A practical preparation of enantiomerically pure (R)- and (S)-2-bromohexadecanoic acids

Article abstract of DOI:10.1016/S0957-4166(00)00388-8

The efficient preparation of enantiomerically pure (R)- and (S)-2-bromohexadecanoic acids with e.e.>95% through resolution with the use of a recoverable chiral auxiliary is described. The procedure involves three reactions: Steglich esterification, DIBAL reduction, and Sharpless oxidation. The assessment of the enantiomeric purity is based on NMR analysis by using (1R,2R)-(+)-diphenylethane-1,2-diamine as a chiral solvating agent. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00388-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 4105–4111
A practical preparation of enantiomerically pure (R)- and
(S)-2-bromohexadecanoic acids
Jinsong Guo,a,* David W. Knappa and Stephanie Boegemanb
aDepartment of Chemistry, Columbia University, New York, NY 10027, USA
bHarvey Mudd College, 301E, 12th Street, Claremont, CA 91711, USA
Received 15 August 2000; accepted 11 September 2000
Abstract
The efficient preparation of enantiomerically pure (R)- and (S)-2-bromohexadecanoic acids with
e.e.>95% through resolution with the use of a recoverable chiral auxiliary is described. The procedure
involves three reactions: Steglich esterification, DIBAL reduction, and Sharpless oxidation. The assess-
ment of the enantiomeric purity is based on NMR analysis by using (1R,2R)-(+)-diphenylethane-1,2-
diamine as a chiral solvating agent. © 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
Determination of the absolute configuration of chiral molecules holds great scientific and
technical importance, and has been a very active research subject. X-ray diffraction, polarimetry,
NMR analysis, and circular dichroism are among the established and commonly used methods.
In 1998, Flynn and coworkers reported the direct determination of the chirality of organic
molecules by scanning tunneling microscopy (STM).1 When (RS)-2-bromohexadecanoic acid
was adsorbed as a two-dimensional crystal onto the basal plane of graphite, these molecules
segregated on the surface into domains of pure (R) or (S) enantiomers. The atomic resolution
obtained in the STM images of these species allows a direct assignment of the chirality of
individual molecules. When assigning the identity of atoms in the images of 2-bromohexa-
decanoic acid, it was assumed that the molecules were lying trans in the plane. The dark spot
was assigned to the carboxyl group and the large bright spot was assigned to the bromine atom,
which is thought to necessarily point up from the graphite substrate. All of these assumptions
are well supported by previous studies.2 However, it is necessary to obtain an enantiomerically
pure sample, image it, and compare the domains to the previously imaged domains. To this end,
enantiomerically pure (R)- and (S)-2-bromohexadecanoic acids have to be made available. The
desired enantiomeric excess (e.e.) was set to be >95%.
* Corresponding author. E-mail: jg133@columbia.edu
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00388-8

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There are two conceivable methods to prepare enantiomerically pure (R)- and (S)-2-bromo-
hexadecanoic acids with e.e. higher than 95%: a multi-step synthesis or resolution of the racemic
2-bromohexadecanoic acid, which is commercially available and inexpensive. Basically, two
synthetic protocols have been reported in the literature: (1) diastereoselective bromination,3 and
(2) enantioselective diazotization and bromide displacement processes.4–6 As far as the title
compounds are concerned, diastereoselective bromination followed by removal of the chiral
auxiliary allowed synthesis of both enantiomers of 2-bromohexadecanoic acid with an e.e. of
about 70%.7 Alternatively, the racemic a-haloalkanoic acids can be separated by chemical or
biochemical resolution. In the literature, an attempt to prepare (+)-2-bromohexadecanoic acid
by lipase-catalyzed enzymatic resolution of ( )-2-bromohexadecanoic acids was reported.8
Unfortunately, no information about its absolute configuration or its e.e. was given. To the best
of our knowledge, to date no well-established procedure is available to prepare both (R)- and
(S)-2-bromohexadecanoic acids with e.e. higher than 95%.
