Rhodium-catalysed conjugate addition of arylboronic acids to enantiopure dehydroamino acid derivatives

Article abstract of DOI:10.1039/c0ob00158a

The rhodium-catalysed conjugate addition of arylboronic acids to an enantiopure acceptor derived from (R)-S-methylcysteine proceeds under substrate control to provide a range of functionalised phenylalanine derivatives with excellent stereocontrol via a highly diastereoselective protonation.

Full text of DOI:10.1039/c0ob00158a

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Rhodium-catalysed conjugate addition of arylboronic acids to enantiopure
dehydroamino acid derivatives†
Jonathan D. Hargrave,a Gerwyn Bish,b Gabriele Kociok Ko¨hna and Christopher G. Frost*a
Received 21st May 2010, Accepted 22nd July 2010
DOI: 10.1039/c0ob00158a
The rhodium-catalysed conjugate addition of arylboronic acids to an enantiopure acceptor derived
from (R)-S-methylcysteine proceeds under substrate control to provide a range of functionalised
phenylalanine derivatives with excellent stereocontrol via a highly diastereoselective protonation.
synthesis.8 In this context, enantiopure oxazolidinone scaffolds
have proved particularly useful due to their simple synthesis and
Introduction
high stereoselectivity across a variety of reactions.9 In this paper
we describe the substrate controlled stereoselective synthesis of
amino acid derivatives employing the rhodium catalysed addition
of arylboronic acids to an enantiopure oxazolidinone scaffold. The
strategy shown in Scheme 2 provides a straightforward method
to convert (R)-S-methylcysteine 1 into a range of functionalised
phenylalanine derivatives with perfect stereocontrol via a highly
diastereoselective protonation.10
The transition-metal catalysed conjugate addition of
organometallics to activated alkenes is regarded as fundamental
methodology for organic synthesis.1 In particular, the rhodium
catalysed conjugate addition of organometallics to activated
alkenes is a powerful synthetic tool for establishing new carbon–
carbon bonds, often with high stereoselectivity.2,3 The introduction
of a practical, efficient method for introducing functionalised aryl
and alkenyl fragments with predictable stereocontrol has caught
the attention of synthetic chemists and emerging examples are
growing in number and complexity.4 In the large majority of
reported additions to prochiral acceptors, a single stereocentre
is established by an asymmetric carbometalation under control
of an enantiopure rhodium complex. A variation on the
standard rhodium catalysed addition process is the asymmetric
arylation of activated alkenes or allenes via enantioselective
protonation.5 An important example of this methodology is the
enantioselective rhodium catalysed additions of boronic acids
to a,b-dehydroamino acid derivatives allowing access to a range
of a-amino acid derivatives with differing enantioselectivities
depending on enantiopure ligand and proton source (Scheme 1).6
Scheme 2 The catalytic synthesis of functionalised phenylalanine deriva-
tives by diastereoselective protonation.
Scheme 1 The synthesis of amino acid derivatives by enantioselective
protonation.
Results and discussion
The desired methyleneoxazolidinone 4 was prepared as described
in the literature (Scheme 3).11 The reaction of (R)-S-methylcysteine
1 with pivaldehyde under Dean–Stark conditions, followed by
treatment with benzyl chloroformate and purification of the
major diastereomer 2 by flash chromatography. The methylth-
iomethyloxazolidinone 2 was converted to the corresponding
sulfone 3 employing m-CPBA. The stereochemistry of the single
Whilst this methodology offers an expeditious route to certain
amino acid derivatives there are limitations when high levels of
enantioselectivity are required. The growing number of examples
of rhodium catalysed conjugate additions to enantiopure accep-
tors inspired us to explore a solution based on substrate control.7
The functionalisation of enantiopure templates to prepare enan-
tioenriched amino acids has long been a cornerstone of organic
1
diastereomer 3 was assigned as (2R,4R) by analogy of H NMR
and NOE spectra with literature data.9,11 Treatment of 3 with DBU
afforded the methyleneoxazolidinone 4 in excellent yield with high
enantioselectivity (>99% ee determined by chiral HPLC analysis).
An initial investigation of the rhodium-catalysed conjugate
addition of phenylboronic acid to 4 employing a variety of reaction
conditions revealed a high-yielding and stereoselective route to
the desired phenylalanine derivative 5 (Table 1). After testing
aDepartment of Chemistry, University of Bath, Claverton Down, Bath, UK
BA2 7AY. E-mail: c.g.frost@bath.ac.uk; Fax: 01225 386231; Tel: 01225
386142
bPfizer Limited, Ramsgate Road, Sandwich, Kent, UK CT13 9NJ
† Electronic supplementary information (ESI) available: General experi-
mental procedures and NMR spectra. CCDC reference number 776776.
