A practical synthesis of enantiopure (S)-4-(4-hydroxybenzyl)-oxazolidin-2-one

Article abstract of DOI:10.1016/S0957-4166(03)00482-8

A high yielding four-step synthesis of enantiopure 4-(4-hydroxybenzyl)-oxazolidin-2-one (S)-1 from N-Boc-L-tyrosine is described. (S)-1 is a key intermediate for the preparation of a number of polymer supported Evans' oxazolidin-2-ones that have been employed previously for solid supported asymmetric synthesis.

Full text of DOI:10.1016/S0957-4166(03)00482-8

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2619–2623
A practical synthesis of enantiopure
(S)-4-(4-hydroxybenzyl)-oxazolidin-2-one
Rachel Green,a Piers J. M. Taylor,a Steven D. Bull,a,* Tony D. James,a,* Mary F. Mahonb and
Andy T. Merrittc
aDepartment of Chemistry, University of Bath, Bath BA2 7AY, UK
bBath Chemical Crystallography, Department of Chemistry, University of Bath, Bath BA2 7AY, UK
cGlaxoSmithkline Research and Development, Medicines Research Centre, Gunnels Wood Road, Stevenage,
Hertfordshire SG1 2NY, UK
Received 29 May 2003; accepted 12 June 2003
Abstract—A high yielding four-step synthesis of enantiopure 4-(4-hydroxybenzyl)-oxazolidin-2-one (S)-1 from N-Boc-L-tyrosine
is described. (S)-1 is a key intermediate for the preparation of a number of polymer supported Evans’ oxazolidin-2-ones that have
been employed previously for solid supported asymmetric synthesis.
© 2003 Elsevier Ltd. All rights reserved.
2. Results and discussion
1. Introduction
We required a synthesis of (S)-1 that was high yielding
and amenable to scale-up. A review of the literature
revealed that five routes (A–E) to (S)-1 had been
reported previously, the details of which are described
in Scheme 1.6 Routes A and B involve a strategy in
There is currently much interest within the synthetic
community directed towards the development of poly-
mer supported chiral auxiliaries for the asymmetric
synthesis of libraries of chiral compounds.1 Within this
area, a number of chiral polymer supported oxazolidin-
2-ones derived from L-tyrosine have been described in
which the carboxylate and amino groups of L-tyrosine
which the chiral auxiliary fragment 4-(4-hydroxyben-
zyl)-oxazolidin-2-one (S)-1 is attached to polymer sup-
port via its phenolic group.2 These chiral polymers have
been employed in asymmetric synthesis for a range of
synthetic transformations including enolate alkyla-
tions,2 aldol reactions,3 Diels–Alder4 and 1,3-dipolar
cycloadditions.5 As part of a research program directed
towards the efficient use of chiral auxiliaries for asym-
metric synthesis we required access to gram quantities
of (S)-1. Consequently, we describe herein a facile four
step synthesis that enables oxazolidin-2-one (S)-1 to be
were protected as an ester and carbamate respectively.
Subsequent reduction of the ester group with NaBH4
affords an alkoxide that undergoes intramolecular
cyclisation onto the carbonyl of the carbamate protect-
ing group yielding oxazolidin-2-one (S)-1.5,7 Route C
was the shortest approach to (S)-1 employing Evans’
original conditions8 for oxazolidin-2-one formation
involving borane mediated reduction of the acid func-
tionality of
resultant amino-alcohol with diethyl carbonate under
basic conditions.3b Route D employed O-benzyl-
L-tyrosine, followed by treatment of the
L
-
prepared from N-Boc-L-tyrosine in good yield, using a
tyrosine that was reduced to the corresponding alcohol
using LiAlH4, followed by treatment with phosgene to
afford an O-benzyl oxazolidin-2-one that was depro-
tected to (S)-1 via hydrogenolysis.3a Finally, route E
synthetic protocol that proceeds via highly crystalline
intermediates that do not require chromatography for
purification.
