Parallel kinetic resolution of 1-phenylethanol using quasi-enantiomeric active esters

Article abstract of DOI:10.1055/s-2008-1032068

The parallel kinetic resolution of racemic 1-phenylethanol using an equimolar combination of quasi-enantiomeric pentafluorophenyl esters is discussed. The levels of diastereoselectivity were excellent (>88% de) leading to separable quasi-enantiomeric esters in good yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032068

LETTER
333
Parallel Kinetic Resolution of 1-Phenylethanol Using Quasi-Enantiomeric
Active Esters
Parallel
Kinetic
l
Resolu
l
tion of
i
1-Phen
o
ylethanol t Coulbeck, Jason Eames*
Department of Chemistry, University of Hull, Cottingham Road, Kingston upon Hull HU6 7RX, UK
Fax +44(1482)466410; E-mail: j.eames@hull.ac.uk
Received 13 November 2007
(S,R)-5 (Scheme 1). The levels of molecular recognition
between (R)-1 and (S)-3, and (S,S)-2 and (R)-3 were ex-
cellent, allowing their efficient parallel kinetic separation.
By comparison, Davies5 has superbly shown the use of a
pair of quasi-enantiomeric lithium amides, (S)-6 and (R)-
7 to resolve the racemic methyl 3-tert-butylcyclopentene
carboxylate (rac-8) to give two separable complementary
b-amino esters syn,syn,anti-9 and syn,syn,anti-10 in high
yield with excellent stereocontrol (95–99% de;
Scheme 2).
Abstract: The parallel kinetic resolution of racemic 1-phenyletha-
nol using an equimolar combination of quasi-enantiomeric pen-
tafluorophenyl esters is discussed. The levels of diastereoselectivity
were excellent (>88% de) leading to separable quasi-enantiomeric
esters in good yields.
Key words: chiral auxiliaries, chiral resolution, kinetic resolution,
molecular recognition, stereoselectivity
Over the last decade, the design and application of novel
parallel kinetic resolutions have attracted significant at-
tention.1 The synthetic outcome of this ingenious strategy
has been developed independently by Davies2 and
Vedejs.3 Vedejs ha s elegantly shown3 the parallel resolu-
tion of 1-(2¢-naphthyl)ethanol (rac-3) using a pair of dou-
bly differentiated quasi-enantiomeric4 pyridinium
chlorides (R)-1 and (S,S)-2 to give two differential car-
bonates (S)-4 and (S,R)-5 in excellent yield with high lev-
els of stereocontrol (Scheme 1). These adducts were
efficiently separated through chemical modification (by
treatment with zinc in acetic acid)3 to give the resolved 1-
(2¢-naphthyl)ethanol (3).
Over the last few years, we have been interested in the
parallel kinetic resolution of Evans-based oxazolidino-
nes,6 such as 4-phenyloxazolidin-2-one (rac-13), using a
combination of quasi-enantiomeric active esters, like (R)-
11 and (S)-12, to give two separable diastereomerically
pure oxazolidinone adducts (R,S)-syn-14 and (S,R)-syn-15
in good yield with excellent levels of diastereocontrol
(>90% de; Scheme 3). We now wish to report an exten-
sion of this methodology towards the parallel kinetic res-
olution of 1-phenylethanol (rac-16) using an equimolar
combination of quasi-enantiomeric active esters (R)-11
and (S)-12 as resolving agents.
