Dynamic one-pot three-component catalytic asymmetric transformation by combination of hydrogen-bond-donating and amine catalysts

Article abstract of DOI:10.1002/anie.201101966

In control: The first dynamic one-pot three-component asymmetric transformation between aldehydes, protected α-cyanoglycine esters, and enals catalyzed by a combination of a simple hydrogen-bond-donating catalyst and a chiral amine catalyst is disclosed.

Full text of DOI:10.1002/anie.201101966

Communications
DOI: 10.1002/anie.201101966
Multicomponent Reactions
Dynamic One-Pot Three-Component Catalytic Asymmetric
Transformation by Combination of Hydrogen-Bond-Donating and
Amine Catalysts**
Shuangzheng Lin, Luca Deiana, Gui-Ling Zhao, Junliang Sun, and Armando Cꢀrdova*
Substituted chiral pyrrolidine and proline derivatives are very
important pharmaceuticals, natural products, organocatalysts,
and building blocks in organic and diversity-oriented syn-
thesis.[1] In this context, biologically active highly substituted
pyrrolidine derivatives containing a quaternary stereocenter
(e.g. 1–4; Figure 1) are found in, and form the core of many
pharmaceutical candidates and natural products.[2]
Multicomponent reactions that involve the formation of
multiple carbon–carbon and carbon–heteroatom bonds, and
multiple stereocenters in one pot, is a rapidly growing area of
research for the synthesis of small molecules that have
complex molecular architectures.[3] Multicomponent trans-
formations reduce the synthetic steps, amount of waste
produced, and amount of solvents required, which are
important factors in “green” chemistry.[4]
Figure 1. Natural products and biologically active proline derivatives
1–4, which contain a quaternary stereocenter in the a position.
The catalytic enantioselective [3+2] cycloaddition of
azomethine ylides with electron-deficient olefins is a powerful
method for creating structural diversity and for the formation
of chiral pyrrolidine and proline derivatives that contain four
stereocenters.[1a–f,5] The catalytic asymmetric transformations
are mostly carried out using preformed dipolar precursors as
substrates.[6–8] However, there are only a few reports on the
catalytic enantioselective synthesis of polysubstituted proline
derivatives containing a chiral quaternary a stereocenter.[9]
According to retrosynthetic analysis, the dynamic one-pot
reaction between aldehydes 5,[10a] protected a-cyanoglycine
esters 6b, and enals 7 should give access to chiral proline
derivatives 8, which have chiral quaternary a stereocenters,
through a [2+3] cycloaddition catalyzed by chiral amine 9
(Scheme 1).[10,11]
However, such transformations can be plagued by
Michael reactions between a-cyanoglycine ester 6 and enal
7 as well as low diastereo- and endo/exo selectivities.[12] Thus,
it is crucial to direct the chemoselectivity (dipolar addition
versus Michael addition) of the dynamic process towards an
in situ imine formation with a subsequent predominant
formation of dipole A over dipole B, and achieve stereose-
lective [2+3] cycloaddition with an in situ generated catalytic
iminium intermediate (Scheme 1).
[*] Dr. S. Lin, L. Deiana, Dr. G.-L. Zhao, Prof. Dr. A. Cꢀrdova
Department of Organic Chemistry, The Arrhenius Laboratory
Stockholm University, 10691 Stockholm (Sweden)
Supramolecular interactions (e.g. hydrogen bonding) are
highly useful for controlling the reaction outcome and the
selectivity of dynamic multicomponent processes in synthetic
chemistry.[13] These interactions are also a powerful means of
activation in asymmetric catalysis.[14–16] Hydrogen-bond-
donating networks in combination with a co-catalyst should
have all the essentials for directing and achieving highly
selective reactions under both thermodynamic and kinetic
control. Thus, we envisioned that by adding a hydrogen-bond-
donating co-catalyst to the dynamic three-component system
the equilibrium could be pushed towards imine formation and
subsequent [2+3] cycloaddition (Scheme 1). Moreover, we
predicted that this would favor the formation of intermediate
A over B by locking its conformation by hydrogen bonding,
and thereby increase the chance of making the transformation
highly diastereoselective.
