A dual arylboronic acid-aminothiourea catalytic system for the asymmetric intramolecular hetero-michael reaction of α,β-unsaturated carboxylic acids

Article abstract of DOI:10.1021/ol501954r

A bifunctional aminoboronic acid has been used to facilitate for the first time the intramolecular aza- and oxa-Michael reactions of α,β- unsaturated carboxylic acids. The combination of an arylboronic acid with a chiral aminothiourea allowed for these re

Full text of DOI:10.1021/ol501954r

Letter
pubs.acs.org/OrgLett
A Dual Arylboronic Acid−Aminothiourea Catalytic System for the
Asymmetric Intramolecular Hetero-Michael Reaction of
α,β‑Unsaturated Carboxylic Acids
Takumi Azuma,† Akihiro Murata,† Yusuke Kobayashi,† Tsubasa Inokuma,†,‡ and Yoshiji Takemoto*,†
†Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
‡Institute of Health Biosciences and Graduate School of Pharmaceutical Sciences, The University of Tokushima, Shomachi,
Tokushima 770-8505, Japan
S
* Supporting Information
ABSTRACT: A bifunctional aminoboronic acid has been
used to facilitate for the first time the intramolecular aza- and
oxa-Michael reactions of α,β-unsaturated carboxylic acids. The
combination of an arylboronic acid with a chiral aminothiourea
allowed for these reactions to proceed successfully in an
enantioselective manner to afford the desired heterocycles in
high yields and ee’s (up to 96% ee). The overall utility of this
dual catalytic system was demonstrated by a one-pot enantioselective synthesis of (+)-erythrococcamide B, which proceeded via
sequential Michael and amidation reactions.
associated with reactions of this type that would need to be
addressed, including (1) the reactivity of α,β-unsaturated
carboxylic acid derivatives4,6 as Michael acceptors being much
lower than that of the corresponding α,β-unsaturated aldehydes,
ketones, and activated ester surrogates;3,5,7 and (2) the carboxylic
acid moiety forming an inert salt with the base,10 preventing it
from behaving as a nucleophile. In fact, to the best of our
knowledge, there have been no reports in the literature
pertaining to the catalytic asymmetric Michael addition of α,β-
unsaturated carboxylic acids either intra- or intermolecularly.11
To address these challenges, we focused our initial efforts on the
boronic acids,12 because boronic acids have been utilized to
activate not only carboxylic acids10 by Yamamoto and Ishihara
but also α,β-unsaturated carboxylic acids13 by Hall’s group14
through the formation of acyloxyborane species.15 Herein, we
report the direct aza- and oxa-Michael reactions of α,β-
unsaturated carboxylic acids using bifunctional aminoboronic
acids, together with the asymmetric versions of these reactions
using a dual catalytic system composed of a boronic acid and a
chiral aminothiourea.16,17
N- and O-containing heterocycles bearing a stereogenic carbon
center adjacent to a heteroatom are important scaffolds, and
heterocycles containing a C2 acetic acid unit can be found in a
large number of natural products (Figure 1), most likely because
of the way in which they are biosynthesized.1,2
Figure 1. Synthetic strategy for the heterocycles containing C2 acetic
acid units through an asymmetric Michael addition of α,β-unsaturated
carboxylic acids.
We initially investigated the Michael reaction of 1a using
boronic acids 3a−d, which have been reported to be efficient
catalysts for the amidation of carboxylic acids10 (Table 1, entries
1−4). Disappointingly, only boronic acid 3d bearing an amine
moiety, which was developed by Whiting,10b,c,18 promoted the
reaction to give the pyrrolidine derivative 2a, albeit in a low yield
(Table 1, entry 4). We also screened various solvents for the
reaction with 3d (Table 1, entries 5−8), which revealed that
acetonitrile dramatically accelerated the reaction (Table 1, entry
The development of a strategy for the construction of these
heterocyclic rings from a simple precursor that would allow for
the simultaneous control of the stereogenic centers would
represent a straightforward approach for the synthesis of these
compounds. With this in mind, it was envisioned that the direct
catalytic asymmetric intramolecular hetero-Michael reaction3−7
of α,β-unsaturated carboxylic acids would provide facile access to
heterocyclic compounds bearing a stereogenic carbon center
adjacent to the heteroatom (Figure 1). Furthermore, the
carboxylic acid moiety could then be used as a versatile synthetic
intermediate.8,9 There are, however, several challenging issues
Received: July 5, 2014
© XXXX American Chemical Society
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Table 1. Screening of the Reaction Conditions
Figure 2. Substrate scope of the Michael addition of α,β-unsaturated
carboxylic acids catalyzed by aminoboronic acid 3d (10 mol %) in
MeCN.