2. Results and discussion
There are two main difficulties in obtaining enantiomerically pure (R)- and (S)-2-bromohexa-
decanoic acids with high e.e. First, the stereogenic center in the molecule is unstable under both
acidic and basic conditions. The isomerization of the stereogenic center may occur through
enolate formation. Second, the long carbon chain makes 2-bromohexadecanoic acid different
from 2-haloalkanoic acids with short chains, which are the common substrates studied in the
references. Many methods provide excellent results on short-chain compounds, but fail on the
16-carbon compounds. For example, the kinetic resolution by lipase worked very well with
3-carbon compounds, affording products with e.e. 95% or higher.8 However, the e.e. of the
6-carbon product was about 73%.8 When we applied this method to 2-bromohexadecanoic acid,
the e.e. of the resolved acid was about 60% or lower. Dehydroabiethylamine was used as a
resolving agent to resolve racemic 2-bromobutyric acid by forming two diastereomeric salts, one
of which crystallized while the other was left in the solution.9 When dehydroabiethylamine was
combined with racemic 2-bromohexadecanoic acid, the reaction mixture underwent a rapid
precipitation instead of the desired fractional crystallization. This drastic difference between our
experiment and the result with 2-bromobutyric acid was assumed to come from the difference in
the chain length.
From the very beginning, we intended to avoid multi-step syntheses, and planned to make the
products in an efficient manner. After we tested the resolution with lipase and dehydroabiethyl-
amine and no satisfactory results were obtained, we decided to focus our effort on resolution
with chiral alcohols, which ended up with success.
The idea of using a chiral alcohol to resolve racemic acids is straightforward. Theoretically,
two reactions and one separation would be necessary. First, the racemic acid is reacted with the
chiral alcohol to give two diastereomeric esters. These two diastereomers should be separable on
thin layer chromatography (TLC) and by column chromatography. After the separation, the
chiral auxiliary is removed without isomerizing the stereogenic centers, to yield the enantiomer-
ically pure acids. Hydrolysis under acidic or basic conditions is the common method for such
removal. However, since the stereogenic center in 2-bromohexadecanoic acid is sensitive to both
acidic and basic conditions, the hydrolysis conditions must be as mild as possible, or a two-step
procedure, reduction and re-oxidation, should be explored. With this idea in mind, we screened

J. Guo et al. / Tetrahedron: Asymmetry 11 (2000) 4105–4111
4107
several ‘chiral alcohols’ for the esterification. These ‘chiral alcohols’ included (1R,2S,5R)-(−)-
menthol, (R)-(+)-sec-phenethyl alcohol, (1S)-endo-(−)-borneol and (R)-(+)-1,1%-bi-2-naphthol.
Experimental results demonstrated that (R)-(+)-1,1%-bi-2-naphthol afforded the best separation.
The diastereomers from the esterification reaction of (R)-(+)-1,1%-bi-2-naphthol with racemic
2-bromohexadecanoic acid showed two spots on TLC and could be separated in large quantity
by column chromatography (see Scheme 1). The rationale behind selecting (R)-(+)-1,1%-bi-2-
naphthol as the ‘chiral alcohol’ was that a phenol ester was supposed to be easier to hydrolyze
than alcohol esters, so hydrolysis conditions to remove the chiral auxiliary might be tuned mild
enough to avoid epimerization of the chiral center.
Scheme 1. (a) DCC, DMAP, CH2Cl2, rt. (b) Separation via MPLC (see Section 4)
The experimental procedure is shown in Schemes 1 and 2. The first step was a Steglich
esterification reaction. The total yield of two diastereomeric mono-esters, 3 and 4, was 92%.
