Asymmetric organocatalytic cascade reactions with a-substituted α,β-unsaturated aldehydes

Article abstract of DOI:10.1002/anie.200903803

Time to α-branch out! The first highly enantioselective aminocatalytic activation of a-substituted αβ-unsaturated aldehydes is presented. The chiral primary amine 1 selectively activates ct-branched enals toward a well-defined iminium ion enamine reaction sequence for both Friedel-Crafts/amination and sulfa-Michael/ amination cascades. The valuable multifunctional products, having two contiguous sterocenters, are isolated in high enantiomeric purity.

Full text of DOI:10.1002/anie.200903803

Communications
DOI: 10.1002/anie.200903803
Organocatalysis
Asymmetric Organocatalytic Cascade Reactions with a-Substituted
a,b-Unsaturated Aldehydes**
Patrizia Galzerano, Fabio Pesciaioli, Andrea Mazzanti, Giuseppe Bartoli, and Paolo Melchiorre*
In the past decade, asymmetric aminocatalysis has become a
fundamental synthetic strategy for the stereoselective con-
struction of chiral molecules.[1] The extraordinary pace of
innovation and progress in aminocatalysis has been dictated
mainly by the discovery of distinct catalytic activation modes
Scheme 1. Targeting a,b-disubstituted unsaturated aldehydes.
which have enabled previously inaccessible transformations.[2]
To the same extent, the design of novel structural classes of
organic catalysts has also ignited the field, enabling the
activation of challenging types of carbonyl substrates.
Whereas chiral secondary amines have proven invaluable
for the asymmetric functionalization of aldehydes, primary
amine catalysis has offered the unique possibility of partic-
ipating in processes between sterically demanding partners.[3]
Therefore it overcomes the inherent difficulties of chiral
secondary amines in generating congested covalent inter-
mediates. Chiral primary amine based catalysts have been
successfully used for the enamine activation of challenging
substrates, such as a,a-disubstituted aldehydes[4] and
ketones.[5] In 2005, Ishihara and Nakano[6a] additionally
extended the potential of chiral primary amines to include
the iminium ion activation of a-acyloxy-acroleins toward a
stereoselective Diels–Alder process.[6] However, the use of
a,b-disubstituted unsaturated aldehydes still represents an
elusive and fundamental target for asymmetric aminocatal-
ysis.[7] This is particularly true when considering that an
alternative asymmetric metal-catalyzed strategy for the
functionalization of this compound class is also lacking.[8]
Herein we show that the chiral primary amine catalyst 1
provides an efficient solution to this longstanding and sought
after issue, activating a,b-disubstituted enals toward a well-
defined iminium/enamine tandem sequence (Scheme 1).
Specifically, we developed organocascade reactions[9] which
combine two intermolecular and stereoselective steps involv-
ing a Michael addition/amination pathway. The described
olefin aryl-amination and thio-amination processes afford
straightforward access to valuable precursors of a-amino
acids which have two adjacent stereogenic centers, one of
which is quaternary, with very high optical purity.
Recently we and others, independently,[4b,5] established
chiral primary amine 1—directly derived from natural
cinchona alkaloids—as an effective catalyst for ketone
activation. We additionally demonstrated the versatility of
1, which can combine orthogonal catalysis modes (iminium
and enamine activations) into one mechanism, thus promot-
ing an intramolecular tandem reaction with a,b-unsaturated
ketones.[10] On this basis, we hypothesized whether the unique
ability of catalyst 1 to engage in iminium ion formation with
encumbered enones while enforcing high geometric control
and facial discrimination, might be extended to the challeng-
ing class of a,b-disubstituted enals. Preliminary investigations
revealed that the TFA salt of 1 was able to promote the
Friedel–Crafts alkylation of 2-methyl-1H-indole with (E)-2-
methylpent-2-enal with high enantioselectivity, indicating
that a selective p-facial shielding of the iminium intermediate
is effective [Eq. (1)]. The poor diastereocontrol, however,
clearly demonstrates that the enamine-based protonation step
escapes catalyst control.
