Cooperative organocatalysis for the asymmetric γ alkylation of α-branched enals

Article abstract of DOI:10.1002/anie.201004761

α Branched leads to γ: The direct and enantioselective γ alkylation of α-substituted α,β-unsaturated aldehydes under dienamine catalysis has been achieved. A cooperative catalysis system that involves dienamine activation of α-branched enals and chiral Bronsted acid catalysis promotes an S_N1-alkylation pathway while ensuring complete γ-site selectivity and high stereocontrol (see scheme; Bn=benzyl). Copyright

Full text of DOI:10.1002/anie.201004761

Angewandte
Chemie
DOI: 10.1002/anie.201004761
Asymmetric Organocatalysis
Cooperative Organocatalysis for the Asymmetric g Alkylation of
a-Branched Enals**
Giulia Bergonzini, Silvia Vera, and Paolo Melchiorre*
The direct, catalytic, and stereoselective functionalization of
carbonyl compounds at the g position represents a highly
challenging and persistent problem for asymmetric synthe-
sis.[1,2] All attempts to solve this problem must address the
challenge of site selectivity as well as stereoselectivity.[3]
Recently, our research group hypothesized whether dien-
amine catalysis could provide a general platform for designing
direct vinylogous processes,[4] by exploiting the ability of
chiral amine catalysts to form a nucleophilic dienamine
intermediate in situ in the condensation with g-enolizable
unsaturated carbonyl compounds. Dienamine catalysis was
introduced in 2006 by Jørgensen and co-workers[5] to promote
the direct, enantioselective g amination of a,b-unsaturated
aldehydes. However, it has since found limited application.[6]
A recently published perspective on the advent of organo-
catalysis did not number dienamine catalysis among the
generic modes of activation and induction.[7] This was
probably a result of the fact that g amination of enals was
originally thought to follow a particular [4 + 2] cycloaddition
path,[5] instead of a more general nucleophilic addition
manifold.
in situ generated stable carbocations with enamine intermedi-
ates, thereby leading to the challenging asymmetric a alkyla-
tion of aldehydes through an SN1 pathway.[11] With the aim of
applying the dienamine-induced vinylogous nucleophilicity
within a substitution pattern, we focused on the SN1-type
g alkylation of unmodified unsaturated carbonyl compounds
(Scheme 1).
Recently, we documented that dienamine catalysis can be
exploited to promote vinylogous nucleophilicity within
Michael addition patterns, upon selective activation of
unmodified cyclic a,b-unsaturated ketones by primary
amine catalysts.[8] Herein, we report that vinylogous reactivity
induced by dienamine catalysis also has synthetic potential for
nucleophilic substitution reactions. Specifically, we describe
the direct asymmetric g alkylation of a-substituted linear a,b-
unsaturated aldehydes through an SN1 pathway. This unpre-
cedented transformation[9] has been accomplished using an
interwoven activation pathway that successfully integrates
dienamine catalysis and Brønsted acid catalysis[10] simulta-
neously.
Scheme 1. Dienamine catalysis and the concept of vinylogy. E=electro-
phile.
The alkylation of carbonyl compounds is the archetypal
nucleophilic substitution reaction. Recently, we and others
have independently established the possibility of intercepting
As a model reaction, we chose the direct g-alkylation of a-
branched aldehyde 3 with bis(4-dimethylaminophenyl)me-
thanol 4, which can easily form a stabilized benzhydryl
carbocation in situ[11b,12] under acidic conditions (Table 1).
Recently, we established the unique ability of 9-amino-9-
deoxy-epi-cinchona alkaloids (chiral primary amines easily
derived from natural sources)[13] to efficiently activate steri-
cally hindered carbonyl compounds, while imparting uncon-
ventional reactivity profiles (e.g. vinylogous nucleophilicity
upon condensation with cyclic enones).[8] Moreover, this class
of catalysts can activate the usually unreactive a-branched
enals toward cascade reactions, thus combining orthogonal
aminocatalytic modes.[13c] The versatility of this catalyst
framework prompted us to explore its behavior in the context
of the elusive g-site activation of a-substituted linear a,b-
unsaturated aldehydes under dienamine catalysis. Indeed,
[*] Prof. Dr. P. Melchiorre
ICREA—Instituciꢀ Catalana de Recerca i Estudis Avanꢁats
Passeig Lluꢂs Companys 23-08010 Barcelona (Spain)
G. Bergonzini, Dr. S. Vera, Prof. Dr. P. Melchiorre
ICIQ—Institute of Chemical Research of Catalonia
Avenida Paꢃsos Catalans 16-43007 Tarragona (Spain)
E-mail: pmelchiorre@iciq.es
Homepage: http://www.iciq.es/portal/862/Melchiorre.aspx
[**] This work was supported by the Institute of Chemical Research of
Catalonia (ICIQ) Foundation and the MICINN (Consolider Ingenio
2010, grant no. CSD2006-0003)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201004761.
