(S)-(+)-N-Acetylphenylglycineboronic Acid: A Chiral Derivatizing Agent for Ee Determination of 1,2-Diols

Article abstract of DOI:10.1021/ol0359970

(Equation Presented) A new chiral derivatizing agent for ee determination of 1,2-diols via ¹H NMR is described. (S)-(+)-N- Acetylphenylglycineboronic acid (1) is synthesized in enantiomerically pure form; its reaction with chiral diols quantitatively yields cyclic boronic esters 5a-g. The latter show a remarkably high diastereodifferentiation of proton NMR signals useful for de determination.

Full text of DOI:10.1021/ol0359970

ORGANIC
LETTERS
2003
Vol. 5, No. 25
4863-4866
(S)-(+)-N-Acetylphenylglycineboronic
Acid: A Chiral Derivatizing Agent for Ee
Determination of 1,2-Diols
Emilia Caselli, Chiara Danieli, Stefania Morandi, Beatrice Bonfiglio,
Arrigo Forni, and Fabio Prati*
UniVersita` di Modena e Reggio Emilia, Via Campi 183, 41100, Modena, Italy
prati.fabio@unimore.it
Received October 14, 2003
ABSTRACT
A new chiral derivatizing agent for ee determination of 1,2-diols via 1H NMR is described. (S)-(+)-N-Acetylphenylglycineboronic acid (1) is
synthesized in enantiomerically pure form; its reaction with chiral diols quantitatively yields cyclic boronic esters 5a−g. The latter show a
remarkably high diastereodifferentiation of proton NMR signals useful for de determination.
1,2-Diols are important molecules both as synthetic inter-
mediates1 and as biologically active molecules.2 The fact that
chiral diols can be easily obtained through enantioselective
bishydroxylation3 highlights the importance of finding reli-
able methods for ee determination. For this purpose NMR
analysis is a general approach that requires conversion of
enantiomers into diastereomeric derivatives through chiral
auxiliaries. Whereas the use of chiral derivatizing agents
(CDAs) for alcohols is well established, and compounds such
as mandelic acid4 or R-methoxy-R-(trifluoromethyl)phenyl-
acetic acid (Mosher’s acid)5 are widely available, there are
no examples of commercially available CDAs specific for
diols. Certain precautions are necessary when a diol is
analyzed: particular care has to be taken in order to derivatize
both functionalities, possible kinetic resolution has to be
avoided, and nearly enantiomerically pure CDA is necessary
in order to avoid formation of other diastereoisomers.
Therefore, an ideal CDA for diols should have a single
functional group capable of quantitatively reacting with both
the hydroxy functionalities and should be easily available
in enantiomerically pure form. Accordingly, previous studies
have proposed compounds bearing either a boronic acid or
a dichlorophosphate functional group and have identified
three molecules (Figure 1, compounds I-III) that react with
a diol to form a cyclic boronate or phosphate ester. In all
three cases, the resulting diastereomeric esters were analyzed
by NMR, a generally useful technique for determining de.
In the first example, the signal nonequivalences induced by
the camphanylboronic acid I6 were observed only in the 13
C
NMR spectra, a low-sensitivity technique not well suited to
quantitation. In a second case, diastereomeric phophates
formed between menthyldichlorophosphate II7 and 1,2-diols
displayed useful nonequivalence only for C2 symmetry
molecules in the 31P NMR spectra, which moreover is not a
routinely monitored nucleus to be observed.
(1) Chiral Intermediates; Challenger, A. C., Ed.; Ashgate Publishing
Limited: Hampshire, England, 2001.
(2) Merck Index, 13th ed.; Merck: Whitehouse Station, New Jersey,
2001.
(3) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483.
(4) Trost, B. M.; Belletire, J. L.; Godleski S.; McDougal, P. G.; Balkovec,
J. M.; Baldwin, J. J.; Christy, M. E.; Ponticello, G. S.; Varga, S. L.; Springer,
J. P. J. Org. Chem. 1986, 51, 2370.
(6) Tokles, M.; Snyder, J. K. Tetrahedron Lett. 1988, 29, 6063.
(7) Garner, C. M.; McWorther, C.; Goerke, A. R. Tetrahedron Lett. 1997,
38, 7717.
(5) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
10.1021/ol0359970 CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/20/2003

