Obtaining enriched compounds via a tandem enantioselective reaction and kinetic resolution polishing sequence

Article abstract of DOI:10.1021/jo202653b

Herein we describe a tandem method of coupling an enantioselective reaction with a nonenzymatic kinetic resolution to prepare highly enantioenriched compounds. The procedure employs a moderately selective enantioselective reaction on a ketone or aldehyde to form an enriched alcohol followed by a kinetic resolution of the alcohol to generate ee's of >99% in yields greater than what is possible with a kinetic resolution. This method highlights an avenue to quickly acquire highly enriched compounds without developing and optimizing a new methodology.

Full text of DOI:10.1021/jo202653b

Note
pubs.acs.org/joc
Obtaining Enriched Compounds via a Tandem Enantioselective
Reaction and Kinetic Resolution Polishing Sequence
Maggie I. Klauck, Sachin G. Patel, and Sheryl L. Wiskur*
Department of Chemistry and Biochemistry, University of South Carolina, 631 Sumter Street, Columbia, South Carolina 29208,
United States
S
* Supporting Information
ABSTRACT: Herein we describe a tandem method of
coupling an enantioselective reaction with a nonenzymatic
kinetic resolution to prepare highly enantioenriched com-
pounds. The procedure employs a moderately selective
enantioselective reaction on a ketone or aldehyde to form an
enriched alcohol followed by a kinetic resolution of the alcohol
to generate ee’s of >99% in yields greater than what is possible
with a kinetic resolution. This method highlights an avenue to
quickly acquire highly enriched compounds without developing and optimizing a new methodology.
roducing enantiomerically pure compounds is of great
importance to both academia and industry. Of the
ee.5 While (S)-MeCBS can reduce ketones to their
corresponding alcohols in ee’s greater than 99%, the reaction
is sensitive to slight changes in the reaction conditions.6 This is
demonstrated from our results in Scheme 1 where
P
methods available, enantioselective reactions and kinetic
resolutions are two common means of achieving enantiomeri-
cally enriched compounds. While there are numerous
enantioselective reactions and kinetic resolutions1 that can
generate highly enantioenriched compounds (enantiomeric
excess (ee) >95%, selectivity factor2 (s) >25 respectively), there
are also many procedures that only achieve moderate
selectivities (50−80% ee, s = 10−15). Traditionally, kinetic
resolutions and enantioselective reactions are done independ-
ently of each other. We will show how moderately selective
enantioselective reactions and kinetic resolutions can be carried
out consecutively in one-pot to quickly produce high ee’s
(>95% ee) with yields over 50%. By “polishing” or enhancing
the ee of substrates that generate low ee in their
enantioselective reactions, enantiomerically pure compounds
can be produced quickly without the need to fully optimize
reaction conditions.
This project arose from the problem of substrate variability in
methodology. Employing a known enantioselective reaction on
a new substrate generally results in less than satisfactory results
on the first effort. The methodology can be optimized, but this
costs valuable time and money, and the optimized procedure
may still not generate high ee for the desired substrate. Instead
of perfecting the methodology, a known enantioselective
reaction can be coupled with a known kinetic resolution that
targets either the major or minor enantiomer to achieve high
ee’s of either the starting material or the product. While this
sequential process has been highlighted with enzymatic kinetic
resolutions3,4 to the best of our knowledge, it has not been
shown with a less selective nonenzymatic resolution in a one-
pot procedure.
Scheme 1. Ketone Reduction
acetophenone is reduced to the enantioenriched (R)-phenyl-
ethanol (1(R)) by the (S)-MeCBS catalyst. As expected, the
neat addition of the ketone gave lower ee’s (69%) than the
dilute, slow addition (80%). The unpredictability of this
reaction from substrate to substrate and from changes in
reaction conditions makes it a good candidate for ee polishing
by a kinetic resolution.
Typically, kinetic resolutions are carried out on racemates,
not enantiomerically enriched compounds. By performing a
kinetic resolution on an enantiomerically enriched substance
instead of a racemic mixture, less conversion is required to
achieve high ee in the starting material. We chose to explore
this concept by utilizing a modified kinetic resolution
developed by Birman,7 which employs the enantioselective
In order to demonstrate the utility of this process, a prochiral
ketone was reduced by the Corey−Bakshi−Shibata catalyst (S)-
MeCBS to produce an enantioenriched alcohol with moderate
Received: December 22, 2011
Published: March 7, 2012
© 2012 American Chemical Society
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acyl transfer catalyst (−)-tetramisole (3), as the second step in
our sequential process. When acetic anhydride is employed at
room temperature, the selectivity factor for the kinetic
resolution of phenylethanol is a moderate s = 12 (Scheme
2).8 When the kinetic resolution was performed on
enantioselective reduction is a boronate salt that will not
undergo acylation (Table 2, entry 1). Since the addition of
methanol is a common workup strategy for the CBS
enantioselective reduction,6 methanol was added as a coupling
reagent to free the alcohol 1(R) for the kinetic resolution.