Angew. Chem. Int. Ed. 2010, 49, 9685 –9688
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9685

Communications
Table 1: Development of a cooperative organocatalytic system for the direct g-alkylation of a-branched
enals.[a]
Structural modification of the
Brønsted acid catalyst 2 revealed a
strong correlation between the acid-
ity and the reactivity—as is strictly
related to the ability to induce
in situ
carbocation
formation
(Table 1, entries 3–7). Catalyst 2e
led to an increase of the enantiose-
lectivity to 92% ee. Finally, a 1:2
ratio of amine to acid combination
maximized the synergistic effects of
the cooperative catalysts (Table 1,
entries 8 and 9). Interestingly, the
opposite configuration of the prod-
uct can be accessed by simply
selecting the appropriate enantio-
mer of the catalyst. Thus, combining
the pseudoenantiomeric catalyst 1c,
derived from quinine, with (R)-2e
afforded 5a with opposite absolute
configuration while maintaining a
high level of selectivity (Table 1,
entry 10).
To gain insight into the specific
role of each individual activation
pathway, we used the mismatched
catalyst combinations to promote
the g alkylation of 3 with 4 (Table 1,
entries 11 and 12). This combina-
tion resulted in a dramatic loss of
reactivity and enantioselectivity.
Moreover, the results obtained
when dienamine and Brønsted acid
catalysis were operating individu-
ally (Table 1, entries 2 and 13) fur-
ther supported a highly constructive
and synergic cooperation in the
Entry
Primary amine
Brønsted acid
Conv [%][b]
ee [%][c]
1
2
3
4
5
6
7
1a
1b
1b
1b
1b
1b
1b
1b
1b
1c
1b
1c
TFA
TFA
28
75
>95
8
4
5
62
>95 (82)
93 (84)
>95 (89)
30
24
33
<5
60
80
n.d.
n.d.
92
93
90
95
(S)-2a
(S)-2b
(S)-2c
(S)-2d
(S)-2e
(S)-2a
(S)-2e
(R)-2e
(R)-2e
(S)-2e
(S)-2a
8[d]
9[d]
10[d]
11
12
13
90[e]
21[e]
<5
14
benzyl amine
[a] Reactions carried out using 3 equivalents of enal 3. 1H NMR analysis of the crude mixture indicated a
highly g-site-selective alkylation pathway. Other products arising from different reaction manifolds (e.g.
a alkylation under enamine catalysis) were sporadically detected in negligible amounts. [b] Determined
by 1H NMR analysis of the crude mixture. [c] Determined by HPLC analysis on chiral stationary phases.
[d] Reactions carried out using 15 mol% of 1 and 30 mol% of 2 and 2 equivalents of enal 3. Numbers in
parenthesis refer to yield of isolated 5a. [e] The opposite S enantiomer of 5a was obtained. The absolute
configuration of 5a was established by chemical correlation (see the Supporting Information for details).
Bn=benzyl, TFA=trifluoroacetic acid.
20 mol% of catalyst 1a, which is directly derived from
quinidine, in combination with 30 mol% of TFA as the acidic
co-catalyst, led to compound 5a as the unique product of the
process, albeit with essentially no stereocontrol (Table 1,
entry 1).[14] However, we were encouraged by the power of
primary amine catalysis to direct the reaction manifold
toward a g-site-selective alkylation. Indeed, the use of
bifunctional primary amine 6’-hydroxy-9-amino-9-deoxy-epi-
quinidine[8,15] 1b dramatically increased the enantioselectivity
as well as the reaction rate of the vinylogous alkylation while
maintaining complete g selectivity (Table 1, entry 2).
