Simple chiral derivatization protocols for 1H NMR and 19F NMR spectroscopic analysis of the enantiopurity of chiral diols

Article abstract of DOI:10.1021/jo8019187

(Chemical Equation Presented) Two practically simple chiral derivatization protocols for determining the enantiopurity of chiral diols by ¹H NMR and ¹⁹F NMR spectroscopic analysis are described, involving treatment of the diol with 2

Full text of DOI:10.1021/jo8019187

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Simple Chiral Derivatization Protocols for H
is currently of great interest to the synthetic community. We
1
9
have recently developed simple three component chiral deriva-
tization protocols for determining the enantiopurity of chiral
amines, diols, and diamines. The enantiomeric excess of
scalemic diols are determined via derivatization with 2-formylphe-
nylboronic acid and a chiral amine to afford mixtures of
diastereoisomeric imino-boronate esters whose ratios are then
determined by H NMR spectroscopic analysis. Since no kinetic
resolution occurs in this derivatization process, the diastereoi-
someric ratio (dr) is an accurate measure of the enantiomeric
NMR and F NMR Spectroscopic Analysis of the
Enantiopurity of Chiral Diols
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Sonia Lozano Yeste, Magdalena E. Powell, Steven D. Bull,*
and Tony D. James*
1
Department of Chemistry, UniVersity of Bath, Bath,
BA2 7AY, United Kingdom
6
s.d.bull@bath.ac.uk; t.d.james@bath.ac.uk
excess of the parent diol.
Comparison of our three component derivatization approach
with the widely used Mosher’s acid derivatization protocol
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ReceiVed September 2, 2008
reveals that it has a number of advantages. The main drawback
of using Mosher’s ester approach for diols is the need to employ
excess chiral derivatizing agent (CDA) to ensure that no kinetic
resolution occurs when both alcohol functionalities react with
two equivalents of the CDA. Contrastingly, our derivatization
approach results in both alcohol functionalities of the diol
reacting rapidly with a single boronic acid template, which
ensures that no kinetic resolution occurs. This means that a wide
range of diols can be rapidly derivatized using moisture
insensitive reagents to quantitatively afford mixtures of dias-
1
tereoisomeric imino-boronate esters whose H NMR spectra
display at least one pair of baseline-resolved diastereotopic
resonances that can be integrated to accurately determine
diastereoisomeric excess (de). However, one potential advantage
of the Mosher’s acid derivatization approach for chiral diols is
1
the ability to determine diastereomeric excess using both H
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9
8,9
and F NMR spectroscopy. Consequently, we now describe
herein the development of second generation three-component
chiral derivatization protocols that also enable the ee of chiral
1
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diols to be accurately determined by F NMR spectroscopic
analysis.
Two practically simple chiral derivatization protocols for
1
determining the enantiopurity of chiral diols by H NMR
Our first strategy was to develop a derivatization protocol
employing a commercially available chiral fluorous amine as a
chiral auxiliary. Therefore, six chiral diols 3a-f were mixed
19
and F NMR spectroscopic analysis are described, involving
treatment of the diol with 2-formylphenylboronic acid and
R-methyl-4-fluorobenzylamine, or its derivatization with
(
4) (a) Freire, F.; Seco, J. M.; Quinoa, E.; Riguera, R. J. Org. Chem. 2005,
4
-fluoro-2-formylphenylboronic acid and R-methyl-benzyl-
7
0, 3778–3790. (b) Freire, F.; Seco, J. M.; Quinoa, E.; Riguera, R. Org. Lett.
amine. Both approaches afford mixtures of imino-boronate
esters whose diastereomeric ratio may be measured by H
NMR or F NMR spectroscopy, the value of which is an
accurate reflection of the enantiopurity of the parent diol.
2005, 7, 4855–4858. (c) Caselli, E.; Danieli, C.; Morandi, S.; Bonfiglio, B.; Forni,
1
A.; Prati, F. Org. Lett. 2003, 5, 4863–4866. (d) Fukui, H.; Fukushi, Y.; Tahara,
S. Tetrahedron Lett. 2003, 44, 4063–4065. (e) Seco, J. M.; Martino, M.; Quinoa,
E.; Riguera, R. Org. Lett. 2000, 2, 3261–3264. (f) Kouda, K.; Ooi, T.; Kusumi,
T. Tetrahedron Lett. 1999, 40, 3005–3008. (g) Garner, C. M.; McWhorter, C.;
Goerke, A. R. Tetrahedron Lett. 1997, 38, 7717–7720. (h) Resnick, S. M.; Torok,
D. S.; Gibson, D. T. J. Org. Chem. 1995, 60, 3546–3549. (i) Brunel, J. M.;
Faure, B. Tetrahedron: Asymmetry 1995, 6, 2353–2356. (j) Burgess, K.; Porte,
A. M. Angew. Chem., Int. Ed. Engl. 1994, 33, 1182–1184. (k) Tokles, M.; Snyder,
J. K. Tetrahedron Lett. 1988, 29, 6063–6066.
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Introduction
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(5) (a) Perez-Fuertes, Y.; Kelly, A. M.; Johnson, A. L.; Arimori, S.; Bull,
S. D.; James, T. D. Org. Lett. 2006, 8, 609–612. (b) Axe, P.; Bull, S. D.;
Davidson, M. G.; Gilfillan, C. J.; Jones, M. D.; Robinson, D. E. J. E.; Turner,
L. E.; Mitchell, W. L. Org. Lett. 2007, 9, 223–226. (c) Taylor, P. J. M.; Bull,
S. D. Tetrahedron: Asymmetry 2006, 17, 1170–1178. (d) Perez-Fuertes, Y.; Kelly,
A. M.; Fossey, J. S.; Powell, M. E.; Bull, S. D.; James, T. D. Nat. Protoc. 2008,
3, 210–214.
The prevalence of chiral diols as synthetic intermediates
3
and as fragments of biologically active compounds has led to
a great demand for reliable techniques to accurately determine
their enantiopurity. Consequently, the development of inexpen-
sive chiral derivatization protocols that allow their enantiomeric
excess to be simply determined by NMR spectroscopic analysis
(6) (a) Kelly, A. M.; Perez-Fuertes, Y.; Arimori, S.; Bull, S. D.; James, T. D.
Org. Lett. 2006, 8, 1971–1974. (b) Chopard, C.; Azerad, R.; Prange, T. J. Mol.
Catal. B 2008, 50, 53–60.
(7) Kelly, A. M.; Bull, S. D.; James, T. D. Tetrahedron: Asymmetry 2008,
19, 489–494.
(8) (a) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543–
2549. (b) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512–519.
(9) Seco, J. M.; Quinoa, E.; Riguera, R. Chem. ReV. 2004, 104, 17–118.
(
(
1) Challener, C. A. Chiral Intermediates; Wiley: London, 2004.
2) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV. 1994,
9
4, 2483–2547.
(3) Hanessian, S. Total Synthesis of Natural Products: The Chiron Approach;
Pergamon: London, 1983.
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0.1021/jo8019187 CCC: $40.75  2009 American Chemical Society
J. Org. Chem. 2009, 74, 427–430 427
Published on Web 12/02/2008

