Benzoxaborole Catalyst for Site-Selective Modification of Polyols

Article abstract of DOI:10.1002/ejoc.201901749

The site-selective modification of polyols bearing several hydroxyl groups without the use of protecting groups remains a significant challenge in synthetic chemistry. To address this problem, novel benzoxaborole derivatives were designed as efficient catalysts for the highly site-selective and protecting-group-free modification of polyols. To identify the effective substituent groups enhancing the catalytic activity and selectivity, a series of benzoxaborole catalysts 1a–k were synthesized. In-depth analysis for the substituent effect revealed that 1i–k, bearing multiple electron-withdrawing fluoro- and trifluoromethyl groups, exhibited the greatest catalytic activity and selectivity. Moreover, 1i-catalyzed benzoylation, tosylation, benzylation, and glycosylation of various cis-1,2-diol derivatives proceeded with good yield and site-selective manner.

Full text of DOI:10.1002/ejoc.201901749

A Journal of
Accepted Article
Title: Benzoxaborole catalyst for site-selective modification of polyols
Authors: Shuhei Kusano, Shoto Miyamoto, Aki Matsuoka, Yuji
Yamada, Ryuta Ishikawa, and Osamu Hayashida
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901749
Link to VoR: http://dx.doi.org/10.1002/ejoc.201901749
Supported by

10.1002/ejoc.201901749
European Journal of Organic Chemistry
FULL PAPER
Benzoxaborole catalyst for site-selective modification of polyols
Shuhei Kusano‡*, Shoto Miyamoto, Aki Matsuoka, Yuji Yamada, Ryuta Ishikawa and Osamu
Hayashida*
A) Boronate mediated cis-1,2-diol activation reported by Aoyama
Abstract: The site-selective modification of polyols bearing several
a) Boronic acid
b) Boronic acid bearing internal coordinating group
hydroxyl groups without the use of protecting groups remains a
significant challenge in synthetic chemistry. To address this problem,
herein novel benzoxaborole derivatives were designed as efficient
catalysts for the highly site-selective and protecting-group-free
modification of polyols. To identify the effective substituent groups
+
Lewis base
O
Me
O
Me
B
Ag2CO3
O
Me
O
Lewis
O
B
O
Me
Me
Me
base
B
O
Ar
enhancing the catalytic activity and selectivity,
a series of
‘Stoichiometric amount of boronic and boronic acid was used’
B) Borinic and boronic acid catalyst system reported by Taylor
benzoxaborole catalysts 1a-k were synthesized. In-depth analysis
for the substituent effect revealed that 1i-k, bearing multiple
electron-withdrawing fluoro- and trifluoromethyl groups, exhibited the
greatest catalytic activity and selectivity. Moreover, 1i-catalyzed
benzoylation, tosylation, benzylation, and glycosylation of various
cis-1,2-diol derivatives proceeded with good yield and site-selective
manner.
R-X
O
O
Ph
Ph
RO
Ph
B
B
O
Borinate
intermediate
N
OH
Ph
HO
H2
OH
cis-1,2-diol
TBSCl
O
TBSO
OH
OH
Et3N
Ar
B
B
O
Boronate
intermediate
OH
Ar
+ Et3N
Introduction
C) This work: Benzoxaborole catalyst system
R‘
R’
• Structural optimization
R
Benzoxaborole, which is a cyclic monoester homologue of
phenyl boronic acid, has had significant impacts in the areas of
the pharmaceutical science and the molecular recognition
chemistry (Fig. 1). The discovery of the antifungal activity in p-
O
• Scope and limitations
(Acylation, sulfonylation, alkylation, glycosylation)
B
OH
• Mechanistic study
Benzoxaborole
‘cis-1,2-diol recognition and activation’ by benzoxaborole
cat.
fluroro benzoxaborole (AN2690) opened
a new field in
R-X
O
pharmaceutical science.[1] Similarly, in the field of molecular
recognition chemistry, the superior binding affinity of
HO
RO
R'
O
B
O
OH
OH
R'
Boronate
intermediate
bnenzoxaborole for cis-1,2-diols enabled
a
saccharide
recognition in neutral aqueous conditions.[2] This remarkable
affinity for cis-1,2-diols displayed by benzoxaborole has enabled
several applications that are otherwise impossible with
phenylboronic acid.[3] These reports show that the key
characteristic of benzoxaborole is its ability to form the tetra-
coordinated boronate adduct (Fig. 1).
