Solvent-dependent enantiodivergent mannich-type reaction: Utilizing a conformationally flexible guanidine/bisthiourea organocatalyst

Article abstract of DOI:10.1002/anie.201005109

Flex control: Malonate and tert-butoxycarbonyl (Boc)-protected imines react in the presence of the flexible catalyst 1 to furnish the S or the R adduct depending upon the solvent used. Kinetic analyses in this enantiodivergent organocatalysis show that en

Full text of DOI:10.1002/anie.201005109

Communications
DOI: 10.1002/anie.201005109
Synthetic Methods
Solvent-Dependent Enantiodivergent Mannich-Type Reaction:
Utilizing a Conformationally Flexible Guanidine/Bisthiourea
Organocatalyst**
Yoshihiro Sohtome,* Shinji Tanaka, Keisuke Takada, Takahisa Yamaguchi, and
Kazuo Nagasawa*
Hydrogen bonding promoted asymmetric catalysis has rap-
idly grown over the past decade.[1] Most organocatalysts
probed to date have conformationally rigid chiral backbones
that participate in structurally rigid transition states.[2] In
contrast, recent findings from our group have shown that
conformationally flexible guanidine/bisthiourea organocata-
lysts 1[3–7] display unique stereodiscrimination processes that
are governed by differential activation entropy (DDS° =
25.4 Jmolꢀ1 Kꢀ1) rather than differential activation enthalpy
(DDH° = ~ 0 kJmolꢀ1) in ortho- and enantioselective 1,4-type
Friedel–Crafts alkylations of sesamol.[8] A new perspective
described herein concerns the possibility of bringing about
dynamic control of the stereochemical outcomes in the
organocatalytic system by tuning the enthalpy and entropy
related external factors (e.g., reaction solvents, the substrate
concentration, and pressure).[9] The development of the
solvent-dependent enantiodivergent Mannich-type reaction
of N-aldimines with malonates that enable selective synthesis
of either enantiomer by employing a single enantiomer of a
chiral catalyst is presented (Scheme 1). The S adducts are
selectively formed with 87–94% ee in reactions run in
m-xylene, whereas R adducts predominate (80–89% ee) in
reactions carried out in acetonitrile. High catalytic efficiencies
are also observed as exemplified by the catalyst turnover
frequencies (TOF) under optimized reaction conditions; the
TOF for the S-selective reaction is 66 hꢀ1, and 25 hꢀ1 for the
R-selective reaction.
Enantiodivergent syntheses utilizing a single chiral cata-
lyst is one of the most straightforward approaches for
selective formation of both enantiomers of a product.[10]
From the time of the disclosure by Mosher and co-workers
in 1972[11] on the asymmetric reduction of unsymmetric
ketones with stoichiometric chiral alkoxyalminiumhydrides,
several metal-based methodologies for enantiodivergent
catalysis, in which the central metal and reaction conditions
were tuned, have been studied.[10–12] In these systems,
individual metal properties, such as Lewis acidity, oxophilic-
ity, azophilicity, and atomic radius, have been exploited for
the formation of a variety monomeric and oligomeric catalytic
active species.[10] In contrast, enantiodivergent reactions
promoted by organocatalysts have been less often
reported.[13,14] In addition, for most cases the enantiodivergent
organocatalytic reactions described to date require the use of
high catalyst loadings (ca. 10 mol%) to attain high conver-
sions (> 90%) and maximum selectivity.[13,14] To broaden the
organocatalytic enantiodivergent catalysis, the development
of a basic strategy that can be applied to a variety of catalytic
stereodivergent reactions is desirable.
Efforts directed at exploring a strategy for using a chiral
organocatalyst in to controlled enantioswitching by tuning
both the enthalpy and entropy related external factors, first
focused on the development of the catalytic Mannich-type
reaction of N-Boc aldimines 2 with malonates 3.[15,16] We
envisioned that since these reactions are irreversible, enan-
tiodifferentiation of the Mannich adducts might be achieved
with the use of a single organocatalyst in which the relative
conformation with respect to the guanidinium and thiourea
functional groups might be altered by changing the reaction
conditions. If successful, the enantiodifferentiation of the
Mannich adducts by a single organocatalyst might be possible.
