Characterization of the Dynamic Equilibrium between Closed and Open Forms of the Benzoxaborole Pharmacophore

Article abstract of DOI:10.1021/acsmedchemlett.6b00300

Benzoxaboroles are a class of five-membered hemiboronic acids that recently attracted significant attention as a new pharmacophore on account of their unique structural and physicochemical properties and their ability to interact selectively with biomolecules. Their structural behavior in water and its effect on their physiological properties remain unclear, especially the question of dynamic hydrolytic equilibrium of the oxaborole ring. Herein, we used NMR spectroscopy, in mixed aqueous-organic solvent, to confirm the strong preference for the closed form of benzoxaborole and its six- and seven-membered homologues over the open boronic acid form. Only with the eight-membered homologue does the cyclic form become unfavorable. Using dynamic VT-NMR studies with designed probe compound 20, we demonstrate that the oxaborole ring undergoes rapid hydrolytic ring closing-opening at ambient temperature at a rate of >100 Hz via a mechanism featuring rate-limiting proton-transfer steps. This knowledge can help provide a better understanding of the behavior of benzoxaboroles in biological systems.

Full text of DOI:10.1021/acsmedchemlett.6b00300

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Letter
Characterization of the dynamic equilibrium between close
and open forms of the benzoxaborole pharmacophore
Sergey Vshyvenko, Marissa Clapson, Itaru Suzuki, and Dennis G Hall
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.6b00300 • Publication Date (Web): 21 Sep 2016
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Characterization of the dynamic equilibrium between close
and open forms of the benzoxaborole pharmacophore
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Sergey Vshyvenko,† Marissa Clapson, Itaru Suzuki,† Dennis G. Hall*
Department of Chemistry, 4-010 Centennial Centre for Interdisciplinary Science, University of Alberta, Edmonton,
Alberta, Canada T6G 2G2
KEYWORDS benzoxaborole, boron heterocycles, hydrolysis, ring size, VT-NMR
ABSTRACT: Benzoxaboroles are a class of five-membered hemiboronic acids that recently attracted significant attention
as a new pharmacophore on account of their unique structural and physicochemical properties, and their ability to inter-
act selectively with biomolecules. Their structural behavior in water and its effect on their physiological properties remain
unclear, especially the question of dynamic hydrolytic equilibrium of the oxaborole ring. Herein, we used NMR spectros-
copy to confirm the strong preference for the close form of benzoxaborole and its 6- and 7-membered homologs over the
open boronic acid form. Only with the 8-membered homolog does the cyclic form become unfavorable. Using dynamic
VT-NMR studies with designed probe compound 20, we demonstrate that the oxaborole ring undergoes rapid hydrolytic
ring closing-opening at ambient temperature at a rate of >100 Hz via a mechanism featuring rate-limiting proton-transfer
steps. This knowledge can help provide a better understanding of the behavior of benzoxaboroles in biological systems.
The benzoxaborole ring system has emerged as a promis-
ing pharmacophore on the strength of the recent approval
of the antifungal drug tavaborole (2, AN2690),1 and the
potency demonstrated by numerous derivatives against an
impressive diversity of target classes (Figure 1).2-8 The par-
ent compound, benzoxaborole (1), was first prepared by
Torssell in 1957.9 It was described as a highly water-soluble
and unusually robust boronic acid derivative with great
resistance to both acidic and basic aqueous deboronation.
At the time, its structure was proposed to be the cyclic
monodehydrated form on the grounds of elemental analy-
sis9 and ebullioscopic molecular weight determination.10
Although the asserted preference for a cyclic hemiboronic
structure 1C over the open form 1O (Figure 1, eq. 1) is rea-
sonable based on the lability of B–O bonds and the stability
of 5-membered rings, until this day there appears to exist
no published experimental evidence for it aside from mass
spectrometry (in the gas phase) and X-ray crystallography
(in solid form).11 Surprisingly, the structural behavior of 1 in
aqueous solutions has never been studied systematically.