Theoretically, only 3 equiv of methanol should be required to
cleave off the boron and free the alcohol for the acylation.
However, under those conditions the ee of 1(R) only increased
slightly and the ester product 2 was produced in minimal yield
(Table 2, entry 2). In order to achieve full boron cleavage an
excess of methanol is required.11 This frees the alcohol so it can
be acylated and the ee of 1(R) can be polished from 64% up to
97% (1(R)′) (Table 2, entry 3). Upon scale up (Table 1, entry
4), (R)-phenylethanol (1(R)′) was recovered with an ee of 99%
in 55% yield. The sequential reaction yielded more than double
the amount of product recovered from the kinetic resolution of
the racemic alcohol (Scheme 2, 23% yield), and the ee was
greater than that obtained from the enantioselective reduction
of the ketone.
Scheme 2. Kinetic Resolution
This same sequential one-pot process was used to obtain the
opposite enantiomer in high ee as the ester product 2(S)a,b by
employing the (R)-MeCBS catalyst instead of its S enantiomer
and keeping the kinetic resolution procedure the same. Now
enriched product is obtained instead of the enriched starting
material. The (R)-MeCBS reduction produced the (S)-
phenylethanol (1(S)) in excess, which was then enantiose-
lectively acylated with acetic anhydride in the kinetic resolution
by 3 to produce the highly enantioenriched ester product
2(S)a, which was recovered in 52% yield with an ee of 96%
(Table 3, entry 1). In an effort to improve the ee, the anhydride
was changed to propionic anhydride and the reaction was run
in chloroform (Birman’s original conditions that gave a
selectivity factor of 31).7 These conditions resulted in an
ester (2(S)b) with a 56% isolated yield and 99% ee (Table 3,
entry 2).
enantioenriched 1 (70% ee (R)), targeting the minor S
enantiomer for derivatization, only 40% conversion was
required to increase the ee of the alcohol 1(R) to >99% (R).
When starting with racemic starting material, a conversion of
70% was required to obtain the same level of enriched 1(R)
(23% yield). By performing the kinetic resolution on an
enantioenriched alcohol, the maximum amount of 1(R) that
can be recovered increases from 30% to 60%, culminating in an
alcohol that is high in ee and has good yields.
The extent of conversion needed to increase the ee of an
enriched substrate by kinetic resolution to 99% ee can be
calculated from the equation derived by Horeau9 (eq 1) via
substituting in the selectivity factor (s), the starting
enantiomeric ratio (er) (Smaj0, Smin0), and the desired er (Smaj
,
S
min). Table 1 shows the calculated minimum conversion
We expanded this one-pot polishing sequence to another
system by pairing the CBS reduction to the newly developed
silylation based kinetic resolution of cyclic alcohols (Table 4).13
The (R)-MeCBS catalyst was used to reduce the prochiral
ketones α-tetralone and thiochromanone to give the alcohols
4a,b in moderate ee (85% for both alcohols, Table 4). After
freeing the alcohol with excess methanol, the kinetic resolution
was used to silylate the minor enantiomer of 4a,b, providing
4a,b′ enriched with ee’s >95% and yields of 68 and 81%. The
amount of silyl chloride added (n in Table 4) was determined
using eq 1 to calculate the theoretical conversion needed to
obtain >95% ee. Because of differences in the selectivity factors
for the silylation-based kinetic resolutions of 4a and 4b (s = 11
and s = 23, respectively), we were able to obtain 4b′ in slightly
higher yield without compromising the ee. If the same kinetic
resolution of 4b was done on racemic starting material, the
highest yield possible of 4′ would be 43% to obtain the
compound with the same ee.