The (R)-R-chloro-R-phenylmethaneboronic ester 3 was not
isolated; displacement of the chlorine by a nitrogen nucleo-
phile (lithium bistrimethylsilylamide) occurs by means of
the SN2 mechanism, and subsequent deprotection and acyl-
ation, using a mixture of acetic acid and acetic anhydride,
furnished diastereomerically pure (de > 98%) pinanediyl (S)-
N-acetylphenylglycineboronic ester (+)-411 in 77% overall
yield. The de of this compound can be unambiguously
1
assigned on the basis of its H NMR resonances according
to literature.12 Pinanediol ester hydrolysis was accomplished
in refluxing HCl to give (S)-(+)-113 as a white solid.14
To explore diastereomeric differentiation of racemic diols,
seven 1,2-diols (a-g, Scheme 2) were chosen bearing
primary, secondary, and tertiary hydroxy functionalities as
well as diols with C2 symmetry.
Figure 1. Structures of reported CDA for diols (I-III) and of
(S)-(+)-N-acetylphenylglycineboronic acid (1).
Derivatization of diols (Scheme 2) was performed in THF
for 1 h: a slight excess (5-10%) of boronic acid (+)-1 was
In the last example, nonequivalence suitable for integration
was displayed in the easily accessible 1H NMR spectra, but
the ∆δ values of the boronic esters formed with the
arylboronic acid III8 were low (5-20 ppb). This letter reports
the use of optically active N-acetylphenylglycineboronic acid
(+)-1 (Figure 1) as a chiral derivatizing agent for diols: both
enantiomers of this compound are easily accessible in
enantiomerically pure form, derivatization with diols is
(8) Burgess, K.; Porte, A. M. Angew. Chem., Int. Ed. Engl. 1994, 33,
1182.
(9) (a) Matteson, D. S. Acc. Chem. Res. 1988, 21, 294. (b) Matteson, D.
S. Chem. ReV. 1989, 89, 1535. (c) Matteson, D. S. J. Organomet. Chem.
1999, 581, 51.
(10) Morandi, F.; Caselli, E.; Morandi, S.; Focia, P. J.; Blasquez, J.;
Shoichet, B. K.; Prati, F. J. Am. Chem. Soc. 2003, 125, 685.
(11) (-)-Pinanediol (S)-r-Acetamido-r-phenylmethaneboronate ((+)-
4). n-BuLi (2.8 mL of a 2.5 M solution in hexane, 7.0 mmol) was added
dropwise to a solution of CH2Cl2 (0.55 mL, 8.6 mmol) in THF (13 mL)
while stirring at -100 °C under argon: dichloromethyllithium precipitated
as a white microcrystalline solid towards the end of the BuLi additions.
After 30 min, the mixture was treated with pinanediolphenylboronate (+)-
210 (1.3 g, 5.3 mmol) and allowed to reach room temperature with stirring.
The tetrahedral boronate adduct precipitated as an abundant white solid at
-80 °C and redissolved upon warming. After 1 h at 0 °C, the reaction
mixture was recooled to -78 °C; LiN(TMS)2 (5.3 mL of a 1 M solution in
THF, 5.3 mmol) was added, and the resulting solution was allowed to warm
gradually to room temperature and stirred overnight. The mixture was then
recooled to -78 °C and treated with a solution of Ac2O (2.0 mL, 21.2
mmol) and AcOH (0.4 mL, 6.5 mmol) in THF (4 mL), allowed to warm to
room temperature, and stirred overnight. The solution was diluted in EtOAc