For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c0ob00158a
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Table 1 Optimisation of reaction parameters
group from a Cbz to an acetyl moiety and no reactivity at all took
place with N-phenylacetyl derivatives.
With the optimised set of reaction conditions, we next ex-
plored the scope of the process with respect to the boronic
acid; in all cases the enantiopure acceptor 4 was employed
as substrate. A diverse range of arylboronic acids (6a–i) was
shown to successfully participate in the conjugate addition to
4 (Scheme 4). It is useful to note that both electron-donating
and electron-withdrawing substituents are tolerated alongside a
range of substitution patterns. The products were obtained as
single diastereomers in good to excellent yields. The high yield
obtained using 4-formylphenylboronic acid 6h was noteworthy,
illustrating the preference for 1,4-conjugate addition over 1,2-
addition under the presented conditions. The high diastereoselec-
tivity was confirmed via 2D COSY NMR spectroscopic analysis,
by the appearance of only one set of diastereotopic coupling
signals in all environments and via chiral HPLC analysis. In
order to establish the resulting stereochemistry of the arylated
oxazolidinones, 2D 1H–1H NOESY experiments were employed.
A NOE interaction was observed between the two diastereotopic
protons, indicating a likely syn facial configuration to one another.
Entry
Rh loading
Catalyst
Additive
Yieldc (%)
1a
2
1 mol%
1 mol%
1 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
[Rh(cod)2]BF4
[Rh(cod)2]BF4
[Rh(cod)2]BF4
[Rh(cod)2]BF4
[Rh(acac)(C2H4)2]2
[RhCl(C2H4)2]2
[Rh(cod)2]BF4
[Rh(cod)2]BF4
[Rh(cod)2]BF4
[Rh(cod)2]BF4
[Rh(cod)2]BF4
[Rh(cod)(MeCN)]BF4
[Rh(cod)2]BF4
—
—
NaF
—
—
—
—
NaF
KOH
TBAF
cod
—
41
60
44
0
0
0
69
81
72
50
70
15
0
3
4b
5
6
7
8
9
10
11
12
13
phenol
All reactions were performed at 110 ◦C for 48 h, in a dioxane : H2O solution
(10 : 1) unless otherwise stated.a 24 h. b Room temperature. c Determined
to be a single diastereomer from the crude 1H NMR spectroscopy and
chiral HPLC analysis (Chiralpak AD or Chiracel OD column).
t
Through-space couplings were observed between the Bu group
and the newly formed benzylic protons, providing further evidence
for this conformation. The resulting syn conformation from
Scheme 3 The synthesis of enantiopure methyleneoxazolidinone.
a variety of rhodium complexes, solvents and proton sources
it emerged that the application of cationic rhodium complex
[Rh(cod)2]BF4 in a dioxane/water mix (10 : 1) resulted in the
highest yield. Interestingly elevated temperatures were crucial for
effective conversion and catalyst loadings of 5 mol% were required
for higher isolated yields. The effect of additives was also studied
with NaF proving beneficial, presumably aiding transmetallation
of PhB(OH)2 with rhodium, via fluoride anion coordination. Due
to the nature of the system involved and the presence of the
carbamate group, reaction times of 48 h were needed. Once key
reaction parameters had been established, our attention turned
towards the versatility of the reaction. It should be noted that
poor reaction yields were observed when changing the protecting
Scheme 4 Exploring the scope of the addition.
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these experiments was further supported by X-ray analysis of
oxazolidinone 5j derived from the oxidation of addition product 5e
(Scheme 5). The conversion of the oxazolidinone moiety into the
a-amino acid can be performed by a variety of methods, depending
on the choice of nitrogen protecting group. In the presented case,
N-Cbz oxazolidinones can be cleaved by direct hydrogenolysis.
Thus, treatment of 5i with palladium on activated carbon under
one atmosphere of hydrogen gave the unnatural amino acid in
accordance with the literature protocol.12
phenylalanine derivatives with excellent stereocontrol via a highly
diastereoselective protonation.
