Asymmetric synthesis of stable α-aminoboronic esters catalyzed by N-heterocylic carbene and copper(i) chloride

Article abstract of DOI:10.1039/c4ra02229g

Bis(pinanediolato)diboron (B₂pnd₂) was used as the nucleophile instead of bis(pinacolato)diboron in the stereospecific synthesis of α-aminoboronic esters catalysed by a triazole-based N-hetereocyclic carbene (NHC) and Cu(i) chloride.

Full text of DOI:10.1039/c4ra02229g

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Asymmetric synthesis of stable a-aminoboronic
esters catalyzed by N-heterocylic carbene and
copper(I) chloride†
Cite this: RSC Adv., 2014, 4, 21131
Received 14th March 2014
Accepted 28th April 2014
*
Jinbo Chen, Ling-yan Chen, Yue Zheng and Zhihua Sun
DOI: 10.1039/c4ra02229g
www.rsc.org/advances
Bis(pinanediolato)diboron (B2pnd2) was used as the nucleophile
instead of bis(pinacolato)diboron in the stereospecific synthesis of
a-aminoboronic esters catalysed by a triazole-based N-hetereocyclic
carbene (NHC) and Cu(I) chloride. The resulting pinanediol-protected
a-aminoboronic esters have significantly improved stability over the
pinacol derivatives.
Fig. 1 Sadighi's catalyst.
Introduction
B2pin2 without using a glove box.23 The activities of a series of
benzimidazole-based N-heterocyclic carbene precursors were
also investigated. It demonstrated that aromatic substitution on
at least one nitrogen atom in the NHC is critical for efficient
catalysis. A fused benzene ring to the imidazole core also
improves catalytic efficiency. However, the same phenomenon
as reported in Ellman's early work was observed: aromatic
substrates generally gave lower yields than aliphatic substrates.
In order to overcome the intrinsic instability of pinacol esters of
a-aminoboronic acid, we attempted to use alternative diboron
source for the synthesis of a-aminoboronates. Herein, on the
basement of our previous work, we report an improved protocol
for asymmetric synthesis of a-aminoboronic esters between N-
tert-butanesulnyl aldimines and bis(pinanediolato)diboron
(B2pnd2). In addition, we compare the catalytic efficiencies of
different NHCs based on three core structures: benzimidazole,
3,4-dihydro-quinazoline, and triazole.
In the design of protease inhibitors, a-aminoboronic acids have
been found to be key pharmacophores in the last decade and are
attracting more and more attention. For example, bortezomib is
an FDA approved anticancer drug that contains a C-terminal
a-aminoboronic acid moiety and targets 26S proteasome.1–5 It is
the rst therapeutic proteasome inhibitor to be tested in
humans. It is approved in the U.S. for treating relapsed multiple
myeloma6 and mantle cell lymphoma. a-Aminoboronic acid has
been incorporated in inhibitors that target dipeptidyl peptidase-
4 for the development of anti-diabetic drugs.7–10 As a result,
asymmetric synthesis of a-aminoboronic acid becomes more
and more important. Several groups have demonstrated their
work towards a-aminoboronic acid.11–14 Among them, Ellman's
group utilized the Sadighi's catalyst15 (an imidazole-based
N-heterocyclic carbene (NHC) copper complex, Fig. 1) to facili-
tate direct addition of bis(pinacolato)diboron (B2pin2) to N-tert-
butanesulnyl aldimines to afford a single diastereomer of
a-aminoboronic acid.12 NHCs are widely used as transition
metal ligands for asymmetric catalysis in modern organic
synthesis.16–22 Although Ellman's method has great advantages,
it also has its own drawbacks. The preparation and storage of
catalyst have to be executed in a glove box. Recently, we devel-
oped a one-pot protocol for efficient synthesis of a-amino-
boronic esters between N-tert-butanesulnyl aldimines and
Results and discussion
Our investigations started with the examination of the reaction
between (R)-N-tert-butanesulnyl aldimine 4a and B2pnd2
under the same condition as that used in our previous work.23
In the presence of 10 mol% of NHC precursor 1 (Fig. 2), Cs2CO3
and copper(I) chloride in benzene or toluene, the reaction could
proceed smoothly and resulted in 82% yield in 12 h (Table 1,
entry 1). The reaction time was much shorter than that using
B2pin2 as the boron reagent in our previous work. In order to
improve the yield, we explored other two types of catalysts
College of Chemistry and Chemical Engineering, Shanghai University of Engineering
Science, 333 Longteng Road, Shanghai 201620, China. E-mail: sungaris@gmail.com
† Electronic supplementary information (ESI) available. CCDC 901852. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c4ra02229g
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Table 2 Additional examples of a-aminoboronic estersa
Fig. 2 NHC ligand precursors 1–3.
Entry
R1
R2
Product
Yieldb
drc
1
2
3
4
5
6
7
8
9
CH3CH2CH2
(CH3)2CH
ClCH2CH2CH2
Admantyl
Cyclopropyl
Ph
PhCH2
4-Me-Ph
4-Cl-Ph
Naphthyl-
H
H
H
H
H
H
H
H
H
H
5a
5b
5c
5d
5e
5f
5g
5h
5i
92%
88%
86%
80%
78%
86%
89%
88%
90%
91%
99 : 1
99 : 1
99 : 1
99 : 1
99 : 1
99 : 1
99 : 1
99 : 1
99 : 1
99 : 1
Table 1 Screening NHCs and bases for the asymmetric synthesis of
a-aminoboronic estersa
10
5j
Entry
