Efficient separation of diastereomeric mixtures of syn - And anti -2,4-pentanediol

Article abstract of DOI:10.1021/acs.oprd.5b00043

A simple and practical process was developed for the efficient separation of diastereomeric syn- and anti-2,4-pentanediol by selective acetalization of a diastereomeric mixture of the 2,4-pentanediols and selective hydrolysis of the corresponding acetals. The process relies upon the reaction rate differences of syn-2,4-pentanediol (syn-diol) and anti 2,4-pentanediol (anti-diol) in acetalization and of the corresponding acetals in hydrolysis: the syn-diol reacts faster to form a more stable acetal than the anti-diol, which in turn is more susceptible to hydrolysis by Bronsted acid. Acetalization of a 2,4-pentanediol diastereomeric mixture (syn/anti = 45:55) with acetophenone (0.95 equiv relative to syn-diol) leads to the formation of a syn-enriched acetal mixture with a syn/anti diastereomeric ratio (dr_s/a) of 6:1, leaving an anti-enriched diol mixture (dr_s/a = 1:7). Subsequent kinetic resolution via selective hydrolysis of the minor anti-acetal with a catalytic amount of 1.0 N HCl at ambient temperature affords the pure syn-acetal (dr_s/a > 99:1) in the organic phase and the anti-enriched 2,4-pentanediols (dr_s/a = 1:6) in the aqueous phase, which are conveniently separated by a phase cut. Hydrolysis of the syn-acetal is facile in alcohol solvents at elevated temperatures (60-80 °C), yielding the pure syn-diol. A second acetalization of the anti-enriched 2,4-pentanediols leads to the pure anti-2,4-pentanediol. This separation gives the syn-diol in 75-79% yield with dr_s/a > 99:1 and the anti-diol in 79-85% yield with dr_a/s > 98:2. Additionally, the acetophenone used for the acetalization can be recovered in 88-92% yield, and therefore, the overall process is high-yielding, atom-economical, and potentially recyclable.

Full text of DOI:10.1021/acs.oprd.5b00043

Article
pubs.acs.org/OPRD
Efficient Separation of Diastereomeric Mixtures of syn- and anti-2,4-
Pentanediol
Heqi Pan, Siyu Tu, and Chunming Zhang*
Corporate R&D, The Dow Chemical Company, 1710 Building, Midland, Michigan 48674, United States
Andrew Young and Philip P. Fontaine
Performance Plastics R&D, The Dow Chemical Company, 2301 North Brazosport Boulevard, Freeport, Texas 77541, United States
S
* Supporting Information
ABSTRACT: A simple and practical process was developed for the efficient separation of diastereomeric syn- and anti-2,4-
pentanediol by selective acetalization of a diastereomeric mixture of the 2,4-pentanediols and selective hydrolysis of the
corresponding acetals. The process relies upon the reaction rate differences of syn-2,4-pentanediol (syn-diol) and anti 2,4-
pentanediol (anti-diol) in acetalization and of the corresponding acetals in hydrolysis: the syn-diol reacts faster to form a more
stable acetal than the anti-diol, which in turn is more susceptible to hydrolysis by Brønsted acid. Acetalization of a 2,4-
pentanediol diastereomeric mixture (syn/anti = 45:55) with acetophenone (0.95 equiv relative to syn-diol) leads to the formation
of a syn-enriched acetal mixture with a syn/anti diastereomeric ratio (drs/a) of 6:1, leaving an anti-enriched diol mixture (drs/a
1:7). Subsequent kinetic resolution via selective hydrolysis of the minor anti-acetal with a catalytic amount of 1.0 N HCl at
ambient temperature affords the pure syn-acetal (drs/a > 99:1) in the organic phase and the anti-enriched 2,4-pentanediols (drs/a
=
=
1:6) in the aqueous phase, which are conveniently separated by a phase cut. Hydrolysis of the syn-acetal is facile in alcohol
solvents at elevated temperatures (60−80 °C), yielding the pure syn-diol. A second acetalization of the anti-enriched 2,4-
pentanediols leads to the pure anti-2,4-pentanediol. This separation gives the syn-diol in 75−79% yield with drs/a > 99:1 and the
anti-diol in 79−85% yield with dra/s > 98:2. Additionally, the acetophenone used for the acetalization can be recovered in 88−
92% yield, and therefore, the overall process is high-yielding, atom-economical, and potentially recyclable.
that features a diastereoselective acetalization and a hydrolytic
kinetic resolution of the corresponding acetals 2, which leads to
a high yield and high diastereomeric purity of both syn-1 and
anti-1 (Scheme 1). Additionally, the acetophenone used for the
acetalization can be recovered in high yield, resulting in an
overall process that is atom-economical and potentially
recyclable.