Scheme 2. (a) DIBAL, −78°C, CH2Cl2. (b) NaIO4, RuCl3, CCl4/CH3CN/H2O, rt

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Bis-ester was isolated in 8% yield and characterized by NMR and MS measurements. After two
times of development in 10:1 hexanes:EtOAc, the solution of the mono-esters clearly showed
two distinct spots on the TLC silica gel plate, both under UV detection at short wavelength and
after staining with CAM (cerium(IV) sulfate and ammonium molybdate in 10% aqueous H2SO4)
solution. The Rf values of these two spots were 0.5 and 0.4, respectively. The almost equal
intensity on TLC plate and the roughly 1:1 ratio of peak integration in the NMR spectrum of
the mixture suggested that there was no kinetic resolution. In other words, the two acid
enantiomers reacted with the chiral auxiliary at almost the same rate.
Although the two diastereomers were separable by plate chromatography or flash column
chromatography, a better result was achieved by using MPLC (medium-pressure liquid chro-
matography). When 1000 mg of mono-ester mixture was applied to the MPLC operation, about
350 mg of pure (+)-3 and 300 mg of pure (+)-4 were obtained. With two pure diastereomers in
hand, it was time to remove the auxiliary and retrieve the optically pure acids. When we tested
hydrolysis under a mild basic condition, epimerization was observed by TLC monitoring.
Without further testing more hydrolysis conditions, we shifted to the alternative method, the
reduction and re-oxidation sequence, which is shown in Scheme 2. As far as the reduction was
concerned, three reductants (NaBH4, LiBH4, and DIBAL) were compared. NaBH4 and LiBH4
gave a slow reaction with a low conversion, but DIBAL could completely convert the starting
material to the product in two hours, from which two optically pure alcohols, (+)-5 and (−)-5,
were obtained in good yields.
Based on the reported [h]D values of (R)-(+)-2-bromo-1-hexadecanol and (S)-(−)-2-bromo-1-
hexadecanol,7 we concluded that (+)-5 was the R-isomer, while (−)-5 was the S-isomer. Thus,
the first diastereomeric ester (+)-3 was formed from (R)-2-bromohexadecanoic acid, and the
second diastereomeric ester (+)-4 was formed from (S)-2-bromohexadecanoic acid. About 86%
of the (R)-(+)-1,1%-bi-2-naphthol (R)-(+)-2 used in the Steglich reaction was recovered from the
DIBAL reduction. Optical rotation measurement showed the recovered binaphthol had the same
optical purity as the commercial one, which indicated no loss of optical purity occurred to the
chiral auxiliary and it could be re-used. The last step was to oxidize the alcohol to acid by
Sharpless oxidation, which is a known experiment.7 The reaction went smoothly to afford
(R)-2-bromohexadecanoic acid or (S)-2-bromohexadecanoic acid in good yields.
1
The enantiomeric purity of the acids was assessed from the H NMR spectrum using
(1R,2R)-(+)-diphenylethane-1,2-diamine as a chiral solvating agent.10,11 The diamine CDCl3
1
solution was added, portion by portion, to the CDCl3 solution of the acid. Then the H NMR
spectrum of the resultant mixture was recorded at once. For the ( )-2-bromohexadecanoic acid,
in the presence of different equivalents of (1R,2R)-(+)-diphenylethane-1,2-diamine, the proton
resonance of H-2 was resolved into two well-defined multiplets of equal intensity. With the
adding of the diamine, although the chemical shifts of the multiplets and the distance between
them varied, two well-resolved multiplets of 1:1 ratio were always observed. For the resolved
(R)-acid, (R)-(+)-1, in the presence of different equivalents of (1R,2R)-(+)-diphenylethane-1,2-
diamine, only one multiplet was observed, with no trace of the other multiplet. This clearly
indicated the e.e. of the resolved (R)-(+)-acid was >95%. Similarly, in the presence of different
equivalents of (1R,2R)-(+)-diphenylethane-1,2-diamine, (S)-(−)-1 also constantly showed a
single multiplet corresponding to the (S)-isomer, with no detectable resonance corresponding to
the (R)-isomer. As in the previous case, the NMR integration suggested >95% enantiomeric
excess for (S)-(−)-1.

