Synthesis of functionalized benzoboroxoles for the construction of boronolectins

Article abstract of DOI:10.1055/s-0031-1289577

Adducts of peptides and arylboronic acids are attractive tools for the selective recognition of carbohydrates. These structures resemble at least some of the properties of natural carbohydrate binders and have therefore been termed lectin mimetics or boro

Full text of DOI:10.1055/s-0031-1289577

PAPER
4059
Synthesis of Functionalized Benzoboroxoles for the Construction of
Boronolectins
Synthesis of
F
a
unctionaliz
lk
Department of Chemistry, University of Hamburg, Bundesstraße 45, 20146 Hamburg, Germany
Fax +49(40)428386519; E-mail: maison@chemie.uni-hamburg.de
Received 24 August 2011; revised 29 September 2011
affinities to non-reducing sugars were achieved with phe-
nylboronic acids of the Wulff type 1 (Figure 1, B) with
donor substituents ortho to the boronic acid moiety.13 In
this context, Hall and co-workers have reported several
Abstract: Adducts of peptides and arylboronic acids are attractive
tools for the selective recognition of carbohydrates. These struc-
tures resemble at least some of the properties of natural carbohy-
drate binders and have therefore been termed lectin mimetics or
boronolectins. In this report, we describe the synthesis of appropri- benzoboroxole derivatives of type 2 that were found to
ately functionalized benzoboroxoles as modular components for the
bind to non-reducing sugars with moderate affinities in
water.14
assembly of boronolectins. These benzoboroxoles have been pre-
pared in a few steps from readily available starting materials. In
conclusion, versatile functionalized benzoboroxoles are reported
that can be used for the construction of larger conjugates by peptide
coupling or copper-mediated cycloadditions (click reactions) with
azides.
A:
OH
B
O
B
HO
2 H2O
+
+
R
OH
R
O
HO
HO
B:
Key words: carbohydrate recognition, boronic acids, click reac-
tions, boronolectins, benzoboroxoles
O
OH
B
B
OH
Do
2
The boronic acid moiety is a promising structural motif
for pharmaceuticals.1 In addition, it is a highly versatile
motif in synthetic organic chemistry including applica-
tions in catalysis, Pd-catalyzed cross-coupling reactions
and hydroborations. Boronic acids are therefore extreme-
ly useful synthetic building blocks. In particular, function-
alized derivatives of phenylboronic acids have received
considerable attention as catalysts and intermediates of
complex natural products such as Vancomycin.2 In addi-
tion to their applications in organic synthesis, phenylbo-
ronic acids are of interest as carbohydrate sensors. This
function is due to their ability to reversibly bind to 1,2-di-
ols (Figure 1, A).3 Carbohydrates are essential elements of
molecular recognition on cell surfaces4 and are involved
in many pharmaceutically relevant processes such as im-
mune responses to pathogens,5 cancer development,6 and
infective diseases.7 The molecular recognition of carbo-
hydrates with small molecules is therefore a highly attrac-
tive area of research.8 Among the many different
approaches,9 boronic acids are a promising class of mole-
cules for carbohydrate recognition and many derivatives
have been demonstrated to bind sugars with reasonable af-
finities and specificities.10 Derivatives of phenylboronic
acids have been particularly successful examples, and a
number of good carbohydrate binders are based on this
structural motif.3,11 However, the field remains challeng-
ing and most carbohydrate binders suffer from relatively
low affinities and specificities in water, particularly for
non-reducing sugars and pyranoses.12 Reasonable binding
1
benzo-
boroxole
Do = NR2, OH
"Wulff-type"
O
H
R
N
N
H
R =
+
O
NH3
NMe2
R
R
B
HO
OH
3
Anslyn's heparin receptor
Figure 1 (A) Reversible formation of boronic esters. (B) Selected
examples of known carbohydrate binders: Wulff type benzoboroxole
1 with a donor substituent in the ortho position, benzoboroxole scaf-
fold 2, and Anslyn’s trimeric heparin receptor 3.
Another attractive strategy to increase binding affinities
and specificities to sugars is the construction of mostly
peptidic hybrids of phenylboronic acids.15 These conju-
gates resemble the characteristics of natural carbohydrate
binding proteins, such as lectins, and were therefore
termed boronolectins. Anslyn has reported particularly at-
tractive multivalent combinations of peptides with boron-
ic acids that imitate the defined tripodal geometry of
natural lectins. One example is receptor 3, which is able to
bind the anticoagulant heparin and is thus used as a hep-
arin sensor for biomedical applications.16
We report here new derivatives of benzoboroxoles that are
appropriately functionalized for easy conjugation to pep-
tides and other biomolecules by bioorthogonal coupling
techniques. These boronic acids are attractive building
blocks for the assembly of boronolectins.
SYNTHESIS 2011, No. 24, pp 4059–4067
x
x.
x
x
.
2
0
1
1
Advanced online publication: 27.10.2011
DOI: 10.1055/s-0031-1289577; Art ID: T83611SS
© Georg Thieme Verlag Stuttgart · New York

4060
F. Wienhold et al.
PAPER
Our first target compounds were benzoboroxole–amino tion of the two diastereomers (3S,5R,6S)-9 and
acid conjugates of type 4 (Scheme 1). Boronic acids of (3R,5R,6S)-9 gave the protected b-hydroxy amino acids
type 4 combine several useful features; namely, a ben- (3S,4S)-10 and (3R,4S)-10.
zoboroxole of the Hall type for sugar binding, an amino
group for the conjugation to multimeric scaffolds, and a
H
Boc
Boc
Boc2O
HPLC separation
carboxylic acid for the introduction of biomolecules such
as peptides in close vicinity to the boronic acid moiety.
Compounds 4 would therefore be valuable for the con-
struction of boronolectins such as 8, with three-fold geo-
metry, by conjugation to known tripodal scaffolds.17
N
N
N
+
N
N
N
O
O
O
rac-BMI
(S)-BocBMI
(R)-BocBMI
1. i-Pr2NH,
n-BuLi, –78 °C
2. 6, –100 °C
Br
O
1. 6 M HCl
2. Boc2O
DMAP, NaOH
Br
1
OH
O
Br
OH
O
2
6
1
N
4
HO
3
5
OH
2
6
+
O
3
Br
OH
O
B
O
O
BocN
NHBoc
5
4
OR
OR
NHR
NHR
(3S,4S)-10, 37%
(3R,4S)-10, 33%
(3S,5R,6S)-9, 16%
(3S,5R,6R)-9, 50%
(3R,5R,6S)-9, 34%
OR
4
5
NHR
7
(yields for two steps)
Scheme 2 Synthesis of b-hydroxy amino acids (3S,4S)-10 and
(3R,4S)-10 using Seebach’s chiral glycine equivalent BocBMI
HO
B
O
Unfortunately, the attempted lithiation and transmetalla-
tion of densely functionalized amino acids 10 failed, and
the introduction of various protecting groups in deriva-
tives 11 and 13 (Scheme 3) did not improve the situation;
peptide
NH
O
peptide
O
O
N
OH
B
H
scaffold
HN
O
O
O
Br
OH
O
B
OH
O
MeLi (3.3 equiv)
t-BuLi (3.3 equiv)
peptide
OMe
NHBoc
OMe
NHBoc
O
B
HO
8
11
12
O
O
Scheme 1 Retrosynthesis of benzoboroxole-amino acid 4 and as-
sembly of tripodal boronolectins 8
B
TMS-CHN2
Et3N
Oi-Pr
49%
(3R,4S)-10
We planned to use 2-bromobenzaldehyde (6) as a precur-
sor of benzoboroxole 4, which would be treated with a
chiral glycine equivalent 7 to give the threonine derivative
5 as an intermediate. In a last step, the boronic acid moiety
would be introduced by lithiation and subsequent trans-
metalation to give benzoboroxole 4.
