Enantiomeric excess of 1,2-diols by formation of cyclic boronates: An improved method

Article abstract of DOI:10.1016/j.tetasy.2005.08.008

A reliable method for determining the enantiomeric composition of 1,2-diols by the formation of diastereomeric cyclic esters with boronic acid is described. Starting from a previously reported structure of boronic chiral derivatizing agent (CDA), seven structurally related racemic CDAs were synthesized and their discriminating ability towards diols measured. The most promising amongst these was synthesized in its enantiomerically pure form according to Matteson's protocol for the stereoselective homologation of pinanediol boronates; this CDA quantitatively and rapidly reacts with 1,2-diols in very mild conditions affording a couple of diastereoisomers, whose composition can be determined via ¹H NMR analysis. In particular, an attractive feature is that the resonance used for the analysis originated from the CDA as a couple of baseline-separated singlets (Δδ up to 0.3 ppm) is useful for integration.

Full text of DOI:10.1016/j.tetasy.2005.08.008

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2918–2926
Enantiomeric excess of 1,2-diols by formation of cyclic
boronates: an improved method
Stefania Morandi, Emilia Caselli, Arrigo Forni, Maria Bucciarelli,
Giovanni Torre and Fabio Prati*
`
Dipartimento di Chimica, Universita di Modena e Reggio Emilia, Via Campi 183, 41100 Modena, Italy
Received 14June 2005; accepted 1 August 2005
Abstract—A reliable method for determining the enantiomeric composition of 1,2-diols by the formation of diastereomeric cyclic
esters with boronic acid is described. Starting from a previously reported structure of boronic chiral derivatizing agent (CDA), seven
structurally related racemic CDAs were synthesized and their discriminating ability towards diols measured. The most promising
amongst these was synthesized in its enantiomerically pure form according to MattesonÕs protocol for the stereoselective homo-
logation of pinanediol boronates; this CDA quantitatively and rapidly reacts with 1,2-diols in very mild conditions affording a
couple of diastereoisomers, whose composition can be determined via 1H NMR analysis. In particular, an attractive feature is that
the resonance used for the analysis originated from the CDA as a couple of baseline-separated singlets (Dd up to 0.3 ppm) is useful
for integration.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
romethyl acetates, mandelates, 2-phenylpropanoates)
are particularly suitable for diols: syntheses of bis-
MosherÕs esters, for instance, are especially susceptible
to kinetic resolutions, while substrate diols with inequiv-
alent OH functionalities give two sets of NMR marker
peaks in narrow regions of the 1H and 19F NMR
spectra.
Boronic acids and boronates play an important role in
many fields of chemical research and technology because
of their application in synthetic organic chemistry1,2
(including stereoselective synthesis),3–5 enzyme inhibi-
tion,6,7 carbohydrate recognition,8 transmembrane
transport9 and separation of glycoproteins.10 Several
of these diverse fields of application are due to the abil-
ity of boronic acids to bind hydroxyl groups, and in par-
ticular to form reversible cyclic esters11 with diols. The
ubiquitous presence of a stereodefined diol moiety in
biomolecules, drugs12 and synthetic intermediates,13,14
highlights the potential of boronic acids for the isolation
and characterization15–18 of this class of compounds.
Chiral boronic acids, bearing a single functional group
capable of reacting with both hydroxyl groups of several
diols avoid both of these problems, giving rise to a dia-
stereomeric mixture of cyclic esters whose composition
can be assessed by NMR techniques. The first report
on such a use of chiral boronic acids belongs to Tokles
and Snyder,15 who measured the anisochronies of the
13C nucleus,13 while later Burgess16 reported useful, even
1
In this respect, enantiomerically pure boronic acids
could be reliable chiral derivatizing agents (CDAs) for
the determination of the enantiomeric composition of
though very low, anisochronies in the H NMR spec-
trum. Typically, a Dd of 10 ppb at 400 MHz was
detected. More recently,19 we have shown that (S)-(+)-
N-acetylphenylglycineboronic acid 1 (Scheme 1), when
reacted with racemic diols, gave rise to a diastereomeric
couple showing baseline resolved peaks with remarkably
high Dd values (70–220 ppb) under routine conditions
(200 MHz, CDCl3), thus allowing the ee determination
of the starting diol. Unfortunately, we observed such a
separation only for the signals originating from the diol,
while very poor or no separation at all were detected for
1
optically active diols via H NMR analysis.15,16,19 In
fact, the point has been well made16,20 that none of the
widely diffused methods for the NMR determination
of ee of alcohols (formation of methoxyphenyltrifluo-
*
Corresponding author. Tel.: +39 0592055056; fax: +39 059373543;
e-mail: prati.fabio@unimore.it
0957-4166/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.08.008

S. Morandi et al. / Tetrahedron: Asymmetry 16 (2005) 2918–2926
2919
(Scheme 1) suggested that the resonance of a group in
this aromatic position should be sensitive to the stereo-
chemical arrangement of the diol, possibly affording the
splitting of its signals. Furthermore, since the methyl
group of (S)-(+)-1 never displayed the desired separa-
tion (only a broadening of the signal was generally
recorded),19 we also planned to evaluate the properties
of benzamides 4–6, aiming to enhance the magnetic
anisotropy of the CDA. Finally, according to a common
way of improving the discrimination of diastereoiso-
meric derivatives,22 we included compounds 7 and 8,
where the more sterically demanding a- or b-naphthyl
groups were introduced, respectively.
H
N
H
N
R
*
HO
H
O
B
O
B
O
O
OH
HO OH
H
R
*
( )
(S)-(+)-1
Scheme 1. Formation of cyclic boronate by reaction of (S)-(+)-1 with
racemic 1,2-diols; the molar composition of the diastereomeric pair can
be determined by 1H NMR analysis.
those from the CDA. Since, for general application of
the proposed method, a marker peak on the CDA is
an attractive feature, we were prompted to develop
new boronic CDAs structures related to (S)-(+)-1. Here-
in, we report the results of our efforts to improve (S)-
(+)-1, allowing the identification of a reliable derivatiz-
ing agent for 1,2-diols.
The next step in this study was the synthesis of the
selected structures 1–8. The first screening of their dis-
criminating ability towards chiral diols was easily evalu-
ated on racemic compounds, which were synthesized
according to Scheme 2, starting from commercially
available arylboronic acids 9–13, which were first pro-
tected as pinacol esters. These cyclic boronates 9a–13a
were obtained in nearly quantitative yields by simple
exposure to an equimolar amount of pinacol (a) in dry
THF, once more confirming the high affinity of boronic
acids for 1,2-diols.
2. Results and discussion
A rational design of new structures derived from 1 sug-
gested retaining its key features, that is, a stereocentre
adjacent to the boron atom bearing an aromatic ring
and an electron-withdrawing group, namely an amide.