From this study, it was evident that the S-enantiomer of 1-
(2¢-naphthyl)ethanol (3) recognised the pyridinium chlo-
ride (R)-1 [to give carbonate (S)-4], whereas the remain-
ing R-enantiomer recognised the complementary quasi-
enantiomeric pyridinium chloride (S,S)-2 (in a near equal
and opposite fashion) to give the corresponding carbonate
We first investigated the mutual kinetic resolution be-
tween 1-phenylethanol (rac-16) and pentafluorophenyl 2-
phenylpropionate (rac-11) in an attempt to probe their rel-
ative molecular recognition pathway (Table 1). Treatment
of an excess of 1-phenylethanol (rac-16; 10 equiv)7 with
t-BuLi (3 equiv) in THF at –78 °C, followed by the addi-
NMe2
O
Me
O
H
t-Bu
OH
Me
N
Cl3C
O
Cl
OMe
Cl3C
O
O
H
(R)-1
(S)-4 88% ee, 46%
rac-3
Et3N, MgBr2
NMe2
H
O
H
Me
H
t-Bu
O
O
N
Cl
OBn
O
O
(S,R)-5 >95% de, 49%
(S,S)-2
Scheme 1 Parallel kinetic resolution of 1-(2¢-naphthyl)ethanol (rac-3) using quasi-enantiomeric pyridinium chlorides (R)-1 and (S,S)-2
SYNLETT 2008, No. 3, pp 0333–0338
x
x.
x
x.
2
0
0
8
Advanced online publication: 23.01.2008
DOI: 10.1055/s-2008-1032068; Art ID: D37007ST
© Georg Thieme Verlag Stuttgart · New York

334
E. Coulbeck, J. Eames
LETTER
OMe
OMe
Me
Me
N
N
Li
Li
(R)-7
(S)-6
Ar = 3,4-dimethoxyphenyl
Me
Ph
Ar
Me
Ph
Ph
CO2Me
CO2Me
CO2Me
N
N
(S)-6 (1.5 equiv)
(R)-7 (1.5 equiv)
t-Bu
t-Bu
t-Bu
THF, –78 °C
syn,syn,anti-10
35%, 97–99% de
syn,syn,anti-9
39%, 95–97% de
rac-8
Scheme 2 Parallel kinetic resolution of methyl 3-tert-butylcyclopentene carboxylate (rac-8) using quasi-enantiomeric lithium amides (S)-6
and (R)-7
MeO
O
O
OC6F5
OC6F5
Me
H
H
Me
(S)-12
(R)-11
MeO
O
O
O
O
O
1. n-BuLi
THF, –78 °C
HN
O
N
O
N
O
2. (R)-11 and
(S)-12
H
Me
Me
H
Ph
rac-13
Ph
(R,S)-syn-14
anti-14:syn-14 = 95:5; 65%
Ph
(S,R)-syn-15
anti-15:syn-15 = 95:5; 61%
Scheme 3 Parallel kinetic resolution of 4-phenyloxazoldin-2-one (rac-13) using quasi-enantiomeric active esters (R)-11 and (S)-12
tion of pentafluorophenyl 2-phenylpropionate (rac-11; 1 nol (rac-16; 10 equiv) in THF at –78 °C, followed by the
equiv), gave after 12 hours an inseparable mixture of es- addition of the active esters rac-18, rac-20, rac-22 and
ters rac,anti-17 and rac,syn-17 in 72% yield with 24% de rac-12, gave the corresponding esters rac,anti-19, rac,an-
(Table 1, entry 1).8 An excess of 1-phenylethanol (rac-16) ti-21, rac,anti-23 and rac,anti-24, and rac,syn-19,
is paramount otherwise the levels of diastereocontrol were rac,syn-21, rac,syn-23 and rac,syn-24, respectively, in
lowered due to competitive epimerisation of ester 17 at good yields (56–71%) with excellent levels of diastereo-
the a-carbon.9 The levels of diastereocontrol could be ob- selection (ca. 88% de)11 (Table 2). From this study, the
tained in >88% diastereomeric excess by the simple addi- substitution pattern of the aryl ring within the active esters
tion of ZnCl2 (Table 1). However, the yields were found rac-12, rac-18, rac-20 and rac-22 appeared to play little
to be highly dependent on the relative proportion of ZnCl2 or no role in the stereochemical outcome of these mutual
used. An excess of ZnCl2 (e.g., 6 equiv) appeared to slow kinetic resolutions (Table 2).
