Direct aldol reactions catalyzed by intramolecularly folded prolinamide dendrons: Dendrimer effects on stereoselectivity

Article abstract of DOI:10.1039/b902960e

Dendritic effects on both the enantioselectivity and diastereoselectivity of the direct aldol reaction were observed for pyridine-2,6-dicarboxamide dendrons terminated with l-prolinamides.

Full text of DOI:10.1039/b902960e

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Direct aldol reactions catalyzed by intramolecularly folded prolinamide
dendrons: dendrimer effects on stereoselectivityw
Kazuhiko Mitsui, Sarah A. Hyatt, Daniel A. Turner, Christopher M. Hadad
and Jon R. Parquette*
Received (in Austin, TX, USA) 12th February 2009, Accepted 11th April 2009
First published as an Advance Article on the web 7th May 2009
DOI: 10.1039/b902960e
Dendritic effects on both the enantioselectivity and diastereo-
selectivity of the direct aldol reaction were observed for pyridine-
2,6-dicarboxamide dendrons terminated with L-prolinamides.
with L-proline.12 In contrast, Portnoy and co-workers observed
that polymer-supported dendritic proline catalysts afforded
generation-dependent increases in enantioselectivity.5b,c
On the basis of these observations, we prepared folded
dendritic organocatalysts based on the pyridine-2,6-dicarbox-
amide branching unit (Fig. 1). The L-prolinamide catalytic units
were linked to the pyridine-2,6-dicarboxamide branch point via
an o-phenylenediamide rather than an anthranilamide linkage
typical of these dendrons.6 To probe the impact of terminal
group congestion on stereoselectivity, we compared the
catalytic properties of two series of dendrons having either an
L-prolinamide group at every (Gn-all) or alternating (Gn-alt.)
terminal positions as a function of generation. Additionally, the
role of dendron structure was explored by evaluating Type I G2
(3 and 7) and Type II G2 (4 and 8) dendrons.6d,e
We examined these dendritic prolinamides13 as catalysts for
the aldol reactions of a series of acyclic and cyclic aldol donors
with 4-nitrobenzaldehyde (10). The aldol reactions were
performed in DMF in the presence of excess ketone, catalytic
acetic acid and water (1000 mol%). The addition of water was
necessary to ensure a reasonable rate of the aldol reaction.14
Previous studies indicate that the addition of water does not
disrupt the folded conformations of this class of dendrimers.6b
The catalyst loading for each reaction was adjusted to maintain a
constant number of catalytic units per reaction for a given ketone.
In contrast to acetone, which exhibited only marginal
changes in selectivity with generation (Table 1, entries 1–9),
significant increases emerged at higher dendron generation for
cyclic and substituted ketones. In fact, plots of % ee vs. generation
The topological resemblance of dendrimers to globular
proteins has inspired intense interest in exploiting the three-
dimensional nature of their structures to improve catalytic
efficiency.1 Although extensive research efforts toward this
goal over the last decade have led to discoveries of a number
of positive dendrimer effects2 in periphery functionalized
catalytic dendrimers, most other dendritic catalysts display
properties similar to the monomeric counterparts most likely
due to the lack of well-defined secondary structures as in
natural enzymes. The positive dendritic effects reported in
these systems stimulate rate enhancements3 or alter regio-
selectivity4 by increasing the congestion and local proximity
of catalytic groups at the dendrimer periphery. Generation-
dependent amplification of enantioselectivity has only been
documented in a few cases and similarly accounted for by the
proximity effect.5 We report herein notable dendritic effects on
the stereoselectivity of direct aldol reactions catalyzed by
dynamically folded dendritic6 organocatalysts.
Natural enzymes achieve nearly perfect selectivities and
remarkable rate enhancements through the dynamically folded
nature of their higher order structures. Recent evidence
suggests that structural dynamics significantly influence the
efficiency of biological7 and non-biological8 catalysts. Con-
sequently, we became interested in probing the ability of our
dynamically folded dendrimers6,9 to enhance the stereo-
selectivity of an organocatalytic reaction.
We focused on the proline-catalyzed direct aldol reaction10
because recent studies provide strong evidence for a single-
proline enamine mechanism for this reaction.11 This mechanistic
information reduces the potential for a proximity effect that
could lead to enhanced selectivity. Accordingly, previous
investigations by others on proline-terminated flexible dendrimers
as organocatalysts for the direct aldol reaction revealed
enantioselectivities that were slightly diminished compared
Department of Chemistry, The Ohio State University,
100 W. 18th Ave., Columbus, OH 43210, USA.
E-mail: parquett@chemistry.ohio-state.edu; Fax: +1-614-292-1685;
Tel: +1-614-292-5886
w Electronic supplementary information (ESI) available: Experimental
conditions for the catalytic aldol reaction, general procedures and
characterizations of dendrons. CCDC 720260 and 727117. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/b902960e
Fig. 1 Folded dendrons with prolinamides at each (Gn-all) or
alternating (Gn-alt.) terminal positions.