This latter is known to stabilize the boronate by intra-
molecular coordination of the carbonyl oxygen to the
electrophilic boron atom,21 thus favouring its esterifica-
tion with the diol.11 Aiming to obtain a marker peak
(possibly as narrow singlet) on our CDA, we reasoned
that a methyl or methoxy group could be conveniently
introduced onto the phenyl ring. Structures 2 and 3 were
therefore selected as first choice (Fig. 1). This idea was
corroborated by NOESY experiments performed on
diastereomeric mixtures derived from the reaction of
(S)-(+)-1 with diols.19 The observed proximity of the
ortho-phenyl hydrogen with the diol CHO proton
These esters are characterized by a moderate stability,
allowing chromatographic purification of the intermedi-
ates and removal of the protecting group at the end of
the synthetic sequence. The well-known homologation
of boronates3–5 was selected as the reaction of choice
to install the stereogenic carbon atom. The addition of
in situ-generated (dichloromethyl)lithium to boronate
at ꢀ100 °C in anhydrous THF resulted in a chain exten-
sion to the a-chloro derivative, which was not isolated,
but in situ treated with lithium bis-trimethylsilylamide
followed by addition of the selected acylating agent (ace-
tic anhydride/acetic acid or benzoylchloride/benzoic
acid). Chromatographic purification of the crude reac-
tion mixture allowed the isolation of the expected pina-
col boronates 1a–8a as white solids, stable on the
laboratory shelf for months, in 24–78% overall yield
from arylboronates. All physical and spectroscopic
characterizations of compounds 1a–8a confirmed the
expected structure; in particular, 13C NMR spectra
(H-decoupled) displayed a typical signal at 45–66 ppm
with high multiplicity, which can be accounted for the
newly inserted stereogenic centre, broadened by the cou-
pling with the adjacent boron atom. A correlation with a
singlet at 3.6–4.7 ppm in 1H NMR spectra (COSY
experiments) confirmed this attribution. Interestingly,
these latter spectra exhibited high nonequivalences of
the pinacol methyl signals (ranging from Dd 60 ppb
observed for 3a, up to 210 ppb for 7a), thus indicating
a marked magnetic anisotropy of the two faces of the
[1,3,2]oxaborolidine.
MeO
H
H
H
N
N
N
O
B
O
B
O
B
HO
OH
HO
OH
HO
OH
1
2
3
MeO
H
N
H
H
Ph
N
Ph
Ph
N
Ph
O
B
O
B
O
HO
B
HO
OH
HO
OH
OH
4
5
6
H
H
N
Removal of the protecting pinacol was first performed
in aqueous 3 M HCl at 100 °C for 1 h, following a
procedure already described.23 This method provided
good yields (68–89%) only in the recovery of acetamides
1–3, whilst disappointing yields (22–45%) or even
complete degradation was observed for benzamido
N
O
HO
B
O
B
OH
HO
OH
7
8
Figure 1. Structures of the designed CDA.

2920
S. Morandi et al. / Tetrahedron: Asymmetry 16 (2005) 2918–2926
H
R
N
Ar
O
Cl
Ar
O
O
O
O
B
B
c,d
OH
OH
b
a
O
O
Ar
B
Ar
B
9-13
9a-13a
1a-8a
e
Ar =
H
N
OMe
9
10
11
R
Ar
O
B
HO
OH
1-8
12
13
Scheme 2. Reagents and conditions: (a) Pinacol, THF, rt; (b) (dichloromethyl)lithium, THF, ꢀ100 °C ! rt; (c) lithium bis(trimethylsilyl)amide,
THF, ꢀ78 °C ! rt; (d) Ac2O/AcOH or PhCOCl/PhCOOH, THF, ꢀ78 °C ! rt; (e) aqueous HCl 10%, 1 h, 100 °C or HCl 4M in MeOH, 1 h, rt.
derivatives 4–6 and naphthyl derivatives 7 and 8, respec-
tively. Several other methods proposed in the litera-
ture3–7,24 for boronate hydrolysis were therefore tried,
and we experienced that the best results, combined with
the mild conditions, were obtained performing an
alcoholysis in methanolic 4M HCl for 1 h at room
temperature, followed by treatment with water. Com-
the absence of any p system on the diol, and conse-
quently the very low induced magnetic anisotropy,
makes them ideal probes to test our CDAs. In fact, if
a separation of the CDA marker peak was detected
for their diastereoisomeric derivatives, higher separa-
tions were likely to be expected for more complex diols,
bearing for instance a phenyl or a carbonyl group, such
as in d–f (Scheme 3).
1
pounds 4–8 were recovered in 82–87% yield. H NMR
and 13C NMR of compounds 1–8 were consistent with
the structures, even though elemental analyses and mass
spectra were unsatisfactory.25 This fact was likely due
to the known easy formation of polymeric anhydride
(often as cyclic trimer), typical of boronic acids. In
fact, simple exposure of these acids to a stoichiometric
amount of pinacol a in dry THF always afforded the
expected boronates 1a–8a in quantitative yields (Scheme
3).
Derivatization of ( )-b,c with ( )-1–8 was simple. The
diol (20–30 mg) was added to a solution of a slight
excess (5%) of a freshly prepared CDA sample in anhy-
drous THF and the resulting solution allowed to react
for 1 h at room temperature. After solvent removal
and desiccation over P2O5 at 2 mmHg for 12 h, the res-
idue was dissolved in CDCl3 and the 1H NMR spectrum
recorded (200 MHz). In most cases, the excess of the
boronic acid was not a problem. When occasionally an
overlap of the signal related to the marker peak of the
unreacted CDA with those of the diastereoisomeric
esters was observed, unreacted CDA was easily sepa-
rated loading the crude mixture on a short silica gel col-
umn and eluting with dichloromethane. The most
representative inequivalences (Dd, ppb) measured for
We were therefore ready to evaluate the discriminating
ability of the synthesized boronic acids towards racemic
1,2-diols. Since our specific aim was to obtain a CDA
with a marker peak, for the first screening, we selected
two very simple molecules, namely ( )-1,2-propanediol
b (Scheme 3) and ( )-3,3-dimethyl-1,2-butanediol c:
H
H
R
N
Ar
O
R
N
Ar
HO
HO
O
B
O
B
O
HO
OH
(1a-g)-(8a-g)
1-8
a-g
Ph
HO
HO
HO
HO
HO
OH
Ph
OH
OH
c
OH
d
a
b
HO
HO
COOMe
COOMe
=
Ph
HO
HO
OH
OH
OH
e
f
g
Scheme 3. Derivatization of racemic diols a–g with CDA 1–8.

