytically generated trisubstituted carbon
nucleophiles: their attenuated reactivity and the difficulties in
controlling enantioface selectivity. Moreover, the significant
variations on the reaction outcome when shifting from methyl to
ethyl or phenyl ketone side-chain seem to indicate that slight
structural changes on the substrate ketone might have huge
impact on reactivity and selectivity. The above observations also
corroborate the multivariable origin of the C/C selectivity in
reactions involving dienolate systems.24
ketones
4 using bifunctional catalyst C7 confirmed the
anticipated pitfalls, resulting in the recovery of unreacted enone
(R1: Ph) or very low conversions to product 5 (R1: Me) as a
mixture of  isomers (Scheme 1b).
We reasoned that highly reactive and sterically less demanding
Michael acceptors such as 1,1-bis(phenylsulfonyl)ethylene 6
might counterbalance the low reactivity of these ketones.
Incidentally, the sulfonyl group in adducts would be susceptible
to several ulterior transformations, including reductive removal.20
To our delight, as the results in Scheme 2 show, -branched
ketones 4 reacted with 6 in the presence of C721, C822 or C923
(formulas in Table 1) to afford adducts 7–9 from reaction at the
-site exclusively, although in variable yields and
enantioselectivity. For example, the reaction between methyl
ketone 4a and 6 in the presence of C9 reached 81% conversion
after 16 h at room temperature, and product 7 was obtained with
79% ee. Catalysts C7 and C8 were less efficient leading to 7 in
yields of 39% and 38% and 63/61% ee, respectively. The
reaction with the ethylketone 4b also proceeded but at much
more paucity giving product 8 with poor enantioselectivity, while
the reaction of phenylketone 4c to give 9 was sluggish.
Scheme 2. Impact of ketone side-chain R1 on the reactivity of derived
dienolates.
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Hypothesis and working plan. To surmount the intrinsic
difficulties mentioned above cyclic ketones were adopted in
which the double bond is tethered at the C-position of the
carbonyl function. The corresponding dienolates might fit better
based on: (i) the higher nucleophilicity of cyclic systems as
compared with the more flexible, open-chain counterparts;25 (ii)
a more rigidified transition state and, thus, more efficient chirality
transfer; (iii) the problem of enolate geometry (E/Z uncertainty)
gets cancelled. For an initial assessment of the reactivity
associated with these nucleophilic systems, we determined the
charge distribution and Fukui nucleophilicity index (f-)26 at the 
carbon of linear (I) and cyclic (II) dienolates (Figure 2).
Computed data27 showed that the differences in negative charge
at that specific carbon is negligible in the two enolates
considered. Similarly, the Fukui indexes of these enolates
showed to be essentially identical (–0.34 and –0.35,
respectively). Accordingly, it appears that purely intrinsic
electronic properties might not be informative in dictating these
reactivity trends, and the role of the bifunctional catalyst as well
as structural factors (steric hindrance, enolate rigidity) or -CH
acidity should also be considered. For a more comprehensive
analysis, energies for the reaction of each enolate system with
bis-sulfone 6 were computed in the presence of a model achiral
squaramide-tertiary amine catalyst (TS(I–II)). As data in Figure 2
show, the computed activation energy for the reaction of cyclic
dienolate II (20.8 kcal/mol) is affordable at room temperature. In
contrast, the activation barrier for the reaction involving acyclic
species I is ca. 24.6 kcal/mol, which correlate with a much more
sluggish reactivity, in good agreement with our preliminary
experimental studies. Calculated data for this model reaction
involving II also support the preference of the -addition
pathway vs. the -addition pathway, the latter showing a barrier
about 6 kcal/mol higher. The preference of the - vs. the -
addition pathway was also found for the catalysed reaction
involving acyclic enolate I (24.6 vs. 27.4 kcal/mol). These data
were revealing given the scarcity of mechanistic information
dealing with latent dienolate systems.28
Cyclic ketone dienolates: catalyst screening and substrate
scope. Encouraged by these theoretical predictions, the
reaction
between
-styryl
cyclohexanone
10A
and
bis(phenylsulfonyl)ethylene 6 was studied in the presence of an
assortment of chiral bifunctional catalysts. By using Takemoto’s
catalyst C129 in CH2Cl2 as solvent at room temperature, product
11A was formed in a poor 26% isolated yield (Table 1, entry 1).
Further screening showed that both the nature of the H-bond
donor site and the structure of the tertiary amine in the catalyst
were critical in terms of reactivity as well as stereoselectivity.
Thus, the reaction did not proceed at all with Rawal’s17
squaramides C2 and C3 (entries 2 and 3), whilst the quinine-
derived thiourea C430 and urea C530 were more active, though
enantioselectivity was poor (entries
4
and 5). Using
squaramide C6, which was effective for the reaction of -
unsubstituted dienolates with nitroolefins,15 reactions
proceeded, but with a modest 60% ee (entry 6). With catalyst
C721 same level of reactivity and a promising stereoselectivity
Table 1. Catalyst screening for the reaction of cyclohexanone 10A with vinyl
sulfone 6 to give 11A.
Entry
Catalyst
Yield (%)[b]
ee (%)[c]
1
2
3
4
5
6
7
8
C1
C2
C3
C4
C5
C6
C7
C8
C9
26
NR
NR
72
79
83
88
87
89
--
--
--
10
40
60
73
98
98
9[d]
Figure 2. Reactivity parameters of two representative ketone dienolates.
[a] Reactions carried out at 0.15 mmol scale, using 2 equiv. of vinyl
disulfone and 10 mol% catalyst in 0.3 mL CH2Cl2 at room temperature. No
product from -addition was detected by 1H NMR (C/C >95:5). [b] Yield
after chromatography. [c] ee determined by chiral HPLC. [d] Reaction run
at 0 °C.
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was observed (entry 7). To our delight with squaramide C8, a
sterically congested catalyst developed by Connon,22 the
reaction between 10A and 6 to afford 11A proceeded in good
isolated yield and, most significantly, in 98% ee (entry 8). A
similar result was obtained (entry 9) with catalyst C9. With both
C8 and C9 selected as the best catalysts, the scope of suitable
alkenyl cycloalkanone substrates was explored . As Table 2
shows, 4-substituted cyclohexanones 12B and 14A provided the
corresponding addition products 13B and 15A in good yield and
high enantioselectivity. Most important, the method turned out to
be equally effective with cycloalkanones of varying ring size. For
instance,
the
C9-catalyzed
reaction
of
-branched
cycloheptanones 16A and 16D afforded adducts 17A and 17D in
yields of 86% and 79%, and selectivities of 96% ee and 93% ee,
respectively. Likewise, reaction with branched cyclooctanone
18A afforded product 19A in high yield, although diminished
(88% ee) enantioselectivity. In this latter case, shifting the
solvent from CH2Cl2 to toluene caused the increase of
enantioselectivity to 94% ee. Under these conditions 18B led to
19B in 88% yield and essentially single enantiomer. The method
also tolerates alkenyl cyclopentanones like 20A and 20E which
produced 21A and 21E with acceptable ee’s. Cyclohexanone
10F was an exception, leading to the corresponding adduct 11F
in good yield, but limited 65% ee. Eventually, the
enantioselectivity could be increased to 80% ee by carrying out
the reaction at –20 °C. In general, similar results were obtained
with both catalysts C8/C9 albeit the latter led to better chemical
yields for cycloalkanones bearing the p-methoxyphenylvinyl
moiety(products 11B, 13B and 19B).
Table 2. Scope of the reaction of -alkenyl cycloalkanones with 6 catalyzed
by C8/C9.[a]
Table 3. Extension to benzofused cycloalkanones.[a]
[a] Reactions carried out at 0.15 mmol scale, using 10 mol% catalyst C8 or
5 mol% catalyst C9 in 0.3 mL of CH2Cl2 unless otherwise stated. Yield of
isolated product after chromatography. Ee determined by chiral HPLC. No
product from -addition was detected by 1H NMR (C/C >95:5).
[a] Reactions carried out at 0.15 mmol scale, using 10 mol% catalyst C8 or
5 mol% catalyst C9 in 0.3 mL of CH2Cl2 unless otherwise stated. Yield of
isolated product after chromatography. Ee determined by chiral HPLC. No
product from -addition was detected by 1H NMR (C/C >95:5). [b]
Reaction carried out in toluene at RT. [c] With 3 equivalents of 6 and 48 h
reaction. [d] 10 mol% of catalyst loading. ND= not determined
Benzo-fused cycloalkanones 22–26 were also excellent
substrates for this catalytic reaction, affording the -quaternary
cycloalkanones 27–31. As the results in Table 3 show, using
catalyst C9 adducts were obtained in good yields and
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remarkably high enantioselectivity regardless the nature of the
substituents at both the aromatic ring (R2) and the olefin (R).
Once again, the method demonstrated general with regard to
the ketone ring size and equally tolerated 5, 6 or 7-membered
cycloalkanones.
intermediate 38 which served to determine the configuration of
adducts.35 Hydrogenation of 35 to give the -dialkyl product 40
shows another possibility. In this case, further Sharpless
oxidative scission of the p-methoxyphenyl moiety36 afforded the
quaternary -keto acid 41 in good overall yield. These are a few
illustrative examples that demonstrate the potential of this
approach to access functionalized cycloalkanones with an all-
carbon quaternary C-stereocenter.
Control experiments showed that for the above reactions the
alternative Brønsted acid14,31 and enamine activation32
approaches were clearly inferior. For example (Scheme 3), in
the presence of 10 mol% (R)-TRIP in toluene at room
temperature no reaction occurred between 10A and 6, while the
same reaction at 40 °C proceeded to give product 11A in 45%
yield, but essentially racemic. Likewise, while the addition of
unsubstituted ketones to vinyl bis(sulfone) 6 has been reported
to proceed selectively via enamine intermediacy,33 attempts to
react 10A with 6 in the presence of chiral primary amines at
room temperature were unfruitful. At 90 °C product 11A was
formed (72% yield) albeit in very low (15% ee) selectivity,
indicating that the amine catalyst is probably acting as a base
rather than via enamine formation. This latter observation
suggests that the enamine pathway is marginal with sterically
congested ketones such as 10A in line with previous
observations by Carter32a,b and Kotsuki32c who have shown that
amine catalysis is still unpractical for branched ketones with -
substituents larger than methyl or ethyl
Scheme 4. Chemical elaboration of the bis(sulfonyl) adducts.
Extension to other carbon electrophiles. Given the
observations noted above, the suitability of carbon electrophiles
other than the vinyl bis(sulfone) 6 was next explored. Initial
attempts with some -substituted Michael acceptors like -
phenyl vinylsulfones and chalcones proved unsuccessful.
However, it was delighting to observe that -substituted
nitroolefins were competent reaction partners.37 For instance,
the reaction of 2-styryl cyclohexanone with nitroolefin 2a in
CH2Cl2 at room temperature catalyzed by C6 afforded a mixture
of the -and -addition adducts in 75:25 ratio, essentially
perfect diastereoselectivity and high enantioselectivity for each
isomer. Further screening of catalysts revealed C1038 superior,
giving rise a 85:15  selectivity ratio and high dr and ee.39
Finally, as Scheme 5 illustrates, further improvement was
achieved by carrying out the reaction at 0 °C and product 42a35
was obtained in 78% isolated yield and with essentially perfect
diastereo- and enantiocontrol (dr>98:2, 99% ee). These results
contrast with the poor behaviour of the parent open chain
branched allyl ketones, vide supra, which under same
conditions resulted to be unreactive. Brief exploration of the
reaction scope with nitroolefins (Scheme 5 top) demonstrated
similar efficiency for related systems. Thus, good yields,  ratio
of about 95:5 and excellent enantioselectivity for the major
isomer were achieved regardless the electron-donor (4-MeC6H4)
Scheme 3. Control experiments involving Brønsted acid and enamine based
activation approaches for this reaction.
Elaboration of adducts. Transformations in Scheme 4 illustrate
the versatility of the adducts as both groups, the alkene and the
sulfone, are amenable for chemical elaboration. For instance,
protection of the carbonyl as ketal and posterior reductive
cleavage of the bis(sulfonyl) group proved feasible. Thus,
ketalization of 11A and subsequent treatment of the resulting 32
with TMSCl/1,2-dimethoxyethane and Mg metal34 afforded the -
ethyl product 34 in good overall yield. A similar reaction
sequence applied to adduct 13B gave rise to product 35
satisfactorily. This sequence, if complemented with an
intermediate bis(sulfone) alkylation step, (e.g., methylation of
32) allows access to superior alkyl systems (e.g., propyl
ketone 36). On the other hand, product 34 could be converted
into diol 39 in a completely stereoselective manner. The
transformation required some carbonyl deprotection/reprotection
tactics, and eventually allowed to get a crystal structure of
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Scheme 5. Catalytic additions to nitroolefins and formaldehyde. aReaction run
for 72 h.
or electron-acceptor (4-ClC6H4, 3-ClC6H4) character of the aryl
groups. Once again, control experiments with 10A and 2a under
Brønsted acid catalysis and amine catalysis, respectively, to
obtain adduct 42a failed or led to no selectivity,39 reinforcing the
unique capacity of the Brønsted base/H-bonding activation
strategy. The utility of this catalytic activation could be extended
to the -hydroxymethylation reaction40 as well. In these
instances the reactions of various cycloalkanones with
paraformaldehyde 44 using catalyst C10 were perfectly site-
selective and adducts 45–48 were formed in ee’s in the range
89–93% irrespective of the cycloalkanone ring size (Scheme 5
bottom).41 In prospect, these results suggest that application of
this Brønsted base/H-bonding strategy might be suitable to
additional carbon electrophiles considerably broadening the pool
of -disubstituted cycloalkanones available until now.
