Development of Chiral Organosuperbase Catalysts Consisting of Two Different Organobase Functionalities

Article abstract of DOI:10.1002/anie.202001419

In the field of chiral Br?nsted base catalysis, a new generation of chiral catalysts has been highly anticipated to overcome the intrinsic limitation of pronucleophiles that are applicable to the enantioselective reactions. Herein, we reveal conceptually new chiral Br?nsted base catalysts consisting of two different organobase functionalities, one of which functions as an organosuperbase and the other as the substrate recognition site. Their prominent activity, which stems from the distinctive cooperative function by the two organobases in a single catalyst molecule, was demonstrated in the unprecedented enantioselective direct Mannich-type reaction of α-phenylthioacetate as a less acidic pronucleophile. The present achievement would provide a new guiding principle for the design and development of chiral Br?nsted base catalysts and significantly broaden the utility of Br?nsted base catalysis in asymmetric organic synthesis.

Full text of DOI:10.1002/anie.202001419

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Accepted Article
Title: Development of Chiral Organosuperbase Catalysts Consisting of
Two Different Organobase Functionalities
Authors: Azusa Kondoh, Masafumi Oishi, Hikaru Tezuka, and
Masahiro Terada
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202001419
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10.1002/anie.202001419
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Development of Chiral Organosuperbase Catalysts Consisting of
Two Different Organobase Functionalities
Azusa Kondoh,[b] Masafumi Oishi,[a] Hikaru Tezuka,[a] and Masahiro Terada*[a]
[a]
Dr. M. Oishi, H. Tezuka, Prof. Dr. M. Terada
Department of Chemistry, Graduate School of Science
Tohoku University
Aramaki, Aoba-ku, Sendai 980-8578 (Japan)
E-mail: mterada@tohoku.ac.jp
[b]
Dr. A. Kondoh
Research and Analytical Center for Giant Molecules
Graduate School of Science, Tohoku University
Aramaki, Aoba-ku, Sendai 980-8578 (Japan)
Supporting information for this article is given via a link at the end of the document.
Abstract: In the field of chiral Brønsted base catalysis, a new
generation of chiral catalysts has been highly anticipated to
overcome the intrinsic limitation of pronucleophiles that are
applicable to the enantioselective reactions. Herein, we reveal
conceptually new chiral Brønsted base catalysts consisting of two
different organobase functionalities, one of which functions as an
organosuperbase and the other as the substrate recognition site.
Their prominent activity, which stems from the distinctive cooperative
function by the two organobases in a single catalyst molecule, was
demonstrated in the unprecedented enantioselective direct Mannich-
type reaction of α-phenylthioacetate as a less acidic pronucleophile.
The present achievement would provide a new guiding principle for
the design and development of chiral Brønsted base catalysts and
significantly broaden the utility of Brønsted base catalysis in
asymmetric organic synthesis.
and expanding the scope of pronucleophiles.[9,10] However,
development of chiral organosuperbase catalysts and the
related chiral strong Brønsted base catalysts, which would
provide the considerable progress in the field, are still less
advanced due to the difficulty in designing catalyst molecules
having both high basicity and high stereocontrolling ability.
Herein, we report “chiral cooperative binary base catalysts” 1 as
conceptually new chiral strong Brønsted base catalysts (Figure
1). The catalysts consist of two different organobase
functionalities, one of which functions as an organosuperbase
and the other as the substrate recognition site. Their prominent
activity was demonstrated in the unprecedented enantioselective
direct Mannich-type reaction of α-phenylthioacetate as a less
acidic pronucleophile to construct a β-amino-α-thiocarbonyl
scaffold.
The development of new molecular catalysts is one of the keys
for paving the way to novel transformations in organic synthesis.
In the field of chiral Brønsted base catalysis, which is one of the
most fundamental and environmentally benign methodologies
for the direct synthesis of enantio-enriched compounds,[1] a long-
standing issue is the expansion of the scope of pronucleophiles
that are applicable to the enantioselective reactions.
