Stereoselective synthesis of 2,3-difunctionalised thioesters using nucleophilic epoxidation of 1-arylthio-1-nitroalkenes

Article abstract of DOI:10.1039/b710237b

Stereoselective nucleophilic epoxidation of protected 3-amino and 3-hydroxy-substituted 1-arylthio-1-nitroalkenes, followed by intramolecular capture involving the amino and hydroxyl protecting groups, has led to the formation of isomeric oxazolidinones 5

Full text of DOI:10.1039/b710237b

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Stereoselective synthesis of 2,3-difunctionalised thioesters using nucleophilic
epoxidation of 1-arylthio-1-nitroalkenes†
Lyndsay Ann Evans,a Harry Adams,a Christopher G. Barber,b Lorenzo Caggiano*‡a and
Richard F. W. Jackson*a
Received 5th July 2007, Accepted 31st July 2007
First published as an Advance Article on the web 17th August 2007
DOI: 10.1039/b710237b
Stereoselective nucleophilic epoxidation of protected 3-amino and 3-hydroxy-substituted
1-arylthio-1-nitroalkenes, followed by intramolecular capture involving the amino and hydroxyl
protecting groups, has led to the formation of isomeric oxazolidinones 5 and 7, and a cyclic carbonate
11. Together with the oxazolidinone precursor anti-a-bromo thioester 15a, the absolute and relative
stereochemistry of these compounds has been determined by X-ray crystallography.
Introduction
The synthesis of enantiomerically pure a-hydroxy-b-amino acids
is of great interest as this structure is present in a variety
of drugs and natural products that exhibit potent biological
activities.1–6 a-Hydroxy-b-amino acid derivatives often display
potent protease inhibition as this structural unit is an efficient
transition-state mimic of peptide hydrolysis.4 Selected examples
include the KMI- and KNI- series of compounds that contain a
3-amino-2-hydroxy-4-phenylbutyric acid derivative as an isostere.7
The KMI compounds are highly potent b-secretase (BACE1)
inhibitors8 and have therapeutic potential for Alzheimer’s disease.9
Kynostatins KNI-227, -27210,11 and -27912 are highly active HIV-
1 protease inhibitors and (−)-bestatin13 is a specific inhibitor of
aminopeptidase B. The side-chain of taxol (paclitaxel), a potent
antitumour compound, also contains an a-hydroxy-b-amino acid
derivative.14
Isomeric b-hydroxy-a-amino acids are present in many biologi-
cally active compounds such as the ustiloxins,15,16 a family of cyclic
peptides that are potent antimitotic agents that display growth
inhibition of various tumour cell lines, and numerous glycopeptide
antibiotics,17 including vancomycin.18 We have shown that 1-
arylthio-1-nitroalkenes with an allylic hydroxyl substituent 1 can
undergo stereoselective nucleophilic epoxidation and subsequent
ring-opening with ammonia to give enantiomerically pure b-
hydroxy-a-amino acid derivatives. The stereochemical outcome
of the epoxidation reaction can be controlled by the combined
influence of the presence, or absence, of a protecting group on
the allylic hydroxyl substituent, and by the choice of nucleophilic
oxidant. The combination of lithium tert-butylperoxide and an
unprotected hydroxyl group gives syn-epoxides, while potassium
tritylperoxide gives anti-epoxides (Scheme 1).19
Scheme
1
Reagents and ◦conditions: (i) tBuOOLi, THF, −78 ◦C;
t
(ii) Ph3COOK, THF, −78 C; (iii) BuMe2SiOTf, 2,6-lutidine, CH2Cl2,
−78 ◦C; (iv) aq. NH3 (d 0.880), CH2Cl2, rt; (v) PhCH2OCOCl.19
Epoxidation of 1-arylthio-1-nitroalkenes 3 possessing an allylic
nitrogen substituent, gives access to protected a-hydroxy-b-amino
acid derivatives (Scheme 2).20 In contrast to the analogous oxygen
substituted systems,19 it was found that epoxidation using either
lithium tert-butylperoxide or potassium tritylperoxide gives the
cis-oxazolidinone 5 in a highly stereoselective fashion after work-
up, presumably via the same syn-epoxide intermediate 4a.20
Scheme 2 Reagents and conditions: (i) tBuOOLi, THF, −78 ◦C or
Ph3COOK, THF, −78 ◦C; (ii) work-up.20
We now report that introduction of a carbamate protecting
group on the epoxide syn-2a allows the stereocontrolled synthesis
of a b-hydroxy-a-amino derivative 7 that is isomeric to cis-5, and
that analogous use of a carbonate protecting group allows the
synthesis of a cyclic carbonate 11. A modified strategy also permits
the synthesis of a syn-a-hydroxy-b-amino acid derivative, masked
as the trans-oxazolidinone 5, previously inaccessible using this
approach.
aDepartment of Chemistry, Dainton Building, The University of Sheffield,
Brook Hill, Sheffield, UK S3 7HF. E-mail: r.f.w.jackson@shef.ac.uk;
Fax: (+44)114 222 9303; Tel: (+44)114 222 9464
bDepartment of Discovery Chemistry, Pfizer Global Research and Develop-
ment, Sandwich, Kent, UK CT13 9NJ
† CCDC reference numbers 653097–653100. For crystallographic data in
CIF or other electronic format see DOI: 10.1039/b710237b
‡ Present address: Department of Pharmacy and Pharmacology, Univer-
sity of Bath, Bath, UK BA2 7AY.
3156 | Org. Biomol. Chem., 2007, 5, 3156–3163
This journal is
The Royal Society of Chemistry 2007
©

View Article Online
Results and discussion
The key starting material, alkene 1b, was prepared by the
previously reported method.19 Although deprotection of the
tert-butyldimethylsilyl (TBS) protecting group of compound 1b
using BF3·OEt2 in dichloromethane21 had previously worked
satisfactorily,19 the process subsequently proved to be somewhat
capricious. A related observation by Yoshida prompted a change
of solvent to acetonitrile,22 which allowed deprotection of the silyl
ether 1b to give the allylic alcohol 1a in a consistent yield of
80% (Scheme 3). As previously reported,19 treatment of the allylic
t
n
t
alcohol 1a with BuOOLi (prepared from BuLi and BuOOH)
gave the epoxide syn-2a as a single diastereoisomer, as judged
1
by H NMR. The stereoselectivity exhibited in this reaction is
Fig. 1 cis-Oxazolidinone 7.
believed to originate from coordination of the Li to the allylic
alcohol, delivering the nucleophilic oxygen syn to the hydroxyl
substituent.19
and the meta-hydrogen of the aromatic ring of another molecule
(2.587 A, not shown).