While studying the chemistry of benzoxaborole (1), Snyder
remarked that it ‘is remarkably resistant to hydrolysis of
the link between the alkoxyl group and the boron atom’.10
Indeed, we are aware of only two instances where a ben-
zoxaborole derivative was observed in its open form; a
specific case involving a stable trifluoroborate derivative
that is less prone to cyclize due to the strength of B–F
bonds,12 and the peculiar 7-hydroxymethylated derivative of
1 whose cyclization would lead to a disfavored [5.5] sys-
tem.13 Owing to Le Châtelier’s Principle, boronic ester
formation is intrinsically unfavored in water. Because the
balance of bond enthalpy is neutral (O–H and B–O bonds
are broken to form similar ones), thermodynamically the
process of Eq. 1 is driven solely by the enthalpy of ring
formation. This factor, along with the entropic benefit from
the release of a water molecule, are the reasons for the
asserted preference for the cyclic, close form of benzoxab-
orole (1C, Figure 1).
Despite the growing role of benzoxaborole derivatives in
pharmaceutical and materials chemistry applications,4-8 the
important questions of their structure in aqueous solutions
(close or open?) and the possible existence of a dynamic
equilibrium between these forms have not been examined
in detail.14 This knowledge is important in order to gain a
better understanding of the physicochemical properties of
benzoxaboroles and their behavior in biological systems,
such as their transport and pharmacokinetics. Herein,
using NMR spectroscopy, we attempt to study the effect of
ring size of boronic acid hemiesters 1, 3-5 on the structure
and stability of these compounds in aqueous organic solu-
F
OH
OH
OH
H
N
NC
B
B
B
O
O
O
R
O
O
F3C
SCYX-7158
1
R = H, benzoxaborole
crisaborole
2 R = F, tavaborole (antifungal)
(psoriasis)
(human African trypanosomiasis)
HO
HO
OH
B
O
B
OH
(1)
H2O
+
1C
1O
Figure 1. Benzoxaborole (1), derivatives of pharmaceutical
interest and its two possible forms in water (eq. 1).
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tions (see Figure 2). Our initial assumption was that if a In contrast, the spectrum of 5 showed the presence of only
1
2
3
4
5
6
7
8
closing-opening equilibrium exists, it can be monitored on
the timescale of NMR spectroscopy due to sufficient differ-
ence between both forms for the chemical shifts of the
methylene groups adjacent to the oxygen atom. Thus,
when the free alcohol closes into a hemiester with the
nearby boronic acid, the electron-withdrawing effect of B–
O conjugation is expected to move the CH2O shift down-
field. In order to substantiate this notion, the analogous
methyl ethers with a similar chemical structure, but lack-
ing the ability to cyclize into a hemiboronic ester, were
employed as NMR standards.
the open form 5O, with the upfield shift characteristic of
the methylene group of control compounds 16 and 19c.
This analysis is consistent with basic principles of thermo-
dynamic stability for small and medium rings, where a very
large preference for the cyclic forms exists in the case of
benzoxaborole (1) and its 6-membered homolog (3). The 8-
membered medium-ring homolog 5 exists exclusively in its
open form, 5O, which is favored based on the less favorable
thermodynamics of 8-membered rings and the entropic
benefits provided by the additional degrees of freedom of
several rotatable bonds on the flexible butanol chain.
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OH
OH
upfield
chemical
shift
1C n = 0
1
B
B
Table 1. H NMR shift of methyleneoxy for benzox-
O
OH
aborole, its homologs, and control compounds.a
+ H2O
3 n = 1
4 n = 2
5 n = 3
OH
n
n
downfield
chemical
shift
en-
try
Compound
compound
δ
CH2O
δ CH2O
(ppm)
1O, 3-5O
1C, 3-5C
(ppm)
OH
OH
1
4.95
4.55
Figure 2. Equlibrium between close and open form of ben-
zoxaborole homologs up to 8-atom ring size.
B
B
OH
O
OMe
While some of the targeted compounds were commercially
available, others were prepared according to standard
synthetic protocols for the synthesis of organoboronic
acids. To this end, commercial 2`-bromobenzylbromide (6)
was chosen as a universal substrate in a divergent route to
all oxaborole homologs and NMR standards. From 6, the
desired alkene intermediates 7 or 8 were produced by the
corresponding vinylation15 or allylation,16 followed by a
hydroboration/oxidation step. Either a methylation of the
resulting alcohol, or installation of a tetrahydropyranyl
ether led to all four bromoarenes 11-14. The final step con-
sisted in a standard lithiation/borylation, which after hy-
drolysis yielded boronic acids 4, 5, 15 and 16 (see Scheme 1).