the rate of ester formation (Table 1, entries 3 vs. 4),
For our parallel kinetic resolution, we chose to use an
whereas, using less than 1.5 equivalents of ZnCl2 in-
equimolar combination of pentafluorophenyl 2-phenyl-
creased the likelihood of the less stereoselective lithium 1-
propionate [(R)-11] and pentafluorophenyl 2-(6-meth-
phenylethoxide background addition pathway (Table 1,
oxynaphthalen-2-yl)propionate
[(S)-12]
as
our
entries 1 vs. 3). The optimum conditions were found to be
three equivalents of ZnCl2, leading to the required ester
anti-17 in 71% yield with >88% de (Table 1, entry 3).
complementary resolving components due to their
known12 separability (Scheme 4). Treatment of 1-phen-
ylethanol (rac-16; 10 equiv) in THF at –78 °C with t-BuLi
With this information in hand, we next probed the mutual (3 equiv) and ZnCl2 (3 equiv), followed by the addition of
kinetic resolution of 1-phenylethanol (rac-16) using a se- an equimolar combination of components (R)-11 (0.5
ries of pentafluorophenyl 2-(4-substituted ar- equiv) and (S)-12 (0.5 equiv), gave the corresponding es-
yl)propionates10 rac-12, rac-18, rac-20 and rac-22 in an ters anti-17 [derived from (R)-11] and anti-24 [derived
attempt to find a complementary resolving partner for the from (S)-12] in 77% and 76% yields with 86% and 88%
parent active ester 11 (Table 2). Addition of t-BuLi (3 diastereomeric excesses, respectively (Scheme 4).
equiv) and ZnCl2 (3 equiv) to a solution of 1-phenyletha-
Synlett 2008, No. 3, 333–338 © Thieme Stuttgart · New York

LETTER
Parallel Kinetic Resolution of 1-Phenylethanol
335
Table 1 Probing the Mutual Kinetic Resolution of 1-Phenylethanol (rac-16) Using Active Ester rac-11
1. t-BuLi
THF, –78 °C
2. ZnCl2
O
Ph
O
Ph
OH
H
Ph
Me
Ph
H
O
O
H
3.
Me
Ph
Me
O
H
Me
H
Me
Ph
OC6F5
rac-anti-17
rac-syn-17
rac-16
(10 equiv)
H
Me
rac-11
Entry
t-BuLi (equiv)
ZnCl2 (equiv)
Ratio of
de
Yield (%)
anti-17/syn-17
1
2
3
4
3.0
3.0
3.0
3.0
0.0
1.5
3.0
6.0
62:38
72:28
94:6
24%
44%
88%
94%
72%
72%
71%
32%
97:3
Table 2 Mutual Kinetic Resolution of 1-Phenylethanol (rac-16) Using Active Esters rac-11, rac-12, rac-18, rac-20 and rac-22
1. t-BuLi (3 equiv)
THF, –78 °C
2. ZnCl2 (3 equiv)
O
Ph
O
Ph
OH
H
Ar
Me
Ar
H
O
O
H
3.