˚
Since it had already been established that intramolecular attack
at C3 of a 2-arylthio-2-nitrooxirane by the carbonyl group of a
carbamate could occur,20 the possibility that the carbonyl group of
a carbonate might also participate was explored. Thus, treatment
of the allylic alcohol 1a with di-tert-butyl dicarbonate in the
presence of N-methylimidazole,26 which reduces the formation of
the symmetrical carbonate by-product, gave the Boc-protected
alcohol 1c in 70% yield. Epoxidation of the alkene 1c with
tBuOOLi gave the cis-cyclic carbonate 11 (47%) (Route A), as
well as an epimeric mixture (10 : 3) of the a-hydroxy thioesters 10
(35%). The a-hydroxy thioesters 10 may result from hydrolysis of
either the presumed epoxide intermediate 8 (Route B1) and/or the
intermediate 9 (Route B2, Scheme 4).
Scheme 3 Reagents and conditions: (i) BF3·OEt2, MeCN, 0 ◦C, 80%;
(ii) BuOOLi, THF, −78 ◦C, 86%; (iii) CCl3CONCO, CHCl3, 86%; (iv)
t
SiO2, CHCl3, 46% (over 2 steps).
Since previous work had shown that epoxidation of 1-arylthio-
1-nitroalkenes bearing an allylic nitrogen, protected as a carba-
mate, resulted in the protecting group ring-opening the epoxide
intermediate generating an oxazolidinone,20 the feasibility of an
isomeric carbamate derived from the syn-epoxide 2a undergoing
a similar process was explored.
Following the strategy reported by Ichikawa et al.,23 treatment
of the syn-epoxide 2a with trichloroacetyl isocyanate gave the
trichloroacetyl carbamate 6 (86%). Although basic hydrolysis of
the trichloroacetyl carbamate would have revealed the unsubsti-
tuted carbamate, we were concerned that the basic conditions
reported by Ichikawa were incompatible with the functionalised
epoxide. Unfortunately, use of a milder deprotection method
involving neutral alumina24 resulted in extensive decomposition.
However, treatment of the trichloroacetyl carbamate 6 with
silica gel, which had previously been used to induce cyclisa-
tion of a dimethylcarbamate group,25 gave the substituted cis-
oxazolidinone 7 (isomeric to the cis-oxazolidinone 5 previously
reported)20 in an overall 46% yield from the syn-epoxide 2a.
Nucleophilic attack through the carbonyl oxygen, which would
ultimately have led to the cis-cyclic carbonate 11 after hydrolysis,
was not observed.
Scheme
4 Reagents and conditions: (i) Boc2O, N-methylimidazole,
toluene, 70%; (ii) tBuOOLi, THF, −78 ◦C; (iii) SiO2; 10 (35% over 2 steps)
and 11 (47% over 2 steps).
The stereochemistry of the cis-cyclic carbonate 11 was de-
termined by X-ray crystallography, shown in Fig. 2. H NMR
showed an ABX3 system, from which the J coupling between
the two protons on the oxazolidinone ring was determined to be
8.5 Hz, typical for a syn-relationship in similar systems.27 The
formation of the cis-carbonate 11 suggests that the syn-epoxide 8
was preferentially formed in the epoxidation step. This implies
1
3
A crystal structure of the cis-oxazolidinone 7 (Fig. 1) confirmed
the relative and absolute stereochemistry, which results from
intramolecular nucleophilic attack with inversion at C-3 of the
epoxide. The crystal structure also revealed an unusually strong
hydrogen bonding interaction between the carbonyl oxygen (O3)
t
that, during nucleophilic epoxidation with BuOOLi, the Boc-
protected allylic oxygen substituent was effective at coordinating
lithium, so delivering the nucleophilic oxidant syn to the carbonate
substituent.
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 3156–3163 | 3157
©

View Article Online
Attempts to convert the syn-a-bromo-b-hydroxy thioester 12b
into the cis-epoxy thioester 13b under a variety of conditions
failed, although there was 1H NMR evidence for the formation of
the trans-epoxide 13a in the crude reaction mixture. The transition
state for the cyclisation leading to the cis-epoxide is expected to
be more crowded than that for formation of the trans-epoxide
13a, and it is therefore likely that epimerisation of 12b to give
12a, followed by cyclisation, occurs preferentially (Scheme 7).
Epimerisation of thioesters is known to be facile.31
Fig. 2 cis-Cyclic carbonate 11.
Synthesis of epoxythioesters
We have previously demonstrated that 2-arylthio-2-nitrooxiranes
undergo regioselective ring-opening with inversion of configura-
tion in the presence of MgBr2·Et2O to afford the corresponding
a-bromo thioesters.28–30 Analogous reaction of the epoxide syn-2a
with MgBr2·Et2O gave the anti-a-bromo-b-hydroxy thioester 12a
(77%), as a single diastereoisomer. Subsequent treatment of the
alcohol 12a with NaH gave the trans-epoxy thioester 13a (47%)
(Scheme 5).
Scheme 7 Reagents and conditions: (i) NaH, THF.
Preparation of protected a-hydroxy-b-amino acid trans-5
Stereoselective nucleophilic epoxidation of 1-arylthio-1-nitro-
alkenes had been previously developed as a route for the
synthesis of anti-a-hydroxy-b-amino acid derivatives, masked as
oxazolidinones (Scheme 2).20 It was anticipated that the unstable
intermediate epoxide might be amenable to trapping by an external
nucleophile that could then act as a leaving group, thereby leading
to the previously inaccessible oxazolidinone trans-5. Addition of
MgBr2·Et2O to the reaction mixture containing the syn-epoxide
4a, followed by silica gel chromatography, gave a mixture of the
anti-a-bromo thioester 15a as a single diastereoisomer (15%),
the desired cyclised product oxazolidinone trans-5 (36%) and the
isomeric oxazolidinone cis-5 (14%) (Scheme 8). The relative and
absolute stereochemistry of the anti-a-bromo thioester 15a was
determined by X-ray crystallography (Fig. 3).
Scheme 5 Reagents and conditions: (i) MgBr2·OEt2, THF, 77%; (ii) NaH,
THF, 47%.
With the aim of preparing the isomeric cis-epoxy thioester
13b, epoxidation of the silyl-protected allylic alcohol 1b with
Ph3COOK (prepared from Ph3COOH and KH) gave the anti-
epoxide 2b with high diastereoselectivity.19 Stereospecific ring-
opening with MgBr2·Et2O gave the syn-a-bromo thioester 14
(87%). A one-pot procedure was also investigated in which
the silyl-protected allylic alcohol 1b was initially treated with
Ph3COOK, followed by the addition of solid MgBr2·Et2O, to give
the syn-a-bromo thioester 14 (79% over two steps). Deprotection
of the silyl group using BF3·OEt2 in acetonitrile22 gave the syn-a-
bromo-b-hydroxy thioester 12b (80%) (Scheme 6).
Scheme 8 Reagents and conditions: (i) tBuOOLi, THF, −78 ◦C; (ii) SiO2,
72%;20 (iii) MgBr2·OEt2(s); (iv) SiO2; 15a (15%), trans-5 (36%), cis-5 (14%)
(from 3a).
It is likely that the conversion of 15a into oxazolidinone trans-5,
the structure of which was confirmed by X-ray crystallography
(Fig. 4), occurs through silica gel promoted nucleophilic attack of
Scheme 6 Reagents and conditions: (i) Ph3COOK, THF, 74% (15 : 1 anti :
syn);19 (ii) MgBr2·OEt2, Et2O, 87%; (iii) BF3·OEt2, MeCN, 0 ◦C, 80%.
3158 | Org. Biomol. Chem., 2007, 5, 3156–3163
This journal is
The Royal Society of Chemistry 2007
©

View Article Online
Conclusions
Intramolecular capture of 2-arylthio-2-nitrooxirane intermediates
has been successfully carried out using carbamate and carbon-
ate protecting groups, generating the b-hydroxy-a-amino acid
derivative, oxazolidinone 7, and the a,b-dihydroxy acid derivative,
cyclic carbonate 11, respectively. The preparation of the previously
inaccessible syn-a-hydroxy-b-amino acid derivative (masked as the
oxazolidinone trans-5) was achieved by a combination of inter-
molecular ring-opening of the epoxide followed by intramolecular
nucleophilic attack. Extension of this ring-opening/ring-closing
strategy has also allowed the synthesis of trans-epoxy thioester
13a and a-bromo thioester 15b which are both potentially useful
synthetic intermediates.
Fig. 3 anti-a-Bromo thioester 15a.
Experimental
All reagents used were purchased from commercial sources or
prepared and purified according to literature procedures. All
moisture/air sensitive reactions were conducted under a positive
pressure of nitrogen in flame dried or oven dried glassware.
Petroleum ether refers to the fraction with a boiling point between
40–60 ◦C.
Nuclear magnetic resonance (NMR) spectra were recorded on
a Bruker AC-250, Bruker AMX2-400 or Bruker DRX-500 NMR
spectrometer at room temperature. Chemical shifts were measured
relative to residual solvent and are expressed in parts per million
(d). Coupling constants (J) are given in Hertz and the measured
values are rounded to the nearest 0.5 Hertz. High-resolution
mass spectra were recorded using a MicroMass LCT operating in
electrospray (ES) mode. Chemical analyses were performed using
a Perkin Elmer 2400 CHN elemental analyser. Optical rotations
were measured on a Perkin Elmer 241 automatic polarimeter
at k 589 nm (Na, D-line) with a path length of 1 dm at the
stated temperature and concentrations. The concentration is
given in g per 100 cm3 and the optical rotations are quoted in
10−1 deg cm2 g−1. Infra-red spectra were recorded on a Perkin
Elmer Paragon 100 FTIR spectrophotometer (mmax in cm−1) as thin
films using NaCl plates. Melting points were determined using a
Linkam HFS91 heating stage, used in conjunction with a TC92
controller and are uncorrected.
Fig. 4 Oxazolidinone trans-5.
the carbonyl group of the Boc-protected amino oxygen on the anti-
a-bromo thioester. A related transformation was reported by Righi
in similar vinylogous substrates.32 Formation of the oxazolidinone
cis-5 presumably arises from direct attack of the Boc group on
the intermediate epoxide 4a, as already shown in Scheme 2. This
process competes with attack by the external bromide nucleophile.
Previous work had shown that the Fmoc protecting group is
less prone to participate in cyclisation processes than the Boc
group, an observation that has been used in the synthesis of
anti-a,b-diamino acid derivatives.20,33 Therefore, in a preliminary
study, stereoselective epoxidation of the Fmoc-protected allylic
amine 3b20 and treatment of the intermediate epoxide 4b with
MgBr2·Et2O gave the a-bromo thioester 15b, a potentially useful
synthetic intermediate, in an unoptimised 35% yield over 2 steps
(Scheme 9).
Thin layer chromatography (TLC) was performed on precoated
plates (Merck aluminium sheets silica 60 F254, art. no. 5554).
Column chromatography was performed using silica gel 60 (Merck
9385).
(2,2,2-Trichloroacetyl)-carbamic acid (S)-1-[(2R,3R)-3-nitro-p-
tolylsulfanyl-oxiranyl]-ethyl ester 6
Trichloroacetyl isocyanate (12 ll, 0.1 mmol, 1.05 eq.) was added
in one portion to a stirred solution of the epoxide syn-2a (pre-
pared according to the procedure previously reported,19 24.4 mg,
0.0956 mmol) in chloroform (2 cm3) under a nitrogen atmosphere
at room temperature. After 1.5 h, the solution was dried over
MgSO4, filtered and the solvent was removed under reduced
pressure to afford the carbamate 6 (36.3 mg, 86%) as a colourless
waxy solid. [a]D22 −44.0 (c 1.0 in CHCl3); mmax (film)/cm−1 3479,
3351, 3290, 2987, 1799, 1725, 1569, 1494 and 824; dH (250 MHz;
CDCl3) 1.47 (3H, d, J 6.5 Hz, CH3CH), 2.29 (3H, s, ArCH3),
Scheme
9
Reagents and conditions: (i) tBuOOLi, THF, −78 ◦C;
(ii) MgBr2·OEt2(s), 35% (2 steps).
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 3156–3163 | 3159
©

View Article Online
3.77 (1H, d, J 8.0 Hz, COCH), 5.19 (1H, dq, J 8.0 and 6.5 Hz,
CH3CHO), 7.18 (2H, d, J 8.5 Hz, Ar), 7.45–7.49 (2H, m, Ar) and
8.47 (1H, s, br, NH); dC (62.5 MHz; CDCl3) 16.8, 21.3, 65.1, 72.4,
81.1, 94.9, 121.1, 130.6, 135.2, 141.3, 148.6 and 157.8.
alcohol 1c (227 mg, 0.67 mmol, 1 eq.) in◦THF (7 cm3) was added
dropwise to the stirred solution at −78 C and after 30 min the
reaction was quenched at that temperature by the addition of silica
gel (2.3 g, 10× w/w). The mixture was allowed to warm to room
temperature, filtered and washed with EtOAc (20 cm3). The solvent
was removed under reduced pressure and the brown residue (171
mg) was dissolved in CHCl3 (50 cm3) and silica gel (1.71 g, 10×
w/w) was added in one portion. The reaction mixture was stirred at
room temperature for 3 h, filtered and washed with EtOAc (20 cm3)
and the solvent was removed under reduced pressure. Purification
by column chromatography (10% EtOAc–petroleum ether) gave
the cis-cyclic carbonate 11 (79 mg, 47%) as an oil. Crystallisation
by slow evaporation from petroleum ether–Et2O gave colourless
cubes which were analysed by X-ray crystallography. Mp 119–
120 ◦C; [a]2D2 −80.0 (c 0.13 in CHCl3); mmax (film)/cm−1 2916, 2854,
1808 and 1695; dH (500 MHz; CDCl3) 1.48 (3H, d, J 6.5 Hz,
CHCHCH3, ABX3), 2.39 (3H, s, ArCH3), 5.07 (1H, dq, J 8.5 and
6.5 Hz, CHCHCH3, ABX3), 5.13 (1H, d, J 8.5 Hz, CHCHCH3,
ABX3) and 7.25–7.27 (4H, m, Ar); dC (125 MHz; CDCl3) 15.6,
21.4, 75.6, 81.0, 121.1, 130.5, 134.5, 140.8, 155.2 and 194.7. m/z
(ES) 275 (MNa+, 100%); found (MNa+) 275.0364, C12H12O4NaS
requires 275.0354. An inseparable 10 : 3 epimeric mixture of a-
hydroxy thioesters 10 (79 mg, 35%) was also isolated by column
chromatography as an oil; mmax (film)/cm−1 3482 (br), 2981, 2937,
1742, 1701 and 1280; dH (500 MHz; CDCl3) (3 : 10 mixture, A :
B) 1.36 (3H (A), d, J 6.5 Hz, CH3CH), 1.43 (3H (B), d, J 6.5 Hz,
(4S,5S)-4-(p-Tolylthiocarbonyl)-5-methyloxazolidin-2-one 7
Trichloroacetyl isocyanate (17.4 ll, 0.146 mmol, 1.05 eq.) was
added in one portion to a stirred solution of the epoxide syn-
2a (prepared according to the procedure previously reported,19
35.5 mg, 0.139 mmol) in chloroform (2 cm3) under a nitrogen
atmosphere at room temperature. After 1.5 h, silica gel (355 mg,
10× w/w) was added in one portion and the mixture was stirred for
a further 1 h at 65 ◦C. The slurry was filtered, washed with EtOAc
(2 × 5 cm3) and the solvent was removed under reduced pressure.
The crude mixture was purified by column chromatography (20%
EtOAc–petroleum ether) to afford the cis-oxazolidinone 7 (16 mg,
46%) as a pale yellow solid. Recrystallisation by slow evaporation
from petroleum ether–Et2O gave colourless needles which were
◦
analysed by X-ray crystallography. Mp 94–96 C; [a]2D2 −76.9 (c
0.33 in CHCl3); mmax (film)/cm−1 3283 (br), 1756 and 1699; dH
(250 MHz; CDCl3) 1.41 (3H, d, J 6.5 Hz, CH3CH), 2.31 (3H, s,
ArCH3), 4.46 (1H, d, J 9.0 Hz, NHCH), 4.94 (1H, dq, J 9.0 and
6.5 Hz, CH3CH), 6.28 (1H, br s, NH) and 7.18–7.20 (4H, m, Ar);
dC (125 MHz; CDCl3) 16.0, 21.4, 64.0, 75.6, 122.2, 130.4, 134.4,
140.5, 158.6 and 197.5; m/z (ES) 525 (M2Na+, 14%), 503 (M2H+,
12), 274 (MNa+, 30) and 252 (MH+, 100); found (MH+) 252.0704,
C12H14NO3S requires 252.0694.
t
t
CH3CH), 1.47 (9H (B), s, Bu), 1.50 (9H (A), s, Bu), 2.35 (3H
(A), s, ArCH3), 2.37 (3H (B), s, ArCH3), 4.26 (1H (B), d, J 3.0 Hz,
CHOH), 4.55 (1H (A), d, J 2.5 Hz, CHOH), 5.06 (1H (A), dq, J 6.5
and 2.5 Hz, CH3CH), 5.15 (1H (B), dq, J 6.5 and 3.0 Hz, CH3CH),
7.20–7.28 (4H (A + B), Ar); dC (125 MHz CDCl3) 14.5 (A), 16.5
(B), 21.3 (A + B), 27.7 (A + B), 73.8 (B), 75.3 (A), 79.4 (A), 79.8
(B), 82.8 (B), 83.1 (A), 123.0 (A + B), 130.1 (A + B), 134.6 (A +
B), 140.0 (A + B), 152.7 (B), 153.5 (A), 199.4 (A), 199.7 (B); m/z
(ES) 349 (MNa+, 100%) and 293 (40); found (MNa+) 349.1077,
C16H22O5NaS requires 349.1086.