S. Morandi et al. / Tetrahedron: Asymmetry 16 (2005) 2918–2926
2921
corresponding nuclei of each diastereomeric couple 1b–
8b and 1c–8c are summarized in Table 1.
respectively (entries 5–7; 13–15). Unfortunately, a non-
baseline resolution of these peaks for 6 (methoxy group)
and 7 (acetyl group) was observed, as a consequence of a
marked broadening of the signals. This feature was also
retained in different solvents, such as C6D6 or d6-DMSO
and forced us to abandon these structures for further
developments. CDA 5 showed baseline resolved peaks
in both derivatives 5b and 5c, with a satisfactory shape
of the signals (a line width <2 Hz was recorded), suitable
for integration; hence, asymmetric synthesis of enantio-
merically pure 5 was performed.
Table 1. Inequivalences (Dd in ppb) measured in the 1H NMR spectra
recorded at 200 MHz in CDCl3 for the diastereoisomeric pairs 1b–8b
and 1c–8c
Diol
Entry CDA Compound Nonequivalences (ppb)
OH
On diol
CH2O
On CDA
OH
R
R
b (R = Me)
1
2
1
2
1b
2b
100 160
60 100
80 —
—
10 (Me)
—
3 b 33
The synthetic strategy relied again on MattesonÕs
homologation of boronates, but this time pinanediol h
was selected as the esterifying alcohol (Scheme 4). In
fact, it is well known3–5,26 that the stereochemical course
of the homologation reaction is strictly controlled by the
(+)- or (ꢀ)-pinanediol, which selectively induces the (S)-
or (R)-absolute configuration, respectively, at the newly
inserted chlorine-bearing carbon atom.
4
5
6
7
8
4
5
6
7
8
4b
5b
6b
7b
8b
70 180
60 110
70 100
230 320
100 160
—
50 (Me)
30 (OMe)
30 (Ac)
10 (Ac)
c (R = tBu)
9
10
1
2
1c
2c
200
160 200
—
—
—
11 c 33
150
150
150 200
160 130
300 360
—
—
10 (OMe)
—
50 (Me)
10 (OMe)
50 (Ac)
—
12
13
14
15
16
4
5
6
7
8
4c
5c
6c
7c
8c
Therefore, 2-methylphenylboronic acid 10 was treated in
anhydrous THF with an equimolar amount of (+)-
pinanediol and the resulting ester (ꢀ)-10h subjected to
the same reaction sequence described for the synthesis
of racemic 5a: (+)-5h (de >98%) was isolated in 44%
overall yield. The diastereoselectivity of the homologa-
tion was determined by using the Hendo proton26 of the
pinanyl moiety (1.17 ppm, doublet) as a diagnostic mar-
ker. Since (+)-pinanediol stereoselectively induces the
formation of (S)-a-chloroboronic esters,3,26 and nucleo-
philic displacement occurs with clean inversion of con-
figuration, the (R)-absolute configuration could be
assigned to (+)-5h. Final hydrolysis with 3 M HCl affor-
ded (R)-(+)-5 in 54% yield as a white solid, which could
be stored for an indefinite time at room temperature
under argon. It is worth noting that, even though harsh
conditions were required for the removal of the pinane-
diol, no racemization occurred during the hydrolysis: in
fact, a sample of (R)-(+)-5 exposed to a small excess of
(+)-pinanediol, afforded (+)-5d in quantitative yield and
de >98%. Moreover, since pinanediol is also commer-
cially available in the laevorotatory form, both enantio-
mers of 5 can be synthesized.
190
—
As already reported for CDA 1,19 high inequivalences
(Dd 60–360 ppb) and baseline resolved peaks were gener-
ally observed for the diol signals for all derivatives. In
this respect, comparing the performances of CDAs 2–8
with 1, the insertion of the methyl or methoxyl group
on the phenyl ring of 1, leading to CDAs 2 and 3,
respectively, resulted in slightly worse separations
(entries 2 and 3 vs 1; entries 10 and 11 vs 9), while the
substitution of the acetyl moiety of 1–3 with the benzoyl
(CDAs 4–6) did not significantly affect the inequiva-
lences (entries 4–6 vs 1–3; entries 12–14 vs 9–11). Con-
versely, CDA
7 showed a marked increase of
stereoisomer-differentiation (entry 7 vs 1; entry 15 vs
9), due to the strong magnetic anisotropy induced by
the sterically demanding a-naphthyl group; it is worth
noting that the b-naphthyl group of CDA 8 did not
affect the separations (entry 8 vs 1; entry 16 vs 9) at all.
Most importantly, inequivalencies were also displayed
in some instances for reagent-derived resonances: even
though lower (Ddmax 50 ppb) with respect to those from
the diol, useful separations were in fact measured for the
methyl, methoxy and acetyl groups of CDAs 5–7,
With enantiomerically pure (+)-5 in hand, we analyzed
several racemic diols b–g, including sterically hindered
e and C2-symmetry f, g compounds. Following the pro-
cedure already described for racemic CDA, cyclic boro-
nates were obtained and the spectra recorded at 200
H
N
Ph
H
e
a
b,c,d
Ph
N
O
B
HO
O
O
O
B
B
O
B
HO OH
OH
O
(R)-(+)-5
10
10h
5h
Scheme 4. Reagents and conditions: (a) (1S,2S,3R,5S)-(+)-Pinanediol, THF, rt; (b) (dichloromethyl)-lithium, THF, ꢀ100 °C ! rt; (c) lithium
bis(trimethylsilyl)amide, THF, ꢀ78 °C ! rt; (d) PhCOCl/PhCOOH, THF, ꢀ78 °C ! rt; (e) aqueous HCl 10%, 1 h, 100 °C.

2922
S. Morandi et al. / Tetrahedron: Asymmetry 16 (2005) 2918–2926
H
N
H
H
N
Ph
Ph
N 50
90
B
Ph
50 (60)
O
B
O
B
110 (130)
Ph
50 (70)
O
O
O
O
O
O
O
170
110
5b
200
t-Bu
150
60
40
5c
5d
H
N
H
H
30
B
Ph
Ph
N
40
B
Ph
N
10 (40)
O
B
O
O
80 (320)
50 (50)
O
O
O
O
O
O
70
H3COOC
80
Ph
Ph
COOCH3
50
70
120
5e
5f
5g
Figure 2. Inequivalencies (in ppb) useful for de determinations observed for racemic diols derivatized with (R)-(+)-5. The reported values are
measured in the 1H NMR spectra in CDCl3 (in brackets the values in C6D6) at 200 MHz.
and 400 MHz, CDCl3 and C6D6 as solvents. Baseline
resolved peaks useful for ee determination were generally
displayed by diol signals at the lowest magnetic field in
chloroform, without sensitive improvement for spectra
recorded in C6D6. The most significant Dd values are
shown in Figure 2. Useful separations were also observed
for signals generated from the CDA, as shown in Figure
increased to 40–320 ppb in C6D6, thus indicating that
this group can be conveniently used as a probe signal
for the de determination of the diastereoisomeric pair.