Me
Ph
Me
O
H
Me
H
Me
Ar
OC6F5
rac-syn
rac-anti
rac-16
(10 equiv)
H
Me
rac
(1 equiv)
Diastereoselectivity
Entry
1
Active ester
Ester
Ratio
de
Yield
71%
CO2C6F5
rac,anti-17/rac,syn-17
rac,anti-19/rac,syn-19
94:6
88%
Me
rac-11
Me
CO2C6F5
2
3
4
94:6
94:6
93:7
88%
88%
86%
61%
66%
56%
Me
rac-18
i-Bu
CO2C6F5
rac,anti-21/rac,syn-21
rac,anti-23/rac,syn-23
Me
rac-20
Cl
CO2C6F5
Me
rac-22
MeO
CO2C6F5
5
rac,anti-24/rac,syn-24
94:6
88%
68%
Me
rac-12
Synlett 2008, No. 3, 333–338 © Thieme Stuttgart · New York

336
E. Coulbeck, J. Eames
LETTER
O
Ph
OH
H
Ph
H
Ph
CO2C6F5
O
Ph
Me
Me
H
Me
H
Me
(R)-11
(0.5 equiv)
rac-16
(10 equiv)
THF, –78 °C
(R,R)-anti-17:(R,S)-syn-17 = 93:7; 77%
t-BuLi (3 equiv)
ZnCl2 (3 equiv)
MeO
MeO
O
Ph
Me
CO2C6F5
O
H
Me
H
Me
H
(S)-12
(0.5 equiv)
(S,S)-anti-24:(S,R)-syn-24 = 94:6; 76%
Scheme 4 Parallel kinetic resolution of 1-phenylethanol (rac-16) using active esters (R)-11 and (S)-12
O
Ph
Ph
Ph
H
Me
LiAlH4
Et2O
Ph
O
H
OH
HO
H
Me
Me
(R)-16 80%
H
Me
(R,R)-anti-17
(R)-25 78%
MeO
OH
Me
H
MeO
O
Ph
(S)-26 74%
LiAlH4
Et2O
Me
O
H
Me
H
Ph
(S,S)-anti-24
Me
HO
H
(S)-16 72%
Scheme 5 LiAlH4 reduction of esters (R,R)-anti-17 and (S,S)-anti-24
From this study, it is evident that the R enantiomer of ac- of quasi-enantiomeric pentafluorophenyl active esters
tive ester 11 recognised the R enantiomer of 1-phenyleth- [e.g., (R)-11 and (S)-12]. The levels of diastereocontrol
anol (16; and vice versa) to give the preferred ester (R,R)- were found to be excellent favouring the formation of the
anti-17. Whereas, the complementary resolving partner corresponding esters (R,R)-anti-17 and (S,S)-anti-24 in
(S)-12 recognised the S enantiomer of 1-phenylethanol good yields. We are currently exploring the scope and
(16) to give the quasi-enantiomeric ester (S,S)-anti-24 as limitation of this diastereoselective coupling procedure,
the major diastereomer (Scheme 4). These particular es- and this will be reported in due course.
ters were easily separable by column chromatography
{DRf 0.18 [light PE (40–60 °C)–Et2O (1:1)]}. Access to
both enantiomers of 1-phenylethanol, (R)-16 and (S)-16,
Acknowledgment
We are grateful to the EPSRC for a studentship (to E.C.) and the
EPSRC National Mass Spectrometry Service (Swansea) for accura-
te mass determinations. We would like to thank Michael Morgan for
conducting some preliminary experiments.
was achieved in 80% and 72% yields, respectively, by
LiAlH4 reduction13 of the corresponding esters (R,R)-anti-
17 and (S,S)-anti-24 (Scheme 5).
The nearest analogy of this work is the kinetic resolution
of 1-phenylethanol (16) using acyl-transfer methodology
involving either chemical14 or biological processes15 util-
ising (sub)stoichiometric chiral mediators.16 The majority
of these methods have been shown to be comparable to
our approach for the separation of the enantiomers of ra-
cemic 1-phenylethanol.
References and Notes
(1) For reviews see: (a) Eames, J. Angew. Chem. Int. Ed. 2000,
39, 885. (b) Eames, J. In Organic Synthesis Highlights, Vol.
V; Wiley-VCH: Weinheim, 2003, Chap. 17, 151–164.
(c) Dehli, J. R.; Gotor, V. Chem. Soc. Rev. 2002, 31, 365.
(d) Dehli, J. R.; Gotor, V. ARKIVOC 2002, (v), 196.
(e) Liao, L.; Zhang, F.; Dmitrenko, O.; Bach, R. D.; Fox, J.
M. J. Am. Chem. Soc. 2004, 126, 4490.
In conclusion, we have reported a diastereoselective par-
allel kinetic resolution approach17 for the resolution of 1-
phenylethanol (rac-16), using an equimolar combination
(2) Preston, S. C. D. Phil. Dissertation; Oxford University: UK,
1989; Diss. Abstr. Int. B 1990, 51, 2896.
Synlett 2008, No. 3, 333–338 © Thieme Stuttgart · New York

LETTER
Parallel Kinetic Resolution of 1-Phenylethanol
337
(3) (a) Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1997, 119, 2584.
For additional studies, see: (b) Vedejs, E.; Rozners, E. J.
Am. Chem. Soc. 2001, 123, 2428. (c) Vedejs, E.; Daugulis,
O. J. Am. Chem. Soc. 2003, 125, 4166.
Namutebi, M.; Northen, J.; Yohannes, Y. Tetrahedron:
Asymmetry 2006, 17, 3406; and references therein.
(11) Measured by 1H NMR (400 MHz) spectroscopy; for
rac,anti-17, the methyl doublets appear at d = 1.43 (d, J = 7.2
Hz, 3 H, MeCH) and 1.42 (d, J = 6.6 Hz, 3 H, MeCH),
whereas for rac,syn-17, the methyl doublets appear at d =
1.41 (d, J = 7.2 Hz, 3 H, MeCH) and 1.35 (d, J = 6.6 Hz, 3
H, MeCH).
(4) For a comprehensive review into quasi-enantiomers, see:
Zhang, Q.; Curran, D. P. Chem. Eur. J. 2005, 11, 4866.
(5) (a) Davies, S. G.; Diez, D.; El Hammouni, M. M.; Garner, A.
C.; Garrido, N. M.; Long, M. J.; Morrison, R. M.; Smith, A.
D.; Sweet, M. J.; Withey, J. M. Chem. Commun. 2003,
2410. For additional studies, see (b) Davies, S. G.; Garner,
A. C.; Long, M. J.; Smith, A. D.; Sweet, M. J.; Withey, J. M.
Org. Biomol. Chem. 2004, 2, 3355. (c) Davies, S. G.;
Garner, A. C.; Long, M. J.; Morrison, R. M.; Roberts, P. M.;
Savory, E. D.; Smith, A. D.; Sweet, M. J.; Withey, J. M. Org.
Biomol. Chem. 2005, 3, 2762.
(6) (a) Coumbarides, G. S.; Dingjan, M.; Eames, J.; Flinn, A.;
Motevalli, M.; Northen, J.; Yohannes, Y. Synlett 2006, 101.
For additional studies, see: (b) Coumbarides, G. S.; Eames,
J.; Flinn, A.; Northen, J.; Yohannes, Y. Tetrahedron Lett.
2005, 46, 849. (c) Coumbarides, G. S.; Dingjan, M.; Eames,
J.; Flinn, A.; Northen, J.; Yohannes, Y. Tetrahedron Lett.
2005, 46, 2897. (d) Chavda, S.; Coulbeck, E.; Coumbarides,
G. S.; Dingjan, M.; Eames, J.; Ghilagaber, S.; Yohannes, Y.
Tetrahedron: Asymmetry 2006, 17, 3386. (e) Boyd, E.;
Chavda, S.; Eames, J.; Yohannes, Y. Tetrahedron:
Asymmetry 2007, 18, 476. (f) Coumbarides, G. S.; Dingjan,
M.; Eames, J.; Flinn, A.; Northen, J. Chirality 2007, 19,
321. (g) Chavda, S.; Coumbarides, G. S.; Dingjan, M.;
Eames, J.; Flinn, A.; Northen, J. Chirality 2007, 19, 313.
(h) Boyd, E.; Coulbeck, E.; Coumbarides, G. S.; Chavda, S.;
Dingjan, M.; Eames, J.; Flinn, A.; Motevalli, M.; Northen,
J.; Yohannes, Y. Tetrahedron: Asymmetry 2007, 18, 2515.
(7) The use of ten equivalents of racemic alcohol has been
reported by: (a) Evans, D. A.; Anderson, J. C.; Taylor, M. K.