L. Deiana, Dr. G.-L. Zhao, Prof. Dr. J. Sun, Prof. Dr. A. Cꢀrdova
Berzelii Center EXSELENT on Porous Materials
The Arrhenius Laboratory, Stockholm University
10691 Stockholm (Sweden)
Prof. Dr. J. Sun
Department of Structural Chemistry, The Arrhenius Laboratory
Stockholm University, 10691 Stockholm (Sweden)
Prof. Dr. A. Cꢀrdova
Department of Natural Sciences, Engineering and Mathematics
Mid Sweden University, 85170 Sundsvall (Sweden)
Fax: (+46)8-154-908
E-mail: acordova@organ.su.se
armando.cordova@miun.se
[**] We gratefully acknowledge the Swedish National Research council
and Wenner-Gren-Foundation for financial support. The Berzelii
Center EXSELENT is financially supported by VR and the Swedish
Governmental Agency for Innovation Systems (VINNOVA).
Herein, we report that the dynamic one-pot three-
component reaction between aldehydes 5, protected a-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201101966.
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Scheme 1. Possible pathways for the one-pot reaction between aldehyde 5, amine 6, and enal 7 to form proline derivatives 8.
cyanoglycine esters 6, and enals 7 can be catalyzed with a
chiral pyrrolidine catalyst 9, provided that an appropriate
hydrogen-bond-donating co-catalyst 10 is employed, to give
proline derivatives 8, which contain a quaternary a stereo-
center, with high endo-, diastereo-, and enantioselectivities.
The choice of the co-catalyst is critical for the chemo-
selectivity (dipolar addition versus Michael addition), stereo-
selectivity, and for acceleration of the rates of both the imine
formation and the cycloaddition.
only the corresponding Michael adduct 8a’’ (Scheme 1) in
high conversion but with no diastereoselectivity, even when
the enal component (7a) was added sequentially after 2 hours
of stirring (Scheme 1). The reaction between 5a, a-cyanogly-
cine ester 6a, and 7a gave predominantly the Michael adduct
8aa’’, but a small amount of the polysubstituted chiral
pyrrolidine 8a was also formed with high endo- and diaste-
reoselectivity, and good enantioselectivity in DMF (Table 1,
entry 1). With this result in hand, extensive screening for
suitable chiral amines 9, hydrogen-bond-donating molecules
10, and reaction conditions could be accomplished. The key
results are shown in Table 1. In all cases the aldehyde moiety
of pyrrolidine 8a was subsequently reduced to give the
alcohol in the yield presented in Table 1.
We began by investigating the reaction between benzal-
dehyde 5a, a-cyanoglycine esters 6, and cinnamic aldehyde
7a catalyzed by chiral amine 9a. However, the reactions gave
Pleasingly, the dynamic one-pot process can be com-
pletely directed towards cycloaddition in THF or DMF, and
no Michael adducts were formed. Thus, the reaction became
chemospecific in the presence of hydrogen-bond-donating
compounds 10. For example, we observed a significant rate
acceleration when the thiourea reported by Schreiner and
Zhang (10a)[14c] or phenol was added as a co-catalyst and the
reactions were completed within 6 hours and 4 hours, respec-
tively (Table 1, entries 2 and 5).[17] Moreover, the small
amount of water released from the imine formation co-
mediated the dynamic process towards cycloaddition, but the
reaction time increased significantly (Table 1, entry 3).[18] The
addition of organic acids (e.g. benzoic acid) as co-catalysts
resulted in excellent stereoselectivity, but the reaction was
slower compared to the reactions that employed 10a and
phenol (Table 1, entry 4 versus entries 2 and 5).[19] Thus,
hydrogen-bond-donating molecules were favorable for the
acceleration of the dynamic process and for directing it
towards the cycloaddition pathway. Notably, we found that
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Communications
Table 1: Screen of catalysts and reaction conditions for the one-pot three-
component reaction between 5a, amine 2a, and enal 7a.[a]
[pKa = 7.2 (DMSO)] exhibited lower activity and the reaction
required 26 hours for completion; however, 8a was formed
with excellent enantioselectivity (Table 1, entry 7). In com-
parison, the oximes that were derived from cyanoacetate
esters [10d: pKa = 4.9 (DMSO)] had the right acidity for
achieving both dramatic rate acceleration and high stereose-
lectivity (Table 1, entries 8–19). To the best of our knowledge,
these types of oximes have never previously been used as
catalysts for organic asymmetric reactions involving carbonyl
compounds. The catalyst screen showed that both protected
and unprotected chiral diarylprolinols 9 co-catalyzed the
reaction with the highest stereoselectivity (Table 1, entries 8,
11, 13, and 14).[21] We were also able to reduce the catalyst
loading of 9 without significantly affecting the reaction times
(Table 1, entries 18 and 19). Based on these results, we
decided to investigate the enantioselective dynamic multi-
component cycloaddition process between aldehydes 5, a-
cyanoglycine ester 6a, and enals 7 by using chiral amine 9b
and oxime 10d as co-catalysts in THF (Table 2).[22]
The organo-co-catalytic asymmetric three-component
reactions gave the corresponding highly substituted a-quater-
nary proline derivatives 8a–8n as the predominant diaste-
reoisomer in good to high yields (Table 2, 56–87%); this
diastereomer was the only one isolated by column chroma-
tography on silica gel. The enantioselectivity of the reaction
was excellent (93–99% ee). Thus, the one-pot procedure
allows for the construction of four contiguous stereocenters,
including a quaternary stereocenter, with high stereocontrol.