INTRODUCTION
■
1,3-diols are present, in either a syn or anti configuration, in a
large variety of natural products and are valuable intermediates
in the synthesis of drugs, natural products, and novel ligands for
homogeneous catalysis.1 These useful building blocks are often
produced as mixtures of syn and anti diastereomers in varying
ratios, and separation of the two isomers can be challenging.
For example, separation of the syn and anti diastereomers of
2,4-pentanediol (1) has been a laborious and inefficient task.2−5
Pritchard and Vollmer reported a separation of syn- and anti-
2,4-pentanediol diastereomers by formation of the cyclic sulfite
ester diastereomers followed by separation via fractional
distillation (a difficult operation because of their similar boiling
points) and then hydrolysis.2 Diastereoselective formation of
the syn cyclic sulfite ester could be effected in a syn/anti
diastereomeric ratio (drs/a) of 96:4, but subsequent alkaline
hydrolysis of the sulfite ester furnished syn-1 with only
moderate enrichment (drs/a = 69:31).3 Alternatively, Gordillo
RESULTS AND DISCUSSION
■
First-Generation Process for the Separation of syn-
and anti-2,4-Pentanediol. Our research program required
large quantities of diastereomerically pure syn-2,4-pentanediol
(syn-1) and anti-2,4-pentanediol (anti-1). Commercially
available 2,4-pentanediol is a mixture of the syn and anti
diastereomers in a ratio of approximately 1:1. After reviewing
potential synthetic routes, we chose to modify the cyclic acetal
separation method originally developed by Nichols and co-
workers for the preparation of the syn-1 (Scheme 2). It featured
a selective acetalization of syn-1, isolation of the resulting syn-
acetal (syn-2) by recrystallization, and then hydrogenolysis of
the acetal protecting group.5
́
and Hernandez obtained syn-1 via conversion to a cyclic
phosphorochloridite in low yield (23%), albeit with high
selectivity (drs/a = 99:1).4 Recently, Nichols and co-workers
prepared syn-1 by selective formation of the syn-acetal (syn-2)
with acetophenone and subsequent hydrogenolysis of the acetal
protecting group.5 None of the previously reported methods
are adequate to obtain both syn-1 and anti-1 in high
diastereomeric purity and high yield. Herein we report a
simple and efficient separation of 2,4-pentanediol diastereomers
In syn-2, the two methyl groups reside in equatorial positions
in the preferred chair conformation. In contrast, in anti-2 one of
the methyl groups is forced into an axial position, where it
Received: February 10, 2015
© XXXX American Chemical Society
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DOI: 10.1021/acs.oprd.5b00043
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pentanediols (syn/anti = 45:55) with acetophenone was carried
out in refluxing hexane in the presence of a catalytic amount of
p-toluenesulfonic acid monohydrate (PTSA), and water
generated in situ was azeotropically removed using a Dean−
Stark trap with a condenser. The use of 1.3 equiv of
acetophenone (relative to syn-1) yielded a mixture of syn-
and anti-acetals 2 with drs/a = 3:1.6 The remaining unreacted
diol 1 was highly enriched in the anti diastereomer anti-1 (drs/a
= 6:94). Reducing the amount of acetophenone to 0.95 equiv
Scheme 1. Separation of syn- and anti-2,4-pentanediol
improved the syn enrichment in the resulting acetal from drs/a
=
3:1 to 6:1, while the anti enrichment of the unreacted 1 was
reduced to drs/a = 11:89 (Table 1). Further reduction of the
acetophenone loading to further enrich syn-2 was not pursued,
as it would lead to decreased anti enrichment in the unreacted
1. Subjecting the recovered unreacted 1 to a second
acetalization with 1.3−1.5 equiv of acetophenone (relative to
the remaining syn-1) resulted in a high enrichment of anti-1
(drs/a < 2:98), which was isolated in 79−85% yield (based on
anti-1 in the starting diastereomeric mixture). This enabled us
to obtain anti-1 in high yield with high diastereomic purity.
