Stability of boronic esters to hydrolysis: A comparative study

Article abstract of DOI:10.1246/cl.2009.750

Boronic esters are key intermediates in the synthesis of biologically active compounds such as thrombin and proteasome inhibitors. However, they have low hydrolytic stability both during synthetic reactions and in biological media. We report the preparati

Full text of DOI:10.1246/cl.2009.750

750
Chemistry Letters Vol.38, No.7 (2009)
Stability of Boronic Esters to Hydrolysis: A Comparative Study
Raffaella Bernardini,ꢀ1 Ambrogio Oliva,1 Alessandro Paganelli,1 Ernesto Menta,2
Mario Grugni,1 Sergio De Munari,1 and Luca Goldoni1
1Cell Therapeutics Inc., Via L. Ariosto, 23, 20091 Bresso, Italy
`
EOS S.p.A. (Ethical Oncology Science), Via Monte di Pieta, 1/A. 20121 Milan, Italy
2
(Received April 30, 2009; CL-090428)
Boronic esters are key intermediates in the synthesis of bio-
Further details of the different classes of compounds are re-
ported in the following sections.
The empty p-orbital of boron is susceptible to interactions
with electron donor atoms (dative bonds). Roy4 showed that
the trans-esterification rate of boronic esters with diols is in-
creased by a nitrogen atom in the diol chain.
On the contrary, interaction with electron donors could sta-
bilize boronic esters diols rendering them less prone to nucleo-
philic attacks. We tried to stabilize our cyclic boronic esters with
extra oxygen or nitrogen atoms capable of coordinating the bor-
on atom forming stable complexes. Examples of such complexes
are known in the literature.6
The diols utilized for the synthesis of boronic esters are
commercially available except 7 and 9. (RS)-4-Aminobutane-
1,2-diol7 hydrochloride (7) (Scheme 1) was obtained by reaction
of 4-bromobut-1-ene (3) with di-tert-butyl iminodicarboxylate
(4) in the presence of potassium carbonate to give derivative
5. The subsequent steps were the Upjohn dihydroxylation with
osmium tetraoxide followed by Boc removal with hydrogen
chloride.
logically active compounds such as thrombin and proteasome in-
hibitors. However, they have low hydrolytic stability both during
synthetic reactions and in biological media. We report the prep-
aration of several boronic esters and a comparative study of their
stability to hydrolysis vs. the corresponding pinanediol boronic
esters, which are among the most hydrolytically stable. We dis-
covered that the boronic esters derived from (1,10-bicyclohexyl)-
1,10-diol are the most stable among those examined.
Boronic acids and esters play an important role in many
fields of chemical research and technology. Examples of impor-
tant reactions involving boronic acids are the multicomponent
Petasis reaction or metal-catalysed Suzuki couplings.
Boronic esters are used as protecting groups and chiral aux-
iliary agents in highly stereoselective asymmetric synthesis. Par-
ticularly useful in organic synthesis is the asymmetric homolo-
gation via ꢀ-chloroboronic esters, which provides an extremely
efficient method for constructing chiral centers.1
The reactivity of boronic acids with hydroxy groups has
been exploited also by medicinal chemists for the synthesis of
potent and selective peptide boronic inhibitors of thrombin2
and proteasome.3
Our group has been involved in recent years in the search for
novel proteasome inhibitors endowed with superior activity and
reduced side effects.3 Boronic esters were one of the key inter-
mediates in the synthesis and a prodrug of the bioactive com-
pound because of their stability at neutral pH and reduced stabil-
ity in the acidic environment of tumor cells. Hence, their hydro-
lytic stability both during synthetic reactions and in a biological
medium was one of the major problems we faced.
(2S,3S)-1,4-Bis(dimethylamino)butane-2,3-diol (9)8 was
obtained by reduction with lithium aluminum hydride of the cor-
responding amide 8 (Scheme 2). The general procedure for the
synthesis of boronic esters consists of the reaction between iso-
butylboronic acid or 2-phenethylboronic acid, dissolved in di-
ethyl ether, with a stoichiometric amount of the appropriate
1,2- or 1,3-diol (Scheme 3). Table 1 summarizes the results of
the hydrolytic stability studies on the synthesized boronic esters
compared to compound 1. Unfortunately, none of the studied di-
ols gave a boronic ester having the hydrolytic stability superior
to that of 1.
After 1 h under the 1H NMR test conditions these esters were
hydrolyzed to a significant extent or even completely.
During hydrolysis, water molecules presumably attack the
boron p-orbital from the less hindered face. Accordingly to
Roy4 observations, the increase of diol steric hindrance slows
A detailed study on the stability of several boronic esters has
already been published by Roy and Brown.4 In this paper we
present further investigations on this subject with the different
aim to find new and more stable boronic esters.
1
For this purpose, an H NMR comparative study has been
performed to evaluate the hydrolytic stability of a number of iso-
butylboronic acids with respect to model compound 1 (pinane-
diol ester; Figure 1).5
The most promising diols were also reacted with 2-phen-
ethylboronic acid in order to evaluate the hydrolytic stability
of the resulting esters both by 1H NMR and HPLC. In this case
the model compound was derivative 2 (Figure 1).
O
HN
O
OtBu
(i)
Br
N
OtBu
+
O
tBuO
O
tBuO
3
4
5
(ii)
OH
OH
O
(iii)
HO
HO
NH
2 HCl
N
OtBu
tBuO
O
O
O
B
O
B
O
7
6
Scheme 1. Reagents and conditions: (i) K2CO3, DMF, rt, 16 h;
(ii) NMO, OsO4, 2.5% w/v in t-BuOH, acetone/water 1/1; (iii)
4.0 M HCl aq, MeOH, rt, 12 h.
1
2
Figure 1. Chemical structures of model compounds 1 and 2.
Copyright Ó 2009 The Chemical Society of Japan