The aza-Michael reaction of α,β-unsaturated carboxylic acid
derivatives was also applied to the synthesis of the piperidine and
tetrahydroquinoline derivatives 2f and 2g, which were formed in
76% and 97% yields, respectively. We then moved on to
investigate the diastereoselectivity of the reaction with substrates
bearing a chiral center derived from an L-amino acid, and the β,γ-
diamino acid derivative 2i was obtained in excellent yield with
complete stereoselectivity. We also used the optimized
conditions to investigate the intramolecular oxa-Michael
reactions of α,β-unsaturated carboxylic acids, which are also
challenging transformations because of the poor nucleophilicity
of the substrate and the inherent likelihood of a retro-Michael
addition. Pleasingly, the oxa-Michael reaction proceeded
smoothly under mild conditions to afford the dihydrobenzofuran
scaffolds as well as the chroman derivatives in excellent yields
(2j−q). Notably, this strategy also provided access to the
isooxazolidine ring 2r in 97% yield.
a
b
1
Determined by H NMR spectroscopy. Isolated yield.
8), whereas other polar solvents such as DMF, acetone, and
dichloroethane had very little impact on the reaction outcome
(Table 1, entries 5−8). The following results show the
importance of having a suitable N-substituent on the amino-
boronic acid (Table 1, entry 8 vs entries 9 and 10): boronic acid
3e bearing the N,N-dimethylamino group gave a lower yield
compared to 3d, which was attributed to the reduced Lewis
acidity of the catalyst resulting from the coordination of the less
hindered amine group to the boron atom (Table 1, entry 9).18
The use of boronic acid 3f bearing a bulkier amino group led to a
dramatic reduction in the rate of the Michael reaction (Table 1,
entry 10), and the N,N-diisopropyl group was found to give the
most suitable results in terms of steric hindrance. In addition to
the steric effects, it was also established that the position of the
amino group was critical to the reaction outcome. For example,
the use of the para-substituted catalyst 3g did not result in the
formation of any of the desired product 2a (Table 1, entry 11).
Furthermore, the low activity of benzoxaborole 3h indicated that
the presence of two hydroxyl groups on the boron atom was
essential for the reaction to proceed efficiently (Table 1, entry
12).
A plausible mechanism for this reaction is shown in Figure 3. It
was envisioned that the aminoboronic acid 3d would form a
seven-membered H-bonded ring between its boronic acid moiety
With the optimized reaction conditions in hand, we proceeded
to investigate the application of this protocol to the synthesis of
other heterocyclic compounds (Figure 2). We initially examined
the effect of the N-protecting group (2b−e). Although the
Michael reaction of the substrate bearing an N-Cbz group did not
proceed even at 110 °C, the N-sulfonyl analogues reacted
smoothly, with the reaction conditions required (i.e., temper-
ature) appearing to be dependent on the acidity of the NH
proton of the substrate (2c−e). It is noteworthy that the reaction
of the N-triflate group proceeded at rt to afford the cyclized
product 2e in 89% yield. These results suggested that the rate-
determining step in this reaction was the deprotonation or C−N
bond forming reaction rather than the formation of an
acyloxyborane species.
Figure 3. Proposed mechanism.
B
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Letter
and amino group (B−O−H···Ni-Pr2) rather than a dative N → B
bond, because of the potential for steric hindrance from the N,N-
diisopropylamino group.8d,18 The trigonal planar boron species
would then form an acyloxyborane complex (complex I) bearing
the carboxylic acid moiety of substrate 1 with the aid of the Lewis
acidity of the boron atom and the Brønsted basic moiety of 3d.
The subsequent C−X (X = N, O) bond-forming step would then
proceed via TS-A or TS-B. In the TS-A pathway, the consecutive
6- and 7-membered H-bonding interactions would promote the
cyclization of the complex with an s-cis conformation, which
would give intermediate III via the tautomerization of cyclo-
adduct II. For the alternative mechanism involving TS-B, the
hydroxyl group on the tetrahedral boronate anion would assist in
the formation of the C−X bond via the s-trans conformation of
the complex. Consideration of the experimental results shown in
Table 1 (entry 12), where the benzoxaborole compound 3g
bearing only one hydroxyl group did not facilitate the Michael
addition, would support the TS-B pathway. Finally, a carboxylic
acid exchange reaction would afford the desired product 2, which
would complete the catalytic cycle of 3d.
desired chromane product 2m was obtained in 31% ee, albeit in a
reduced chemical yield (Table 2, entry 4). Following a period of
extensive screening,19 it was established that the yield and
enantioselectivity could be improved significantly (79% yield,
59% ee) using a mixed solvent system composed of MTBE and
CCl4 (Table 2, entry 5). Screening of the chiral catalysts19
revealed that the newly designed aminothiourea 4c gave a
satisfactory result in terms of the yield and enantioselectivity
(Table 2, entry 6). Both 3b and 4c were essential for the reaction
to proceed (Table 2, entries 7 and 8), which strongly suggested
that the reaction proceeded via an acyloxyborane species with
subsequent activation by an aminothiourea. Although the exact
function and role of 4c remains unclear at this stage, the
decreased H-bond-donating ability of the thiourea moiety may
have prevented the formation of an inert complex between 4c
and 1 through anion binding,16,19 and consequently enhanced
the formation of an acyloxyborane species.