Experimental
IR spectra were recorded on a Perkin-Elmer 1600 FT IR spec-
trophotometer, using NaCl discs. 1H NMR spectra were obtained
on a Bruker Avance 300 spectrometer operating at 300 MHz,
unless otherwise noted, with tetramethylsilane as an internal
standard. J values are given in Hz. 13C NMR spectra were
obtained on a Bruker Advance 300 spectrometer operating at
75 MHz, unless otherwise noted. All dry solvents were freshly
distilled under nitrogen prior to use. Mass spectra were obtained
on a Bruker Time-of-Flight mass spectrometer (ESI-TOF). Enan-
tiomeric excesses were determined using HPLC (see data see
individual compounds details) with a UV detector at 254 nm.
Tetrahydrofuran was distilled over alumina column. Petroleum
ether refers to that fraction obtained between 40–60 ◦C. All other
reagents were obtained from commercial suppliers and used as
received. All glassware used under anhydrous conditions was dried
in an oven and allowed to cool under nitrogen prior to use. All
reactions were carried out under argon unless otherwise stated.
Flash chromatography was conducted under medium pressure,
using matrix 60 silica.
Procedure for the synthesis of (2R,4R)-benzyl-2-tert-butyl-4-
Scheme 5 Modification of oxazolidinones and X-ray structure. Structure
(methylthiomethyl)-5-oxooxazolidine-3- carboxylate (2)
deposited with the CCDC; entry number 776776.†
(R)-S-Methylcysteine 1 (6.75 g, 0.05 mmol) was treated with
a solution of sodium hydroxide (1.99 g, 0.05 mmol) in water
(200 mL) for 5 min and then evaporated to dryness under reduced
pressure to leave a white solid. A solution of pivaldehyde (4.30 mL,
0.05 mmol) in hexane (150 mL) was added to the solid, and the
suspension was stirred and heated to reflux in the presence of a
Dean–Stark water separator for 24 h. The reaction mixture was
then cooled and evaporated to dryness. The resulting pale yellow
gum was suspended in anhydrous dichloromethane (150 mL) and
treated with benzyl chloroformate (12.43 mL, 0.087 mmol) at
A mechanism for the diastereoselective protonation that is
consistent with the presented experimental observations is shown
in Scheme 6.13 Following transmetalation of the arylboronic acid
to the active rhodium complex, the substrate is proposed to
associate on the least hindered face of the oxazolidinone ring anti
t
to the bulky Bu group. This is followed by carbometalation of
1
the activated alkene to reveal a h -C rhodium species which is
anticipated to be in equilibrium with an oxa-p-allyl species, both
lying on the Re face of the ring. Protonation must occur, anti to the
tBu group via pre-coordination of the proton source to rhodium
to afford the syn product as a single diastereomer.14
0
◦C for 3 h and then a further 36 h at room temperature. A
solution of 10% sodium bicarbonate (200 mL) was then added
and stirring was continued for a further 3 h. The layers were
then separated and the organic portion dried over MgSO4, filtered
and evaporated to dryness. The crude product was then purified
by silica chromatography (4 : 1, petroleum ether : ethyl acetate) to
obtain the major diastereomer as a clear oil (7.81 g, 46%); Rf (4 : 1,
petroleum ether : ethyl acetate) 0.45; IR (film, cm-1) n 3434, 2921,
1663, 1430, 1380, 1235, 1197, 1163, 1072, 1007, 871, 802, 654,
607; 1H NMR (250 MHz, CDCl3) d 7.42–7.39 (5H, m, Ar), 5.59
(1H, s, CH), 5.21 (2H, s, CH2), 4.55 (1H, dd, J = 6.0, 7.8 Hz,
CH), 3.03 (1H, dd, J = 7.8, 13.9 Hz, CH2), 2.88 (1H, dd, J =
6.0, 13.9 Hz, CH2), 2.13 (3H, s, SCH3), 0.99 (9H, s, (CH2)3); 13
C
NMR (75.5 MHz, CDCl3) d 171.7, 156.2, 135.3, 129.2, 129.1,
129.1, 96.6, 69.0, 57.4, 37.3, 37.0, 25.2, 16.4; HRMS (ESI) calcd
for C17H23NO4S [MH+]: m/z 338.1421; found m/z 338.1422.
Scheme 6 Mode of diastereoselective protonation.
