Nature-inspired cascade catalysis: Reaction control through substrate concentration - Double vs. quadruple domino reactions

Article abstract of DOI:10.1039/c1cc10245a

The design of biologically inspired, multi-component cascade reactions enables the targeted synthesis of assorted structurally complex products. Similar to regulation in cells the reaction path is controlled by the substrate concentration and complex enantiopure products with high structural diversity are provided. The Royal Society of Chemistry.

Full text of DOI:10.1039/c1cc10245a

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COMMUNICATION
Nature-inspired cascade catalysis: reaction control through substrate
concentration—double vs. quadruple domino reactionsw
´
Magnus Rueping,* KyoungLang Haack, Winai Ieawsuwan, Henrik Sunden, Magda Blanco
and Fenja R. Schoepke
Received 13th January 2011, Accepted 14th February 2011
DOI: 10.1039/c1cc10245a
The design of biologically inspired, multi-component cascade
reactions enables the targeted synthesis of assorted structurally
complex products. Similar to regulation in cells the reaction path
is controlled by the substrate concentration and complex
enantiopure products with high structural diversity are provided.
The development of reactions with efficiency comparable to
that seen in natural biosynthesis has always been the greatest
goal of organic synthesis. Enzyme catalyzed reactions are
especially atom efficient, as well as being highly chemo-,
regio-, and stereoselective. Starting from simple reactants,
complex structures with multiple stereocenters are highly
selectively created in only a few steps. The enzymatic processes
often utilize domino1 and multi-component reactions2 and
their efficiency makes them increasingly attractive for the
organic chemistry community3 so that recently organocatalytic
triple and quadruple domino reactions were developed.4,5
Furthermore, the biological activity and the complexity of the
structures found in nature stimulated chemists to develop
methods which provide access to a multitude of skeletally diverse
small molecules, essential for biological assays, in an easy and
Scheme 1 Reaction sequence of the double- and quadruple-domino
effective manner. Recently introduced concepts, in particular
DOS (diversity oriented synthesis)6 and BIOS (biology oriented
synthesis),6d,e,7 offer the opportunity to accomplish this goal.
In contrast to organic synthesis, enzymatic reactions are
highly regulated, often being subject to activation or inhibition
by a particular substrate. This ensures that the synthesis of a
particular target substance is favored. For example, pyruvate,
an important metabolic intermediate, is found in numerous
metabolic pathways.8 If pyruvate is present in low concentra-
tions within yeast cells, it is oxidatively decarboxylated by
pyruvate-dehydrogenase to acetyl-CoA but at high concentra-
tions it is decarboxylated to acetaldehyde by pyruvate decar-
boxylase. Furthermore, even higher intracellular concentrations
of pyruvate trigger anaplerotic carboxylation to oxalacetate.
In this communication we describe the development of a bio-
logically inspired, one-pot multi-component domino reaction
reaction cascade.
which facilitates the directed synthesis of product 4 or, alter-
natively, 5 (Scheme 1). The reaction path can be controlled
by varying the concentration of the substrates 1, 2 and 3.
Furthermore, the presence of different functional groups within
the products renders them as versatile building blocks for
the generation of structurally complex molecules in diversity
oriented synthesis.6,7
Conversion of a,b-unsaturated aldehyde 1 into the corres-
ponding saturated aldehyde 6 is the key step in both reaction
sequences and was achieved via biomimetic transfer hydro-
genation in the presence of Hantzsch dihydropyridine 3
(HEH).9 Due to their relatively low activity, a,b-unsaturated
aldehydes have to be activated in order to be hydrogenated by
the Hantzsch ester.10 In general the activation of aldehydes
and nitroalkenes can be achieved either by Lewis bases or by
Brønsted acids at high temperature. In this context it has
been shown that the acid catalyzed reduction of nitroolefins 2
in the presence of a,b-unsaturated aldehydes 1 leads selectively
to nitroalkanes while the carbonyl compounds can almost
RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany.
E-mail: Magnus.Rueping@rwth-aachen.de;
Fax: +49 (0)241-809-2665
w Electronic supplementary information (ESI) available: Experimental
details and characterization data. See DOI: 10.1039/c1cc10245a
c
3828 Chem. Commun., 2011, 47, 3828–3830
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fully be recovered.11 The chemoselective reduction of an a,b-
unsaturated aldehyde 1, in the presence of a nitroolefin 2 was
not described. Therefore, we decided to examine this reaction
as its successful achievement would allow a subsequent 1,4
addition resulting in a first domino-hydrogenation-Michael
reaction sequence.
excellent enantioselectivities (up to 499% ee) throughout.