The pure syn-2 was initially obtained by recrystallization of
syn-enriched 2 (drs/a = 6:1) from isopropanol.5 This gave syn-2
in 50−55% yield (based on syn-1) with drs/a = 98:2. However,
approximately 40% of the syn-2 remained in the filtrate and was
not recovered. The syn/anti ratio of 2 in the filtrate varied from
2:1 to 1:1 (Scheme 4).
The purified syn-2 was then subjected to hydrogenolysis in
the presence of 5% palladium on carbon (5% Pd/C) in
methanol at a hydrogen pressure of 50−60 psi, which gave syn-
1 with drs/a = 98:2 (Scheme 5). While we were able to obtain
syn-1 with high diastereomic purity by hydrogenolysis, we
occasionally experienced incomplete reaction, likely as a result
of catalyst deactivation. In such cases, it was necessary to
resubject the materials to the hydrogenolysis conditions with
new catalyst.
Study of Hydrolysis of the Acetals. Although we were
able to obtain both syn-1 and anti-1 by minor modification of
Nichols’ method, this process suffered from a substantial loss of
yield in the recrystallization of the syn-acetal and occasional
incomplete hydrogenolysis in the cleavage of the acetal
protecting group. Therefore, a more efficient and robust
process for separation of syn- and anti-2,4-pentanediol was
desired. Thus, we explored alternative methods for the
purification of syn-2 and the cleavage of the acetal protecting
group.
experiences unfavorable syn-pentane interactions with the acetal
substituent (Scheme 3). These diaxial nonbonded interactions
disfavor the formation of anti-2. Thus, the equilibrium position
of an acetalization using a limiting amount of acetophenone to
react with a mixture of syn-1 and anti-1 should favor the
formation of syn-2. This selective acetalization was indeed
observed and was utilized to obtain syn-1.5 We envisioned that
by adapting this reaction we could achieve our desired isolation
of both 2,4-pentanediol diastereomers.
It is well-known that hydrolysis of an acetal generally occurs
under acidic conditions, and different hydrolysis reactivities for
diastereomeric syn- and anti-acetals has been reported.7−9 We
We first examined the impact of the acetophenone loading
on the acetalization selectivity. The reaction of a mixture of 2,4-
Scheme 2. Nichols’ cyclic acetal route to syn-2,4-pentanediol
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Scheme 3. Configurations of the syn- and anti-acetals
Table 1. Effects of the acetophenone loading on the
Scheme 5. Hydrogenolysis of syn-2 to syn-1
acetalization selectivity
starting diol
syn/anti
equiv of
acetophenone
resulting acetal
recovered diol
a
b
b
entry
syn/anti
syn/anti
1
2
3
45:55
45:55
1.3
3:1
6:1
2:1
6:94
0.95
1.3
11:89
c
11:89
2:98
a
b
Relative to syn-1 in the starting diastereomeric mixture. Estimated
c
1
by H NMR analysis. Recovered from entry 2.
envisioned that the isomeric mixture of acetal 2 might be
separable via a kinetic resolution. Specifically, selective
hydrolysis of anti-2 in a mixture of syn-2 and anti-2 could
lead to pure syn-2.
We examined the hydrolysis of a mixture of syn-2 and anti-2
(drs/a = 2:1, which was recovered from the supernatant of the
syn-2 recrystallization step) with 5 mol % 1.0 N hydrochloric
acid solution in different solvents (Table 2). It was found that
anti-2 was selectively hydrolyzed and syn-2 was left essentially
untouched when the hydrolysis was conducted at room
temperature in aprotic solvents such as tetrahydrofuran
(THF), methylene chloride (CH2Cl2), toluene, and hexane.
In this manner, syn-2 was obtained in 93−95% yield with
excellent diastereomeric purity (drs/a > 99:1), and anti-1 was
also isolated with high diastereomeric purity (drs/a = 4−7:100).
Conversely, in a protic solvent such as methanol (CH3OH), the
hydrolysis proceeded faster and with lower selectivity, leading
to a lower yield of syn-2 and a less anti-enriched diol 1 mixture.
The hydrolysis of syn-2 (drs/a = 99:1) was then examined in
methanol. It was found that the hydrolysis was slow at ambient
Scheme 4. Initial preparation of syn-2 and anti-1
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a
Table 2. Hydrolysis of a mixture of syn- and anti-2 in different solvents
syn-acetal
anti-diol
b
c
b
d
entry
solvent
time (h)
syn/anti
yield (%)
syn/anti
yield (%)
1
2
3
4
5
hexane
toluene
CH2Cl2
THF
63
60
48
16
16
99:1
99:1
99:1
99:1
99:1
95
95
95
93
74
5:100
7:100
4:100
5:100
50:100
85
84
87
80
CH3OH
110
a
b
1
Hydrolysis was conducted with 20 mmol of acetal and 1 mmol of 1.0 N HCl in 30 mL of a solvent at ambient temperature. Determined by H
c
d
1
NMR analysis. Yields estimated by H NMR analysis. Isolated yields based on mass.