Procedure for the synthesis of (2R,4R)-benzyl 2-tert-butyl-4-
(methylsulfonylmethyl)-5-oxooxazolidine-3-carboxylate (3)
In conclusion, the rhodium catalysed conjugate addition of
arylboronic acids to an enantiopure oxazolidinone template pro-
ceeds under substrate control to provide a range of functionalised
To a solution of (2R,4R)-benzyl 2-tert-butyl-4-(methylthio-
methyl)-5-oxooxazolidine-3-carboxylate 2 (1 g, 2.96 mmol) in
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DCM (50 mL) was added a solution of 3-chloroperoxybenzoic
acid (1.66 g, 7.41 mmol) in DCM (25 mL). The resulting solution
was stirred at room temperature for 24 h and then water (50 mL)
was added to the reaction mixture. The two layers were separated
and the organics were dried over MgSO4, filtered and evaporated to
dryness. The crude product was purified by silica chromatography
(4 : 1, petroleum ether: ethyl acetate), and recrystalised in ethanol
to give the title compound as a white solid, as a single diastereomer
(1.08 g, 98%); Rf (4 : 1, petroleum ether : ethyl acetate) 0.25; mp
gel (ethyl acetate : petrol, 1 : 4 by volume) to afford the desired
product.
(2S,4R)-benzyl-4-benzyl-2-tert-butyl-5-oxooxazolidine-3-
carboxylate (5a)
Title compound was isolated as a colourless oil (99 mg, 60%);
Rf (9 : 1, petroleum ether : ethyl acetate) 0.19; [a]2D4 -33.3 (c
0.35,CH3Cl) IR (film, cm-1) n 3346, 3089, 3065, 3032, 2951, 2360,
2250, 1717, 1631, 1586, 1531, 1498, 1454, 1440, 1407, 1368, 1305,
1252, 1217, 1157, 1062, 1026, 952; 1H NMR (300 MHz, CDCl3) d
7.32–7.26 (4H, m, Ar), 7.22–7.10 (6H, m, Ar), 5.49 (1H, s, CH),
5.07 (1H, d, J = 11.8 Hz, CH2), 4.85 (1H, d, J = 11.8 Hz, CH2),
4.41 (1H, dd, J = 5.6, 7.4 Hz, CH), 3.13 (1H, dd, J = 5.6, 13.9 Hz,
CH2), 3.04 (1H, dd, J = 5.6, 13.9 Hz, CH2), 0.91 (9H, s, (CH3)3);
13C NMR (75.5 MHz, CDCl3) d 171.3, 155.1, 136.1, 134.4, 134.3,
128.8, 128.0, 127.9, 127.8, 126.3, 95.6, 67.6, 58.3, 38.6, 36.4, 24.2;
HRMS (ESI) calcd for C22H25NNaO4 [M+Na+]: m/z 390.1709;
found 390.1681.
◦
89 C (ethanol); [a]2D4 +11 (c 1.0, EtOH); IR (film, cm-1) n 3059,
2923, 2848, 1941, 1867, 1800, 1600, 1582, 1492, 1452, 1372, 1328,
1181, 1154, 1068, 1028, 965; 1H NMR (300 MHz, CDCl3) d 7.38–
7.2 (5H, m, Ar), 5.52 (1H, s, CH), 5.18 (1H, d, J = 11.8 Hz, CH2),
5.08 (1H, d, J = 11.8 Hz, CH2), 4.88 (1H, dd, J = 3.7, 7.5 Hz, CH),
3.55–3.45 (1H, m, CH2), 3.28 (1H, dd, J = 3.7, 14.3 Hz, CH2),
2.96 (3H, s, SCH3), 0.85 (9H, s, (CH3)3); 13C NMR (75.5 MHz,
CDCl3) d 171.1, 155.7, 135.3, 129.1, 129.0, 97.2, 69.1, 57.4, 53.8,
42.6, 37.1, 25.0; HRMS (ESI) calcd for C17H23NO6S [M+NH4+]:
m/z 387.1584; found m/z 387.1583.