[*] P. Galzerano,[+] F. Pesciaioli,[+] Dr. A. Mazzanti, Prof. G. Bartoli,
Prof. Dr. P. Melchiorre
Nevertheless, the ability of 1 to impart high stereocontrol
in the iminium activation of a-branched enals prompted us
toward a more intriguing target: the creation of multifunc-
tional compounds, having two contiguous stereocenters, in a
one-step process. In addition to the benefit of generating
Dipartimento di Chimica Organica “A. Mangini”, Alma Mater
Studiorum—Universitꢀ di Bologna
Viale Risorgimento 4, 40136 Bologna (Italy)
E-mail: p.melchiorre@unibo.it
Prof. Dr. P. Melchiorre
ICREA Research Prof. at the Institute of Chemical Research of
Catalonia (ICIQ)
Avda. Paꢁsos Catalans 16, 43007 Tarragona (Spain)
E-mail: pmelchiorre@iciq.es
[+] These authors contributed equally to this work.
[**] This work was supported by Bologna University and by MIUR
National Project “Stereoselezione in Sintesi Organica”.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200903803.
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Chemie
complex scaffolds in a rapid and atom-economical way, the
combination of multiple asymmetric transformations in a
cascade sequence[9] also imparts increased enantiomeric
excess to the final product when compared to the corre-
sponding discrete transformations.[11]
Our organocascade strategy was first examined by mixing
three commercially available reagents, (E)-2-methylpent-2-
enal, 2-methyl-1H-indole and diethyl azodicarboxylate
(Table 1, entry 1). Such a combination is rather challenging,[12]
ology, we focused on a sulfa-Michael/amination sequence,
using mercaptanes 6 which have easily removable and
orthogonal sulfur protecting groups (Table 2).[14]
The tandem sequence[10d] provides a fast way to stereose-
À
lectively forge a quaternary stereocenter contiguous to a C S
tertiary one. As summarized in Table 2, the reaction shows a
Table 2: Organocascade catalysis with a-branched a,b-unsaturated
aldehydes: sulfa-Michael/amination strategy.[a]
Table 1: Organocascade catalysis with a,b-disubstituted enals: indole
and azodicarboxylate combinations.
Entry R1
R2
Thiol t [8C] Yield [%][b] d.r.[c] ee [%][d]
1
Me Et
Me Et
Me Et
6a
6b
6b
0
0
54 (7a)
57 (7b)
6.5:1 >99
2[e]
3[e]
4[f]
5[h]
6
5:1
6:1
72
89
92
92
99
Entry R1 R2
R3 R4
R5
Yield [%][a] d.r.[b] ee [%][c]
À20 27 (7b)
40 45 (7c)[g]
40 47 (7d)
40 40 (7e)
Et
CH3(CH2)2 6b
4:1
1
2
3
Me Et
Me Et
Me Et
Me Et
Me Et
Me Et
Me Et
Et CH3(CH2)2
Me
Me
Me
H
H
H
H
H
H
H
Cl
CO2Et 57 (5a)
CO2Bn 49 (5b)
CO2tBu 80 (5c)
CO2tBu 51 (5d)
CO2tBu 43 (5e)
8:1 99
6:1 99
11:1 98
3:1 94
4:1 91
3:1 96
3:1 91
3:1 83
Ph Et
Me Ph
6b
6a
4:1
20:1
4[d]
5[e]
6[d]
7[d]
8
[a] Reactions conditions: 2 (1 equiv), 6 (1.2 equiv), and 4 (1.5 equiv).
[b] Yield of the isolated, single, major diastereoisomer. [c] Determined by
1H NMR analysis of the crude reaction mixture. [d] Determined by HPLC
analysis using chiral stationary phases. [e] Reaction carried out in
toluene. [f] The ee value was determined after reduction and cyclization
to form oxazolidinone. [g] Sum of diastereoisomers (4.5:1 ratio).
[h] Yield and ee value were determined after in situ reduction and
cyclization. Boc=tert-butyloxycarbonyl.
OMe CO2tBu 54 (5 f)
Me
H
H
H
CO2tBu 47 (5g)
CO2tBu 31 (5h)
1
[a] Yield of isolated 5. [b] Determined by H NMR analysis of the crude
reaction mixture. [c] Determined by HPLC analysis using chiral stationary
phases. [d] Reaction conducted at À108C over 96 h. [e] Reaction
conducted at 08C over 65 h.
good substrate generality: both tert-butyl (6a) and benzyl
(6b) mercaptanes are suitable nucleophiles, although the
latter induces a less selective organocascade path (Table 2,
entries 1–3). There appears to be a remarkable latitude in the
electronic and steric demands of the aldehydic component.