While the one-pot polishing sequence was successful for the
previous reactions, when applied to a polishing sequence
involving an enantioselective IPC allylation,14 the procedure
could not be performed in one pot. Instead, the polishing
procedure only worked if the product of the allylation was
purified by column chromatography before being subjected to
the kinetic resolution. Benzaldehyde was reacted with the
(+)-IPC allylating reagent to give product 6 with a moderate ee
of 71%.15 After purification, the major enantiomer of 6 was
targeted in an acylation-based kinetic resolution (s = 54) using
Table 1. Theoretical Conversions Required To Increase ee
of Starting Material to 99% for s = 12
1/(s−1)
s
⎡
⎢
⎢
⎤
⎥
⎥
0
⎛
⎜
⎞
⎟
⎟
⎛
⎝
⎞
⎠
S
S
maj
min
⎜
⎜
⎟
⎟
C = 1 −
0
⎜
⎝
S
S
maj
min
⎢
⎣
⎠ ⎥
⎦
(1)
a
entry starting ee of 1 calcd % conv of 2 max theor yield (%) of 1
1
2
3
4
5
6
0
50
60
70
80
90
69
49
44
38
32
23
31
51
56
62
68
77
a
Conversions to product 2 calculated from eq 1.
needed to obtain 99% enriched starting material when different
initial ee’s are employed; starting materials with greater initial
ee require less conversion to obtain highly enriched material.10
In theory, performing a kinetic resolution on a starting material
with a moderate ee of 50% could result in a 20% higher yield of
enriched material versus performing the same resolution on a
racemate (Table 1, entries 1 and 2).
Next, the enantioselective reduction and kinetic resolution
were employed in a sequential process with the goal of
obtaining a one-pot tandem process. The challenge with
performing these reactions in one-pot is that the product of the
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Table 2. One-Pot Process Linking the Enantioselective Reduction to the Kinetic Resolution
b
entry
MeOH (equiv)
ee of 1(R) (%)
ee 1(R)′ (%)
conv of 1(R) to 2 (%)
yield of 1(R)′ (%)
a
1
0
66
65
64
65
66
73
97
99
0
7
a
2
3
a,c
3
4
excess
excess
31
nd
c,d
55
a
b
c
Reaction was run on a 0.5 mmol scale. Conversion based on NMR. Reaction mixture was concentrated by rotary evaporator to remove the excess
d
methanol and THF was added prior to the kinetic resolution. Reaction was run on a 2.0 mmol scale.
Table 3. One-Pot Sequential Process Where the Kinetic Resolution Acylates the Major Enantiomer
c
a
entry
R
ee 1(S) (%)
ee 1(S)′ (%)
ee 2(S) (%)
conv 2(S) (%)
yield 2(S) (%)
1
a = Me
b = Et
80
82
43
48
96
99
55
59
52
56
b
2
a
b
c
See ref 12. The reaction was run at 0 °C in chloroform. Reactions were concentrated by rotary evaporator to remove excess methanol, and solvent
was added prior to the kinetic resolution.
Table 4. One-Pot Sequential Process Where the Kinetic Resolution Silylates the Minor Enantiomer
a
b
entry
X
conv of 5 (%)
n
ee of 4 (%)
ee of 4′ (%)
ee of 5 (%)
yield of 4′ (%)
1
2
a = CH2
b = S
16
13
0.3
0.2
85
85
96
95
39
19
68
81
a
b
Reactions were concentrated by rotary evaporator to remove excess methanol, and THF was added prior to the kinetic resolution. Theoretical
conversion based on eq 1.
Scheme 3. Asymmetric Allylation followed by Acylation-Based Kinetic Resolution
the catalyst benzotetramisole (8) to give the ester 7 in high ee
(99%) and moderate yield (51%) (Scheme 3).
and yield is advantageous and overcomes the problem of
limited commercial availability of catalyst enantiomers (such as
3). This methodology allows researchers to quickly obtain
highly enriched materials for new substrates while giving them
the option of obtaining either the starting material or the
product in high ee with good yields.
In conclusion, we have shown how enantioselective reactions
and kinetic resolutions with moderate selectivities can be
utilized sequentially in one-pot to produce enantiomerically
pure materials with high ee (>95%) and good yields (>50%),
which gives comparable results to the enzymatic processes in
the literature.3,4 By combining the two reactions, the inherent
disadvantages of kinetic resolutions (less than 50% maximum
yield) and enantioselective reactions (substrate variability,
moderate ee’s) can be overcome. The ability to recover both
enantiomers as either the starting material or product in high ee
EXPERIMENTAL SECTION
■
General Methods. All reagents used were obtained from
commercial sources and were used as received. Reactions were carried
out under a nitrogen atmosphere unless otherwise stated. Dry
tetrahydrofuran (THF) was obtained by degassing and then passing
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through an activated alumina column. Flash column chromatography
was performed on silica gel (32−63 μm). The chemical shifts are
reported as δ values (ppm) relative to the residual chloroform peak.
Reactions were monitored by thin-layer chromatography (TLC),
carried out on aluminum-backed silica gel 60 F254 sheets and visualized
by UV light and either a potassium permanganate stain or a
phosphomolybdic acid stain. The conversions and selectivities for
the kinetic resolution experiments were determined from the
enantiomer excess (ee) of the product and recovered starting material
using known methods.1a Racemic ester product standards were
synthesized from reacting the alcohol with the corresponding
anhydride and catalytic amounts of N,N-dimethylaminopyridine. The
product’s NMR spectra were consistent with known literature values.
Reduction of Acetophenone to Phenylethanol. Fast
Addition. A small stir bar was added to an oven-dried 2 dram
vial which was flushed with nitrogen several times and then
capped. To the reaction vessel BH3·THF (2 mL of 1.0 M, 2.0
mmol) was carefully added via syringe under nitrogen, followed
by the addition of (S)-MeCBS (200 μL of 1 M in toluene, 0.2
mmol). Acetophenone was added neat (235 μL, 2.0 mmol) and
the reaction was stirred for 90 min at room temperature. The
reaction was quenched with 1 mL of methanol (evolution of H2
gas), stirred for at least 30 min, and then concentrated in vacuo.
Aqueous HCl (2 mL of 1 M) and 2 mL of ether were then
added. The solution was extracted with ether (4 × 2 mL), and
the organic layers were combined and then washed with 1 M
HCl (2 × 2 mL), water (2 mL), and finally brine (2 mL). The
organic layer was then dried over Na2SO4, the solid filtered off,
and the solution concentrated in vacuo to give 0.178 g of pure
phenylethanol as a thick colorless oil (79% yield). The product
was analyzed by HPLC on a Chiralcel OD-H column using
96% hexanes and 4% 2-propanol solvent system at 1 mL/min,
210 and 254 nm detection to give the following retention
times: 10.29 min (R) and 12.84 min (S), 69.2% ee (R).5
Slow Addition. The reaction was carried out as described
previously, but the acetophenone was added as a solution (2.0
mmol acetophenone in 0.7 mL THF) dropwise over 68 min (0.141 g,
63% yield, 80% ee (R)).
carefully added BH3·THF (2 mL of 1.0 M, 2.0 mmol) via
syringe under nitrogen, followed by the addition of (S)-MeCBS
(200 μL of 1 M in toluene, 0.2 mmol). Acetophenone was
added neat (235 μL, 2.0 mmol), and the reaction was stirred for
90 min at room temperature. The reaction was quenched with
1 mL of methanol (evolution of H2 gas) and stirred for at least
30 min, and the solvent was removed in vacuo. The reaction
vessel was then flushed with argon several times and capped. A
stock catalyst solution was made by dissolving (−)-tetramisole
(0.104 g, 0.50 mmol) and i-Pr2NEt base (640 μL, 3.7 mmol) in
THF in a 5.00 mL volumetric flask. The stock catalyst solution
(2000 μL, 0.20 mmol of (−)-tetramisole, 1.6 mmol of i-
Pr2NEt) was added to the reaction vessel followed by acetic
anhydride (152 μL, 1.6 mmol). After 13 h, the reaction was
quenched with 1 mL of methanol and allowed to stir for 10
min, concentrated in vacuo, and then purified by column
chromatography (silica gel, 10 cm tall, 3 cm wide) using a
hexane and ethylacetate solvent system (250 mL of 9:1
followed by 200 mL of 1:1) to yield 0.133 g of phenylethanol
(55% yield, 98.6% ee (R)) and 0.102 g of the ester product 2a
(31% yield, 4.90% ee (S)).
Target Major Enantiomer. (Table 3, Entry 1, 1-Phenylethyl
Acetate (2a)). Reaction was carried out as described above
except (R)-MeCBS catalyst was used in the reduction.
Target Major Enantiomer. (Table 3, Entry 2, 1-Phenylethyl
Propionate (2b)). Reaction was carried out as described above
except (R)-MeCBS catalyst was used in the reduction, and
propionic anhydride was used (193 μL, 1.5 mmol) in the
kinetic resolution which was carried out at 0 °C in dry
chloroform. Purification on silica column yielded 0.064 g of
phenylethanol (26% yield, 47.5% ee (S)) and 0.200 g of the
ester product 2b (56% yield, 99.0% ee (S)). The ester product
2b was analyzed by HPLC on a Chiralpak IC column using
96% hexanes and 4% 2-propanol solvent system at 1 mL/min,
210 and 254 nm detection to give the following retention
times: 4.63 min (R) and 4.96 min (S), 69.2% ee (R).5,7
1
1-Phenylethyl Propionate (2b). H NMR (300 MHz, CDCl3): δ
7.37−7.7.29 (m, 5H), 5.91 (q, J = 6.6 Hz, 1H), 2.36 (q, J = 6.1 Hz,
2H), 1.54 (d, J = 6.9 Hz, 3H), 1.15 (t, J = 7.8 Hz, 3H). 13C NMR (75
MHz, CDCl3): δ 173.7, 141.9, 128.5, 127.8, 126.0, 72.1, 27.9, 22.3, 9.1.
Sequential Reduction and Silylation Kinetic Resolution.
Table 4, Entry 2. A small stir bar was added to an oven-dried 1
dram vial which was then flushed with nitrogen several times
and then capped. To the reaction vessel was carefully added
BH3·THF (0.5 mL of 1.0 M, 0.5 mmol) via syringe under
nitrogen, followed by the addition of (R)-MeCBS (50 μL of 1
M in toluene, 0.1 mmol). The α-tetralone was added neat (67
μL, 0.5 mmol), and the reaction was stirred overnight at room
temperature. The reaction was quenched with 0.5 mL of
methanol (evolution of H2 gas) and stirred for at least 30 min,
and the solvent was removed in vacuo. To the reaction vessel
was then added a small stir bar, 4 Å sieves, (−)-tetramisole
(0.026 g, 0.125 mmol), and i-Pr2NEt (26 μL, 0.15 mmol). The
reaction vessel was then flushed with nitrogen several times and
capped, and 2.5 mL of dry THF was added. A stock Ph3SiCl
solution was made by dissolving triphenylchlorosilane (0.454 g,
1.49 mmol) in THF in a 5.00 mL volumetric flask. The reaction
vessel was placed in a −78 °C 2-propanol bath and allowed to
equilibrate for at least 15 min. The stock Ph3SiCl solution (500
μL, 0.15 mmol Ph3SiCl) was added to the reaction and allowed
to stir overnight. After 20 h, the reaction was quenched with 0.5
mL of methanol and allowed to stir for 10 min while warming
to room temperature. The crude mixture was then concen-
trated in vacuo, washed with saturated NH4Cl, and extracted
with CH2Cl2 (4 × 1 mL). The organic layers were dried with
Na2SO4, the solid was filtered off, and the solution was
concentrated in vacuo and then purified by column
chromatography (silica gel, 12 cm tall, 3 cm wide) using a
hexane and dichloromethane solvent system (120 mL of 30%
hexane in DCM, followed by 50 mL of DCM, then 120 mL of
1-Phenylethanol (1(R)). 1H NMR (300 MHz, CDCl3): δ 7.40−7.24
(m, 5H), 4.91 (q, J = 3.9 Hz, 1H), 1.82 (s, 1H), 1.50 (d, J = 6.3 Hz,
3H). 13C NMR (75 MHz, CDCl3): δ 146.0, 128.7, 127.7, 125.6, 70.6,
25.3.
Typical Procedure for the Acylation-Based Kinetic Reso-
lution of Phenylethanol. A stock catalyst solution was made by
dissolving (−)-tetramisole (0.102 g, 0.50 mmol) and i-Pr2NEt base
(685 μL, 4 mmol) in THF in a 5.00 mL volumetric flask. A stir bar was
added to an oven-dried 10-mL round-bottom flask which was then
flushed with nitrogen several times and capped. The stock catalyst
solution (2000 μL, 0.2 mmol of (−)-tetramisole, 1.6 mmol of i-
Pr2NEt), phenylethanol (240 μL, 2.0 mmol), and acetic anhydride
(152 μL, 1.6 mmol) were added to the reaction vessel, and the
solution was stirred for 24 h at room temperature. The reaction was
quenched with 1.0 mL of methanol, stirred for 30 min, concentrated in
vacuo, and then purified by flash chromatography (silica gel, 10 cm
tall, 3 cm wide) using a hexane and ethyl acetate solvent system (200
mL of 9:1 followed by 200 mL of 1:1) to yield 0.057 g of
phenylethanol (23% yield, 99.4% ee (R)) and 0.196 g of the ester
product 2a (61% yield, 42.7% ee (S)). The product was analyzed by
HPLC on a Chiralpak IC column using 96% hexanes and 4% 2-
propanol solvent system at 1 mL/min, 210 and 254 nm detection to
give the following retention times: 5.46 min (R) and 6.07 min (S),
42.7% ee (R).5,7
1
1-Phenylethyl Acetate (2(S)a). H NMR (300 MHz, CDCl3): δ
7.37−7.28 (m, 5H), 5.89 (q, J = 6.6 Hz, 1H), 2.08 (s, 3H), 1.55 (d, J =
6.9 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 170.3, 141.7, 128.4,
127.9, 126.1, 72.3, 22.2, 21.4.