Procedure for the synthesis of (R)-benzyl
2-tert-butyl-4-methylene-5-oxooxazolidine-3-carboxylate (4)
(2S,4R)-benzyl-2-tert-butyl-4-(naphthalen-1-ylmethyl)-5-oxo-
oxazolidine-3-carboxylate (5b)
To a solution of (2R,4R)-benzyl 2-tert-butyl-4-(methylsulfonyl-
methyl)-5-oxooxazolidine-3-carboxylate 3 (509 mg, 1.37 mmol)
in dichloromethane (15 mL) at 0 ◦C was added DBU (1,8-
diazabicyclo[5.4.0]undec-7-ene) (228 ml, 1.51 mmol) dropwise. The
solution was stirred for 30 min at 0 ◦C and then treated with water
(10 mL). The layers were separated and the organic phase was
further washed with water (2 ¥ 10 mL), dried over MgSO4 and
evaporated to dryness to give the crude product which was filtered
through a short column of silica gel (eluent petroleum ether : ethyl
acetate, 1 : 1) to give the product as a colourless oil (370 mg, 93%);
Rf (1 : 1, petroleum ether : ethyl acetate) 0.5; [a]2D4 -20.0. (c 0.8,
CHCl3); IR (film, cm-1) n 2971, 1795, 1727, 1656, 1480, 1398,
Title compound was isolated as a colourless oil (62 mg, 87%);
Rf (9 : 1, petroleum ether : ethyl acetate) 0.1; [a]2D4 -15 (c 0.2,
CH2Cl2); IR (film, cm-1) n 3673, 2960, 2360, 1792, 1718, 1456,
1395, 1334, 1305, 1229, 1197, 1118, 1034, 977; 1H NMR (300 MHz,
CDCl3) d 8.06 (1H, d, J = 8.2 Hz, Ar), 7.78 (1H, d, J = 8.2 Hz,
Ar), 7.71–7.69 (1H, m, Ar), 7.36–7.12 (7H, m, Ar), 6.91 (2H,
br. s, Ar), 5.49 (1H, s, CH2), 4.94 (1H, d, J = 12.0, CH2), 4.64
(1H, app. t, J = 7.2 Hz, CH2), 4.38 (1H, br. s, CH), 3.65 (1H,
dd, J = 7.3, 14.0 Hz, CH2), 3.48 (1H, dd, J = 7.3, 14.0 Hz,
CH2), 0.98 (9H, s, (CH3)3); 13C NMR (75.5 MHz, CDCl3) d
171.9, 156.3, 135.4, 134.1, 132.8, 132.3, 129.3, 128.9, 128.9, 128.7,
128.4, 126.6, 126.0, 125.7, 123.7, 96.8, 68.5, 57.9, 37.4, 36.9, 25.5;
HRMS (ESI) calcd for C26H27NO4 [M+NH4+]: m/z 435.2278;
found 435.2277. HPLC Diacel Chiralcel OD–H, hexane : propan-
2-ol (95 : 5), 1.0 mL min-1, tR = 43.5 min.
1
1362, 1327, 1270, 1208, 1181, 1118, 1091, 1038, 1011, 914; H
NMR (300 MHz, CDCl3) d 7.31–7.29 (5H, m, Ar), 5.63 (1H, s,
CH), 5.60 (2H, app. s, CH, CH), 5.17 (2H, s, CH2), 0.84 (9H, s,
(CH3)3); 13C NMR (75.5 MHz, CDCl3) d 164.9, 152.7, 135.0,
130.5, 129.2, 129.1, 129.0, 104.7, 94.3, 69.1, 39.0, 24.7; HRMS
(ESI) calcd for C16H19NO4 [M+NH4+]: m/z 307.1652; found m/z
307.1651. HPLC Diacel Chiralcel OD–H, hexane : propan-2-ol
(95 : 5), 1.0 mL min-1, tR = 6.1 min.
(2S,4R)-benzyl-4-(benzo[d][1,3]dioxol-5-ylmethyl)-2-tert-butyl-5-
oxooxazolidine-3-carboxylate (5d)
Title compound was isolated as a colourless oil (65 mg, 46%);
Rf (9 : 1, petroleum ether : ethyl acetate) 0.28; [a]2D4 -16.5 (c 1.1,
CH2Cl2); IR (film, cm-1) n 3410, 2970, 2360, 2132, 1792, 1720,
1651, 1503, 1491, 1445, 1394, 1369, 1336, 1307, 1271, 1248, 1232,
General procedure for the rhodium-catalysed conjugate addition of
arylboronic acids to (R)-benzyl 2-tert-butyl-4-methylene-5-
oxooxazolidine-3-carboxylate
1
1191, 1176, 1121, 1038, 1019, 933; H NMR (250 MHz, CDCl3)
A suspension of (R)-benzyl-2-tert-butyl-4-methylene-5-oxooxa-
zolidine-3-carboxylate 4 (100 mg, 0.34 mmol), arylboronic acid
(1.38 mmol, 4 equiv.) 6a–i, sodium fluoride (58 mg, 1.38 mmol) and
[Rh(cod)2][BF4] (7 mg, 0.017 mmol, 5 mol%), in dioxane (3.0 mL)
and water (0.3 mL) was refluxed at 110 ◦C for 48 h under an
atmosphere of nitrogen. The resulting solution was cooled to room
temperature and evaporated under reduced pressure. The resulting
residue was re-dissolved in ethyl acetate (20 mL) and washed with
water (2 ¥ 20 mL). The organic layer was further washed with
brine (2 ¥ 20 mL), dried over MgSO4, and concentrated in vacuo.
