Chemoselective Boron-Catalyzed Nucleophilic Activation of Carboxylic Acids for Mannich-Type Reactions

Article abstract of DOI:10.1021/jacs.5b04175

The carboxyl group (COOH) is an omnipresent functional group in organic molecules, and its direct catalytic activation represents an attractive synthetic method. Herein, we describe the first example of a direct catalytic nucleophilic activation of carbox

Full text of DOI:10.1021/jacs.5b04175

Communication
pubs.acs.org/JACS
Chemoselective Boron-Catalyzed Nucleophilic Activation of
Carboxylic Acids for Mannich-Type Reactions
Yuya Morita,† Tomohiro Yamamoto,† Hideoki Nagai,† Yohei Shimizu,*,† and Motomu Kanai*,†,‡
†Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
‡ERATO, Japan Science Technology Agency, Kanai Life Science Catalysis Project, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
S
* Supporting Information
found in the scientific literature, examples for the catalytic
ABSTRACT: The carboxyl group (COOH) is an
omnipresent functional group in organic molecules, and
its direct catalytic activation represents an attractive
synthetic method. Herein, we describe the first example
of a direct catalytic nucleophilic activation of carboxylic
acids with BH3·SMe2, after which the acids are able to act
as carbon nucleophiles, i.e. enolates, in Mannich-type
reactions. This reaction proceeds with a mild organic base
(DBU) and exhibits high levels of functional group
tolerance. The boron catalyst is highly chemoselective
toward the COOH group, even in the presence of other
carbonyl moieties, such as amides, esters, or ketones.
Furthermore, this catalytic method can be extended to
highly enantioselective Mannich-type reactions by using a
(R)-3,3′-I2-BINOL-substituted boron catalyst.
nucleophilic activation of carboxylic acids resulting in carbon
nucleophiles, i.e. enolates, for the subsequent reaction with polar
electrophiles, remain extremely limited.8 This scarcity of reports
is most likely due to the nontrivial catalytic formation of
dianionic enolates from carboxylic acids. Nevertheless, notable
advances for the use of carboxylic acid derived enolates have been
made recently. Zakarian, for example, has reported the
asymmetric alkylation and conjugate addition of carboxylic
acids with stoichiometric amounts of chiral lithium amides.9 Both
of these reactions accomplish excellent levels of enantioselectiv-
ity, and the latter also achieves outstanding diastereoselectivity.
However, the versatility of these reactions is, especially for
multifunctional substrates, somewhat restricted by the use of
excess BuLi and the limitation to acetic acids with an α-aryl
substitution pattern. Herein, we report the first example of a
direct catalytic nucleophilic activation (enolate formation) of
carboxylic acids to act as carbon nucleophiles (Figure 1). The
arboxyl groups (COOH) are ubiquitous in a wide variety of
Corganic compounds, including biologically active natural
products and pharmaceuticals such as nonsteroidal anti-
inflammatory drugs (NSAIDs)1 or antibiotics.2 Given the
prevalence and importance of the COOH group, its direct
catalytic functionalization represents a highly desirable addition
to the methodological toolkit for the organic synthesis of
complex molecules.3 Moreover, it offers an attractive opportunity
to introduce structural diversifications in late stages of drug lead
optimization processes.4 A fundamental issue that remains to be
addressed in this context is the chemoselective activation of the
COOH moiety in the presence of other functional groups within
the same molecule. Apart from a desirable functional group
tolerance, such a strategy would also be beneficial for the
synthetic atom and step efficiency5 by avoiding unnecessary
protection/deprotection steps.
A seminal study on the catalytic electrophilic activation of
carboxylic acids by Yamamoto successfully demonstrated the
utility of boron mediators. Since then, boron catalysts have been
used for Diels−Alder reactions and [3 + 2] dipolar cyclo-
additions of α,β-unsaturated carboxylic acids,6 as well as for the
amidation and esterification of carboxylic acids.6b,7 A particularly
noteworthy example was reported by Hall, who accomplished a
Diels−Alder reaction that was selective toward α,β-unsaturated
carboxylic acids.6b In this reaction, a boronic acid chemo-
selectively activates a COOH group in the presence of an α,β-
unsaturated ester group, which is innately more reactive in
comparison. Even though several impressive studies concerning
the catalytic electrophilic activation of carboxylic acids can be
Figure 1. Chemoselective catalytic nucleophilic activation of carboxylic
acids.