Tetrahedron Lett. 1993, 34, 5563. (b) Miller, S. J.;
(12) For active esters: Rf [light PE (40–60 °C)–Et2O, 9:1] 0.69
[for (R)-11] and 0.50 [for (S)-12]. For further information
see ref. 10.
(13) For a representative procedure, see ref. 7d.
(14) For representative reviews, see: (a) Fu, G. Acc. Chem. Res.
2000, 33, 412. (b) Miller, S. J. Acc. Chem. Res. 2004, 37,
601. (c) France, S.; Guerin, D. J.; Miller, S. J.; Lectka, T.
Chem. Rev. 2003, 103, 2985. (d) Spivey, A. C.; Arseniyadis,
S. Angew. Chem. Int. Ed. 2004, 43, 5436. (e) Vedejs, E.;
Jure, M. Angew. Chem. Int. Ed. 2005, 44, 3974. (f) Pamies,
O.; Bäckvall, J.-E. Chem. Rev. 2003, 103, 3247.
(g) Robinson, E. J. E.; Bull, S. D. Tetrahedron: Asymmetry
2003, 14, 1407.
(15) For a review, see: (a) Ghanem, A.; Aboul-Enein, H. Y.
Chirality 2005, 17, 1. For comprehensive examples, see:
(b) Morgan, B.; Oehlschlager, A. O.; Stokes, T. M. J. Org.
Chem. 1992, 57, 3231. (c) Brown, S. M.; Davies, S. G.; de
Sousa, J. A. A. Tetrahedron: Asymmetry 1993, 4, 813.
(d) Naemura, K.; Murata, M.; Tanake, R.; Yano, M.; Hirose,
K.; Tobe, Y. Tetrahedron: Asymmetry 1996, 7, 1581.
(e) Naemura, K.; Murata, M.; Tanake, R.; Yano, M.; Hirose,
K.; Tobe, Y. Tetrahedron: Asymmetry 1996, 7, 3285.
(f) Cordova, A.; Tremblay, M. R.; Clapham, B.; Janda, K. D.
J. Org. Chem. 2001, 66, 5645. (g) Swaleh, S. M.;
Hungerhoff, B.; Sonnenschein, H.; Theil, F. Tetrahedron
2002, 58, 4085. (h) Hungerhoff, B.; Sonnenschein, H.;
Theil, F. J. Org. Chem. 2002, 67, 1781.
Copeland, G. T.; Papaioannou, N.; Horstmann, T. E.; Ruel,
E. M. J. Am. Chem. Soc. 1998, 120, 1629. (c) Bull, S. D.;
Davies, S. G.; Garner, A. C.; Kruchinin, D.; Key, M. S.;
Roberts, P. M.; Savory, A. D.; Smith, A. D.; Thomson, J. E.
Org. Biomol. Chem. 2006, 4, 2945. (d) Coulbeck, E.;
Eames, J. Tetrahedron: Asymmetry 2007, 18, 2313. (e) See
also ref. 18. (f) For our study, an excess of alcohol rac-16
was used to minimize epimerisation of the product, potential
racemisation of the active ester(s) and as a competitive
Lewis base.
(16) Eames, J. Synthesis by Resolution and Inversion, In Science
of Synthesis, 36; Thomas, E. J.; Clayden, J. C., Eds.; Georg
Thieme Verlag: Stuttgart, 2007, 341–421.