Scheme 6. TS structures and selected parameters for the model reaction
between -branched dienolate II and bis(phenylsulfonyl)ethene.
spite of serious efforts, the alternative Takemoto-type activation
mode,29 with the sulfone oxygens hydrogen-bonded to the
squaramide NH groups, could not be found, probably due to the
low H-bond acceptor character and high steric hindrance of the
sulfone group. In agreement with the experimental observations,
transition state TS-R presents the lowest activation energy (22.1
kcal/mol for catalyst C7) in comparison to 24.3 kcal/mol
predicted for TS-S (slightly higher values of 22.9 and 24.9
kcal/mol, respectively, for catalyst C8). The strongest H-bonds
(shortest XHY bond) were measured for the interaction
between oxyanion II and the two squaramide NH moieties (1.80
and 1.78 Å for catalyst C7) in TS-R, in comparison to the values
found for TS-S (1.85 and 1.83 Å). Similarly, the weak interaction
between one oxygen of the bis-sulfone group and the protonated
amine group in C7 is less notorious in TS-S vs TS-R (2.08 and
1.98 Å bond distances, respectively). This same trend in H-
bonds strength was calculated for TS involving catalyst C8,
although the slightly longer (OH) values between dienolate
oxygen and squaramide NH groups (1.88/1.81 Å vs. 1.80/1.78
Å) in this latter case appear to indicate a worse accommodation
Origin of stereoselectivity and plausible H-bond network. In
order to shed light on the most favorable arrangement of the
substrates and the catalyst during the transition state, we
undertook DFT calculations for the model reaction between the
vinyl cyclohexanone enolate II, vinyl bis-sulfone 6 and either
catalyst C7 (R=ArF: 3,5-(CF3)2C6H3) or C8 (R: tBu).27 As could be
anticipated for this type of bifunctional Brønsted base/H-bonding
catalysis, the located TS structures each showed well defined H-
bond networks that strongly bias the spatial arrangement of
reactants, determining the stereochemical outcome of the
reaction. Calculations at the M06/def2tzvpp (IEFPCM, solvent =
dichloromethane)//B3LYP/6-31g(d,p) level of theory for the
reaction above identified two Papai-type42 TS exclusively,
namely TS-R, leading to the R-configured product, and TS-S,
leading to the S enantiomer, for each catalyst (Scheme 6). In
t
of the large Bu group. Summarizing, it seems that an optimally
congested microenvironment is formed around protonated
catalyst C7 for best fitting of both reactants through an efficient
H-bond network.
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mixture was directly submitted to silica gel flash column chromatography
(hexane/EtOAc 80:20) to give the title compound as a white solid. m.p.
67–69 °C. Yield: 135 mg, 98%. [α]D25= –69.0° (c= 1.00, 98% ee, CH2Cl2).
1H NMR (300 MHz, CDCl3) δ 8.05–7.99 (m, 2H), 7.72–7.65 (m, 1H),
7.60–7.52 (m, 4H), 7.50–7.44 (m, 3H), 7.42–7.34 (m, 2H), 7.29 (d, J= 7.2
Hz, 1H), 7.20–7.12 (m, 2H), 6.37 (d, J= 4.4 Hz, 3H), 4.43 (t, J= 4.0 Hz,
2H), 4.04–3.80 (m, 4H), 2.79 (dd, J= 16.2, 4.0 Hz, 1H), 2.34 (dd, J= 16.2,
4.0 Hz, 2H), 2.05 (d, J= 14.1 Hz, 2H), 1.82–1.43 (m, 7H). 13C NMR (75
MHz, CDCl3) δ 138.9, 137.6, 137.3, 134.7, 134.1, 132.3, 131.2, 130.8,
129.6, 129.0, 128.9, 128.9, 127.9, 126.8, 111.7, 81.4, 65.2, 65.1, 49.5,
32.5, 30.4, 27.9, 23.5, 21.0. MS (ESI, m/z): C30H36N2O5S2 [MNH4+]:
calcd.: 570.7385, found: 570.1994.
Conclusions
In summary, we have reported that bifunctional Brønsted
base/H-bonding catalysis activation is able to generate
dienolates from -branched allylic ketones and induce their
reaction with various carbon electrophiles to occur at C mainly
or exclusively. Under these catalytic conditions the reaction of -
branched cyclic ketone dienolates with vinyl bis(sulfone)
afforded the corresponding all-carbon quaternary-addition
adducts with very high enantioselectivities. The parent acyclic
dienolate systems are comparatively less reactive, but still the
reactions may proceed with paucity for ’-methyl ketones (not so
for the ’-ethyl and ’-phenyl ketones). Quantum calculations
with model -substituted ketone dienolates predict correctly the
observed preference of  vs. -reactivity as well as the sense of
enantioinduction based on a Pápai-type activation geometry.
Importantly, the approach may be extended to additional carbon
electrophiles, such as nitroolefins and formaldehyde, thus
offering a robust platform for further development.
Compound 34. Ketal 32 (138 mg, 0.25 mmol) was dissolved in MeOH (2
mL) and magnesium powder (61 mg, 2.5 mmol) was added. The
resulting suspension was cooled to 0 °C and a drop of trimethylsilyl
chloride and a drop of 1,2-dibromoethane were added. The resulting
mixture was warmed to room temperature observing the formation of
hydrogen, and the reaction was followed by TLC (hexane/EtOAc 80:20).
After completion of the reaction (2 h) the mixture was filtered through a
pad of Celite and washed with MeOH. The solvent was removed under
reduced pressure and the residue was dissolved in dichloromethane (10
mL). The organic solution was washed with water (2  10 mL), dried over
MgSO4, volatiles were removed under reduced pressure and the
resulting crude compound was purified by silica gel flash column
chromatography (hexane/EtOAc 95:5) to give the title compound as a
colourless oil. Yield: 38 mg, 56%. [α]D25= –16.2° (c= 0.80, 98% ee,
CH2Cl2). 1H NMR (300 MHz, CDCl3) δ 7.39 (d, J= 7.1 Hz, 2H), 7.30 (t, J=
7.4 Hz, 2H), 7.19 (t, J= 7.2 Hz, 1H), 6.34 (d, J= 16.7 Hz, 1H), 6.23 (d, J=
16.7 Hz, 1H), 4.03–3.82 (m, 4H), 1.94–1.82 (m, 1H), 1.74–1.51 (m, 8H),
1.51–1.38 (m, 1H), 0.74 (t, J= 7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ
138.9, 134.4, 130.3, 129.1, 128.8, 127.4, 126.7, 126.1, 113.3, 65.9, 65.6,
49.0, 32.7, 29.8, 25.7, 24.2, 21.3, 8.4. MS (ESI, m/z) C18H25O2 [MH+]:
calcd.: 273.3955, found: 273.1722.
Experimental Section
Reaction of cyclic ketones 10–20 and 22–26 with 1,1-
bis(phenylsulfonyl)ethylene 6. General Procedure: Catalyst C8 (10
mol%) or C9 (5 mol%) was added to a solution of the corresponding
cyclic α-alkenyl ketone (0.15 mmol) and 1,1-bis(phenylsulfonyl)ethylene
(69 mg, 0.23 mmol) in CH2Cl2 at 0 °C (ketones 10–20) or room
temperature (ketones 22–26). The resulting solution was stirred until the
reaction was completed (typically 16 h) as monitored by TLC
(hexane/EtOAc 80:20). Then the mixture was directly submitted to a flash
column chromatography, affording the corresponding adducts as
essentially pure compounds.
Compound 37. Ketal 34 (16 mg, 0.6 mmol) was dissolved in a mixture of
THF (0.5 mL) and aqueous 6M HCl (0.5 mL) and the resulting mixture
was stirred at room temperature overnight. THF was eliminated under
reduced pressure and the remaining aqueous phase was extracted with
dichloromethane (3  2 mL). The combined organic layer was dried over
MgSO4 and volatiles were removed under reduced pressure to give the
title compound essentially pure (liquid). Yield: 12.2 mg, 89%. [α]D25= –
30.3° (c= 0.50, 98% ee, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ 7.40–7.27
(m, 4H), 7.26–7.22 (m, 1H), 6.30 (d, J= 3.9 Hz, 2H), 2.62–2.47 (m, 1H),
2.42–2.29 (m, 1H), 2.14–2.04 (m, 1H), 1.99–1.59 (m, 7H), 0.84 (t, J= 7.5
Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 213.2, 137.1, 133.2, 130.6, 128.6,
127.5, 126.1, 54.8, 39.6, 36.0, 30.3, 27.3, 21.6, 8.2.
Compound 11A: Obtained from ketone 10A (30 mg, 0.15 mmol) using
catalyst C9. Yield: 68 mg, 89%. White solid. m.p. 92 °C. [α]D25= –95.8°
(c= 1.00, 98% ee, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ 8.02–7.85 (m,
2H), 7.71–7.61 (m, 3H), 7.57–7.45 (m, 3H), 7.45–7.25 (m, 7H), 6.42 (d, J
= 16.6 Hz, 1H), 6.12 (d, J= 16.6 Hz, 1H), 4.56 (t, J= 4.3 Hz, 1H), 3.18 (dd,
J= 16.6, 4.0 Hz, 1H), 2.64–2.51 (m, 1H), 2.49–2.37 (m, 2H), 2.26 (dd, J=
16.6, 4.6 Hz, 1H), 2.06–1.69 (m, 5H). 13C NMR (75 MHz, CDCl3) δ 211.0,
138.3, 137.3, 136.1, 134.5, 134.1, 132.6, 130.3, 130.2, 129.5, 128.9,
128.8, 128.3, 126.6, 80.8, 54.4, 39.7, 36.1, 31.1, 27.0, 21.3. MS (ESI,
m/z): C28H32N2O5S2 [M+NH4+] calcd.: 526.6855, found: 526.1727.
Compound 38. Alkene 37 (62 mg, 0.25 mmol) and citric acid (72 mg,
0.75 mmol) were dissolved in a mixture of tert-butanol (36 mL) and water
(1 mL). To the resulting solution N-methylmorpholine N-oxide (136 mg,
0.75 mmol) and osmium tetraoxide (2.5 wt % in tBuOH) (1.2 mL, 0.1
mmol) were added and the reaction mixture was stirred at 55 °C for 24 h.
Part of the solvent was eliminated under reduced pressure and the
aqueous phase was extracted with dichloromethane (3  2 mL). The
combined organic layers were dried over MgSO4 and volatiles were
removed under reduced pressure and the residue was purified by silica
gel flash column chromatography (hexane/EtOAc 85:15) to give the title
compound as an oil. Yield: 38 mg, 60%. [α]D25= –18.1° (c= 1.00, 98% ee,
CH2Cl2). 1H NMR (300 MHz, CDCl3) δ 7.51–7.34 (m, 4H), 7.34–7.24 (m,
1H), 5.49 (d, J= 4.2 Hz, 1H), 3.99 (d, J= 2.5 Hz, 2H), 2.12–1.78 (m, 3H),
1.70 (d, J= 4.0 Hz, 1H), 1.66–1.17 (m, 8H), 0.96 (t, J= 7.4 Hz, 3H). 13C
NMR (75 MHz, CDCl3) δ 138.2, 128.6, 127.7, 126.7, 107.7, 83.3, 79.1,
51.9, 31.9, 27.2, 22.5, 20.6, 18.8, 8.9. MS (ESI, m/z) C16H21O2 [M–OH-]:
calcd.: 245.1536, found: 245.1551.
Compound 13B: Obtained from ketone 12B (39 mg, 0.15 mmol) using
catalyst C9 (12 mg, 0.0075 mmol). White solid. m.p. 107 °C. Yield: 70%
(59 mg, 0.105 mmol). [α]D25= 10.8° (c= 1.00, 92% ee, CH2Cl2). 1H NMR
(300 MHz, CDCl3) δ 7.86–7.72 (m, 4H), 7.66–7.51 (m, 2H), 7.49–7.22 (m,
6H), 6.89 (d, J= 8.8 Hz, 2H), 6.13 (d, J= 16.7 Hz, 1H), 5.98 (d, J= 16.7
Hz, 1H), 4.89–4.80 (m, 1H), 3.83 (s, 3H), 2.98 (d, J= 20.0 Hz, 1H), 2.74–
2.54 (m, 1H), 2.42–2.32 (m, 1H), 2.32–2.21 (m, 1H), 2.13 (d, J= 14.2 Hz,
1H), 1.75 (d, J= 14.2 Hz, 1H), 1.68 (dd, J= 9.1, 4.6 Hz, 2H), 1.16 (s, 3H),
1.06 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 212.0, 159.6, 138.3, 134.1,
134.1, 130.8, 130.3, 129.7, 129.7, 129.1, 128.8, 128.8, 127.7, 114.2,
80.9, 55.3, 52.5, 51.0, 38.3, 36.3, 33.0, 32.1, 30.9, 27.3. MS (ESI, m/z):
C31H35O6S2 [MH+]: calcd. 567.1875, found: 567.1882.