DMP
30%
p-TsOH
O
O
Br
O
B
O
H
H
MeLi (2.2 equiv)
t-BuLi (2.2 equiv)
NBoc
NBoc
In a first attempt, we used Seebach’s chiral glycine deriv-
ative (BocBMI), which is readily available from glycine
and pivalaldehyde.18 Racemic BMI may be separated into
both optical isomers by fractionated crystallization with
mandelic acid. Alternatively, we used preparative HPLC
separation on a chiral stationary phase (see the Supporting
Information) to gain access to sufficient quantities of
enantiomerically pure (R)- and (S)-BocBMI. The fol-
lowing addition of the enolate derived from BocBMI to
2-bromobenzaldehyde (6) was performed according to
Scheme 2, following the original Seebach protocol. The
reaction proceeded with low diastereoselectivity to give a
mixture of three diastereomers 9, which were separable by
chromatography. Hydrolysis and subsequent Boc-protec-
H
H
OH
OH
O
13
O
14
traces
O
O
B
Oi-Pr
HO
i-PrMgCl (5 equiv)
t-BuLi (3.3 equiv)
B(Oi-Pr)3
B
O
O
Br
OH
O
OH
Me
N
NH2
BocN
7%
(3S,5R,6S)-9
15
Scheme 3 Synthesis of protected amino acids and their conversion
into boronic acids
Synthesis 2011, No. 24, 4059–4067 © Thieme Stuttgart · New York

PAPER
Synthesis of Functionalized Benzoboroxoles
4061
To avoid complex protecting group manipulations in the
amino acids of type 10, we decided to introduce the amino
acid part after installing the boronic acid moiety, and fo-
cused on triazole derivative 22 as a target structure
(Scheme 5). The triazole linkage would be generated in a
[3+2] cycloaddition of azide 24 and alkyne 23,20 which, in
turn, would be prepared from aldehyde 25. A nice feature
of this approach is that alkyne 23 is not only a precursor
for the amino acid conjugate 22, but can also be used for
the conjugation of benzoboroxoles to various other bio-
molecules through copper-catalyzed cycloaddition proto-
cols.
O
O
O
B
O
Oi-Pr
OH
OH
NH2
O
B
MeLi
NH2
(3.3 equiv)
i-PrMgCl
(5 equiv)
t-BuLi
Br
O
17
16
(3.3 equiv)
O
O
O
O
B
A key intermediate in our sequence was alkyne 23, and we
evaluated two different routes to this compound
(Scheme 6). A first attempt started from the commercially
available aldehyde 25, which was protected with pinacol
to give the corresponding pinacolate 26 in quantitative
yield.21 This pinacolate was treated with TMS-acetylide to
give the corresponding addition product, which, upon
treatment with LiOH, gave the target compound 23. Alter-
natively, the nucleophilic addition of TMS-acetylide to 2-
bromobenzaldehyde 6 proceeded smoothly and gave the
propargylic alcohol 27 in excellent yield. Introduction of
the boronic acid was performed by halogen–metal ex-
change and subsequent treatment with B(Oi-Pr)3 to give
28 in moderate yield. The TMS group in 28 was removed
by treatment with LiOH to provide alkyne 23 in excellent
yield (Scheme 6).
OH
NHBoc
Oi-Pr
OH
NHBoc
O
B
MeLi
Br
(2.2 equiv)
i-PrMgCl
(2.2 equiv)
t-BuLi
O
18
19, 13%
(2 equiv)
O
O
O
B
O
Ot-Bu
NHBoc
Oi-Pr
Ot-Bu
NHBoc
O
MeLi
B
(1.1 equiv)
t-BuLi
Br
O
(2 equiv)
20
21, 48%
Scheme 4 Halogen–metal exchange with protected derivatives of p-
bromophenylalanine
With alkyne 23 in hand, we attempted the copper-cata-
lyzed cycloaddition with the known azido alanine 29
(Table 1).22 However, standard protocols for click-reac-
tions gave only disappointing results. It has previously
been reported that boronic acids are often problematic
substrates for copper-catalyzed click-reactions, with de-
boronation being the major side reaction.23 A common
workaround is the addition of fluoride, which has been
used to suppress deboronation in these conversions be-
fore.24 However, the use of sodium ascorbate and CuSO4
with CsF or CuBr and tetrabutylammonium fluoride
(TBAF) (Table 1, entries 1 and 2) gave none of the desired
cycloaddition product 30. A slight improvement was real-
ized when the reaction was performed under microwave
conditions (Table 1, entry 3), and a mixture of boronic
none of the desired compounds 12 or 14 were obtained. In
most cases, dehalogenated species were the major side-
products formed in these reactions. Boronic ester 14 was
identified in trace amounts by MS analysis, and only for
the conversion of (3S,5R,6S)-9 was a small quantity of the
deprotected boronic acid 15 isolated (Scheme 3).
A few attempts with less functionalized model com-
pounds confirmed our assumption that the high density of
functional groups in the b-hydroxy amino acids was the
reason for the failure of the borylations. Only in the con-
version of fully protected p-bromophenylalanine (20) was
the corresponding boronic ester 21 obtained in acceptable
yield (Scheme 4). Similar observations have been report-
ed by Morin.19
HO
HO
O
B
O
B
O
+
N3
OR
O
N
NHR
N
N
OR
RHN
22
23
24
HO
OH
B
O
25
Scheme 5 Retrosynthesis of triazole derivative 22
Synthesis 2011, No. 24, 4059–4067 © Thieme Stuttgart · New York

4062
F. Wienhold et al.
PAPER
1. n-BuLi
2. LiOH
with a significant amount of the 1,5-regioisomer 31
(Table 1, entry 4). Finally, a mixture of CuBr, TBTA, and
CsF24 was used, and the reaction gave 1,4-regioisomer 30
in quantitative yield (Table 1, entry 5). Using these condi-
tions, different biomolecules may be conjugated to boron-
ic acid 23 as demonstrated with the sugar azide 33.26 The
cycloaddition again provided the desired triazole deriva-
tive 34 in good yield (Scheme 8).
TMS
HO
O
O
HO
OH
then 1 M HCl
B
O
B
O
25
quant.
34%
two steps
route A
26
23
a) LiOH
b) 1 M HCl
route B
93%
MeLi
n-BuLi
TMS
t-BuLi
HO
CuBr, TBTA
O
O
B(Oi-Pr)3
O
O
CsF, 5 h, r.t.
Br
O
Br
OH
B
O
HO
23
B
O
O
O
O
37%
TMS
O
90%
54%
TMS
O
O
N3
N
6
27
28
N
N
33
34
Scheme 6 Two different approaches to alkyne 23
Scheme 8 Copper-catalyzed cycloaddition of alkyne 23 and azide
33
acid 30 and the corresponding deboronated derivative 32
was obtained in moderate yield.