1C
17
OH
2
3
OH
4.06
3.75
3.58
3.29
B
B
O
OH
OMe
3C
18
OH
HO
B
B
O
OH
OMe
15
4C
OH
B
OH
4
5
3.46
3.29
B
OH
OH
OMe
OH
16
5O
Proton NMR analysis of the parent benzoxaborole 1 and all
the higher homologs 3-5 was achieved in acetone-d6:D2O
(9:1) mixture, necessary for compound solubility, at room
temperature (293 K = 20 °C). It was deemed important to
perform this analysis in the presence of excess water in
order to approach the conditions of physiological systems.
Based on the large chemical shift differences of 0.4-0.5 ppm
for the –CH2O– resonance between these compounds and
the corresponding control methyl ethers, it can be deduced
that only the close forms of 1, 3, 4 are present at room
19a 3.68
19b 3.51
19c 3.48
( )n
OH
19a n = 1
19b n = 2
19c n = 3
a NMR studies were performed in acetone-d6/D2O 9:1 mix-
ture at 300 K.
To assess the proportions of close and open forms and
thermodynamics of this process, VT experiments were
performed. It was found that compounds 1, 3 and 5 re-
mained unchanged in the entire range of temperatures
from 203 to 303 K. In contrast, the 7-membered ring com-
pound 4 was found to exist in a mixture of both forms in
proportions that varied depending on the temperature.
Quite unexpectedly, the amount of the open form, boronic
acid 4O, which is almost inexistent at 303K, started to in-
crease upon lowering the temperature (see Figure 3). At
203K (–70 °C), the open form accounts for about one-third
of the mixture (see SI, Table S2). This outcome is con-
sistent with the notion that two different entropic factors
are competing in this equilibrium: 1) the release of a water
molecule accompanying the cyclization to the close form,
thus increasing the overall entropy of the system, vs 2) the
temperature (Table 1).
vinylMgBr,
toluene, CuCl,
–70 °C to rt
i. BH3-SMe2,
THF, 0°C
Br
Br
Br
Br
OH
ii. H2O2,
1N aq. NaOH,
0 °C
or:
allylMgBr,
THF, 0 °C
n
n
6
9, n = 1
7, n = 1
8, n = 2
10, n = 2
dihydropyran,
CH2Cl2,
TsOH, rt
i. n-BuLi, THF, –75 °C;
ii. B(O-i-Pr)3,
Br
B(OH)2
–75 °C to rt
OR
OR
or:
MeI, NaH,
iii. 1N HCl, H2O
n
n
11, n = 1, R = THP
12, n = 2, R = THP
13, n = 1, R = Me
14, n = 2, R = Me
4, n = 1, R = H
5, n = 2, R = H
15, n = 1, R = Me
16, n = 2, R = Me
THF, 0 °C to rt;
Scheme 1. Preparation of NMR probe compounds
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ACS Medicinal Chemistry Letters
OH
HO
entropic benefits from the degrees of freedom of many
(HO)2B
O
O
B(OH)2
B
B
1
2
3
4
5
6
7
8
rotatable bonds in the flexible alkanol side chain of open
forms, especially in the higher homologs 4O and 5O (see
Figure 4). We believe that at the lower temperatures, the
release of water in the cyclization does not significantly
increase the entropy of the system owing to the more
structured character of water and its stronger coordination
to the boronic hemiester. The water molecule may remain
closely associated with the cyclic compound (e.g., 4C •H2O)
at these low temperatures. The 4O:4C ratio obtained at
different temperatures allowed a determination of the free
energy of this process ΔGO/C = −2.6 kJ/mol (see SI).
ka
kb
F
F
20a
20b
Figure 5. Possible equilibrium between two isomeric forms of
diboronic acid 20 in aqueous solution.