(250 mL) and H2O (50 mL); the organic phase was washed (NaHCO3 to
basic pH, 40 mL H2O, 50 mL of brine), dried on MgSO4, filtrated, and
concentrated in vacuo to yield a brownish oil that was purified by gradient
chromatography (Et2O/MeOH 9:1 to 1:1), affording (+)-4 as a white solid
(1.3 g, 77%), which was recrystallized from MeOH, mp 210-213 °C, [R]D
) +73.8 (c 0.93, CHCl3). 1H NMR (CDCl3): δ 0.78 (3H, s, pinanyl CH3),
1.20 (1H, d, J ) 10.5, pinanyl Hendo), 1.20 (3H, s, pinanyl CH3), 1.28 (3H,
s, pinanyl CH3), 1.33-2.25 (5H, m, pinanyl protons), 2.14 (3H, s, COOCH3),
3.91 (1H, s, CHB), 4.10 (1H, dd, J ) 8.6, 2.3, pinanyl CHOB), 7.08-7.37
(5H, m, Ph), 7.69 (1H, bs, NHCO). 13C NMR (CDCl3): δ 20.2, 25.5, 27.8,
28.6, 30.3, 37.7, 39.4, 41.3, 50.4 (br, CHB), 53.7, 78.1, 85.2, 127.3, 127.6,
129.6, 142.1, 176.2. EIMS: m/z 327 (71%, M+), 284 (7), 229 (11), 212
(11), 192 (29), 176 (43), 175 (63), 150 (66), 148 (52), 131 (100), 130 (53),
117 (37), 106 (65), 93 (82), 91 (43), 79 (24), 77 (22), 67 (11), 55 (12).
Anal. Calcd for C19H26BNO3: N ) 4.28; C ) 69.74; H ) 8.01. Found: N
) 4.45; C ) 69.57; H ) 7.91.
1
quantitative, and the H NMR spectra of the corresponding
boronic esters show a remarkably high separation (∆δ )
70-220 ppb) of signals useful for diastereomeric excess
determination.
Synthesis of (+)-1 was accomplished through Matteson
homologation9 reaction of pinanediol phenylboronate10 (+)-2
(Scheme 1). This reaction inserts a halogenated carbon atom
Scheme 1. Diastereoselective Synthesis of (+)-1
(12) (a) Tsai, D. J. S.; Jesthi, P. K.; Matteson, D. S. Organometallics
1983, 2, 1543. (b) Matteson, D. S.; Sadhu, K. M.; Peterson, M. L. J. Am.
Chem. Soc. 1986, 108, 810.
(13) (S)-(+)-N-Acetylphenylglycineboronic Acid (1). The boronic ester
(+)-4 (65 mg, 0.2 mmol) was refluxed for 1 h in 3 N HCl (4.3 mL, 13.0
mmol, prepared with degassed H2O) under Ar. The resulting reaction
mixture was washed twice with EtOAc (10 and 6 mL) and the aqueous
phase concentrated in vacuo, affording the free boronic acid as a white
1
amorphous solid. Yield 95%, [R]D ) +250.5 (c 0.42, CH3OH). H NMR
(200 MHz, CD3OD): δ 2.34 (3 H, s, -COCH3); 3.85 (1 H, s, HR); 7.11-
7.33 (5 H, m, Ph). 13C NMR (200 MHz, CD3OD): δ 15.5 (COCH3); 53.1
(CHB); 125.9; 128.3; 140.7; 178.3 (C ) O). EI-MS: 194 (3%, M+ + 1);
149 (41); 106 (52); 105 (100); 91 (28); 77 (32); 51 (7).
(14) To verify the stability of (+)-1 and to assess that no racemization
occurred under the relatively harsh conditions of the hydrolysis, a sample
of (+)-1 was stored under argon for 15 days at room temperature and then
converted to (+)-4 by reaction with a slight excess of (+)-pinanediol: (+)-4
was recovered in 97% yield and de > 98%.
in the R-position to the boron, and the stereochemical
outcome of the reaction is highly controlled (de > 98%) by
the boronic acid protective group pinanediol, which is
commercially available in both enantiomeric forms. In
particular, (-)-pinanediol is known9a to induce (R)-stereo-
chemistry.
4864
Org. Lett., Vol. 5, No. 25, 2003

