E. Coulbeck, J. Eames / Tetrahedron Letters 50 (2009) 4449–4451
4451
1. t-BuOLi (3 equiv.)
2. ZnCl2 (3 equiv.), THF
3. reflux, 2 h
diastereoselective coupling procedure, and the results will be re-
ported in due course.
O
Ar
OH
Ph
Et
Me
O
4.
Ph
CO2C6F5
H
Ar
Me
H
H
Acknowledgements
Et
(S)-10
(1 equiv.)
H
(rac)-
(10 equiv.)
(S,S)-anti-
We are grateful to the EPSRC (to E.C.) for a studentship and to
the EPSRC National Mass Spectrometry Service (Swansea) for accu-
rate mass determinations.
Entry
1
Secondary alcohol
Ester
d.e.
Yield
15%
Me
Br
OH
H
References and notes
(rac)-18
(S,S)-anti-23
94%
Me
Me
1. For representative reviews, see: (a) Fu, G. Acc. Chem. Res. 2000, 33, 412–420; (b)
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.
Chem., Int. Ed. 2005, 44, 3974–4001; (f) Pamies, O.; Bäckvall, J.-E. Chem. Rev.
2003, 103, 3247–3261; (g) Robinson, E. J. E.; Bull, S. D. Tetrahedron: Asymmetry
2003, 14, 1407–1446; (h) Eames, J. Sci. Synth. 2008, 36, 341–421.
2. For comprehensive examples, see: (a) Morgan, B.; Oehlschlager, A. O.; Stokes, T.
M. J. Org. Chem. 1992, 57, 3231–3236; (b) Brown, S. M.; Davies, S. G.; de Sousa, J. A.
A. Tetrahedron: Asymmetry 1993, 4, 813–822; (c) Naemura, K.; Murata, M.;
Tanake, R.; Yano, M.; Hirose, K.; Tobe, Y. Tetrahedron: Asymmetry 1996, 7, 1581–
1584; (d) Naemura, K.; Murata, M.; Tanake, R.; Yano, M.; Hirose, K.; Tobe, Y.
Tetrahedron: Asymmetry 1996, 7, 3285–3294; (e) Cordova, A.; Tremblay, M. R.;
Clapham, B.; Janda, K. D. J. Org. Chem. 2001, 66, 5645–5648; (f) Swaleh, S. M.;
Hungerhoff, B.; Sonnenschein, H.; Theil, F. Tetrahedron 2002, 58, 4085–4089; (g)
Hungerhoff, B.; Sonnenschein, H.; Theil, F. J. Org. Chem. 2002, 67, 1781–1785.
3. Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1996, 118, 1809–1810.
OH
H
(rac)-19
(rac)-20
(S,S)-anti-24
(S,S)-anti-25
2
3
91%
88%
40%
62%
OMe OH
H
Me
Me
OH
H
4. Evans, D. A.; Anderson, J. C.; Taylor, M. K. Tetrahedron Lett. 1993, 34, 5563–5566.
5. 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, 2945–2964.
6. Coulbeck, E.; Eames, J. Tetrahedron: Asymmetry 2007, 18, 2313–2325.
7. Al-Shaye, N.; Boa, A. N.; Coulbeck, E.; Eames, J. Tetrahedron Lett. 2008, 49, 4661–
4665.
(rac)-21
(S,S)-anti-26
88%
38%
4
8. Coulbeck, E.; Eames, J. Synlett 2008, 333–338.
9. For a comprehensive review into quasi-enantiomers, see: Zhang, Q.; Curran, D.
P. Chem. Eur. J. 2005, 11, 4866–4880.
Scheme 8. Resolution of secondary alcohols (rac)-18–21 using pentafluorophenyl
2-phenylbutanoate (S)-10.
10. n-BuLi (in hexanes) and PhLi (in dibutyl ether) have been shown to contain
trace amounts 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). For additional information see Ref. 8.
entry 4). From this study, it appeared that competitive oxidation
occurs for the less nucleophilic alcohols (rac)-12 and (rac)-15. This
oxidation presumably occurs via an Oppenauer-type process
involving the active ester (S)-10 as the hydride acceptor.17 In com-
parison, increasing the steric demand of the phenyl ring in (rac)-1
increased the levels of diastereocontrol without promoting oxida-
tion to the corresponding ketone. Using a series of 1-(2-substi-
11. Separation is generally achieved by column chromatography {DRF 0.18 [light
petroleum (bp 40–60 °C):diethyl ether (1:1)]}.
12. Competitive formation of t-butyl 2-phenylpropanoate does not occur.
13. Fu has reported the use of a tertiary alcohol [e.g., 2-methyl-2-butanol (t-amyl
alcohol)] as a solvent within the 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, 2794–2795.