To improve the level of stereocontrol, we envisioned the
possibility of integrating dienamine catalysis and chiral
Brønsted acid catalysis. A phosphoric acid can induce the
formation of a chiral contact ion-pair from alcohol 4[16], which
may synergistically engage in a matched combination with the
chiral covalent dienamine intermediate that arises from the
condensation of the primary amine with enal 3. To pursue this
cooperative prospect,[17] we combined 1b with the simple and
easily available phosphoric acid (S)-2a, thereby greatly
presence of the matched-pair combination. These observa-
tions provoke interesting mechanistic considerations. We
believe that the primary amine activates the enal moiety
toward vinylogous nucleophilicity by means of dienamine
catalysis, while the chiral phosphate anion that arises from 2
has the dual role of acting as counter anion for both the
protonated quinuclidine moiety (within the cinchona scaf-
fold) and the benzhydryl cation formed in situ. Moreover, the
great influence of the hydrogen-bond donor at the 6ꢀ-position
of the primary amine 1b on both reactivity and stereoselec-
tivity of the g alkylation prompted us to propose a mecha-
nistic model in which both the electrophilic and nucleophilic
chiral intermediates interact through a network of noncova-
lent interactions, as depicted in Scheme 2.[19]
The dual-catalyst system was then applied to the direct g-
alkylation of a variety of a-branched g-enolizable enals.[20]
The results reported in Table 2 illustrate how different
substituents at the g position can be accommodated without
affecting either the site selectivity or the enantioselectivity of
the SN1 alkylation (Table 2, entries 1–6). Use of the substi-
tuted phosphoric acid 2e instead of the simple acid 2a led to
higher levels of stereocontrol (Table 2, entries 2, 3, and 5).
improving the enantioselectivity to
a practical level
(Table 1, entry 3).[18]
9686 www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 9685 –9688

Angewandte
Chemie
Scheme 3. Primary-amine-catalyzed g alkylation of 1-cycloalkene-1-car-
boxaldehyde.
Scheme 2. Proposed mechanistic model.
In summary, the reported g-site-selective alkylation of a-
branched enals represents the first example of a catalytic,
asymmetric vinylogous substitution reaction of unmodified
carbonyl compounds. This unprecedented chemical trans-
formation affords functionalized compounds ready for further
manipulation at the a and b positions, even through appealing
cascade sequences. This study confirms the ability of chiral
primary amine catalysis to impart unique reactivity profiles
with challenging compound classes such as a-branched enals.
Here, dienamine catalysis has been exploited to promote
vinylogous nucleophilicity within substitution reaction mani-
folds. Given the versatility of chiral phosphoric acids in
electrophilic activation, we believe that the cooperative
catalysis system involving dienamine catalysis and Brønsted
acid catalysis will find applications for other asymmetric
g functionalization of carbonyl compounds.
Table 2: Asymmetric g alkylation of a-branched enals.[a]
Entry R1
R2 x [mol%]
2
Product Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
9
10
Bn
Bn
Me
allyl
allyl
iPr
Me 15
Me 15
Me 15
Me 20
Me 15
Me 20
Et 20
Et 20
Bn 20
Ph 20
Me 15
Me 20
2a 5a
2e 5a
2e 5b
2a 5c
2e 5c
2a 5d
2a 5e
2a 5 f
2a 5g
2a 5h
2a 5i
2a 5j
2a 5k
82
84
98
91
65
80
58
82
72
71
63
61
72
90
95
89
87
94
87
82
72
73
45
90
82
86
Received: July 31, 2010
Published online: November 4, 2010
Et
Bn
Bn
Me
Keywords: alkylation · asymmetric catalysis · dienamines ·
.
organocatalysis · vinylogous reaction
11[d] Ph
12[d] p-ClC6H4
13[d] p-MeOC6H4 Me 20
[a] Reactions carried out using 2 equivalents of enal. 1H NMR analysis of
the crude mixture indicated a highly g-site-selective alkylation pathway.
Quinidine-derived primary amine 1 and the S enantiomer of chiral
phosphoric acids 2 were used. [b] Yield of the isolated compounds 5.
[1] For reviews on vinylogous processes, see: a) G. Casiraghi, F.
Zanardi, G. Appendino, G. Rassu, Chem. Rev. 2000, 100, 1929 –
1972; b) S. F. Martin, Acc. Chem. Res. 2002, 35, 895 – 904; c) S. E.
Denmark, J. R. Heemstra, Jr., G. L. Beutner, Angew. Chem.
2005, 117, 4760 – 4777; Angew. Chem. Int. Ed. 2005, 44, 4682 –
4698.
[c] Determined by HPLC analysis on
a chiral stationary phases.
[d] Reactions carried out at 108C.
[2] For a catalytic asymmetric g functionalization of furanones
through a direct vinylogous Michael addition, see: a) B. M.
Trost, J. Hitche, J. Am. Chem. Soc. 2009, 131, 4572 – 4573; for a
potentially general methodology based on nucleophilic phos-
phine catalysis, see: b) S. W. Smith, G. C. Fu, J. Am. Chem. Soc.