J. Guo et al. / Tetrahedron: Asymmetry 11 (2000) 4105–4111
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3. Conclusion
In general, a long hydrocarbon chain on a-haloalkanoic acids makes resolution more difficult.
The procedure disclosed herein allows for an efficient resolution of (R)- and (S)-2-bromohexa-
decanoic acids with high enantiomeric purity (e.e.>95%), starting from commercially available
and inexpensive ( )-2-bromohexadecanoic acids. This protocol provided the desired two enan-
tiomers with required optical purity, which are currently under STM study.12
4. Experimental
4.1. General
All materials were purchased from Aldrich. Solvents were distilled prior to use and dried by
standard methods. Analytical and preparative TLC was run on precoated silica-gel plates
(Analtech, 20×20 cm, 250 or 500 microns). The MPLC system consisted of an FMILAB Q-1SSY
,
pump (Fluid Metering, Inc.) and an ULTRA Pack™ SI-40B column (Silica gel, 40 mm, 60 A,
size B 26×300 mm) (Yamazen Corporation). The eluting solvent was 20:1 hexanes:EtOAc. The
flow rate was set to 6 milliliters per minute. When 1000 mg of mono-ester mixture was applied
to the MPLC operation, about 350 mg of pure 3 and 300 mg of pure 4 were obtained. NMR
data were collected on Bruker DMX 500 (500 MHz), 400 (400 MHz), and 300 (300 MHz) NMR
1
spectrometers employing standard pulse sequences, operating at 500, 400, and 300 MHz for H
NMR and 75 MHz for 13C NMR, respectively. Chemical shifts of 1H and 13C NMR signals were
determined in ppm relative to the solvent signals of residual CDCl3 at lH 7.24 ppm and lC 77.4
ppm, respectively. FAB mass spectra were recorded using a JEOL JMS-HX 110HF/HX 110HF
tandem mass spectrometer. Infrared spectra were recorded on Perkin–Elmer Paragon 1000
FT-IR or Perkin–Elmer 1420 ratio recording infrared spectrophotometers. Optical rotations
were measured on a Jasco DIP-1000 digital polarimeter.
4.2. Preparation of (R)-1,1%-bi-2-naphthyl (R)-2-bromohexadecanoate (+)-3 and (R)-1,1%-bi-2-
naphthyl (S)-2-bromohexadecanoate (+)-4
To a flask which contained 118 mg (0.35 mmol) of racemic 2-bromohexadecanoic acid ( )-1,
100 mg (0.35 mmol) of (R)-(+)-1,1%-bi-2-naphthol ((R)-(+)-2), 80 mg (0.38 mmol) of DCC, and
47 mg (0.38 mmol) of DMAP, was added 8 ml of freshly distilled CH2Cl2. The reaction mixture
was stirred at room temperature for one hour. The solid was filtered off and the organic solution
was concentrated to dryness under reduced pressure and purified by column chromatography
eluting with 20:1 hexanes:EtOAc to yield 194 mg (92.4%) of (+)-3 and (+)-4.
4.2.1. (R)-1,1%-Bi-2-naphthyl (R)-2-bromohexadecanoate (+)-3
[h]1D9=+75.8 (c 1.00, CHCl3). IR (film): 3600–3100, 3020, 2880, 2820, 1730, 1602, 1580 cm−1.
1H NMR (500 MHz, CDCl3): l 8.10 (d, J=8.9 Hz, 1H), 7.98 (d, J=8.2 Hz, 1H), 7.88 (d, J=8.9
Hz, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.53 (t, J=7.0 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H), 7.37–7.25 (m,
7H), 7.05 (d, J=8.4 Hz, 1H), 5.10 (bs, 1H), 3.97 (t, J=7.4 Hz, 1H), 1.53 (m, 2H), 1.29 (bs,
16H), 1.19 (m, 2H), 1.10 (m, 2H), 0.99 (m, 3H), 0.90 (t, J=7.0 Hz, 4H). 13C NMR (75 MHz,
CDCl3): l 169.5, 152.2, 148.0, 133.9, 133.8, 132.8, 131.5, 131.0, 129.5, 128.8, 128.4, 128.1, 127.3,

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J. Guo et al. / Tetrahedron: Asymmetry 11 (2000) 4105–4111
127.0, 126.2, 124.9, 124.0, 123.5, 121.4, 118.6, 114.0, 45.3, 34.7, 32.4, 30.2, 30.1, 29.9, 29.8, 29.5,
29.1, 27.1, 23.1, 14.6. HRFABMS calcd for C36H43BrO3: 602.2396; found: 602.2392.