These values, when compared with those already
reported in the literature,16 represent a significant
improvement in the separation of the reagent-derived
signals and further demonstrate the usefulness of this
technique for the ee determination of 1,2-diols. In fact,
even if direct chromatographic analyses by enantioselec-
tive GC or HPLC are ideal, a chemical derivatization of
the diol sample has generally has to be carried out,14 due
to the low vapour pressure (GC) or weak absorption in
UV–vis region (HPLC). The proposed 1H NMR method
combines efficient derivatization in very mild conditions
with remarkable stereoisomer discrimination.
1
3, where expanded regions of the H NMR spectrum
(400 MHz) of the diastereomeric pair 5e are considered.
3. Conclusion
In summary, we have shown that the enantiomeric com-
1
position of 1,2-diols can be conveniently assessed by H
NMR analysis of their cyclic boronates, easily and
quantitatively obtained by simple exposure of the diol
to the boronic acid (R)-(+)-5. This latter is obtainable
in both enantiomerically pure forms by stereoselective
homologation of commercially available 2-methyl-
phenylboronic acid. The crude product can be conve-
1
niently analyzed by H NMR: high inequivalencies are
observed not only for the diol signals, but most impor-
tantly, resonance used for the analysis originated from
the CDA as a couple of baseline-separated singlets.
Figure 3. 1H NMR spectrum (CDCl3, 400 MHz) of the diastereoiso-
meric pair 5e. Spectral regions relative to the resonances of CH–CH3
(I), CHB (II), CH3Ph (III) and CH3–CH (IV).
4. Experimental
4.1. General
1H and 13C NMR spectra were recorded on a Bruker
DPX-200 or Avance 400 spectrometer; chemical shifts
The inequivalencies measured for the reference signal
(CH3Ph) were Dd 10–110 ppb in chloroform and

S. Morandi et al. / Tetrahedron: Asymmetry 16 (2005) 2918–2926
2923
(d) are reported in ppm downfield from TMS as internal
standard (s singlet, d doublet, t triplet, q quartet, m mul-
tiplet, br broad signal); coupling constants (J) are given
in hertz. Two-dimensional NMR techniques (COSY,
HMBC and HSQC) were utilized to aid in the assign-
(8%), 161 (28%), 134(100%), 118 (12%), 105 (48%), 91
(65%), 77 (13%). Anal. Calcd for C13H19BO3: C, 66.70;
H, 8.18. Found: C, 66.52; H, 8.11.
4.2.4. Pinacol 1-naphthylboronate 12a. Yield: 99%, mp
51–52 °C. 1H NMR (CDCl3): d 1.44 (12H, s, CH3),
7.43–7.60 (3H, m, arom), 7.84 (1H, dd, J = 8.3,
1.9 Hz, arom), 7.94(1H, d, J = 8.3 Hz, arom), 8.09
(1H, dd, J = 6.8, 1.4Hz, arom), 8.77 (1H, d,
J = 8.0 Hz, arom). 13C NMR (CDCl3): d 26.3, 85.1,
126.3, 126.8, 127.7, 129.7, 129.8, 132.9, 134.6, 137.0,
138.3 (C–B not seen). EI-MS: m/z 254(69%, M +), 239
(12%), 210 (15%), 196 (12%), 181 (19%), 168 (38%),
154(100%), 127 (12%), 85 (6%), 57 (5%). Anal. Calcd
for C16H19BO2: C, 75.62; H, 7.54. Found: C, 75.79; H,
7.50.
1
ment of signals in H and 13C spectra, in particular for
CDA (+)-5. Mass spectra were determined on a Finni-
gan MAT SSQ A mass spectrometer (EI, 70 eV). Melt-
ing points were obtained on a Gallenkamp apparatus.
Optical rotations were recorded at +20 °C on a Per-
kin–Elmer 241 polarimeter and specific rotations are in
10ꢀ1 deg cm2 gꢀ1
.
All reactions requiring anhydrous conditions were per-
formed under argon using oven-dried glassware. Sol-
vents (THF and diethyl ether) were dried according to
classical procedures and distilled from Na and benzo-
phenone before use. Temperature of ꢀ100 °C was
reached by addition of liquid nitrogen to a pre-cooled
(ꢀ78 °C) bath containing an 1:1 EtOH–MeOH mixture.
4.2.5. Pinacol 2-naphthylboronate 13a. Yield: 96%, mp
62–65 °C. 1H NMR (CDCl3): d 1.42 (12H, s, CH3),
7.45–7.59 (2H, m, arom), 7.80–7.97 (4H, m, arom),
8.41 (1H, s, H1 arom). 13C NMR (CDCl3): d 24.9,
83.9, 125.8, 126.9, 127.7, 127.9, 128.6, 130.4, 132.9,
135.1, 136.2 (C–B not seen). EI-MS: m/z 254(58%,
M+), 239 (12%), 168 (88%), 154(100%), 128 (10%),
120 (12%), 85 (16%). Anal. Calcd for C16H19BO2: C,
75.62; H, 7.54. Found: C, 75.73; H, 7.63.
Chromatographic purification of the compounds was
accomplished on silica gel (0.05–0.20 mm). Arylboronic
acids 9–13 were purchased from Sigma–Aldrich.
4.2. General procedure for the synthesis of pinacol
arylboronates 9a–13a
4.3. General procedure for the synthesis of ( )-pinacol
methaneboronates 1a–8a
A selected boronic acid 9–13 (3.4mmol) and pinacol
(3.4mmol) were dissolved in anhydrous Et 2O; the mix-
ture was stirred for 1 h at rt and concentrated under
reduced pressure. The crude product was purified by
distillation or by chromatography (3:7 EtOAc–EtPet),
yielding the ester in the form of white crystalline solid.
n-BuLi (2.5 M solution in hexane, 3.3 mmol) was added
dropwise to a solution of CH2Cl2 (4.1 mmol) in THF
(3 mL) while being stirred at ꢀ100 °C under argon:
LiCHCl2 precipitated as a white microcrystalline solid.