2009, 131, 14231 – 14233; c) R. Sinisi, J. Sun, G. C. Fu, Proc. Natl.
Acad. Sci. USA 2010, doi/10.1073/pnas.1003597107.
[3] In general, the critical regiochemical issue can be addressed by
judiciously preparing preformed, stable dienolate equivalents.
Selected catalytic, asymmetric examples: a) S. P. Brown, N. C.
Goodwin, D. W. C. MacMillan, J. Am. Chem. Soc. 2003, 125,
1192 – 1194; b) S. E. Denmark, J. R. Heemstra, Jr., J. Am. Chem.
Soc. 2006, 128, 1038 – 1039; c) M. Sickert, C. Schneider, Angew.
Chem. 2008, 120, 3687 – 3690; Angew. Chem. Int. Ed. 2008, 47,
3631 – 3634.
There appears to be remarkable latitude in the electronic
and steric demands of the aldehydic component (Table 2,
entries 7–13). Different aliphatic substituents and even a
phenyl group in the a position of the enals are well-tolerated,
thus enabling access to a broad variety of multifunctional
molecules with complete g-site selectivity and moderate to
high levels of enantioselectivity. Remarkably, when R1 is an
aromatic group (Table 2, entries 11–13), the g-alkylation
protocol opens direct access to enantioenriched benzylic
carbon stereocenters.
Finally, we explored the possibility of extending primary-
amine-induced vinylogous nucleophilicity to 1-cycloalkene-1-
carboxaldehyde. The cooperative catalysis system afforded
the g-alkylation product 6 with high regio- and enantioselec-
tivity (Scheme 3).
[4] Vinylogous nucleophilicity is the transmission of electronic
effects through a conjugated p system. The principle of vinylogy
accounts for the use of g-enolizable a,b-unsaturated carbonyl
compounds as precursors of nucleophilic dienolate equivalents,
Angew. Chem. Int. Ed. 2010, 49, 9685 –9688
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 9687

Communications
formally inverting the usual reactivity of this class of compounds.
R. C. Fuson, Chem. Rev. 1935, 16, 1 – 27.
Melchiorre, Angew. Chem. 2009, 121, 8032 – 8034; Angew. Chem.
Int. Ed. 2009, 48, 7892 – 7894.
[5] S. Bertelsen, M. Marigo, S. Brandes, P. Dinꢁr, K. A. Jørgensen, J.
Am. Chem. Soc. 2006, 128, 12973 – 12980.
[14] Details of catalyst and reaction optimization studies are
provided in the Supporting Information. Solvent, concentration,
and temperature are important factors that influence both
enantioselectivity and reactivity. The formation of a by-product
arising from carbocation trapping by the alcohol 4, as reported in
Ref. [11d], was observed during the reaction. Both the temper-
ature and the solvent facilitate full conversion of the limiting
reactant 4 into the alkylation product 5, not by avoiding by-
product formation but more likely by speeding up the reversible
regeneration of the carbocation.
[15] For the first use of catalyst 1b, see: W. Chen, W. Du, Y. Duan, Y.
Wu, S.-Y. Yang, Y.-C. Chen, Angew. Chem. 2007, 119, 7811 –
7814; Angew. Chem. Int. Ed. 2007, 46, 7667 – 7670.
[16] Q.-X. Guo, Y.-G. Peng, J.-W. Zhang, L. Song, Z. Feng, L.-Z.
Gong, Org. Lett. 2009, 11, 4620 – 4623.
[17] Selected examples of cooperative, catalytic systems; thiourea
and Brønsted acid: a) H. Xu, S. J. Zuend, M. G. Woll, Y. Tao,
E. N. Jacobsen, Science 2010, 327, 986 – 990; carbene and Lewis
acid: b) B. Cardinal-David, D. E. A. Raup, K. A. Scheidt, J. Am.
Chem. Soc. 2010, 132, 5345 – 5347; carbene and aminocatalysis:
c) S. P. Lathrop, T. Rovis, J. Am. Chem. Soc. 2009, 131, 13628 –
13630; Brønsted base and Lewis acid: d) T. Yang, A. Ferrali, F.
Sladojevich, L. Campbell, D. J. Dixon, J. Am. Chem. Soc. 2009,
131, 9140 – 9141; bimetallic dual system: e) G. M. Sammis, H.
Danjo, E. N. Jacobsen, J. Am. Chem. Soc. 2004, 126, 9928 – 9929.