chemoselective formation of enolates was induced in a wide
range of carboxylic acids by using a mild organic base (1,8-
diazabicyclo[5.4.0]undec-7-ene; DBU) in combination with a
catalytic amount of a boron mediator. The chemoselectivity of
this reaction is reflected in high levels of functional group
tolerance, and the catalytically formed boron enolates can
subsequently react with imines in Mannich-type reactions. The
described method can also be extended to asymmetric Mannich-
type reactions, and the resulting N-protected β-amino acid
derivatives represent an important structural motif in many
biologically active compounds.10
We began our study inspired by the pioneering work of
Evans,11 who used unsaturated diborondiolates, generated from
propionic acid, 2 equiv of R2BOTf (R = n-butyl or cyclohexyl),
and iPr2NEt at 0 °C, in aldol reactions with benzaldehyde at −78
°C. The corresponding aldol adducts were obtained in high yield
and moderate diastereoselectivity (87% yield, syn/anti = 35/65−
Received: April 22, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b04175
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Journal of the American Chemical Society
Communication
a
Table 1. Substrate Scope for the Chemoselective Boron-Catalyzed Mannich-Type Reactions of Carboxylic Acids
a
Isolated yield and diastereomer ratio were determined after conversion of the Mannich products into methyl esters (see Supporting Information).
b
c
d
The diastereomer ratio was determined by 1H NMR analysis. 20 mol % of BH3·SMe2 was used. 2.0 equiv of imine were used. THF was used as
solvent. Determined by HPLC analysis. 33 mol % of BH3·SMe2 was used.
e
f
20/80). These results clearly indicate that the generation of a
carboxylic acid derived enolate, arguably the most difficult step in
the nucleophilic activation of carboxylic acids, is possible under
mildly basic conditions when using a stoichiometric combination
of a boron reagent and an amine. The necessity for stoichiometric
amounts of R2BOTf was tentatively assigned to the formation of
relatively stable chelated boron aldolate intermediates, which
should prohibit the catalyst turnover step. Therefore, we targeted
Mannich-type reactions, another fundamental family of C−C
bond forming reactions, which proceed through a presumably
less stable boron-containing intermediate, thus putatively
facilitating the catalyst turnover step. The Mannich-type reaction
between propionic acid (1a) and Ts-protected aromatic aldimine
2a (Ts = p-toluenesulfonyl) was studied as a model reaction in
order to optimize reaction conditions (Table S1). Mild organic
bases such as DBU, Et3N, and iPr2NEt were unable to generate
the targeted Mannich adduct 3aa in the absence of a boron
catalyst, and therefore, we subsequently examined the impact of
several boron compounds (10 mol %) on this reaction. BF3·Et2O,
B(OMe)3, Bu2BOTf, B(OH)3, or PhB(OH)2 did not afford 3aa,
while catechol borane (CatBH) afforded the Mannich adduct
3aa in 25% yield. Ultimately, BH3·SMe2 displayed the best
catalytic performance, furnishing the desired Mannich adduct in
excellent yield and high anti-selectivity (95% yield, syn/anti = 1/
10).12
heteroaromatic imines furnished the corresponding products in
good yield and diastereoselectivity (3ac−3af). Aliphatic imines
also afforded targeted products, albeit in marginally lower yields
(3ag−3ai). It is noteworthy that this method also allowed the use
of readily isomerizable aliphatic imines with an acidic α-proton
such as an imine derived from cyclohexanecarboxaldehyde (2i).
In this case, however, the use of 20 mol % of BH3·SMe2 and 2
equiv of imine were required in order to obtain 3ai in high yield.
An α,β-unsaturated imine furnished exclusively the correspond-
ing 1,2-adduct 3aj without loss of reactivity.
Subsequently, we examined the versatility of this reaction with
respect to carboxylic acid substrates using Ts-protected aromatic
aldimine 2a. BH3·SMe2 preferentially binds and activates the
COOH group through the formation of reversible covalent
bonds, and a selective activation of the COOH moiety was
observed even in the presence of other carbonyl groups such as
amides, esters, or ketones (3ba−3da). Considering the acidity of
α-protons in carboxyl, amide, ester, and keto groups (pKa = 33.3,
31.9, 27.2, and 23.4, respectively),13 the observed chemo-
selectivity is surprising and highly noteworthy. The reaction was
moreover able to proceed chemoselectively in the presence of a
wide variety of other functional groups, such as ethers, thioethers,
chloroalkyls, bromoalkyls, CC alkynyls, and CC alkenyls
(3ea−3ja). Furthermore, carboxylic acids with α-functional
groups such as methoxy, bromo, trifluoromethyl, or unprotected
indolyl moieties could also be used in this reaction (3ka−3na).