R
Figure 2. Organoboron reagents and catalysts activating cis-1,2-diol structure
We
recently
commenced
the
development
of
benzoxaborole-based functional molecules,[4] utilizing the
selective recognition of cis-1,2-diol via the boronate formation. In
this context, we here envisioned the catalytic application of
benzoxaborole for the site selective modification of non- or
partially protected polyols bearing cis-1,2-diol scaffold (Fig. 2C).
We hope that the benzoxaborole catalyst reported herein allows
the straightforward synthesis of polyol derivatives without the
need for protecting groups.
• Pharmaceutical (e.g. AN2690)
O
B
• Molecular recognition
OH
• Catalyst (This work)
Benzoxaborole
Key point
HO
O
cis-1,2-diol
O
B
OH
O
O
B
Boronate
formation
OH
In synthetic organic chemistry, the site-selective
modification of a polyol such as a carbohydrate bearing multiple-
hydroxyl groups with similar reactivity, usually requires lengthy
and inefficient synthetic processes due to the need for multiple
protection-deprotection sequences.[5] To overcome this
problematic issue in the polyol modification, the catalyst-
controlled reactions using dialkyltin dichloride,[6] chiral copper (II)
catalyst,[7] iron (III) catalyst,[8] and chiral organocatalysts[9-13]
have been developed in the last decade to achieve the direct
and selective modification of polyols without protecting groups.
Alternatively, the pioneering work by Aoyama et al.
Figure 1. The applications of benzoxaborole.
[*]
Dr. S. Kusano, S. Miyamoto, A. Matsuoka, Dr. Y. Yamada, Dr. R.
Ishikawa, Prof. O. Hayashida
Department of Chemistry, Faculty of Science
Fukuoka University
Nanakuma 8-19-1, Fukuoka 814-0180, Japan.
E-mail: shuhei.kusano@riken.jp
hayashida@fukuoka-u.ac.jp
Homepage: http://molecular-bioregulation.riken.jp/index.html
Present Address: RIKEN Center for Sustainable Resource Science,
2-1 Hirosawa, Wako, Saitama 351-0198, Japan
[‡]
demonstrated that the boronate adduct generated from
a
Supporting information for this article is given via a link at the end of
the document.
stoichiometric amount of boronic acid and Lewis base, or borinic
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10.1002/ejoc.201901749
European Journal of Organic Chemistry
FULL PAPER
acid precursor, enhances the nucleophilicity of the equatorial
oxygen atom on the cis-1,2-diol (Fig. 2A).[14] Based on these
reports, Taylor et al. exploited the diphenylborinic acid catalyst
for acylation,[15a] tosylation,[15b] alkylation,[15c] and glycosylation[16]
of non- or partially-protected pyranosides. In the same studies, a
boronic acid and Lewis base co-catalyst system was used for
catalysts displayed significantly improved catalytic activity (Fig.
S4 and S5). Especially, catalyst 1k was the most potent,
competing the transformation of 2a to 3a in a quantitative
manner in only 30 minutes. The tosylation of 2a catalyzed by 1k
also proceeded quantitatively within 150 minutes (Fig. S6).
site-selective
silylation
(Fig.
2B).[17]
Very
recently,
Table 1. Catalytic activity of 1a-k in the benzoylation of cis-1.2-
benzoazaborole was also reported as a cis-1,2-diol activating
catalyst.[18]
cyclohexanediol
Inspired by the previous studies by Aoyama and Taylor,
we set about out our own catalytic system based on
benzoxaborole. The tetra-coordinated boronate generated from
benzoxaborole and cis-1,2-diol should be activated and hence
allowing the site-selective modification of polyols. Furthermore,
the highly Lewis acidity of benzoxaborole among organoboron
reagents promises to promote the formation of the active
boronate intermediate.[2] We in this study designed the
electronically and sterically modified benzoxaboroles 1a-k to
elicit the relationship between structure and catalytic activity.
Herein, we report the successful development of the
benzoxaborole catalyst 1 and its scope and limitations.