OH
i. i-PrMgBr,
THF‚ –70 °C;
i. n-BuLi,
THF, –75 °C;
HO
Br OH Br
HO
O
Br
B
B
9
I
10
11
12
13
14
15
16
17
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19
20
21
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Br
ii.
ii. B(O-i-Pr)3,
–75 °C to rt
iii. aq. 1N HCl,
2h
F
F
OHC
23
21
20a/20b
22
F
THF, –70 °C to rt
Scheme 2. Preparation of dynamic NMR probe 20.
The synthesis of compound 20 began with a selective meta-
lation17 of 2-bromoiodobenzene (21), followed by electro-
philic quenching with 2-bromo-5-fluorobenzaldehyde (22)
(Scheme 2). The resulting alcohol 23, was doubly metalat-
ed and added to tris(isopropyl)borate. The desired product
was isolated by column chromatography and submitted to
VT-NMR studies. Variable temperature experiments were
performed in both 90% acetone/10% H2O and 90% ace-
tone/10% D2O solutions in order to calculate the equilibri-
um constants at different temperatures and attempt to
estimate the equilibrium isotopic effect. Our initial exper-
iments showed that equilibrium is established rapidly in
both systems at different temperatures ranging from ambi-
ent to −70 °C. The VT profile was performed under several
increments (213 to 303K) at 400 MHz frequency under
dilute conditions (0.06 M) to help prevent unwanted ag-
gregation of boronic acid 20. At low, pre-coalescence tem-
perature, the 19F NMR spectra show two separate forms of
the probe compound in uneven proportions (Figure 6).
Upon heating, peak broadening occurs with eventual coa-
lescence into a single resonance. Expectedly, a significant
temperature-dependent drift of the 19F chemical shift oc-
curred,18 which complicated the accurate determination of
the coalescence temperature (TC). DNMR analysis for the
interconversion of unequally populated equilibrating spe-
cies is much less common compared to degenerate pro-
cesses. However, rate constants of direct and reverse reac-
tions, ka (for 20a to 2ob) and kb (for 20b to 20a) and equi-
librium constants can be estimated before coalescence by
utilizing the modified Gutowsky-Holm equation from half-
height peak widths, h, for both forms 20a and 20b.19,20
Figure 3. VT studies of compound 4 in acetone/D2O solution
and temperature dependence of ratio 4O/4C
OH
B
HO
OH2
O
HO
B
B
O
OH
+ H2O
OH
4O
4C
4C H2O
Entropy from open-chain
favored at low temperature
Entropy from relase of free water
favored at high temperature
Temperature
303 K
200 K
Figure 4. Proposed behavior of 7-membered compound 4 at
different temperatures.
The above measurements characterize the steady state of
an equilibrium occurring between two different forms; the
dynamic parameters of the equilibrium cannot be assessed
by means of these probes. Consequently, our next objective
was to design a DNMR probe molecule to gain direct evi-
dence of a dynamic, reversible hydrolytic equilibrium
between the close and open forms of 1 via the breaking and
reclosing of the endocyclic B–O bond in aqueous solution.
Although several possible probes were considered, we
elected to target the unsymmetrical diboronic acid 20
containing a single secondary benzylic alcohol flanked by
two distinct arylboronic acid units (see Figure 5). It was
anticipated that probe 20 would display a dynamic behav-
ior similar to that of benzoxaborole 1, and therefore it may
establish an equilibrium between two isomeric benzoxabo-
roles 20a and 20b that could be monitored by means of 19F
NMR.
The resulting data indicates that the exchange between the
two isomeric forms occurs in the D2O solvent mixture at a
rate up to six times slower compared to that observed in
H2O at comparable temperatures (see Tables S2 and S3).
This behavior can also be deduced by the respective coales-
cence temperatures of ~290K and ~255K, thus confirming
that the D2O system requires a higher temperature to reach
a fast equilibrium. Overall these results suggest that a
proton-transfer step with at least one molecule of water is
involved in the exchange between 20a and 20b (see Figure
7). Analysis of the data using the modified Gutowsky-Holm
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equations allows an estimation of the interconversion rate representation of the closing-opening hydrolytic equilibri-
1
2
3
4
5
6
7
8
(see SI). At low temperatures (e.g., 223 K) where isomers
are distinguishable, equilibrium in acetone-D2O is slow. In
the acetone-H2O mixture, however, a relatively faster ex-
change occurs with a frequency around 30 Hz. Close to
coalescence temperature, exchange constants reach 111 and
93 Hz respectively. At room temperature, equilibrium in
acetone-H2O occurs as fast as 135 Hz.
um of benzoxaborole (1).