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Table 1 Direct aldol reaction of 4-nitrobenzaldehyde with acetone
catalyzed by prolinamide dendronsa
G3-alt. (9). In contrast to cyclopentanone, the % ee of the
syn-aldol product progressively decreased with generation for
both dendron series. Generation-dependent increases in the
anti–syn ratio were also observed in each series ranging from
4.4 : 1 for G1-all (2) to 21 : 1 for G3-all (5) and from 4.6 : 1 for
G1-alt. (6) to 32 : 1 for G3-alt. (9). In both series, the Type-II-G2
dendrons (4 and 8) provided lower anti–syn ratios than the
corresponding higher generation Type I catalysts (Table 1,
entries 22 and 26).
Yieldb
Mol% (%)
drc
anti–syn
% eed
anti–syn
Entry
Catalyst
The fact that the reaction of cyclic ketones with 10 experi-
enced much larger generational effects than acetone suggests
that steric effects play a role in mediating the dendritic effects on
selectivity. In order to explore the generality of this observation,
the reaction of 2-butanone (11) with 10 was performed.
A generation-dependent increase in % ee from 63 to 94% for
Gn-all and from 88 to 92% for Gn-alt. series was observed for
anti-aldol product 12 (Table 2). Similar to cyclohexanone, the
syn-aldol product (not shown) experienced a decrease in % ee
from 64 to 36% for Gn-all and from 78 to 50% for Gn-alt. In
contrast to the anti product, the % ee of regioisomer 13 showed
an increase from 58 to 78% for Type-I-Gn-all and from 26 to
78% for Type-I-Gn-alt. Similarly, the Type-II-G2 catalysts
afforded lower % ee than the corresponding Type-I-G2
dendrons in both series (Table 2, entries 4 and 7).
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
G0 (1)
20
10
5
5
2.5
20
75
59
50
55
38
70
42
44
64
98
87
87
87
91
77
90
87
88
99
90
73
69
99
92
87
87
92
—
—
—
—
—
—
—
—
49
36
59
45
55
58
56
58
G1-all (2)
I-G2-all (3)
II-G2-all (4)
G3-all (5)
G1-alt. (6)
I-G2-alt. (7) 10
II-G2-alt. (8) 10
G3-alt. (9)
G0 (1)
G1-all (2)
I-G2-all (3)
II-G2-all (4)
G3-all (5)
G1-alt. (6)
I-G2-alt. (7)
II-G2-alt. (8)
G3-alt. (9)
G0 (1)
G1-all (2)
I-G2-all (3)
II-G2-all (4)
G3-all (5)
G1-alt. (6)
5
8
4
2
2
1
8
4
4
—
66
1 : 2.2
1 : 2.9
1.6 : 1
1.5 : 1
1.6 : 1
1 : 2.6
2.2 : 1
2.6 : 1
2.5 : 1
5.3 : 1
4.4 : 1
15 : 1
6.5 : 1
21 : 1
4.6 : 1
24.5 : 1
14 : 1
32 : 1
33/6
63/14
92/71
92/84
92/72
36/26
88/50
90/32
90/48
64/28
59/48
96/26
84/3
97/10
78/79
93/44
93/29
96/28
2
X-Ray crystal structures of G1-alt. (6) and the N-benzyl
derivative of G1-all (N-Bn) (SI-40) confirmed a syn–syn
conformation of the pyridine-2,6-dicarboxamide moiety. All
four N–H groups of both structures were involved in intra-
molecular hydrogen bonds that preorganize the structure
(Fig. 2). In contrast to the flattened conformation of G1-alt.,
G1-all (N-Bn) adopts a P-helical bias in the solid state.
Circular dichroic spectra (CD) of the N-benzyl derivatives15
of G1-all (SI-40) and G2-all (SI-41) revealed apparent
excitonic couplets centered at ca. 290 nm, corresponding to
p - p* transitions of the o-diamidobenzene chromophore
(Fig. 3). Time-dependent density functional theory (TD-DFT)
calculations, performed at the B3LYP/TZVP16 level of theory,
20
10
5
5
2.5
20
I-G2-alt. (7) 10
II-G2-alt. (8) 10
G3-alt. (9)
5
a
Reactions were performed at rt in DMF in the presence of ketone
(27 eq.), acetic acid (1 eq. per prolinamide) and 1000 mol% H2O for 48 h
b
(entries 1–9) and 24 h (entries 10–27). Isolated yield. Determined
c
by 1H-NMR. Determined by chiral HPLC.
d
revealed nearly identical selectivity trends for both the
Gn-all and Gn-alt. systems (see ESIw). For example, the
enantioselectivity of the anti-aldol product of the reaction
of 10 with cyclopentanone increased from 33 to 92% ee
for Gn-all and to 90% for Gn-alt., upon progressing
from L-prolinanilide (G0, 1) to G3 dendrons (Table 1,
entries 10–18). Similarly, the enantioselectivity of the syn-aldol
product increased from 6% for G0 (1) to 72% for G3-all (5)
and to 48% for G3-alt. (9). The diastereomeric ratios reversed
from syn-selective for G0 (1) and G1 (2/6) to anti-selective for
both series of G2 and G3 dendrons. It is noteworthy that these
selectivity trends were nearly independent of the prolinamide
density at the periphery (Gn-all versus Gn-alt.) and that the
Type I and Type II G2 dendrons afforded similar selectivities
(Table 1, entries 12, 13 and 16, 17).
Table 2 Direct aldol reaction of 4-nitrobenzaldehyde with 2-butanone
catalyzed by prolinamide dendronsa
% eed
Yieldb
Mol% (%)
% eeb
(13) 12 : 13
drc (12) (12)
anti–syn anti–syn
Entry Catalyst
1
2
3
4
5
6
7
8
9
G0 (1)
G1-all (2)
I-G2-all (3)
II-G2-all (4)
G3-all (5)
G1-alt (6)
I-G2-alt. (7) 10
II-G2-alt. (8) 10
20
10
5
97
50
45
48
2.6 : 1
1.5 : 1
3.0 : 1
2.6 : 1
4.5 : 1
2.6 : 1
7.8 : 1
4.5 : 1
7.7 : 1
76/56
63/64
92/26
90/44
94/36
88/78
92/54
92/60
92/50
69
58
66
40
78
26
58
36
78
1 : 1.2
2.7 : 1
1.5 : 1
2.4 : 1
3.0 : 1
5
2.5 35
20
58
52
49
48
1 : 1.4
Comparable selectivity trends were observed in the reaction
of 10 with cyclohexanone using the prolinamide-dendron
catalysts (Table 1, entries 19–27). G0 (1) and G1 (2/6) catalysts
afforded the anti and syn-aldol products with similar diastereo-
selectivities and enantioselectivities ranging from 59 to 78%
for the anti product. The ee of the anti-aldol product improved
from 64% for G0 (1) to 97% for G3-all (5) and to 96% for
2.2 : 1
1.8 : 1
2.4 : 1
G3-alt. (9)
5
a
Reactions were performed at rt in DMF in the presence of ketone
(27 eq.), acetic acid (1 eq. per prolinamide) and 1000 mol% H2O for 48 h.
b
c
d
Isolated yield. Determined by 1H-NMR. Determined by chiral
HPLC.
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Fig. 3 Experimental (CH3CN, 25 1C) and calcd. CD spectra.
on the P-helical crystallographic structure of G1-all (SI-40)
match well with the experimental CD spectra, indicating a
similar P-helical bias in solution. In contrast, the calculated
CD spectra for the M structure did not match experimental
spectra (see ESIw).
The increase in P-helical bias going from the G1 to G2
dendron correlates well with the corresponding improvements
in selectivity. However, it is noteworthy that despite the
flattened structure of G1-alt. in the solid state, the Gn-all
and Gn-alt. series display nearly parallel selectivity trends.
Although a potential source of chirality, the increase in
P-helical bias at higher generation also indicates a concomi-
tant increase in structural order.6 Therefore, given the
conformational differences between the two dendritic series,
it is likely that the dendritic effects emerge from an increase in
structural preorganization, rather than from the chiral
influence of the helical bias or from a proximity effect.
In conclusion, dendritic effects that amplify the stereo-
selectivity of an organocatalytic process were observed.
A few selectivity trends can be summarized as follows: (i) a
significant enhancement in selectivity is generally achieved
using low generation dendrons rather than much larger
dendrimers, (ii) the % ee of the anti-aldol is enhanced for
higher generation dendrons and similar among G2 and G3
dendrons, (iii) the Type I G2 dendron system in general affords
similar or slightly higher selectivities than the corresponding
Type II G2 catalyst, and (iv) the alterations of stereoselectivities
are most pronounced with cyclic and substituted ketones.
This work was supported by the National Science
Foundation CRC program (CHE-0526864). The authors
thank Judy Gallucci for solving the crystal structure of 6.
13 For examples of prolinamide catalysts, see: G. Guillena, C. Na
´
jera
and D. J. Ramon, Tetrahedron: Asymmetry, 2007, 18, 2249–2293.
´
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solubility in transparent solvents such as CH3CN. Under catalytic
conditions, the amount of free proline NH groups is likely to be low.
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Notes and references
1 For catalytic dendrimers, see: (a) R. Van Heerbeek, P. C. J. Kamer,
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100, 5829.
¨
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Chem. Commun., 2009, 3261–3263 | 3263