4.2.2. (R)-1,1%-Bi-2-naphthyl (S)-2-bromohexadecanoate (+)-4
[h]1D8=+32.6 (c 1.00, CHCl3). IR (film): 3600–3100, 3022, 2885, 2821, 1732, 1602, 1580 cm−1.
1H NMR (500 MHz, CDCl3): l 8.09 (d, J=8.9 Hz, 1H), 7.98 (d, J=8.2 Hz, 1H), 7.88 (d, J=8.9
Hz, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.53 (t, J=7.0 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H), 7.37–7.24 (m,
7H), 7.06 (d, J=8.3 Hz, 1H), 5.06 (bs, 1H), 3.98 (t, J=7.5 Hz, 1H), 1.40 (m, 2H), 1.29 (bs,
16H), 1.17 (m, 2H), 1.02 (m, 3H), 0.89 (t, J=7.1 Hz, 5H), 0.71 (m, 1H). 13C NMR (75 MHz,
CDCl3): l 169.3, 152.1, 147.9, 133.9, 133.8, 132.8, 131.4, 130.9, 129.5, 128.8, 128.4, 128.1, 127.3,
127.0, 126.1, 124.9, 124.0, 123.5, 121.4, 118.6, 113.9, 45.5, 34.6, 32.4, 30.1, 30.04, 29.9, 29.8, 29.4,
29.1, 27.1, 23.1, 14.6. HRFABMS calcd for C36H43BrO3: 602.2396; found: 602.2410.
4.3. (R)-(+)-2-Bromo-1-hexadecanol (R)-(+)-5
To a dried flask which contained 59.6 mg (0.1 mmol) of (+)-3 was added 3 ml of freshly
distilled CH2Cl2. The solution was cooled to −78°C. Then 0.25 ml of 1 M DIBAL hexanes
solution was slowly added. The reaction mixture was stirred at −78°C and monitored by TLC
until starting material was completely consumed. 0.5 ml of MeOH was added to the reaction
mixture, then 5 ml of CH2Cl2 was added and the mixture was brought to room temperature. 1
ml of water was added and the mixture was stirred for 30 minutes. After filtration through
Celite, the mixture was concentrated under reduced pressure and separated by flash chromatog-
raphy eluting with 5% EtOAc in hexanes to yield 24.6 mg (77.6%) of (R)-(+)-5 (with recovered
24.1 mg (86%) of binaphthol (R)-(+)-2). [h]2D2=+20.4 (c 1.00, CHCl3). IR (film): 3600–3100,
1
2920, 2851, 1457, 1376, 1071, 1029, 720, 634, 531 cm−1. H NMR (400 MHz, CDCl3): l 4.12 (m,
1H), 3.76 (m, 2H), 1.97 (bs, 1H), 1.82 (m, 2H), 1.50 (m, 1H), 1.40 (m, 1H), 1.23 (bs, 22H), 0.86
(t, J=7.0 Hz, 3H). 13C NMR (75 MHz, CDCl3): l 67.7, 60.6, 35.3, 32.3, 30.1, 29.9, 29.8, 29.76,
29.4, 27.8, 23.1, 14.5. HRFABMS calcd for C16H33BrO: 321.1618; found: 321.1608.