exploited O-benzyl-N-Boc-L-tyrosine as starting mate-
rial that was reduced to its N-Boc-amino-alcohol, prior
to N-Boc deprotection and treatment of the resulting
amino-alcohol with phosgene to afford an O-benzyl-
* Corresponding authors. E-mail: s.d.bull@bath.ac.uk; t.d.james@
bath.ac.uk
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00482-8

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
2620
R. Green et al. / Tetrahedron: Asymmetry 14 (2003) 2619–2623
Scheme 1. Reagents and conditions: (i) SOCl2, MeOH, >95% (A);5 or EtOH, HCl (B);7 (ii) (a) K2CO3, (b) EtOCOCl, NaHCO3,
>95%, (A);5 or BnOCOCl, Na2CO3 (aq.), CHCl3, (B);7 (iii) (a) NaBH4, THF, D, 82%; (b) K2CO3, toluene, D, 50% (A);5 (iv)
NaBH4, LiI, THF, D, 90% (B);7 (v) (a) BH3·SMe2, BF3·OEt2, THF, D; (b) 5 M NaOH (aq.), D; (c) 6 M HCl (aq.), 83% (three
steps) (C);3b (vi) (a) NaHCO3 (aq.), (b) (EtO)2CO, K2CO3, 125°C, 86% (two steps) (C);3b (vii) (a) LiAlH4, THF, 60°C, (b) COCl2,
i
toluene, 82% (two steps) (D);3a (viii) (a) PrOCOCl, Et3N, THF, (E), (b) NaBH4 (E);2 (ix) HCl, Et2O–EtOAc, 25°C, 93% (E);2 (x)
COCl2, KOH–K2CO3 (aq.), toluene, 0–25°C, 98% (E);2 (xi) H2, cat. Pd/C, EtOH (D);3a (xii) H2, cat. Pd/C, MeOH–EtOAc, 25°C,
96% (E).2
oxazolidin-2-one that was once again deprotected to
ring formation on a large scale was unattractive. Conse-
quently, we considered an alternative synthesis of (S)-1
that would combine the relatively non-polar O-benzyl-L-
(S)-1 under hydrogenolytic conditions.2
Preliminary investigations into the synthesis of oxazo-
lidin-2-one (S)-1 using routes A–C proved unsatisfactory
in our hands, both in terms of yield and reproducibility,
primarily due to difficulties associated with the purifica-
tion of non-crystalline polar intermediates containing
unprotected phenolic substituents. Whilst these polarity
problems could potentially be overcome in routes D and
tyrosine substrates employed in routes D and E, with the
intramolecular alkoxide/N-carbamate cyclisation strat-
egy for oxazolidin-2-one ring formation used in routes
A and B. It was proposed that this strategy would enable
(S)-1 to be prepared in four steps from commercially
available N-Boc-L
-tyrosine,9 without the necessity of
using phosgene as a reagent for oxazolidin-2-one ring
formation, according to the synthetic protocol described
in Scheme 2.
E using O-benzyl-
L-tyrosine derivatives as substrates, the
prospect of employing phosgene for oxazolidin-2-one
Scheme 2. Reagents and conditions: (i) 3 equiv. BnBr, K2CO3, Bu4NI (12.5 mol%), DMF; (ii) LiAlH4, THF, 0°C“rt; (iii) NaH,
THF; (iv) H2, Pd/C, MeOH/EtOAc.

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
R. Green et al. / Tetrahedron: Asymmetry 14 (2003) 2619–2623
2621
The carboxylate and phenolate functionalities of N-
Boc- -tyrosine (S)-2 were perbenzylated via treatment
with K2CO3 and 3.0 equiv. of BnBr in DMF, in the
presence of a catalytic amount of Bu4NI, to afford
lidin-2-one molecule to the NꢀH group of an adjacent
oxazolidin-2-one affording long hydrogen-bonded ‘lad-
ders’ in which the 4-aryl substituents of each oxazo-
lidin-2-one molecule are alternately staggered
orthogonal to the plane of the hydrogen bonded ladder.