In conclusion, we have developed an efficient synthetic
approach to a new benzoboroxole–amino acid conjugate
30, which was obtained in a few steps from readily avail-
able starting materials. Conjugate 30 combines three use-
ful functionalities: (1) a benzoboroxole moiety for
carbohydrate binding; (2) an amine group for attachment
to multimeric scaffolds, and (3) a carboxylic acid for the
conjugation of biomolecules such as peptides or sugars.
We have designed boronic acid 30 as modular compo-
nents for the assembly of tripodal boronolectins. Alterna-
tively, the intermediate alkyne 23 may be used for the
conjugation of various biomolecules to the benzoboroxole
core for a specific tailoring of their sugar-binding proper-
ties.
Fokin and Sharpless have shown that the addition of
tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA)
can improve the yields of click conversions.25 By using
CuSO4 in the presence of TBTA, sodium ascorbate, and
CsF, we were thus able to obtain the desired product along
HO
B
O
O
N
OH
N
N
NHBoc
30
+
OH
O
O
23
conditions
N
OH
NHBoc
N3
OH
N
N
The following compounds were prepared according to literature
protocols: rac-BMI,18 (R)- and (S)-BocBMI27 (rac-BocBMI was
separated by HPLC on a chiral stationary phase. For details see the
Supporting Information), pinacolate 26,21 azidoalanine 29,22 and 6-
azido-D-galactose 33.26
NHBoc
29
32
+
HO
B
O
N
TLC was performed on silica gel aluminum sheets. Reagents used
for developing plates were cerium reagent (5 g molybdatophospho-
ric acid, 2.5 g cerium sulfate tetrahydrate, 25 mL sulfuric acid and
225 mL H2O), KMnO4 (0.5% in 1N NaOH w/v), and detection by
UV light was used when applicable. Flash column chromatography
was performed on silica gel (60–200 mm). 1H NMR chemical shifts
are referenced to residual non-deuterated solvent (CDCl3,
dH = 7.26 ppm; DMSO-d6, dH = 2.50 ppm). 13C NMR chemical
shifts are referenced to the solvent signal (CDCl3, dC = 77.16 ppm;
N
N
NHBoc
O
OH
31
Scheme 7 Cycloadditions of alkyne-substituted benzoboroxole 23
and azido alanine 29
Table 1 Conditions and Product Distribution for Cycloadditions According to Scheme 7
Entry
Conditions
30 (%)
31 (%)
32 (%)
1
2
3
4
5
sodium ascorbate, CuSO4, CsF, r.t.
CuBr, TBAF, r.t.
0
0
0
0
0
0
sodium ascorbate, CuSO4, CsF, 100 °C, MW, 30 min
sodium ascorbate, CuSO4, CsF, TBTA, r.t., 5 h
CuBr, CsF, TBTA, r.t., 5 h
13
0
24
0
15
30
0
quant.
0
Synthesis 2011, No. 24, 4059–4067 © Thieme Stuttgart · New York

PAPER
Synthesis of Functionalized Benzoboroxoles
4063
DMSO-d6, dC = 28.06 ppm). NMR spectra were recorded at 200
(50), 400 (100), or 600 (150) MHz on Bruker Avance instruments.
ESI mass spectra were recorded with a TOF Bruker MicroTOF in-
strument operated either in positive or negative mode. Samples
were dissolved in MeCN–MeOH mixtures and directly injected by
using a syringe. If indicated with abs., solvents were dried by distil-
lation from sodium under a nitrogen atmosphere prior to use.
ing crude product was used without any further purification in the
next step. H2O–THF (20 mL, 1:1 v/v), NaOH (0.12 g, 3.1 mmol),
and DMAP (0.01 g, 0.1 mmol) were added to the product and the
reaction mixture was cooled to 0 °C. Boc2O (0.62, 2.8 mmol) was
added and the solution was allowed to warm to r.t. and stirred for 12
h. The solvent was removed in vacuo and the remaining solid was
extracted with EtOH (3 × 30 mL). The crude product was purified
by HPLC.
Imidazolidinones (3S,5R,6S)-9, (3S,5R,6R)-9, and (3R,5R,6S)-9
Diisopropylamine (1.55 mL, 11 mmol) was dissolved in abs. THF
(35 mL) and cooled to –78 °C under an N2 atmosphere. n-BuLi
(2.22 M in hexane, 5.85 mL, 13 mmol) was added and the solution
was stirred for 10 min. A solution of (R)-BocBMI (2.56 g, 10 mmol)
in abs. THF (3 mL) was added (the reaction mixture became yel-
low). After 30 min, the mixture was cooled to –100 °C and benzal-
dehyde (1.5 mL, 11 mmol) was added. The reaction was quenched
with sat. aq ammonium chloride solution (30 mL) and the aqueous
layer was extracted with Et2O (2 × 75 mL), the combined organic
layers were dried over Na2SO4 and the solvent was removed in vac-
uo. The crude product was purified by flash chromatography (silica;
PE–EtOAc, 2:1) to give three diastereomers (3S,5R,6S)-9,
(3S,5R,6R)-9, and (3R,5R,6S)-9 in a ratio of 16:50:34 (total 3.84 g,
8.7 mmol, 87%).
b-Hydroxyamino Acid (3S,4S)-10
The title compound was synthesized following the general proce-
dure for hydrolysis and Boc-protection from (3S,5R,6S)-9 (416 mg,
0.94 mmol). Compound (3S,4S)-10 (126 mg, 0.35 mmol, 37%) was
isolated after purification by HPLC (RP 18; MeCN–H2O, 35%; 230
nm; 3 mL/min) as a colorless solid.
1H NMR (400 MHz, DMSO-d6): d = 1.20 [s, 9 H, C(CH3)3], 4.41
(dd, J = 10.0, 2.3 Hz, 1 H, CHNH), 5.40 (d, J = 1.8 Hz, 1 H,
CHOH), 5.86 (d, J = 10.1 Hz, 1 H, OH), 6.29 (d, J = 10.0 Hz, 1 H,
NH), 7.18 (dt, J = 7.7, 1.6 Hz, 1 H, ArH), 7.36 (t, J = 7.0 Hz, 1 H,
ArH), 7.59–7.52 (m, 2 H, ArH).
13C NMR (100 MHz, DMSO-d6): d = 27.9, 56.7, 71.6, 78.1, 120.9,
127.1, 129.0, 129.0, 131.9, 140.5, 155.2, 171.7.
HRMS (ESI): m/z [M – H]– calcd for C14H18BrNO5: 358.0296;
found: 358.0295.
Imidazolidinone (3S,5R,6S)-9
1H NMR (400 MHz, DMSO-d6): d = 0.90 [s, 9 H, C(CH3)3], 1.24 [s,
9 H, OC(CH3)3], 2.93 (s, 3 H, NCH3), 4.56–4.53 (m, 1 H, CHN),
5.00 [s, 1 H, CHC(CH3)3], 5.46 (dd, J = 2.6, 6.7 Hz, 1 H, CHOH),
5.80 (d, J = 6.7 Hz, 1 H, OH), 7.15 (dt, J = 7.9, 1.5 Hz, 1 H, ArH),
7.29 (t, J = 7.3 Hz, 1 H, ArH), 7.36 (d, J = 7.5 Hz, 1 H, ArH), 7.52
(d, J = 7.9 Hz, 1 H, ArH).
b-Hydroxyamino Acid (3R,4S)-10
The title compound was synthesized following the general proce-
dure for hydrolysis and Boc-protection from (3R,5R,6S)-9 (1.56 g,
3.5 mmol). Compound (3R,4S)-10 (352 mg, 0.98 mmol, 28%) was
isolated after purification by HPLC (RP 18; MeCN–H2O,
10→40%; 230 nm; 3 mL/min).