[18] Just before submission of this manuscript, a similar primary
amine–phosphoric acid combination was used for the iminium
ion catalyzed asymmetric epoxidation of a-branched enals, see:
O. Lifchits, C. M. Reisinger, B. List, J. Am. Chem. Soc. 2010, 132,
10227 – 10229.
[19] Alkylation at the cinchona quinoline ring with benzhydrylium
ions generated in situ should be considered as a possible
secondary pathway, see: M. Baidya, M. Horn, H. Zipse, H.
Mayr, J. Org. Chem. 2009, 74, 7157 – 7164.
[20] Alcohols that lead to unstable carbocations are not compatible
substrates in the present g alkylation, thereby affording the
products with low enantioselectivity.
[6] a) B.-C. Hong, M.-F. Wu, H.-C. Tseng, G.-F. Huang, C.-F. Su, J.-
H. Liao, J. Org. Chem. 2007, 72, 8459 – 8471; b) R. M. de Fi-
gueiredo, R. Frꢂhlich, M. Christmann, Angew. Chem. 2008, 120,
1472 – 1475; Angew. Chem. Int. Ed. 2008, 47, 1450 – 1453; c) K.
Liu, A. Chougnet, W.-D. Woggon, Angew. Chem. 2008, 120,
5911 – 5913; Angew. Chem. Int. Ed. 2008, 47, 5827 – 5829.
[7] D. W. C. MacMillan, Nature 2008, 455, 304 – 308.
[8] G. Bencivenni, P. Galzerano, A. Mazzanti, G. Bartoli, P.
Melchiorre, Proc. Natl. Acad. Sci. USA 2010, doi/10.1073/
pnas.1001150107.
[9] The alkylation of unsaturated aldehydes generally proceeds at
the a position, see: a) S. A. G. de Graaf, P. E. R. Oosterhoff, A.
van der Gen, Tetrahedron Lett. 1974, 15, 1653 – 1656; b) K.
Takabe, H. Fujiwara, T. Katagiri, J. Tanaka, Tetrahedron Lett.
1975, 16, 1237 – 1238; for notable exceptions, see: c) S. Saito, M.
Shiozawa, M. Ito, H. Yamamoto, J. Am. Chem. Soc. 1998, 120,
813 – 814; d) Y. Terao, T. Satoh, M. Miura, M. Nomura,
Tetrahedron Lett. 1998, 39, 6203 – 6206.
[10] Reviews on Brønsted acid catalysis: a) T. Akiyama, Chem. Rev.
2007, 107, 5744 – 5758; b) A. G. Doyle, E. N. Jacobsen, Chem.
Rev. 2007, 107, 5713 – 5743; c) H. Yamamoto, N. Payette in
Hydrogen Bonding in Organic Synthesis (Ed.: P. M. Pihko)
Wiley-VCH, Weinheim 2009, pp. 73 – 140.
[11] a) R. R. Shaikh, A. Mazzanti, M. Petrini, G. Bartoli, P. Mel-
chiorre, Angew. Chem. 2008, 120, 8835 – 8838; Angew. Chem. Int.
Ed. 2008, 47, 8707 – 8710; b) P. G. Cozzi, F. Benfatti, L. Zoli,
Angew. Chem. 2009, 121, 1339 – 1342; Angew. Chem. Int. Ed.
2009, 48, 1313 – 1316; c) A. R. Brown, W.-H. Kuo, E. N. Jacob-
sen, J. Am. Chem. Soc. 2010, 132, 9286 – 9288; d) L. Zhang, L.
Cui, X. Li, J. Li, S. Luo, J.-P. Cheng, Chem. Eur. J. 2010, 16, 2045 –
2049; for a recent highlight, see: e) P. Melchiorre, Angew. Chem.
2009, 121; 1386 – 1389; Angew. Chem. Int. Ed. 2009, 48, 1360 –
1363.
[12] H. Mayr, T. Bug, M. F. Gotta, N. Hering, B. Irrgang, B. Janker, B.
Kempf, R. Loos, A. R. Ofial, G. Remennikov, H. Schimmel, J.
Am. Chem. Soc. 2001, 123, 9500 – 9512.
[13] For reviews, see: a) P. Melchiorre, G. Bartoli, Synlett 2008, 1759 –
1771; b) Y.-C. Chen, Synlett 2008, 1919 – 1930, and references
therein; c) P. Galzerano, F. Pesciaioli, A. Mazzanti, G. Bartoli, P.
9688 www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 9685 –9688