4.4. (S)-(−)-2-Bromo-1-hexadecanol (S)-(−)-5
Following the same procedure, from 420 mg of ester (+)-4, 193 mg (86%) of alcohol (S)-(−)-5
was obtained. [h]D20=−19.1 (c 1.00, CHCl3). IR (film): 3600–3100, 2920, 2851, 1457, 1376, 1071,
1
1029, 720, 634, 531 cm−1. H NMR (400 MHz, CDCl3): l 4.12 (m, 1H), 3.76 (m, 2H), 1.99 (bs,
1H), 1.82 (m, 2H), 1.50 (m, 1H), 1.40 (m, 1H), 1.24 (bs, 22H), 0.86 (t, J=7.0 Hz, 3H). 13C NMR
(75 MHz, CDCl3): l 67.7, 60.6, 35.3, 32.3, 30.1, 29.9, 29.8, 29.75, 29.4, 27.8, 23.1, 14.5.
HRFABMS calcd for C16H33BrO: 321.1618; found: 321.1629.
4.5. (R)-(+)-2-Bromohexadecanoic acid (R)-(+)-1
A solution of 70 mg (0.22 mmol) of alcohol (R)-(+)-5 in 1.4 ml of CCl4, 1.4 ml of CH3CN was
treated with 2.1 ml of H2O, 190 mg (0.89 mmol) of NaIO4 and 17 mg (0.082 mmol) of
RuCl3·3H2O. The resulting heterogeneous mixture was vigorously stirred at room temperature.
After 3 and a half hours, the reaction mixture was diluted with 14 ml CH3CN, the remaining
solids were removed through Celite, and the solution was evaporated to dryness under reduced
pressure, then was added 40 ml CH2Cl2 and washed with water. The organic layer was dried

J. Guo et al. / Tetrahedron: Asymmetry 11 (2000) 4105–4111
4111
over Na2SO4, filtered and evaporated to give crude acid, which was purified by boiling in
hexanes in the presence of charcoal. After filtration and evaporation, the solid was left overnight
and then dissolved in MeCN. Filtration through Celite and evaporation afforded (R)-(+)-1 as a
white solid (58 mg, 80%). [h]2D2=+21.2 (c 1.00, CHCl3). IR (CHCl3 solution): 3300–2500, 2981,
1
2890, 2820, 1699 cm−1. H NMR (400 MHz, CDCl3): l 4.22 (t, J=7.4 Hz, 1H), 2.01 (m, 2H),
1.46 (m, 1H), 1.38 (m, 1H), 1.24 (bs, 22H), 0.86 (t, J=6.9 Hz, 3H). 13C NMR (75 MHz, CDCl3):
l 175.9, 45.7, 35.1, 32.3, 30.0, 29.9, 29.8, 29.7, 29.2, 27.6, 23.1, 14.5. HRFABMS calcd for
C16H31BrO2: 335.1586; found: 335.1597.
4.6. (S)-(−)-2-Bromohexadecanoic acid (S)-(−)-1
Following the same procedure, from 129 mg of (S)-(−)-5, 110 mg (82%) of (S)-(−)-1 was
obtained. [h]D22=−21.2 (c 1.00, CHCl3). IR (CHCl3 solution): 3300–2500, 2981, 2890, 2820, 1699
1
cm−1. H NMR (400 MHz, CDCl3): l 4.22 (t, J=7.4 Hz, 1H), 2.01 (m, 2H), 1.46 (m, 1H), 1.38
(m, 1H), 1.24 (bs, 22H), 0.86 (t, J=6.9 Hz, 3H). 13C NMR (75 MHz, CDCl3): l 176.1, 45.8,
35.1, 32.3, 30.1, 29.9, 29.8, 29.7, 29.2, 27.6, 23.1, 14.5. HRFABMS calcd for C16H31BrO2:
335.1586; found: 335.1588.
Acknowledgements
This work was carried out in Professor Koji Nakanishi’s research group at Columbia
University. We gratefully acknowledge their invaluable support and help. We thank Vinka
Parmakovich for the MS measurements. These studies were made possible by the National
Science Foundation and I. I. Rabi Scholars program.
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