(Z)-(3S)-3-(tert-Butoxycarbonyloxy)-1-nitro-1-p-tolylthio-but-
1-ene 1c
N-Methylimidazole (76 ll, 0.95 mmol, 1 eq.) was added dropwise
to a stirred cooled solution (∼5 ◦C) of the allylic alcohol 1a
(227 mg, 0.95 mmol, 1 eq.), prepared according to the procedure
previously reported,19 and di-tert-butyl dicarbonate (208 mg,
0.95 mmol, 1 eq.) in toluene (14 cm3) under a nitrogen atmosphere.
The reaction mixture was allowed to warm to room temperature
and was stirred for 40 min. The crude reaction mixture was filtered
through a short plug of silica gel and the solvent was evaporated
to give the Boc-protected allylic alcohol 1c (226 mg, 70%) as an
oil. [a]2D2 −44.3 (c 0.84 in CHCl3); mmax (film)/cm−1 2983, 2931,
1744, 1537 and 1277; dH (250 MHz; CDCl3) 1.40 (3H, d, J 6.5 Hz,
CH3CH), 1.44 (9H, s, tBu), 2.25 (3H, s, ArCH3), 5.68 (1H, dq, J
8.0 and 6.5 Hz, CH3CH), 7.03–7.11 (2H, m, Ar), 7.24–7.36 (2H,
m, Ar) and 7.39 (1H, d, J 8.0 Hz, CHC); dC (125 MHz; CDCl3)
19.8, 21.0, 27.7, 71.1, 83.2, 128.5, 130.3, 130.9, 138.7, 143.6, 148.3
and 152.5; m/z (ES) 362 (MNa+, 70%), 335 (100), 306 (7) and 279
(18); found (MNa+) 362.1044, C16H21NO5NaS requires 362.1038.
S-(p-Tolyl) (2S,3S)-2-bromo-3-hydroxybutanethioate 12a
Magnesium bromide ethyl etherate (296 mg, 1.15 mmol, 1.5 eq.)
was added to a stirred solution of the epoxide syn-2a (pre-
pared according to the procedure previously reported,19 196 mg,
0.77 mmol, 1 eq.) in THF (4 cm3) under a nitrogen atmosphere. The
mixture was stirred for 2.5 h at room temperature and quenched
with water (3 cm3). The aqueous layer was extracted with EtOAc
(2 × 5 cm3) and the combined organic extracts were dried over
MgSO4, filtered and the solvent was removed under reduced
pressure. The residue was purified by column chromatography
(20% EtOAc–petroleum ether) to give the a-bromo-b-hydroxy
thioester 12a (170 mg, 77%) as a yellow oil. [a]2D2 +57 (c 1.0 in
CHCl3); mmax (film)/cm−1 3435 (br), 2925 and 1685; dH (400 MHz;
CDCl3) 1.45 (3H, d, J 6.5 Hz, CH3CH), 2.42 (3H, s, ArCH3),
2.53 (1H, br s, OH), 4.30–4.33 (1H, m, CH3CH), 4.48 (1H, d, J
6.5 Hz, CHBr), 7.27 (2H, d, J 8.5 Hz, Ar) and 7.36 (2H, d, J
8.5 Hz, Ar); dC (100 MHz; CDCl3) 20.1, 21.4, 57.2, 69.1, 123.0,
130.3, 134.4, 140.4 and 195.0; m/z (ES) 291 and 289 (MH+, 100%),
245 and 243 (30); found (MH+) 288.9910. C11H14BrO2S requires
288.9898.
(4S,5S)-4-(p-Tolylthiocarbonyl)-5-methyl-[1,3]-dioxolan-2-one 11
and S-(p-tolyl) (2RS,3S)-3-(tert-butoxycarbonyloxy)-2-
hydroxybutanethioate 10
nBuLi (2.5 M in hexanes, 320 ll, 0.80 mmol, 1.2 eq.) was added
dropwise to a stirred solution of tert-butyl hydroperoxide◦(3.8 M in
toluene, 260 ll, 1.0 mmol, 1.5 eq.) in THF (10 cm3) at −78 C under
a nitrogen atmosphere. A solution of the Boc-protected allylic
3160 | Org. Biomol. Chem., 2007, 5, 3156–3163
This journal is
The Royal Society of Chemistry 2007
©

View Article Online
S-(p-Tolyl) (2R,3S)-3-methyloxirane-2-carbothioate 13a
chromatography (20% EtOAc–petroleum ether) to give the syn-
a-bromo-b-silyloxy thioester 14 (226 mg, 79%) as an oil, which
was identical to the compound prepared previously.
Sodium hydride (60% w/w dispersion in oil, 32 mg, 0.8 mmol,
1 eq.) was added in one portion to a stirred cooled (0 ◦C) solution
of the thioester 12a (230 mg, 0.8 mmol, 1 eq.) in THF (10 cm3)
under a nitrogen atmosphere. The reaction was monitored by TLC
[eluent, petroleum ether–EtOAc (8 : 2)] and quenched after 15 min
with saturated aqueous ammonium chloride solution (10 cm3).
EtOAc (10 cm3) was added, the organic phase was separated, dried
over MgSO4 and the solvent was removed under reduced pressure.
The crude mixture was purified by column chromatography (10%
EtOAc–petroleum ether) to afford the epoxide 13a (78 mg, 47%)
as a colourless oil. [a]2D2 +97.0 (c 1.0 in CHCl3); mmax (film)/cm−1
2924 and 1693; dH (250 MHz; CDCl3) 1.44 (3H, d, J 5.0 Hz,
CH3CH), 2.37 (3H, s, ArCH3), 3.35 (1H, qd, J 5.0 and 2.0 Hz,
CH3CH), 3.42 (1H, d, J 2.0 Hz, CHC) and 7.12–7.24 (4H, m, Ar);
dC (125 MHz; CDCl3) 17.2, 21.2, 56.4, 60.8, 122.4, 130.1, 134.5,
139.8 and 196.7; m/z (ES) 231 (MNa+, 100%); found (MNa+)
231.0447, C11H12O2NaS requires 231.0456.
S-(p-Tolyl) (2R,3S)-2-bromo-3-hydroxybutanethioate 12b
Boron trifluoride diethyl etherate (39 ll, 0.31 mmol, 2 eq.)
was added to a stirred cooled (0 ◦C) solution of the syn-a-
bromo-b-silyloxy thioester 14 (61.5 mg, 0.153 mmol) in dry
acetonitrile (7 cm3) under a nitrogen atmosphere. The clear
solution immediately turned yellow and was stirred at 0 ◦C for
a further 15 min before being quenched with pH 7 phosphate
buffer (7 cm3). The solution changed from yellow to colourless.