The crude material was purified by flash chromatography on silica
d 7.32–7.26 (3H, m, Ar), 7.24–7.18 (2H, m, Ar), 6.64 (1H, s, Ar),
6.57 (2H, br. s, Ar), 5.82 (2H, s, OCH2), 5.48 (1H, s, CH), 5.08
(1H, d, J = 12.0 Hz, CH2), 4.94 (1H, d, J = 12.0 Hz, CH2),
4.34 (1H, dd, J = 5.6, 7.5 Hz, CH), 3.04 (1H, dd, J = 7.5,
14.2 Hz, CH2), 2.95 (1H, dd, J = 5.6, 14.2 Hz, CH2), 0.91 (9H, s,
(CH3)3); 13C NMR (75.5 MHz, CDCl3) d 172.3, 156.2, 148.0,
146.9, 135.5, 130.8, 129.0, 128.9, 122.9, 110.2, 108.6, 101.2, 96.6,
68.8, 59.4, 39.4, 37.4, 25.3; HRMS (ESI) calcd for C23H25N1NaO6
[M+Na+]: m/z 434.1579; found m/z 434.1567. HPLC Diacel
Chiralcel OD–H, hexane : propan-2-ol (95 : 5), 1.0 mL min-1, tR =
25.4 min.
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(2S,4R)-benzyl-4-(4-(methylthio)benzyl)-2-tert-butyl-5-
CH2Cl2); IR (film, cm-1) n 3621, 3211, 3066, 2971, 2360, 1792,
oxooxazolidine-3-carboxylate (5e)
1721, 1607, 1578, 1481, 1456, 1393, 1346, 1305, 1277, 1232, 1199,
1170, 1121, 1036, 1018, 979, 731; H NMR (300 MHz, CDCl3)
1
Title compound was isolated as a colourless oil (105 mg, 89%);
Rf (9 : 1, petroleum ether : ethyl acetate) 0.13; [a]2D4 -9.2 (c 1.4,
CH2Cl2); IR (film, cm-1) n 3435, 2360, 2101, 1792, 1644, 1496,
1481, 1393, 1347, 1310, 1283, 1232, 1199, 1175, 1121, 1036, 931;
1H NMR (300 MHz, CDCl3) d 7.33–7.26 (3H, m, Ar), 7.22–7.16
(2H, m, Ar), 7.03 (4H, br. s, Ar), 5.47 (1H, s, CH), 5.06 (1H,
d, J = 11.8, CH2), 4.87 (1H, d, J = 11.8, CH2), 4.36 (1H, dd,
J = 5.8, 7.6 Hz, CH), 3.07 (1H, dd, J = 7.6, 13.9 Hz, CH2),
2.99 (1H, dd, J = 5.8, 13.9 Hz, CH2), 2.37 (3H, s, SCH3), 0.92
(9H, s, (CH3)3); 13C NMR (75.5 MHz, CDCl3) d 172.4, 156.2,
137.3, 135.4, 134.0, 130.3, 129.0, 129.0, 127.2, 127.1, 96.6, 68.8,
59.3, 39.1, 37.5, 25.3, 16.3; HRMS (ESI) calcd for C23H27NO4S
[M+NH4+]: m/z 431.1999; found 431.1999.
d 9.86 (1H, s, CHO), 7.63 (2H, d, J = 8.2 Hz, Ar), 7.32–7.24
(5H, m, Ar), 7.19–7.14 (2H, m, Ar), 5.51 (1H, s, CH), 5.02
(1H, d, J = 12.0 Hz, CH2), 4.88 (1H, d, J = 12.0 Hz, CH2),
4.42 (1H, dd, J = 5.6, 7.3 Hz, CH), 3.20 (1H, dd, J = 7.3,
13.9 Hz, CH2), 3.09 (1H, dd, J = 5.6, 13.9 Hz, CH2), 0.94
(9H, s, (CH3)3); 13C NMR (75.5 MHz, CDCl3) d 192.2, 172.0,
156.1, 144.2, 135.6, 135.2, 130.5, 130.2, 129.2, 129.1, 129.0, 96.8,
68.9, 59.0, 39.8, 37.5, 25.3; HRMS (ESI) calcd for C23H25N1NaO5
[M+Na+]: m/z 418.1630; found m/z 418.1622. HPLC Diacel
Chiralcel OD–H, hexane : propan-2-ol (90 : 10), 1.0 mL min-1, tR =
27.4 min.