H
H
O
B
H
B
OH2
HO
O
H
O
H
HO
HO
O
B(OH)2
B
OH
O
B(OH)2
B
O
or
F
F
F
20bC
TS A
kO
TS C
slow
kC
9
OH
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20
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HO
HO B(OH)2
B
F
24 (20bO/20aO
)
k'C
k'O
H
slow
H
H
H2O
OH
H
O
O
O
B
O
H
OH
OH
HO
(HO)2B
O
B
B
(HO)2B
O
B
or
F
F
F
20aC
TS D
TS B
Figure 7. Suggested hydrolytic mechanism and structures of
transition states between the two isomeric forms of 20.
Figure 6. VT equilibrium of 20 in acetone-H2O (9:1).
Altogether, these results provide a semi-quantitative char-
acterization of the dynamic equilibrium between the open
and close forms of benzoxaboroles, leading to the proposed
mechanistic scheme depicted in Figure 7. Recent evidence
suggests that boronic esters hydrolyze faster at neutral pH
in their trigonal, neutral form compared to the correspond-
ing hydroxy-boronate anionic form.21 Thus, water coordina-
tion in neutral 20bC is followed by the proton transfer step
depicted in TSA, leading to ring opening and formation of
diboronic acid 24 (i.e., 20bO/20aO). Because ring opening
is anticipated to be much slower than ring closure (kC > kO;
k’C > k’O), open intermediate 24 is anticipated to exist in
minute concentration and is not observable by NMR. Fast
ring closure of 24 may occur by reversion to 20bC or alter-
natively towards the other isomer 20aC via TSB. Because
ring opening by water is the rate-determining step of the
overall equilibrium interconversion, a strong isotopic re-
tardation effect can be observed in D2O co-solvent. It is
important to note that although non-cooperativity be-
tween both boronyl units was assumed, it cannot be ruled
out. Though it may be geometrically difficult, intramolecu-
lar 6-atom hydrolytic pathways may occur via transition
states TSC and TSD. Relative to benzoxaborole (1), it is also
possible that the secondary alcohol of 24 benefits from a
favorable Thorpe-Ingold effect to give a somewhat inflated
closure rate constant. Finally, as demonstrated by the
uneven peak integrations at pre-coalescence temperatures,
one of the two isomers exists in slightly higher proportions,
which is explained presumably by the differential Lewis
acidity of the two boronyl units (the presence of a meta-
fluoride lowers the pKa of phenylboronic acid by approxi-
mately one unit22). Regardless of its distinct characteristics,
we believe that probe compound 20 provides a reasonable
In summary, this study confirms the strong preference for
the close form of benzoxaborole (1) and its 6- and 7- mem-
bered homologs over the open boronic acid form in aque-
ous-organic solvent at ambient temperature. Only with the
8-membered homolog does the cyclic form become unfa-
vorable. Surprisingly, the 7-membered homolog showed an
increasingly high proportion of the open form at lower
temperatures, a trend that can be ascribed to the more
organized structure of water and its tighter coordination to
the boron atom leading to a diminished entropic prefer-
ence toward the cyclization. It was also demonstrated that
the closing-opening equilibrium can be monitored by NMR
spectroscopy at low temperatures and previously unattain-
able parameters can be extracted. A probe molecule, dibo-
ronic acid 20, was designed for studying the dynamics of
the hydrolytic equilibrium between the close and open
forms. It was shown that the exchange between the two
isomeric close forms of diboronic acid 20 occurs with a
significant frequency even at low temperatures. Further-
more, a strong isotopic retardation effect was observed
with deuterated water, thus confirming the participation of
water and proton transfer steps in the transition state of
interconversion. Overall, this study into the structural
behavior of benzoxaboroles and its homologs in aqueous-
organic solution provides a deeper understanding of this
new and important pharmacophore. Insofar as probe 20
accurately reflects the behavior of benzoxaborole (1), re-
versible hydrolysis of the oxaborole ring occurs rapidly
(>100 Hz) under physiological conditions.