EtOAc (5 cm3) was added and the organic layer was separated,
dried over Na2SO4, filtered and the solvent was removed under
reduced pressure. The crude mixture was purified by column
chromatography (20% EtOAc–petroleum ether) to afford the a-
bromo-b-hydroxy thioester 12b (35 mg, 80%) as a colourless oil.
[a]D22 −33 (c 1.12 in CHCl3); mmax (film)/cm−1 3445, 2978, 2926, 1684
and 800; dH (500 MHz; CDCl3) 1.34 (3H, d, J 6.5 Hz, CH3CH),
2.38 (3H, s, ArCH3), 2.67 (1H, br s, OH), 4.19 (1H, qd, J 6.5 and
4.5 Hz, CH3CH), 4.46 (1H, d, J 4.5 Hz, CHBr) and 7.20–7.35 (4H,
m, Ar); dC (125 MHz; CDCl3) 20.2, 21.4, 60.0, 68.0, 123.0, 130.3,
134.4, 140.5 and 194.9; m/z (ES) 313 and 311 (MNa+, 100%);
found (MNa+) 310.9708, C11H13O2NaSBr requires 310.9717.
S-(p-Tolyl) (2R,3S)-3-(tert-butyldimethylsilyloxy)-2-
bromobutanethioate 14
Magnesium bromide diethyl etherate (145 mg, 0.560 mmol, 1.5 eq.)
was added to a stirred solution of the epoxide anti-2b (pre-
pared according to the procedure previously reported,19 138 mg,
0.373 mmol, 1 eq.) in Et2O (1.5 cm3) under a nitrogen atmosphere.
The mixture was stirred overnight at room temperature and
quenched with water (10 cm3). The aqueous layer was extracted
with EtOAc (2 × 5 cm3) and the combined organic extracts
were dried over MgSO4, filtered and the solvent was removed
under reduced pressure. The residue was purified by column
chromatography (20% EtOAc–petroleum ether) to give the syn-a-
bromo-b-silyloxy thioester 14 (132 mg, 87%) as an oil. [a]2D2 −58.3 (c
0.64 in CHCl3); mmax (film)/cm−1 2929, 2856, 1712, 1257 and 1137;
dH (400 MHz; CDCl3) 0.08 (3H, s, SiCH3), 0.10 (3H, s, SiCH3),
S-(p-Tolyl) (2S,3S)-3-(tert-butoxycarbonylamino)-2-
bromobutanethioate 15a, (4S,5R)-4-methyl-5-(p-
tolylthiocarbonyl)oxazolidin-2-one trans-5 and (4S,5S)-4-
methyl-5-(p-tolylthiocarbonyl)oxazolidin-2-one cis-5
nBuLi (2.5 M in hexanes, 145 ll, 0.363 mmol, 1.2 eq.) was added
dropwise to a stirred solution of tert-butyl hydroperoxide (3.8◦M
in toluene, 118 ll, 0.454 mmol, 1.5 eq.) in THF (6 cm3) at −78 C
under a nitrogen atmosphere. A solution of the Boc-protected
allylic amine 3a (prepared according to the procedure previously
reported,20 102.2 mg, 0.302 mmol) in THF (3 cm3) was added
dropwise to the stirred solution at −78 ◦C. After 10 min solid
magnesium bromide ethyl etherate (780 mg, 3.0 mmol, 10 eq.) was
added and the reaction was allowed to warm to room temperature
and stirred overnight. EtOAc (6 cm3) was added and the organic
fraction was separated, washed with water (3 × 15 cm3), brine
(15 cm3), dried over MgSO4, filtered and the solvent was removed
under reduced pressure. Purification by column chromatography
(10% EtOAc–petroleum ether) gave the anti-a-bromo thioester
15a (17.4 mg, 15%) as a white solid. Crystallisation by vapour
diffusion techniques using petroleum ether–Et2O gave colourless
plates which were analysed by X-ray crystallography. Mp 93–
t
0.91 (9H, s, Bu), 1.30 (3H, d, J 6.0 Hz, CH3CH), 2.37 (3H, s,
ArCH3), 4.27 (1H, qd, J 6.0 and 5.5 Hz, CH3CH), 4.39 (1H, d, J
5.5 Hz, CHBr) and 7.20–7.30 (4H, m, Ar); dC (100 MHz; CDCl3)
−4.8, −4.4, 18.1, 21.4, 21.5, 25.7, 60.5, 69.5, 123.8, 130.2, 134.3,
140.1 and 193.9; m/z (ES) 427 and 425 (MNa+, 30%), 405 and
403 (MH+, 100); found (MH+) 403.0762, C17H28BrO2SSi requires
403.0763.
One-pot procedure
Trityl hydroperoxide (295 mg, 1.07 mmol, 1.5 eq.) was added to
a stirred solution of KH (35% dispersed in mineral oil, 106 mg,
0.93 mmol, 1.3 eq.) in THF (8 cm3) under a nitrogen atmosphere
at −78 ◦C. A solution of the silyl-protected allylic alcohol
1b (prepared according to the procedure previously reported,19
251 mg, 0.71 mmol) in THF (8 cm3) was added dropwise
to the reaction mixture at −78 ◦C, followed by the addition
of magnesium bromide diethyl etherate (275 mg, 1.07 mmol,
1.5 eq.) in one portion. The reaction mixture was allowed to
warm to room temperature overnight and was quenched with
the addition of water (10 cm3). The aqueous layer was extracted
with EtOAc (8 cm3) and the combined organic extracts were
dried over MgSO4, filtered and solvent was evaporated under
reduced pressure. The crude mixture was purified by column
◦
94 C; [a]2D2 −65 (c 1.0 in CHCl3); mmax (film)/cm−1 3310 (br),
2977, 2926, 1768, 1702, 1163 and 809; dH (500 MHz; CDCl3)
t
1.27 (3H, d, J 7.0 Hz, CH3CH), 1.45 (9H, s, Bu), 2.38 (3H, s,
ArCH3), 4.20–4.29 (1H, br m, CHNH), 4.90 (1H, d, J 3.0 Hz,
CHBr), 4.93 (1H, d, J 7.0 Hz, CHNH) and 7.21–7.33 (4H, m,
Ar); dC (125 MHz; CDCl3) 17.3, 21.4, 28.4, 48.8, 58.8, 80.1,
123.3, 130.3, 134.5, 140.4, 154.8 and 193.8; m/z (ES) 412 and
t
410 (MNa+, 35%) and 274 (M+ − Bu − Br, 100); found (MNa+)
410.0417, C16H22NO3NaSBr requires 410.0401. The oxazolidinone
trans-5 (27 mg, 36%) was isolated as a white solid. Crystallisation
by vapour diffusion techniques from petroleum ether–Et2O gave
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 3156–3163 | 3161
©

View Article Online
colourless plates which were analysed by X-ray crystallography.