With the optimized reaction conditions in hand, we proceeded
to investigate the scope and limitations of this transformation
(Figure 4). These scoping reactions afforded the benzofuran
As shown in the proposed mechanism, the amino group of the
aminoboronic acid would not be directly involved in the
activation of the nucleophilic moiety of 1. It was therefore
envisioned that the reaction would be further facilitated by the
addition of an external base and that the use of a chiral base
catalyst would enable an asymmetric reaction. To evaluate this
hypothesis, we investigated the reaction of α,β-unsaturated
carboxylic acid 1m with boronic acids 3b and 3d in the presence
of several amines 4 as a dual catalytic system (Table 2).
Figure 4. Asymmetric Michael addition catalyzed by boronic acid 3b (20
mol %) and thiourea 4c (20 mol %).
Table 2. Screening of the Reaction Conditions for the
Asymmetric Michael Reaction
derivatives 2j and 2k in good yields with moderate to good
enantioselectivities.20 The chromane derivatives were generally
obtained in excellent yields and stereoselectivities (93−96% ee’s)
regardless of the substituent on the aromatic ring (2n−q). In
contrast, the asymmetric aza-Michael reaction proceeded slowly
to give the Michael adduct 2a with only 50% ee.
One of the greatest advantages of this method was
demonstrated by our efficient asymmetric synthesis of
erythrococcamide B21 (7a) (Scheme 1). The asymmetric oxa-
Scheme 1. Total Synthesis of (+)-Erythrococcamide B via
One-Pot Reaction
a
b
1
Determined by H NMR spectroscopy. Estimated by chiral HPLC
c
after treatment with TMSCHN2. The reactions were performed using
10 mol % of 3d (and 4a) in the absence of MS 4 Å. The ratio of
MTBE/CCl4 was 1:2 (v/v). Isolated yield.
d
e
An acceleration effect was observed when the aminoboronic
acid 3d was used in conjunction with Et3N (4a) in MeCN (entry
1 vs 2). Encouraged by these results, we proceeded to investigate
the use of a chiral aminothiourea16 instead of Et3N (Table 2,
entry 3). Although the reaction itself proceeded efficiently, no
enantioinduction was observed during this reaction. It is
noteworthy that the replacement of 3d with the simple boronic
acid 3b effectively suppressed the racemic reaction, and the
Michael reaction of the α,β-unsaturated carboxylic acid 5
proceeded to completion within 24 h under the optimized
conditions to give the corresponding carboxylic acid 6 in 94%
yield and 94% ee. Pleasingly, the oxa-Michael reaction of 5
followed by the one-pot amidation with isobutylamine
proceeded smoothly to give highly enantioenriched (+)-eryth-
rococcamide B (7a). It is noteworthy that no racemization was
observed during the one-pot reaction process. Subsequent
C
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derivatization was readily achieved by changing the amine unit,
and the amide 7b, bearing a different N-substituent, was also
synthesized in an analogous manner.20
In conclusion, we have described for the first time the use of
aminoboronic acids as efficient catalysts for the direct intra-
molecular hetero-Michael addition of α,β-unsaturated carboxylic
acids. In addition, we have developed an asymmetric version of
this protocol using a dual catalytic system composed of an
aminothiourea and an arylboronic acid22 and demonstrated the
potential of this system for the facile construction of heterocyclic
compounds with a high level of enantioselectivity. Further
studies toward elucidating the mechanism of this reaction as well
as identifying further uses for this dual catalytic system are
currently underway in our laboratory and will be reported in due
course.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, analytical and spectroscopic data for
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
(11) Wang, S.-Q.; Wang, Z.-W.; Yang, L.-C.; Dong, J.-l.; Chi, C.-Q.;
Sui, D.-N.; Wang, Y.-Z.; Ren, J.-G.; Hung, M.-Y.; Jiang, Y.-Y. J. Mol.
Catal. A: Chem. 2007, 264, 60.
*E-mail: takemoto@pharm.kyoto-u.ac.jp.
Notes
(12) For recent books and reviews, see: (a) Ishihara, K.; Yamamoto, H.
Eur. J. Org. Chem. 1999, 527. (b) Lewis Acids in Organic Synthesis;
Yamamoto, H., Ed.; Wiley-VCH: Weihneim, 2000. (c) Duggan, P.;
Tyndall, E. M. J. Chem. Soc., Perkin Trans. 1 2002, 1325. (d) Boronic
Acids, 2nd ed.; Hall, D. G., Ed.; Wiley-VCH: Weinheim, 2011.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge a Grant-in-Aid for Scientific Research
(Y.T.) on Innovative Areas ‘Advanced Molecular Trans-
formations by Organocatalysts’ from MEXT, Japan.
́
(e) Dimitrijevic, E.; Taylor, M. S. ACS Catal. 2013, 3, 945.
(13) (a) Al-Zoubi, R.; Marion, O.; Hall, D. G. Angew. Chem., Int. Ed.
2008, 47, 2876. (b) Zheng, H.; Hall, D. G. Tetrahedron Lett. 2010, 51,
3561. (c) Zheng, H.; McDonald, R.; Hall, D. G. Chem.Eur. J. 2010, 16,
5454.
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