Light-Driven Enantioselective Organocatalytic β-Benzylation of Enals

Article abstract of DOI:10.1002/anie.201612159

A photochemical organocatalytic strategy for the direct enantioselective β-benzylation of α,β-unsaturated aldehydes is reported. The chemistry capitalizes upon the light-triggered enolization of 2-alkyl-benzophenones to afford hydroxy-o-quinodinomethanes. These fleeting intermediates are stereoselectively intercepted by chiral iminium ions, transiently formed upon condensation of a secondary amine catalyst with enals. Density functional theory (DFT) studies provided an explanation for why the reaction proceeds through an unconventional Michael-type addition manifold, instead of a classical cycloaddition mechanism and subsequent ring-opening.

Full text of DOI:10.1002/anie.201612159

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Communications
Chemie
International Edition: DOI: 10.1002/anie.201612159
German Edition: DOI: 10.1002/ange.201612159
Organocatalysis
Light-Driven Enantioselective Organocatalytic b-Benzylation of Enals
Luca DellꢀAmico, Victor M. Fernꢁndez-Alvarez, Feliu Maseras,* and Paolo Melchiorre*
Abstract: A photochemical organocatalytic strategy for the
direct enantioselective b-benzylation of a,b-unsaturated alde-
hydes is reported. The chemistry capitalizes upon the light-
triggered enolization of 2-alkyl-benzophenones to afford
hydroxy-o-quinodinomethanes. These fleeting intermediates
are stereoselectively intercepted by chiral iminium ions,
transiently formed upon condensation of a secondary amine
catalyst with enals. Density functional theory (DFT) studies
provided an explanation for why the reaction proceeds through
an unconventional Michael-type addition manifold, instead of
a classical cycloaddition mechanism and subsequent ring-
opening.
Figure 1. a) The classical photoenolization/Diels–Alder strategy for the
one-pot synthesis of chiral cyclic compounds (2). b) The discovered
Michael-type addition of the photoenol A to the chiral iminium ion C
leading to the enantioenriched b-benzylated aldehyde 5. Filled grey
circle represents a bulky substituent on the chiral amine catalyst.
EWG=electron-withdrawing group.
T
he photoenolization/Diels–Alder sequence[1] is an estab-
lished synthetic strategy (Figure 1a) which has found wide-
spread application for the one-step construction of stereo-
chemically dense benzannulated carbocyclic molecules (2).[2]
The approach exploits the light-triggered enolization of 2-
alkyl-benzophenones (1) affording transient hydroxy-o-qui-
nodinomethanes (A),[3] which are highly reactive intermedi-
ates that can serve as dienes in [4+2] cycloadditions with
electron-poor alkenes of type B. Herein, we document that
the reactivity of the photoenol A is not restricted to cyclo-
addition mechanisms, but can also participate in conjugate
addition manifolds.[4] More specifically, we have found that
a chiral iminium ion intermediate (C),[5] formed upon
condensation of a secondary amine catalyst (4) and a,b-
unsaturated aldehydes (3), can stereoselectively intercept A
and lead to the exclusive formation of the Michael addition
product 5 (Figure 1b). No traces of the expected Diels–Alder
adduct of type 2 were detected.
addition path instead of a classical cycloaddition manifold,
followed by the retro-aldol-mediated ring-opening of 2. From
a synthetic perspective, the chemistry described in Figure 1b
is relevant since it provides a straightforward method for the
direct b-benzylation of enals (3), a transformation for which
there are few effective catalytic enantioselective precedents.[6]
Metal-catalyzed conjugate additions to enals are generally
plagued[7] by the intrinsic instability of the benzyl-metallic
reagents and the competing 1,2-addition manifold, while
organocatalytic iminium-ion-based strategies have been suc-
cessful only for a specific class of highly activated nitro-
toluene substrates.[8]
To account for this unexpected reactivity, we have
conducted theoretical studies which indicate that the reaction
proceeds through an unconventional direct Michael-type
The initial motivations for this study stemmed from our
recent discovery that a chiral bifunctional organic catalyst, by
activation of a dienophilic maleimide of type B, could allow
the stereoselective trap of the photoenol A, thus leading to
enantioenriched cycloaddition products of type 2.[9] This
strategy provided the first effective enantioselective catalytic
variant of the photoenolization/Diels–Alder sequence.[10]
Building on this precedent, we wondered whether the
electrophilic iminium ion intermediate C[5] could provide
another organocatalytic tool useful for successfully intercept-
ing A (Figure 1b). The feasibility of our plan was tested by
reacting the commercially available 2-methylbenzophenone
(1a) and trans-2-pentenal (3a) in the presence of commer-
cially available diphenylprolinol trimethylsilylether (4a)[11] as
the chiral amine catalyst (Table 1). The experiments were
conducted over 20 hours, in toluene, and under irradiation by
an ordinary 15 W black light bulb (BLB; lmax = 365 nm).