Conventionally, chiral tertiary amines have been widely
employed as chiral Brønsted base catalysts.[2] Recently, chiral
uncharged organobases with higher basicity than tertiary amines,
Figure 1. Newly-developed Chiral Cooperative Binary Base Catalyst 1.
Chiral cyclic scaffolds embedded with an organobase
functionality are common motifs in chiral Brønsted base
such
as
chiral
guanidines,
P1-phosphazenes,
and
catalysts (Figure 2a).[3,4,8]
A cyclic scaffold facilitates the
cyclopentenimines, have also emerged as efficient chiral
Brønsted base catalysts.[3-6] However, the insufficient basicity of
these conventional chiral organobases limits the scope of
pronucleophiles to highly acidic compounds, such as β-
dicarbonyl compounds and nitroalkanes, which restricts the
viable molecular transformations that are available under chiral
Brønsted base catalysis. Therefore, the development of a new
generation of chiral Brønsted base catalysts that can overcome
the intrinsic limitations of pronucleophiles is highly desirable.[7] In
this context, our research program has been focusing on the
development of much stronger chiral uncharged organobases,
namely chiral organosuperbases.[8] Our previous achievements,
as well as the contributions of other groups, for the
enantioselective reactions of less acidic pronucleophiles have
revealed the benefit of chiral Brønsted bases having high
basicity in developing new catalytic enantioselective reactions
formation of an effective chiral environment around the reaction
site by limiting the conformational flexibility of the catalyst
molecules. We previously developed
a chiral pseudo-C2-
symmetric 7,7-membered spirocyclic organosuperbase “GP”
having a bis(guanidino)iminophosphorane as a core structure,[8]
which could efficiently catalyze enantioselective reactions of less
acidic pronucleophiles.[9] However, chiral cyclic organobases, in
particular chiral cyclic organosuperbases having high basicity,
are often difficult to synthesize, which limits their structural
diversity and thus prevents their application to a wide range of
reactions. Alternatively, chiral acyclic organobases with an
additional acidic functionality as a substrate recognition site are
also common motifs of chiral Brønsted base catalysts (Figure
2b).[2,5] Such so-called chiral “acid-base” bifunctional catalysts
are more readily accessible than cyclic ones with more structural
diversity. However, application of this motif to chiral
1
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10.1002/anie.202001419
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bond between the two organobase functionalities to form a cyclic
structure, in particular a seven-membered cyclic structure
(Figure 2e).[11] Thus, the two organobase functionalities would
work cooperatively to form an effective chiral environment
around the substrate recognition site by limiting the
conformational flexibility in the conjugate acid form. Importantly,
our design permits chiral Brønsted base catalysts having both
high basicity and a potential cyclic structure in the conjugate
acid form, while avoiding tedious syntheses of cyclic catalyst
molecules. As shown in Figure 2d, the newly-designed catalyst
molecule
1
possesses
a
P2-phosphazene
as
an
organosuperbase (base A in Figure 2c) and a chiral guanidine
as a hydrogen bond donor for substrate recognition (base B in
Figure 2c). The two organobase functionalities are connected by
a chiral two-carbon linker (linker C in Figure 2c) derived from an
α-amino acid, which allows the formation of a seven-membered
cyclic structure with an intramolecular hydrogen bond in the
conjugate acid form of the catalyst molecule. A series of catalyst
molecules were successfully synthesized and isolated as stable
HBF4 complexes in a convergent manner from three readily
accessible components including
a
triaminophosphonium
(source A) as a P2-phosphazene precursor,[12] chiral cyclic
thioureas (source B or B’) as a guanidine precursor,[13,14] and
chiral 1,2-diaminoethane derivatives (source C) as a linker
(Figure 3).[15] The established convergent synthesis would
facilitate the optimization of the catalyst when applied to a
variety of enantioselective reactions.