13C NMR (100 MHz, DMSO-d6): d = 26.2, 27.6, 31.8, 40.5, 61.3,
71.1, 80.1, 80.1, 122.0, 126.8, 128.7, 129.2, 132.3, 141.6, 152.2,
170.7.
HRMS (ESI): m/z [M + Na]+ calcd for C20H29BrN2O4: 463.1203;
found: 463.1199.
1H NMR (400 MHz, DMSO-d6): d = 1.33 [s, 9 H, C(CH3)3], 4.33
(dd, J = 5.3, 9.2 Hz, 1 H, CHNH), 5.02 (d, J = 5.2 Hz, 1 H, CHOH),
5.84 (br s, 1 H, OH), 6.70 (d, J = 9.2 Hz, 1 H, NH), 7.20 (dt, J = 7.6,
1.4 Hz, 1 H, ArH), 7.35 (t, J = 7.4 Hz, 1 H, ArH), 7.49 (dd, J = 7.7,
1.0 Hz, 1 H, ArH), 7.56 (dd, J = 8.0, 1.0 Hz, 1 H, ArH), 12.40 (br s,
1 H, COOH).
13C NMR (100 MHz, DMSO-d6): d = 27.9, 57.9, 72.0, 78.3, 121.9,
127.0, 129.0, 129.1, 131.9, 140.2, 154.7, 171.1.
HRMS (ESI): m/z [M – H]– calcd for C14H18BrNO5: 358.0296;
found: 358.0292.
Imidazolidinone (3S,5R,6R)-9
1H NMR (400 MHz, DMSO-d6): d = 1.07 [s, 9 H, C(CH3)3], 1.38 [s,
9 H, OC(CH3)3], 2.84 (s, 3 H, NCH3), 4.32 (d, J = 3.3 Hz, 1 H,
CHN), 4.89 [s, 1 H, CHC(CH3)3], 5.26 (dd, J = 3.9, 4.7 Hz, 1 H,
CHOH), 5.81 (d, J = 5.1 Hz, 1 H, OH), 7.18 (dt, J = 7.8, 1.7 Hz,
1 H, ArH), 7.35 (t, J = 7.1 Hz, 1 H, ArH), 7.52 (dd, J = 8.0, 1.0 Hz,
1 H, ArH), 7.74 (dd, J = 7.8, 1.5 Hz, 1 H, ArH).
b-Hydroxyamino Acid (11)
13C NMR (100 MHz, DMSO-d6): d = 27.0, 28.0, 30.5, 36.8, 62.9,
72.3, 80.5, 80.8, 121.4, 127.1, 129.0, 131.0, 131.7, 141.7, 155.3,
167.5.
HRMS (ESI): m/z [M + Na]+ calcd for C20H29BrN2O4: 463.1203;
found: 463.1206.
b-Hydroxyamino acid (3R,4S)-10 (47 mg, 0.13 mmol) was dis-
solved in MeOH (5 mL) and trimethylsilyl diazomethane (2.0 M in
hexane, 0.07 mL, 0.14 mmol) was added. The resulting solution was
stirred for 1 h at r.t. before adding a second portion of trimethylsilyl
diazomethane (2.0 M in hexane, 0.07 mL, 0.14 mmol). The solution
was stirred for 12 h and heated to 40 °C for 2 h. After an additional
amount of trimethylsilyl diazomethane (2.0 M in hexane, 0.21 mL,
0.42 mmol) and a few drops of Et3N were added, the solution was
stirred for 7 h at r.t. The solvent was removed in vacuo and the crude
product was purified by HPLC (RP 18; MeCN–H2O, 5→95% in 10
min; 3 mL/min; 230 nm). The desired product 11 (24 mg, 0.06
mmol, 49%) was obtained as an oil.
Imidazolidinone (3R,5R,6S)-9
1H NMR (400 MHz, DMSO-d6): d = 0.87 [s, 9 H, C(CH3)3], 1.50 [s,
9 H, OC(CH3)3], 2.85 (s, 3 H, NCH3), 4.21 (s, 1 H, CHCON), 5.09–
4.99 [m, 1 H, CHC(CH3)3], 5.69 (s, 1 H, CHOH), 6.22–5.93 (m,
1 H, OH), 7.16 (d, J = 7.3 Hz, 1 H, ArH), 7.31 (t, J = 7.4 Hz, 1 H,
ArH), 7.50 (d, J = 8.1 Hz, 1 H, ArH), 7.52 (d, J = 7.9 Hz, 1 H,
ArH).
1H NMR (600 MHz, CD3OD): d = 1.39 [s, 9 H, C(CH3)3], 3.55 (s,
3 H, CO2CH3), 4.59 (d, J = 5.4 Hz, 1 H, CHNH), 5.24 (d,
J = 5.4 Hz, 1 H, CHOH), 7.2 (t, J = 7.5 Hz, 1 H, ArH), 7.36 (t,
J = 7.5 Hz, 1 H, ArH), 7.53 (dd, J = 7.9, 1.59 Hz, 1 H, ArH), 7.55
(d, J = 7.9 Hz, 1 H, ArH).
13C NMR (150 MHz, CD3OD): d = 28.6, 52.2, 59.4, 73.9, 80.9,
123.4, 128.4, 129.7, 130.5, 133.6, 141.3, 157.3, 172.3.
13C NMR (100 MHz, DMSO-d6): d = 26.0, 28.2, 31.1, 40.2, 60.6,
68.4, 79.3, 80.4, 120.4, 126.2, 128.7, 131.4, 131.5, 140.7, 167.8.
HRMS (ESI): m/z [M + Na]+ calcd for C20H29BrN2O4: 463.1203;
found: 463.1205.
Hydrolysis and Boc-Protection; General Procedure
Imidazolidinone 9 (1.0 mmol) was dissolved in 6 M HCl and stirred
for 12 h at reflux. The solvent was removed in vacuo and the result-
HRMS (ESI): m/z [M + Na]+ calcd for C15H20BrNO5: 396.0417;
found: 396.0420.
Synthesis 2011, No. 24, 4059–4067 © Thieme Stuttgart · New York

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F. Wienhold et al.
PAPER
b-Hydroxyamino Acid (13)
CHNH), 7.24 (d, J = 7.7 Hz, 2 H, ArH), 7.66 (d, J = 7.8 Hz, 2 H,
ArH).
13C NMR (150 MHz, CD3OD): d = 25.1, 25.2, 28.5, 28.7, 38.2, 38.8,
38.9, 56.1, 56.2, 56.2, 80.6, 85.1, 129.8, 135.8, 142.2, 157.8, 157.9,
175.1, 175.3, 175.4
11B NMR (128 MHz, CDCl3): d = 27.6.
b-Hydroxyamino acid (3R,4S)-10 (50 mg, 0.14 mmol), dimeth-
oxypropane (0.25 mL, 2.00 mmol) and a small quantity of p-tolu-
enesulfonic acid were dissolved in acetone (10 mL) and stirred at
70 °C for 2.5 h. The solvent was removed in vacuo and the residue
was dissolved in CH2Cl2 (20 mL), washed with H2O (3 × 10 mL)
and the combined organic layers were dried over Na2SO4. The crude
product was purified by HPLC (RP 18; MeCN–H2O, 5→95% in 15
min; 3 mL/min; 230 nm). The product 13 (17 mg, 0.04 mmol, 30%)
was obtained as a colorless solid.