Different aliphatic substituents and even a phenyl group in
both the a and b position of the enals are well-tolerated
(Table 2, entries 4–6), enabling access to a broad variety of
multifunctional complex molecules that have adjacent ste-
reocenters with high stereoselectivity. For example, when a-
substituted cinnamic aldehyde is involved in the organo-
cascade, the corresponding product 7e is produced as a single
stereoisomer (Table 2, entry 6). Notably, compounds 7 can be
isolated as a single diastereoisomer by using standard flash
column chromatography.
because of the competitive coupling between the p-rich
nucleophile and the electrophilic component 4. A survey of
the reaction conditions revealed that using enal 2/nucleophile
3/electrophile 4, in a 1:1.2:1.5 ratio, in the presence of the
catalytic salt—made by combining 1 (20 mol%) and TFA
(30 mol%) in CHCl3 (0.5m)—provides product 5a with
excellent levels of stereoinduction and in good yield, thus
minimizing deleterious side reactions. We next examined the
scope of the presented aryl-amination of disubstituted olefins.
As shown in Table 1, excellent stereoselectivity is achieved
with azodicarboxylates having orthogonal protecting groups
(Table 1, entries 1–3). Given the superior diastereomeric ratio
and chemical yield, tert-butyl azodicarboxylate was selected
for additional exploration.
Different substituents on the indole core are well-
tolerated, since electronic and architectural modification of
the aromatic ring can be accomplished without affecting the
efficiency of the system, leading to valuable tryptophan
derivatives 5 in moderate to good yield and diastereomeric
ratio and with high optical purity (Table 1, entries 4–7).[13] As
expected, the presence of a more encumbered ethyl group
(R1) at the a position of the enal decreases the overall
reaction rate (Table 1, entry 8). The requirement to perform
the cascade at room temperature leads to a slightly lower level
of stereocontrol in the formation of product 5h (83% ee).
To probe the scope of the nucleophilic component and
expand the synthetic utility of this organocascade method-
Finally, we explored the possibility of extending the
organocascade to 1-cycloalkene-1-carboxaldehydes[7] to
access complex products having a quaternary stereogenic
center embedded in a cycle. Catalyst 1 also proved efficient
with this substrate class, leading to compound 8 with complete
enantiocontrol [Eq. (2)].
The configuration of a derivative of compound 7a was
unambiguously determined by anomalous dispersion X-ray
crystallography,[15] whereas the relative and absolute config-
urations of a derivative of compound 8 were assigned by
NMR NOE analyses and by means of TD-DFT calculations
of the electronic circular dichroism (ECD) spectra, as
described in the Supplementary Information.
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[7] Chiral secondary amines enforce moderate stereoselectivity in
the activation of 1-cycloalkene-1-carboxaldehydes, see: a) S.
Karlsson, H.-E. Hꢀgberg, Eur. J. Org. Chem. 2003, 2782; b) D. H.
King, Z. Meng, D. Denhart, R. Mattson, R. Kimura, D. Wu, Q.
Gao, J. E. Macor, Org. Lett. 2005, 7, 3437.
[8] Chiral Lewis acid mediated activation of a-branched unsatu-
rated compounds is generally based on the use of bidentate
chelating carbonyl groups. See for example: a) M. P. Sibi, J.
Coulomb, L. M. Stanley, Angew. Chem. 2008, 120, 10061; Angew.
Chem. Int. Ed. 2008, 47, 9913, and references therein. For a
metal-catalyzed activation of a-substituted enones, see: b) W.-J.
Lu, Y.-W. Chen, X.-L. Hou, Angew. Chem. 2008, 120, 10287;
Angew. Chem. Int. Ed. 2008, 47, 10133.
[9] For reviews, see: a) D. Enders, C. Grondal, M. R. M. Hꢁttl,
Angew. Chem. 2007, 119, 1590; Angew. Chem. Int. Ed. 2007, 46,
1570; b) K. C. Nicolaou, D. J. Edmonds, P. G. Bulger, Angew.
Chem. 2006, 118, 7292; Angew. Chem. Int. Ed. 2006, 45, 7134. For
meaningful examples using secondary amine catalysis, see: c) Y.
Huang, A. M. Walji, C. H. Larsen, D. W. C. MacMillan, J. Am.
Chem. Soc. 2005, 127, 15051; d) M. Marigo, T. Schulte, J.
Franzen, K. A. Jørgensen, J. Am. Chem. Soc. 2005, 127, 15710;
e) D. Enders, M. R. M. Hꢁttl, C. Grondal, G. Raabe, Nature
2006, 441, 861.
[10] a) F. Pesciaioli, F. De Vincentiis, P. Galzerano, G. Bencivenni, G.