Chemistry Letters Vol.38, No.7 (2009)
751
Table 2. Hydrolysis of compounds 1 and 14–16
N
N
O
O
OH
OH
OH
OH
Compd
Structure
Time/h
Hydrolysis/%a
(i)
1
0
2
O
B
O
1
N
N
24
8
9
1
24
1
0
4
0
4
O
B
Scheme 2. Reagents and conditions: (i) LiAlH4 1.0 M in THF,
24 h, Et2O, rt.
14
O
O
H
Et2O
R
R
HO
HO
O
O
OH
OH
O
O
O
H
+
B
B
B
15
16
H
O
O
- 2 H2O
H
24
R= i-Pr, Bn
1
0
0
O
Scheme 3. General procedure for the synthesis of boronic esters
1, 2, and 10–17.
B
60
O
135
0.2
aFrom 1H NMR integral data.
Table 1. Hydrolysis of compounds 1 and 10–13
Compd
Structure
Time/h
1
Hydrolysis/%a
0
Table 3. Hydrolysis of compounds 2 and 17
O
B
O
Compd
Structure
Time/h
Hydrolysis/%a
NMR HPLC
1
24
1
2
N
1
21
1
3.0
4.9
0.1
0.7
0
0.4
0
O
B
O
B
O
100
2
10
11
O
N
O
O
O
B
O
NH2
1
80
B
17
21
0
aFrom 1H NMR integral data.
O
NH2
1
100
100
12
13
B
O
O
0.1
B
Our study of the stability of boronic esters to hydrolysis has
shown that the most important factor affecting this reaction is the
steric hindrance created around the boron atom by the diol moie-
ty. We discovered that boronic esters of (1,10-bicyclohexyl)-1,10-
diol as 16 and 17 are much more stable to hydrolysis with respect
to pinanediol boronic esters 1 and 2.
O
OH
aFrom 1H NMR integral data.
down boronic acid esterification. Our study demonstrates that the
hydrolysis rate of the corresponding boronic ester is also re-
duced.
References and Notes
In order to extend hindrance to both faces of the complex,
we synthetised esters of isobutylboronic acid with (1R,2R)-
(ꢁ)-1,2-dicyclohexyl-1,2-ethandiol, 1,2:5,6-di-O-cyclohexyl-
idene-D-mannitol, and (1,10-bicyclohexyl)-1,10-diol.9 As shown
by the data reported in Table 2, these esters have a stability com-
parable or superior to 1.
In particular, the boronic ester of the (1,10-bicyclohexyl)-
1,10-diol 16 was much more stable to hydrolysis than the corre-
sponding pinanediol ester 1. The derivative 16 was hydrolysed
only to a barely detectable extent after 135 h in the 1H NMR test
conditions.
The most interesting diol, (1,10-bicyclohexyl)-1,10-diol, was
also reacted with 2-phenethylboronic acid to study the hydroly-
sis of the resulting boronic ester compared to compound 2, both
by 1H NMR and HPLC. The results are summarized in Table 3.
Once again, compound 17 containing (1,10-bicyclohexyl)-1,10-
diol showed a greatly enhanced stability toward hydrolysis ver-
sus the corresponding pinanediol ester 2.
Among the favourable features of (1,10-bicyclohexyl)-1,10-
diol are also a low molecular weight and an easy supply by pi-
nacol synthesis.10
1
2
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CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
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D. Seebach, H. Daum, Chem. Ber. 1974, 107, 1748.
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Published on the web (Advance View) July 5, 2009; doi:10.1246/cl.2009.750