HRMS (ESI): m/z [M – H]– calcd for C20H30BNO6: 390.2093;
found: 390.2092.
1H NMR (400 MHz, CDCl3): d (mixture of two rotamers) = 1.51–
1.41 [m, 9 H, C(CH3)3], 1.80–1.70 [m, 6 H, C(CH3)2], 4.13 (d,
J = 8.2 Hz, CHNH), 4.24 (d, J = 8.0 Hz, CHNH), 5.60 (d,
J = 8.2 Hz, CHOH), 5.64 (d, J = 8.0 Hz, CHOH), 7.21 (dt, J = 7.9,
1.6 Hz, 1 H, ArH), 7.38 (t, J = 7.5 Hz, 1 H, ArH), 7.55 (dd, J = 8.1,
1.0 Hz, 1 H, ArH), 7.59 (d, J = 7.2 Hz, 1 H, ArH).
13C NMR (100 MHz, CDCl3): d = 24.1, 25.0, 26.3, 27.5, 28.2, 28.3,
66.1, 66.3, 77.9, 81.3, 81.6, 95.1, 95.8, 123.1, 128.1, 128.5, 130.3,
133.0, 136.3, 150.7, 151.9, 175.0, 176.5.
b-Hydroxyamino Acid (20)
Arylbromide 16 (240 mg, 1 mmol) and Boc2O (1.09 g, 5 mmol)
were dissolved in t-BuOH (15 mL) and a small amount of DMAP
was added. The reaction mixture was stirred at 30 °C for 60 h. The
solvent was removed in vacuo and the crude product was purified
by flash chromatography (silica; n-hexane–EtOAc, 19:1). The prod-
uct 20 (94 mg, 0.2 mmol, 23%) was obtained as a colorless oil.
1H NMR (400 MHz, CD3OD): d = 1.39 [s, 9 H, C(CH3)3], 1.41 [s,
9 H, C(CH3)3], 2.85 (dd, J = 13.8, 8.8 Hz, 1 H, CH2), 3.02 (dd,
J = 13.8, 6.0 Hz, 1 H, CH2), 4.21 (dd, J = 6.0, 8.8 Hz, 1 H, CHNH),
7.15 (d, J = 8.3 Hz, 2 H, ArH), 7.43 (d, J = 8.3 Hz, 2 H, ArH).
13C NMR (100 MHz, CD3OD): d = 28.2, 28.7, 38.2, 57.0, 80.6, 82.9,
121.5, 132.4, 138.0, 157.8, 172.7.
HRMS (ESI): m/z [M – H]– calcd for C17H22BrNO5: 398.0609;
found: 398.0607.
b-Hydroxyamino Acid (15)
HRMS (ESI): m/z [M + Na]+ calcd for C18H26BrNO4: 422.0943;
found: 422.0946.
Imidazolidinone (3S,5R,6S)-9 (31 mg, 0.07 mmol) was dissolved in
abs. toluene (10 mL) and cooled to 0 °C under an N2 atmosphere. i-
PrMgCl (14% in THF, LiCl complex, 0.35 mL, 0.35 mmol) was
added dropwise and the solution was stirred for 15 min at 0 °C. Af-
ter cooling to –78 °C, t-BuLi (1.6 M in hexane, 0.23 mL, 0.35
mmol) was added. After stirring for 10 min, triisopropyl borate
(0.08 mL, 0.35 mmol) was added. The reaction mixture was al-
lowed to warm to r.t. slowly and stirred for 12 h. H2O (10 mL) was
added and the pH was adjusted to 1–2 by adding 50% H2SO4. The
aqueous phase was extracted with EtOAc (3 × 5 mL), dried over
Na2SO4, and the solvent was removed in vacuo. The crude product
was purified by flash chromatography (silica; n-hexane–EtOAc,
1:1) and the product 15 (1 mg, 0.005 mmol, 7%) was obtained as a
colorless oil.
Boronic Ester (21)
Arylbromide 20 (28 mg, 0.07 mmol) was dissolved in abs. toluene
(10 mL) and cooled to –78 °C under an N2 atmosphere. With
10 min intervals MeLi (5% in Et2O, 0.08 mL, 0.08 mmol), t-BuLi
(1.5 M in hexane, 0.1 mL, 0.14 mmol) and 2-isopropoxy-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane (0.06 mL, 0.28 mmol) were added.
The reaction mixture was allowed to warm to r.t. slowly and H2O
(10 mL) was added. The layers were separated, the aqueous phase
was extracted with CH2Cl2 (3 × 10 mL), and the combined organic
layers were dried over Na2SO4. The crude product was purified by
flash chromatography (silica; n-hexane–EtOAc, 9:1) and the prod-
uct 21 (15 mg, 0.03 mmol, 48%) was obtained as a colorless oil.
1H NMR (400 MHz, CDCl3): d (mixture of two diastereomers) =
1.34 [s, 12 H, C(CH3)2], 1.41 [s, 18 H, C(CH3)3], 3.09–3.07 (m, 2 H,
CH2), 4.45 (dd, J = 6.0, 8.0 Hz, 1 H, CHNH), 4.95 (d, J = 8.1 Hz,
1 H, CHNH), 7.17 (d, J = 7.9 Hz, 2 H, ArH), 7.73 (d, J = 7.9 Hz,
2 H, ArH).
1H NMR (400 MHz, CD3OD): d = 4.49 (d, J = 7.2 Hz, 1 H, CHN),
6.07 (d, J = 7.2 Hz, 1 H, CHO), 7.71–7.67 (m, 1 H, ArH), 7.90–7.84
(m, 3 H, ArH).
13C NMR (100 MHz, CD3OD): d = 59.9, 77.6, 125.7, 128.8, 132.5,
136.3, 137.8, 151.3, 160.5, 201.0.
11B NMR (128 MHz, CD3OD): d = 18.6.
HRMS (ESI): m/z [M – H]– calcd for C9H10BNO4: 206.0630; found:
13C NMR (100 MHz, CDCl3): d = 25.0, 28.1, 28.5, 29.8, 38.6, 54.8,
79.8, 82.1, 83.9, 129.1, 134.9, 139.8, 155.2, 170.9.
11B NMR (128 MHz, CDCl3): d = 31.7.
206.0634.
HRMS (ESI): m/z [M + Na]+ calcd for C24H38BNO6: 470.2684;
Boronic Ester (19)
Arylbromide 18 (34 mg, 0.10 mmol) was dissolved in abs. THF (5
mL) and cooled to –78 °C under an N2 atmosphere. With 15 min in-
tervals MeLi (5% in Et2O, 0.14 mL, 0.22 mmol), i-PrMgCl (14% in
THF, LiCl complex, 0.22 mL, 0.22 mmol), t-BuLi (1.6 M in hexane,
0.12 mL, 0.20 mmol), and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (0.08 mL, 0.40 mmol) were added dropwise. The re-
action mixture was allowed to warm to r.t. slowly and stirred for 2 h.
HCl (aq, 0.5 M, 20 mL) was added and the layers were separated.