This hydrogen bonded ladder structural motif has been
observed previously in the solid state structures of
(S)-4-(chlorophenylmethyl)-oxazolidin-2-one13 and (S)-
4-benzyl-oxazolidin-2-one14 as detailed in the CCDC
database.15
L
O-benzyl-N-Boc-
yield.10 Subsequent reduction of (S)-3 with LiAlH4 in
THF (0°C“rt) afforded N-Boc-O-benzyl- -tyrosinol
L
-tyrosine benzyl ester (S)-3 in 87%
L
(S)-4 in 88% yield.11 Treatment of (S)-4 with NaH in
THF at room temperature resulted in intramolecular
cyclisation of the resulting alkoxide onto the N-Boc-
protecting group to afford (S)-4-(4-benzyloxybenzyl)-
oxazolidin-2-one (S)-5 as the sole product in 78%
yield.12 The enantiomeric excess of (S)-5 was confirmed
to be >99% e.e. via chiral HPLC analysis over a
Chiralcel OD® stationary phase in comparison with a
racemic sample of 5. Finally, debenzylation of (S)-5,
using the hydrogenolytic conditions of Burgess et al.,2
was carried out using Pd/C in a mixed solvent of
MeOH/EtOAc, to afford the target 4-(4-hydroxyben-
zyl)-oxazolidin-2-one (S)-1 in an excellent 92% yield
(Scheme 2). The enantiomeric excess of (S)-1 was con-
firmed as >99% e.e. by conversion to (S)-5 via treat-
ment with excess benzyl bromide, K2CO3, and Bu4NI in
DMF, followed by chiral HPLC analysis as described.
It should be noted that all of the intermediates in this
synthetic protocol are crystalline, enabling purification
at each step of the synthesis to be achieved via simple
recrystallisation of the crude reaction products, thus
enabling enantiopure (S)-1 to be prepared in an overall
3. Conclusion
A high yielding four step synthesis of enantiopure
4-(4-hydroxybenzyl)-oxazolidin-2-one (S)-1 from N-
Boc-L-tyrosine via crystalline intermediates is described.
(S)-1 is a key intermediate for the preparation of a
number of polymer supported Evans’ oxazolidin-2-ones
that have been employed previously for solid supported
asymmetric synthesis.
4. Experimental
Anhydrous THF was obtained via distillation under
nitrogen from sodium benzophenone ketyl. All com-
mercial reagents were used without purification unless
stated otherwise. Reactions were monitored by TLC on
Whatman aluminium backed UV254 silica gel plates.
Melting points were measured on a Bu¨chi 535 melting
point apparatus and are uncorrected. Specific rotations
were measured with an AA-10 automatic polarimeter
from Optical Rotations Ltd. Proton and carbon mag-
netic resonance spectra (1H and 13C NMR) were
recorded on a Bruker 300 MHz spectrometer. The
assignment of 13C NMR data was assisted by DEPT
experiments. Mass spectra were carried out at Swansea,
University of Wales (Finnigan MAT 8340 instrument).
High Performance Liquid Chromatography was per-
formed on SP Thermo Separation products spectra
SERIES and Spectra Physics Systems using a Chiralcel
OD® column obtained from Fisher Scientific supplies.
55% yield from N-Boc-L-tyrosine without recourse to
chromatography.
2.1. X-Ray crystal structure of 4-(4-benzyloxybenzyl)-
oxazolidin-2-one 5
4-(4-Benzyloxybenzyl)-oxazolidin-2-one (S)-5 was suffi-
ciently crystalline for an X-ray crystal structure to be
determined, the results of which are depicted in Figure
1. Packing within the unit cell was dominated by hydro-
gen bonding between the carbonyl group of one oxazo-
4.1. O-Benzyl-N-Boc- -tyrosine benzyl ester {(S)-3-(4-
L
benzyloxyphenyl)-2-tert-butoxycarbonyl amino-propionic
acid benzyl ester} 3
Potassium carbonate (29.59 g, 214.5 mmol), benzyl
bromide (15.3 mL, 128.7 mmol) and tetra-
butylammonium iodide (1.98 g, 5.4 mmol) were added
to a solution of N-Boc- -tyrosine (S)-2 (12.1 g, 42.9
L
mmol) in DMF (150 mL). The mixture was stirred for
48 h at rt followed by addition of water (200 mL) and
extraction with ethyl acetate (3×150 mL). The organic
fractions were combined, washed with 1N HCl and
brine, dried over sodium sulphate, and the solvent
removed in vacuo to afford a dark orange oil that was
recrystallised (Et2O/petrol) to afford a crystalline solid
(17.23 g, 87%). Mp 85–86°C, lit.16 74–75°C; [h]D21=−7.9
1
Figure 1. X-Ray crystal structure plot illustrating intermolec-
ular hydrogen bonding between molecules of (S)-5 in the
solid state.
