Enantioselective N-heterocyclic carbene catalyzed formal [3+2] cycloaddition using α-aroyloxyaldehydes and oxaziridines

Article abstract of DOI:10.1016/j.tetasy.2016.10.012

An enantioselective N-heterocyclic carbene catalysed formal [3+2] cycloaddition has been developed for the synthesis of oxazolindin-4-one products. The reaction of oxaziridines and α-aroyloxyaldehydes under N-heterocyclic carbene catalysis provides the fo

Full text of DOI:10.1016/j.tetasy.2016.10.012

Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantioselective N-heterocyclic carbene catalyzed formal [3+2]
cycloaddition using a-aroyloxyaldehydes and oxaziridines
a,
Ryan W. F. Kerr a, Mark D. Greenhalgh a, Alexandra M. Z. Slawin a, Polly L. Arnold b, , Andrew D. Smith
⇑
⇑
a EaStCHEM School of Chemistry, University of St Andrews, North Haugh, St Andrews KY16 9ST, UK
b EaStCHEM School of Chemistry, The University of Edinburgh, David Brewster Road, Edinburgh EH9 3FJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
An enantioselective N-heterocyclic carbene catalysed formal [3+2] cycloaddition has been developed for
the synthesis of oxazolindin-4-one products. The reaction of oxaziridines and -aroyloxyaldehydes under
N-heterocyclic carbene catalysis provides the formal cycloaddition products with excellent control of the
diastereo- and enantioselectivity (12 examples, up to >95:5 dr, >99:1 er). A matched-mismatched effect
between the enantiomer of the catalyst and oxaziridine was identified, and preliminary mechanistic
studies have allowed the proposal of a model to explain these observations.
Received 13 October 2016
Accepted 26 October 2016
Available online xxxx
a
Ó 2016 Published by Elsevier Ltd.
1. Introduction
azolium enolate precursors in enantio- and diastereoselective [4
+2] and [2+2] cycloadditions (Scheme 1).8,10
N-Heterocyclic carbenes (NHCs) occupy a privileged position
within the field of Lewis base organocatalysis due to the wide range
of reactive intermediates accessible from readily available starting
materials.1 Beyond the classical acyl anion equivalent reactivity
mode, the development of NHC catalysis has resulted in numerous
O
R1
OR2
R1
O
methods that proceed by acyl azolium,
a,b-unsaturated acyl azo-
Redox
esterifications
O
lium, azolium enolate, homoenolate and radical cation intermedi-
ates.1,2 Within this field, azolium enolates have been applied to a
range of reactions, including highly enantio- and diastereoselective
intramolecular cyclizations,3 desymmetrizations,4 and (formal) [4
+2],5 [2+2],6 and to a lesser extent [3+2] cycloadditions.7 Tradition-
ally, azolium enolate species have been generated from the direct
addition of NHCs to ketenes,6b,c however the inherent difficulties
associated with substrate synthesis and stability has resulted in
the development of alternative methods.2 The most common
approach to azolium enolate intermediates is through the use of
X
X
R4
R5
O
[4+2]
R3
R1
H
O
NHC
[2+2]
O
R1
O
Ar1
This work
[3+2]
O
Ar2
Rf
O
R1
NSO2R6
R8
NHC redox catalysis, in which
as -haloaldehydes, -aryloxyaldehydes or epoxyaldehydes) or
enals are used. In previous work we introduced the use of -aroy-
loxyaldehydes in NHC redox catalysis.8 These serve as bench-stable
alternatives to -haloaldehydes that are traditionally difficult to
prepare and store. To date,
a-functionalized aldehydes (such
O
R7
a
a
a
Scheme 1. Applications of a-aroyloxyaldehydes in NHC redox catalysis.
a
a
-aroyloxyaldehydes have been applied
for the NHC-catalyzed synthesis of esters and amides,8 including
application in the acylative kinetic resolutions of alcohols,9 and as
The development of stereoselective methods for the synthesis
of heterocyclic compounds is a major area of chemical research
due to their ubiquitous use in pharmaceuticals and agrochemicals.
Natural products containing the oxazolidin-4-one core structure
have only recently been isolated, and show promising levels of
anti-bacterial and anti-fungal activity.11 The development of new
⇑
Corresponding authors.
E-mail addresses: polly.arnold@ed.ac.uk (P.L. Arnold), ads10@st-andrews.ac.uk
(A.D. Smith).
http://dx.doi.org/10.1016/j.tetasy.2016.10.012
0957-4166/Ó 2016 Published by Elsevier Ltd.
Please cite this article in press as: Kerr, R. W. F.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.10.012

2
R. W. F. Kerr et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
catalytic stereoselective methods for the synthesis of oxazolidin-4-
ones is therefore of interest to allow broader access to these bioac-
tive heterocyclic compounds. Recently, a number of methods for
the stereoselective synthesis of oxazolidin-4-ones have been
reported involving oxidation of a catalytically-generated enolate
with an oxaziridine in a formal [3+2] cycloaddition (Scheme 2).12
In 2010, Ye et al. reported the formal [3+2] cycloaddition between
ketenes 1 and oxaziridines 2 using either an NHC or cinchona alka-
the use of only a single oxaziridine 6 was demonstrated. Feng
and Liu have developed an alternative method using Brønsted
base-catalyzed oxyamination of azalactones using a range of
oxaziridines.16 By using 2 equivalents of racemic oxaziridine an
efficient kinetic resolution of the oxaziridine was also realized,
with selectivity factors of up to 52 being reported.14
Building upon these precedents, herein the expansion of the
range of methods available for the generation of enantioenriched
oxazolidin-4-one products is investigated through the use of a-
loid catalyst (Scheme 2, a).13
a,a-Disubstituted syn-oxazolidin-4-
one products 4 were obtained in good yield and with generally
high diastereo- and enantiocontrol using racemic 2-chlorophenyl
oxaziridine derivative ( )-2. Notably, when using 1.2 equivalents
of the oxaziridine ( )-2, enantioenriched oxaziridine was recovered
from the reaction, which is indicative of a kinetic resolution pro-
cess.14 The scope of this method is limited however by the stability
and range of ketene precursors available. We have recently
reported a complementary isothiourea-catalyzed method using
homoanhydrides 5 as the ammonium enolate precursor to give
anti-oxazolidin-4-one products 8 (Scheme 2, b).15 In this method,
the use of racemic oxaziridine led to products with high enantios-
electivity, but low diastereoselectivity. The use of enantiopure oxa-
ziridine gave anti-oxazolidin-4-ones 8 with high enantio- and
diastereoselectivity, consistent with conservation of the oxaziri-
dine stereocentre throughout the reaction process. Although a
number of examples were reported, this method was limited to
aryl- and vinylacetic acid-derived homoanhydrides 5, and again
aroyloxyaldehydes as bench-stable azolium enolate precursors in
NHC redox catalysis (Scheme 2, c). This approach allows access
to anti-5-alkyl-oxazolidin-4-one products, previously inaccessible
in enantioenriched form using organocatalytic methods.
2. Results and discussion
Initial studies focused on the optimization of the reaction of
aroyloxyaldehyde 13 with racemic oxaziridine ( )-6 using different
N-heterocyclic carbene precursors. Using -pyroglutamic acid
a-
L
derived triazolium 15, which had shown activity in Ye’s formal [3
+2] cycloaddition methodology using ketenes,13 gave no product
(Table 1, entry 1). Aminoindanol-derived catalysts 16–18 were
next studied due to previous activity in catalyzing formal [4+2]
and [2+2] cycloadditions using
a-aroyloxyaldehydes (entries 2–
4).10 Of these, N-mesityl-substituted triazolium 18 gave anti-oxa-
zolidin-4-one 14 in the highest yield (entry 4). Using enantioen-
riched oxaziridine (3R)-6 and exchanging the counterion of the
triazolium salt from chloride 18 to tetrafluoroborate 11 resulted
in an increase in diastereoselectivity, giving oxazolidin-4-one 14
as essentially a single diastereo- and enantiomer (entries 5–6).
a) Ye et al., 2010
N
N
Ar3
N
Ar2
Ar2
O
R1
Ar1
OH
BF4
O
NTs Cl
NTs
3
(10 mol%)
O
C
O
Table 1
Cs2CO3 (20 mol%)
PhMe, r.t., 24 h
Reaction optimizationa
Ar1
R1
Cl
Ar2 = 3,5-(CF 3)2-C6H3
O
1
( )-2
(1.2 equiv.)
O
Cat. (10 mol%)
Ar3 = 2-i-Pr-C6H4
4
Cs2CO3 (1.1 equiv.)
NTs
10 examples
NTs
Ph
O
+
H
37-78%, up to 94:6 drsyn:anti
3Å MS, solvent
r.t., 18 h
•
•
unstable ketene starting materials
1
O
Ph
up to >99:1 er (syn)
OCOAr
•
= alkyl one aryl oxaziridine used
R
6
14
• syn-oxazolidin-4-one products formed
13
Ar = 4-NO2-C6H4
b) Smith et al., 2015
Catalysts:
i-Pr
O
O
N
BF4
N
N
X
O
N
BF4
Ph
S
N
N
N
N
Ph
N
O
O
O
R
Mes
R2
N
N
7
NTs
(10 mol%)
NTs
Ph
Ph
O
R2
R2
O
OTBS
Ph
(3R)-6
Cs2CO3 (2 equiv.)
Ph
5
CH2Cl2, −78 °C → r.t.
8
15
16
17
18
11
, R = Ph
, X = Cl
(1.5 equiv.)
9 examples
, R = C6F5
, X = BF4
49-95%, up to >95:5 dranti:syn
• R2 = aryl or alkenyl
up to >99:1 er (anti)
• one aryl oxaziridine used
• anti-oxazolidin-4-one products formed
Entry Cat. 13
6
Solvent
Yieldb (%) drc
erd
—
(equiv) (equiv)
1
2
3
4
5
6
7
8
9
10
15
16
17
18
18
11
11
11
11
11
1.5
1.5
1.5
1.5
1.5
1.5
1
1
1
1
1 ( )
1 ( )
1 ( )
1 ( )
1 (3R)
1 (3R)
2 (3R)
2 (3R)
3 (3R)
3 ( )
THF
THF
THF
THF
THF
THF
THF
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
0
—
NDe
O
c) This work
8 (25)
2 (19)
27 (49)
21 (47)
23 (51)
23 (53)
36 (62)
44 (78)
30
63:37
83:17
81:19
93:7
>95:5
>95:5
>95:5
>95:5
78:22
N
N
BF4
Mes
NDe
N
NDe
98:2
99:1
>99:1
>99:1
>99:1
95:5
O
O
NSO2R4
11
R3
R3
(10 mol%)
NSO2R4
R6
O
H
R6
R5
Cs2CO3 (1.1 equiv.)
3Å MS, 1,4-Dioxane
O
OCOAr4
R5
r.t., 18 h
9
10
(3R)-
12
(3 equiv.)
a
12 examples
Reactions were performed on a 0.2 mmol scale, in flame-dried glassware and
14-62%, up to >95:5 dranti:syn
• R3 = alkyl • Ar4 = 4-NO2-C6H4
• aryl and alkyl oxaziridines used
under an argon atmosphere.
up to >99:1 er (anti)
Isolated yield. Yields determined by quantitative 1H NMR spectroscopy using
b
• anti-oxazolidin-4-one products formed
1,3,5-trimethoxybenzene as internal standard given in parentheses.
Determined by 1H NMR spectroscopy of the crude reaction mixture.
c
d
Determined by chiral HPLC analysis of the isolated product.
ND = not determined.
Scheme 2. Lewis-base catalyzed methods for the stereoselective synthesis of
e
oxazolidin-4-one derivatives.
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R. W. F. Kerr et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
3
The absolute configuration of the product was confirmed by single
crystal X-ray analysis.17 Finally, increasing the equivalents of oxa-
ziridine (3R)-6 and by using 1,4-dioxane as the solvent gave oxazo-
lidin-4-one 14 in an improved isolated yield (44%, entries 7–9).
Analytically pure product was obtained using a sodium bisulfite
wash to remove imine and aldehyde side-products, followed by
flash silica column chromatography. Analysis of the crude reaction
mixture by quantitative 1H NMR spectroscopy however identified a
much higher yield (78%), indicating that the moderate isolated
yields were a result of difficulties in product isolation. The use of
racemic oxaziridine ( )-6 under the optimized reaction conditions
gave oxazolidin-4-one 14 with lower diastereo- and enantiocontrol
(entry 10). This demonstrates the importance of using enantioen-
riched oxaziridine in this process, and indicates a more productive
and selective reaction takes place between the azolium enolate
derived from the (5aR,10bS)-enantiomer of the N-heterocyclic car-
bene and the (R)-enantiomer of the oxaziridine. However, in these
reactions the oxaziridine was fully consumed (to give the corre-
sponding imine), and thus the potential for a kinetic resolution
process could not be assessed.
As previous methods focused on the use of a single aryl-substi-
tuted oxaziridine, the use of alternative oxaziridines was investi-
gated. Based on the optimization studies it was reasoned that
enantioenriched oxaziridines were needed for this study. Using a
modification of Jørgensen’s cinchona alkaloid-catalyzed oxaziridi-
nation of imines,18 in which hydroquinidine was used in place of
the optimal catalyst, a selection of enantioenriched oxaziridines
were synthesized and tested in the developed methodology
(Table 2). Enantioenriched 3- and 4-fluorophenyl-substituted
oxaziridines 19 and 20 (88:12 and 87:13 er, respectively) gave
oxazolidin-4-ones 23 and 24 in moderate yield but with excellent
diastereo- and enantiocontrol (entries 1–2). 4-Trifluorophenyl-
substituted oxaziridine 21 could only be isolated in 78.5:21.5 er,
and accordingly oxazolidin-4-one product 25 was obtained with
slightly lower diastereoselectivity, but still with excellent
enantioselectivity (entry 3). The use of an alkyl-substituted oxazir-
idine 22 was also investigated. Although oxaziridine 22 was only
obtained in 60.5:39.5 er, the oxazolidin-4-one product 26 was still
generated in good yield and with good diastereoselectivity and
excellent enantioselectivity (entry 4). Alternative enantioenriched
oxaziridines, including those bearing electron-donating groups,
could not be synthesized in sufficiently enantioenriched form to
be synthetically useful in this methodology.19
Table 2
Reaction scope: variation of oxaziridinea
O
11
(10 mol%)
O
Cs2CO3 (1.1 equiv.)