OH
OH
OBz
OH
cat. (10 mol %)
BzCl (1.2 eq), DIPEA (1.2 eq)
CD3CN (50 mM)
r.t., 1 h
2a
3a
Catalyst
Yield (%)a)
Time course yield of the benzoylated
product 3a using the three most active
catalysts 1i-k along with 1a
1a
11
4
1b
1c
22
14
24
17
40
16
68
84
> 98
100
1k
1d
1j
75
1i
1e
50
Results and Discussion
1f
25
1g
Benzoxaborole catalyst
corresponding tertiary alcohol precursor utilizing known
procedures (Scheme S1).[19] Benzoxaborole
exhibited
1 was synthesized from the
1a
0
1h
0
20
40
60
1
Reaction time (min.)
1i
remarkable stability both as a solid and in a solution. When left
on the bench, no decomposition was admitted over several
months (Fig. S1). All of the benzoxaoboroles 1 are well
crystallized with the exception of 1j and 1k substituted with
trifluoromethyl group. As such, X-ray crystallographic analysis
was undertaken on compounds 1b and 1d.[20] In the solid state,
compound 1b and 1d exists in the dimeric form, linked through
two intermolecular hydrogen bonds (Fig. S2 and S3).[19, 21] No
significant difference in the structural parameters, including bond
lengths and angles, was observed between 1b and 1d.
1j
1k
R
Catalysts
R
Me
Me
R
3
2
O
1e : R = H
1f : R = OMe
1g : R = F
1a : R = H
1b : R = OMe
1c : R = F
O
1
O
B
B
B
OH
1d OH
OH
The catalytic activities of 1a−k were evaluated by
employing the benzoylation of cis-1,2-cyclohexanediol 2a as a
model reaction. The yield of the benzoylated product produced
by each catalyst after one hour is summarized in Table 1.
Comparing catalysts 1a-c substituted at para-position to the
boron atom, the electron-withdrawing fluoro group in 1c exerted
greater catalytic activity while the diminished activity of 1b
bearing electron-donating methoxy group relative to
unsubstituted 1a. A profound effect was seen in 3-position of the
benzoxaborole. The installation of phenyl group (1e) was more
effective rather than the alkyl substitution (1a and 1d). Next, by
exploring the electronic effect on the phenyl group (1e-g), we
identified that para-fluorophenyl group on 1g was significantly
increased the catalytic activity. The benzo-annulated
benzoxaborole 1h (napthoxaborole) showed slightly higher
activity in comparison to benzoxaborole 1a. Considering those
positive substituent effects, we designed 1i-k functionalized with
multiple fluoro or trifluoromethyl groups. As expected, these
R
CF
3CF3
R
F3C
Me
Me
CF3
O
F
F
B
O
O
OH
1i : R = F
1j : R = CF3
B
B
1h
OH
1k OH
[a] This yield was determined by 1H NMR using mesitylene as an internal
standard. The product 3a is a racemic mixture.
The cis-1,2-diol selectivity of the benzoxaborole catalysts
1a-k was evaluated by competitive benzoylation in the presence
of the equimolar amounts of cis- and trans-1,2-cyclohexanediol
(2a and 2b) (Table 2). Commensurate with the tendency of the
catalytic activity, the active catalysts 1i-k exhibited the higher
cis-1,2-diol selectivity with higher conversion yield. By using
most active catalyst 1k, a ratio of >20:1 of benzoylated product
cis-3a to trans-3b could be achieved. The cis-1,2-diol selectivity
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10.1002/ejoc.201901749
European Journal of Organic Chemistry
FULL PAPER
achieved using catalyst 1k is superior to that of diphenylborinic
acid (Table S2).
and summarized in Table 3 (see also Fig. S9). As with similar
tendency of previously reported phenylboronic acid derivative,
the electron withdrawing groups were found to increase the Ka
values. The DFT-calculated binding affinity for 2a at the
B3LYP/6-311++G(d,p) level in vacuum showed good agreement
with the experimental results using ARS (Table S3).
Consequently, we found that the binding preference of 1a−k
towards cis-1,2-diol is consistent with the catalytic activity.
Following this, the substituent effect in the nucleophilic step was
investigated utilizing the DFT-calculated Mulliken charges as the
indicator of the nucleophilicity of the oxygen atom (Table S4).