Compound 32. Ketone 11A (125 mg, 0.25 mmol), ethylene glycol (60 µL,
1.0 mmol) and triethyl orthoformate (80 µL, 0.50 mmol) were dissolved in
1,2-DCE (0.6 mL) and camphorsulphonic acid (16 mg, 0.07 mmol) was
added. The resulting solution was stirred at 70 °C overnight. Then the
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10.1002/chem.201901694
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FULL PAPER
Compound 39. Product 39 was obtained as a white spume following the
same acetalization procedure described above starting from hemiketal 38
(25 mg, 0.10 mmol). Yield: 29 mg, 96%. [α]D25= 20.1° (c= 0.50, 98% ee,
CH2Cl2). 1H NMR (300 MHz, CDCl3) δ 7.41–7.19 (m, 5H), 5.54 (d, J= 4.7
Hz, 1H), 4.04–3.87 (m, 2H), 3.73–3.61 (m, 3H), 2.80 (d, J= 10.7 Hz, 1H),
2.35–2.21 (m, 1H), 2.08–1.95 (m, 1H), 1.89 (d, J= 13.3 Hz, 2H), 1.74–
1.67 (m, 1H), 1.62–1.50 (m, 2H), 1.49–1.36 (m, 3H), 1.32–1.20 (m, 2H),
0.98 (t, J= 7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 139.1, 128.0, 126.9,
126.4, 83.6, 79.0, 62.1, 61.7, 52.7, 28.7, 27.9, 22.7, 20.6, 18.8, 8.7. MS
(ESI, m/z) C18H27O5 [MH+]: calcd.: 307.1904, found: 307.1917.
Chem. 2014, 12, 3531-3543; c) Y. Yin, Z. Jiang, ChemCatChem 2017,
9, 4306-4318; d) X. Jusseau, L. Chabaud, C. Guillou, Tetrahedron 2014,
70, 2595-2615; e) Q. Zhang, X. Liu, X. Feng, Curr. Org. Synth. 2013,
10, 764-785.
[4]
Reviews: a) S. E. Denmark, J. R. Heemstra, G. L. Beutner, Angew.
Chem. Int. Ed. 2005, 44, 4682-4698; b) S. V. Pansare, E. K. Paul,
Chem. Eur. J. 2011, 17, 8770-8779. For selected examples, see: c) S.
E. Denmark, G. L. Beutner, J. Am. Chem. Soc. 2003, 125, 7800-7801;
d) L. Ratjen, P. García-García, F. Lay, M. E. Beck, B. List, Angew.
Chem. Int. Ed. 2011, 50, 754-758; e) V. Gupta, S. Sudhir, T. Mandal, C.
Schneider, Angew. Chem., Int. Ed. 2012, 51, 12609-12612; f) S. Basu,
V. Gupta, J. Nickel, C. Schneider, Org. Lett. 2014, 16, 274-277.
Selected examples: a) B. M. Trost, J. Hitce, J. Am. Chem. Soc. 2009,
131, 4572-4573; b) A. Yamaguchi, S. Matsunaga, M. Shibasaki, Org.
Lett. 2008, 10, 2319-2322; c) L. Yin, H. Takada, N. Kumagai, M.
Shibasaki, Angew. Chem. Int. Ed. 2013, 52, 7310-7313; d) N. E.
Shepherd, H. Tanabe, Y. Xu, S. Matsunaga, M. Shibasaki, J. Am.
Chem. Soc. 2010, 132, 3666-3667; e) X. Xiao, H. Mei, Q. Chen, X.
Zhao, L. Lin, X. Liu, X. Feng, Chem. Commun. 2015, 51, 580-583; f) D.
Yang, L. Wang, F. Han, D. Zhao, B. Zhang, R. Wang, Angew. Chem.
Int. Ed. 2013, 52, 6739-6742; g) D. Yang, L. Wang, F. Han, D. Zhao, R.
Wang, Chem. Eur. J. 2014, 20, 8584-8588; h) H.-J. Zhang, C.-Y. Shi, F.
Zhong L. Yin, J. Am. Chem. Soc. 2017, 139, 2196-2199.
Reaction of 10A with nitrostyrene 2a to give 42a: Catalyst C10 (9 mg,
0.015 mmol) was added to a solution of ketone 10A (30 mg, 0.15 mmol)
and nitroolefin 3a (45 mg, 0.30 mmol) in CH2Cl2 at 0 °C. The resulting
solution was stirred until the reaction was completed as monitored by
TLC (48 h). Then the mixture was directly submitted to a flash column
chromatography (hexane/EtOAc 95:5) to afford the title compound.
Colourless oil. Yield: 41 mg, 78%. [α]D25= –123.4° (c= 1.00, 99% ee,
CH2Cl2). 1H NMR (300 MHz, CDCl3) δ 7.43–7.25 (m, 8H), 7.18 (dd, J=
7.4, 2.0 Hz, 2H), 6.18 (d, J= 4.0 Hz, 2H), 5.23 (dd, J= 13.0, 3.8 Hz, 1H),
4.64 (dd, J= 12.9, 11.4 Hz, 1H), 4.03 (dd, J= 11.3, 3.8 Hz, 1H), 2.88–2.73
(m, 1H), 2.45–2.21 (m, 2H), 2.08–1.91 (m, 1H), 1.76–1.57 (m, 4H). 13C
NMR (75 MHz, CDCl3) δ 212.6, 136.4, 135.8, 134.7, 129.5, 129.2, 128.9,
128.6, 128.4, 127.8, 126.3, 77.8, 56.5, 49.1, 39.7, 38.9, 28.1, 21.6. MS
(ESI, m/z) C22H24NO3 [MH+]: calcd.: 350.1756, found: 350.1761.
[5]
[6]
Reviews: a) I. D. Jurberg, I. Chatterjee, R. Tannerta, P. Melchiorre,
Chem. Commun. 2013, 49, 4869-4883; b) V. Marcos, J. Alemán, Chem.
Soc. Rev. 2016, 45, 6812-6832. Selected examples: c) G. Bencivenni,
P. Galzeranoa, A. Mazzanti, G. Bartoli, P. Melchiorre, Proc. Natl. Acad.
Sci. USA 2010, 107, 20642-20647 (correction PNAS 2013, 110, 4852-
4853); d) V. Zhan, Q. He, X. Yuan, Y.-C. Chen, Org. Lett. 2014, 16,
6000-6003; e) Q. Guo, A. J. Fraboni, S. E. Brenner-Moyer, Org. Lett.