Ligand precursor
Base
Yieldb
drc
a
Unless otherwise noted, all the reactions were carried using ligand
precursor 3 10 mol%, CuCl 10 mol%, Cs2CO3 10 mol%, N-tert-
1
2
3
4
5
6
1
2
3
3
3
3
t-BuONa
t-BuONa
t-BuONa
DBU
Cs2CO3
CsF
82%
62%
88%
82%
92%
78%
99 : 1 butanesulnyl imines (2.0 mmol), benzene or toluene 10 mL, rt, 12 h.
b
Isolated yield. c Determined by 1HNMR.
99 : 1
99 : 1
99 : 1
99 : 1
99 : 1
a
Unless otherwise noted, all the reactions were carried using ligand
precursor 1–3 10 mol%, CuCl 10 mol%, base 10 mol%, N-tert-
butanesulnyl imines (2.0 mmol) benzene or toluene 10 mL, rt, 12 h.
b
Isolated yield. c Determined by 1HNMR.
Scheme 1 Synthesis of 5b0 from (S)-N-tert-butanesulfinyl imine 4b.
(2 and 3, Fig. 2). One is a six-membered NHC precursor 2, the
other is a triazole-based NHC precursor 3. In contrast to the
result of NHC precursor 1, precursor 3 showed better perfor- improved from 75% (ref. 23) to 91%. It is worth noting that
mance and afforded the desired product in 88% yield, while the pinanediol ester products could be puried by normal
precursor 2 just gave moderate yield (Table 1, entries 2 and 3). ash column chromatography, while the pinacol esters as
In addition, in order to improve the reaction efficiency, we also reported previously must be puried using water inactivated
changed other different bases such as Cs2CO3, DBU and CsF silica gel. In addition, we took a test to further exam the
(Table 1, entries 3–6). It was proved that Cs2CO3 had the best stability of the product. We compared product 5f and the
performance and resulted in 92% yield. Excellent diastereo- corresponding pinacol product. Product 5f could be stored in
meric ratios (dr) up to 99 : 1 were achieved in all cases regard- the atmosphere at room temperature for several days without
less of NHC or base. This is not surprising because the main signicant degradation, while the corresponding pinacol
determining factor in this asymmetric synthesis case is the ester quickly turned into the tert-butanesulnyl amide
N-tert-butanesulnyl group.
without pinacol boronate attached in about 36 h. It
Under the optimized conditions,
a
wide range of conrmed that using pinanediol as boronate provided addi-
substituted N-tert-butanesulnyl imines have been tested tional stability over at least a week.
using precursors 3 to generate NHC in situ. The scope of the
(S)-N-tert-butanesulnyl protected products seemed easier to
substrates is summarized in Table 2. Entries 1–5 cover crystallize in contrast to the corresponding products from (R)-N-
aliphatic chains or rings, some of which contain additional tert-butanesulnyl. We were thus able to obtain diffraction
substitutions like chloride. For these substrates, they all gave quality crystals of product 5b0 (Scheme 1). Its crystal structure
comparable results with yields generally in 78–92% to pina- (Fig. 3) conrmed the expected stereocenter.
col esters as reported in our previous work. For aromatic
As functional groups such as chloride is tolerated (5c), it
substrates, it showed better performance using 3 to generate opens up a convenient way toward making N-cyclic amino-
NHC ligand. All the isolated yields for aromatic substrates boronic acid derivatives. For example, treatment of 5c with base
were better than those in Ellman's original report or that in led to cyclization and gave 7 in 83% yield (Scheme 2). Removal
our previous work (Table 2, entries 6–10). Especially for the of N-protection gave a proline equivalent of aminoboronic ester
substrate containing
a
naphthyl group, the yield was 8 in 90% yield.12
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Scheme 2 Synthesis of a proline equivalent aminoboronate 8.
Conclusions
In summary, we found that in NHC–copper(I) catalyzed asym-
metric synthesis of a-aminoboronic esters using bis(pinane-
diolato)diboron (B2pnd2) as nucleophile, a triazole-based NHC
performed much better than either benzimidazole or 3,4-dihy-
dro-quinazoline based NHCs. The yields for aromatic N-tert-
butanesulnyl imine substrates were largely improved owing to
the higher stabilities of the pinanediol-attached products. In
addition, the tolerance of alkyl halides allows the formation of
N-cyclic a-aminoboronic esters. We expect the new NHC
precursors will offer improved access to a-aminoboronic esters
in drug discovery and industrial applications.
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Acknowledgements
We thank Dr Erkang Fan at the University of Washington for
helpful discussions. Financial support for this work was provided
by Shanghai Saijia Chemicals Ltd., Shanghai Municipal Educa-
tion Commission (no. 14ZZ159), Shanghai Municipal Science and
Technology Commission (no. 12430501300) and the Orientalist
(Chair Professor) Funding from Shanghai Municipal Education
Commission. We also thank the nancial support from the
Special Scientic Foundation for Outstanding Young Teachers in
Shanghai Higher Education Institutions (ZZGJD13020), and Start-
up Funding of Shanghai University of Engineering Science.
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