Figure 2. Molecular Design for Chiral Brønsted Base Catalysts. a) Typical
chiral cyclic Brønsted base catalysts. b) Typical chiral “acid-base” bifunctional
catalysts. c) Our molecular design for chiral organosuperbases consisting of
two different organobase functionalities. d) Chiral cooperative binary base
catalyst consisting of a P2-phosphazene and a guanidine. e) Formation of a
cyclic structure with an intramolecular hydrogen bond in the conjugate acid
form of diaminoalkanes.
organosuperbases is not feasible because intramolecular
quenching of the organosuperbase moiety by the acid
functionality would occur to form a zwitterionic species with
considerable reduction of the basicity. By taking into account the
virtues of both motifs, we have develop a conceptually new
molecular design for chiral organosuperbases: a chiral acyclic
organic molecule having two different organobase functionalities,
one of which functions as an organosuperbase (base A) and the
other as the substrate recognition site (base B) (Figure 2c). The
key feature of the molecular design is the distinctive cooperative
function by two organobases in a single catalyst molecule,
namely, a chiral cooperative binary base catalyst. We expected
that the conjugate acid of a chiral cooperative binary base
catalyst, which is generated through the deprotonation of a
pronucleophile and the actual key species in the stereo-
determining step of the enantioselective reaction, would form a
chiral cyclic structure with an intramolecular hydrogen bond
between the two organobase functionalities A and B. Indeed, it
is well-known that the conjugate acids of diaminoalkanes, as
well as those of amidines and guanidines connected with an
amino group, are highly stabilized by an intramolecular hydrogen
Figure 3. A Series of HBF4 Complexes of 1. Bn = benzyl, Boc = tert-
butoxycarbonyl.
In order to validate the catalytic performance of the newly-
synthesized chiral organosuperbases, we applied them to a
direct addition reaction of less acidic pronucleophiles.
Specifically, the enantioselective direct Mannich-type reaction of
α-phenylthioacetate[16] was selected as an ideal probe (Table 1).
This unprecedented enantioselective reaction is a challenging
catalytic reaction of less acidic acyclic ester derivative as a
pronucleophiles.[17] It also provides direct access to an enantio-
enriched α-thio-β-aminocarbonyl scaffold, which is
a
synthetically useful building block and often found in a family of
sulfur-containing bioactive compounds.[18,19]
2
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10.1002/anie.202001419
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Table 1. Screening of Reaction Conditions.[a]
decreased the diastereoselectivity (entry 5). Interestingly, the
absolute configuration of the major diastereomer was identical to
that of the product obtained with the initial catalyst. This result
suggests that the chiral guanidine moiety is the primary
substrate recognition site for the enantioselective formation of
the major diastereomer of 4aa. Next, catalysts having various
substituents on the guanidine moiety and the linker were applied
to the reaction (entries 6-9). The substituents at both positions
had an appreciable impact on the stereoselectivities, especially
on the enantioselectivity. Among the catalysts tested, the
catalyst having 2-naphthyl groups on the guanidine moiety and a
benzyl group on the linker provided the highest
stereoselectivities (entry 9). The reaction was found to be
completed within 30 min with improvement in both the
diastereomeric ratio and the ee value of the major diastereomer
of 4aa (entry 10). These results suggest that the product could
be partially epimerized by extending the reaction time.[21] Further
improvement of the stereoselectivities was achieved by reducing
the reaction temperature from -80 °C to -96 °C, and these
reaction conditions were used as the optimum reaction
conditions for screening the scope of imines (entry 11). The
absolute configuration of the major diasteromer of 4aa was
unambiguously determined to be (2S,3R) by single-crystal X-ray
diffraction analysis.[22]
The scope of imines is summarized in Scheme 1. A variety of
aromatic imines including those having an electron-donating
group or an electron-withdrawing group at the para position, 3b-
3e, and sterically hindered ortho-tolyl imine 3g, were applicable
to this reaction, providing the corresponding adducts in high
yields with a good level of diastereoselectivities and high
enantioselectivities. The reaction of heteroaromatic 2-furyl imine
3i also proceeded without any problem. Furthermore, aliphatic
imine 3j was applicable to this reaction, but the diastereomeric
ratio was lower than those of aromatic imines. However, a high
level of ee of the major diastereomer was still maintained.