Mp 108–109 C; found: C 57.1%, H 4.9%, N 5.8%, C12H13NO3S
data) R1 = 0.0398, wR2 = 0.0803. Absolute structure parameter
◦
0.01(7).
requires C 57.35%, H 5.2%, N 5.6%); [a]2D2 −45 (c 0.23 in CHCl3);
mmax (film)/cm−1 3290 (br), 2916, 1767 and 1698; dH (500 MHz;
CDCl3) 1.43 (3H, d, J 6.0 Hz, CH3CH), 2.38 (3H, s, ArCH3), 4.02
(1H, qd, J 6.0 and 4.5 Hz, CH3CH), 4.63 (1H, d, J 4.5 Hz, CHO),
5.32 (1H, br s, NH) and 7.22–7.30 (4H, m, Ar); dC (125 MHz;
CDCl3) 21.4, 21.7, 52.3, 85.0, 121.8, 130.3, 134.5, 140.4, 156.7 and
197.9. m/z (ES) 274 (MNa+, 60%) and 252 (MH+, 100); found
(MNa+) 274.0522, C12H13NO3NaS requires 274.0514.
Crystal data for 15a: C16H22BrNO3S, M = 388.32, monoclinic,
3
˚
˚
a = 8.587(3), b = 5.2659(18), c = 19.647(7) A, U = 884.2(5) A ,
space group P21 (C2 , no. 4), Z = 2, l (Mo-Ka) = 2.454 mm−1,
2
6409 reflections collected, 3063 independent (Rint = 0.0504). Final
R indices [I > 2r(I)] R1 = 0.0433, wR2 = 0.0914. R indices (all
data) R1 = 0.0577, wR2 = 0.0971. Absolute structure parameter
0.037(12).
Crystal data for trans-5: C12H13NO3S, M = 251.29, monoclinic,
3
˚
˚
Oxazolidinone cis-5 was also isolated◦(11 mg, 14%) as a white
a = 5.249(3), b = 5.794(3), c = 20.357(12) A, U = 617.4(6) A ,
◦
solid, mp 100–102 C (lit. mp 102–103 C20). The Boc-protected
space group P21 (C2 , no. 4), Z = 2, l (Mo-Ka) = 0.258 mm−1,
2
allylic amine 3a starting material was also recovered (9.1 mg, 9%).
6821 reflections collected, 2777 independent (Rint = 0.0599). Final
R indices [I > 2r(I)] R1 = 0.0568, wR2 = 0.1300. R indices (all
data) R1 = 0.0750, wR2 = 0.1356. Absolute structure parameter
0.05(13).
S-(p-Tolyl) (2S,3S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-2-
bromobutanethioate 15b
nBuLi (2.5 M in hexanes, 70 ll, 0.175 mmol, 1.2 eq.) was added
dropwise to a stirred solution of tert-butyl hydroperoxide (3.8◦M
in toluene, 57 ll, 0.218 mmol, 1.5 eq.) in THF (4 cm3) at −78 C
under a nitrogen atmosphere. A solution of the Fmoc-protected
allylic amine 3b (prepared according to the procedure previously
reported,20 67 mg, 0.145 mmol) in THF (2 cm3) was added
dropwise to the stirred solution at −78 ◦C. After 10 min solid
magnesium bromide ethyl etherate (380 mg, 1.45 mmol, 10 eq.) was
added and the reaction was allowed to warm to room temperature
and stirred overnight. EtOAc (5 cm3) was added and the organic
fraction was separated, washed with water (3 × 10 cm3), brine
(15 cm3), dried over MgSO4, filtered and the solvent was removed
under reduced pressure. Purification by column chromatography
(20% Et2O–petroleum ether) gave the anti-a-bromo thioester 15b
(26.1 mg, 35%) as a yellow oil. [a]2D2 −36.7 (c 0.3 in CHCl3); mmax
(film)/cm−1 3328, 2947, 1702, 1509, 1244 and 741; dH (250 MHz;
CDCl3) 1.25 (3H, d, J 7.0 Hz, CH3CH), 2.31 (3H, s, ArCH3),
4.10–4.45 (4H, m, CHCH2O and CH3CH), 4.77 (1H, d, J 3.0 Hz,
CHBr), 5.21 (1H, br d, J 8.5 Hz, NH), 7.14–7.38 (8H, m, Ar),
7.51 (2H, d, J 8.5 Hz, Ar) and 7.69 (2H, d, J 8.5 Hz, Ar);
dC (125 MHz; CDCl3) 17.5, 21.4, 47.2, 49.4, 57.6, 66.9, 120.0,
123.1, 125.0, 127.1, 127.8, 130.3, 134.4, 140.5, 141.3, 143.8, 155.4
and 193.9; m/z (ES) 534 and 532 (MNa+, 100%); found (MNa+)
532.0554, C26H24NO3NaSBr requires 532.0558.
Acknowledgements
We thank EPSRC and Pfizer for support under the Industrial
CASE scheme.
Notes and references
1 R. Andruszkiewicz, Pol. J. Chem., 1998, 72, 1–48.
2 D. C. Cole, Tetrahedron, 1994, 50, 9517–9582.
3 E. Juaristi, D. Quintana and J. Escalante, Aldrichimica Acta, 1994, 27,
3–11.
4 G. Cardillo and C. Tomasini, Chem. Soc. Rev., 1996, 25, 117–128.
5 M. Liu and M. P. Sibi, Tetrahedron, 2002, 58, 7991–8035.
6 S. C. Bergmeier, Tetrahedron, 2000, 56, 2561–2576.
7 T. Mimoto, J. Imai, S. Tanaka, N. Hattori, O. Takahashi, S. Kisanuki,
Y. Nagano, M. Shintani, H. Hayashi, H. Sakikawa, K. Akaji and Y.
Kiso, Chem. Pharm. Bull., 1991, 39, 2465–2467.