2016, 18, 2628-2631; f) M.-L. Shi, G. Zhan, S.-L. Zhou, W. Du, Y.-C.
Chen, Org. Lett. 2016, 18, 6480-6483.
Reaction of 10A with formaldehyde to give 45: Catalyst C10 (9 mg,
0.015 mmol) was added to a solution of ketone 10A (20 mg, 0.10 mmol)
and paraformaldehyde (30 mg, 1 mmol) in CH2Cl2 at room temperature.
The resulting solution was stirred until the reaction was completed as
monitored by TLC (16 h). Then the mixture was directly submitted to a
flash column chromatography (hexane/EtOAc 90:10), affording the titled
25
compound essentially pure. White foam. Yield: 18 mg, 79%. [α]D
=
20.7° (c= 0.50, 89% ee, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ 7.38–
7.27 (m, 5H), 6.36 (d, J= 16.6 Hz, 1H), 6.14 (d, J= 16.6 Hz, 1H), 3.83 (d,
J= 11.4 Hz, 1H), 3.44 (d, J= 11.5 Hz, 1H), 2.64 (td, J= 13.8, 6.0 Hz, 1H),
2.49 (bs, 1H), 2.38–2.28 (m, 1H), 2.04 (m, 3H), 1.84 (m, 2H), 1.70 (m,
1H). 13C NMR (75 MHz, CDCl3) δ 214.9, 136.4, 133.2, 129.8, 128.6,
128.0, 126.3, 67.9, 57.3, 40.0, 34.6, 27.5, 21.5. MS (ESI, m/z) C15H19O2
[MH+]: calcd.: 231.1385, found: 231.1389.
[7]
[8]
a) Y. Gu, Y. Wang, T.-Y. Yu, Y.-M. Liang, P.-F. Xu, Angew. Chem. Int.
Ed. 2014, 53, 14128-14131; b) X. Li, M. Lu, Y. Dong, W. Wu, Q. Qian, J.
Ye, D. J. Dixon, Nat. Commun. 2014, 5, 4479.
Allyl ketones: a) B. Zhu, W. Zhang, R. Lee, Z. Han, W. Yang, D. Tan,
K.-W. Huang, Z. Jiang, Angew. Chem. Int. Ed. 2013, 52, 6666-6670; b)
Z. Jing, X. Bai, W. Chen, G. Zhang, B. Zhu, Z. Jiang, Org. Lett. 2016,
18, 260-263; c) B. Ray, S. Mukherjee, J. Org. Chem. 2018, 83, 10871-
10880; d) M.-Y. Han, W.-Y. Luan, P.-L. Mai, P. Li, L. Wang, J. Org.
Chem. 2018, 83, 1518-1524. Allyl pyrazoleamides: e) T.-Z. Li, Y. Jiang,
Y.-Q. Guan, F. Sha, X.-Y. Wu, Chem. Commun. 2014, 50, 10790-
10792. 1,1-Dicyanoalkylidenes: f) T. B. Poulsen, M. Bell, K. A.
Jørgensen, Org. Biomol. Chem. 2006, 4, 63-70; g) L. Dell’Amico, G.
Rassu, V. Zambrano, A. Sartori, C. Curti, L. Battistini, G. Pelosi, G.
Casiraghi, F. Zanardi, J. Am. Chem. Soc. 2014, 136, 11107-11114.
Alkylidene 2-oxindoles: h) Q. Chen, G. Wang, X. Jiang, Z. Xu, L. Lin, R.
Wang, Org. Lett. 2014, 16, 1394-1397; i) C. Curti, G. Rassu, V.
Zambrano, L. Pinna, G. Pelosi, A. Sartori, L. Battistini, F. Zanardi, G.
Casiraghi, Angew. Chem. Int. Ed. 2012, 51, 6200-6204; j) N. Di Iorio, P.
Righi, S. Ranieri, A. Mazzanti, R G. Margutta, G. Bencivenni, J. Org.
Chem. 2015, 80, 7158-7171. Allyl thioesters: k) J. Wang, J. Chen, C. W.
Kee, C.-H. Tan, Angew. Chem. Int. Ed. 2012, 51, 2382-2386. -Aryl
-enals: l) J.-K. Xie, Y. Wang, J.-B. Lin, X.-R. Ren, P.-F. Xu, Chem.
Eur. J. 2017, 23, 6752-6756; m) X. Bai, G. Zeng, T. Shao, Z. Jiang,
Angew. Chem. Int. Ed. 2017, 56, 3684-3688.
Acknowledgements
Finantial support was provided by the University of the Basque
Country UPV/EHU (UFI QOSYC 11/22, GIU18/159), and
Ministerio de Economía
y
Competitividad (MEC, Grant
CTQ2016-78487-C2), Spain, O.M. thanks MEC and I.U. to
Basque Government for fellowship. G.Z. and E.G.-B thank the
European Funding Horizon 2020-MSCA (ITN-EJD CATMEC
14/06-721223). We also thank SGiker (UPV/EHU) for providing
NMR, HRMS, X-Ray and computation resources.
Keywords: Brønsted bases • quaternary centers •
organocatalysis • dienolates • synthetic methods
[9]
a) A. Yamaguchi, N. Aoyama, S. Matsunaga, M. Shibasaki, Org. Lett.
2007, 9, 3387-3390; b) M. Frias, R. Mas-Ballesté, S. Arias, C. Alvarado,
J. Alemán, J. Am. Chem. Soc. 2017, 139, 672-679; c) M. Frias, A. C.
Carrasco, A. Fraile, J. Alemán, Chem. Eur. J. 2018, 24, 3117-3121. For
a proline catalyzed Mannich reaction leading to MBH-type aldehydes,
see: c) N. Utsumi, H. Zhang, F. Tanaka, C. F. Barbas, III, Angew.
Chem. Int. Ed. 2007, 46, 1878-1880.
[1]
[2]
[3]
F. A. Carey, R. J. Sundberg, Advanced Organic Chemistry, Part B:
Reaction and Synthesis, Springer, New York, 2007.
R. Cano, A. Zakarian, G. P. McGlacken, Angew. Chem. Int. Ed. 2017,
56, 9278-9290.
a) G. Casiraghi, L. Battistini, C. Curti, G. Rassu, F. Zanardi, Chem.
Rev. 2011, 111, 3076-3154; b) C. Schneider, F. Abels, Org. Biomol.
This article is protected by copyright. All rights reserved.