SCHEME 1. Three-Component Coupling Reaction of
SCHEME 2. Synthesis of 4-Fluoro-2-formylphenylboronic
Acid 9
(
rac)-r-Methyl-4-fluorobenzylamine 1, 2-Formylphenyl
Boronic Acid 2 and Diols 3a-f to Afford Diastereomeric
Imino-Boronate Esters 4a-f/5a-f
SCHEME 3. Three-Component Coupling Reaction of
(
rac)-r-Methyl-benzylamine 10, 4-Fluoro-2-formylphenyl
Boronic Acid 9 and Diols 3a-g to Afford Diastereomeric
Imino-Boronate Esters 11a-g/12a-g
with one equivalent of (rac)-R-methyl-4-fluorobenzylamine 1
and one equivalent of 2-formyl-phenylboronic acid 2 in CDCl3
for five minutes, resulting in quantitative formation of 50:50
mixtures of diastereomeric imino-boronate esters 4a-f/5a-f.
(
Scheme 1, Supporting Information). As expected, baseline
resolution of the imine resonances of each pair of diastereomeric
1
imino-boronate esters 4a-f/5a-f was observed in their H
NMR spectra in all cases. Moreover, nonequivalent fluorine
resonances were also observed for each pair of diastereomeric
1
9
imino-boronate esters 4a-f/5a-f in their proton decoupled
F
NMR spectra, with a ∆δF ) 0.05-0.75 ppm (Supporting
Information). Therefore, it follows from previous precedent that
using enantiopure R-methyl-4-fluorobenzylamine 1 as a chiral
auxiliary in this derivatization protocol will enable the enan-
tiopurity of scalemic diols to be accurately determined from
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10
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their H NMR or F NMR spectra.
We then turned our attention to developing a more widely
applicable fluorous protocol that would enable the enantiomeric
purity of both diols and amines to be determined by F NMR
spectroscopy. Consequently, it was decided to prepare 4-fluoro-
the resultant diastereomeric iminoboronate esters 11a-g/12a-g
revealed that baseline resolution had been achieved for at least
two sets of resonances in all cases (Scheme 3, Table 1). For
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1
example, analysis of the 400 MHz H NMR spectra of a 50:50
2
-formylphenylboronic acid 9 as a new bifunctional template
mixture of iminoboronate esters 11e and 12e revealed that
baseline resolution had been achieved for four distinct pairs of
diastereomeric signals. Importantly, in all cases split-
ting of the imine signal was observed (0.05-0.35 ppm) in a
for carrying out our three-component derivatization protocol.
This would result in formation of diastereomeric imino-
boronate ester complexes containing fluorous tags within their
central aryl cores, thus enabling any chiral amine (or chiral diol)
to be used as a chiral auxiliary for derivatization. Therefore,
commercially available 2-bromo-5-fluoro-benzaldehyde 6 was
treated with trimethyl orthoformate in methanol at room
temperature to afford acetal 7 in 99% yield. Treatment of acetal
1
region of the H NMR spectra that was free of any other
resonances. This feature is highly desirable since these imine
resonances provide diagnostic resonances for integration that
are independent of the diol being derivatized. Importantly, it
was found that derivatization of each diol 3a-g gave two sets
7
with one equivalent of n-BuLi in THF at -78 °C resulted in
1
of diastereomeric iminoboronate ester resonances in their H
halogen-lithiation exchange to afford an aryl anion that was
quenched with trimethylborate to give boronate ester 8, that was
immediately treated with 2 M HCl(aq) to afford boronic acid 9
as a crystalline solid in 55% yield over two steps (Scheme 2).
The scope and limitation of this new boronic acid template
NMR spectra, clearly indicating that free rotation around the
aryl-boron bond was occurring on the NMR time scale.
19
We then investigated whether F NMR spectroscopic analysis
could be used to distinguish between the pairs of diastereoiso-
meric imino-boronate ester derivatives 11a-g/12a-g as orig-
9
was then investigated Via treatment of a range of seven diols
1
9
inally envisaged. Therefore, acquiring proton decoupled
F
3
a-g with 4-fluoro-2-formyl-phenylboronic acid 9 using (rac)-
NMR spectra of the mixtures of diasteromeric boronate esters
11a-g/12a-g revealed pairs of well resolved aryl-fluorine
resonances in a 1:1 ratio in each case, with a ∆δF splitting for
each diastereomeric pair ranging from 0.03-0.30 ppm (Table
1).
R-methylbenzylamine 10 as a chiral auxiliary. Analysis of the
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4
00 MHz H NMR spectra of the resultant 50:50 mixture of
(
10) Enantiopure (R)- and (S)-R-methyl-4-fluorobenzylamine 1 are com-
mercially available from Alfa Aesar at £34.20 per gram.
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28 J. Org. Chem. Vol. 74, No. 1, 2009