Scheme 6. Hydrolysis of syn-2
temperature (20−25 °C). Unreacted syn-2 was still observed
after 40 h. The reaction was accelerated at elevated temperature
(60 °C) and was complete in 6−10 h. syn-1 was isolated in 90−
95% yield (drs/a = 99:1), and the acetalizing reagent
acetophenone was recovered in 88−100% yield (Scheme 6).
This study showed that selective hydrolysis of anti-2 could
happen in an aprotic solvent, while the hydrolysis of syn-2 was
facile at elevated temperature in a polar protic solvent. This
hydrolytic kinetic resolution strategy is a key element of the
efficient separation of syn-1 and anti-1.
Second-Generation Process for the Separation of syn-
and anti-2,4-Pentanediol. Implementation of the selective
hydrolysis strategy started with direct treatment of the
acetalization reaction mixture with 5 mol % 1.0 N HCl at
ambient temperature. anti-2 was selectively hydrolyzed as
desired, affording a mixture of syn-2 (drs/a = 100:1 to 100:0),
acetophenone, and anti-enriched 1 (drs/a = 1:6). This one-pot
procedure accomplished the selective acetalization of syn-1 and
selective hydrolysis of anti-2, streamlining the separation and
improving the recovery of both diastereomers. Phase separation
of the reaction mixture gave an organic phase containing syn-2
(drs/a =100:1−0) along with acetophenone and an aqueous
phase containing anti-enriched 1 (drs/a = 1:6).
Next, hydrolysis of the syn-2 with 5 mol % 1.0 N HCl in
methanol10 at 60 °C furnished the desired syn-1 and
acetophenone. These products were conveniently separated
by organic/aqueous extraction. syn-1 was obtained in 75−79%
yield (based on syn-1 in the starting diastereomic mixture of 1)
with high diastereomeric purity (drs/a = 100:1 to 100:0).
Meanwhile, the acetophenone was recovered in 92% yield.
Finally, pure anti-1 was obtained by a second selective
acetalization of the anti-enriched 1 mixture. The aqueous phase
from the previous acetalization containing the anti-enriched 1
(drs/a = 1:6) was directly treated with acetophenone (1.3 equiv
with respect to the minor component syn-1) in refluxing hexane
and the water was azeotropically distilled out. This afforded
pure anti-1, which was isolated in 79−85% yield (relative to
anti-1 in the starting diastereomic mixture of 1) with drs/a
=
1:100 to 2:100. A crop of acetals 2 (drs/a = 2:1 to 1:1) in yields
of 15−20% (relative to the total starting 1) was also isolated.
This acetal mixture could be recycled into subsequent batches
in the hydrolytic kinetic resolution step to obtain additional syn-
1 and anti-1. Theoretically, the yields of syn-1 and anti-1 both
could be 100% via recycling and reusing the crop of acetal
mixture from the second acetalization. The result is a simple
and efficient process for separation and isolation of syn-1 and
anti-1 (Scheme 7). This improved process was also applied to
prepare other syn- and anti-1,3-diols.11
CONCLUSION
■
An efficient process for the separation and isolation of syn- and
anti-2,4-pentanediol was developed, inspired by the Nichols
cyclic acetal method. Selective acetalization of the syn-diol
diastereomer from a mixture of syn- and anti-diols (syn/anti =
45:55) gave a mixture of syn-enriched acetals (drs/a = 6:1) and
anti-enriched diols (drs/a ≈ 1:7). Without isolation, the
resulting mixture was treated with 5 mol % 1.0 N HCl to
afford pure syn-acetal (syn-2) and anti-enriched diol 1. This
facile one-pot synthesis of syn-2 streamlined the experimental
procedure and eliminated the recrystallization step, leading to
improved yields of syn-2. Moreover, cleavage of the acetal
protecting group of syn-2 was accomplished by a convenient
hydrolysis in methanol with 5 mol % 1.0 N HCl, which
replaced the previous need for high-pressure hydrogenolysis.