We did not observe any dipolar addition products from the
possible reaction between amine 6a and two molecules of
enal 7. In fact, mixing just enal 7a (0.75 mmol) and 6a
(0.375 mmol) in the presence of 9b and 10d gave the
corresponding imine, but no dipolar addition occurred. We
also investigated the use of aliphatic aldehyde components 5
(e.g. isobutyraldehyde, pivalaldehyde, n-butanal), however
only traces of products 8 were formed. To demonstrate the
synthetic utility of the transformation and the possibility of
employing it in diversity-oriented synthesis,[23] we further
modified the proline derivatives 8 (Scheme 2). Consequently,
Entry Amine 9 Cat. 10
t
[h]
Yield endo/exo[c] d.r.[c] ee
[%][b] [%][d]
1
2
3
4
5
6
7
8
9a[e,f]
9a
9a
9a
9a
9a
9a
9a
9a
9a
9b
9c
9d
9e
9 f
9g
9h
–
10a
–
6[e] 15[e]
7:1
3:1
3:1
9:1
3:1
10:1
4:1
9:1
9:1
8:1
11:1
7:1
11:1
4:1
15:1
10:1
11:1
11:1
11:1
4:1
19:1 73
9:1 95
9:1 97
8:1 99
7:1 76
10:1 98
14:1 99
19:1 98
19:1 98
18:1 97
19:1 97
6:1 30
15:1 94
19:1 94
8:1 27
9:1 17
8:1 10
19:1 97
19:1 97
15:1 94
14:1 97
15:1 97
14:1 81
6
25
76
64
57
51
29
74
77
benzoic acid 26
phenol
10b
10c
10d
10e
10 f
10d
10d
10d
10d
10d
10d
10d
10d
10d
10 f
4
4
26
4
9
3.5 74
10
11
12
13
14
15
16
17
18
19
20
21
22
23
3
5
4
78
77
63
4.5 67
4
52
4
4
5
74
34
76
94
80
79
9b[g]
9b[h]
9a[i,j]
9a[k,j]
9a[l,j]
9a[f]
7
3.5 41
10 f
10 f
10 f
4
3
4
11
42
77
4:1
6:1
8:1
[a] A mixture of 5a (0.50 mmol), 6a (0.375 mmol), enal 7a (0.25 mmol;
added after 2 h), 10 (0.188 mmol), and catalyst 9 (0.05 mmol) in 0.5 mL
of solvent was stirred at RT. [b] The yield of the isolated pure alcohol,
which was synthesized by the reduction of the aldehyde moiety of 8a
(two steps), after column chromatography on silica gel. [c] Determined
1
by H NMR analysis of the crude reaction mixture. [d] Determined after
reduction of the aldehyde moiety of 8a by HPLC analysis on a chiral
stationary phase. [e] Michael adduct 8a’’ was isolated in 55% yield, 1:1
d.r., 92% ee, and 96% ee. [f] Reaction was performed in DMF. [g] Used
10 mol% of 9b. [h] Used 5 mol% of 9b at 48C. [i] Reaction was
performed in CHCl3. [j] The imine that was generated in situ from 5a and
6a oligomerized, thus resulting in a reduced yield. [k] Reaction was
performed in toluene. [l] Reaction was performed in CH3CN. DMF=
dimethylformamide, THF=tetrahydrofuran, TES=triethylsilyl, TMS=
trimethylsilyl.
oximes derived from malonate and cyanoacetate esters (10b–
f) also can co-catalyze the reaction. They were chosen since
we believed that their intramolecular hydrogen bonding and
similarity with the amine component 6a would have a
beneficial effect. For example, the oxime derived from
malononitrile 10b [pKa = 5.6 (DMSO)][20] accelerated the
reaction but unwanted side reactions and decomposition
occurred and reduced the formation of 8a (Table 1, entry 6).