NTs
NTs
R
O
+
H
3Å MS, 1,4-dioxane
r.t., 18 h
O
R
OCOAr
23-26
13
19-22
The application of a variety of
a-aroyloxyaldehydes in the
(R)-
Ar = 4-NO2-C6H4
(3 equiv.)
developed method was next investigated using oxaziridine (3R)-
6 to give a range of 5-alkyl-substituted oxazolidin-4-one products
(Table 3). 5-Benzyl-substituted oxazolidin-4-ones 33–35 bearing
ether and acetal functional groups were obtained in moderate
yields but with excellent diastereo- and enantiocontrol. Extended
alkyl chains were also introduced, including those bearing pro-
tected alcohol and amine functionalities, to give oxazolidin-4-
ones 36–38 with similarly high levels of diastereo- and
enantiocontrol.
Entry Oxaziridine
Product
Yieldb
(%)
drc
erd
O
NTs
O
NTs
O
1
46
93:7
98.5:1.5
F
19
(3R)-
F
88:12 er
Table 3
23
.
Reaction scope: variation of a
-aroyloxyaldehydea
O
O
11
(10 mol%)
O
NTs
Cs2CO3 (1.1 equiv.)
O
O
O
NTs
NTs
R
R
NTs
Ph
O
+
H
O
3Å MS, 1,4-dioxane
r.t., 18 h
O
Ph
2
28
>95:5
>99:1
OCOAr
F
33-38
27-32
(3R)-6
(3R)-20
Ar = 4-NO2-C6H4
>99:1 er
87:13 er
(3 equiv.)
F
24
.
O
O
O
O
O
Bn
NTs
NTs
NTs
NTs
Ph
O
NTs
O
O
O
Ph
Ph
O
3
40
90:10 97.5:2.5
MeO
CF3
b
b
b
33
34
35
, 24%
, 44%
, 24%
94:6 drc
93:7 drc
>95:5 drc
21
(3R)-
>99:1 erd
99:1 erd
>99:1 erd
78.5:21.5 er
CF3
25
.
O
N
O
O
O
O
n-Bu
NTs
n-Pent
NTs
Ph
36, 16%b
NTs
NTs
Ph
BnO
O
O
O
NTs
O
Ph
4
62
80:20
94:6
O
n-Pent
37, 14%b
38, 24%b
22
(3R)-
94:6 drc
95:5 drc
90:10 drc
60.5:39.5 er
>99:1 erd
>99:1 erd
>99:1 erd
26
.
a Reactions conditions: 27–32 (0.2 mmol), oxaziridine (3R)-6 (0.6 mmol), 11
(0.02 mmol), Cs2CO3 (0.22 mmol), 1,4-dioxane (0.05 M), rt, 18 h.
b Isolated yield.
a
Reactions conditions: 13 (0.2 mmol), oxaziridine (3R)-19–22 (0.6 mmol), 11
(0.02 mmol), Cs2CO3 (0.22 mmol), 1,4-dioxane (0.05 M), rt, 18 h.
b
Isolated yield.
c Determined by 1H NMR spectroscopy of the crude reaction mixture.
d Determined by chiral HPLC analysis of the isolated product.
c
Determined by 1H NMR spectroscopy of the crude reaction mixture.
d
Determined by chiral HPLC analysis of the isolated product.
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R. W. F. Kerr et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
O
O
a)
O
O
11 (10 mol%)
O
S
O
O
11
(10 mol%)
Cs2CO3 (1.1 equiv.)
NTs
O
S
Cs2CO3 (1.1 equiv.)
N
NTs
Ph
N
+
O
H
+
O
H
3Å MS, 1,4-dioxane
r.t., 18 h
O
O
Ph
3Å MS, 1,4-dioxane
r.t., 18 h
OCOAr
OCOAr
13
(3R)-6
14, 44%
Ar = 4-NO2-C6H4
>95:5 dranti:syn
>99:1 er
13
40
, 20%
39
( )-
(3 equiv.)
>99:1 er (anti)
Ar = 4-NO2-C6H4
>95:5 dr
88:12 er
(3 equiv.)
O
b)
O
ent-11 (10 mol%)
Scheme 3. NHC-catalyzed formal [3+2] cycloaddition using ketimine-derived
oxaziridine ( )-39.
Cs2CO3 (1.1 equiv.)
NTs
O
NTs
+
H
3Å MS, 1,4-dioxane
r.t., 18 h
O
Ph
OCOAr
Ph
13
(3R)-6
42, 21%
O
O
Ar = 4-NO2-C6H4
15:85 dranti:syn
>99:1 er
(3 equiv.)
14
14
)
89:11 er (anti, :ent-
SmI2 (2 equiv.)
>99:1 er (syn)
NTs
Ph
NH
Ph
41, 57%
>95:5 dr
>99:1 er
O
THF (0.03 M)
O
—78 °C → r.t., 15 min
Scheme 5. Investigation of matched/mismatched effects, using (a) pre-catalyst 11
and oxaziridine (3R)-6 (matched); and (b) pre-catalyst ent-11 and oxaziridine (3R)-
6 (mismatched).
14
>95:5 dr
>99:1 er
Scheme 4. N-Detosylation of oxazolidin-4-one 14 using samarium(II) iodide.
11
O
O
R1
R1
To extend the scope of the developed method beyond those
previously reported, the use of ketimine-derived oxaziridines
was investigated. Under the standard reaction conditions, the
use of oxaziridine ( )-39 synthesized from saccharin in two
steps gave 2,2-disubstituted oxazolidin-4-one 40 in moderate
yield but with good enantio- and excellent diastereoselectivity
(Scheme 3). The relative configuration of the product was
assigned using nOe spectroscopy,20 and the absolute configura-
tion assigned by analogy to oxazolidin-4-one 14. The 2,2-disub-
stituted oxazolidin-4-one 40 was only metastable and so the
configuration could not be further confirmed using single crys-
tal X-ray analysis. The removal of the N-tosyl group of the oxa-
zolidinone products was also demonstrated using samarium(II)
iodide (Scheme 4). The deprotected oxazolidin-4-one 41 was
obtained in good yield and with complete retention of dia-
stereo- and enantiopurity.