TABLE 1. Chemical Shift Differences (δ) in the 300 MHz H NMR and 400 MHz 19F NMR Spectra of 50:50 Mixtures of Diastereomeric
1
Imino-Boronate Esters 11a-g/12a-g Derived from 4-Fluoro-2-formylphenylboronic acid 9,(rac)-r-Methylbenzylamine 10 and Chiral Diols
3
a-g
of the H NMR and 19F NMR spectra of each sample revealed
that the calculated diastereoisomeric excess for the resultant
mixtures of (2S,3R,R-R)-11e and (2R,3S,R-R)-12e of 80%, 90%,
1
The detection limits of this new chiral derivatization protocol
for determining the enantiopurity of scalemic samples of diol
e were then explored. Therefore, samples of methyl-(2S,3R)-
dihydroxy-3-phenyl-propionoate 3e of 80%, 90% and 98% ee
respectively were treated with enantiopure (R)-R-methyl-ben-
zylamine 10 and 2-formyl-4-fluorophenyl boronic acid 9 to
afford three samples of their corresponding imino-boronate
ester complexes (2S,3R,R-R)-11e and (2R,3S,R-R)-12e. Analysis
3
1
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and 98% de ( H NMR) and 80%, 90% and 96% de ( F NMR)
were in excellent agreement with the known enantiopurity of
the starting diol 3e of 80%, 90% and 98% ee respectively
(Figure 1). These values are well within the accepted 5% error
limit normally accepted for CDA analysis using NMR spec-
J. Org. Chem. Vol. 74, No. 1, 2009 429