In previously developed catalytic asymmetric Mannich-type
reactions of aromatic a-amido sulfones, stoichiometric
amounts of Cs2CO3 were used as an external base for in situ
preparation of the N-aldimine acceptors 2 in the presence of
10 mol% of the catalyst 1·HCl.[17] To evaluate the occurrence
of using a chiral catalyst in a controlled way so as to reverse
enantioselectivity, it was important to avoid achiral-base-
Scheme 1. A design concept for organocatalytic enantiodivergent
reaction by utilizing 1. Boc=tert-butyloxycarbonyl.
[*] Dr. Y. Sohtome, S. Tanaka, K. Takada, T. Yamaguchi,
Prof. Dr. K. Nagasawa
Department of Biotechnology and Life Science, Faculty of
Technology, Tokyo University of Agriculture and Technology
2-24-16 Naka-cho, Koganei, Tokyo 184-8588 (Japan)
Fax: (+81)42-388-7295
E-mail: sohtomey@cc.tuat.ac.jp
knaga@cc.tuat.ac.jp
[**] We thank the Grant-in-Aid for Young Scientist (B) and The Uehara
Memorial foundation.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201005109.
9254
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Chemie
mediated racemic pathways. Therefore, an alternative proto-
col for the Mannich-type reaction of N-Boc imines 2 was
developed in which the catalyst 1 is formed by reaction of
1·HCl with a base.
noted. As shown in entries 7 and 15 in Table 1, guanidine/
bisthiourea 1a promotes rapid S-selective reactions that
proceed to completion within 1.5 hours, and the R-selective
reactions require 3 hours for completion. Moreover, catalyst
loading can be reduced without any loss of enantioselectivity
(Table 1, entry 8: TOF = 66 hꢀ1 in S-selective reaction,and
entry 16: 25 hꢀ1 in R-selective reaction).
The scope and limitations of the enantiodivergent reac-
tions were probed next (Table 2). The organocatalytic reac-
tions promoted by 1a in m-xylene or toluene consistently
Extensive screening[18] led to the identification of catalyst
1a, which displays dramatic solvent-dependent enantiodiver-
gence in the Mannich-type reaction of 2a with 3a.[18,19] For
example, reactions in nonpolar solvents such as dichloro-
methane, toluene, chlorobenzene, and m-xylene led to the
production of (+)-(S)-4aa (Table 1, entries 1–5). In contrast,
Table 1: Optimization studies on the 1a-catalyzed enantiodivergent
Mannich-type reactions of 2a with 3a.
Table 2: 1a-Catalyzed enantiodivergent Mannich-type reactions with
various aromatic N-Boc imines 2.