The aqueous layer was extracted with EtOAc (3 × 10 mL), the or-
ganic layers were combined, dried over Na2SO4, and the solvent
was removed in vacuo. The crude product was purified by HPLC
(RP 18; MeCN–H2O, 10→90% in 15 min; 2 mL/min; 230 nm) to
give the desired product 19 (5 mg, 0.01 mmol, 13%) as a colorless
solid.
found: 470.2685.
Benzoboroxole (23; Route A)
n-BuLi (1.4 M in hexane, 1.6 mL, 2.2 mmol) was added under an
N2 atmosphere to a stirred solution of (trimethylsilyl)acetylene
(0.34 mL, 2.4 mmol) in anhydrous Et2O (7 mL) at 0 °C. After
15 min, aldehyde 26 (0.50 g, 2.2 mmol) was added and the reaction
mixture was stirred for 2.5 h at 0 °C. The reaction was quenched
with aq NaHCO3 (10 mL) and the layers were separated. The aque-
ous phase was extracted with Et2O (3 × 10 mL) and washed with
brine (5 mL). The combined organic layers were dried over Na2SO4,
filtered, and evaporated to dryness under reduced pressure. The
crude product was dissolved in THF–H2O (10 mL, 1:1 v/v), treated
with LiOH (105 mg, 4.4 mmol) and stirred for 12 h at r.t. The sol-
vent was removed in vacuo and the residue was dissolved in CH2Cl2
(10 mL). The solution was washed with aq 1 M HCl (5 mL) and the
organic layer was separated, washed with brine (5 mL) and dried
1H NMR (600 MHz, CD3OD): d = 1.34–1.37 (m, 21 H, CH3), 2.94–
2.85 (m, 1 H, CH2), 3.12–3.19 (m, 1 H, CH2), 4.37–4.32 (m, 1 H,
Synthesis 2011, No. 24, 4059–4067 © Thieme Stuttgart · New York

PAPER
Synthesis of Functionalized Benzoboroxoles
4065
over Na2SO4, filtered and concentrated under reduced pressure. The
crude product was purified by flash chromatography (silica; CH2Cl2
to CH2Cl2–MeOH, 50:1) to give the desired boronic acid 23 (115
mg, 0.7 mmol, 34%) as a colorless solid.
Click Reactions; General Procedure A
Alkyne (0.34 mmol), azide (0.34 mmol), sodium ascorbate (7 mg,
0.03 mmol), CuSO4 (6 mg, 0.04 mmol), and CsF (260 mg, 1.71
mmol) were dissolved in dist. DMF (5 mL) and heated in a micro-
wave for 30 min at 100 °C (Pmax 200 W). The reaction mixture was
concentrated to dryness in vacuo and the crude residue was dis-
solved in CH2Cl2 (10 mL), washed with H2O (10 mL), EDTA (1 M),
and dried over Na2SO4. The crude product was purified by flash
chromatography (silica; CH2Cl2–MeOH, 20:3).
Benzoboroxole (23; Route B)
To a solution of 28 (0.21 g, 0.9 mmol) in H2O–THF (15 mL, 1:2
v/v), LiOH (0.03 g, 1.4 mmol) was added and the resulting mixture
was stirred for 12 h at r.t. The reaction mixture was concentrated in
vacuo and the residue was dissolved in CH2Cl2 (50 mL). The solu-
tion was washed with aq 1 M HCl (2 × 10 mL). The organic layer
was separated, washed with brine (5 mL), and dried over Na2SO4,
filtered and concentrated under reduced pressure. The crude product
was purified by flash chromatography (silica; CH2Cl2–MeOH,
100:1) to afford the alkyne 23 as a colorless oil (0.13 g, 0.8 mmol,
93%).
1H NMR (400 MHz, CDCl3): d = 2.62 (d, J = 2.2 Hz, 1 H), 5.88 (s,
1 H), 7.61–7.39 (m, 3 H), 7.81–7.74 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 70.8, 74.6, 80.8, 121.8, 128.3,
130.6, 131.8, 153.5.
General Procedure B
Alkyne (0.2 mmol), azide (0.2 mmol), TBTA (10 mg, 0.02 mmol),
CuSO4 (3 mg, 0.02 mmol), sodium ascorbate (3 mg, 0.02 mmol),
and CsF (90 mg, 0.6 mmol) were dissolved in DMF (5 mL) and
stirred for 5 h at r.t. The reaction mixture was concentrated to dry-
ness in vacuo and the crude residue was purified twice by flash
chromatography (silica; CH2Cl2–MeOH, 10:3).
General Procedure C
Alkyne (0.2 mmol) and azide (0.2 mmol), TBTA (10 mg, 0.02
mmol), CuBr (3 mg, 0.02 mmol), and CsF (90 mg, 0.6 mmol) were
dissolved in H2O–DMF–t-BuOH (1:3:1 v/v, 5 mL) and stirred for
5 h at r.t. The reaction mixture was concentrated to dryness in vacuo
and the crude residue was purified twice by flash chromatography
(silica; CH2Cl2–MeOH, 10:3).
11B NMR (128 MHz, CDCl3): d = 32.4.
HRMS (ESI): m/z [M + H]+ calcd for C9H7BO2: 159.0612; found:
159.0612.
Propargylic Alcohol (27)
Benzoboroxole Amino Acid (30)
n-BuLi (1.4 M in hexane, 3.9 mL, 5.4 mmol) was added to a stirred
solution of (trimethylsilyl)acetylene (0.85 mL, 5.9 mmol) in anhy-
drous Et2O (7 mL) at 0 °C under an N2 atmosphere. After 15 min,
2-bromobenzaldehyde 6 (0.63 mL, 5.4 mmol) was added and the re-
action mixture was stirred for 2.5 h at 0 °C. The reaction was
quenched with aq NaHCO3 (10 mL) and the layers were separated.
The aqueous phase was extracted with Et2O (2 × 10 mL) and
washed with brine (5 mL). The combined organic layers were dried
over Na2SO4, filtered, and evaporated to dryness under reduced
pressure. The crude product was purified by flash chromatography
to give the title compound 27 as a colorless oil (1.37 g, 4.8 mmol,
90%).
1H NMR (200 MHz, CDCl3): d = 0.21 (s, 9 H), 3.22–3.05 (m, 1 H),
5.76 (s, 1 H), 7.21–7.09 (m, 1 H), 7.39–7.27 (m, 1 H), 7.57–7.48
(m, 1 H), 7.80–7.71 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = –0.1, 64.7, 92.1, 103.8, 123.2,
128.0, 128.8, 130.1, 133.1, 139.4.
Starting from alkyne 23 (30 mg, 0.2 mmol) and azidoalanine 29 (43
mg, 0.2 mmol), TBTA (10 mg, 0.02 mmol), CuBr (3 mg, 0.02
mmol), and CsF (90 mg, 0.6 mmol), the title compound 30 (86 mg,
0.2 mmol, 99%) was obtained as a colorless solid following General
Procedure C.
1H NMR (400 MHz, CD3OD): d (mixture of two diastereomers) =
1.36 (s, 4 H), 1.39 (s, 5 H), 4.31–4.24 (m, 1 H), 4.72–4.62 (m, 1 H),
4.84–4.76 (m, 1 H), 6.08 (s, 1 H), 7.12–7.02 (m, 3 H), 7.49–7.43
(m, 1 H), 7.64–7.57 (m, 1 H).