Scheme 2. Derivatization of Racemic Diols a-g with (+)-1
used in order to avoid kinetic resolutions, and complete
conversion of the diols (20-30 mg) to boronic esters 5a-g
was always observed within 30 min, even for highly sterically
hindered diols such as c and e. Subsequent removal of the
solvent in vacuo and desiccation over P2O5 at 2 mmHg for
12 h furnished the diastereoisomeric couples of the boronic
esters 5a-g, which did not require further purification. The
structure of compounds 5a-g was confirmed by mass
1
spectrometry and H NMR and 13C NMR spectroscopy. A
careful study was conducted in order to assign all the proton
resonances correctly (see Supporting Information), and 1H-
1H COSY, 1H-13C HMQC, DEPT 135, and NOESY spectra
were recorded when necessary. To our satisfaction, NMR
(200 MHz) spectra of N-acetylphenylglycineboronic esters
5a-g always clearly revealed the presence of the two
diastereoisomers; differences in the chemical shift of signals
of diastereotopic groups were significant, with ∆δ values
ranging from 20 to 220 ppb for the proton (Figure 2) and
from 120 to 890 ppb for the carbon.
Baseline resolved peaks useful for de determination (∆δ
from 70 to 220 ppb) were always observed except for
compound 5c. Even though the splitting of the signals
originated from the CDA is an attractive feature, in our
spectra the proton resonances derived from the diols are
better separated than those from the boronic acid. In
particular, neither the proton R to the boron nor the acetamido
methyl singlet generally split as hoped. Our results are
nevertheless significant if compared with those last pub-
lished8 since the ∆δ values are increased by 1 order of
magnitude, probably due to the proximity of the CDA chiral
center to the diol. Furthermore, NOESY experiments con-
ducted on compounds 5a and 5d point to a proximity
between the proton Hb of the diol and the phenyl ortho
hydrogens of the CDA: this suggests that the insertion of a
methoxy group in this position of the phenyl ring could
probably lead to a useful CDA signal for de determination.
To verify that reliable ee values of a chiral diol are
obtainable from diastereotopic proton signals, samples of 1,2-
Figure 2. Nonequivalence 1H NMR (∆δ values in ppb) observed
in diastereoisomeric couples of boronic esters 5a-g. Useful
nonequivalences for de determination are in red.
propanediol a in different ee (96, 77.4, 58.2, and 5%) were
prepared using the commercially available (R)-a (98% ee)
and (()-a, and derivatizations with (S)-(+)-1 were performed
as described. 1H NMR spectra of the samples were recorded
and de values calculated on the diol methyl signals (Figure
3) on the basis of the height of the peaks;15 values of 96,
78, 55, and 7% ee were obtained.
These results show that the de values are always in good
agreement with the expected ee of the diol, and even traces
of one diastereoisomer are detectable by this technique.
To summarize, this work explores the advantages of using
chiral R-acetamido-R-phenylglycineboronic acid (S)-(+)-1
as CDA for 1,2-diols. This compound is obtainable in
enantiomerically pure form; its reaction with diols is
quantitative, and the resulting diastereoisomers are easily
1
analyzed by H NMR in standard conditions (CDCl3 as a
(15) Pirkle, W. H.; Hoover, D. J. In Topics in Stereochemistry; Allinger,
N. L., Eliel, E. L., Wilen, S. H., Eds.; John Wiley & Sons: New York,
1982; Vol. 13, 276.
Org. Lett., Vol. 5, No. 25, 2003
4865

2), and the determined de values are in good agreement with
the known ee of the diol. Modifications of the structure of
(+)-1 are in progress in our lab in order to obtain diagnostic
signals on the resonances of the CDA.
Acknowledgment. We thank Dr. C. Rossi and Dr. A.
Benedetti of the Centro Interdipartimentale Grandi Strumenti
of Modena for NMR assistance. We are grateful to the
Ministero dell’Istruzione, dell’Universita` e della Ricerca
(MIUR, Rome) for financial support.
Supporting Information Available: Spectroscopic char-
acterization (1H NMR, 13C NMR, and mass spectra) for
compounds 5a-g. This material is available free of charge
via the Internet at http://pubs.acs.org.
Figure 3. 1H NMR spectra relative to the signals of the diaste-
reotopic methyl group of boronic ester 5a: I-IV refer to samples
obtained from diol a in 5, 58.2, 77.4, and 96% ee, respectively.
solvent, 200 MHz). Remarkably high ∆δ values (70-220
ppb) of diastereomeric proton signals are obtained (Figure
OL0359970
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Org. Lett., Vol. 5, No. 25, 2003