Cs2CO3
N
NTs
R2
H
O
OCOAr
N
N
Ar = 4-NO2-C6H4
Mes
I
O
H
O
R1
R1
N
N
H
O
N
ArOCO
N
N
N
R2
TsN
Mes
Mes
VI
II
H+
NTs
O
R2
R1
O
OH
R1
N
N
N
ArOCO
N
Finally, we sought to provide some insight into the mechanism
of the reaction (Scheme 5). During optimization studies, the use of
enantioenriched oxaziridine (3R)-6 was essential for high dia-
stereo- and enantioselectivity (Table 1, entries 9–10, Scheme 5,
a). The apparent synergistic effect between the configuration of
the catalyst and oxaziridine was further probed by performing
the reaction using the opposite enantiomer of the catalyst ent-11
with enantioenriched oxaziridine (3R)-6 (Scheme 5, b). The syn-
oxazolidin-4-one product 42 was obtained (15:85 dranti:syn) in
lower yield but with excellent enantioselectivity (>99:1 er). The
absolute configuration of the major product obtained using either
enantiomer of the NHC pre-catalyst, 11 or ent-11, and oxaziridine
(3R)-6 (Scheme 5, a and b) can be explained by the catalyst control-
ling the configuration of the C(5) position, whilst the configuration
of the C(2) position is defined by the configuration of the oxaziri-
dine. The lower yield and diastereoselectivity obtained using
(ent)-11 and oxaziridine (3R)-6 is indicative of a mismatched
effect. The absolute configuration of the minor anti-product 14
obtained was the same as that obtained using pre-catalyst 11, thus
indicating that in the mismatched case, the stereocentre present in
the oxaziridine overrides the usual facial selectivity observed using
azolium enolates derived from the (5aS,10bR)-enantiomer of the
NHC. These results are consistent with the configuration of the
oxaziridine stereocentre being conserved. This contrasts the mech-
anism proposed by Ye et al. for the formal [3+2] cycloaddition
between ketenes and oxaziridines using an NHC catalyst, in which
N
N
Mes
Mes
azolium enolate
Breslow
OH
V
intermediate
R1
III
−H+
N
N
ArCO2
N
Mes
IV
Scheme 6. Proposed mechanism.
intermediates to give the final oxazolidin-4-one product.13
Although we cannot rule out a similar mechanism herein, the
retention of configuration from the C(3) position of the oxaziridine
to the C(2) position of the oxazolidin-4-one is most easily
explained by direct chirality transfer in which the configuration
of the stereocentre is conserved throughout the process.
Based on these observations, a mechanism for the formal [3+2]
cycloaddition may be proposed (Scheme 6). Deprotonation of the
triazolium salt 11 provides the free carbene I, which adds to the
a
-aroyloxyaldehyde to give adduct II. Proton transfer gives Bres-
low intermediate III, which followed by elimination of para-
nitrobenzoate gives azolium enol IV. Deprotonation provides the
key azolium enolate V. Nucleophilic attack on the oxaziridine at
the oxygen results in
a-oxidation of the azolium enolate and
NAO bond cleavage of the oxaziridine to give zwitterionic acyl azo-
lium intermediate VI. Finally, lactamization provides the oxazo-
lidin-4-one product and regenerates the free carbene I.
a-oxidation of the azolium enolate to provide an oxirane and achi-
ral imine was proposed, followed by recombination of the two
Please cite this article in press as: Kerr, R. W. F.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.10.012

R. W. F. Kerr et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
5
Waters Xevo G2-S spectrometer. Synthesis of aromatic imines,21
3. Conclusion
aliphatic imines,22 authentic racemic oxaziridines,23
a-aroy-
loxyaldehydes10a,10d and N-heterocyclic carbene precatalysts
(15,24 16,25 1725 and 1826) were synthesized using literature
procedures.
An asymmetric N-heterocyclic carbene catalyzed formal [3+2]
cycloaddition has been developed using
a-aroyloxyaldehydes
and oxaziridines. A range of oxazolidin-4-one products, previ-
ously inaccessible in enantioenriched form using organocatalysis,
were obtained with excellent control of diastereo- and
enantioselectivity. The use of a ketimine-derived oxaziridine was
also demonstrated, providing access to enantiomerically-enriched
2,2-disubstituted oxazolidin-4-one products. N-Detosylation of
the oxazolidin-4-one products was shown to proceed with reten-
tion of stereochemical purity, and preliminary mechanistic studies
have allowed the proposal of a catalytic cycle.
4.2. Clꢀ to BFꢀ4 anion exchange of N-heterocyclic carbine
precatalyst 18 to 11
4.2.1. (5aR,10bS)-2-Mesityl-5a,10b-dihydro-4H,6H-indeno[2,1-
b][1,2,4]triazolo[4,3-d][1,4]oxazin-2-ium tetrafluoroborate 11
(5aR,10bS)-2-Mesityl-5a,10b-dihydro-4H,6H-indeno[2,1-b]
[1,2,4]triazolo[4,3-d][1,4]oxazin-2-ium chloride 18 (467 mg,
1.27 mmol) was added to a suspension of sodium tetrafluoroborate
(346 mg, 3.17 mmol) in acetone (10 mL) and heated at 50 °C for
18 h. The flask was cooled to rt and the suspension was filtered
and washed with acetone (3 ꢁ 10 mL). The solvent was concen-
trated under vacuum to give a brown solid, which was dissolved
in CH2Cl2 (10 mL) and filtered through CeliteÒ. The CeliteÒ was
washed with CH2Cl2 (3 ꢁ 10 mL) and the solvent concentrated
under vacuum to give title compound 11 as a colourless solid with
spectroscopic data in accordance with the literature9b (499 mg,
4. Experimental
4.1. General
Reactions involving moisture sensitive reagents were carried
out under an argon atmosphere using standard vacuum line tech-
niques. All glassware was flame-dried and cooled under vacuum.
Solvents (tetrahydrofuran and toluene) were obtained anhydrous
and purified by passage through an alumina column (Mbraun
SPS-800). Anhydrous 1,4-dioxane was obtained by distillation over
calcium hydride. All other solvents and commercial reagents were
used as supplied without further purification. Room temperature
(rt) refers to 20–25 °C. Temperatures of ꢀ40 °C were obtained
using an immersion cooler and an acetone bath. Analytical thin
layer chromatography was performed on pre-coated aluminium
plates (Kieselgel 60 F254 silica). TLC visualization was carried out
with ultraviolet light (254 nm), followed by staining with a 1%
aqueous KMnO4 solution. Flash column chromatography was per-
formed on Kieselgel 60 silica in the solvent system stated or on
the BiotageÒ IsoleraTM 4. 1H, 13C and 19F nuclear magnetic resonance
(NMR) spectra were acquired on either a Bruker Avance II 400
(400 MHz, 1H; 101 MHz, 13C; 376 MHz, 19F), Bruker Avance 500
1.19 mmol, 94%); ½a D20
ꢂ
= +29.8 (c 0.50, CHCl3); mp 262–263 °C
{Lit.9b 270 °C}; 1H NMR (400 MHz, d6-DMSO) dH: 2.11 (6H, s, N(2)
Ar(2,6)CH3), 2.37 (3H, s, N(2)Ar(4)CH3), 3.16 (1H, d, J 17.0, C(6)
HaHb), 3.49 (1H, dd, J 17.0, 5.0, C(6)HaHb), 4.98 (1H, app. t, J 4.5, C
(5a)H), 5.07 (1H, d, J 16.1, OC(4)HaHb), 5.26 (1H, d, J 16.1, OC(4)
HaHb), 6.08 (1H, d, J 4.2, C(10b)H), 7.21 (2H, s, N(2)Ar(3,5)H),
7.31–7.49 (3H, m, ArH), 7.60 (1H, d, J 7.5, ArH), 11.12 (1H, s, C(1)
H). 19F NMR (376 MHz, d6-DMSO) dF: ꢀ148.20, ꢀ148.25.