13C NMR (150 MHz, CD3OD): d = 28.7, 28.7, 53.0, 74.8, 80.5,
122.6, 122.6, 124.2, 124.3, 127.2, 127.3, 130.2, 151.3, 151.4, 154.4,
157.3, 175.0.
11B NMR (128 MHz, CD3OD): d = 10.2.
HRMS (ESI): m/z [M + Na]+ calcd for C17H21BN4O6: 411.1446;
found: 411.1447.
Benzoboroxole Amino Acid (31)
Benzoboroxole (28)
Starting from alkyne 23 (30 mg, 0.2 mmol), azidoalanine 29 (43 mg,
0.2 mmol), TBTA (10 mg, 0.02 mmol), CuSO4 (3 mg, 0.02 mmol),
sodium ascorbate (3 mg, 0.02 mmol), and CsF (90 mg, 0.6 mmol),
the title compound 31 (22 mg, 0.06 mmol, 30%) was obtained as a
colorless solid by following General Procedure B.
1H NMR (400 MHz, CD3OD): d = 1.33 (s, 9 H), 4.29 (t, J = 6.23,
4.19 Hz, 1 H), 4.63–4.57 (m, 1 H), 4.81 (br s, 1 H), 5.84 (br s, 1 H),
7.21 (t, J = 7.07 Hz, 1 H), 7.28 (t, J = 7.29 Hz), 7.38 (d,
J = 7.82 Hz, 1 H), 7.64 (br s, 1 H).
13C NMR (100 MHz, CD3OD): d = 28.7, 53.3, 57.2, 70.1, 80.5,
124.1, 127.8, 128.7, 129.3, 129.4, 144.1, 157.3.
HRMS (ESI): m/z [M + Na]+ calcd for C17H21BN4O6: 411.1446;
found: 411.1442.
Propargylic alcohol 27 (0.57 g, 2.0 mmol) was dissolved in abs. tol-
uene (10 mL) and cooled to –40 °C under an N2 atmosphere. With
1 h intervals, MeLi (5% in Et2O, 2.5 mL, 4.0 mmol), t-BuLi (1.7 M
in pentane, 2.4 mL, 4.0 mmol) and triisopropyl borate (2.3 mL, 10.0
mmol) were added. The mixture was allowed to warm to r.t. slowly
and stirred for 12 h. After dilution with EtOAc (20 mL), the organic
layer was washed with aq 1 M HCl (2 × 10 mL), dried over Na2SO4,
and the solvent was removed in vacuo to give a brown oil (0.50 g),
which was purified by flash chromatography (silica; n-hexane–
EtOAc, 4:1). The desired alkyne 28 (0.17 g, 0.7 mmol, 37%) was
isolated as a colorless solid as well as starting material (0.14 g, 0.5
mmol, 25%).
1H NMR (200 MHz, CDCl3): d = 0.19 (s, 9 H), 5.90 (s, 1 H), 7.58–
7.38 (m, 3 H), 7.80–7.74 (m, 1 H).
Amino Acid (32)
13C NMR (50 MHz, CDCl3): d = –0.1, 71.7, 91.6, 102.1, 122.1,
Starting from alkyne 23 (53 mg, 0.34 mmol), azidoalanine 29 (77
mg, 0.34 mmol), sodium ascorbate (7 mg, 0.03 mmol), CuSO4 (6
mg, 0.04 mmol), and CsF (260 mg, 1.71 mmol), the title compound
32 (31 mg, 0.08 mmol, 24%) was obtained as a colorless solid by
following General Procedure A.
128.2, 130.5, 131.9, 154.3.
11B NMR (128 MHz, CDCl3): d = 32.1.
HRMS (ESI): m/z [M – H]– calcd for C12H15BO2Si: 229.0862;
found: 229.0859.
Synthesis 2011, No. 24, 4059–4067 © Thieme Stuttgart · New York

4066
F. Wienhold et al.
PAPER
(9) (a) Mazik, M.; König, A. J. Org. Chem. 2006, 71, 7854.
1H NMR (600 MHz, CD3OD): d = 1.36 (s, 9 H), 4.36–4.33 (m, 1 H),
4.68–4.60 (m, 1 H), 4.86 (br s, 1 H), 5.89 (s, 1 H), 7.44–7.26 (m,
5 H), 7.69 (s, 1 H).
13C NMR (150 MHz, CD3OD): d = 28.9, 52.9, 57.1, 70.3, 80.6,
124.2, 127.8, 128.7, 129.5, 144.2, 152.5.
HRMS (ESI): m/z [M + H]+ calcd for C17H22N4O5: 363.1663; found:
363.1668.
(b) Mazik, M. ChemBioChem 2008, 9, 1015. (c) Mazik, M.
Chem. Soc. Rev. 2009, 38, 935. (d) Davis, A. P.; Wareham,
R. S. Angew. Chem. Int. Ed. 1999, 38, 2978. (e) Ferrand,
Y.; Crump, M. P.; Davis, A. P. Science 2007, 318, 619.
(f) Nativi, C.; Cacciarini, M.; Francesconi, O.; Vacca, A.;
Moneti, G.; Ienco, A.; Roelens, A. J. Am. Chem. Soc. 2007,
129, 4377.
(10) James, T. D.; Phillips, M. D.; Shinkai, S. Boronic Acids in
Saccharide Recognition; The Royal Society of Chemistry:
Cambridge, 2006.
(11) (a) Kuivila, H. G.; Keough, A. H.; Soboczenski, E. J. J. Org.
Chem. 1954, 19, 780. (b) Yoon, J.; Czarnik, A. W. J. Am.
Chem. Soc. 1992, 114, 5874. (c)James, T. D.; Sandanayake,
K. R. A. S.; Shinkai, S. Angew. Chem., Int. Ed. Engl. 1996,
35, 1910.
(12) (a) Norrild, J. C.; Eggert, H. J. Am. Chem. Soc. 1995, 117,
1479. (b) Bielecki, M.; Eggert, H.; Norrild, J. C. J. Chem.
Soc., Perkin Trans. 2 1999, 449.
(13) (a) Lauer, M.; Böhnke, H.; Grotstollen, R.; Salehnia, M.;
Wulff, G. Chem. Ber. 1985, 118, 246. (b) Collins, B. E.;
Sorey, S.; Hargrove, A. E.; Shabbir, S. H.; Lynch, V. M.;
Anslyn, E. V. J. Org. Chem. 2009, 74, 4055.
Benzoboroxole (34)
Starting from alkyne 23 (20 mg, 0.13 mmol) and 6-azido-D-galac-
tose 33 (36 mg, 0.13 mmol), TBTA (4 mg, 0.008 mmol), CuBr (2
mg, 0.01 mmol), and CsF (57 mg, 0.38 mmol), the title compound
34 (30 mg, 0.07 mmol, 54%) was obtained as a colorless solid by
following General Procedure C.