After 30 min, the mixture was treated with the selected
pinacol arylboronate 9a–13a (2.6 mmol) and allowed
to reach rt overnight. LiN(TMS)2 (1 M solution in
THF, 2.6 mmol) was added at ꢀ78 °C, and the reaction
mixture then allowed to warm gradually. After 16 h at
rt, the mixture was re-cooled at ꢀ78 °C and treated with
the proper acylating agent, allowed to reach rt and stir-
red overnight. In the case of acetamido derivatives 1a–
3a, 7a and 8a, the acylating mixture was a solution of
Ac2O/AcOH (8.5/3.1 mmol) in THF (2 mL), whilst a
solution of benzoylchloride/benzoic acid (6.2/3.1 mmol)
in THF (3 mL) was used for benzamido derivatives 4a–
6a. The resulting solution was partitioned between
EtOAc (45 mL) and H2O (20 mL), the organic phase
dried over MgSO4 concentrated in vacuo affording the
crude product, which was purified by chromatography
(Et2O–MeOH 95:5 or 9:1 for acetamido derivatives;
EtOAc–EtPet 7:3 or 1:1 for benzamido derivatives).
4.2.1. Pinacol phenylboronate 9a. Yield: 95%, mp 27–
1
28 °C, bp 100–102 °C/8 mmHg. H NMR (CDCl3): d
1.38 (12H, s, CH3), 7.33–7.53 (3H, m, arom), 7.84
(2H, dd, J = 8.0, 2.0 Hz, arom). 13C NMR (CDCl3): d
25.2, 84.1, 128.0, 131.6, 135.1 (C–B not seen). EI-MS:
m/z 204(17%, M +), 198 (55%), 118 (62%), 105 (100%),
77 (15%), 43 (48%). Anal. Calcd for C12H17BO2: C,
70.63; H, 8.40. Found: C, 70.77; H, 8.61.
4.2.2. Pinacol 2-methylphenylboronate 10a. Yield: 93%,
colourless viscous liquid which slowly solidified in the
1
refrigerator. H NMR (CDCl3): d 1.39 (12H, s, CH3),
2.60 (3H, s, PhCH3), 7.15–7.28 (2H, m, arom), 7.31–
7.43 (1H, m, arom), 7.78–7.88 (1H, m, arom). 13C
NMR (CDCl3): d 22.2, 24.9, 83.4, 124.7, 129.8, 130.8,
135.9, 144.8 (C–B not seen). EI-MS: m/z 218 (7%,
M+), 203 (7%), 119 (100%), 161 (37%), 132 (10%), 91
(23%), 65 (27%), 43 (96%). Anal. Calcd. for
C13H19BO2: C, 71.59; H, 7.78. Found: C, 71.41; H, 7.73.
4.3.1. Pinacol ( )-1-acetamido-1-phenylmethaneboronate
1a. After chromatography (Et2O–MeOH 9:1), 1a was
obtained as a white solid, mp 184–187 °C, in 60% yield.
1H NMR (CDCl3): d 0.85 (6H, s, CH3), 0.98 (6H, s,
CH3), 2.05 (3H, s, COCH3), 3.62 (1H, s, CHB), 7.02
(2H, d, J = 6.8 Hz, H2 arom), 7.09–7.26 (3H, m, H3,4
arom), 9.59 (1H, br s, NH). 13C NMR (CDCl3): d
17.5, 24.8, 25.2, 52.9 (br, CB), 80.9, 126.0, 127.0,
128.2, 141.1, 176.8. EI-MS: m/z 275 (56%, M+), 260
(13%), 217 (19%), 175 (48%), 150 (60%), 131 (100%),
4.2.3. Pinacol 2-methoxyphenylboronate 11a. Yield:
1
97%, mp 80–81 °C. H NMR (CDCl3): d 1.37 (12H, s,
CH3), 3.84(3H, s, OC H3), 6.87 (1H, d, J = 8.3 Hz, H3
arom), 6.97 (1H, t, J = 7.2 Hz, H5 arom), 7.40 (1H, dt,
J = 8.3, 1.8 Hz, H4 arom), 7.69 (1H, dd, J = 7.2, 1.8
Hz, H6 arom). 13C NMR (CDCl3): d 24.8, 55.8, 83.4,
110.5, 120.2, 132.4, 136.7, 164.2 (C–B not seen). EI-
MS: m/z 234(55%, M +), 219 (23%), 203 (10%), 176

2924
S. Morandi et al. / Tetrahedron: Asymmetry 16 (2005) 2918–2926
118 (69%), 106 (51%), 91 (28%), 84(29%), 77 (26%), 55
(21%), 43 (90%). Anal. Calcd for C15H22BNO3: C,
65.48; H, 8.06; N, 5.09. Found: C, 65.66; H, 8.31; N,
5.01.
127.5, 128.2 (2C), 128.7 (2C), 130.0, 133.4, 134.9,
139.1, 171.6. EI-MS: m/z 351 (61%, M+), 336 (6%),
293 (22%), 251 (13%), 224 (16%), 207 (43%), 145
(13%), 105 (100%), 77 (46%). Anal. Calcd for
C21H26BNO3: C, 71.81; H, 7.46; N, 3.99. Found: C,
72.03; H, 7.69; N, 4.13.
4.3.2. Pinacol ( )-1-acetamido-1-(2-methylphenyl)meth-
ane-boronate 2a. Column chromatography (Et2O–
MeOH 95:5) afforded 2a in the form of a white solid,
mp 138–140 °C, in 78% yield. 1H NMR (CDCl3): d
0.94(6H, s, C H3), 1.07 (6H, s, CH3), 2.14(3H, s,
COCH3), 2.32 (3H, s, PhCH3), 4.06 (1H, s, CHB),
6.97–7.18 (4H, m, arom), 7.97 (1H, br s, NH). 13C
NMR (CDCl3): d 18.0, 19.8, 24.5, 24.9, 47.5 (br, CB),
80.8, 125.5, 125.8, 126.3, 129.9, 134.7, 138.8, 176.0. EI-
MS: m/z 289 (50%, M+), 274(12%), 231 (23%), 189
(15%), 164(36%), 145 (100%), 120 (31%), 104(58%),
93 (12%), 91 (19%). Anal. Calcd for C16H24BNO3: C,
66.45; H, 8.37; N, 4.84. Found: C, 66.28; H, 8.46; N,
4.94.
4.3.6. Pinacol ( )-1-benzamido-1-(2-methoxyphenyl)-
methane-boronate 6a. Chromatography (light petro-
leum–ethyl acetate 3:7) afforded the title compound 6a
as a pale yellow viscous oil, 26% yield. 1H NMR
(CDCl3): d 1.02 (6H, s, CH3), 1.08 (6H, s, CH3), 3.69
(3H, s, OCH3), 4.42 (1H, d, J = 1.9 Hz, CHB), 6.73–
6.88 (2H, m, H2 disubstituted Ph), 7.05–7.17 (2H, m,
H3,H5 disubstituted Ph), 7.32–7.57 (3H, m, H4, H6 disub-
stituted Ph, H4 monosubstituted Ph), 7.88–7.97 (2H, m,
H2 monosubstituted Ph), 9.01 (1H, br s, NH). 13C
NMR (CDCl3): d 24.5, 24.8, 45.0 (br, CB), 55.0, 82.7,
109.9, 120.3, 126.6, 127.1, 127.5, 127.88, 127.9, 128.5,
129.7, 131.7, 133.0, 156.6, 171.4. EI-MS: m/z 367 (63%,
M+), 352 (18%), 309 (31%), 267 (27%), 161 (20%), 148
(75%), 133 (53%), 105 (100%), 91 (41%), 77 (31%), 55
(23%). Anal. Calcd for C21H26BNO4: C, 68.68; H, 7.14;
N, 3.81. Found: C, 68.51; H, 7.04; N, 4.00.