(c 29.7, EtOAc); lit.16=−8.0 (c 10, DMF); H NMR
(CDCl3, 300 MHz): l 1.41 (9H, s, OC(CH3)3), 2.98 (2H,
d, J=5.65 Hz, C6H4CH2), 4.52 (1H, m, CH), 4.89 (1H,

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
2622
R. Green et al. / Tetrahedron: Asymmetry 14 (2003) 2619–2623
d, J=8.3 Hz, NH), 4.95 (2H, s, PhCH2OAr), 5.06 (2H,
m, CH2O), 6.76 (2H, app d, Ar-H, J=8.6 Hz), 6.87
(2H, app d, Ar-H, J=8.6 Hz), 7.21–7.38 (10H, bm,
Ar-H); 13C NMR (CDCl3, 75 MHz): l 28.3 (CH3), 37.4
(CH2), 54.5 (CH), 67.0 (C), 70.0 (CH2), 79.9 (CH2),
114.9 (CH), 127.9 (CH), 128.6 (CH), 130.4 (CH2), 130.5
(CH), 135.2 (C), 137.0 (C), 155.1 (C), 157.8 (C), 171.80
(C); m/z (CI+) 462 (MH+, 41%).
MHz): l 41.2 (CH2), 54.6 (CH), 70.3 (CH2), 70.8 (CH2),
116.7 (CH), 128.3 (CH), 128.8 (CH), 129.0 (CH), 129.4
(CH), 130.9 (C), 137.7 (C), 158.7 (C), 160.6 (C); m/z
(EI+) 283 (MH+, 8%); HPLC: Chiralcel OD® column,
solvent=hexane/isopropyl alcohol (80:20), flow rate=1
mL/min, retention times=(S)-5=28.7 min, (R)-5=35.2
min.
4.4. (S)-4-(4-Hydroxy-benzyl)-oxazolidin-2-one 1
4.2. O-Benzyl-N-Boc- -tyrosinol {(S)-[1-(4-Benzyloxy-
L
Oxazolidin-2-one (S)-5 (2.00 g, 7.1 mmol) and Pd/C
(5%) (744 mg, 0.35 mmol) were placed in a dry Schlenk
tube under a hydrogen atmosphere. A mixture of
methanol/ethyl acetate (1:1, 30 mL) was added via
syringe. The resulting mixture was stirred at rt for 12 h,
filtered through a pad of Celite®, which was washed
thoroughly with ethyl acetate. The combined organic
solvent was then removed in vacuo to yield (S)-1 (1.25
g, 6.5 mmol, 92%) as a white powder. Mp 179–181°C,
lit.7 175–178°C; [h]2D1=−12.3 (c 6.5, MeOH), lit.5a=−
benzyl)-2-hydroxyethyl]-carbamic acid tert-butyl ester}
4
A solution of ester (S)-3 (9.72 g, 21.1 mmol) in THF
(40 mL) was added to a vigorously stirred solution of
LiAlH4 (31.6 mL, 1.0 M, 31.6 mmol) in THF at 0°C
over a period of 45 min (CAUTION evolution of
hydrogen). The reaction mixture was then stirred at rt
for 1 h before quenching via dropwise addition of
aqueous potassium hydroxide solution (85 mL, 10%).
The resulting solution was filtered through a pad of
Celite® to remove the gelatinous white precipitate,
before being extracted with ethyl acetate. The organic
layers were combined, washed with brine (3×20 mL),
dried with magnesium sulphate, and the solvent
removed in vacuo to afford the title compound (6.62 g,
18.5 mmol, 88%) as a cream powder. Mp 102–103°C,
lit.17 108–109°C; [h]2D1=−18.0 (c 17.4, EtOAc), lit.17=
1
11.8 (c 5.0, EtOH); H NMR (MeOD, 300 MHz): l
2.67 (2H, m, C6H4CH2), 4.01 (2H, m, O-CHAHB, CH),
4.27 (1H, m, O-CHAHB), 6.64 (2H, app d, Ar-H, J=8.5
Hz), 6.95 (2H, app d, Ar-H, J=8.5 Hz); 13C NMR
(MeOD, 75 MHz): l 41.4 (CH2), 55.6 (CH), 70.8
(CH2), 116.8 (CH), 128.6 (CH), 130.9 (C), 157.9 (C),
162.7 (C); m/z (EI+) 193 (MH+, 5%); HRMS (ES+) for
C10H11NO3 [M+NH4]+ requires 211.1077, Found
211.1079.