Unfortunately, there were no mutual correlation between the
Mulliken charges and the catalytic activity. The Mulliken charge
may be unavailable index for nucleophilicity of the boronate
adduct, unlikely the borinate adduct in Taylor’s report.[14] Overall,
electron-withdrawing groups on benzoxaborole catalyst 1 seem
to promote the formation of anionic boronate intermediate
through the inductive effects, and hence increases the catalytic
activity (and vice versa), although its effect on the nucleophilic
step was unclear. Underlying mechanistic study addressing the
substituent effect is of our great interest to exploit a further
active and selective catalyst.
Table 2. 1-catalyzed Competitive benzoylation of 2a and 2b
cat. (5 mol %)
OH
OH
OBz
OBz
OH
BzCl (0.3 mmol)
DIPEA (0.3 mmol)
+
+
OH
0.3 mmol
2a
OH
0.3 mmol
2b
OH
CH3CN (0.20 M)
r.t., 4 h
3a
3b
Catalyst
Conversion (%)a)
3a : 3ba)
4.8 : 1
2.5 : 1
6.1 : 1
4.5 : 1
5.5 : 1
5.6 : 1
11 : 1
1a
1b
1c
1d
1e
1f
28
26
33
23
33
21
36
29
50
55
65
1g
1h
1i
2.1 : 1
12 : 1
Table 3. ARS assay evaluating cis-diol affinity of 1a-k
R‘
R’
R‘ R’
R
O
1j
12 : 1
Na
R
O
B
O
B
O
O
O
1a-k
OH
1k
> 20 : 1
Ka
+
O
OH
CH3CN/HEPES buffer (4:1)
SO3Na
[a] This product ratio and conversion yield were determined by 1H NMR.
OH
SO3Na
O
To elucidate the substituent effect to the catalytic activity,
we carried out both experimental and theoretical analyses for
the boronate adduct, which is anticipated to be the active
intermediate. For this purpose, we at first confirmed whether the
boronate is involved as an active intermediate by monitoring the
11B NMR of 1c during the benzoylation of 2a (Fig. S7). In the
absence of cis-1,2-diol 2a, only single signal (d = 36.4 ppm)
corresponding to trigonal benzoxaborole 1c was observed. Up
on the addition of 2a, a new signal (d = 30.4 ppm) corresponding
to tetra-coordinating boronate adduct was appeared in upfield
region. This new signal was disappeared upon the addition of
benzoyl chloride and converged to the signal of 1c. These NMR
shifts indicated that the boronate is in fact the active
intermediate and participates in the catalytic system as expected.
Alizarin Red S (ARS)
Catalyst
1a
Ka (M-1)a)
2
(1.7 ± 0.3)×10
1b
1c
71 ± 17
2
(3.1 ± 0.1)×10
2
1d
1e
(1.6 ± 0.1)×10
2
(3.9 ± 0.7)×10
2
1f
(2.4 ± 0.2)×10
2
1g
1h
1i
(7.0 ± 0.2)×10
[2a-b, 22]
.
2
Next, we aimed to disclose how the substituent groups on
the benzoxaborole influence the catalytic activity. The
substituent groups could be concerned with modulating the
formation of the boronate adduct or the nucleophilic reaction of
the boronate adducts (Fig. S8). To confirm the former
consideration, the binding affinity of 1a−k towards cis-1,2-diols
(2.1 ± 0.2)×10
3
(1.6 ± 0.2)×10
3
1j
(2.3 ± 0.3)×10
3
1k
(4.8 ± 0.6)×10
was evaluated by utilizing Alizarine Red
S (ARS) as a
chromophoric 1,2-diol.[2a-b, 23] The UV-Vis titration was performed
in pH 7.4 HEPES buffer (CH3CN-H2O, 4:1), and the association
constants (Ka) of 1a-k were calculated from the titration curve
[a] These association constants are the average of the three separates
experiments. The detail of the measurement condition is described in
supporting information.