Initial experiments confirmed the possibility of trapping the
fleeting A, generated from 1a. This observation came about
with an unanticipated reactivity, since the light-triggered
process led to the exclusive formation of the conjugate
[*] Prof. Dr. P. Melchiorre
ICREA—Catalan Institution for Research and Advanced Studies
Passeig Lluꢀs Companys 23, 08010, Barcelona (Spain)
Prof. Dr. F. Maseras
Departament de Quimica, Universitat Autꢁnoma de Barcelona
08193 Bellaterra (Spain)
Dr. L. Dell’Amico, Dr. V. M. Fernꢂndez-Alvarez, Prof. Dr. F. Maseras,
Prof. Dr. P. Melchiorre
ICIQ—Institute of Chemical Research of Catalonia
the Barcelona Institute of Science and Technology
Avenida Paꢃsos Catalans 16, 43007, Tarragona (Spain)
E-mail: fmaseras@iciq.es
pmelchiorre@iciq.es
Homepage: http://www.iciq.org/research/research group/prof-
paolo-melchiorre/
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201612159.
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Table 1: Exploratory studies.
Entry
Catalyst (R)
Solvent
Additive
Yield [%][a]
ee [%][b]
1
2
3
4
4a (TMS)
4a (TMS)
4a (TMS)
4b (TBS)
4b (TBS)
none
toluene
–
–
DPP
DPP
DPP
DPP
38
52
60
61
0
90
83
86
90
–
o-Cl2C6H4
o-Cl2C6H4
o-Cl2C6H4
o-Cl2C6H4
o-Cl2C6H4
5[c]
6
18
–
[a] Yield of isolated 5a. [b] Determined by HPLC analysis on a chiral
stationary phase. [c] Reaction in the dark. BLB=black light bulb
(lmax =365 nm), DPP=diphenylphosphoric acid, o-Cl2C6H4 =1,2-
dichlorobenzene, TMS=trimethylsilyl, TBS=tert-butyldimethylsilyl.
addition product 5a with high stereocontrol, albeit with poor
chemical yield (entry 1). A screening of the reaction media
identified 1,2-dichlorobenzene as the most appropriate sol-
vent (entry 2). The addition of an acidic additive (diphenyl-
phosphoric acid, DPP, 20 mol%) had a beneficial effect on
the reactivity (entry 3), while modification of the catalyst
scaffold, by introducing a bulkier silyl protecting group,
resulted in a better enantioselectivity (entry 4).
We then conducted control experiments to better clarify
the nature of the photochemical organocatalytic process. As
expected, the reaction was completely inhibited in the dark
(Table 1, entry 5). When the process was performed in the
absence of the aminocatalyst 4, the racemic adduct 5a was
isolated in 18% yield after 20 hours (entry 6). Thus, the high
stereocontrol inferred by the chiral amine 4b indicated that
the rate acceleration afforded by the catalyst must be large
enough to overcome a racemic background process.[12] In all
of these experiments, we could not detect any traces of the
Diels–Alder adduct 2a.[13]
Adopting the optimized reaction conditions described in
Table 1, entry 4, we then demonstrated the generality of the
asymmetric organocatalytic photoenolization/conjugate addi-
tion sequence (Figure 2a) by evaluating a variety of enals (3).