The hydrolysis method offered syn-1 in both high overall yield
(75−79%) and excellent diastereomeric purity (drs/a = 100:0−
1) and enabled recovery of the acetophenone (92%). anti-1 was
also readily obtained in 79−85% yield with high diastereomeric
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Scheme 7. Second-generation process for the separation of syn- and anti-2,4-pentanediol
1
purity (drs/a = 1−2:100). As the acetal mixture obtained from
the second acetalization could be recycled to obtain additional
syn-1 and anti-1, theoretically syn- and anti-2,4-pentanediol
could be quantitatively obtained. Compared with the previous
process involving recrystallization and hydrogenolysis steps,
this simplified process is more cost-effective, more robust for
scale-up, and presents fewer safety concerns. Furthermore, this
is the only method that affords both diastereomers of 2,4-
pentanediol in high purity. Several hundred grams each of syn-
and anti-2,4-pentanediol were conveniently prepared. Applica-
tion of this facile method to the separation of other syn- and
anti-1,3-diols is ongoing.11
were recorded on a Bruker-400 (FT 400 MHz, H; 101 MHz,
13C) instrument in CDCl3.
First-Generation Process. Acetalization of 2,4-Pentane-
diol with Acetophenone. 2,4-Pentanediol (115.77 g, a mixture
of syn and anti diastereomers with drs/a = 45:55 as determined
1
by H NMR analysis, of which 500 mmol was the syn-diol and
611 mmol was the anti-diol), PTSA (1.00 g, 5.2 mmol),
acetophenone (57.07 g, 475 mmol, 0.95 equiv relative to the
syn-1), and hexane (600 mL) were loaded into a 1 L three-neck
round-bottom flask equipped with a Dean−Stark trap with a
condenser (for azeotropic removal of water), a thermometer, a
magnetic stirrer, and a nitrogen pad. The mixture was heated
under reflux (reaction temperature 68−70 °C) under a
nitrogen atmosphere for 40 h. Water generated from the
reaction was azeotropically removed into the Dean−Stark trap
(9.20 g of water was collected). The mixture was cooled to
ambient temperature and allowed to settle for phase separation.
The top hexane layer containing the acetal product 2 and the
bottom oil layer containing the unreacted 2,4-pentanediols 1
were separated by phase cut. The ratio of syn-2 and anti-2 in the
EXPERIMENTAL SECTION
■
Solvents and common reagents were purchased from either
Fisher or Sigma-Aldrich and were used as received. 2,4-
Pentanediol was purchased from TCI America, Sigma-Aldrich,
1
or Alfa Aesar, and its drs/a was estimated by H NMR analysis.
Acetophenone was purchased from Alfa Aesar. PTSA and 5%
1
Pd/C were purchased from Aldrich. H and 13C NMR spectra
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1
hexane layer was drs/a = 6.0:1 as determined by H NMR
The filtrate was concentrated under reduced pressure by rotary
evaporation and further dried at 25 °C/1−2 mmHg to afford
the desired syn-1 (15.01 g, 100% yield, drs/a = 100:2). 1H NMR
(400 MHz/CDCl3) δ 4.07 (m, 2H), 2.89 (br, 2H), 1.55 (m,
2H), 1.22 (d, J = 6.0 Hz, 6H). 13C NMR (101 MHz/CDCl3) δ
69.1 (s), 46.5 (s), 24.3 (s).
analysis, and the ratio of syn-1 and anti-1 in the oil layer was
1
drs/a = 1:7.7 as determined by H NMR analysis.
The hexane layer was washed with (1) 2.0 N NaOH (10 mL)
+ water (250 mL) and (2) water (250 mL × 3), concentrated,
and dried under reduced pressure to give crude syn-2 as a
semisolid (92.99 g, 90.1% yield, drs/a = 6:1 as determined by 1H
NMR analysis).
Selective Hydrolysis of the syn/anti-Acetal Mixture with 5
mol % HCl. A mixture of syn- and anti-2 (4.12 g, 20 mmol, drs/a
= 2:1), a solvent (30 mL of CH2Cl2, THF, methanol, toluene,
or hexane), and 1.0 N HCl (1.0 mL, 5 mol %) was stirred at
ambient temperature until anti-2 disappeared as monitored by
1H NMR spectroscopy. Sodium bicarbonate powder (0.164 g,
2.0 mmol) was added, and the mixture was stirred for 30 min.