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10.1002/ejoc.201901749
European Journal of Organic Chemistry
FULL PAPER
With the highly active catalyst 1i in hand,[24] we
investigated the catalyst-controlled benzoylation, tosylation, and
benzylation of cis-1,2-diol derivatives (Table 4). For these
reactions, we used the catalyst 1i instead of more active 1j and
1k since it is well-crystallized and easily operable. Firstly, the
simple structured of linear- and cyclic-diols (2a-c) were
employed as substrates (Entry 1-3). Catalyst 1i tolerated for
both linear and cyclic diols and provided the mono-modified
product 3. In the case of the linear diols 2c and 2d, the
secondary hydroxyl group was slightly modified even in the
presence of primary alcohol (Entry 2 and 3). This preference
was contrastive that the borinic acid catalyst exclusively
provided primary alcohol modified product.[15] We subsequently
explored the site-selective modification of carbohydrates
including non- or partially protected methyl glycoside derivatives
6a-e having cis-1,2-diol moiety. As shown in Table 4 (Entry 4-8),
the 3-OH group was selectively modified with good yield in most
cases. The tosylation of 6d-f gave moderate yield (Entry 6-8).
One limitation of our catalyst system was observed in the
reaction of D-ribofuranoside derivative. Whilst is proceeded with
good yield, the 2-OH and 3-OH groups were indistinguishable
(Table S5).
5
6
7
8
3f: R = Bz (91)
OH
O
OH
O
TBSO
TBSO
HO
HO
HO
RO
4f: R = Ts (73)
OMe
OMe
2f
5f: R = Bn (92)
3g: R = Bz (83)
OMe
OMe
Me
O
Me
O
OH
OH
4g: R = Ts (63)
5g: R = Bn (88)
3h: R = Bz (86)
4h: R = Ts (60)
5h: R = Bn (81)
3i: R = Bz (80)
4i: R = Ts (58)
5i: R = Bn (92)c)
OR
OH
2g
HO
HO
OMe
OMe
Me
HO
Me
HO
O
O
OR
HO
2h
OH
OH
OH
HO
OH
RO
O
O
HO
2i
HO
OMe
OMe
[a] Isolated yield. [b] This product ratio was determined by 1H NMR. [c]
containing 19% regioisomer. Benzoylation: 1i (10 mol %), BzCl (1.2 eq.),
DIPEA (1.2 eq.), CH3CN, r.t., 4 hours. Tosylation: 1i (10 mol %), TsCl (1.5
or 3.0 eq.), DIEPA (1.5 or 3.0 eq.), CH3CN, r.t., 24 hours. Alkylation: 1i (10
mol %), BnBr (1.5 eq.), KI (1.0 eq.), K2CO3 (1.1 eq.), CH3CN, 60 ℃, 24
hours. The products 3a-5a are a racemic mixture.
Table 4. Site-selective modification of polyol derivatives catalyzed by 1i
After the successful site-selective modifications of
pyranoside derivatives, we turned our attention to 1i-catalyzed
Koenigs-Knorr glycosylation using 2 as an acceptor and per-
acetylated bromosugar (6 and 7) as donors (Table 5). In all
cases, the b-glycosylated product at 3-OH position of the
acceptor was predominantly obtained in moderate to good yields.
Per-benzylated chlorosugar 8 was also tolerated in the 1i-
catalyzed glycosylation with mannoside 2f, and b-linked
disaccharide 14 was obtained in 65% yield (entry 6).
F
cat.
F
Benzoylation
Tosylation
Benzylation
3: R = Bz,
4: R = Ts,
5: R = Bn
HO
RO
F
O
OH
OH
B
2
1i OH
Entry
1
Substrate
Product
Yield (%)a)
3a: R = Bz (83)
4a: R = Ts (91)
5a: R = Bn (>98)
OH
OR
OH
Table 5. Site-selective glycosylation catalyzed by 1i
OH
OH
OH
2a
O
1i (10 mol %), Ag2O (1.2 eq.)
+
O
HO
(1.2 eq.)