14. Representative experimental procedure: 1-phenylethyl 2-phenylbutanoate (S,S)-
anti-11 derived from the resolution of 1-phenylethanol (rac)-1 using
pentafluorophenyl 2-phenylbutanoate (S)-10: Lithium tert-butoxide (73 mg,
0.91 mmol), anhydrous zinc chloride (0.124 g, 0.91 mmol), and THF (5 mL)
tuted-phenyl)ethanols
(rac)-18–20
under
our
standard
conditions, gave the esters (S,S)-anti-23–25 in 15%, 40%, and 62%
yields, respectively, with 94%, 91%, and 88% diastereoisomeric ex-
cesses, respectively (Scheme 8, entries 1–3). The less sterically
demanding 1-arylethanol (rac)-21 gave the corresponding ester
(S,S)-anti-26 in 38% yield with 88% diastereoisomeric excess
(Scheme 8, entry 4).
Access to enantiomerically enriched 1-phenylethanol (S)-1 in
good yield (78%) with 84% ee18 was achieved by transesterification
of the ester (S,S)-11 with sodium ethoxide followed by hydrolysis
with lithium hydroxide. The resulting 2-phenylbutanoic acid 27
was found to be racemic (Scheme 9).19
were sequentially added to
a
round-bottomed flask containing 1-
phenylethanol (rac)-1 (0.37 g, 3.03 mmol) under a nitrogen atmosphere. The
resulting solution was refluxed for 2 h and then allowed to cool to room
temperature over 1 h. Pentafluorophenyl 2-phenylbutanoate (S)-10 (0.10 g,
0.30 mmol) in THF (5 mL) was added and the resulting solution was stirred for
12 h. The reaction was quenched by the addition of saturated aqueous NH4Cl
(10 mL). The organic layer was extracted with dichloromethane (3 Â 25 mL),
washed with water (50 mL), dried (over MgSO4), and evaporated under
reduced pressure. The residue was purified by flash column chromatography
on silica gel eluting with light petroleum ether (40–60 °C): diethyl ether (9:1)
to give a pair of inseparable diastereoisomers (ratio: anti-:syn- 95.5:4.5; 91%
de) of 1-phenylethyl 2-phenylbutanoates (S,S)-anti- and (S,R)-syn-11 (42 mg,
52%) as colorless oils {RF 0.82 [light petroleum (bp 40–60 °C):diethyl ether
(1:1)]}. For characterisation data, see Ref. 6. All compounds synthesized have
satisfactory 1H and 13C NMR, IR, and HRMS spectra with >95% purity.
15. The use of 10 equiv4–8 of racemic alcohol has also been reported by Miller, S. J.;
Copeland, G.T.;Papaioannou, N.;Horstmann, T.E.;Ruel,E.M. J.Am. Chem. Soc.1998,
120, 1629–1630. For our study, an excess of 1-phenylethanol (rac)-1 was used to
minimize the kinetic resolution concentration effect, epimerization of the product,
potential racemization of the active ester(s), and as a competitive Lewis base.
16. The major diastereoisomeric ester (S,S)-anti-8 can be formed stereospecifically
in 82% yield with 99.4% de by using 1-phenylethanol (S)-1 (>99% ee) and
pentafluorophenyl 2-phenylpropanoate (S)-6.
In conclusion, we have reported an enantiomer selective resolu-
tion of 1-phenylethanol (rac)-1 using pentafluorophenyl 2-phenyl-
butanoate (S)-10 (derived from
a commercially available 2-
phenylbutanoic acid 27) as our resolving component. The levels
of diastereocontrol were found to be excellent favoring the forma-
tion of the corresponding (S,S)-anti-esters in moderate to good
yields. We are currently exploring the scope and limitation of this
17. (a) Cao, H. Y.; Grée, R. Tetrahedron Lett. 2009, 50, 1493–1494; (b) Linghu, X.;
Satterfield, A. D.; Johnson, J. S. J. Am. Chem. Soc. 2006, 128, 9302–9303; (c) Hodge,
P.; Sung, D. W. L.; Stratford, P. W. J. Chem. Soc., Perkin Trans. 1 1999, 2335–2342.
18. The enantiomeric excess was determined by derivatisation with (S)-Ibuprofen
using a DMAP-mediated DCC coupling procedure.
19. The enantiomeric excess was determined through statistical anhydride
formation by treatment with DCC. For further information, see: Coulbeck, E.;
Eames, J. Tetrahedron: Asymmetry 2009, 20, 635–640.
O
Ph
Ph
1. NaOEt, THF
Ph
Et
(rac )-27; 70%
CO2H
Ph
Me
Me
O
2. LiOH, H2O2
THF-H2O (3:1)
HO
(S)-1; 78%; 84%e.e.
H
H
H
Et
H
(S,S)-11; 88% d.e.
Scheme 9. Formation of 1-phenylethanol (S)-1.