The volatiles were removed under reduced pressure. The
residual oil was partitioned in water (10 mL) and hexane (50
mL). syn-2 in the hexane layer and diol 1 in the water layer
were separated by phase cut. The hexane layer was
Isolation of anti-2,4-Pentanediol. The above oil layer was
subjected to acetalization again as described above with
acetophenone (13.36 g, 111.2 mmol, 1.4 equiv relative to the
syn-1 in the oil) and PTSA (0.21 g, 1.1 mmol) in hexane (600
mL) at reflux in a 1 L three-neck round-bottom flask equipped
with a Dean−Stark trap with a condenser for azeotropic
removal of water, a thermometer, a nitrogen pad, and a
magnetic stirrer for 16 h (1.90 g of water was collected in the
Dean−Stark trap). The resulting mixture was allowed to settle
and cooled to ambient temperature. The top hexane layer and
the bottom oil layer were separated by phase cut. The oil phase
was diluted with CH2Cl2 (100 mL). Solid sodium bicarbonate
(2.40 g) was added in small portions with stirring. After 15 min
of stirring, the solids were filtered off. The filtrate was
concentrated and dried under reduced pressure to give anti-
2,4-pentanediol (50.24 g, 78.94% yield, drs/a = 2:100 as
determined by 1H NMR analysis). 1H NMR (400 MHz/
CDCl3) δ 4.17 (m, 2H), 2.59 (br, 2H, OH), 1.61 (dd, J1 = 6.4
Hz, J2 = 1.2 Hz, 2H), 1.24 (d, J = 6.4 Hz, 6H). 13C NMR (101
MHz/CDCl3) δ 65.1 (s), 45.8 (s), 23.3 (s).
1
concentrated to dryness and analyzed for syn-2 by H NMR
spectroscopy. Diol 1 in the water phase was isolated according
to the procedure for isolation of anti-1. The results are listed in
Table 2.
Hydrolysis of syn-2 to syn-1. A mixture of syn-2 (2.07 g, 10
mmol, drs/a = 100:2), MeOH (15 mL), and 1.0 N HCl (0.5 mL,
5 mol %) was heated at 58−60 °C for 12 h and then cooled to
ambient temperature. Sodium bicarbonate powder (0.30 g) was
added in small portions with stirring. The resulting mixture was
stirred for 30 min at ambient temperature. The solvent was
evaporated under reduced pressure via rotary evaporation. The
residue was taken up in hexane (100 mL) and water (20 mL).
The resulting mixture was stirred for 30 min and then allowed
to settle for phase separation. The hexane phase was washed
with water (10 mL). The water layers were combined, washed
with hexane (20 mL), and concentrated to dryness by
azeotropic distillation with ethanol. The residue was triturated
with CH2Cl2 (50 mL), and an insoluble solid was filtered off.
The CH2Cl2 filtrate was concentrated to give syn-1 (0.94 g,
90.3% yield, drs/a = 100:2). The hexane layers were combined,
washed with water (20 mL), and then concentrated to dryness,
affording acetophenone (1.05 g, 88% yield).
The hexane phase was concentrated to dryness using a rotary
evaporator under reduced pressure to give a crop of mixed
acetals (21.0 g, drs/a = 1.3:1 as determined by 1H NMR
analysis).
Purification of the syn-Acetal by Recrystallization. Crude
acetal syn-2 (269.61 g, 1307 mmol, drs/a = 6:1) and isopropanol
(80 mL) were loaded into a 500 mL round-bottom flask
equipped with a stirrer, a thermometer, a cold-water condenser,
and a nitrogen pad. The mixture was heated under reflux with
stirring until all of solids were dissolved and then was allowed
to cool to ambient temperature overnight. The resulting
precipitated solid was collected by filtration, rinsed with cold
isopropanol (0−5 °C, 45−50 mL), suction-dried, and dried
under vacuum (1−2 mmHg/ambient temperature) to afford
pure syn-2 (155.2 g, 752.4 mmol, drs/a = 100:2 as determined
by 1H NMR analysis). 1H NMR (400 MHz/CDCl3) δ 7.39 (m,
4H), 7.29 (m, 1H), 3.79 (m, 2H), 1.53 (s, 3H), 1.28−1.37 (m,
2H), 1.22 (d, J = 6.4 Hz, 6H). 13C NMR (101 MHz/CDCl3) δ
142.4 (s), 128.6 (s), 127.4 (s), 126.6 (s), 101.1 (s), 66.5 (s),
40.0 (s), 33.1 (s), 21.8 (s).