4.3. General procedure for the enantioenriched oxaziridine
synthesis
The following is a modification of a procedure reported by
Jørgensen et al.18 Imine (1 equiv) was dissolved in toluene
(0.1 M) and cooled at ꢀ40 °C using a cryogenic bath. Next mCPBA
(677%, ꢃ1.1 equiv.) and hydroquinidine (10 mol %) were added
and the suspension was vigorously stirred for 24 h. The reaction
mixture was warmed to rt and concentrated under vacuum. The
crude residue was purified by flash chromatography to give the
title compound.
(500 MHz, 1H; 126 MHz, 13C) or
a Bruker Avance III 500
(500 MHz, 1H; 126 MHz, 13C) spectrometer at ambient tempera-
ture in the deuterated solvent stated. All chemical shifts are quoted
in parts per million (ppm) relative to the residual solvent as the
internal standard. All coupling constants, J, are quoted in Hz and
determined by analysis using MestReNova v9.0.1 software. Multi-
plicities are indicated by: s (singlet), d (doublet), t (triplet), q (quar-
tet), m (multiplet), dd (doublet of doublets), ddd (doublet of
doublet of doublets), dt (doublet of triplets), td (triplet of doublets),
ddt (doublet of doublets of triplets), tdd (triplet of doublets of dou-
blets) and qd (quartet of doublets). The abbreviation Ar is used to
denote aromatic, br to denote broad and app. to denote apparent.
4.3.1. (3R)-3-Phenyl-2-tosyl-1,2-oxaziridine (3R)-6
Using general procedure 4.3—(E)-N-benzylidene-4-toluenesul-
fonamide (3.7 g, 14.3 mmol), mCPBA (677%, 5 g, 16.0 mmol),
hydroquinidine (450 mg, 1.4 mmol) in toluene (140 mL) gave, after
column chromatography (10% EtOAc in hexane) and recrystalliza-
tion (EtOAc and hexane), the title compound (3R)-6 as a colourless
solid with spectroscopic data in accordance with the literature15
Infrared spectra (mmax) were recorded on a Shimadzu IRAffinity-1
(1.69 g, 6.15 mmol, 43%); ½a D20
ꢂ
= +81.3° (c 1.00, CHCl3); mp 82–
Fourier transform infrared spectrophotometer using either thin
films or solids with a Pike MIRacleTM ATR accessory. Analysis was
performed with Shimadzu IRsolution v1.50 software and only the
characteristic peaks are quoted. Melting points were recorded on
an Electrothermal 9100 melting point apparatus and are uncor-
rected. HPLC analyses were obtained on a Shimadzu HPLC consist-
ing of a Shimadzu DGU-20A5 degasser, Shimadzu LC-20AT liquid
chromatograph, Shimadzu SIL-20AT auto sampler, Shimadzu
CBM-20A communications bus module, Shimadzu SPD-M20A
diode array detector, Shimadzu CTO-20A. Mass spectrometry (m/
z) data were acquired either by: electrospray ionization (ESI) at
the University of St Andrews using a Micromass LCT spectrometer;
nanospray ionization (NSI) at the EPSRC National Mass Spectrom-
etry Facility, Swansea, on a Thermofisher LTQ Orbitrap XL spec-
trometer; or atmospheric pressure chemical ionization (APCI) at
the EPSRC National Mass Spectrometry Facility, Swansea, on a
84 °C {Lit.15 86–89 °C}; Chiral HPLC analysis Chiralpak AS-H (95:5
hexane:i-PrOH, flow rate 1.0 mL minꢀ1
, 220 nm, 30 °C) tR(R):
9.6 min, tR(S): 14.0 min, >99:1 er; 1H NMR (400 MHz, CDCl3) dH:
2.50 (3H, s, ArCH3). 5.46 (1H, s, C(3)CH), 7.55–7.36 (7H, m, ArH),
7.90–7.96 (2H, m, SO2Ar(2,6)H).
4.3.2. (3R)-2-Tosyl-3-(3-(fluoro)phenyl)-1,2-oxaziridine (3R)-19
Using general procedure 4.3—(E)-N-(3-fluorobenzylidene)-4-
methylbenzenesulfonamide (2.09 g, 7.14 mmol), mCPBA (677%,
2.40 g, 8 mmol), hydroquinidine (228 mg, 0.7 mmol) in toluene
(70 mL) gave, after column chromatography (10% EtOAc in hexane)
and recrystallization (CHCl3 and hexane), the title compound (3R)-
19 as a colourless solid with spectroscopic data in accordance with
the literature16 (357 mg, 1.22 mmol, 17%); ½a 2D0
ꢂ
= +70.5 (c 1.00,
CHCl3); mp 55–57 °C {Lit. mp unreported}; Chiral HPLC analysis
Please cite this article in press as: Kerr, R. W. F.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.10.012

6
R. W. F. Kerr et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Chiralpak AD-H (95:5 hexane:i-PrOH, flow rate 1 mL minꢀ1
,
(10 mol%), cesium carbonate (0.22 mmol) and anhydrous 1,4-diox-
ane (4 mL) under an argon atmosphere. The reaction mixture was
allowed to stir at rt for 18 h. Sodium bisulfite solution (4 mL, aq.
10% w/v) was added and the reaction stirred at rt for 4 h. The reac-
tion mixture was diluted with Et2O (10 mL) and washed sequen-
tially with water (10 mL), saturated aqueous NH4Cl (10 mL),
saturated aqueous NaHCO3 (10 mL) and brine (10 mL). The organic
layer was dried over MgSO4, filtered and concentrated under
reduced pressure. The crude residue was purified by flash column
chromatography to give the title compound.
211 nm, 40 °C) tR(S): 7.9 min, tR(R): 8.7 min, 88:12 er; 1H NMR
(400 MHz, CDCl3) dH: 2.50 (3H, s, ArCH3), 5.45 (1H, s, C(3)H),
7.08–7.20 (2H, m, C(3)Ar(2,4)H), 7.28 (1H, app dt, J 7.7, 1.3, C(3)
Ar(6)H), 7.39 (1H, app td, J 8.0, 5.5, C(3)Ar(5)H), 7.43–7.46 (2H,
m, SO2Ar(3,5)H), 7.90–7.95 (2H, m, SO2Ar(2,6)H); 19F{1H} NMR
(376 MHz, CDCl3) dF: ꢀ111.6.