O
CH3CN, r.t., 16 h
X
2
R = Bz (>98)
3c : 3c’ = 15 : 1b)
OH
AcO
AcO
BnO
BnO
OAc
O
OBn
O
OR
OH
AcO
AcO
AcO
OH
OH
O
R = Ts (93)
c
4c : 4c’ = 14 :1b)
OR
AcO
AcO
BnO
2c
Br
Br
Cl
6
7
8
R = Bn (>98)
5c : 5c’ = 5.5 : 1b)
c’
Entry
1
Donor
Acceptor
Product
Yield (%)a)
82
OH OR
3
4
R = Bz (68)
3d : 3d’ = 9.1 : 1b)
6
2f
OH
O
TBSO
AcO
AcO
AcO
OH OH
HO
O
d
OMe
O
OR OH
4d: R = Ts (88)
5d: R = Bn (83)
3e: R = Bz (82)
4e: R = Ts (77)
5e: R = Bn (91)
AcO
9
2d
d’
OMe
2
6
2h
81
Me
O
AcO
AcO
AcO
HO
O
O
OH
OH
OTBS
O
OTBS
O
OH
AcO
10
OMe
OMe
RO
HO
OH
OH
2e
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10.1002/ejoc.201901749
European Journal of Organic Chemistry
FULL PAPER
In this context, various reactions catalyzed by benzoxaborole
are currently being explored in our laboratry to accomplish the
structural diversity of polyols.
3
4
5
6
6
7
7
8
2i
2h
2i
75
75
61
65
OH
OAc
O
O
AcO
AcO
O
11
HO
AcO
OMe
OMe
Me
AcO
AcO
OAc
O
O
HO
Acknowledgements
O
OH
AcO
12
This work was supported financially by the Grant-in-Aid for
Early-Career Scientists (No. 18K14229) from the Japan Society
for the Promotion of Science (JSPS), Takahashi Industrial and
Economics Research Foundation, ,and Shionogi Award from
The Society of Synthetic Organic Chemistry, Japan to S.K. and
by the Ministry of Education, Culture, Sports, Science and
Technology (MEXT) KAKENHI (Grant-in-Aid for Scientific
Research on Innovative Areas), Grant Number 18H04529 “Soft
Crystals” to R.I.
OH
AcO
AcO
OAc
O
O
O
HO
AcO
OMe
13
2f
OH
O
TBSO
BnO
BnO
OBn
O
HO
OMe
O
BnO
14
[a] Isolated yield.
The typical reaction conditions for the electrophilic
modification of a polyol require the exclusion of water to avoid its
competitive reaction with the electrophilic reagents. In contrast,
the organic transformation in water gains great attention
because of the environmental concerns.[25] Accordingly, a polyol
Conflict of interest
The authors declare no conflict of interest.
modification that tolerates aqueous media is
a desirable
Keywords: Benzoxaborole • polyol • cis-1,2-diol • site-selective
synthetic strategy. Recently, the well-designed acylation[26] and
glycosylation[27] of carbohydrates in aqueous media have been
reported. We thus postulated that carbohydrate modification in
water could be enabled by benzoxaborole, due to its outstanding
cis-1,2-diol affinity and activation. To this end, we assessed the
1i-catalyzed benzylation of 2h in CH3CN/H2O co-solvent to verify
the tolerance of the benzoxaborole catalyst to aqueous solvent
systems (Table S6). Pleasingly, benzylated 5h was produced in
moderate yield in 5:1 ratio of CH3CN/H2O. The reaction was
even possible in a solvent with over 50% water content, albeit
with diminished yields. This is because the decomposition of
benzylbromide by water occurs faster than desired benzylation
reaction. However, this demonstrates the intrinsic potential of
benzoxaborole catalysis in the aqueous media. The use of
relatively stable and water-soluble electrophiles could enable the
further application of benzoxaborole catalyst for the aqueous
transformation.
modification • glycosylation
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Benzoxaborole catalysts for site-selective modification of cis-1,2-diols
Shuhei Kusano*, Shoto Miyamoto, Aki
Matsuoka, Yuji Yamada, Ryuta Ishikawa
and Osamu Hayashida*
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This work
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• Structural optimization
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OH
OH
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• Scope and limitations
• Mechanistic study
Boronate
intermediate
OH
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Benzoxaborole
‘cis-1,2-diol recognition and activation’
Benzoxaborole catalyst for site-
selective modification of polyols
Novel benzoxaborole derivatives were designed as efficient catalysts for the highly
site-selective and protecting-group-free modification of polyols such a carbohydrate.
Additionally, the benzoxaborole catalyst could be tolerated to the diverse
modifications of polyols including acylation, sulfonylation, alkylation, and
glycosylation.
Key Topic: Organoboron catalyst
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