1 or or-
ganobase
yield
[%][b]
ee
entry
R
Ar
dr[c]
[%][d]
1
2
1a
TBD
P1-tBu
P2-tBu
1b
Ph
-
Ph
83
<1
<1
99[e]
99
95
95
94
99
98
99
79 : 21
-
59
-
-
3
-
-
-
-
4
-
-
58 : 42
52 : 48
59 : 41
68 : 32
65 : 35
77 : 23
82 : 18
88 : 12
-
5
Ph (R)
iPr
Bn
Bn
Bn
Bn
Bn
Ph
46
59
78
18
85
92
95
6
1c
Ph
7
1d
Ph
8
1e
1-naphthyl
2-naphthyl
2-naphthyl
2-naphthyl
9
1f
10[f]
11[f,g]
1f
1f
[a] Conditions: 2a (0.10 mmol), 3a (0.12 mmol), 1·2HBF4 (0.010 mmol) with
KHMDS (0.020 mmol) or organobase (0.010 mmol), THF (1.0 mL), -80 °C, 24
h. [b] Isolated yields unless otherwise noted. [c] Determined by 1H NMR
analysis of the crude reaction mixture. [d] Determined by chiral stationary-
phase HPLC analysis for the major diastereomer. [e] NMR yield. [f] Performed
for 30 min. [g] Performed at -96 °C. THF = tetrahydrofuran
Our initial study was conducted with catalyst 1a having phenyl
groups on both the guanidine moiety and the linker. The catalyst
was generated in situ by treating a HBF4 complex of 1a with two
equivalents of potassium bis(trimethylsilyl)amide (KHMDS) prior
to use. Treatment of benzyl α-phenylthioacetate (2a) with N-Boc
imine 3a in the presence of 10 mol% 1a in THF at -80 °C for 24
h provided the desired product 4aa in good yield (entry 1). In
addition, substantial enantioselectivity was detected, which
revealed that the newly-developed organosuperbase was indeed
able to serve as a chiral Brønsted base catalyst. As a control
experiment, the reaction was attempted with achiral bases
possessing different basicities (entries 2-4). The use of less
basic guanidine (TBD = 1,5,7-triazabicyclo[4.4.0.]dec-5-ene,
pKBH+ = 26.0 in CH3CN)[20] and P1-phosphazene (P1-tBu, pKBH+
= 27.0 in CH3CN, 15.7 in DMSO)[12,20] resulted in no reaction
(entries 2 and 3). In contrast, the use of P2-phosphazene having
much higher basicity (P2-tBu, pKBH+ = 33.5 in CH3CN, 21.5 in
DMSO)[12] dramatically accelerated the reaction (entry 4). These
results clearly indicate that the catalyst basicity imparted by the
P2-phosphazene moiety of 1a is essential for promoting this
reaction. The effect of the substituents on the catalysts was then
examined. First, the catalyst having the opposite absolute
configuration at the chiral center on the linker was tested, which
Scheme 1. Scope of Imines. [a] Performed for 20 min.
In order to gain insight into the requisite elements of the catalyst
molecule for its high stereocontrolling ability, some control
experiments were carried out (Scheme 2). First, the reaction
was conducted with 1g possessing the N-methylated guanidine
moiety (Scheme 2a). The ee values of both enantiomers were
3
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COMMUNICATION
dramatically decreased. This result indicates that the N-H proton
on the guanidine moiety plays a key role in the stereoselective
C-C bond forming event. The catalyst 1h having a one-carbon
elongated linker was also examined (Scheme 2b). In this case,
the product was obtained in high yield but low stereoselectivities.