of a wide range of diols using H and/or 19F NMR spectroscopic
analysis. We believe that the simplicity and speed of this
approach and the wide range of substrates that it is capable of
resolving warrants its consideration as a versatile method for
determining the enantiomeric excess of chiral diols (or chiral
amines) produced in asymmetric protocols.
1
Experimenal Section
4
-Fluoro-2-formylphenylboronic Acid 9. n-Butyl-lithium (1.6
M in hexane, 56 mL, 89 mmol) was added dropwise via a syringe
pump over a period of 1 h to a solution of 1-bromo-4-fluoro-2-
dimethoxymethyl-benzene 7 (19 g, 76 mmol) in toluene/THF (4:1,
2
0 mL) at -78 °C under a nitrogen atmosphere. The mixture was
stirred at -78 °C for an additional 30 min before being warmed to
-
20 °C and transferred dropwise Via cannula to a solution of
trimethylborate (9.2 g, 89 mmol) in toluene (10 mL) at -78 °C.
The resulting solution was stirred at -78 °C for 1 h, warmed to
-
20 °C, before addition of 2 M HCl(aq) (74 mL) and the rapidly
stirred solution allowed to warm slowly to room temperature. The
organic layer was dried (MgSO ), and solvent removed in vacuo
to afford an oil that was recrystallized (hexane/Et O) to afford the
title compound 9 (6.90 g, 41.00 mmol) as a white solid in 55%
4
2
1
3
yield. m.p: 123-125 °C. H NMR (300 MHz, CDCl ) δ: 1.6 (2H,
broad s), 7.5 (1H, dt, J ) 8.1, 2.5 Hz), 7.7 (1H, dd, J ) 8.8, 2.6
FIGURE 1. Expansion of H NMR and 19F NMR spectra of mixtures
of (2S,3R,R-R)-11e and (2R,3S,R-R)-12e prepared from derivatization
of diol (2S,3R)-3e of 80%, 90% and 98% ee.
1
13
Hz), 8.3 (1H, dd, J ) 7.9, 6.4 Hz), 9.8 (1H, s); C NMR (75.5
11
MHz, CDCl
MHz, CDCl
m/z): Calcd [M + Na] ; 191.0292, Found [M + Na] ; 191.0286.
3
) δ: 121.4, 121.6, 124.7, 141.6, 197.5; B NMR (96
19
3
3
) δ 28.7; F NMR (400 MHz, CDCl ) δ: -108.2; MS
+
+
(
troscopy, indicating that no kinetic resolution had occurred in
the derivatization process. Therefore, these results clearly
demonstrate that this new second generation CDA enables both
H and F NMR spectroscopic analysis to be used to accurately
determine the enantiomeric excess of a range of chiral diols in
a highly practical manner. Furthermore, literature precedent
indicates that combining 2-formyl-4-fluorophenylboronic acid
with an enantiopure diol should provide an equally effective
Supporting Information Available: General experimental
procedures and synthesis of 1-bromo-4-fluoro-benzene 7. Table
1
19
1
19
of H and F NMR chemical shift differences of 50:50 mixtures
of diastereoisomeric imino-boronate esters 4a-f/5a-f derived
5
,6
1
from (rac)-R-methylbenzylamine 10 and chiral diols 3a-f. H
1
9
and F NMR spectra of 50:50 mixtures of diastereoisomeric
imino-boronate esters 4a-f/5a-f and 11a-g/12a-g. This
material is available free of charge via the Internet at
http://pubs.acs.org.
9
1
CDA for determining the ee of chiral amines via both H and
1
9
F NMR spectroscopy.
In conclusion, we have developed a second generation
derivatization protocol for determining the enantiomeric excess
JO8019187
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30 J. Org. Chem. Vol. 74, No. 1, 2009