4.3.3. (3R)-2-Tosyl-3-(4-(fluoro)phenyl)-1,2-oxaziridine (3R)-20
Using general procedure 4.3—(E)-N-(4-fluorobenzylidene)-4-
methylbenzenesulfonamide (4.18 g, 14.3 mmol), mCPBA (677%,
4.8 g, 16 mmol), hydroquinidine (456 mg, 1.4 mmol) in toluene
(140 mL) gave, after column chromatography (10% EtOAc in hex-
ane) and recrystallization (CHCl3 and hexane), the title compound
(3R)-20 as a colourless solid with spectroscopic data in accordance
4.4.1. (2R,5R)-5-Methyl-2-phenyl-3-tosyloxazolidin-4-one 14
Using general procedure 4.4—(3R)-3-phenyl-2-tosyl-1,2-oxazir-
idine (3R)-6 (165 mg, 0.6 mmol), 1-oxopropan-2-yl 4-nitroben-
zoate 13 (45 mg, 0.2 mmol), cesium carbonate (71.5 mg,
0.22 mmol), N-heterocyclic carbene precatalyst 11 (8.4 mg,
0.02 mmol) in anhydrous 1,4-dioxane (4 mL) gave, after purifica-
tion by BiotageÒ IsoleraTM 4 [SNAP Ultra 10 g, 36 mL minꢀ1, hexane:
EtOAc (100:0 2 CV, 100:0 to 90:10 10 CV, 90:10 3 CV)], the title
compound 14 (23 mg, 0.088 mmol, 44%) as an off-white crystalline
with the literature27 (1.40 g, 4.77 mmol, 33%); ½a 2D0
ꢂ
= +67.3 (c 1.00,
CHCl3); mp 80–82 °C {Lit. mp unreported}; Chiral HPLC analysis
Chiralpak AS-H (95:5 hexane:i-PrOH, flow rate 1 mL minꢀ1
,
201 nm, 40 °C) tR(S): 6.2 min, tR(R): 9.9 min, 87:13 er; 1H NMR
(400 MHz, CDCl3) dH: 2.50 (3H, s, ArCH3), 5.44 (1H, s, C(3)CH),
7.02–7.10 (2H, m, C(3)Ar(3,5)H), 7.40–7.46 (4H, m, C(3)Ar(2,6)H
+SO2Ar(3,5)H), 7.90–7.95 (2H, m, SO2Ar(2,6)H); 19F{1H} NMR
(376 MHz, CDCl3) dF: ꢀ108.2.
solid. mp 112–115 °C; ½a D20
ꢂ
= +45.2 (c 1.00, CHCl3); Chiral HPLC
analysis, Chiralpak AD-H (95:5 hexane:i-PrOH, flow rate
1.5 mL minꢀ1
, 211 nm, 40 °C) tR(2R,5R): 11.1 min, tR(2S,5S):
21.7 min, >99:1 er; mmax (thin film, CHCl3) 1739 (C@O), 1371
(CAN), 1168 (ArASO2N); 1H NMR (400 MHz, CDCl3) dH: 1.42 (3H,
d, J 6.8, C(5)CH3), 2.41 (3H, s, ArCH3), 4.53 (1H, qd, J 6.8, 1.1, C(5)
H), 6.56 (1H, d, J 1.1, C(2)H), 7.13–7.24 (2H, m, N(3)SO2Ar(3,5)H),
7.38–7.41 (4H, m, C(2)Ar(2,3,5,6)H), 7.47–7.42 (1H, m, C(2)Ar(4)
H), 7.52–7.61 (2H, m, N(3)SO2Ar(2,6)H); 13C NMR (101 MHz, CDCl3)
dC: 17.0 (C(5)CH3), 21.9 (ArCH3), 73.6 (C(5)H), 90.7 (C(2)H), 127.2 (C
(2)ArC(2,6)H), 128.4 (N(3)SO2ArC(2,6)H), 128.8 (C(2)ArC(3,5)H),
129.6 (N(3)SO2ArC(3,5)H), 130.1 (C(2)ArC(4)H), 135.0 (N(3)SO2-
ArC(1)), 136.8 (C(2)ArC(1)), 145.7 (N(3)SO2ArC(4)), 171.1 (C(4)@
O); HRMS (NSI+) C17H18NO4S+ [M+H]+ requires 332.0951, found
332.0952 (+0.3 ppm).
4.3.4. (3R)-2-Tosyl-3-(4-(trifluoromethyl)phenyl)-1,2-oxaziridine
(3R)-21
Using general procedure 4.3—(E)-4-methyl-N-(4-(trifluo-
romethyl)benzylidene)benzenesulfonamide
(1.63 g,
5 mmol),
mCPBA (677%, 1.5 g, 6 mmol), hydroquinidine (163 mg, 0.7 mmol)
in toluene (50 mL) gave, after column chromatography (10% EtOAc
in hexane) and recrystallization (EtOAc and hexane), the title com-
pound (3R)-21 as a colourless solid with spectroscopic data in
accordance with the literature28 (515 mg, 1.5 mmol, 30%); ½a 2D0
ꢂ
=
+7.8 (c 1.00, CHCl3); mp 82–84 °C {Lit.28 87–90 °C}; Chiral HPLC
analysis Chiralpak AS-H (95:5 hexane:i-PrOH, flow rate
1.0 mL minꢀ1
, 201 nm, 40 °C) tR(R): 7.5 min, tR(S): 9.7 min,
78.5:21.5 er; 1H NMR (400 MHz, CDCl3) dH: 2.51 (3H, s ArCH3),
5.51 (1H, s, C(3)CH), 7.42–7.47 (2H, m, SO2Ar(3,5)H), 7.55–7.60
(2H, m, C(3)Ar(2,6)H), 7.62–7.72 (2H, m, C(3)Ar(3,5)H), 7.90–7.95
(2H, m, SO2Ar(2,6)H); 19F{1H} NMR (376 MHz, CDCl3) dF: ꢀ63.0.
4.4.2. (2R,5S)-5-Methyl-2-phenyl-3-tosyloxazolidin-4-one 42
Using general procedure 4.4—(3R)-3-phenyl-2-tosyl-1,2-oxazir-
idine (3R)-6 (165 mg, 0.6 mmol), 1-oxopropan-2-yl 4-nitroben-
zoate 13 (45 mg, 0.2 mmol), cesium carbonate (71.5 mg,
0.22 mmol), N-heterocyclic carbene precatalyst ent-11 (8.4 mg,
0.02 mmol) in anhydrous 1,4-dioxane (4 mL) gave, after purifica-
tion by BiotageÒ IsoleraTM 4 [SNAP Ultra 10 g, 36 mL minꢀ1, hex-
ane:EtOAc (100:0 2 CV, 100:0 to 90:10 10 CV, 90:10 3 CV)], the
title compound 42 as a colourless oil (23 mg, 0.068 mmol, 34%);
4.3.5. (3R)-3-Pentyl-2-tosyl-1,2-oxaziridine (3R)-22
Using general procedure 4.3—(E)-N-hexylidene-4-methylben-
zenesulfonamide (3.61 g, 14.3 mmol), mCPBA (677%, 4.8 g,
16 mmol), hydroquinidine (456 mg, 1.4 mmol) in toluene
(140 mL) gave, after column chromatography (5% EtOAc in hex-
ane), the title compound (3R)-22 as a colourless oil (850 mg,
½
a 2D0
= +42.6 (c 0.50, CHCl3); Chiral HPLC analysis, Chiralpak ID
ꢂ
(95:5 hexane:i-PrOH, flow rate 1.5 mL minꢀ1, 211 nm, 30 °C) tR(2-
S,5R): 20.2 min, tR(2R,5R): 22.4 min, >99:1 er; mmax (thin film,
CHCl3) 1751 (C@O), 1375 (CAN), 1175 (ArASO2N); 1089 (CAO);
1H NMR (500 MHz, CDCl3) dH: 1.48 (3H, d, J 6.7, C(5)CH3), 2.40
(3H, s, ArCH3), 4.49 (1H, qd, J 6.7, 1.3, C(5)H), 6.39 (1H, d, J 1.3, C
(2)HPh), 7.14–7.16 (2H, m, N(3)SO2ArC(3,5)H), 7.29–7.40 (4H, m,
C(2)ArC(2,3,5,6)H), 7.41–7.49 (3H, m, N(3)SO2ArC(2,6)H+C(2)ArC
(4)H); 13C NMR (126 MHz, CDCl3) dC: 17.2 (C(5)CH3), 21.8 (ArCH3),
74.4 (C(5)H), 90.8 (C(2)H), 128.1 (C(2)ArC(3,5)H), 128.4 (N(3)SO2-
ArC(2,6)H), 128.5 (C(2)ArC(2,6)H), 129.6 (N(3)SO2ArC(3,5)H),
130.4 (C(2)ArC(4)H), 135.3 (N(3)SO2ArC(1)), 136.3 (C(2)ArC(1)),
145.5 (N(3)SO2ArC(4)), 170.9 (C(4)@O); HRMS (NSI+) C17H18NO4S+
[M+H]+ requires 332.0951, found 332.0953 (+0.6 ppm).