(17) Experimental Procedure for 1-Phenylethyl 2-
Phenylpropionate [(R,R)-anti-17] and 1-Phenylethyl 2-
(6-Methoxynaphthalen-2-yl)propionate [(S,S)-anti-24]
Derived from the Parallel Kinetic Resolution of 1-
Phenylethanol (rac-16) Using Active Esters (R)-11 and
(S)-12: t-BuLi (1.81 mL, 1.7 M in pentane, 3.07 mmol) was
added to a stirred solution of 1-phenylethanol (rac-16; 1.25
g, 1.24 mL, 10.25 mmol) in THF at –78 °C. A solution of
ZnCl2 (3.07 mL, 1 M in Et2O, 3.07 mmol) was added and the
resulting solution was stirred for 2 min. An equimolar
combination of pentafluorophenyl 2-phenylpropionate [(R)-
11; 0.16 g, 0.51 mmol] and pentafluorophenyl 2-(6-
methoxynaphthalen-2-yl)propionate [(S)-12; 0.203 g, 0.51
mmol] in THF (20 mL) was added, and the resulting solution
was stirred for 12 h. The reaction was quenched by the
addition of sat. aq NH4Cl (5 mL) and H2O (10 mL). The
organic layer was extracted with CH2Cl2 (3 × 50 mL),
washed with H2O (10 mL), dried (over MgSO4) and
evaporated under reduced pressure. The residue was purified
by flash column chromatography on silica gel eluting with
light PE (40–60 °C)–Et2O (9:1) to give a pair of inseparable
diastereomers (anti/syn, 93:7) of 1-phenylethyl 2-
phenylpropionates (R,R)-anti-17 and (R,S)-syn-17 (0.10 g,
77%) as an oil {RF [light PE (40–60 °C)–Et2O (1:1)] 0.80}
and a pair of inseparable diastereomers (anti/syn, 94:6) of 1-
phenylethyl 2-(6-methoxynaphthalen-2-yl)propionates
(S,S)-anti-24 and (S,R)-syn-24 (0.13 g, 76%) as an oil {Rf
[light PE (40–60 °C)–Et2O (1:1)] 0.62}. Pentafluorophenol,
if present, can be removed by an aq NaOH extraction. All
(8) Alternatively, n-BuLi (in hexanes) and PhLi (in dibutyl
ether) could be used but they contained traces of lithium
butoxide which can lead to the formation of an inseparable
by-product, butyl 2-phenylpropionate (in 16% and 5% yields
for n-BuLi and PhLi, respectively). Characterisation data for
butyl 2-phenylpropionate; Rf [light PE (40–60 °C)–Et2O,
1:1] 0.80. IR (film): 1674 (C=O) cm–1. 1H NMR (400 MHz,
CDCl3): d = 7.15–7.28 (m, 5 H, 5 × CH, Ph), 3.99 (td, J = 1.5,
6.8 Hz, 2 H, OCH2), 3.63 (q, J = 7.2 Hz, 1 H, CHMe), 1.43–
1.52 (m, 2 H, CH2), 1.42 (d, J = 7.2 Hz, 3 H, CHMe), 1.18–
1.28 (m, 2 H, CH2), 0.79 (t, J = 7.5 Hz, 3 H, Me). 13C NMR
(100 MHz, CDCl3): d = 174 (C=O), 140.6 (i-C, Ph), 128.4,
127.4, 126.9 (3 × CH, Ph), 64.5 (OCH2), 45.5 (PhCH), 30.4,
18.9 (2 × CH2), 18.4 (MeCH), 13.6 (MeCH2). HRMS: m/z
[M+] calcd for C13H18O2: 206.1299; found: 206.1301.
(9) Using racemic lithium 1-(4-methoxyphenyl)ethoxide,
epimerisation of esters such as (S,S)-anti-24 and (S,R)-syn-
24, has been shown to occur at a significantly faster rate than
simple transesterification.
(10) Boyd, E.; Chavda, S.; Coulbeck, E.; Coumbarides, G. S.;
Dingjan, M.; Eames, J.; Flinn, A.; Krishnamurthy, A. K.;
Synlett 2008, No. 3, 333–338 © Thieme Stuttgart · New York

338
E. Coulbeck, J. Eames
LETTER
compounds synthesised had satisfactory 1H and 13C NMR,
IR and HRM spectra with >95% purity.