Sequential Reduction and Kinetic Resolution. Target Minor
Enantiomer (Table 2, Entry 4). A stir bar was added to an oven-
dried 25 mL round-bottom flask which was then flushed with
argon several times and capped. To the reaction vessel was
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1% methanol in DCM) to yield 0.050 g of tetralol (68% yield,
95.7 ee (S)) and 0.033 g of the silyl ether product 5a (16%
yield, 27.1% ee (S)). The alcohol was analyzed by HPLC on a
Chiralcel OD-H column with 4% isopropanol in hexanes at 0.5
mL/min, 210 and 254 nm detection to give the following
retention times: 20.5 min (S) and 22.9 min (R).13 The silyl
ether was deprotected by adding 1−2 mL of tetrabutylammo-
nium fluoride in THF which was then stirred at room
temperature overnight. To the crude mixture was added 1−2
mL of saturated NH4Cl and the deprotected alcohol was
extracted with CH2Cl2 (4 × 1 mL), concentrated, and then
purified on a silica column using CH2Cl2 followed by 1%
methanol in CH2Cl2. The deprotected alcohol was then
analyzed by HPLC using the same procedure as described
above. Table 4, entry 2: Reaction was carried out and purified
as described above except thiochromanone was used (0.084 g,
0.5 mmol). The alcohol was analyzed by HPLC on a Chiralcel
OD-H column with 4% isopropanol in hexanes at 1.0 mL/min,
210 and 254 nm detection to give the following retention
times: 19.6 min (S) and 25.2 min (R).13
Kinetic Resolution Procedure for 4a. To an oven-dried 1 dram
vial was added a small stir bar, 4 Å sieves, (−)-tetramisole (0.026 g,
0.125 mmol), the alcohol 4a (0.076 g, 0.5 mmol), and i-Pr2NEt (44
μL, 0.25 mmol). The reaction vessel was then flushed with nitrogen
several times and capped, and 2.25 mL of dry THF was added. A stock
Ph3SiCl solution was made by dissolving triphenylchlorosilane (0.453
g, 1.49 mmol) in THF in a 5.00 mL volumetric flask. The reaction
vessel was placed in a −78 °C 2-propanol bath and allowed to
equilibrate for at least 15 min. The stock Ph3SiCl solution (850 μL,
0.25 mmol Ph3SiCl) was added to the reaction and allowed to stir
overnight. After 20 h, the reaction was quenched with 0.5 mL of
methanol and allowed to stir for 10 min while warming to room
temperature. The crude mixture was then concentrated in vacuo,
washed with saturated NH4Cl, and extracted with CH2Cl2 (4 × 1 mL).
The organic layers were dried with Na2SO4, the solid was filtered off,
and the solution was concentrated in vacuo and then purified by
column chromatography (silica gel, 12 cm tall, 3 cm wide) using a
hexane and dichloromethane solvent system (120 mL of 30% hexane
in DCM, followed by 50 mL of DCM, then 120 mL of 1% methanol in
DCM) to yield 0.046 g of 4a (62% yield, 50.6% ee) and 0.081 g of the
silyl ether product 5a (49.5% yield, 73.0% ee).