1H NMR (400 MHz, CDCl3): d (mixture of two diastereomers) =
1.40–1.22 (m, 9 H), 1.41–1.48 (s, 3 H), 3.91 (d, J = 2.5 Hz, 1 H),
4.20–4.12 (m, 2 H), 4.32–4.27 (m, 1 H), 4.44–4.35 (m, 1 H), 4.64–
4.52 (m, 2 H), 5.53–5.43 (m, 1 H), 6.44–6.40 (m, 1 H), 7.55–7.30
(m, 4 H), 7.89–7.76 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 24.4, 24.5, 25.0, 26.0, 26.0, 50.6,
67.2, 67.2, 70.5, 70.8, 71.2, 76.3, 76.5, 96.3, 109.2, 110.0, 110.0,
121.9, 122.6, 122.7, 122.7, 127.9, 128.2, 128.9, 129.2, 130.4, 130.6,
131.3, 131.4, 148.0, 148.1, 148.2, 155.3, 155.4.
(14) (a) Dowlut, M.; Hall, D. G. J. Am. Chem. Soc. 2006, 128,
4226. (b) Berube, M.; Dowlut, M.; Hall, D. G. J. Org. Chem.
2008, 73, 6471. (c) Pal, A.; Berube, M.; Hall, D. G. Angew.
Chem. Int. Ed. 2010, 49, 1492.
11B NMR (128 MHz, CDCl3): d = 32.8.
HRMS (ESI): m/z [M + H]+ calcd for C21H26BN3O7: 444.1937;
(15) (a) Edwards, N. Y.; Sager, T. W.; McDevitt, J. T.; Anslyn,
E. V. J. Am. Chem. Soc. 2007, 129, 13575. (b) Pal, A.;
Bérubé, M.; Hall, D. Angew. Chem. Int. Ed. 2010, 49, 1492.
(c) Duggan, P. J.; Offermann, D. A. Tetrahedron 2009, 65,
109. (d) Zou, Y.; Broughton, D. L.; Bicker, K. L.;
Thompson, P. R.; Lavigne, J. J. ChemBioChem 2007, 8,
2048. (e) Levonis, S. M.; Kiefel, M. J.; Houston, T. A.
Chem. Commun. 2009, 2278.
found: 444.1940.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
(16) Wright, A. T.; Zhong, Z.; Anslyn, E. V. Angew. Chem. Int.
Ed. 2005, 44, 5679.
Support by the DFG is gratefully acknowledged.
(17) (a) Pannier, N.; Maison, W. Eur. J. Org. Chem. 2008, 2008,
1278. (b) Humblet, V.; Misra, P.; Bhushan, K. R.; Nasr, K.;
Ko, Y.-S.; Tsukamoto, T.; Pannier, N.; Frangioni, J. V.;
Maison, W. J. Med. Chem. 2009, 52, 544. (c) Nasr, K.;
Pannier, N.; Frangioni, J. V.; Maison, W. J. Org. Chem.
2008, 73, 1056. (d) Maison, W.; Frangioni, J. V.; Pannier,
N. Org. Lett. 2004, 6, 4567.
References
(1) (a) Trippier, P. C.; McGuigan, C. Med. Chem. Commun.
2010, 1, 183. (b) Touchet, S.; Carreaux, F.; Carboni, B.;
Bouillon, A.; Boucher, J.-L. Chem. Soc. Rev. 2011, 40, 3895.
(2) (a) Nicolaou, K. C.; Li, H.; Boddy, C. N. C.; Ramanjulu, J.
M.; Yue, T.-Y.; Natarajan, S.; Chu, X.-J.; Bräse, S.; Rübsam,
F. Chem. Eur. J. 1999, 5, 2584. (b) Nicolaou, K. C.; Boddy,
C. N. C.; Li, H.; Koumbis, A. E.; Hughes, R.; Natarajan, S.;
Jain, N. F.; Ramanjulu, J. M.; Bräse, S.; Solomon, M. E.
Chem. Eur. J. 1999, 5, 2602. (c) Nicolaou, K. C.; Koumbis,
A. E.; Takayanagi, M.; Natarajan, S.; Jain, N. F.; Bando, T.;
Li, H.; Hughes, R. Chem. Eur. J. 1999, 5, 2622.
(d) Nicolaou, K. C.; Mitchell, H. J.; Jain, N. F.; Bando, T.;
Hughes, R.; Winssinger, N.; Natarajan, S.; Koumbis, A. E.
Chem. Eur. J. 1999, 5, 2648. (e) Lee, D.; Taylor, M. S.
J. Am. Chem. Soc. 2011, 133, 3724.
(3) Lorand, J. P.; Edwards, J. O. J. Org. Chem. 1959, 24, 769.
(4) Roseman, S. J. Biol. Chem. 2001, 276, 41527.
(5) (a) Drickamer, K.; Taylor, M. E. Annu. Rev. Cell Biol. 1993,
9, 237. (b) Wallis, R. Immunobiology 2002, 205, 433.
(6) Dube, D. H.; Bertozzi, C. R. Nat. Rev. Drug Discovery 2005,
4, 477.
(7) (a) Pieters, R. J. Med. Res. Rev. 2007, 27, 796.
(b) Astronomo, R. D.; Burton, D. R. Nat. Rev. Drug
Discovery 2010, 9, 308.
(18) Fitzi, R.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1986, 25,
345.
(19) Malan, C.; Morin, C. J. Org. Chem. 1998, 63, 8019.
(20) (a) Huisgen, R.; Szeimies, G.; Möbius, L. Chem. Ber. 1967,
100, 2494. (b) Huisgen, R. Angew. Chem., Int. Ed. Engl.
1963, 2, 565. (c) Meldal, M.; Tornøe, C. W. Chem. Rev.
2008, 108, 2952. (d) Huisgen, R.; Szeimies, G. Chem. Ber.
1965, 98, 1153. (e) Huisgen, R. Pure Appl. Chem. 1989, 61,
613. (f) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew.
Chem. Int. Ed. 2001, 40, 2004.
(21) Schnurch, M.; Holzweber, M.; Mihovilovic, M. D.; Stanetty,
P. Green Chem. 2007, 9, 139.
(22) Panda, G.; Rao, N. V. Synlett 2004, 714.
(23) (a) Dai, C.; Cheng, Y.; Cui, J.; Wang, B. Molecules 2010, 15,
5768. (b) Scrafton, D. K.; Taylor, J. E.; Mahon, M. F.;
Fossey, J. S.; James, T. D. J. Org. Chem. 2008, 73, 2871.
(24) Jin, S.; Choudhary, G.; Cheng, Y.; Dai, C.; Li, M.; Wang, B.
Chem. Commun. 2009, 5251.
(25) (a) Wang, Q.; Chan, T. R.; Hilgraf, R.; Fokin, V. V.;
Sharpless, K. B.; Finn, M. G. J. Am. Chem. Soc. 2003, 125,
3192. (b) Chan, T. R.; Hilgraf, R.; Sharpless, K. B.; Fokin,
V. V. Org. Lett. 2004, 6, 2853.
(8) (a) Ernst, B.; Magnani, J. L. Nat. Rev. Drug Discovery 2009,
8, 661. (b) Yan, J.; Fang, H.; Wang, B. Med. Res. Rev. 2005,
25, 490.
Synthesis 2011, No. 24, 4059–4067 © Thieme Stuttgart · New York

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(26) Yang, J.; Fu, X.; Jia, Q.; Shen, J.; Biggins, J. B.; Jiang, J.;
Zhao, J.; Schmidt, J. J.; Wang, P. G.; Thorson, J. S. Org.
Lett. 2003, 5, 2223.
(27) Fitzi, R.; Seebach, D. Tetrahedron 1988, 44, 5277.
Synthesis 2011, No. 24, 4059–4067 © Thieme Stuttgart · New York