ASSOCIATED CONTENT
Supporting Information
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(5) Baker, S. J.; Tomsho, J. W.; Benkovic, S. J. Boron-
The Supporting Information is available free of charge on the
1
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Containing Inhibitors of Synthetases. Chem. Soc. Rev. 2011, 40
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(6) Zhang, J.; Zhu, M.; Lin, Y.; Zhou, H. The Synthesis of Ben-
zoxaboroles and Their Applications in Medicinal Chemistry. Sci.
China Chem. 2013, 56 (10), 1372-1381.
(7) Liu, C. T.; Tomsho, J. W.; Benkovic, S. J. The Unique
Chemistry of Benzoxaboroles: Current and Emerging Applica-
tions in Biotechnology and Therapeutic Treatments. Bioorg.
Med. Chem. 2014, 22 (16), 4462-4473.
ACS Publications website at DOI:
Tables S1-S3, full experimental details and compound charac-
terization data, NMR spectral reproductions (PDF)
AUTHOR INFORMATION
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(8) Adamczyk-Woźniak, A.; Borys, K. M.; Sporzyński, A. Re-
cent Developments in the Chemistry and Biological Applications
of Benzoxaboroles. Chem. Rev. 2015, 115 (11), 5224-5247.
(9) Torssell, K. Zur Kenntnis Der Arylborsauren .3.
Bromierung Der Tolyborsauren Nach Wohl-Ziegler. Arkiv för
Kemi 1957, 10, 507-511.
(10) Snyder, H. R.; Reedy, A. J.; Lennarz, W. J. Synthesis of Ar-
omatic Boronic Acids – Aldehydo Boronic Acids and a Boronic
Acid Analog of Tyrosine. J. Am. Chem. Soc. 1958, 80 (4), 835-838.
(11) Zhdankin, V. V.; Persichini III, P. J.; Zhang, L.; Fix, S.;
Kiprof, P. Synthesis and Structure of Benzoboroxoles: Novel
Organoboron Heterocycles. Tetrahedron Lett. 1999, 40 (37),
6705-6708.
Corresponding Author
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* Email: dennis.hall@ualberta.ca
Present Addresses
† SV: Gilead Alberta ULC, 1021 Hayter Road NW, Edmonton,
Alberta, T6S 1A1.
IS: Osaka University, Research Center for Environmental
Preservation, 2-4 Yamadaoka, Suita, Osaka 565-0871, Japan
Author Contributions
(12) Park, Y. H.; Ahn, H. R.; Canturk, B.; Jeon, S. I.; Lee, S.;
Kang, H.; Molander, G. A.; Ham, J. A Facile One-pot Preparation
The manuscript was written through contributions of all
authors. All authors have given approval to the final version
of the manuscript.
of
Potassium
Hydroxyaryl-
and
(Hydroxy-
alkyl)aryltrifluoroborates. Org. Lett. 2008, 10 (6), 1215-1218.
(13) Ye, L.; Ding, D.; Feng, Y.; Xie, D.; Wu, P.; Guo, H.; Meng,
Q.; Zhou, H. Convenient and Versatile Synthesis of Formyl-
Substituted Benzoxaboroles. Tetrahedron 2009, 65, 8738-8744.
(14) Lulinski, S.; Madura, I.; Serwatowski, J.; Szatylowicz, H.;
Zachara, J. A Tautomeric Equilibrium Between Functionalized 2-
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(17) Kowada, T.; Yamaguchi, S.; Fujinaga, H.; Ohe, K. Near-
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ACKNOWLEDGMENT
This research was generously funded by the Natural Science
and Engineering Research Council of Canada (Discovery
Grant 203287-2012 to D.G.H.) and the University of Alberta.
The authors thank Mr. Mark Miskolzie for help with VT-
NMR studies.
ABBREVIATIONS
DNMR, dynamic NMR; NMR, nuclear magnetic resonance;
TS, transition structure; VT-NMR, variable temperature
NMR.
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