(2S,4R)-benzyl 4-(4-fluorobenzyl)-2-tert-butyl-5-oxooxazolidine-
3-carboxylate (5i)
(2S,4R)-benzyl 4-biphenyl-2-tert-butyl-5-oxooxazolidine-
Title compound was isolated as a colourless oil (102 mg, 77%);
Rf (9 : 1, petroleum ether : ethyl acetate) 0.26; [a]2D4 10.0 (c 0.5,
CH2Cl2); IR (film, cm-1) n 3323, 2983, 2939, 2880, 2360, 2253,
2082, 1773, 1720, 1511, 1468, 1386, 1376, 1305, 1238, 1181, 1109,
1047; 1H NMR (300 MHz, CDCl3) d 7.34–7.28 (3H, m, Ar),
7.21–7.17 (2H, m, Ar), 7.09–7.04 (2H, m, Ar), 6.84–6.76 (2H,
m, Ar), 5.48 (1H, s, CH), 5.05 (1H, d, J = 11.6 Hz, CH2), 4.91
(1H, d, J = 11.6 Hz, CH2), 4.35 (1H, dd, J = 5.4, 7.3 Hz, CH),
3.10 (1H, dd, J = 7.3, 13.9 Hz, CH2), 2.99 (1H, dd, J = 5.4,
13.9 Hz, CH2), 0.92 (9H, s, (CH3)3); 13C NMR (75.5 MHz, CDCl3)
d 172.3, 162.1 (d, JC–F = 279 Hz), 156.2, 135.9, 132,9, 131.4, 131.3,
129.1, 129.0, 115.6 (d, JC–F = 21.7 Hz), 96.6, 68.9, 59.4, 38.8,
37.5, 25.2; 19F NMR (376 MHz, CDCl3) d -115.8 ppm; HRMS
(ESI) calcd for C22H24FNNaO4 [M+Na+]: m/z 408.1587; found
408.1529. HPLC Diacel Chiralcel OD–H, hexane : propan-2-ol
(95 : 5), 1.0 mL min-1, tR = 11.9 min.
3-carboxylate (5f)
Title compound was isolated as a colourless oil (67 mg, 51%);
Rf (9 : 1, petroleum ether : ethyl acetate) 0.20; [a]2D4 -6.6 (c 0.3,
CH2Cl2); IR (film, cm-1) n 3430, 2963, 2350, 2340, 2100, 1792,
1716, 1644, 1520, 1486, 1456, 1394, 1347, 1264, 1232, 1199, 1172,
1036; 1H NMR (300 MHz, CDCl3) d 7.50–7.46 (2H, m, Ar), 5.40–
7.32 (4H, m, Ar), 7.28–7.22 (4H, m, Ar), 7.22–7.14 (4H, m, Ar),
5.49 (1H, s, CH), 5.06 (1H, d, J = 11.6 Hz, CH2), 4.86 (1H, d,
J = 11.6 Hz, CH2), 4.43 (1H, dd, J = 5.6, 7.7 Hz, CH), 3.16
(1H, dd, J = 7.7, 13.9 Hz, CH2), 3.07 (1H, dd, J = 5.6, 13.9 Hz,
CH2), 0.94 (9H, s, (CH3)3); 13C NMR (75.5 MHz, CDCl3) d 172.4,
156.2, 141.2, 140.2, 136.2, 135.5, 130.3, 129.1, 129.0, 128.7, 127.9,
127.8, 127.6, 127.4, 96.7, 68.8, 59.3, 39.3, 37.5, 25.3; HRMS
(ESI) calcd for C28H29N1NaO4 [M+ Na+]: m/z 466.1989; found
466.1992. HPLC Diacel Chiralcel OD–H, hexane : propan-2-ol
(90 : 10), 1.0 mL min-1, tR = 10.5.