4.3.3. Pinacol ( )-1-acetamido-1-(2-methoxyphenyl)-
methane-boronate 3a. Chromatography (Et2O–MeOH
95:5) afforded 3a as a white solid, mp 136–137 °C, in
25% yield. 1H NMR (CDCl3): d 1.11 (6H, s, CH3),
1.17 (6H, s, CH3), 2.13 (3H, s, COCH3), 3.81 (3H, s,
OCH3), 4.38 (1H, d, J = 3.4Hz, C HB), 6.79 (1H, br s,
NH), 6.83 (1H, dt, J = 8.1, 1.0 Hz, H3 arom), 6.91
(1H, dd, J = 7.5, 1.0 Hz, H5 arom), 7.18 (1H, dt,
J = 8.1, 1.7 Hz, H4 arom), 7.31 (1H, dd, J = 7.5, 1.7
Hz, H6 arom). 13C NMR (CDCl3): d 19.0, 25.8, 26.1,
46.0 (br, CB), 56.2, 82.1, 111.1, 121.7, 127.8, 128.6,
130.9, 157.1, 177.1. EI-MS: m/z 305 (88%, M+), 290
(12%), 262 (8%), 247 (23%), 205 (12%), 190 (12%), 178
(27%), 161 (17%), 148 (100%), 133 (62%), 117 (23%),
91 (30%), 77 (19%), 55 (18%). Anal. Calcd for
C16H24BNO4: C, 62.97; H, 7.93; N, 4.59. Found: C,
63.15; H, 7.81; N, 4.79.
4.3.7. Pinacol ( )-1-acetamido-1-(naphth-1-yl)methane-
boronate 7a. Purification by column chromatography
(diethyl ether–methanol 95:5) of the crude residue affor-
1
ded 7a as a white solid, mp 217–218 °C, 38% yield. H
NMR (CDCl3): d 0.86 (6H, s, CH3), 1.07 (6H, s,
CH3), 2.23 (3H, s, COCH3), 4.73 (1H, s, CHB), 7.24–
7.52 (5H, m, NH and arom), 7.68 (1H, d, J = 7.7 Hz,
arom), 7.83 (1H, d, J = 8.3, 1.2 Hz, arom), 8.08 (1H,
d, J = 8.3 Hz, arom). 13C NMR (CDCl3): d 18.6, 26.2,
26.4, 49.5 (br, CB), 82.4, 123.3, 125.4, 126.67, 127.70,
127.3, 129.7, 132.3, 134.9, 138.1, 178.0. EI-MS: m/z
325 (45%, M+), 310 (32%), 267 (6%), 225 (8%), 199
(48%), 181 (66%), 167 (36%), 156 (100%), 141 (39%),
129 (48%), 115 (24%), 91 (16%), 84 (81%), 49 (69%).
Anal. Calcd for C19H24BNO4: C, 70.17; H, 7.44; N,
4.31. Found: C, 69.95; H, 7.56; N, 4.17.
4.3.4. Pinacol ( )-1-benzamido-1-phenylmethaneboronate
4a. After chromatography (light petroleum–ethylace-
tate 3:7), 4a was isolated in 37% yield as a white solid,
mp 190–193 °C. 1H NMR (CDCl3): d 0.91 (6H, s,
CH3), 0.99 (6H, s, CH3), 3.89 (1H, s, CHB), 7.06–7.55
(8H, m, arom), 7.87–8.00 (2H, m, arom), 9.84(1H, br
s, NH). 13C NMR (CDCl3): d 25.6, 25.9, 54.3 (br, CB),
82.2, 127.1, 128.4, 129.3, 129.9, 130.1, 135.0, 142.3,
173.5. EI-MS: m/z 337 (44%, M+), 336 (30%), 322
(5%), 279 (10%), 254(10%), 237 (19%), 221 (11%), 211
(35%), 210 (30%), 193 (29%), 161 (10%), 132 (8%), 117
(9%), 106 (171%), 105 (100%), 104(30%), 91 (8%), 77
(43%), 55 (7%). Anal. Calcd for C20H24BNO3: C, 71.23;
H, 7.17; N, 4.15. Found: C, 71.38; H, 7.02; N, 4.39.
4.3.8. Pinacol ( )-1-acetamido-1-(naphth-2-yl)methane-
boronate 8a. Chromatographic purification (diethyl
ether–methanol 95:5) afforded 8a as a whitish solid, mp
1
229–231 °C, 38% yield. H NMR (CDCl3): d 0.89 (6H,
s, CH3), 1.04(6H, s, C H3), 2.09 (3H, s, COCH3), 3.89
(1H, s, CHB), 7.24(1H, dd, J = 8.6, 1.7 Hz, arom),
7.38–7.50 (3H, m, arom), 7.65–7.84(3H, m, arom), 8.54
(1H, br s, NH). 13C NMR (CDCl3): d 19.1, 25.9, 26.3,
53.2 (br, CB), 82.1, 125.7, 126.4, 127.2, 127.3, 128.88,
128.94, 133.5, 134.8, 139.8, 177.6. EI-MS: m/z 325
(54%, M+), 310 (4%), 267 (12%), 225 (19%), 200 (35%),
181 (100%), 167 (54%), 156 (42%), 141 (23%), 91 (12%),
84(23%). Anal. Calcd for C 19H24BNO4: C, 70.17; H,
7.44; N, 4.31. Found: C, 69.90; H, 7.63; N, 4.13.