10.1002/chem.201901694
Chemistry - A European Journal
FULL PAPER
[10] a) G. Tong, B. Zhu, R. Lee, W. Yang, D. Tan, C. Yang, Z. Han, L. Yan,
K.-W. Huang, Z. Jiang, J. Org. Chem. 2013, 78, 5067-5072; b) B. Qiao,
Y.-J. Huang, J. Nie, J.-A. Ma, Org. Lett. 2015, 17, 4608-4611.
[21] a) W. Yang, D.-M. Du, Org. Lett. 2010, 12, 5450-5453; b) L. Dai, S.-X.
Wang, F.-E. Chen, Adv. Synth. Catal. 2010, 352, 2137-2141.
[22] F. Manoni, S. J. Connon, Angew. Chem. Int. Ed. 2014, 53, 2628-2632.
[23] A. Odriozola, M. Oiarbide, C. Palomo, Chem. Eur. J., 2017, 23, 12758-
12762.
[11] a) J. Stiller, E. Marqués-López, R. P. Herrera, R. Fröhlich, C.
Strohmann, M. Christmann, Org. Lett. 2011, 13, 70-73; b) E. Marqués-
López, R. P. Herrera, T. Marks, W. C. Jacobs, D. Könning, R. M. de
Figueiredo, M. Christmann, Org. Lett. 2009, 11, 4116-4119; c) B. Han,
Y.-C. Xiao, Z.-Q. He, Y.-C. Chen, Org. Lett. 2009, 11, 4660-4663; d) D.
Enders, X. Yang, C. Wang, G. Raabe, J. Runsik, Chem. Asian. J. 2011,
6, 2255-2259; e) B. Han, Z.-Q. He, J.-L. Li, R. Li, K. Jiang, T.-Y. Liu, Y.-
C. Chen, Angew. Chem. Int. Ed. 2009, 48, 5474-5477. For a review,
see: f) V. Marcos, J. Alemán, Chem. Soc. Rev. 2016, 45, 6812-6832.
[12] Reference 6e includes three examples of (essentially racemic) direct -
functionalization of -unsaturated ketones.
[13] Reviews: a) A.Y. Hong, B. M. Stoltz, Eur. J. Org. Chem. 2013, 2745-
2759; b) J. P. Das, I. Marek, Chem. Commun. 2011, 47, 4593-4623; c)
M. Bella, T. Caspery, Synthesis 2009, 1583-1614; d) P. G. Cozzi, R.
Hilgraf, N. Zimmerman, Eur. J. Org. Chem. 2007, 5969-1614; e) B. M.
Trost, C. Jiang, Synthesis 2006, 369-396; f) Quaternary Stereocenters
(Eds.: J. Christoffers, A. Baro), Wiley-VCH, Weinheim, 2005; g) C. J.
Douglas, L. E. Overman, Proc. Nat. Acad. Sci. 2004, 101, 5363-5367;
h) K. W. Quasdorf, L. E. Overman, Nature 2014, 516, 181-191; i) T.
Ling, F. Rivas, Tetrahedron 2016, 72, 6729-6777; j) Y. Liu, S.-J. Han,
W.-B. Liu, B. M. Stoltz, Acc. Chem. Res. 2015, 48, 740-751.
[24] a) R. Gompper, H. U. Wagner, Angew. Chem. Int. Ed. Engl. 1976, 15,
321-333; b) H. L. van Maanen, H. Kleijn, J. T. B. H. Jastrzebski, M. T.
Lakin, A. L. Spek, G. van Koten, J. Org. Chem. 1994, 59, 7839-7848; c)
S. Saito, M. Shiozawa, M. Ito, H. Yamamoto, J. Am. Chem. Soc. 1998,
120, 813-814.
[25] Nucleophilicity enhancement of cyclic vs acyclic carbanions: E. P.
Kündig, A. F. Cunningham, Jr., Tetrahedron 1988, 44, 6855-6860.
[26] The Fukui functions were calculated from the NBO charge distribution:
a) W. Yang, W. J. Mortier, J. Am. Chem. Soc. 1986, 108, 5708-5711; b)
P. W. Ayers, W. Yang, L. J. Bartolotti, The Fukui Function in Chemical
Reactivity Theory: A Density Functional View, Taylor & Francis, Boca
Raton, FL, 2009, pp 255-267.
[27] DFT calculations were carried out with the Gaussian16 set of programs
and the M06-2X functional. For computational details, see the
Supplementary Information.
[28] For
a theoretical justification of the preferred -addition pathway
(vinylogous reactivity) of certain alkylidene 2-oxindoles against
nitroolefins, see: C. Curti, L. Battistini, A. Sartori, G. Rassu, G. Pelosi,
M. Lombardo, F. Zanardi, Adv. Synth. Catal. 2018, 360, 711-721.
[29] a) T. Okino, Y. Hoashi, Y. Takemoto, J. Am. Chem. Soc. 2003, 125,
12672-12673; b) T. Okino, Y. Hoashi, Y. Takemoto, J. Am. Chem. Soc.
2005, 127, 119-125.
[14] a) X. Yang, F. D. Toste, J. Am. Chem. Soc. 2015, 137, 3205-3208; b) X.
Yang, F. D. Toste, Chem. Sci. 2016, 7, 2653-2656.
[15] I. Iriarte, O. Olaizola, S. Vera, I. Ganboa, M. Oiarbide, C. Palomo,
Angew. Chem. Int. Ed. 2017, 56, 8860-8864.
[30] a) S. M. McCooey, S. J. Connon, Angew. Chem. Int. Ed. 2005, 44,
6367-6370; b) J. Ye, D. J. Dixon, P. S. Hynes, Chem. Commun. 2005,
4481-4483; c) B. Vakulya, S. Varga, A. Csámpai, T. Soós, Org. Lett.
2005, 7, 1967-1969; d) B.-J. Li, L. Jiang, M. Liu, Y.-C. Chen, L.-S. Ding,
Y. Wu, Synlett 2005, 603-606.
[16] Selected reviews on bifunctional Brønsted bases: a) S.-K. Tian, Y.
Chen, J. Hang, L. Tang, P. McDaid, L. Deng, Acc. Chem. Res. 2004,
37, 621-631; b) C. Palomo, M. Oiarbide, R. López, Chem. Soc. Rev.
2009, 38, 632-653; c) A. Ting, J. M. Goss, N. T. McDougal, S. E.
Schaus, Top. Curr. Chem. 2010, 291, 145-200; d) Asymmetric
Organocatalysis 2: Brønsted Base and Acid Catalysts, and Additional
Topics (Ed.: K. Maruoka) Thieme, Stuttgart, 2012, pp 1-118; e) X.