Figure 2b shows that different aliphatic groups at the b-
position are viable substituents. Short (adducts 5a and 5b)
and long alkyl chains, containing either aromatic or alkene
functionalities (5e and 5 f), as well as a more sterically
hindered isopropyl group (5c), are all well tolerated. The
reaction of the carboxybenzyl (Cbz)-protected 5-amino-2-
pentenal affords the cyclic compound 5g, originating from
a spontaneous intramolecular condensation between the
aldehyde and the amino group within the b-benzylated
product precursor. The method is synthetically useful, with
a good efficiency maintained when running the reaction on
a 1 mmol scale (5a). Cinnamaldehyde derivatives are also
competent substrates (Figure 2c) since different substitution
patterns at the aromatic moiety of 3 are well tolerated,
regardless of their electronic properties (5h–j). A heteroaryl
framework can also be included in the product, as shown by
the furyl-substituted adduct 5k.
Figure 2. a) Survey of the enals 3 which can participate in the photo-
chemical b-benzylation process. Reactions of b) aliphatic and c) aro-
matic b-substituted enals. Reactions performed on a 0.2 mmol scale.
Yields of the isolated products 5 are given. The enantiomeric excesses
were determined by HPLC analysis on a chiral stationary phase.
*Performed in toluene using the catalyst 4a.
We then sought to explore the scope of the benzophenone
substrate 1 (Figure 3a). Different substituents on both the
enolizable (products 5l–o) and the non-enolizable aromatic
ring of 1 (5p–s) are well tolerated (Figure 3b). The presence
of substituents at the benzylic position (R2) of 1 brings about
the formation of two contiguous stereogenic centers (5t–w).
When R2 = Ph, a valuable diarylmethine stereocenter is
forged with very high fidelity (5t). Finally, as a demonstration
of the synthetic versatility of the b-benzylated products, 5p,
obtained from a 1 mmol scale reaction, was easily converted
into the cyclic adduct 6, whose absolute configuration was
unambiguously inferred by single-crystal X-ray analysis (Fig-
ure 3c).[14]
After delineating its synthetic potential, we sought to shed
light on the mechanism of the reported process, for the
uncommon ability of the photoenol A to undergo a conjugate
addition was mechanistically intriguing. Since we could not
collect any experimental evidence supporting a [4+2] cyclo-
addition pathway followed by the opening of the cyclic
intermediate 2,[13] the question remained as to why this
generally preferred pathway was disabled in the present
system. We investigated the mechanism using a density
functional theory (DFT) computational study[15] at the M06-
2X level in a toluene solvent. DFT calculations are estab-
lished tools for mechanistically elucidating organocatalytic[16]
and light-triggered processes.[17] They have recently been used
to support a hetero-Diels–Alder/ring-opening sequence as the
underlying mechanism of the light-driven carboxylation of
2
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Figure 4. Reaction mechanism in the absence of a proton shuttle. Free
energies in kcalmolÀ1. Filled grey circle represents the trimethylsiloxy
group of the chiral amine catalyst 4a.
Figure 4 are not surprising, as one would expect both the
cycloaddition and the Michael addition to be mechanistically
viable. But this data is in sharp disagreement with the
experimental results. The cycloaddition transition state TS1
(7.0 kcalmolÀ1) is 1.1 kcalmolÀ1 lower in energy than the
Michael addition transition state TS2 (8.1 kcalmolÀ1), mean-
ing that the Diels–Alder adduct 2b should be the preferred
kinetic product. In addition, since 2b is the more stable
product, there is no chance that it could evolve towards 5b
through a retro-aldol/ring-opening process.[13]
Since we could not computationally reproduce the
experimental observation, we considered the potential role
of additional species in the reaction media, and how they
could affect the relative energy of the transition states
reported in Figure 4. The condensation of 4 and 3 to afford
C, assisted by DPP as an acidic additive, releases water into
the system.[20] Both water and the resulting diphenylphos-
phate can act as a proton shuttle. Proton shuttles have been
shown to lower the barrier of processes involving proton
transfer,[21] a key step underlying the Michael addition
mechanism (see TS2 in Figure 4). Since the DPP anion has
no acidic protons and cannot serve as hydrogen-bonding
donor, we repeated the calculations including an explicit
water molecule as the most likely proton shuttle.[22] The
results are summarized in Figure 5.