4.3.5. Pinacol ( )-1-benzamido-1-(2-methylphenyl)meth-
ane-boronate 5a. Column chromatography (light
petroleum–ethylacetate 1:1) afforded 5a as a white solid,
1
mp 171–172 °C, 24% yield. H NMR (CDCl3): d 1.02
(6H, s, CH3), 1.11 (6H, s, CH3), 2.37 (3H, s, PhCH3),
4.27 (1H, d, J = 1.6 Hz, CHB), 7.02–7.18 (4H, m, H3–
4.4. General procedures for the hydrolysis of pinacol
methylboronates to free boronic acids 1–8
H6 disubstituted Ph), 7.38–7.64(3H, m, H ,H4 mono-
3
substituted Ph), 7.83–7.93 (2H, m, H2 monosubstituted
Ph), 8.18 (1H, br s, NH). 13C NMR (CDCl3): d 19.9,
24.6, 24.9, 55.4 (br, CB), 81.0, 125.6, 125.8, 126.6,
Method A: Pinacol methaneboronates (0.2 mmol) were
treated with degassed HCl 3 M (4mL) at 100 °C for
1 h under argon. The reaction mixture was extracted

S. Morandi et al. / Tetrahedron: Asymmetry 16 (2005) 2918–2926
2925
with EtOAc (10 mL) and the aqueous phase concen-
trated in vacuo to afford the boronic acids as vitreous
solids, which were dried over P2O5 until a constant
weight.
monosubstituted Ph), 7.25 (1H, dt, J = 6.8, 2.1 Hz, H5
disubstituted Ph), 7.53–7.67 (2H, m, H4 disubstituted
Ph, H4 monosubstituted Ph), 7.69–7.81 (1H, m, H6
disubstituted Ph), 7.95–8.50 (2H, m, H2 monosubsti-
tuted Ph). 13C NMR (CD3OD): d 41.4 (br, CB), 55.0,
111.4, 121.1, 126.1, 127.5, 128.3, 129.1, 129.8, 158.7,
172.9.
Method B: Pinacol methaneboronates (0.2 mmol) were
stirred for 1 h in 4M HCl in anhydrous MeOH
(2.5 mL) at rt. The solvent was evaporated in vacuo
and the residue partitioned between Et2O (5 mL) and
H2O (3 mL); the aqueous phase was concentrated under
reduced pressure, yielding the free boronic acids as vitre-
ous solids, which were dried over P2O5 until constant
weight.
4.4.7.
( )-1-Acetamido-1-(naphth-1-yl)methaneboronic
1
acid 7. Method B: 82%. H NMR (CD3OD): d 2.43
(3H, d, J = 0.9 Hz, COCH3), 4.63 (1H, s, CHB), 7.22
(1H, dt, J = 7.2, 1.0 Hz, H2 disubstituted Ph), 7.37–
7.55 (4H, m, arom), 7.71 (1H, d, J = 8.2 Hz, arom),
7.79–7.91 (1H, m, arom), 8.00–8.13 (1H, m, arom).
13C NMR (CD3OD): d 16.5, 52.0 (br, CB), 121.4,
124.2, 124.8, 126.4, 126.7, 127.1, 129.5, 132.2, 135.2,
179.7.
MS fragmentation and elemental analyses of boronic
acids 1–8 were not obtainable, because of the formation
of dehydration products. Nevertheless, exposure of a
solution of these acids in THF to an equimolar amount
of pinacol always afforded the expected esters 1a–8a in
quantitative yield with satisfactory MS fragmentation
and elemental compositions.
4.4.8.
( )-1-Acetamido-1-(naphth-2-yl)methaneboronic
1
acid 8. Method B: 87%. H NMR (CD3OD): d 2.36
(3H, d, J = 1.1 Hz, COCH3), 3.98 (1H, s, CHB), 7.28
(1H, dd, J = 8.5, 1.7 Hz, arom), 7.33–7.50 (2H, m,
arom), 7.56 (1H, s, arom), 7.72–7.85 (3H, m, arom).
13C NMR (CD3OD): d 15.0, 53.6 (br, CB), 122.9,
124.7, 124.8, 125.6, 127.0, 127.2, 127.3, 132.5, 133.6,
138.4, 177.8.
4.4.1. ( )-1-Acetamido-1-phenylmethaneboronic acid
1
1. Method A: 89% yield. H NMR (CD3OD): d 2.34
(3H, s, COCH3), 3.85 (1H, s, CHB), 7.11–7.33 (5H, m,
arom). 13C NMR (CD3OD): d 15.5, 53.1 (br, CB),
125.9, 128.3, 140.7, 178.3.
4.5. Asymmetric synthesis of (R)-(+)-5
4.4.2.
( )-1-Acetamido-1-(2-methylphenyl)methane-
1
boronic acid 2. Method A: 70%. H NMR (CD3OD):
d 2.30 (3H, s, COCH3), 2.40 (3H, s, PhCH3), 4.13 (1H,
s, CHB), 6.90–7.40 (4H, m, arom). 13C NMR (CD3OD):
d 15.1, 18.4, 51.1 (br, CB), 123.4, 125.4, 125.5, 129.7,
134.4, 138.0, 177.8.
4.5.1. (+)-Pinanediol (2-methylphenyl)methaneboronate
(ꢀ)-10h. Boronic acid 10 (1.00 g, 7.4mmol) and (+)-
pinanediol (1.26 g, 7.4mmol) were dissolved in anhy-
drous THF (8 mL). The mixture was stirred for 1 h at
rt and concentrated in vacuo. The crude product was
purified by chromatography (EtOAc–EtPet 2:8), yield-
ing the ester (1.95 g, 98%) as colourless viscous oil,
4.4.3.
( )-1-Acetamido-1-(2-methoxyphenyl)methane-
1
1
boronic acid 3. Method A: 68%. H NMR (CD3OD):
d 2.35 (3H, d, J = 1.3 Hz, COCH3), 3.83 (3H, s,
OCH3), 4.23 (1H, s, CHB), 6.82–7.26 (4H, m, arom).
13C NMR (CD3OD): d 15.0, 40.0 (br, CB), 54.5, 110.0,
120.1, 125.2, 126.7, 128.1, 156.4, 178.1.
[a]D = ꢀ3.5 (c 2.0, CHCl3). H NMR (CDCl3): d 0.93
(3H, s, pinanyl CH3), 1.29 (1H, d, J = 10.7 Hz, pinanyl
Hendo), 1.35 (3H, s, pinanyl CH3), 1.52 (3H, s, pinanyl
CH3), 1.90–2.53 (5H, m, pinanyl protons), 2.59 (3H, s,
PhCH3), 4.48 (1H, dd, J = 8.5, 1.9 Hz, pinanyl CHOB),
7.14–7.43 (3H, m, H3–H5 arom), 7.82 (1H, dd, J = 6.7,
1.9 Hz, arom). 13C NMR (CDCl3): d 22.3, 24.1, 26.6,
27.1, 28.8, 35.8, 38.5, 39.6, 51.5, 78.0, 85.8, 124.8,
129.8, 130.8, 136.0, 144.8 (C–B not seen). EI-MS: m/z
270 (54%, M+), 255 (30%), 229 (17%), 214(16%), 201
(100%), 187 (25%), 174(92%), 134(50%), 119 (42%),
91 (27%), 83 (58%), 67 (46%), 55 (25%). Anal. Calcd
for C17H23BO2: C, 75.57; H, 8.58. Found: C, 75.39; H,
8.69.