These results clearly demonstrate the high levels of chemical
compatibility attainable with this method.
Having established a suitable catalyst, we proceeded to
investigate the substrate scope of this reaction (Table 1).
Aromatic imines containing an electron-withdrawing trifluor-
omethyl group, an electron-donating methoxy group, or
B
DOI: 10.1021/jacs.5b04175
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To demonstrate the potential utility of this method in late-
stage functionalizations of complex molecules, we examined its
applicability to biologically relevant molecules, containing
multiple functional groups. The anti-inflammatory drug
indomethacin (1o), for example, afforded 3oa in good yield
and high diastereoselectivity, while the use of steroidal O-
acetyllithocholic acid (1p) resulted in the predominant
formation of two out of four possible diastereomers (3pa).
Remarkably, the reaction of loxoprofen (1q) and jasmonic acid
(1r) occurred selectively at the sterically congested α-position of
the COOH group, despite the presence of the inherently more
reactive α-position of the keto group (3qa and 3ra). A
chemoselective reaction toward the α-carbon atom of the
COOH group in Cbz-Glu-OMe (1s) successfully furnished
product 3sa, which encouraged us to examine other, more
elaborate peptide substrates. To our delight, we observed that the
Mannich-type reaction was also selective toward the α-carbon
atom of the COOH group in dipeptide 1t, even though the
diastereoselectivity was relatively low (3ta). As the reaction also
proceeded with tripeptide 1u and tetrapeptide 1v, it is feasible to
conclude that these boron-catalyzed Mannich-type reactions
provide sufficient chemoselectivity toward carboxylic acids in
order to find applications in the derivatization of complex
molecules in late stages of their syntheses.
use of 3,3′-I2-BINOL (L6) improved both yield and
enantioselectivity (72% yield, 81% ee; entry 6). Subsequently,
we investigated the effect of the N-protecting group of the
imines. Imine 2k, bearing an N-2-mesitylenesulfonyl group,
exhibited higher enantioselectivity (77% yield, 90% ee; entry 7)
relative to 2a, and imine 2l, containing an N-tert-butylsulfonyl
(Bus) group, produced 3wl in even higher yield and higher
enantioselectivity (95% yield, 90% ee; entry 8). A comple-
mentary solvent screening revealed that the use of a binary
toluene/THF solvent afforded the products in quantitative yield
and excellent enantioselectivity (94% ee; entry 9).16
With the optimized reaction conditions in hand, we examined
the substrate scope of these boron-catalyzed asymmetric
Mannich-type reactions by employing a series of Bus-protected
aromatic imines (Table 3). Aromatic imines with electron-
Table 3. Substrate Scope for the Boron-Catalyzed Asymmetric
a
Mannich-Type Reactions of Carboxylic Acids
This method may also be extended to asymmetric Mannich-
type reactions by using an asymmetric boron catalyst. Although
enantioselective catalytic Mannich-type reactions of readily
enolizable aldehydes or ketones are well-established,14 direct
asymmetric catalytic Mannich-type reactions under proton
transfer conditions, using pronucleophiles in the carboxylic
oxidation states, still remain extremely rare.15 Our optimization
studies initially examined the reaction between acetic acid (1w)
and Ts-protected aromatic aldimine 2a (Table 2), wherein a
Table 2. Optimization for the Boron-Catalyzed Asymmetric
Mannich-Type Reactions of Carboxylic Acids
a
Isolated yield, diastereomer ratio, and enantiomeric excess were
determined after conversion of the Mannich products into methyl
b
c
esters (see Supporting Information). Isolated yield. Determined by
d
e
1H NMR analysis. Determined by chiral HPLC analysis. 20 mol % of
BH3·SMe2 and 22 mol % of L5 were used. A Ts-protected imine was
used instead of a Bus-protected imine. 1.0 equiv of propionic acid
f
g
(1a) was used.
withdrawing groups 2n, 2o, and 2p generally furnished products
in high yield and excellent enantioselectivity (entries 3−5).