The one-pot reaction with malonate-derived oxime 10c
Scheme 2. a) 6b, 9b, 10d, THF, 48C, 70%; b) 6a, 9b, 10d, THF, 48C,
79%; c) NaBH4 (3 equiv), MeOH, 08C, 75%; d) NaClO2, KH2PO4,
=
(CH3)2C CHCH3, tBuOH:H2O (5:1), 96%; e) NaBH4, CoCl2·6H2O,
MeOH, 08C!RT, 34%.
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Table 2: Catalytic asymmetric domino reactions between enal 1 and ester 2.[a]
the [2+3] cycloaddition step by using preformed
imines as substrates. The cycloaddition between the
imine derived from 5a and 6a, and enal 7a without
co-catalyst was finished after 17 hours and gave the
corresponding proline 8a in 77% yield with 9:1 d.r.
(4:1 endo/exo) and 97% ee. In comparison, the same
reaction using oxime 10d as an additive was much
faster; it was complete within 2 hours to give 8a in
78% yield with 19:1 d.r. (11:1 endo/exo) and 97% ee.
These results demonstrate that the hydrogen-bond
donation of 10d significantly accelerates the rate and
improves the diastereoselectivity of the cycloaddi-
tion reaction. Based on our experimental results, X-
Entry
R
R1
8
Yield
[%][b]
endo/exo[c]
d.r.[c]
ee
[%][d]
1
2
8a
8b
79[e]
75
11:1
6:1
19:1
97
98
>19:1
3
4
5
6
8c
8d
8e
8 f
83
9:1
7:1
>19:1
>19:1
14:1
97
95
96
97
1
ray crystallographic, H NMR, and HRMS analyses,
87[f]
73
we propose the following mechanistic pathway to
account for the observed chemoselectivity and
stereochemistry of the dynamic multicomponent
transformation (Scheme 1 and Scheme 3).
10:1
12:1
71[e,f]
10:1
The hydrogen-bond-donating molecule is crucial
for the fast formation of the imine and thus pushes
the equilibrium of the reaction towards the imine
formation. Most likely this occurs by activation of
the carbonyl group of aldehyde 5.[14] Next, the
intramolecular hydrogen-bonding network, which
can be created by 10, will activate the imine and
lock its conformation to C (Scheme 3). The imine
will now undergo proton shifts to form intermediates
A1–A3, which are stabilized by the hydrogen-bond-
ing network. In parallel, chiral amine 9 will form the
iminium intermediate I, which is efficiently shielded
at the Si face by the bulky aryl groups. Next, the
activated species A, for which the conformation is
locked by hydrogen bonding with co-catalyst,
approaches the opposite face, and stereoselective
7
8g
85
16:1
17:1
96
8
8h
8i
79
13:1
11:1
14:1
15:1
96
97
95
97
98
9
87
10
11
12
8j
83
10:1
11:1
8k
8l
88[f]
62[e,g]
8:1
>19:1
>19:1
>19:1
13
14
8m
8n
80
14:1
15:1
93
96
56[e,g]
>19:1
>19:1
ꢀ
C C bond formation occurs from the Re face of
[a] A mixture of 5 (0.50 mmol), 6 (0.375 mmol), and enal 7 (0.25 mmol, added after
2 h), 10d (0.188 mmol) and catalyst 9b (12.5 mmol) in 0.5 mL THF was stirred for
6 h at 48C. [b] Yield of isolated pure 8 after column chromatography on silica gel.