(+)-IPC2Ballyl (0.5 mL of 1.0 M in dioxane, 0.5 mmol) was carefully
added via syringe under nitrogen. Freshly distilled benzaldehyde was
added neat (50 μL, 0.5 mmol), and the reaction was stirred for 3 h at
room temperature. To the reaction were added 0.25 mL of 3 M NaOH
and 0.25 mL of 30% H2O2, and the mixture was allowed to stir
overnight. Water was added to the reaction mixture, the mixture was
extracted with ether (3 × 1 mL), the organic layers were combined
and dried with Na2SO4, the solid was filtered off, and the solution was
concentrated in vacuo and then purified by column chromatography
(silica gel, 12 cm tall, 3 cm wide) using a hexane and ether solvent
system (400 mL of 9:1 hexane/ether, followed by 300 mL of 4:1
hexane/ether) to yield 0.085 g of 6 with impurity (70.9 ee (R)). The
allylation product 6 was then added to an oven-dried 1 dram vial with
a small stir bar, Na2SO4 (0.200 g), and (+)-benzotetramisole (0.012 g,
0.05 mmol) which was then flushed with nitrogen several times and
capped. To the reaction vessel were added i-Pr2NEt (60 μL, 0.35
mmol) and 4 mL of dry CHCl3. The reaction was placed in a 0 °C 2-
propanol bath and allowed to equilibrate for at least 15 min. The
isobutyric anhydride (60 μL, 0.35 mmol) was added, and the reaction
was stirred for 24 h. More isobutyric anhydride was added to increase
conversion (6 μL, 0.4 mmol), and the reaction mixture was allowed to
stir overnight. The reaction was quenched with 0.5 mL of methanol,
concentrated in vacuo, and then purified by column chromatography
(silica gel, 13 cm tall × 3 cm wide) using a hexane and ether solvent
system (400 mL of 9:1 hexane/ether, followed by 300 mL of 4:1
hexane/ether) to yield 0.036 g of 6(R)′ (45.2% recovered, 5.6% ee
(R)) and 0.056 g of 7 (51.4% yield, 98.7% ee (R)). The alcohol 6(R)′
was analyzed by HPLC on a Chiralcel OD-H column with 4% 2-
propanol in hexanes at 0.5 mL/min, 210 and 254 nm detection to give
the following retention times: 21.6 min (R) and 25.6 min (S). The
ester 7 was analyzed by HPLC on a Chiralcel OD-H column with 1%
isopropanol in hexanes at 0.5 mL/min, 210 and 254 nm detection to
give the following retention times: 21.2 min (R) and 26.3 min (S).
Kinetic Resolution Procedure for 6. A stock catalyst solution
was made by dissolving (+)-benzotetramisole (0.025 g, 0.099 mmol)
and i-Pr2NEt (240 μL, 1.39 mmol) in dry CHCl3 in a 10 mL
volumetric flask. To an oven-dried 1 dram vial was added a small stir
bar, the racemic alcohol 6 (0.074 g, 0.5 mmol), and Na2SO4 (0.200 g),
which was then flushed with nitrogen several times and capped. To the
reaction vessel was added 2 mL of the catalyst stock solution (0.25
mmol i-Pr2NEt, 0.02 mmol (+)-benzotetramisole). The reaction was
placed in a 0 °C isopropanol bath and allowed to equilibrate for at
least 15 min. The isobutyric anhydride (42 μL, 0.25 mmol) was added
and the reaction was stirred for 24 h. The reaction was quenched with
0.5 mL of methanol, concentrated in vacuo, and then purified by
column chromatography (silica gel, 10 cm tall × 2 cm wide) using a
hexane and ethyl acetate solvent system (100 mL of 9:1 hexane/ethyl
acetate followed by 50 mL of 3:2) to yield 0.039 g of 6′ (51%
recovered, 71.0% ee) and 0.036 g of 7 (33% yield, 98.7% ee).14,16
(R)-Phenyl-3-buten-1-ol (6). 1H NMR (400 MHz, CDCl3): δ
7.30−7.26 (m, 4H), 7.23−7.19 (m, 1H), 5.79−5.69 (m, 1H), 5.12−
5.05 (m, 2H), 4.67 (dd, J = 7.6, 5.2 Hz), 2.47−2.40 (m, 2H). 13C
NMR (100 MHz, CDCl3): δ 143.8, 134.4, 128.4, 127.5, 125.8, 118.4,
73.3, 43.8.
Kinetic Resolution Procedure for 4b. The reaction was carried
out as described above except alcohol 4b was used instead of 4a. The
HPLC conditions were the same as described previously.
Tetralol (4a). 1H NMR (400 MHz, CDCl3): δ 7.44−7.42 (m, 1H),
7.22−7.20 (m, 2H), 7.12−7.10 (m, 1H), 4.77 (t, J = 4.6 Hz, 1H),
2.86−2.71 (m, 2H), 2.18−1.76 (m, 5H). 13C NMR (100 MHz,
CDCl3): δ 138.9, 137.2, 129.1, 128.8, 127.6, 126.2, 76.8, 68.1, 32.3,
29.3, 18.9.
Product (5a). 1H NMR (400 MHz, CDCl3): δ 7.68 (d, J = 6.0 Hz,
6H), 7.47−7.37 (m, 9H), 7.28 (d, J = 6.8, 1H), 7.17−7.07 (m, 3H),
4.986 (t, J = 5.6 Hz, 1H), 2.85 (m, 1H), 2.73−2.65 (m 1H), 2.11−2.04
(m, 1H), 1.95−1.84 (m, 2H), 1.73−1.70 (m, 1H). 13C NMR (100
MHz, CDCl3): δ 139.1, 137.2, 135.7, 135.0, 130.1, 128.9, 128.8, 128.0,
127.2, 125.8, 70.4, 32.7, 29.2, 19.3.
(R)-1-Phenylbut-3-en-1-yl isobutyrate (7). 1H NMR (400
MHz, CDCl3): δ 7.35−7.26 (m, 5H), 5.81 (dd, J = 8.0, 5.6 Hz,
1H), 5.76−5.66 (m, 1H), 5.10−5.03 (m, 2H), 2.68−2.52 (m, 3H),
1.17 (q, J = 6.8 Hz). 13C NMR (100 MHz, CDCl3): δ 176.2, 140.4,
133.4, 128.4, 127.8, 126.4, 118.0, 74.62, 41.0, 34.1, 19.0, 18.9. Optical
rotation [α]25D = +54.2 (c = 1.10, CHCl3). HRMS (ESI) (M+): calcd
for C14H18O2+ 218.1307, obsd 218.1305. IR (neat, cm−1): 2974, 1734,
1456, 1387, 1189, 1152, 1068, 917, 758, 698.
Thiochromanol (4b). 1H NMR (400 MHz, CDCl3): δ 7.32 (d, J =
7.6 Hz, 1H), 7.19−7.12 (m, 2H), 7.09−7.05, (m, 1H), 4.81 (dd, J =
4.8, 2.8 Hz, 1H), 3.33 (dt, J = 12, 3.2, Hz, 1H), 2.89−2.84 (m, 1H),
2.39−2.32 (m, 1H), 2.1−2.01 (m, 1H), 1.78 (br, 1H). 13C NMR (100
MHz, CDCl3): δ 134.7, 133.4, 130.5, 128.6, 126.9, 124.4, 66.7, 30.1,
21.6.
Product (5b). 1H NMR (400 MHz, CDCl3): δ 7.63−7.56 (m, 6H),
7.48−7.35 (m, 9H), 7.12−7.10 (m, 2H), 6.96 (d, J = 7.6 Hz, 1H),
6.91−6.87 (m, 1H), 4.93 (dd, J = 5.4, 2.6 Hz, 1H), 3.50 (dt, J = 11.6,
3.2, 1H), 2.85−2.79 (m, 1H), 2.25−2.18 (m, 1H), 1.97−1.89 (m, 1H).
13C NMR (100 MHz, CDCl3): δ 136.5, 135.7, 135.3, 134.5, 130.2,
129.7, 128.0, 127.8, 126.6, 123.8, 68.5, 30.8, 22.0.
ASSOCIATED CONTENT
■
S
* Supporting Information
Chiral HPLC traces, copies of NMR spectra for new
compounds, and duplicate run data. This material is available
free of charge via the Internet at http://pubs.acs.org.
Sequential Allylation and Acylation Kinetic Resolution. A stir
bar was added to an oven-dried 1 dram vial which was then flushed
with nitrogen several times and capped. To the reaction vessel
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dx.doi.org/10.1021/jo202653b | J. Org. Chem. 2012, 77, 3570−3575

The Journal of Organic Chemistry
Note
(16) Absolute chirality of 6 determined by HPLC and compared to
known separation on a Chiralcel OD-H column: Jain, P.; Antilla, J. C.
J. Am. Chem. Soc. 2010, 132, 11884.
AUTHOR INFORMATION
Corresponding Author
*E-mail: wiskur@mailbox.sc.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge support from the National Science
Foundation CAREER Award CHE-1055616, the American
Chemical Society Petroleum Research Fund (44683-G1), and
the University of South Carolina Research and Productive
Scholar Award and startup funds from the University of South
Carolina.
REFERENCES
■
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(15) Yield could not be determined due to the coelution of an
impurity.
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dx.doi.org/10.1021/jo202653b | J. Org. Chem. 2012, 77, 3570−3575