Entry 2: Ar
Solvent Product
T
t
Yield ee
[8C] [h] [%][a] [%][b,c]
1[d,h] 2b: 4-MeC6H4
m-xylene 4ba
m-xylene 4ca
m-xylene 4da
m-xylene 4ea
0
0
0
0
0
1.5 99
+92
+91
+93
+90
+97
+94
+89
+97
+87
ꢀ89
ꢀ89
ꢀ80
ꢀ82
ꢀ84
ꢀ80
ꢀ84
ꢀ86
ꢀ82
2[d]
3[d]
2c: 3-MeC6H4
2d: 2-MeC6H4
2
3
2
8
97
98
99
99
Entry Solvent
1a [mol%] T [8C] t [h] Yield [%][a] ee [%][b,c]
1
Et2O
10
10
10
ꢀ10 24
ꢀ10 24
ꢀ10 24
ꢀ10 24
ꢀ10 24
96
99
97
98
95
99
+42
+71
+90
+90
+86
+92
+92
+92
ꢀ31
ꢀ16
ꢀ72
ꢀ76
ꢀ79
ꢀ88
ꢀ88
ꢀ88
4[d,h] 2e: 4-ClC6H4
2
3
CH2Cl2
toluene
5
2 f: 4-MeOC6H4 m-xylene 4 fa
2g: 2-naphthyl m-xylene 4ga
6[d]
0
1.5 99
4
chlorobenzene 10
7[d,e] 2h: 2-furyl
8[d,e] 2i: 2-thienyl
9[d,g] 2a: Ph
m-xylene 4ha
toluene 4ia
m-xylene 4ab
ꢀ10
ꢀ10
0
1
1
2
97
98
97
5
6
7
8
m-xylene
m-xylene
m-xylene
m-xylene
THF
10
10
10
1
0
0
0
24
1.5 99
1.5 99
10[d] 2b: 4-MeC6H4
11[d] 2c: 3-MeC6H4
12[d,f] 2d: 2-MeC6H4
13[d] 2e: 4-ClC6H4
MeCN
MeCN
MeCN
MeCN
4ba
4ca
4da
4ea
4 fa
4ga
4ha
4ia
ꢀ40 18 98
ꢀ40 15 96
ꢀ30 14 90
9
10
10
10
10
10
10
10
1
ꢀ10 24
ꢀ10 24
ꢀ10 24
ꢀ10 24
ꢀ10 24
ꢀ30 24
97
96
99
99
98
98
99
99
10
11
12
13
14
15
16
EtOAc
iPrCN
EtCN
MeCN
MeCN
MeCN
MeCN
ꢀ40
6
99
14
2 f: 4-MeOC6H4 MeCN
ꢀ40 20 88
ꢀ40 12 97
ꢀ30 10 92
ꢀ40 12 97
15[d] 2g: 2-naphthyl MeCN
16[d] 2h: 2-furyl
17[d,f] 2i: 2-thienyl
18[d,g] 2a: Ph
MeCN
MeCN
MeCN
ꢀ30
3
4
4ab
ꢀ10
2
99
ꢀ30
[a] Yield of isolated product. [b] Determined by chiral HPLC analysis
using a chiral column. [c] The ee value of (S)-4 is defined as plus and that
of (R)-4 as minus. [d] The absolute stereochemistry of 4 was determined
on the basis of its optical rotation.[16] [e] Used 2 mol% of 1a [f] Used
3 mol% of 1a. [g] Used 5 mol% of 1a. [h] The reaction was carried out at
0.1m with respect to 2.
[a] Yield of isolated product. [b] Determined by HPLC analysis using a
chiral column. [c] The ee value of (S)-4 is defined as plus and that of (R)-4
as minus. The absolute stereochemistry of 4aa was determined on the
basis of its optical rotation.[16j]
when reactions were carried out in polar aprotic solvents,
(ꢀ)-(R)-4aa was obtained as the major product (Table 1,
entries 9–13). Among the polar aprotic solvents examined,
nitriles gave the highest R selectivity (Table 1, entries 11–13).
With suitable solvents for enantioswitching in hand, our
efforts then focused on optimization of both the S- and
R-selective reactions. In the course of this effort, significant
temperature effects on 1a-catalyzed enantiodivergent Man-
nich-type reactions were observed. Specifically, as the reac-
tion temperature increased the S selectivity in m-xylene
showed S selectivity (Table 2, entries 1–9). Fine tuning of the
reaction conditions led to high S selectivity (87–97% ee) for
reactions involving a range of aromatic N-Boc imines. The
reactions of aromatic imines bearing para, meta, and ortho
substituents gave products in 97–99% yield with S selectivity
in the range of 91–93% ee (Table 2, entries 1–3). A longer
reaction time is required for the reaction of imine 2 f, which
contains an electron-donating group at the para position of
the aromatic ring, nevertheless excellent enantioselectivity
was observed (Table 2, entry 5). 2-Naphthyl-, 2-furyl- and
2-thienyl-substituted imines also afford products in yields of
97–99% with ee values of 89–97% (Table 2, entries 6–8).
Although the benzyl malonate 3b displays a lower reactivity
increased (Table 1, entry 5 versus entry 6), whereas
a
decrease in reaction temperature increased the R selectivity
in reactions in acetonitrile (Table 1, entry 13 versus entry 14).
High reaction rates for reactions catalyzed by 1a were also
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9255

Communications
Table 3: Differential activation parameters.
in the catalytic system, increasing the catalyst loading
DDH° [kJmolꢀ1
]
DDS° [Jmolꢀ1 Kꢀ1
]
significantly enhances the reaction rate. In the presence of
5 mol% of 1a, the Mannich-type reaction of 2a with 3b is
completed in 2 hours and affords product in 97% yield with
87% ee (Table 2, entry 9). Importantly, when the reaction is
carried out in acetonitrile reversal of the enantioselectivity is
observed compared to that seen with m-xylene and toluene.
The Mannich-type reactions in acetonitrile give the corre-
sponding R products in 88–99% yield with 80–89% ee
(Table 2, entries 10–18).
Entry
Solvent
1
2
3
4
5
6
7
8
toluene
m-xylene
chlorobenzene
CH2Cl2
EtOAc
THF
+15.1
+19.9
+9.99
+16.8
ꢀ24.0
ꢀ29.4
ꢀ19.4
ꢀ14.6
+82.3
+99.6
+59.6
+79.7
ꢀ87.3
ꢀ106
EtCN
MeCN
ꢀ57.2
ꢀ37.2
Considering that Gibbs free energy is defined as DDG° =
DDH°ꢀTDDS°, the difference in temperature profiles
between the S-selective reaction and R-selective reaction in
the present organocatalytic system suggest that enthalpy-
entropy compensation may contribute to the solvent-depen-
dent enantioswitching. This speculation, along with the goal
of characterizing the chiral recognition processes that take
place in the bond-forming reaction,[21] led us to perform a
kinetic analysis of the reaction using Eyring plots[9,22–24] to
obtain the differential activation parameters.
stereodetermining step of solvent-dependent organocatalytic
reactions promoted by 1a. Positive values of DDH° and
S-R
DDS°
in S-selective reactions run in nonpolar solvent
S-R
systems are obtained (Table 3, entries 1–4). In these cases,
differential activation entropies (DDS°S-R) contribute to low-
ering the DDG° of reactions having unfavorable enthalpic
S-R
contributions. In contrast, negative values of DDH° and
R-S
DDS°
control the stereodiscrimination processes in
R-S
In the differential Eyring treatment,[22] the relative rates of
formation of (S)-(+)- and (R)-(ꢀ)-4aa in S-selective and
R-selective reactions are expressed by Equations (1) and (2),
respectively, where DDS° represents the differential activa-
tion entropy and DDH° represents the differential activation
enthalpy.
R-selective reactions in aprotic polar solvents (Table 3,
entries 5–8), in which the DDH°R-S term has a major influence
on lowering the DDG° in the R-selective reactions. Thus,
R-S
the observed solvent-dependent stereodiscrimination in
1a-catalyzed Mannich-type reaction resides in compensating
differences in the enthalpies and entropies of activation.[25]
Additional efforts designed to probe the link between kinetics
and molecular mechanism are underway.[26]
lnðkS=kRÞ ¼ ꢀDDH°S-R=RT þ DDS°S-R=R
lnðkR=kSÞ ¼ ꢀDDH°R-S=RT þ DDS°R-S=R
ð1Þ
ð2Þ
In conclusion, we have developed an enantiodivergent
catalytic Mannich-type reaction by utilizing conformationally
flexible organocatalysts. The simple methodology has a broad
aromatic N-Boc imine substrate scope and it enables selective
access to both enantiomers of the Mannich adducts using a
single chiral organocatalyst. Kinetic analyses uncovered that
the origin of solvent-dependent stereodiscrimination is con-
trolled by the enthalpy-entropy compensation. The stereose-
lectivities of S-selective Mannich-type reactions in nonpolar
solvents are governed by the differences in the entropies of
activation (DDS°S-R), whereas the stereodiscrimination pro-
cesses of R-selective reactions are governed by differences in
the enthalpies of activation (DDH°R-S). We believe that these
findings will serve as a foundation for the design of new
stereoswitchable asymmetric organocatalytic processes.