Second-Generation Process. One-Pot Process for
Selective Acetalization and Selective Hydrolysis. 2,4-Penta-
nediol (115.77 g, a mixture of syn and anti diastereomers with
drs/a = 45:55 as determined by 1H NMR analysis, of which 500
mmol was syn-1 and 611 mmol was anti-1), PTSA (0.38 g, 2.0
mmol), acetophenone (57.07 g, 475 mmol, 0.95 equiv relative
to syn-1), and hexane (650 mL) were loaded into a 1 L three-
neck round-bottom flask equipped with a Dean−Stark trap with
a condenser for azeotropic removal of water, a thermometer, a
magnetic stirrer, and a nitrogen pad. The mixture was heated
under reflux (reaction temperature 68−70 °C) under a
nitrogen atmosphere for 18 h. Water generated from the
reaction was azeotropically removed into the Dean−Stark trap
The filtrate was concentrated to dryness under reduced
pressure, giving a mixture of syn- and anti-acetals (114.4 g, drs/a
= 2:1).
Hydrogenolysis of syn-2. A 100 mL Parr reactor was
charged with purified syn-2 (30.03 g, 145.6 mmol), 5% Pd/C
(3.00 g), methanol (30 mL), and one drop of concentrated
H2SO4 (0.2−0.3 g). This mixture was subjected to hydro-
genolysis at a hydrogen pressure of 50−80 psi at 60 °C, stirred
at 300 rpm overnight, and cooled to ambient temperature. The
hydrogen was released, and the reaction system was purged
with nitrogen. The mixture was filtered through a bed of Celite
(10 g), and the wet cake was washed with a small amount of
1
(9.56 g of water was collected). H NMR analysis of the
reaction mixture indicated that the ratio of syn-2 and anti-2 was
drs/a = 6.3:1 and the ratio of syn-1 and anti-1 was drs/a = 1:7.0.
The reaction mixture was cooled to ambient temperature (25
°C), and 1.0 N HCl (25 mL, 25 mmol, 5 mol % relative to syn-
1) and the contents of the Dean−Stark trap (9.56 g of water
generated from the condensation and a small amount of
hexanes) were also added to the reaction mixture. The mixture
was stirred at ambient temperature until all of the anti-2
disappeared (17−20 h) as monitored by 1H NMR spectroscopy
(1H NMR analysis of the resulting mixture showed a syn-2/
methanol.12 A sample of the filtrate was analyzed by H NMR
1
spectroscopy (in case the reaction was not complete, the filtrate
was resubjected to hydrogenolysis with new palladium catalyst).
F
DOI: 10.1021/acs.oprd.5b00043
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
acetophenone molar ratio of 6:1 and a syn-1/anti-1 ratio of
1:6). The resulting mixture was allowed to settle for phase
separation. The top hexane layer containing syn-2 and
acetophenone was kept in the reaction vessel (vessel A), and
the bottom aqueous layer containing anti-enriched 1 was
drained into a new vessel (vessel B). The hexane phase in vessel
A was washed with water (25 mL × 3), and the water washings
were added to vessel B.
ASSOCIATED CONTENT
* Supporting Information
Spectral information for 1, syn-1, anti-1, and syn-2. This
material is available free of charge via the Internet at http://
pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: czhang@dow.com.
■
Hydrolysis of syn-2 and Isolation of syn-1 and
Acetophenone. The volatiles in vessel A were evaporated
under reduced pressure to leave a residue of 92.36 g. Methanol
(250 mL), water (10 mL), and 1.0 N HCl (25 mL) were added
to the reaction vessel containing the residue. The mixture was
heated at reflux for 4−8 h, resulting in deprotection of the
acetal group. After the mixture was cooled to ambient
temperature, sodium bicarbonate powder (2.5 g, 30 mmol)
was added in portions, and the reaction mixture was stirred for
1 h and then concentrated under reduced pressure to remove
the volatiles. The residue was taken up in water (50 mL) and
hexane (300 mL), and the solution was stirred for 10−15 min
and then allowed to settle for phase separation. The top hexane
layer was extracted with water (50 mL × 2), and the washes
were combined with the bottom aqueous layer. The hexane
phase was concentrated under reduced pressure using a rotary
evaporator to give acetophenone (50.57 g, 88.6% recovery).
The combined water phases were evaporated and further
azeotropically dried with 100 mL of toluene under reduced
pressure using rotary evaporation. CH2Cl2 (100 mL) was added
to triturate the residue. The insoluble salts were filtered off
through a pad of Celite (5 g), rinsing with CH2Cl2 (50 mL).