4.4.4. ( )-1-Benzamido-1-phenylmethaneboronic acid
4. Method A: 45%; method B 86%. 1H NMR
(CD3OD): d 4.05 (1H, s, CHB), 7.10–7.36 (5H, m,
arom), 7.58–7.83 (3H, m, arom), 8.08–8.18 (2H, m,
arom). 13C NMR (CD3OD): d 56.7 (br, CB), 126.9,
127.2, 129.3, 129.9, 130.4, 135.9 (C@O not seen).
4.4.5.
( )-1-Benzamido-1-(2-methylphenyl)methane-
1
boronic acid 5. Method A: 22%; method B: 87%. H
NMR (CD3OD): d 2.38 (3H, s, PhCH3); 4.24 (1H, s,
CHB); 7.02–7.21 (4H, m, H3–H6 disubstituted Ph),
7.66 (2H, t, J = 7.6 Hz, H3 monosubstituted Ph), 7.79
(1H, t, J = 7.6 Hz, H4 monosubstituted Ph), 8.15 (2H,
t, J = 7.6 Hz, H2 monosubstituted Ph). 13C NMR
(CD3OD): d 18.5, 50.7 (br, CB), 124.0, 125.1, 125.4,
128.4, 129.0, 134.42, 134.44, 139.1, 172.8.
4.5.2. (+)-Pinanediol (1R)-1-benzamido-1-(2-methylphen-
yl)-methaneboronate (+)-5h. A solution of methylene
chloride (230 lL, 3.6 mmol) in THF (3 mL) was cooled
at ꢀ100 °C and treated with a 2.5 M solution of
butyllithium in hexanes (1.1 mL, 2.6 mmol) under an
argon flow and magnetic stirring: LiCHCl2 precipitated
as a white microcrystalline solid. After 30 min, a solu-
tion of the above pinanediol arylboronate (ꢀ)-10h
(600 mg, 2.2 mmol) in anhydrous THF (2 mL) was
added dropwise at ꢀ100 °C over a 20 min period. The
mixture was gradually allowed to reach 0 °C over 6 h
and stirred at this temperature for one additional hour.
4.4.6.
( )-1-Benzamido-1-(2-methoxyphenyl)methane-
1
boronic acid 6. Method A: 43%; method B: 82%. H
NMR (CD3OD): d 3.79 (3H, s, OCH3), 4.26 (1H, s,
CHB), 6.91–7.14(3H, m, H disubstituted Ph and H3
3

2926
S. Morandi et al. / Tetrahedron: Asymmetry 16 (2005) 2918–2926
Thereafter, the solution was cooled at ꢀ78 °C and
LiN(TMS)2 (1 M solution in THF, 2.6 mL, 2.6 mmol)
added and the reaction mixture allowed to warm gradu-
ally. After 16 h at rt, the mixture was cooled again at
ꢀ78 °C, treated with a solution of freshly distilled ben-
zoylchloride (620 lL, 5.3 mmol) and benzoic acid
(320 mg, 2.7 mmol) in THF (3 mL) allowed to reach rt
and stirred overnight. The resulting brownish solution
was partitioned between Et2O (60 mL) and H2O
(20 mL) and the aqueous phase extracted repeatedly
with Et2O (60, 40 and 20 mL). The collected organic
phases were dried over MgSO4, filtered and concen-
trated under reduced pressure affording the crude prod-
uct as a viscous brown oil which was purified by
gradient chromatography (EtPet–EtOAc from 7:3 to
3:7). The pure product 5h was isolated as a white amor-
phous solid, mp 75 °C, 45% overall yield from 10h.
thank the Fondazione Cassa di Risparmio di Modena
for funding the purchase of the 400 MHz NMR
spectrometer.
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1
[a]D = +6.1 (c 1.8, CHCl3). H NMR (CDCl3): d 0.80
(3H, s, pinanyl CH3), 1.21 (3H, s, pinanyl CH3), 1.31
(1H, d, J = 10.3 Hz, pinanyl Hendo), 1.33 (3H, s, pinanyl
CH3), 1.51–2.30 (5H, m, pinanyl protons), 2.39 (3H, s,
PhCH3), 4.19 (1H, dd, J = 8.0, 1.8 Hz, pinanyl CHOB),
4.41 (1H, d, J = 1.9 Hz, CHB), 7.01–7.20 (4H, m, H3–
H6 disubstituted Ph), 7.36–7.61 (3H, m, H3 and H4 mono-
substituted Ph), 7.70–7.92 (3H, m, H2 monosubstituted
Ph and NH). 13C NMR (CDCl3): d 21.3, 25.5, 27.7,
28.6, 30.3, 37.7, 39.5, 41.3, 46.6 (br, CB), 53.5, 78.2,
85.6, 127.0, 127.2, 127.4, 129.3, 130.1 (2C), 131.6,
134.4, 136.2, 140.4, 172.2. EI-MS: m/z 403 (39%, M+),
251 (14%), 224 (17%), 207 (33%), 126 (29%), 105
(100%), 93 (42%), 77 (35%), 71 (21%), 55 (14%). Anal.
Calcd for C25H30BNO3: C, 74.45; H, 7.50; N, 3.47.
Found: C, 74.32; H, 7.68; N, 3.39.
4.5.3.
(1R)-1-Benzamido-1-(2-methylphenyl)methane-
boronic acid (+)-5). Compound (+)-5h (400 mg,
0.99 mmol) was treated with degassed HCl 3 M
(22 mL) at 100 °C for 1 h under argon. The reaction
mixture was extracted with Et2O (40, 20 mL) and the
aqueous phase concentrated under reduced pressure
to afford a white solid which was dried over P2O5 until
constant weight, yielding 136 mg (54% yield) of (+)-5.
1
Mp 56–57 °C; [a]D = +26.6 (c 0.7, CH3OH). H NMR
and 13C NMR were identical to those shown by ( )-5.
To assess that no racemization occurred during the
hydrolysis, a sample of (+)-5 was converted to (+)-5h
by reaction with a slight excess of (+)-pinanediol; this
latter was recovered in a quantitative yield and de >98%.
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M.; Jensen, S. E.; Jones, J. B.; Strynadka, N. C. J.
Biochemistry 2000, 39, 5312–5321.
Acknowledgements
We thank Dr. C. Rossi and Dr. C. Restani of the Centro
Interdipartimentale Grandi Strumenti of Modena, for
NMR assistance. We are grateful to the Ministero
25. Martichonok, V.; Jones, B. J. J. Am. Chem. Soc. 1996,
118, 950–958.
`
dellÕIstruzione, dellÕUniversita e della Ricerca (MIUR,
26. Matteson, D. S.; Sadhu, M. K.; Peterson, M. L. J. Am.
Chem. Soc. 1986, 108, 810–819.
Rome) for financial support (COFIN 2003). We also