Additional efforts to apply the concepts described above to
other classes of asymmetric transformations, including dia-
stereoswitching and organocascade processes, are underway.
In accord with Equations (1) and (2), plots of natural
logarithms of the relative rates of formation of (S)-(+)- and
(R)-(ꢀ)-4aa versus reciprocal temperatures were fitted to
straight lines with good correlation coefficients (Figure 1).
These observations confirm that a single mechanism is
operable in the catalytic process occurring in each solvent in
the temperature range explored.[23d]
As seen by inspecting the data in Table 3, both enthalpy
(DDH°) and entropy (DDS°) compensation govern the
Received: August 16, 2010
Revised: September 7, 2010
Published online: October 26, 2010
Keywords: asymmetric synthesis · enantiodivergent catalysis ·
.
enthalpy · entropy · organocatalysis
Figure 1. Eyring plots of ln[(100+% ee)/(100ꢀ% ee)] vs. 1/T for
1a-catalyzed Mannich-type reactions in various solvents. a) S-Selective
reactions in toluene (closed circle; R2 =0.949), m-xylene (cross;
R2 =0.983), chlorobenzene (closed triangle; R2 =0.992), and CH2Cl2
(closed diamond; R2 =0.956). b) R-Selective reactions in EtOAc (open
circle; R2 =0.967), THF (open triangle; R2 =0.998), EtCN (open
square; R2 =0.955), and MeCN (open diamond; R2 =0.981).
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a) G. A. Hembury, V. V. Borovkov, Y. Inoue, Chem. Rev. 2008,
108, 1; b) D. Heller, H. Buschmann, Top. Catal. 1998, 5, 159; c) Y.
Inoue, Chem. Rev. 1992, 92, 741; d) H. Buschmann, H.-D. Scharf,
N. Hoffmann, P. Esser, Angew. Chem. 1991, 103, 480; Angew.
Chem. Int. Ed. Engl. 1991, 30, 477.
[24] For discussions about differential activation parameters (DDH°
and DDS°) in enantioselective catalysis, see: a) I. Tꢁth, I. Guo,
B. E. Hanson, Organometallics 1993, 12, 848; b) J. Otera, K.
Sakamoto, T. Tsukamoto, A. Orita, Tetrahedron Lett. 1998, 39,
3201; c) T. Nishida, A. Miyafuji, N. Y. Ito, T. Katsuki, Tetrahe-
dron Lett. 2000, 41, 7053; d) D. Enders, E. C. Ullrich, Tetrahe-
dron: Asymmetry 2000, 11, 3861; e) R. R. Knowles, S. Lin, E. N.
Jacobsen, J. Am. Chem. Soc. 2010, 132, 5030.
[25] Plots of the differential activation parameters DDH° and DDS°
gave rise to a reasonably straight line. In several reports, linear
relationships in the enthalpy-entropy compensation plots have
been used to indicate that a single electrostatic interaction mode
is operative in the complexation processes. See the Supporting
Information for details as well as: a) J. E. Leffler, E. Grunwald,
Rates and Equilibria of Organic Reactions, Wiley, New York,
1963; for a recent example of a photochemical reaction, see:
b) G. Fukahara, T. Mori, Y. Inoue, J. Org. Chem. 2009, 74, 6714;
and references cited therein; for an example of asymmetric
reduction of a-ketoesters with chiral NADH model, see: c) R.
Saito, S. Naruse, K. Takano, K. Fukuda, A. Katoh, Y. Inoue, Org.
Lett. 2006, 8, 2067; for a selected example of chromatography,
see: d) J. Li, P. W. Carr, J. Chromatogr. A 1994, 670, 105.
[26] See the Supporting Information for preliminary mechanistic
studies.
Angew. Chem. Int. Ed. 2010, 49, 9254 –9257
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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