1
−17.0 (c 10.5, CHCl3); H NMR (CDCl3, 300 MHz): l
1.33 (9H, s, OC(CH3)3), 2.68 (2H, d, C6H4CH2, J=6.8
Hz), 3.43 (1H, dd, CHAHBOH, J=10.9 Hz, 5.3 Hz),
3.55 (1H, dd, CHAHBOH, J=10.9 Hz, 3.8 Hz), 3.72
(1H, m, N-CH), 4.72 (1H, bs, NH), 4.95 (2H, s,
PhCH2OAr), 6.83 (2H, app d, Ar-H, J=8.5 Hz), 7.04
(2H, app d, Ar-H, J=8.5 Hz), 7.18–7.37 (5H, bm,
Ar-H); 13C NMR (CDCl3, 75 MHz): l 27.3 (CH3), 35.5
(CH2), 52.8 (CH), 63.1 (C), 68.9 (CH2), 78.6 (CH2),
114.9 (CH), 126.0 (CH), 126.4 (CH), 126.9 (CH), 127.5
(CH), 129.1 (CH), 129.3 (C), 155.2 (C), 156.5 (C); m/z
(EI+) 357 (MH+, 39%).
4.5. Determining the enantiomeric excess of (S)-1 via
conversion to (S)-5
Potassium carbonate (2.96 g, 2.15 mmol), benzyl bro-
mide (0.153 mL, 1.29 mmol) and tetrabutylammonium
iodide (20 mg) were added to a solution of (S)-1 (83
mg, 0.43 mmol) in DMF (1.5 mL). The mixture was
stirred for 48 h at rt followed by addition of water (20
mL) and extraction with ethyl acetate (3×15 mL). The
organic fractions were combined, washed with 1N HCl
and brine, dried over sodium sulphate, and the solvent
removed in vacuo to afford (S)-5 (115 mg, 0.41 mmol)
as a crystalline solid which was analysed via chiral
HPLC using a Chiralcel OD® column and shown to be
>99% e.e.
4.3. (S)-4-(4-Benzyloxybenzyl)-oxazolidin-2-one 5
A solution of alcohol (S)-4 (5.2 g, 14.54 mmol) in THF
(50 mL) was added to a suspension of sodium hydride
(1.45 g, 36.4 mmol) in THF (200 mL) over a period of
20 min, stirred for 12 h, then quenched with a saturated
solution of aqueous ammonium chloride (70 mL). The
reaction mixture was then extracted with ethyl acetate
(3×25 mL), the organic layers combined, washed with
aqueous hydrochloric acid (100 mL, 5% solution), satu-
rated NaHCO3 solution (100 mL), and brine (100 mL),
and then dried over magnesium sulphate. The solvent
was then removed in vacuo to yield the title compound
(3.12 g, 78%) as a white crystalline solid. Mp 133-
134°C, lit.7 136–138°C; [h]2D1=−85.1 (c 50.5, EtOAc),
lit.7=−84.8 (c 5.0, CHCl3); 1H NMR (CDCl3, 300
MHz): l 2.82 (2H, m, C6H4CH2), 4.05 (1H, m, N-CH),
4.15 (1H, dd, CHAHBO, J=8.5 Hz, 5.5 Hz), 4.39 (1H,
app t, CHCHAHBO, J=8.5 Hz), 4.98 (2H, s,
PhCH2OAr), 5.05 (1H, bs, NH), 6.87 (2H, app d,
Ar-H, J=8.5 Hz), 7.02 (2H, app d, Ar-H, J=8.5 Hz),
7.25–7.38 (5H, bm, Ar-H); 13C NMR (CDCl3, 75
Acknowledgements
We would like to thank the EPSRC (R.G.) and the
Royal Society (S.D.B. and T.D.J.) for funding, Glaxo-
SmithKline for a CASE award (R.G.) and the EPSRC
Mass Spectrometry Service at Swansea, University of
Wales, for their assistance.
References
1. (a) Obrecht, D.; Villalgordo, J. M. Solid-Supported Com-
binatorial and Parallel Synthesis of Small Molecular-
Weight Compound Libraries; Tetrahedron Organic
Chemistry Series: Oxford, 1998; Vol. 17; (b) Kirchoff, J.
H.; Lormann, M. E.; Brase, S. Chim. Oggi 2001, 19, 8.