Noteworthy, nitroaldehydes 4 are useful synthons for the
preparation of biologically relevant and synthetically valuable
d-amino alcohol and g-amino acid derivatives.15
Considering the reaction mechanism, as well as the products
and their functional groups, we wondered to what extent the
concentration influenced regulation seen in cellular processes
could analogously be achieved in these reactions by changing
the substrate concentration and thus altering the reaction
pathway. The aldehyde and nitro functionalities present in
the domino product 4 are available for onward reaction as
impressively described by Enders and coworkers.4a If the
concentration of the a,b-unsaturated aldehyde 1 is now
increased, the previously generated domino product 4 should
undergo an iminium catalyzed Michael addition to 1, forming
the triple reaction intermediate 7 (Scheme 1). At this stage,
under the given reaction conditions, the presence of two
aldehyde groups should facilitate an intramolecular aldol
condensation to give carbocycle 5. Cumulatively, by increasing
the concentration of the a,b-unsaturated aldehyde 1, or by
reducing the availability of the Hantzsch-ester 3, a new quadruple
reaction in which four stereocenters are formed should occur.
In order to validate our design, we examined various
substrate concentrations of the educts in this Lewis base
catalyzed reaction. It was shown that the reaction of aldehyde
1, b-nitrostyrene 2 and dihydropyridine 3 in an equivalent
ratio of 4.0 : 1.0 : 2.2 did indeed yield the quadruple reaction
product 5 rather than product 4.
By employing a secondary amine catalyst, it should be
possible to lower the LUMO of the carbonyl compound to
such an extent that, in the presence of nitroolefins, the hydro-
genation of the a,b-unsaturated carbonyl compounds is favored.
Subsequently, the reduced carbonyl compound 6 can serve as a
substrate for the formation of an enamine which in a nucleophilic
attack adds to nitroolefin 212 to provide the domino product 4
with the formation of multiple stereocenters. Yet, such an
enantio- and chemoselective double addition sequence has not
been described.
Initial experiments showed that L-proline is able to selectively
catalyze the reduction of aldehyde 1a (R1 = Ph) in the
presence of b-nitrostyrene 2a (R2 = Ph). The previously
reported chemoselectivity of the Brønsted acid catalyzed
reaction is thereby reversed. Upon screening of different
reaction parameters, optimal conditions for the reduction–
addition sequence have been identified.13 The resulting domino
product 4a was subsequently reduced to the d-nitro alcohol 9a.
The desired product 9a was obtained in 72% yield and 99% ee
when the domino reaction was performed at 10 1C with diphenyl-
prolinol–TMS–ether (8)14 as the catalyst and silica gel as an
additive.
Using the optimized conditions we examined the substrate
scope of this new reaction sequence (Table 1, entries 1–12).
The substitution pattern of the a,b-unsaturated aldehyde and
the nitroolefins used were both varied. The subsequent reduction
of the domino-hydrogenation-Michael products with NaBH4
provided the desired alcohols 9a–l in good yields and with
In subsequent studies regarding the substrate scope, the
carbocyclic aldehydes 5a–j could all be isolated in almost an
enantiomerically pure form (Table 1, entries 13–22) albeit with
slightly lower yields than in the simple domino reaction.
However, if it is considered that four reaction steps occur in
a multi-component, one-pot reaction in order to build these
Table 1 Scope of the double and quadruple-domino reactions
Entry
R1
R2
9a
Yieldb
drc
eed,e
Entry
5f
Yieldb
eed,g
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
o-Br-Ph
p-OMe-Ph
C4H9
C7H15
Ph
a
b
c
d
e
f
g
h
i
72
91
80
92
78
92
95
77
81
89
66
80
5 : 1
5 : 1
17 : 1
6 : 1
6 : 1
99
13
14
15
16
17
18
19
20
21
22
a
b
c
d
e
f
g
h
i
43
35
53
50
50
46
49
44
60
61
499
499
499
499
499
499
499
98
o-OMe-Ph
m-OMe-Ph
p-OMe-Ph
o-F-Ph
p-F-Ph
p-Me-Ph
m,p-di-Cl-Ph
Ph
499
499
99
499
499
84
499
96
499
499
499
4 : 1
7 : 1
26 : 1
450 : 1
10 : 1
450 : 1
450 : 1
9h
10
11
12
99
499
Ph
Ph
Ph
j
k
l
j
a
b
Reaction conditions: (i) 1 (2.0 eq.), 2 (1.0 eq.), HEH 3 (2.2 eq.), silica gel and 8 (20 mol%). (ii) NaBH4, THF, 30 min. Yield after
c
d
chromatography. Diastereomeric ratio before chromatography. Enantiomeric excess was determined by HPLC using Chiralpak AD–H, AS–H
e
or Chiralcel OD–H. The assignment of the absolute configuration was made based on the absolute configuration of compound 5i. Reaction
f
g
conditions: 1 (4.0 eq.), 2 (1.0 eq.), HEH 3 (2.2 eq.), silica gel and 8 (20 mol%). The absolute configuration was determined by X-ray crystal
structure analysis of compound 5i.13 h Reaction was performed at rt.
c
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Chem. Commun., 2011, 47, 3828–3830 3829

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complex products, the yields of the final products are acceptable.
The absolute configuration of the products was determined by
X-ray crystal structure analysis of compound 5i.13 Further-
more 5a–j can be used as scaffolds for the synthesis of a broad
range of structurally complex molecules.
4 Selected examples of triple cascade reactions: (a) D. Enders, M. R.
M. Huttl, C. Grondal and G. Raabe, Nature, 2006, 441, 861;
(b) D. Enders, M. R. M Huttl, G. Raabe and J. W. Bats, Adv.
Synth. Catal., 2008, 350, 267; (c) A. Carlone, S. Cabrera,
M. Marigo and K. A. Jørgensen, Angew. Chem., Int. Ed., 2007,
46, 1101; (d) O. Penon, A. Carlone, A. Mazzanti, M. Locatelli,
L. Sambri, G. Bartoli and P. Melchiorre, Chem.–Eur. J., 2008, 14,
4788; (e) G. Bencivenni, L.-Y. Wu, A. Mazzanti, B. Giannichi,
F. Pesciaioli, M.-P. Song, G. Bartoli and P. Melchiorre, Angew.
Chem., Int. Ed., 2009, 48, 7200; (f) K. Jiang, Z.-J. Jia, S. Chen,
L. Wu and Y.-C. Chen, Chem.–Eur. J., 2010, 16, 2852; Selected
examples of quadruple domino reactions: (g) P. Kotame,
B.-C. Hong and J.-H. Liao, Tetrahedron Lett., 2009, 50, 704;
(h) B.-C. Hong, P. Kotame, C.-W. Tsai and J.-H. Liao, Org. Lett.,
2010, 12, 776; (i) F.-L. Zhang, A.-W. Xu, Y.-F. Gong, M.-H. Wei
and X.-L. Yang, Chem.–Eur. J., 2009, 15, 6815; (j) D. Enders,
C. Wang, M. Mukanova and A. Greb, Chem. Commun., 2010, 46,
2447; (k) K. Jiang, Z.-J. Jia, X. Yin, L. Wu and Y.-C. Chen, Org.
Lett., 2010, 12, 2766.
5 Recent examples from our group: (a) M. Rueping and M. Y. Lin,
Chem.–Eur. J., 2010, 16, 4169; (b) M. Rueping, E. Sugiono and
E. Merino, Chem.–Eur. J., 2008, 14, 6329; (c) M. Rueping,
E. Merino and E. Sugiono, Adv. Synth. Catal., 2008, 350, 2127;
(d) M. Rueping, A. Kuenkel, F. Tato and J. W. Bats, Angew.
Chem., Int. Ed., 2009, 48, 3699; (e) M. Rueping, A. Parra, U. Uria,
F. Besselievre and E. Merino, Org. Lett., 2010, 12, 5680;
(f) M. Rueping and A. Parra, Org. Lett., 2010, 12, 5281;
(g) M. Rueping, A. Kuenkel and R. Frohlich, Chem.–Eur. J.,
2010, 16, 4173.
6 (a) S. L. Schreiber, Science, 2000, 287, 1964; (b) M. D. Burke and
S. L. Schreiber, Angew. Chem., Int. Ed., 2004, 43, 46;
(c) T. E. Nielsen and S. L. Schreiber, Angew. Chem., Int. Ed.,
2008, 47, 48; (d) M. Kaiser, S. Wetzel, K. Kumar and
H. Waldmann, Cell. Mol. Life Sci., 2008, 65, 1186;
(e) C. G. Wermuth, The Practice of Medicinal Chemistry, 3rd
edn, Ch. 9, Academic Press, 2008.
7 W. Wilk, T. J. Zimmermann, M. Kaiser and H. Waldmann, Biol.
Chem., 2010, 391, 491.
8 (a) J. T. Pronk, H. Y. Steensma and J. P. van Dijken, Yeast, 1996,
12, 1607; (b) M. C. Scrutton and M. F. Utter, Annu. Rev. Biochem.,
1968, 37, 249; (c) U. Sauer and B. J. Eikmanns, FEMS Microbiol.
Rev., 2005, 29, 765.
To the best of our knowledge, the quadruple reaction
cascade that we have developed is the first example of a
complex asymmetric cascade reaction in which the course of
the reaction can be controlled by merely changing the substrate
concentration. Similar to enzymatic processes in the metabolism,
it is possible to selectively synthesize the quadruple product 5
or the domino product 4 by simply increasing or decreasing
the aldehyde concentration. With regard to the mechanism,
the quadruple reaction introduced here is an example of
a Lewis base catalyzed iminium–enamine–iminium–enamine
activation sequence.