Bartoli, A. Mazzanti, P. Melchiorre, Angew. Chem. 2008, 120,
8831; Angew. Chem. Int. Ed. 2008, 47, 8703; b) G. Bencivenni, L.-
Y. Wu, A. Mazzanti, B. Giannichi, F. Pesciaioli, M.-P. Song, G.
Bartoli, P. Melchiorre, Angew. Chem. 2009, 121, 7336 – 7339;
Angew. Chem. Int. Ed. 2009, 48, 7200 – 7203; c) L.-Y. Wu, G.
Bencivenni, M. Mancinelli, A. Mazzanti, G. Bartoli, P. Mel-
chiorre, Angew. Chem. 2009, 121, 7329 – 7331; Angew. Chem. Int.
Ed. 2009, 48, 7196 – 7199; See also: d) X. Wang, C. M. Reisinger,
B. List, J. Am. Chem. Soc. 2008, 130, 6070.
In summary, we have described an efficient solution to the
longstanding issue associated with the aminocatalytic activa-
tion of a,b-disubstituted enals. The use of the primary amine
catalyst 1 allows inclusion of this challenging substrates class
into iminium/enamine cascade sequences which lead to
valuable precursors of a-amino acids having two adjacent
stereogenic centers, one of which is quaternary, with very high
enantiomeric purity. In addition to the synthetic merit of this
method, we anticipate that the versatility of catalyst 1 will be
useful for designing more complex asymmetric, catalytic
transformations of a-branched unsaturated compounds, thus
expanding the field of application of aminocatalysis.
Received: July 11, 2009
Published online: September 10, 2009
Keywords: aldehydes ·cascade reactions ·molecular complexity·
organocatalysis · quaternary stereocenters
.
[11] Horeauꢂs principle of chiral amplification: J. P. Vigneron, M.
Dhaenens, A. Horeau, Tetrahedron 1973, 29, 1055.
[1] For reviews, see: a) P. Melchiorre, M. Marigo, A. Carlone, G.
Bartoli, Angew. Chem. 2008, 120, 6232; Angew. Chem. Int. Ed.
2008, 47, 6138; b) C. F. Barbas III, Angew. Chem. 2008, 120, 44;
Angew. Chem. Int. Ed. 2008, 47, 42; c) S. Mukherjee, J. W. Yang,
S. Hoffmann, B. List, Chem. Rev. 2007, 107, 5471; d) G. Lelais,
D. W. C. MacMillan, Aldrichimica Acta 2006, 39, 79.
[2] For recent overviews: a) P. Melchiorre, Angew. Chem. 2009, 121,
1386; Angew. Chem. Int. Ed. 2009, 48, 1360; b) D. W. C.
MacMillan, Nature 2008, 455, 304.
[3] L.-W. Xu, J. Luo, Y. Lu, Chem. Commun. 2009, 1807.
[4] Selected examples: a) M. P. Lalonde, Y. Chen, E. N. Jacobsen,
Angew. Chem. 2006, 118, 6514; Angew. Chem. Int. Ed. 2006, 45,
6366; b) S. H. McCooey, S. J. Connon, Org. Lett. 2007, 9, 599.
[5] For reviews on primary amine 1-catalyzed reactions of ketones,
see: a) G. Bartoli, P. Melchiorre, Synlett 2008, 1759; b) Y.-C.
Chen, Synlett 2008, 1919, and references therein.
[6] a) K. Ishihara, K. Nakano, J. Am. Chem. Soc. 2005, 127, 10504.
For a more recent example, see: b) T. Kano, Y. Tanaka, K.
Osawa, T. Yurino, K. Maruoka, Chem. Commun. 2009, 1956. In
this report, a single, low enantioselective example of Diels–
Alder reaction using 2-methyl but-2-enal has been described.
[12] During the preparation of the manuscript, the first example of
organocatalytic aryl-amination of b-substituted enals was de-
scribed: B. Simmons, A. M. Walji, D. W. C. MacMillan, Angew.
Chem. 2009, 121, 4413; Angew. Chem. Int. Ed. 2009, 48, 4349.
[13] The aryl-amination cascade with a,b-disubstituted enals bearing
an aryl group at either the a or b position gave a sluggish
reaction rate. Carrying out the reaction at higher temperature
(408C) does not afford the desired improvement, while facilitat-
ing the competitive coupling between the p-rich nucleophile and
the azodicarboxylate.
[14] For
a comprehensive review on asymmetric sulfa-Michael
additions, see: D. Enders, K. Lꢁttgen, A. A. Narine, Synthesis
2007, 959.
[15] CCDC 741211 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
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