Procedure for synthesis of (2S,4R)-benzyl-4-(4-
(methylsulfonyl)benzyl)-2-tert-butyl-5-oxooxazolidine-3-
carboxylate (5j)
(2S,4R)-benzyl-4-(4-methoxybenzyl)-2-tert-butyl-5-
oxooxazolidine-3-carboxylate (5g)
Title compound was isolated as a colourless oil (112 mg, 83%); Rf
(9 : 1, petroleum ether : ethyl acetate) 0.19; IR (film, cm-1) n 3019,
2971, 2400, 1790, 1720, 1599, 1570, 1478, 1394, 1310, 1269, 1215,
To a solution of (2S,4R)-benzyl 4-(4-(methylthio)benzyl)-2-tert-
butyl-5-oxooxazolidine-3-carboxylate 5e (41 mg, 0.09 mmol) in
DCM (10 ml) at 0 ◦C was added 3-chloroperoxybenzoic acid
(55.5 mg, 0.24 mmol) portion-wise. The solution was stirred at
room temperature for 5 h, quenched with dilute acetic acid (5 ml),
and washed with water (20 ml). The organic layer was dried over
MgSO4 and the crude material was recrystalised in ethanol to
give the title compound as a white solid (41 mg, 95%); Rf (9 : 1,
petroleum ether : ethyl acetate) 0.09; mp 145 ◦C (ethanol); IR
(film, cm-1) n 3447, 3035, 2973, 2876, 2256, 1792, 1721, 1644, 1497,
1482, 1456, 1399, 1308, 1228, 1201, 1180, 1229, 1082, 1041, 1017,
969, 912, 885, 821, 780; 1H NMR (300 MHz, CDCl3) d 7.71 (2H, d,
J = 8.2 Hz, Ar), 7.36–7.19 (7H, m, Ar), 5.51 (1H, s, CH), 5.08 (1H,
d, J = 11.8, CH2), 4.95 (1H, d, J = 11.8 Hz, CH2), 4.38 (1H, dd, J =
5.1, 7.6 Hz, CH2), 3.24–3.08 (2H, m, CH2), 2.94 (3H, s, SCH3),
0.93 (9H, s, (CH3)3); 13C NMR (62.9 MHz, CDCl3) d 171.6, 155.6,
143.2, 139.2, 134.8, 130.5, 128.9, 128.8, 128.7, 127.5, 96.3, 68.7,
58.5, 44.5, 39.2, 37.1, 24.8; HRMS (ESI) calcd for C23H27NO6S
[M+NH4+]: m/z 463.1897; found m/z 463.1898. Diacel Chiralcel
OD–H, hexane : propan-2-ol (90 : 10), 1.0 mL min-1, tR = 10.4 min.
1
1121, 1036, 756; H NMR (300 MHz, CDCl3) d 7.32–7.27 (3H,
m, Ar), 7.22–7.18 (2H, m, Ar), 7.02 (2H, d, J = 8.6 Hz, Ar), 6.68
(2H, d, J = 8.6 Hz, Ar), 5.47 (1H, s, CH), 5.07 (1H, d, J = 12.0 Hz,
CH2), 4.90 (1H, d, J = 12.0 Hz, CH2), 4.36 (1H, dd, J = 5.4,
7.5 Hz, CH), 3.69 (3H, s, CH3), 3.07 (1H, dd, J = 7.5, 13.9 Hz,
CH2), 2.98 (1H, dd, J = 5.4, 13.9 Hz, CH2), 0.92 (9H, s, (CH3)3);
13C NMR (75.5 MHz, CDCl3) d 172.4, 158.9, 156.2, 135.5, 130.8,
129.2, 129.0, 128.9, 114.2, 96.5, 68.7, 59.4, 55.6, 38.8, 37.4, 25.3;
HRMS (ESI) calcd for C23H27NO5Na [M+Na+]: m/z 420.1786;
found 420.1789. HPLC Diacel Chiralcel OD–H, hexane : propan-
2-ol (95 : 5), 1.0 mL min-1, tR = 12.1 min.
(2S,4R)-benzyl-4-(4-formylbenzyl)-2-tert-butyl-5-oxooxazolidine-
3-carboxylate (5h)
Title compound was isolated as a colourless oil (112 mg, 83%);
Rf (9 : 1, petroleum ether : ethyl acetate) 0.08; [a]2D4 -18.3 (c 3,
5124 | Org. Biomol. Chem., 2010, 8, 5120–5125
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Acknowledgements
We are grateful to the EPSRC (DTA) and Pfizer Limited (CASE
award to JH) for funding. The EPSRC Mass Spectrometry Service
at the University of Wales Swansea and Dr Anneke Lubben from
the Mass Spectrometry Service at the University of Bath are also
thanked for their assistance.
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