In summary, we have developed a substrate regulated,
asymmetric, metal-free reaction in which the reaction pathway
can be controlled via the concentration. Depending on the
concentration of the individual substrates, targeted selection
between a double and a quadruple reaction can be made. The
products of both reaction cascades were isolated for a wide
range of substrates in good to very good yields and with
excellent enantioselection.
With the aid of this first example of chemoselective reaction
control through substrate concentration it is possible, with
resourceful reaction planning, to access numerous complex
products with high functional diversity and good stereoselectivity,
using simple educts in only a few reaction steps as is often seen
in nature. This is an example of synthetic chemistry mimicking
nature in its precise reaction control. Therefore, the reaction
presented above is bound to serve as a template for further
studies of efficient reaction control through the substrate
concentration.
9 Recent reviews on HEH: (a) D. Mauzerall and F. H. Westheimer,
J. Am. Chem. Soc., 1955, 77, 2261; (b) C. Wang, X. F. Wu and
J. L. Xiao, Chem.–Asian J., 2008, 3, 1750; (c) M. Rueping,
E. Sugiono and F. R. Schoepke, Synlett, 2010, 852; For a study
on the hydride-donor abilities of HEH see: (d) D. Richter and
H. Mayr, Angew. Chem., Int. Ed., 2009, 48, 1958.
10 (a) J. W. Yang, M. T. H. Fonseca and B. List, Angew. Chem., Int.
Ed., 2004, 43, 6660; (b) S. G. Ouellet, J. B. Tuttle and D. W.
C. MacMillan, J. Am. Chem. Soc., 2005, 127, 32.
We gratefully acknowledge financial support by the European
Research Council (starting grant) as well as the Fonds der
Chemischen Industrie and the Foundation in Memory of Bengt
Lundqvist for stipends given to FRS and HS.
Notes and references
11 Y. Inoue, S. Imaizumi, H. Ito, T. Shinya, H. Hashimoto and
S. Miyano, Bull. Chem. Soc. Jpn., 1988, 61, 3020.
12 Review: S. B. Tsogoeva, Eur. J. Org. Chem., 2007, 1701.
1 Reviews on domino reactions: (a) L. F. Tietze, Chem. Rev., 1996,
96, 115; (b) L. F. Tietze and U. Beifuss, Angew. Chem., Int. Ed.
Engl., 1993, 32, 131; (c) L. F. Tietze, G. Brasche and K. Gericke,
Domino Reactions in Organic Synthesis, Wiley-VCH, Weinheim,
2006; (d) H.-C. Guo and J.-A. Ma, Angew. Chem., Int. Ed., 2006,
45, 354.
2 (a) D. J. Ramon and M. Yus, Angew. Chem., Int. Ed., 2005, 44,
1602; (b) J. Zhu and H. Benayme, Multicomponent Reactions,
Wiley-VCH, Weinheim, 2005; (c) D. M. D’Souza and T. J.
J. Mueller, Chem. Soc. Rev., 2007, 36, 1095.
13 For details please see ESIw.
14 For reviews on diphenylprolinol–TMS–ether catalysis see:
(a) C. Palomo and A. Mielgo, Angew. Chem., Int. Ed., 2006, 45,
7876; (b) A. Mielgo and C. Palomo, Chem.–Asian J., 2008, 3, 922;
First application: (c) M. Marigo, T. C. Wabnitz, D. Fielenbach
and K. A. Jørgensen, Angew. Chem., Int. Ed., 2005, 44, 794;
(d) Y. Hayashi, H. Gotoh, T. Hayashi and M. Shoji, Angew.
Chem., Int. Ed., 2005, 44, 4212.
3 Organocatalytic domino reactions: (a) D. Enders, C. Grondal and
M. R. M. Huttl, Angew. Chem., Int. Ed., 2007, 46, 1570; (b) X. Yu
and W. Wang, Org. Biomol. Chem., 2008, 6, 2037; (c) T. Poisson,
Synlett, 2008, 147; (d) A.-N. Alba, X. Companyo, M. Viciano and
R. Rios, Curr. Org. Chem., 2009, 13, 1432; (e) C. Grondal,
M. Jeanty and D. Enders, Nat. Chem., 2010, 2, 167.
15 Reviews for organocatalysis in natural product synthesis:
(a) E. Marques-Lopez, R. P. Herrera and M. Christmann, Nat.
Prod. Rep., 2010, 27, 1138; (b) R. M. de Figueiredo and
M. Christmann, Eur. J. Org. Chem., 2007, 2575; (c) M. J. Gaunt,
C. C. C. Johansson, A. McNally and N. T. Vo, Drug Discovery
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c
3830 Chem. Commun., 2011, 47, 3828–3830
This journal is The Royal Society of Chemistry 2011