A water molecule can engage in a hydrogen-bonding
network with A to form the adduct G, which is only
2.0 kcalmolÀ1 above the separate species. The approach of
G to C has only one transition state (TS1-H2O), which leads to
the Michael addition product E. No transition state could be
located for the cycloaddition manifold. Remarkably, the
structure of TS1-H2O is conformationally similar to that of
TS1 (Figure 4), which affords the cycloaddition adduct 2b
instead. We confirmed, by an intrinsic reaction coordinate
(IRC) calculation, that TS1-H2O exclusively relaxes to the
intermediate H with the proton being transferred from the
photoenol to the iminium ion nitrogen atom by a water-
Figure 3. Substrate scope for the photoenolization/b-benzylation
sequence. a) The developed photochemical organocatalytic reaction.
b) Survey of the benzophenones 1 which can participate in the
reaction. c) Product manipulation and stereochemical assignment.
Reactions performed on a 0.2 mmol scale. Yields of the isolated
products 5 are given. The enantiomeric excesses were determined by
HPLC analysis on a chiral stationary phase. *Performed in toluene
using catalyst 4a.
benzophenones (1) proceeding by the trapping of A with
CO2.[17b]
The reaction of crotonaldehyde and 1a, yielding 5b
(Figure 2b), catalyzed by 4a was chosen as the model system.
Systematic conformational analyses were carried out, and we
discuss here only the results concerning the most stable
conformations.[18] We computed the reaction between the
transiently generated A and the chiral iminium ion C. The
results are summarized in Figure 4. We could locate two
transition states, one leading to the intermediate D (the
precursor of the cycloaddition adduct 2b) and the other to E
(which provided the Michael addition product 5b upon
hydrolysis). The cycloaddition transition state (TS1) leads to
the very stable D (À47.4 kcalmolÀ1) through the formation of
À
two carbon–carbon (C C) bonds. The alternative transition
À
state (TS2), which involves only one C C bond-forming
event, leads to the intermediate F upon proton transfer from
A to the iminium ion nitrogen atom. Then F, which is also
quite stable (À30.7 kcalmolÀ1), undergoes an intramolecular
proton transfer through TS3, ultimately leading to
E
(À44.8 kcalmolÀ1).[19] The computed reaction pathways in
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Keywords: asymmetric catalysis · benzylation · organocatalysis ·
photochemistry · synthetic methods
[1] a) P. G. Sammes, Tetrahedron 1976, 32, 405 – 422; b) “Photo-
enolization and its applications”: P. Klꢀn, J. Wirz, A. Gud-
mundsdottir in CRC Handbook of Organic Photochemistry and
Photobiology, 3rd ed. (Ed.: A. Griesbeck), CRC, Boca Raton,
2012, Chap. 26, pp. 627 – 651.
[2] For selected examples, see: a) K. C. Nicolaou, D. Gray, J. Tae,
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[3] For the original report, see: a) N. C. Yang, C. Rivas, J. Am.
Chem. Soc. 1961, 83, 2213. For the mechanism of formation of
the photoenol A, see: b) J. C. Scaiano, Acc. Chem. Res. 1982, 15,
252 – 258.
Figure 5. Free-energy profile of the reaction assisted by a proton
shuttle. The optimized structure of intermediate H (at À29.7 kcal
molÀ1) is highlighted. Free energies in kcalmolÀ1
.
assisted proton shuttle mechanism. The structure of H shows
how the water molecule participates in multiple hydrogen-
bonding interactions with both the H-N+ moiety within the
[4] Generally, the formation of conjugate-addition-type adducts is
rationalized on the basis of a [4+2]/ring-opening sequence. For
a nonstereoselective precedent that invokes a direct Michael-
type addition mechanism, see: R. M. Wilson, K. Hannemann,
W. R. Heineman, J. R. Kirchhoff, J. Am. Chem. Soc. 1987, 109,
4743 – 4745.
=
enammonium ion and the O C group of the benzophenone.