This result reveals the importance of the relative arrangement of
the two organobase functionalities in the catalyst molecule,
implying that the distinctive cooperative function by the P2-
phosphazene moiety and the guanidine moiety is indeed
operative to control the stereoselectivities of the reaction. Chiral
bis(guanidino)iminophosphorane having typical substituents
GP1, of which potential has been exhibited in several
reactions,[8] was then applied to this reaction to compare its
catalytic activity (Scheme 2c). The reaction proceeded smoothly
to provide 4aa in quantitative yield, but with very low diastereo-
and enantioselectivities albeit under unoptimized reaction
conditions for GP. Considering the fact that no chiral
organobases other than GP possess comparable basicity to 1,
this result not only shows the advantage of the newly-developed
catalyst, but also strongly demonstrates the importance of the
development of novel chiral organosuperbases to open up new
avenues for unprecedented molecular transformations under
chiral Brønsted base catalysis.
less acidic 2b did not proceed with P2-phosphazene-based
catalyst 1 even at the higher temperature of -40 °C, the P3-
phosphazene based-catalyst 5f possessing enhanced basicity
promoted the reaction to provide the corresponding Mannich
adduct 4ba in moderate yield with moderate stereoselectivities.
Thus, our molecular design for chiral Brønsted base catalysts
potentially allows for the fine tuning of the catalyst basicity with
an organosuperbase functionality in addition to fine tuning of a
chiral environment around the reaction site with substituents on
a chiral organobase functionality as a substrate recognition site
and a linker. These tunable properties of the newly-designed
catalysts are markedly beneficial for further development of new
catalytic enantioselective reactions with the expansion of the
scope of pronucleophiles.
Scheme 3. Exploratory Study of Direct Mannich-type Reaction of α-
Phenylthioacetamide.
In conclusion, we have developed chiral Brønsted base catalysts
consisting of a P2-phosphazene as an organosuperbase and a
chiral guanidine as a hydrogen bond donor for substrate
recognition. The molecular design is based on a conceptually
new idea for
a distinctive cooperative function by two
organobases in a single catalyst molecule. The prominent
catalytic activity of the chiral cooperative binary base catalyst
was demonstrated in the enantioselective direct Mannich-type
reaction of α-phenylthioacetate as a less acidic pronucleophile to
construct
a
β-amino-α-thiocarbonyl scaffold in
a
highly
enantioselective manner. The results of our investigation would
provide a new guiding principle for the design and development
of chiral Brønsted base catalysts and would broaden the utility of
chiral Brønsted base catalysis in organic synthesis. Further
studies are in progress to develop novel catalytic
enantioselective reactions and expand the scope of
pronucleophiles by using the newly-developed catalysts and to
develop highly efficient catalysts based on the newly-established
molecular design.
Acknowledgements
This research was supported by a Grant-in-Aid for Scientific
Research from the JSPS (No. 16H06354 to M.T. and No.
16K05680 to A.K.).
Scheme 2. Control Experiments.
Keywords: organocatalyst • organosuperbase • asymmetric
Finally, an exploratory study of the reaction of α-
phenylthioacetamide 2b revealed another promising aspect of
our molecular design (Scheme 3). Whereas the reaction of much
catalysis • phosphazene • guanidine
4
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10.1002/anie.202001419
Angewandte Chemie International Edition
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Chiral Brønsted base catalysts, which consist of a P2-phosphazene as an organosuperbase and a chiral guanidine as a hydrogen
bond donor for substrate recognition, were developed based on a conceptually new idea for a distinctive cooperative function by two
organobases in a single catalyst molecule. The prominent catalytic activity was demonstrated in the enantioselective direct Mannich-
type reaction of less acidic α-phenylthioacetate.
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