8 Y. Hamada, N. Igawa, H. Ikari, Z. Ziora, J.-T. Nguyen, A. Yamani, K.
Hidaka, T. Kimura, K. Saito, Y. Hayashi, M. Ebina, S. Ishiura and Y.
Kiso, Bioorg. Med. Chem. Lett., 2006, 16, 4354–4359.
9 M. Asai, C. Hattori, N. Iwata, T. C. Saido, N. Sasagawa, B. Szabo´,
Y. Hashimoto, K. Maruyama, S.-i. Tanuma, Y. Kiso and S. Ishiura,
J. Neurochem., 2006, 96, 533–540.
10 T. Mimoto, J. Imai, S. Kisanuki, H. Enomoto, N. Hattori, K. Akaji
and Y. Kiso, Chem. Pharm. Bull., 1992, 40, 2251–2253.
11 S. Kageyama, T. Mimoto, Y. Murakawa, M. Nomizu, H. Ford, Jr., T.
Shirasaka, S. Gulnik, J. Erickson, K. Takada, H. Hayashi, S. Broder,
Y. Kiso and H. Mitsuya, Antimicrob. Agents Chemother., 1993, 37,
810–817.
12 T. Mimoto, N. Hattori, H. Takaku, S. Kisanuki, T. Fukazawa, K.
Terashima, R. Kato, S. Nojima, S. Misawa, T. Ueno, J. Imai, H.
Enomoto, S. Tanaka, H. Sakikawa, M. Shintani, H. Hayashi and Y.
Kiso, Chem. Pharm. Bull., 2000, 48, 1310–1326.
X-Ray crystallography
13 H. Umezawa, T. Aoyagi, H. Suda, M. Hamada and T. Takeuchi,
J. Antibiot., 1976, 29, 97–99.
14 K. C. Nicolaou, W. M. Dai and R. K. Guy, Angew. Chem., Int. Ed.
Engl., 1994, 33, 15–44.
Crystallographic data were collected and measured on a Bruker
Smart CCD area detector with an Oxford Cryosystems low
temperature system at T = 150(2) K.
Crystal data for 7: C12H13NO3S, M = 251.29, monoclinic, a =
15 Y. Koiso, M. Natori, S. Iwasaki, S. Sato, R. Sonoda, Y. Fujita, H.
Yaegashi and Z. Sato, Tetrahedron Lett., 1992, 33, 4157–4160.
16 Y. Koiso, Y. Li, S. Iwasaki, K. Hanaoka, T. Kobayashi, R. Sonoda, Y.
Fujita, H. Yaegashi and Z. Sato, J. Antibiot., 1994, 47, 765–773.
17 J. L. Pace and G. Yang, Biochem. Pharmacol., 2006, 71, 968–980.
18 C. M. Harris, H. Kopecka and T. M. Harris, J. Am. Chem. Soc., 1983,
105, 6915–6922.
19 Z. M. Adams, R. F. W. Jackson, N. J. Palmer, H. K. Rami and M. J.
Wythes, J. Chem. Soc., Perkin Trans. 1, 1999, 937–948.
20 L. Ambroise, E. Dumez, A. Szeki and R. F. W. Jackson, Synthesis,
2002, 2296–2308.
3
˚
˚
9.243(5), b = 5.497(3), c = 12.258(7) A, U = 620.4(6) A , space
group P21 (C2 , no. 4), Z = 2, l (Mo-Ka) = 0.256 mm−1, 5727
2
reflections collected, 2147 independent (Rint = 0.0954). Final R
indices [I > 2r(I)] R1 = 0.0664, wR2 = 0.1539. R indices (all
data) R1 = 0.1055, wR2 = 0.1731. Absolute structure parameter
0.14(19).
Crystal data for 11: C12H12O4S, M = 252.28, orthorhombic, a =
3
˚
˚
7.5636(11), b = 10.4554(16), c = 15.375(2) A, U = 1215.9(3) A ,
21 D. R. Kelly, S. M. Roberts and R. F. Newton, Synth. Commun., 1979,
space group P212121 (D4 , no. 19), Z = 4, l (Mo-Ka) = 0.266 mm−1,
2
9, 295–299.
13372 reflections collected, 2758 independent (Rint = 0.0424). Final
R indices [I > 2r(I)] R1 = 0.0315, wR2 = 0.0770. R indices (all
22 A. Yoshida, Y. Tejima, N. Takeda and S. Oida, Tetrahedron Lett., 1984,
25, 2793–2796.
3162 | Org. Biomol. Chem., 2007, 5, 3156–3163
This journal is
The Royal Society of Chemistry 2007
©

View Article Online
23 Y. Ichikawa, M. Yamazaki and M. Isobe, J. Chem. Soc., Perkin Trans.
1, 1993, 2429–2432.
24 P. Kocˇovsky´, Tetrahedron Lett., 1986, 27, 5521–5524.
25 L. Caggiano, D. J. Fox and S. Warren, Chem. Commun., 2002, 2528–
2529.
26 Y. Basel and A. Hassner, J. Org. Chem., 2000, 65, 6368–6380.
27 N. Yoshikawa, T. Suzuki and M. Shibasaki, J. Org. Chem., 2002, 67,
2556–2565.
29 R. F. W. Jackson, J. M. Kirk, N. J. Palmer, D. Waterson and M. J.
Wythes, J. Chem. Soc., Chem. Commun., 1993, 889–890.
30 R. F. W. Jackson, N. J. Palmer, M. J. Wythes, W. Clegg and M. R. J.
Elsegood, J. Org. Chem., 1995, 60, 6431–6440.
31 P. J. Um and D. G. Drueckhammer, J. Am. Chem. Soc., 1998, 120,
5605–5610.
32 G. Righi, C. Potini and P. Bovicelli, Tetrahedron Lett., 2002, 43, 5867–
5869.
28 M. Ashwell, R. F. W. Jackson and J. M. Kirk, Tetrahedron, 1990, 46,
33 E. Dumez, A. Szeki and R. F. W. Jackson, Synlett, 2001, 1214–
1216.
7429–7442.
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 3156–3163 | 3163
©