Although the reactivity of imine 2q, containing an electron-
donating methoxy substituent at the para-position, was lower,
the corresponding product was still obtained in excellent
enantioselectivity (entry 6). Imines 2r and 2s, bearing
electron-withdrawing or -donating substituents at the meta-
position, afforded the target compounds in good yield and
excellent enantioselectivity (entries 7 and 8). Imines 2t and 2u,
with electron-rich heteroaromatic rings, as well as imines 2v and
2w, with sterically demanding naphthyl groups, exhibited
moderate reactivity, while the enantioselectivity remained high
(entries 9−12). Aliphatic imine 2i was also competent by using
3,3′-Br2-BINOL (L5), instead of 3,3′-I2-BINOL (L6), though
the enantioselectivity was moderate (entry 13). The carboxylic
acid substrates are not limited to acetic acid (1w), as e.g.
propionic acid (1a) also furnished the corresponding Mannich
a
t
Determined by 1H NMR analysis using BuOMe as an internal
b
standard. Determined by chiral HPLC analysis after conversion of the
Mannich products into methyl esters. A binary toluene/THF (19/1)
solvent was used.
c
slight excess of 1w (1.1 equiv) with respect to 2a was used in
order to suppress undesired 2-fold Mannich-type reactions.
Compared with N-Ts-L-Val (L1: entry 1) and other amino acid
based ligands (data not shown), BINOL (L2) furnished products
in higher enantioselectivity but relatively low yield (19% yield,
43% ee; entry 2). Even though 3,3′-Ph2-BINOL (L3) afforded
merely trace amounts of product 3wa (2% yield, entry 3), other
3,3′-disubstituted BINOL derivatives showed promising results
(58−73% yield, 41−72% ee; entries 4 and 5), and especially the
C
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Journal of the American Chemical Society
Communication
adducts with both electron-rich and -deficient aromatic imines in
excellent yield and enantioselectivity, even though the
diastereoselectivity remains to be improved (entries 14−16).
Isovaleric acid (1x) afforded product 3xa in high diastereo- and
enantioselectivity (entry 17), and sterically demanding isobutyric
acid (1y) afforded 3yl, which contains a quaternary carbon atom
at the α-position, in excellent enantioselectivity (entry 18).
After esterification of the Mannich adducts, the Bus-group
could be successfully removed with aluminum chloride and
anisole as described by Enders,17 whereby the stereochemistry of
the products was retained (see Supporting Information (SI)).
Our working hypothesis for the catalytic cycle is postulated in
Figure 2. First, BH3 reacts with carboxylic acid 1 and/or ligand
ACKNOWLEDGMENTS
■
This work was partially supported by a Grant-in-Aid for Scientific
Research on Innovative Areas “Advanced Molecular Trans-
formations by Organocatalysts” from MEXT (M.K.) and a
Grant-in-Aid for Scientific Research (C) from the JSPS (Y.S.).
REFERENCES
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Figure 2. Proposed catalytic cycle for the boron-catalyzed Mannich-type
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was calculated to be ca. 23)13 by DBU generates boron enolate B,
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acyloxyborane A for the next catalytic cycle.18
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In summary, we have developed the first catalytic protocol for
the chemoselective formation of enolates from a wide variety of
carboxylic acids by using BH3·SMe2. The catalytically generated
enolates were subsequently used in Mannich-type reactions with
a wide range of imine electrophiles. These highly chemoselective
reactions require DBU as an organic base, proceed under mild
conditions, and display outstanding functional group tolerance.
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Mannich-type reactions by using chiral BINOL-substituted
boron catalysts. The versatility of the presented concept, i.e.
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(12) The relative configurations of the products were determined after
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(13) Computational calculations of pKa values are described in the SI.
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(16) The absolute configurations of the products were determined
after conversion to known compounds (see SI).
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and spectral data. The Supporting
Information is available free of charge on the ACS Publications
website at DOI: 10.1021/jacs.5b04175.
(17) Enders, D.; Seppelt, M.; Beck, T. Adv. Synth. Catal. 2010, 352,
1413.
(18) Isolated boron tripropionate reacted with imine 2a, producing
3aa in high to moderate yield under the standard reaction conditions.
This result supports our hypothesis that acyloxyborane is an active
intermediate for the reaction (see SI).
AUTHOR INFORMATION
■
Corresponding Authors
*y-shimizu@mol.f.u-tokyo.ac.jp
*kanai@mol.f.u-tokyo.ac.jp
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/jacs.5b04175
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX