Parallel kinetic resolution of racemic 1-phenylethanol using quasi-enantiomeric combinations of carboxylic acids mediated by N,N′-dicyclohexylcarbodiimide and 3,5-lutidine

Article abstract of DOI:10.1016/j.tetlet.2008.05.036

The parallel kinetic resolution of racemic 1-phenylethanol using an equimolar combination of quasi-enantiomeric 2-arylpropionic and butanoic acids mediated by a N,N′-dicyclohexylcarbodiimide (DCC)/3,5-lutidine coupling is discussed. The levels of diastereoselectivity were high leading to separable quasi-enantiomeric esters in good yield.

Full text of DOI:10.1016/j.tetlet.2008.05.036

Tetrahedron Letters 49 (2008) 4661–4665
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Parallel kinetic resolution of racemic 1-phenylethanol using
quasi-enantiomeric combinations of carboxylic acids mediated
by N,N0-dicyclohexylcarbodiimide and 3,5-lutidine
*
Najla Al Shaye, Andrew N. Boa, Elliot Coulbeck, Jason Eames
Department of Chemistry, University of Hull, Cottingham Road, Kingston upon Hull HU6 7RX, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The parallel kinetic resolution of racemic 1-phenylethanol using an equimolar combination of quasi-
enantiomeric 2-arylpropionic and butanoic acids mediated by a N,N0-dicyclohexylcarbodiimide (DCC)/
3,5-lutidine coupling is discussed. The levels of diastereoselectivity were high leading to separable
quasi-enantiomeric esters in good yield.
Received 11 April 2008
Revised 30 April 2008
Accepted 7 May 2008
Available online 11 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
The kinetic resolution of secondary alcohols by enantioselective
alkyl and arylcarbonyl transfer involving stoichiometric and sub-
stoichiometric chiral mediators is well documented.1 One non-
enzymatic approach that has attracted significant attention has
been the use of chiral 4-dimethylaminopyridine (DMAP) equiva-
lents2 as sub-stoichiometric mediators.3 Fu and co-workers have
reported the use of a planar-chiral iron complex (ꢀ)-34 as a sub-
stoichiometric chiral mediator for the kinetic resolution of 1-phen-
ylethanol (rac)-1 using acetic anhydride as an acyl transfer motif
(Scheme 1).5 This process was shown to be highly enantiomer-
selective when performed in t-amyl alcohol (2-methylbutan-2-ol)
allowing the unreacted 1-phenylethanol (S)-1 to be isolated with
99% ee by enantioselective acetylation of its (R)-enantiomer [(R)-
1] to give the corresponding acetate (R)-2 (selectivity factor,
s = 43 at 55% conversion)6 (Scheme 1).5
Ac2O
(-)-(Sa)-4 (1 mol%)
OH
H
HO
Ph
)-1; 6% e.e.
H
H
OAc
Me
toluene, -78 oC
6% conversion
Ph
(
Me
Me
Ph
s
= 22
rac)-1
(
S
(R)-2; 90% e.e.
NaOH, MeOH
NEt2
N
H
OH
Me
Ph
(R)-1; 90% e.e.
Ph
Ph
(-)-(Sa)-4
Scheme 2. Kinetic resolution of 1-phenylethanol (rac)-1 using the chiral mediator
(ꢀ)-(Sa)-4.
In comparison, Spivey and co-workers have developed a related
resolution for 1-phenylethanol (rac)-1 using a chiral atropisomeric
DMAP equivalent (ꢀ)-(Sa)-4 (Scheme 2).7 However, they chose to
resolve (rac)-1 by sequential enantioselective acetylation of its
(R)-enantiomer 1 [to give the enantiomerically enriched acetate
(R)-2 (with 90% ee) and the partially resolved 1-phenylethanol
(S)-1 (6% ee)], followed by simple hydrolysis/transesterification
with NaOH in MeOH to give the target 1-phenylethanol (R)-1 with
90% ee (s = 22 at 6% conversion) (Scheme 2).7 The low enantiomeric
excess for the resolved 1-phenylethanol (S)-1 was due to the low
percentage conversion for this resolution.
Me2N
Vedejs and co-workers focused8 their attention on the use of a
stoichiometric chiral pyridinium chloride (R)-6 as an efficient acti-
vated chiral DMAP equivalent for the resolution of (rac)-1 in the
presence of anhydrous zinc chloride (as a Lewis acid) and triethyl-
amine (as the Brønsted base) (Scheme 3). However, this methodol-
ogy relied on the pre-formation of the active pyridinium chloride
(R)-6 [formed by addition of trichlorobutyl chloroformate to the
chiral DMAP equivalent (R)-5] prior to the resolution of (rac)-1.8
This acyl transfer reagent was shown to be highly (S)-enantiomer
selective towards (rac)-1, giving the corresponding ester (S)-7 with
93% ee (s = 38 at 25% conversion) (Scheme 3).8
(-)-3
(2 mol%)
Ac2O
OH
H
HO
Ph
H
H
OAc
Me
N
Fe
Ph
Ph
Ph
Ph
Me
Me
t
-amyl alcohol
Ph
(
55% conversion
s = 43
Ph
(
rac)-1
(
S)-1; 99% e.e.
R)-2
Ph
(-)-3
Scheme 1. Kinetic resolution of 1-phenylethanol (rac)-1 using the chiral mediator
(ꢀ)-3.
* Corresponding author. Tel.: +44 1482 466401; fax: +44 1482 466410.
E-mail address: j.eames@hull.ac.uk (J. Eames).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.036

4662
N. A. Shaye et al. / Tetrahedron Letters 49 (2008) 4661–4665
NMe2
N
NMe2
O
O
Cl
Me Me
Cl3C
Cl
Ph
Ar
t
-Bu
OC6F5
t
-Bu
OC6F5
O
O
N
Me Me
Me
)-12
Me
Ar = 6-methoxynaphthalen-2-yl
OMe
OMe
Cl3C
O
O
(S
(
R)-13
(R)-5
(R)-6
O
O
O
O
O
O
Me Me
Cl3C
(
R
)-6
ZnCl2, Et3N
CH2Cl2, 0 o
25% conversion
Ph
Ar
OH
H
O
O H
N
N
O
Me
Me
Ph
Me
Ph
S)-7; 93% e.e.
Me
C
Ph
)-syn-14
Ph
Ar = 6-methoxynaphthalen-2-yl
(
s
= 38
(
rac)-1
(
S,
R
(R,S)-syn-15
Scheme 3. Kinetic resolution of 1-phenylethanol (rac)-1 using the pyridinium
chloride (R)-6.
EITHER
1. -BuLi, ZnCl2
2. ( )-12 and (R)-13
O
Ph
O
Ph
n
S
OH
H
Ar
Ph
O
Me
O
Me
Ph
(
Me
OR
1. MeMgBr
Me
Ar = 6-methoxynaphthalen-2-yl
)-anti-17
Either 77% with 86% d.e. Either 76% with 88% d.e.
or 62% with 74% d.e. or 66% with 68% d.e.
Me
As a way of increasing the levels of enantiomer selection, Vedejs
devised a novel parallel kinetic resolution strategy9 for the removal
of both enantiomers in parallel by using a combination of two com-
plementary chiral pyridinium chlorides (R)-6 and (S,S)-8 (Scheme
4).10 Addition of these two quasi-enantiomeric11 pyridinium chlo-
rides (R)-6 and (S,S)-8 to a stirred solution of a racemic secondary
alcohol [e.g., 1-(1-methylphenyl)ethanol (rac)-9] in the presence of
magnesium dibromide and triethylamine gave two complemen-
tary esters (S)-10 and (S,R)-11, respectively, in good yield with
excellent levels of enantiomeric/diastereoisomeric excess (Scheme
4). By performing this double kinetic resolution in situ, this process
removed the inherent concentration effect (present in a single
kinetic resolution) thereby improving the relative enantio- and
diastereoisomeric outcomes.10
Over the last few years, we have been interested in the parallel
kinetic resolution of 1-phenylethanol (rac)-1 using quasi-enantio-
meric combinations of stoichiometric active esters (S)-12 and
(R)-13,12 and oxazolidin-2-ones (S,R)-syn-14 and (R,S)-syn-1513 as
complementary acyl transfer reagents to give the corresponding
esters (S,S)-anti-16 and (R,R)-syn-17 with some success (Scheme 5).
In an attempt to improve these levels of diastereoselection, we
were interested in developing a diastereoselective N,N0-dicyclohex-
ylcarbodiimide (DCC) coupling procedure14 for the synthesis of
esters, such as 16, which utilised the in situ formation of (quasi-
enantiomeric) chiral pyridinium salts, such as 20, derived from
the corresponding chiral carboxylic acid, for example, 2-phenyl-
propionic acid (rac)-19 and achiral pyridine 18 (Scheme 6). To this
end, we report our study into the use of quasi-enantiomeric 2-aryl-
rac)-1
2. (
(
S
,
R
)-syn-14 and
(
S
,
S
)-anti-16
(R,R
R,S)-syn-15
Scheme 5. Parallel kinetic resolution of 1-phenylethanol (rac)-1 using quasi-
enantiomeric combinations of stoichiometric active esters (S)-12 and (R)-13, and
oxazolidin-2-ones (S,R)-syn-14 and (R,S)-syn-15.
O
Ph
OH
Me
Me
Me
Me
Me
Me
(
rac)-19
N
Cy
O
N
O
N
C N
Cy
Ph
18
CyHN
NCy
CH2Cl2
20
OH
Me
Ph
H
O
Ph
(
rac)-1
Ph
O
Me
Me
rac)-anti- and
rac)-syn-16
(
(
Scheme 6. Proposed mutual kinetic resolution of 1-phenylethanol (rac)-1 using
2-phenylpropionic acid (rac)-19 mediated by DCC and 3,5-lutidine 18.
propionic and butanoic acids as complementary diastereoselective
alkyl-carbonyl transfer components for the parallel kinetic resolu-
tion of 1-phenylethanol (rac)-1 using a DCC coupling procedure15
involving 3,5-lutidine 18 as a covalent nucleophilic mediator and
stereochemical directing pro-leaving group.
NMe2
NMe2
Cl
Me
t
-Bu
t-Bu
Cl
N
O
Me Me
N
O
Me
O
OMe
OBn
Cl3C
O
For our study, we first probed the mutual kinetic resolution of
2-phenylpropionic acid (rac)-19 with an equimolar amount of
racemic 1-phenylethanol 1 using our proposed DCC/3,5-lutidine
coupling protocol in order to determine the relative levels of com-
plementary recognition (Schemes 6 and 7). Addition of (rac)-1 to a
stirred solution of (rac)-19, DCC and 3,5-lutidine 1816 in dichloro-
methane gave after 12 h an inseparable diastereoisomeric mixture
of esters (rac)-anti- and (rac)-syn-16 in 69% yield with 66% de
(Scheme 7).17 The levels of stereocontrol were determined by 1H
NMR spectroscopy (400 MHz) by integration of the corresponding
methyl doublets in (rac)-anti- and (rac)-syn-16.18 Interestingly,
without the addition of 18, self-coupling of (rac)-19 occurs pre-
dominantly to give the corresponding anhydrides (rac)-anti- and
(meso)-syn-21 as an inseparable equimolar mixture in 95% yield
(Scheme 7). The formation of the esters (rac)-anti- and (rac)-syn-
16 must proceed either via addition of 3,5-lutidine 18 to the
Me
(R)-6
(S,S
)-8
O
Me Me
Cl3C
Me
H
O
O
Me
S)-10; 46%; 83% e.e.
(
R
)-6 + (
MgBr2, Et3N
CH2Cl2, 0 o
S,S)-8
OH
(
Me
C
Me
H
O
H
Me
Me
Me
O
O
(
rac)-9
Me
Me
(S,R)-11; 46%; >94% d.e.
Scheme 4. Parallel kinetic resolution of 1-(1-methylphenyl)ethanol (rac)-9 using
pyridinium chlorides (R)-6 and (S,S)-8.

N. A. Shaye et al. / Tetrahedron Letters 49 (2008) 4661–4665
4663
OH
H
phenylpropionic acid (S)-19 (96% ee) with 1-phenylethanol (S)-1
(>97% ee) in 48% yield.
Ph
Me
O
Ph
O
O
Ph
Our attention next turned to finding a complementary partner
for our original carboxylic acid, 2-phenylpropionic acid 19. For this
study, we chose to investigate the mutual kinetic resolution of a
small series of structurally related racemic 2-aryl-propionic and
butanoic acids (rac)-22, (rac)-23, (rac)-24, (rac)-25, (rac)-26 and
(rac)-27 with 1-phenylethanol (rac)-1 under our standard DCC/
3,5-lutidine conditions (Scheme 8). Treatment of these 2-aryl-pro-
pionic and butanoic acids with 1-phenylethanol in the presence of
DCC and 3,5-lutidine gave the corresponding esters (rac)-anti- and
(rac)-syn-28 [in 59% yield with 70% de (ratio 85:15)], (rac)-anti-
and (rac)-syn-29 [in 64% yield with 70% de (ratio 85:15)], (rac)-
anti- and (rac)-syn-30 [in 60% yield with 70% de (ratio 85:15)],
(rac)-anti- and (rac)-syn-31 [in 63% yield with 58% de (ratio
79:21)], (rac)-anti- and (rac)-syn-32 [in 56% yield with 68% de (ra-
tio 84:16)] and (rac)-anti- and (rac)-syn-33 [in 50% yield with 64%
de (ratio 82:18)] with near equal levels of diastereoselection
(Scheme 8). The only exception was the carboxylic acid (rac)-25
which was less diastereoselective (58% de) (Scheme 8).
With this information at hand, we next turned our attention to
probing the parallel kinetic resolution of (rac)-1 using two combi-
nations of enantiomerically pure quasi-enantiomeric carboxylic
acids (R)-22 and (S)-19, and (R)-22 and (S)-26 as shown in Schemes
9 and 10, respectively. Treatment of a solution of (rac)-1, DCC and
3,5-lutidine in dichloromethane with an equimolar amount of
carboxylic acids (R)-22 and (S)-19, and (R)-22 and (S)-26 gave the
corresponding inseparable mixtures of diastereoisomeric esters
(R,R)-anti- and (R,S)-syn-28 [in 71% yield with 68% de (ratio
84:16) for (R)-22] and (S,S)-anti- and (S,R)-syn-16 [in 72% yield with
66% de (ratio 83:17) for (S)-19], and (R,R)-anti- and (R,S)-syn-28 [in
55% yield with 66% de (ratio 83:17) for (R)-22] and (S,S)-anti- and
(S,R)-syn-32 [in 67% yield with 68% de (ratio 84:16) for (S)-26],
respectively, in good yields, with good to excellent levels of
diastereocontrol (up to 68% de) (Schemes 9 and 10). These levels
of complementary stereocontrol were near identical to their corre-
sponding mutual kinetic resolution (as shown in Scheme 8).
For the remainder of our study, we chose to use the more polar
naproxen (S)-27 as a complementary component due to its known
separability from related profen-derived adducts.12,13 Treatment of
an equimolar combination of (R)-22 and (S)-27 with (rac)-1, DCC
and 3,5-lutidine in dichloromethane gave a separable mixture of
diastereoisomeric adducts (R,R)-anti- and (R,S)-syn-28 [in 64% yield
with 72% de (ratio 86:14) for (R)-22] and (S,S)-anti- and (S,R)-syn-
33 [in 58% yield with 64% de (ratio 82:18) for (S)-27] (Scheme 11).
The complementary esters (R,R)-anti- and (R,S)-syn-28 were sepa-
rated efficiently from the more polar naproxen-derived esters
(S,S)-anti- and (S,R)-syn-33, by flash column chromatography on
silica gel, eluting with light petroleum ether (bp 40–60 °C)/diethyl
ether (1:1) (DRF = 0.16) (Scheme 11).
(
rac)-1
Ph
Ph
Ph
O
Me
OH
O
Me
Ph
3,5-lutidine 18
DCC, CH2Cl2, rt
Me
rac)-anti-16
Me
Me
(
(
rac)-syn-16
(
rac)-19
83:17; 69%
OH
Ph
Me
O
O
O
O
H
rac)-1
(
Ph
Ph
Ph
Ph
O
O
Me
OH
DCC, CH2Cl2, rt
Me
Me
Me
Me
(
rac)-19
(
rac)-anti-:(meso)-syn-21
(
rac)-anti-:(rac)-syn-16
50:50; 95%
50:50; <5%
Scheme 7. Mutual kinetic resolution of 1-phenylethanol (rac)-1 using 2-phenyl-
propionic acid (rac)-19 mediated by DCC and 3,5-lutidine 18.
intermediate isourea [derived from addition of DCC to (rac)-19]
and/or the anhydride 21. This reaction does not proceed via inter-
mediate ketene formation, as each diastereoisomer [e.g., (S,S)-anti-
16] can be synthesised stereospecifically (ꢁ94% de) by coupling 2-
OH
Ph
Me
O
Ph
O
Ph
O
H
(rac)-1
Ar
Ar
Ar
O
Me
O
Me
OH
3,5-lutidine 18
DCC, CH2Cl2, rt
R
R
R
(rac)-anti-
(rac)-syn-
(rac)-
Ratio
anti-:syn-
Yield
59%
D.e.
(rac)-Ester
Carboxylic acid
O
O
Ph
Ph
Ph
85:15
70%
OH
O
Me
Et
Et
(rac)-anti-28 and
(rac)-syn-28
(rac)-22
O
O
Ph
Ph
Ph
64%
60%
85:15
85:15
70%
OH
OH
O
Me
i-Pr
i-Pr
(rac)-anti-29 and
(rac)-syn-29
(rac)-23
O
O
Ph
4-MeC6H4
4-MeC6H4
70%
O
Me
Me
Me
(rac)-anti-30 and
(rac)-syn-30
(rac)-24
O
O
Ph
4-ClC6H4
4-i-BuC6H4
Ar
4-ClC6H4
4-i-BuC6H4
Ar
63%
56%
50%
79:21
84:16
82:18
58%
68%
64%
OH
OH
OH
O
Me
The configurational stability of this molecular recognition pro-
cess was studied using a pair of quasi-enantiomeric alcohols,
Me
Me
(rac)-anti-31 and
(rac)-syn-31
(rac)-25
O
O
Ph
O
Ph
O
Ph
O
O
Me
Ph
Ph
Ph
OH
H
O
Me
O
Me
OH
Me
Me
Et
Et
Et
Ph
Me
(rac)-anti-32 and
(rac)-syn-32
(rac)-26
(
R,
R
)-anti-28
(
R
,S
)-syn-28
84:16; 71%
(
R
)-22
(
rac)-1
O
O
Ph
3,5-lutidine 18
DCC, CH2Cl2, rt
O
Ph
O
O
Ph
O
O
Me
Ph
Ph
Ph
Me
O
Me
Me
OH
Me
Ar = 6-methoxynaphthalen-2-yl
Me
Me
Me
)-19
(rac)-anti-33 and
(rac)-syn-33
(rac)-27
(
S,S
)-anti-16
(S,R)-syn-16
83:17; 72%
(
S
Scheme 8. Mutual kinetic resolution of 1-phenylethanol (rac)-1 using carboxylic
acids (rac)-22–27 mediated by DCC and 3,5-lutidine.
Scheme 9. Parallel kinetic resolution of 1-phenylethanol (rac)-1 using carboxylic
acids (R)-22 and (S)-19 mediated by DCC and 3,5-lutidine.

4664
N. A. Shaye et al. / Tetrahedron Letters 49 (2008) 4661–4665
O
Ph
O
O
Ph
OH
Ph
Ph
Ph
OH
H
O
Me
OH
O
Me
Ph
Np
Me
O
Np
O
Ph
O
(R)-1
Et
Et
Et
Ph
Me
Ph
Ph
Ar
Ph
Ar
OH
O
Me
O
Me
Me
OH
(
R
,
R
)-anti-28
(
R,S)-syn-28
83:17; 55%
(
R
)-22
(
rac)-1
Et
Et
Et
Me
(S)-34
3,5-lutidine 18
DCC, CH2Cl2, rt
O
Ph
O
O
Ph
(R,R)-anti-28
(R,S)-syn-35
82:18; 44%
(R)-22
Np = naphthalen-2-yl
4-i-BuC6H4
4-i
-BuC6H4
4-
i-BuC6H4
O
Me
OH
O
Me
3,5-lutidine 18
DCC, CH2Cl2, rt
Me
O
Ph
Me
)-26
Me
O
Np
O
Ar
(
S,
S)-anti-32
(S,R)-syn-32
84:16; 67%
(
S
O
Me
O
OH
Me
Me
Me
Scheme 10. Parallel kinetic resolution of 1-phenylethanol (rac)-1 using carboxylic
acids (R)-22 and (S)-26 mediated by DCC and 3,5-lutidine.
(S)-27
(S,S)-anti-36
(S,R)-syn-33
83:17; 65%
Ar = 6-methoxy-
naphthalen-2-yl
O
Np
O
Ph
O
Ph
O
Ph
O
Ph
Ar
Ph
Ph
Ph
O
Me
O
Me
OH
H
O
Me
O
Me
OH
Et
(S,S)-anti-35
Me
(R,R)-anti-33
Et
Et
Et
Ph
Me
(R,
R
)-anti-28
(
R,S)-syn-28
86:14; 64%
(
R
)-22
(
rac)-1
Scheme 12. Parallel kinetic separation of alcohols (R)-1 and (S)-34 using carboxylic
acids (R)-22 and (S)-27 mediated by DCC and 3,5-lutidine.
3,5-lutidine 18
DCC, CH2Cl2, rt
O
Ph
O
Ph
O
Ar
Ar
Ar
O
Me
O
Me
OH
Me
Me
Me
Ar = 6-methoxynaphthalen-2-yl
)-27
O
Ph
Ph
(S
,S
)-anti-33
(
S,
R
)-syn-33
LiAlH4
THF
82:18; 58%
(
S
Ph
Ph
O
Me
OH
HO
Me
Et
(R,R)-anti-28; 72% d.e.
Scheme 11. Parallel kinetic resolution of 1-phenylethanol (rac)-1 using carboxylic
acids (R)-22 and (S)-27 mediated by DCC and 3,5-lutidine.
Et
(
R)
-37; 90%
(R)-1; 47%
72% e.e.18
O
Ph
Ph
1-phenylethanol (R)-1 and 1-(naphthalen-2-yl)ethanol (S)-34 for
the mutual kinetic separation of 2-phenylbutanoic acid (R)-22
and 2-(6-methoxynaphthalen-2-yl)propionic acid (S)-27 (Scheme
12). Treatment of an equimolar mixture of quasi-enantiomeric car-
boxylic acids (R)-22 and (S)-27 with DCC and 3,5-lutidine in dichlo-
romethane, followed by the addition of a quasi-enantiomeric
mixture of alcohols (R)-1 and (S)-34, gave a mixture of distinct
and diastereoisomerically pure esters (R,R)-anti-28 and (R,S)-
syn-35 [ratio 82:18 relative to the (R)-configuration in 22], and
(S,S)-anti-36 and (S,R)-syn-33 [ratio 83:17 relative to the (S)-config-
uration in 27] (Scheme 12). These relative levels of mutual selectiv-
ity were determined by 400 MHz 1H NMR spectroscopy. From this
study it was evident that no racemisation of the carboxylic acids
(R)-22 and (S)-27 had occurred [due to the absence of the
diastereoisomeric esters (S,S)-anti-35 and (R,R)-anti-33] and that
no epimerisation of the products had occurred [due to the absence
of (S,R)-syn-28 and (R,S)-syn-36] (Scheme 12).
LiAlH4
THF
Ar
Ar
O
Me
OH
HO
Me
Me
Ar = 6-methoxynaphthalen-2-yl
)-anti-33; 64% d.e.
Me
38; 81%
(
S)
-
(
S
)
-1; 55%
64% e.e.18
(S,S
Scheme 13. Reduction of esters (R,R)-anti-28 and (S,S)-anti-33 to give enantiome-
rically enriched 1-phenylethanol 1.
alcohols using enantiomerically pure carboxylic acids mediated
by a N,N0-dicyclohexylcarbodiimide and DMAP coupling reported
by Yus and Heuman.14,21 They have shown that 1-phenylethanol
1 could be resolved to give modest enantiomeric excess (43% ee)
using (R)-2,4-dichlorophenoxypropionic acid as resolving compo-
nent. We are currently exploring the scope and a limitation of
our diastereoselective DCC coupling reaction and the outcomes
will be reported in due course.
Access to both enantiomers of 1-phenylethanol 1 were achieved
by LiAlH4 reduction of the inseparable esters (R,R)-anti- and (R,S)-
syn-28 (ratio 86:14; 72% de), and (S,S)-anti- and (S,R)-syn-33 (ratio
82:18; 64% de) to give the enantiomerically enriched 1-phenyl-
ethanol (R)-119 (in 47% yield with 72% ee) and (S)-119 (in 55% yield
with 64% ee), respectively (Scheme 13). The complementary pri-
mary alcohol (S)-38 was separated efficiently by flash column
chromatography on silica gel from 1-phenylethanol (S)-1 {DRF
[light petroleum ether (bp 40–60 °C)/diethyl ether (9:1)] = 0.20},
whereas, the remaining alcohol (R)-37 was only partially separable
from (R)-1.
In conclusion, we have developed a diastereoselective parallel
kinetic resolution approach for the resolution of 1-phenylethanol
(rac)-1, using an equimolar combination of quasi-enantiomeric
carboxylic acids [e.g., (R)-22 and (S)-27]. The levels of diastereo-
control were found to be excellent favouring the formation of the
corresponding esters (R,R)-anti-28 and (S,S)-anti-33 in good
yields.20 Simple reduction of adducts (R,R)-anti-28 and (S,S)-anti-
33 using LiAlH4 gave the corresponding enantiomerically enriched
(R)- and (S)-enantiomers of 1-phenylethanol 1. The nearest anal-
ogy to this study is the kinetic resolution of racemic secondary
Acknowledgements
We are grateful to the EPSRC (to E.C.) for a studentship, the
Saudi Government for financial support (to N.A.S.), and the EPSRC
National Mass Spectrometry Service (Swansea) for accurate mass
determinations.
References and notes
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Miller, S. J. Acc. Chem. Res. 2004, 37, 601–610; (c) France, S.; Guerin, D. J.; Miller,
S. J.; Lectka, T. Chem. Rev. 2003, 103, 2985–3012; (d) Spivey, A. C.; Arseniyadis,
S. Angew. Chem., Int. Ed. 2004, 43, 5436–5441; (e) Vedejs, E.; Jure, M. Angew.
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2003, 103, 3247–3261; (g) Robinson, E. J. E.; Bull, S. D. Tetrahedron: Asymmetry
2003, 14, 1407–1446; (h) Somfai, P.Angew. Chem., Int. Ed. 1997, 36, 2731–2733.

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V. B.; Uffman, E. W.; Jiang, H.; Li, X.; Kilbane, C. J. J. Am. Chem. Soc. 2004, 126,
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Am. Chem. Soc. 1999, 121, 5091–5092.
18. For (rac)-anti-16, the methyl doublets appear at 1.43 ppm (3H, d, J = 7.2 Hz,
PhCHCH3O) and 1.42 ppm (3H, d, J = 6.6 Hz, PhCHCH3). Whereas, for (rac)-syn-
16, the methyl doublets appear at 1.41 ppm (3H, d, J = 7.2 Hz, PhCHCH3O) and
1.35 ppm (3H, d, J = 6.6 Hz, PhCHCH3).
19. The enantiomeric excess of 1-phenylethanol was determined by (400 MHz)
1H NMR spectroscopy by derivatisation with (R)-Mosher’s acid (2-methoxy-
2-phenyl-2-trifluoroacetic acid) using
procedure.
a DCC/DMAP (0.2 equiv) coupling
5. Ruble, J. C.; Latham, H. A.; Fu, G. C. J. Am. Chem. Soc. 1997, 119, 1492–
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2006, 62, 295–301.
8. Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1996, 118, 1809–1810.
9. For parallel kinetic resolution reviews, see: (a) Eames, J. Angew. Chem., Int. Ed.
2000, 39, 885–888; (b) Eames, J. In Organic Synthesis Highlights; VCH-Wiley,
2003; v. Chapter 17; (c) Dehli, J. R.; Gotor, V. Chem. Soc. Rev. 2002, 31, 365–370;
(d) Dehli, J. R.; Gotor, V. ARKIVOC 2002, v, 196–202.
10. Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1997, 119, 2584–2585.
11. For a comprehensive review of quasi-enantiomers, see: Zhang, Q.; Curran, D. P.
Chem. Eur. J. 2005, 11, 4866–4880.
20. Representative experimental procedure: N,N0-dicyclohexylcarbodiimide (DCC)
(0.27 g, 1.34 mmol) in CH2Cl2 (2 mL) was added to a stirred solution of 2-
phenylbutanoic acid (R)-22 (0.20 g, 1.22 mmol) and 2-(6-methoxynaphthalen-
2-yl)propionic acid (S)-27 (0.28 g, 1.22 mmol) in CH2Cl2 (20 mL) at rt. 3,5-
Lutidine (0.13 g, 1.22 mmol) was added and the resulting solution was stirred
for 2 min. 1-Phenylethanol (rac)-1 (0.29 g, 2.44 mmol) in CH2Cl2 (2 mL) was
added and the resulting solution was stirred for 12 h. The solution was filtered
(to remove DCU). Brine (10 mL) was added and solution was extracted with
CH2Cl2 (3 ꢂ 25 mL). The combined organic layers were dried (over MgSO4) and
evaporated under reduced pressure. The residue was purified by flash column
chromatography on silica gel eluting with light petroleum ether (bp 40–60 °C)/
diethyl ether (1:1) to give an inseparable mixture (86:14) of (R,R)-anti- and
(R,S)-syn-28 (0.21 g, 64%) as a colourless oil; RF [light petroleum ether (bp 40–
25
25
12. Coulbeck, E.; Eames, J. Synlett 2008, 333–338.
60 °C)/diethyl ether (1:1)] = 0.68; ½aꢃD +2.55 (c 4.4, CHCl3) {theoretical—½aꢃ
13. Coulbeck, E.; Eames, J. Tetrahedron: Asymmetry 2007, 18, 2313–2325.
14. (a) Chinchilla, R.; Najera, C.; Yus, M.; Heumann, A. Tetrahedron: Asymmetry
1990, 1, 851–854; (b) Chinchilla, R.; Najera, C.; Yus, M.; Heumann, A.
Tetrahedron: Asymmetry 1991, 2, 101–104; (c) Mazon, A.; Najera, C.; Yus, M.;
Heumann Tetrahedron: Asymmetry 1990, 2, 1455–1466.
+2.51 for (R,R)-anti-28:(R,S)-syn-28 in the ratio 86:14} and an inseparabDle
mixture of (S,S)-anti- and (S,R)-syn-33 (0.24 g, 58%) as a white solid; mp 94–
25
100 °C; RF [light petroleum ether (bp 40–60 °C)/diethyl ether (1:1)] = 0.52; ½aꢃD
25
+23.88 (c 6.6, CHCl3) {theoretical—½aꢃD +2.51 for (S,S)-anti-33:(S,R)-syn-33 in
the ratio 82:18}.
15. We assume that the chirality present in DCC plays no stereochemical role in
these reactions.
16. Using a sub-stoichiometric amount of 3,5-lutidine 18 (0.2 equiv) gave after
12 h the corresponding esters (rac)-anti- and (rac)-syn-16 in a combined 57%
yield with a diastereoisomeric ratio of 82:18.
17. Replacing 3,5-lutidine with 4-dimethylaminopyridine (DMAP) gave the
corresponding ester (rac)-(anti)-16 in 69% yield with lower diastereocontrol
[54% de (ratio 77:23 anti-:syn-)].
21. For related studies see: (a) Ammazzalorso, A.; Amoroso, R.; Bettoni, G.; De
Filippis, B.; Giampietro, L.; Pierini, M.; Tricca, M. L. Tetrahedron Lett. 2002, 43,
4325–4328; (b) Ammazzalorso, A.; Amoroso, R.; Bettoni, G.; De Filippis, B.;
Fantacuzzi, M.; Giampietro, L.; Maccallini, C.; Tricca, M. L. Eur. J. Org. Chem.
2006, 4088–4091; (c) Matsugi, M.; Hagimoto, Y.; Nojima, M.; Kita, Y. Org.
Process Res. Dev. 2003, 7, 583–584; (d) Camps, P.; Perez, F.; Soldevilla, N.
Tetrahedron: Asymmetry 1997, 8, 1877–1894; (e) Calmes, M.; Glot, C.; Michel,
T.; Rolland, M.; Martinez, J. Tetrahedron: Asymmetry 2000, 11, 737–741.