From this intermediate, an intramolecular proton transfer
readily forms the Michael adduct precursor E.[19] The key
feature of the water-assisted mechanism is the free energy of
TS1-H2O, which is 2.2 kcalmolÀ1 lower than the free energy
for TS1 reported in Figure 4, thus explaining why the Michael
addition manifold dominates over the classical cycloaddition
mechanism.
In conclusion, we have demonstrated that chiral iminium
ions can stereoselectively intercept photochemically gener-
ated hydroxy-o-quinodinomethanes. The chemistry, which
provides a rare example of enantioselective catalytic b-
benzylation of electron-poor olefins, proceeds through an
unconventional Michael-type addition path instead of a clas-
sical cycloaddition manifold. Computational studies revealed
that the intrinsic preference for the cycloaddition is offset in
this system by a network of proton-transfer mechanisms
facilitated by the presence of proton shuttles. Similar
behaviors can be expected in related systems where such
key structural elements are conserved.
[5] G. Lelais, D. W. C. MacMillan, Aldrichimica Acta 2006, 39, 79 –
87.
[6] For a recent example of enantioselective catalytic direct addition
of benzyl radicals to electron-poor olefins, see: H. Huo, K.
Harms, E. Meggers, J. Am. Chem. Soc. 2016, 138, 6936 – 6939.
[7] To our knowledge, no catalytic asymmetric conjugate additions
of benzyl metal reagents to enals have been reported. For
a nonstereoselective process, see: P. S. Van Heerden, B. C. B.
Bezuidenhoudt, J. A. Steenkamp, D. Ferreira, Tetrahedron Lett.
1992, 33, 2383 – 2386.
[8] a) T. Li, J. Zhu, D. Wu, X. Li, S. Wang, H. Li, J. Li, W. Wang,
Chem. Eur. J. 2013, 19, 9147 – 9150; b) L. DellꢁAmico, X.
Companyꢂ, T. Naicker, T. M. Brꢃuer, K. A. Jørgensen, Eur. J.
Org. Chem. 2013, 5262 – 5265.
[9] L. DellꢁAmico, A. Vega-PeÇaloza, S. Cuadros, P. Melchiorre,
Angew. Chem. Int. Ed. 2016, 55, 3313 – 3317; Angew. Chem. 2016,
128, 3374 – 3378.
[10] Asymmetric catalytic approaches are complicated by the fleeting
nature A. For an asymmetric method using a stoichiometric
amount of a chiral complexing agent, see: B. Grosch, C. N.
Orlebar, E. Herdtweck, W. Massa, T. Bach, Angew. Chem. Int.
Ed. 2003, 42, 3693 – 3696; Angew. Chem. 2003, 115, 3822 – 3824.
[11] B. S. Donslund, T. K. Johansen, P. H. Poulsen, K. S. Halskov,
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Acknowledgments
Financial support was provided by the CERCA Programme
(Generalitat de Catalunya), MINECO (projects CTQ2013-
45938-P and CTQ2014-57661-R, Severo Ochoa Excellence
Accreditation 2014–2018, SEV-2013-0319), the AGAUR
(2014 SGR 1059 and 2014 SGR 0409), and the European
Research Council (ERC 681840-CATA-LUX to P.M.). L.D.
thanks the Marie Curie COFUND action (2014-1-ICIQ-
IPMP) for a postdoctoral fellowship. V.F. is grateful to
MINECO for an FPI fellowship (ref BES-2012–057655).
[12] In analogy with our preceding study (Ref. [9]), we evaluated the
possibility that the chiral amine 4a attenuates the rate of the
racemic background process by reducing the concentration of A
in solution by means of an electron-transfer mechanism. Flash
photolysis quenching studies of A at the millisecond resolution
established that 4a does not significantly influence its formation.
We also established that the presence of pentenal 3a or
cinnamaldehyde did not affect the formation of A to any extent.
[13] In all of the experiments conducted in this study, we could not
detect any trace of the Diels–Alder adducts of type 2. In
addition, when an authentic sample of the cyclic adduct 2a
(synthesized according to: E. Block, R. Stevenson, J. Chem. Soc.