Characterisation data for:
d = 7.66 (d, J = 8.4 Hz, 1 H, CH, Ar), 7.63 (d, J = 8.4 Hz, 1
H, CH, Ar), 7.55 (br s, 1 H, CH, Ar), 7.33 (dd, J = 1.8, 8.3
Hz, 1 H, CH, Ar), 7.08–7.19 (m, 7 H, 7 × CH, Ar, Ph), 5.86
(q, J = 6.6 Hz, 1 H, PhCHMeO), 3.90 (s, 3 H, OMe, Ar), 3.88
(q, J = 7.2 Hz, 1 H, ArCHMe), 1.56 (d, J = 7.2 Hz, 3 H,
ArCHMe), 1.50 (d, J = 6.6 Hz, 3 H, PhCHCMeO). 13C NMR
(100 MHz, CDCl3): d = 173.7 (C=O), 147.5 (i-CO, Ar),
141.6 (i-C, Ph), 135.6 (i-C, Ar), 133.6, 128.9 (2 × i-C, Ar),
129.3,1 127.0,1 126.4,1 126.0,1 118.8,1 105.51 (6 × CH, Ar),
128.2,2 127.5,1 125.7,2 (5 × CH, Ph), 72.5 (PhCHMeO), 55.3
(OMe), 45.6 (ArCHMe), 22.3 (PhCHMeO), 18.4
1-Phenylethyl 2-Phenylpropionate [(R,R)-anti-17]:
transparent solid; mp 81–83 °C; Rf [light PE (40–60 °C)–
Et2O, 1:1] 0.80; [a]D20 +10.53 (c = 3.0, CHCl3) {lit.19 [a]D
+9.9 (c = 0.87, CHCl3)}. IR (CHCl3): 1730 (C=O) cm–1. 1H
NMR (400 MHz, CDCl3): d = 7.14–7.30 (m, 8 H, 8 × CH,
PhA and PhB), 7.00–7.05 (m, 2 H, 2 × CH, PhA or PhB), 5.78
(q, J = 6.6 Hz, 1 H, PhCHMeO), 3.68 (q, J = 7.2 Hz, 1 H,
PhCHMe), 1.43 (d, J = 7.2 Hz, 3 H, PhCHMe), 1.42 (d, J =
6.6 Hz, 3 H, PhCHMeO). 13C NMR (100 MHz, CDCl3): d =
173.5 (C=O), 141.6 (i-C, PhCHMeO), 140.4 (i-C,
20
+
(ArCHMe). HRMS: m/z [MNH4 ] calcd for C22H26NO3:
352.1907; found: 352.1907. MS: m/z (%) = 334 (20) [M+],
PhCHMe), 128.5,2 128.3,2 127.6,2 127.5,1 127.0,1 125.6,2
(10 × CH, PhA, PhB), 72.4 (PhCHMeO), 45.7 (PhCHMe),
185 (100) [ArCHMe+], 105 (60) [PhCHMe+].
(18) Fu has reported the use of 2-methyl-2-butanol (t-amyl
alcohol) as a solvent within the efficient resolution of 1-
phenylethanol using a chiral DMAP equivalent. For
additional information, see: Ruble, J. C.; Tweddell, J.; Fu, G.
C. J. Org. Chem. 1998, 63, 2794.
+
22.3 (PhCHMeO), 18.3 (PhCHMe). HRMS: m/z [MNH4 ]
calcd for C17H22NO2: 272.1645; found: 272.1648. MS: m/z
(%) = 254 (10) [M+], 105 (100) [PhCHMe+].
1-Phenylethyl 2-(6-Methoxynaphthalene-2-yl)propionate
[(S,S)-anti-24]: white solid; mp 94–96 °C; Rf [light PE (40–
60 °C)–Et2O (1:1)] 0.62; [a]D20 +26.6 (c = 3.2, CHCl3). IR
(CHCl3): 1723 (C=O) cm–1. 1H NMR (400 MHz, CDCl3):
(19) Yang, H.; Henke, E.; Bornscheuer, U. T. Tetrahedron:
Asymmetry 1999, 10, 957.
Synlett 2008, No. 3, 333–338 © Thieme Stuttgart · New York

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