The filtrate liquid was concentrated to dryness under reduced
pressure using rotary evaporation and further dried in a vacuum
Notes
The authors declare no competing financial interest.
REFERENCES
■
(1) (a) Bode, S. E.; Wolberg, M.; Muller, M. Synthesis 2006, 557−
̈
588. (b) Oishi, T.; Nakata, T. Synthesis 1990, 635−645.
(c) Rychnovsky, S. D. Chem. Rev. 1995, 95, 2021−2040. (c) Schneider,
C. Angew. Chem., Int. Ed.. 1998, 37, 1375−1378.
(2) (a) Pritchard, J. G.; Vollmer, R. L. J. Org. Chem. 1963, 28, 1545−
1549. (b) Eliel, E. L.; Hutchins, R. O. J. Am. Chem. Soc. 1969, 91,
2703−2715. (c) Bailey, W. F.; Eliel, E. L. J. Am. Chem. Soc. 1974, 96,
1798−1806. (d) For an attempted but unsuccessful separation of syn-
and anti-2,4-pentanediol by fractional distillation, see: Lim, D.;
Kolinsky, M.; Votavova, E.; Ryska, M.; Lukas, J. J. Polym. Sci., Part
B: Polym. Lett. 1966, 4, 573−576.
(3) Caron, G.; Kazlauskas, R. J. Tetrahedron: Asymmetry 1994, 5,
657−664.
(4) Gordillo, B.; Hernan
́
dez, J. Org. Prep. Proced. Int. 1997, 29, 195−
199.
(5) Bonner, L.; Frescas, S.; Nichols, D. E. Synth. Commun. 2004, 34,
2767−2771.
(6) A single epimer was observed for the syn-acetal (syn-2), whereas a
mixture of two epimers was observed for the anti-acetal (anti-2) in a
ratio of approximately 1:1 as determined by H NMR analysis.
(7) Fife, T. H.; Natarajan, R. J. Am. Chem. Soc. 1986, 108, 8050−
8056.
(8) Bode, S. E.; Muller, M.; Wolberg, M. Org. Lett. 2002, 4, 619−621.
(9) Pihlaja, K. Ann. Univers. Turkuensis, Ser. A1 1967, 144; Chem.
Abstr. 1968, 69, 76439.
(10) The reaction proceeded equally well in ethanol and isopropanol.
(11) This method was also used to prepare syn-3,5-heptanediol and
anti-3,5-heptanediol (The Dow Chemical Company, unpublished
results).
(12) The filter cake must be kept wet to prevent it from catching fire.
Thus, after filtration, a small amount of water was added to the wet
cake.
1
oven to give the desired syn-1 (41.47 g, 78.9% yield, drs/a
100:0−1).
=
̈
Purification and Isolation of anti-2,4-Pentanediol. To
vessel B containing the aqueous phase were added hexane (650
mL) and acetophenone (17.0 g, 141 mmol, 1.4 equiv relative to
1
syn-1 as estimated by H NMR analysis). The mixture was
refluxed with a Dean−Stark trap with a condenser for
azeotropic removal of water (36 h). The reaction mixture was
cooled to ambient temperature and allowed to settle for phase
separation. The bottom oil layer containing anti-1 was drained
into a separate vessel (vessel C), and the top hexane layer
remained in vessel B.
Water (50 mL) was added to vessel B to wash the hexane
phase. The water layer was added to vessel C. This process was
repeated one more time.
Hexane (100 mL) was added to vessel C to wash the
combined water phases. The hexane layer was combined with
that in vessel B. The combined hexane solution was
concentrated under reduced pressure to give a crop of mixed
1
acetals (31.5 g, drs/a = 1:0.84 based on H NMR analysis).
The water phase in vessel C was neutralized by the addition
of solid sodium bicarbonate in portions (approximately 3.0 g
total was added). The water was evaporated under reduced
pressure at 45 °C using rotary evaporation. The residue was
dried azeotropically with toluene (100 mL) and then taken up
in CH2Cl2 (100 mL). The insoluble salts were filtered off
through a pad of Celite (5 g), rinsing with CH2Cl2 (50 mL).
The filtrate was concentrated and dried in vacuum to give anti-
1 (52.42 g, 81.6% yield, drs/a = 2:100).
G
DOI: 10.1021/acs.oprd.5b00043
Org. Process Res. Dev. XXXX, XXX, XXX−XXX