3.14 mmol, 22%); ½a D20
ꢂ
= +21.5° (c 1.00, CHCl3); Chiral HPLC analy-
sis, Chiralpak OJ-H (99:1 hexane:i-PrOH, flow rate 1.5 mL minꢀ1
,
211 nm, 40 °C) tR(S): 9.8 min, tR(R): 11.2 min, 60.5:39.5 er; mmax
(thin film) 2957 (CAH), 2930 (CAH), 2860 (CAH), 1346 (CAN),
1165 (ArASO2N), 1090 (CAO); 1H NMR (400 MHz, CDCl3) dH: 0.88
(3H, m, CH2CH3), 1.22–1.36 (2H, m, CH2), 1.41–1.53 (4H, m,
2 ꢁ CH2), 1.73–1.88 (2H, m, CH2), 2.47 (3H, s, ArCH3), 4.65 (1H, t,
J 4.9, CH2CHNO), 7.34–7.51 (2H, m, Ar(3,5)H), 7.70–8.06 (2H, m,
Ar(2,6)H); 13C NMR (101 MHz, CDCl3) dC: 13.9 (CH2CH3), 21.8
(ArCH3), 22.4 (CH2), 23.3 (CH2), 30.4 (CH2), 31.3 (CH2), 78.4 (C(3)
H), 129.3 (ArC(2,6)H), 130.0 (ArC(3,5)H), 131.7 (ArC(1)), 146.2
(ArC(4)); HRMS (ESI+) C13H19NO3SNa+ [M+Na]+ requires 292.0978,
found 292.0974 (ꢀ1.3 ppm).
4.4.3. (2R,5R)-2-(3-Fluorophenyl)-5-methyl-3-tosyloxazolidin-
4-one 23
4.4. General procedure for the synthesis of oxazolidin-4-one
Using general procedure 4.4—(3R)-2-tosyl-3-(3-fluorophenyl)-
1,2-oxaziridine (3R)-19 (175.8 mg, 0.6 mmol), 1-oxopropan-2-yl
4-nitrobenzoate 13 (45 mg, 0.2 mmol), cesium carbonate
(71.5 mg, 0.22 mmol), N-heterocyclic carbene precatalyst 11
To a flame-dried round bottom flask containing a stirrer bar and
3 Å molecular sieves were added
a-aroyloxyaldehyde (0.2 mmol),
oxaziridine (0.6 mmol), N-heterocyclic carbene precatalyst
Please cite this article in press as: Kerr, R. W. F.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.10.012

R. W. F. Kerr et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
7
(8.4 mg, 0.02 mmol) in anhydrous 1,4-dioxane (4 mL) gave, after
purification by BiotageÒ IsoleraTM 4 [SNAP Ultra 10 g, 36 mL minꢀ1
hexane:EtOAc (100:0 2 CV, 100:0 to 90:10 10 CV, 90:10 3 CV)], the
CDCl3) dH: 1.42 (3H, d, J 6.8, C(5)HCH3), 2.42 (3H, s, ArCH3), 4.52
(1H, qd, J 6.8, 1.1, C(5)HCH3), 6.56 (1H, s, C(2)HAr), 7.20–7.25
(2H, m, (C(2)Ar(2,6)H), 7.40–7.50 (2H, m, N(3)SO2Ar(3,5)H), 7.54–
7.65 (4H, d, J 6.6, C(2)Ar(3,5)H + N(3)SO2Ar(2,6)H); 13C NMR
(101 MHz, CDCl3) dC: 16.8 (C(5)CH3), 21.7 (ArCH3), 73.6 (C(5)H),
,
title compound 23 as a colourless oil (32 mg, 0.09 mmol, 46%);
½
a 2D0
= +31.5 (c 1.00, CHCl3); Chiral HPLC analysis, Chiralpak AD-H
ꢂ
(95:5 hexane:i-PrOH, flow rate 1.5 mL minꢀ1, 211 nm, 40 °C) tR(2-
R,5R): 11.6 min, tR(2S,5S): 21.6 min, 98.5:1.5 er; mmax (thin film);
1751 (C@O), 1371 (CAN), 1187 (R-SO2N), 1056, (CAO); 1H NMR
(400 MHz, CDCl3) dH: 1.41 (3H, d, J 6.8 C(5)CH3), 2.43 (3H, s, ArCH3),
4.50 (1H, qd, J 6.8, 1.1, C(5)HCH3), 6.51 (1H, d, J 1.1, C(2)HAr), 6.95–
6.98 (1H, m, C(2)Ar(2)H), 7.06–7.18 (2H, m, C(2)Ar(4,5)H), 7.20–
7.30 (2H, m, N(3)SO2Ar(3,5)H), 7.35 (1H, app. td, J 8.0, 5.6, C(2)Ar
(6)H), 7.60–7.66 (2H, m, N(3)SO2Ar(2,6)H); 13C NMR (126 MHz,
CDCl3) dC: 16.9 (C(5)CH3), 21.9 (ArCH3), 73.7 (C(5)H), 89.8 (C(2)
89.6 (C(2)H), 123.7 (q, JCAF 272.5, CF3), 125.7 (q, JCAF 3.8, (C(2)
ArC(3,5)H), 127.5 (C(2)ArC(2,6)H), 128.1 (N(3)SO2ArC(2,6)H),
1
3
2
129.6 (N(3)SO2ArC(3,5)H), 132.1 (q, JCAF 32.6, (C(2)ArC(4)), 134.7
(N(3)SO2ArC(1)), 140.6 (C(2)ArC(1)), 146.0 (N(3)SO2ArC(4)), 170.6
(C(4)@O); 19F{1H} NMR (376 MHz, CDCl3) dF: ꢀ62.8; HRMS (NSI+)
C
18H17F3NO4S+ [M+H]+ requires 400.0825, found 400.0823
(-0.5 ppm).