Fanga, C.-J. Wang, Chem. Commun. 2015, 51, 1185-1197; f) H. B.
Jang, J. S. Oh, C. E. Song, Bifunctional Cinchona Alkaloid
Organocatalysts, in Asymmetric Organocatalysis 2: Brønsted Base and
Acid Catalysts, and Additional Topics (Ed.: K. Maruoka), Thieme,
Stuttgart, 2012, pp 119-168.
[31] I. Felker, G. Pupo, P. Kraft, B. List, Angew. Chem. Int. Ed. 2015, 54,
1960-1964.
[32] a) J. Y. Kang, R. G. Carter, Org. Lett. 2012, 14, 3178-3181; b) J. Y.
Kang, R. C. Johnston, K. M. Snyder, P. H.-Y. Cheong, R. G. Carter, J.
Org. Chem. 2016, 81, 3629-3637; c) R. Horinouchi, K. Kamei, R.
Watanabe, N. Hieda, N. Tatsumi, K. Nakano, Y. Ichikawa, H. Kotsuki,
Eur. J. Org. Chem. 2015, 4457-4463.
[33] Q. Zhu, L. Cheng, Y. Lu, Chem. Commun. 2008, 6315-6317.
[34] G. H. Lee, I. K. Youn, E. B. Choi, H. K. Lee, G. H. Yon, H. C. Yang, C.
S. Pak, Curr. Org. Chem. 2004, 8, 1263-1287.
[17] a) Y. Zhu, J. P. Malerich, V. H. Rawal, Angew. Chem. Int. Ed. 2010, 49,
153-156. For selected reviews on squaramide catalysts, see: b) R. I.
Storer, C. Aciro, L. H. Jones, Chem. Soc. Rev. 2011, 40, 2330-2346; c)
J. Alemán, A. Parra, H. Jiang, K. A. Jørgensen, Chem. Eur. J. 2011, 17,
6890-6899; d) P. Chauhan, S. Mahahan, U. Kaya, D. Hack, D. Enders,
Adv. Synth. Catal. 2015, 357, 253-281.
[35] CCDC 1821643 (38), 1823074 (42a) and 1903280 (46) contain the
supplementary crystallographic data for this paper. These data are
provided free of charge by The Cambridge Crystallographic Data
Centre. See the Supporting Information for details.
[18] a) I. Urruzuno, O. Mugica, M. Oiarbide, C. Palomo, Angew. Chem. Int.
Ed. 2017, 56, 2059-2063; b) X.-Q. Dong, H.-L. Teng, M.-C. Tong, H.
Huang, H.-Y. Taoa, C.-J. Wang, Chem. Commun. 2010, 46, 6840-6842.
[19] Selected reviews on Michael additions: a) J. L. Vicario, D. Badía, L.
Carrillo, E. Reyes, Organocatalytic Enantioselecive Conjugate Addition
[36] P. H. J. Carlsen, T. Katsuki, V. S. Martin, K. B. Sharpless, J. Org. Chem.
1981, 46, 3936-3938.
[37] Reviews on conjugate additions to nitroolefins: a) O. M. Berner, L.
Tedeschi, D. Enders, Eur. J. Org. Chem. 2002, 1877-1894; b) D. Roca-
López, D. Sadaba, I. Delso, R. P. Herrera, T. Tejero, P. Merino,
Tetrahedron: Asymmetry 2010, 21, 2561-2601; c) L. S. Aitken, N. R.
Arezki, A. Dell’Isola, A. J. A. Cobb, Synthesis 2013, 2627-2628.
[38] K. Ishihara, Y. Ogura, Org. Lett. 2015, 17, 6070-6073.
[39] See the Supporting Information for details.
Reactions:
A Powerful Tool for the Stereocontrolled Synthesis of
Complex Molecules, RSC Publishing, Cambridge, 2010; b) S. B.
Tsogoeva, Eur. J. Org. Chem. 2007, 1701-1716; c) D. Almasi, D. A.
Alonso, C. Najera, Tetrahedron: Asymmetry 2007, 18, 299-365; d) E.
Reyes, U. Uria, J. L. Vicario, L. Carrillo, The Catalytic Enantioselective
Michael Reaction, Org. React. 2016, 90, 1-898.
[40] a) X.-L Liu,Y.-H. Liao, Z.-J. Wu, L.-F. Cun, X.-M. Zhang, W.-C. Yuan, J.
Org. Chem. 2010, 75, 4872-4875; b) S. De, M. K. Das, S. Bhunia, A.
Bisai, Org. Lett. 2015, 17, 5922-5925. For a review, see: c) S. Meninno,
A. Lattanzi, Chem. Rec. 2016, 16, 2016-2030.
[20] Reviews on sulfones: a) N. S. Simpkins, Tetrahedron 1990, 46, 6951-
6984; b) N. S. Simpkins, Sulphones in Organic Synthesis, Pergamon
Press, Oxford, 1991. Sulphones in organocatalysis: c) A.-N. R. Alba, X.
Companyó, R. Ríos, Chem. Soc. Rev. 2010, 39, 2018-2033; d) M.
Nielsen, C. B. Jacobsen, N. Holub, M. W. Paixao, K. A. Jørgensen,
Angew. Chem. Int. Ed. 2010, 49, 2668-2679; e) Q. Zhu, Y. Lu, Aust. J.
Chem. 2009, 62, 951-955.
[41] It should be noted that while the configuration of C in adducts 38 and
42a is S, configuration of C in adduct 46 is R. The origin of this
enantioreversal remains unknown yet, although it might be related to
the large difference in size and -extension between both types of
electrophiles, i.e. Michael acceptors vs. formaldehyde.
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[42] a) B. Kótai, G. Kardos, A. Hamza, V. Farkas, I. Pápai, T. Soós, Chem.
Eur. J. 2014, 20, 5631-5639; b) C. Trujillo, I. Rozas, A. Botte, S. J.
Connon, Chem. Commun. 2017, 53, 8874-8877.
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I. Urruzuno, O. Mugica, G.
Zanella, S. Vera, E. Gómez-
Bengoa, M. Oiarbide,* and C.
Palomo*
Page No. – Page No.
-Branched Ketone Dienolates: Base-
Catalyzed Generation and Regio- and
Enantioselective Addition Reactions.
Getting quaternary: It is found that under bifunctional Brønsted base/H-bond
catalysis -substituted ketone dienolates, especially the cyclic ones, may be
generated and smoothly reacted with representative carbon acceptors (vinyl
sulfones, nitroolefins, formaldehyde) through the C (>95:5 ratio of regioisomers),
leading to all-carbon quaternary stereogenic centers in good yields and very high
enantioselectivity.
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