[c] Determined by 1H NMR analysis of the crude reaction mixture. [d] Determined by
HPLC analysis on a chiral stationary phase. [e] The yield of the isolated pure alcohol,
intermediate II either by a concerted endo-selective
mechanism (cycloaddition) or a stepwise (Michael/
Mannich) mechanism to give iminium intermediate
III.[25] Subsequent hydrolysis regenerates catalyst 9
which was synthesized by the reduction of the aldehyde moiety of 8 (two steps), after and gives the polysubstituted proline derivative 8. It
column chromatography on silica gel. [f] Used 20 mol% of 9b. [g] Used 0.125 mmol
of 10d and stirred reaction mixture for 6 h.
is known that the [2+3] dipolar cycloaddition can
proceed by a stepwise mechanism.[7o] However, we
did not observe any Michael adduct intermediates by
1H NMR analysis. A stepwise mechanism cannot be
either reduction or oxidation gave the corresponding chiral
pyrrolidine 11a, acid 12a, and diamine 12aa. Reduction of the
cyano group is possible and gives access to chiral diamines
containing both a secondary and primary amine structural
motif (12aa), which is a useful combination both in organo-
catalysis as well as medicinal chemistry.[1] The absolute
stereochemistry of the highly substituted quaternary proline
derivatives 8 was confirmed by the X-ray crystallographic
analysis of 8c (2S, 3R, 4R, 5S; Figure 2).[24]
excluded since DFT calculations of the transition states of the
transformation, reported in reference [10], indicate a step-
wise mechanism (Prof. Jose Vicario personal communica-
tion).
As shown above, the employment of hydrogen-bond-
donating additives 10 has a dramatic effect on the reaction
outcome and the rate of the dynamic multicomponent
process. It significantly accelerated the iminium formation,
as determined by 1H NMR analysis. We also separately
investigated the hydrogen-bond-donating effect of 10d for
Figure 2. ORTEP picture of the crystalline compound 8c.
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Communications
Keywords: asymmetric catalysis · cycloadditions ·
.
multicomponent reactions · nitrogen heterocycles ·
organocatalysis
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Scheme 3. Proposed reaction pathway (R3 =aliphatic or aryl group,
gray circle=bulky aryl groups).
In summary, we have developed the first highly diastereo-
and enantioselective organo-co-catalytic dynamic one-pot
asymmetric transformation between, aldehydes, protected a-
cyanoglycine esters, and enals. The catalytic dynamic three-
component process affords cyano-, formyl-, and ester-func-
tionalized a-quaternary proline derivatives with four contig-
uous stereocenters (93–99% ee). The biomimetic cooperative
combination of hydrogen-bond and iminium activation of the
carbonyl components was essential to achieve chemo- and
stereoselective cycloaddition under kinetic control. The
application of simple oximes, which were derived from
cyanoacetate esters, as hydrogen-bond-donating molecules
gave significant rate acceleration. Further applications of
hydrogen-bond donation in combination with amino catalysis
for controlling dynamic processes (e.g. dynamic multicompo-
nent combinatorial synthesis), pathways, and
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ꢀ
C C bond-forming transformations as well as mechanistic
studies are ongoing in our laboratories.
Received: March 20, 2011
Published online: June 24, 2011
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[17] The utilization of other alcohols gave 8a after 3 hours: anisol
(35% yield, endo/exo 9:1, d.r. 6:1, 98% ee), CF3CH2OH (17%
yield, d.r. 6:1, endo/exo 10:1, 99% ee), (CF3)2CHOH (20% yield,
d.r. 5:1, endo/exo 9:1, 98% ee).
[18] Increasing the amount of water to 5 equiv decreased the yield of
the reaction.
Angew. Chem. Int. Ed. 2011, 50, 7624 –7630
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Communications
[19] The addition of 20 mol% of organic acid (for example, benzoic
[24] CCDC 792082 (8c)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.
[25] The importance of the intramolecular hydrogen bond of 10d was
further shown when the O-acetylated 10d was used instead. This
change resulted in a significantly decreased reaction rate for the
9a-mediated transformation and 8a was isolated in 37% yield
with 19:1 d.r. (3.1 endo/exo) and 96% ee. For the exact
comparison see Table 1, entry 8.
acid, acetic acid, and trifluoroacetic acid) did not improve the
rate of the reaction.
[20] The pKa were determined by 1H NMR analysis in DMSO
(dimethylsulfoxide) according to A. P. Kurtz, T. D. J. DꢆSilva, J.
Pharm. Sci. 1987, 76, 599.
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[22] The reaction with amine component 6b (R = Et), 5a, and 7a
gave the corresponding pyrrolidine 8 in 70% yield, 11:1 (endo/
exo), 19:1 d.r., and 96% ee.
[23] a) S. L. Schreiber, Science 2000, 287, 1964; b) S. L. Schreiber,
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7630 www.angewandte.org
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Angew. Chem. Int. Ed. 2011, 50, 7624 –7630