Perkin Trans. 1 1973, 308–313) was subjected to the optimized
photo-organocatalytic conditions, we did not detect the open
product 5a. Along with the unreacted adduct 2a, a minor
amount (ca. 20%) of the dehydration product of type 6 (see
Figure 3c) was recovered. This experiment indicates that the
Conflict of interest
The authors declare no conflict of interest.
4
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retro-aldol-mediated ring-opening of 2 is not a viable pathway
[19] K. L. Sorgi, C. A. Maryanoff, D. F. McComsey, D. W. Graden,
for the formation of 5a.
B. E. Maryanoff, J. Am. Chem. Soc. 1990, 112, 3567 – 3579.
[20] Both water and DPP are beneficial for reactivity. The reactions
in Figures 2 and 3 were performed using reagent-grade solvents.
When using rigorously dry solvents, an appreciable decrease in
reactivity was observed, while the absence of DPP severely
reduced the reaction rate. For explicative results concerning the
reaction of 1a with cinnamaldehyde to give 5h (reaction over 24
hours, conditions as in Figure 2c): reagent-grade toluene: 57%
yield, 94% ee; dry toluene: 41% yield, 94% ee; reagent-grade
toluene in the absence of DPP: 30% yield, 92% ee.
[21] a) L. Bellarosa, J. Dꢅez, J. Gimeno, A. Lledꢂs, F. J. Suꢀrez, G.
Ujaque, C. Vicent, Chem. Eur. J. 2012, 18, 7749 – 7765; b) J.
Monot, P. Brunel, C. E. Kefalidis, N. A. Espinosa-Jalapa, L.
Maron, B. Martꢅn-Vaca, D. Bourissou, Chem. Sci. 2016, 7, 2179 –
2187.
[14] Crystallographic data for 6 have been deposited with the
Cambridge Crystallographic Data Centre, accession number
CCDC 1417311 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre.
[15] See the Supporting Information for full computational details. A
data set collection of computational results is available in the
IoChem-BD repository and can be accessed via htpp://dx.doi.
org/10.19061/iochem-bd-1-28. See: M. ꢄlvarez-Moreno, C.
de Graaf, N. Lꢂpez, F. Maseras, J. M. Poblet, C. Bo, J. Chem.
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[16] For selected reviews, see: a) E. H. Kerske, K. N. Houk, Acc.
Chem. Res. 2013, 46, 979 – 989; b) W. M. C. Sameera, F. Maseras,
WIREs Comput. Mol. Sci. 2012, 2, 375 – 385.
[17] a) V. M. Fernꢀndez-Alvarez, M. Nappi, P. Melchiorre, F. Mase-
ras, Org. Lett. 2015, 17, 2676 – 2679; b) Y. Masuda, N. Ishida, M.
Murakami, J. Am. Chem. Soc. 2015, 137, 14063 – 14066. For
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3944 – 3963.
[22] Water-assisted proton shuttle mechanisms have been extensively
discussed in quantum mechanical investigations of organocata-
lytic processes. For a review, see: P. H.-Y. Cheong, C. Y. Legault,
J. M. Um, N. C¸ elebi-ꢆlcꢇm, K. N. Houk, Chem. Rev. 2011, 111,
5042 – 5137.
[18] M. Besora, A. A. C. Braga, G. Ujaque, F. Maseras, A. Lledꢂs,
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Manuscript received: December 14, 2016
Final Article published: && &&, &&&&
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Communications
Organocatalysis
L. Dell’Amico, V. M. Fernꢁndez-Alvarez,
F. Maseras,*
P. Melchiorre*
&&&& — &&&&
Light-Driven Enantioselective
Organocatalytic b-Benzylation of Enals
Unconventional Michael: The iminium
ion activation of a,b-unsaturated alde-
hydes allowed stereoselective intercep-
tion of photochemically generated hy-
droxy-o-quinodinomethane intermediates
(A). The chemistry, which provides
a direct entry into enantioenriched b-
benzylated aldehydes, proceeds through
an unconventional Michael-type addition
path instead of a classical cycloaddition
manifold. Computational studies have
shed light upon the origin of this unex-
pected reactivity.
6
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