4.4.6. (2R,5R)-5-Methyl-2-pentyl-3-tosyloxazolidin-4-one 26
Using general procedure 4.4—(3R)-3-pentyl-2-tosyl-1,2-oxazir-
idine (3R)-22 (162 mg, 0.6 mmol), 1-oxopropan-2-yl 4-nitroben-
zoate 13 (45 mg, 0.2 mmol), cesium carbonate (71.5 mg,
0.22 mmol), N-heterocyclic carbene precatalyst 11 (8.4 mg,
0.02 mmol) in anhydrous 1,4-dioxane (4 mL) gave, after purifica-
tion by BiotageÒ IsoleraTM 4 [SNAP Ultra 10 g, 36 mL minꢀ1, hex-
ane:EtOAc (100:0 1 CV, 100:0 to 90:10 20 CV, 90:10 3 CV)], the
title compound 26 as a transparent oil (40 mg, 0.12 mmol, 62%);
2
2
H), 114.1 (d, JCAF 22.6, C(2)ArC(2)H), 177.1 (d, JCAF 21.2, C(2)ArC
(4)H), 122.94 (d, JCAF 3.1, C(2)ArC(6)H), 128.3 (N(3)SO2ArC(2,6)
H), 129.7 (N(3)SO2ArC(3,5)H), 130.5 (d, JCAF 8.1 C(2)ArC(5)H),
134.8 (N(3)SO2ArC(1)), 139.3 (d, JCAF 6.4, C(2)ArC(1)), 146.0 (N
4
3
3
1
(3)SO2ArC(4)H), 162.85 (d, JCAF 248.0, C(2)ArC(3)F), 170.9 (C(4)@
O). 19F{1H} NMR (376 MHz, CDCl3) dF: ꢀ111.8; HRMS (NSI+) C17
-
H
17FNO4S+ [M+H]+ requires 350.0857, found 350.0859 (+0.6 ppm).
4.4.4. (2R,5R)-2-(4-Fluorophenyl)-5-methyl-3-tosyloxazolidin-
4-one 24
½
a 2D0
= +22.4 (c 1.00, CHCl3); Chiral HPLC analysis, Chiralpak AD-
ꢂ
H (98:2 hexane:i-PrOH, flow rate 1 mL minꢀ1, 201 nm, 30 °C) tR(2-
R,5R): 16.2 min, tR(2S,5S): 33.7 min, 94:6 er; mmax (thin film,
CHCl3) 1739 (C@O), 1372 (CAN), 1168 (ArASO2N); 1066 (CAO);
1H NMR (400 MHz, CDCl3) dH: 0.81–1.01 (3H, m, CH2CH3), 1.14–
1.58 (9H, m, 3 ꢁ CH2 + C(5)CH3), 1.75–1.96 (1H, m, C(2)HCHaHb),
1.97–2.14 (1H, m, C(2)HCHaHb), 2.47 (3H, s, ArCH3), 4.39 (1H,
qd, J 6.7, 1.2, C(5)HCH3), 5.66 (1H, ddd, J 7.9, 2.4, 1.2, C(2)
HCH2), 7.33–7.44 (2H, m, ArC(3,5)H), 7.78–8.16 (2H, m, ArC(2,6)
H); 13C NMR (101 MHz, CDCl3) dC: 14.1 (CH2CH3), 17.2 (C(5)
CH3), 21.9 (ArCH3), 22.7 (CH2), 23.6 (CH2), 31.4 (CH2), 35.5 (C(2)
CH2), 73.1 (C(5)H), 90.9 (C(2)H), 128.3 (ArC(2,6)H), 129.9 (ArC
(3,5)H), 135.4 (ArC(1)), 145.8 (ArC(4)CH3), 171.2 (C(4)@O);
Selected data for minor diastereoisomer: 1H NMR (400 MHz,
CDCl3) dH: 4.20 (1H, qd, J 6.7, 0.9, C(5)HCH3), 5.55 (1H, ddd, J
6.5, 2.0, 0.9, C(2)HCH2); 13C NMR (101 MHz, CDCl3) dC: 16.8 (C
(5)CH3), 35.6 (C(2)CH2), 73.7 (C(5)H), 128.3 (N(3)SO2ArC(2,6)H);
HRMS (NSI+) C16H24NO4S+ [M+H]+ requires 326.1421, found
326.1421 (+0.1 ppm).
Using general procedure 4.4—(3R)-2-tosyl-3-(4-fluorophenyl)-
1,2-oxaziridine (3R)-20 (175.8 mg, 0.6 mmol), 1-oxopropan-2-yl
4-nitrobenzoate 13 (45 mg, 0.2 mmol), cesium carbonate
(71.5 mg, 0.22 mmol), N-heterocyclic carbene precatalyst 11
(8.4 mg, 0.02 mmol) in anhydrous 1,4-dioxane (4 mL) gave, after
purification by BiotageÒ IsoleraTM 4 [SNAP Ultra 10 g, 36 mL minꢀ1
,
hexane:EtOAc (100:0 2 CV, 100:0 to 90:10 10 CV, 90:10 3 CV)], the
title compound 24 as a colourless oil (20 mg, 0.06 mmol, 28%);
½
a 2D0
= +24.4 (c 0.50, CHCl3); Chiral HPLC analysis, Chiralpak IC
ꢂ
(80:20 hexane:i-PrOH, flow rate 1.5 mL minꢀ1, 211 nm, 40 °C) tR(2-
R,5R): 6.3 min, tR(2S,5S): 7.5 min, >99:1 er; mmax (thin film, CHCl3)
1749 (C@O), 1371 (CAN), 1229 (CAF), 1172 (R-SO2N), 1088
(CAO); 1H NMR (400 MHz, CDCl3) dH: 1.42 (3H, d, J 6.7, C(5)
HCH3), 2.43 (3H, s, ArCH3), 4.52 (1H, qd, J 6.7, 1.1, C(5)HCH3),
6.52 (1H, d, J 1.1 (C(2)HAr), 7.02–7.06 (2H, app. t, J 8.6, C(2)Ar
(3,5)H), 7.22–7.27 (2H, m, N(3)SO2Ar(3,5)H), 7.28–7.34 (2H, m, C
(2)Ar(2,6)H), 7.57–7.61 (2H, m, N(3)SO2Ar(2,6)H). 13C NMR
(126 MHz, CDCl3) dC: 17.0 (C(5)CH3), 21.9 (ArCH3), 73.6 (C(5)H),
2
90.0 (C(2)H), 115.8 (d, JCAF 21.8, C(2)ArC(3,5)H), 128.3 (N(3)SO2-
ArC(2,6)H), 129.2 (d, JCAF 8.6, C(2)ArC(2,6)H) 129.7 (N(3)SO2ArC
(3,5)H), 132.9 (d, JCAF 3.4, C(2)ArC(1)), 134.9 (N(3)SO2ArC(1)),
4.4.7. (2R,5R)-5-Benzyl-2-phenyl-3-tosyloxazolidin-4-one 33
Using general procedure 4.4—(3R)-3-phenyl-2-tosyl-1,2-oxazir-
idine (3R)-6 (165 mg, 0.6 mmol), 1-oxo-4-phenylbutan-2-yl 4-
nitrobenzoate 27 (55 mg, 0.2 mmol), cesium carbonate (71.5 mg,
0.22 mmol), N-heterocyclic carbene precatalyst 11 (8.4 mg,
0.02 mmol) in anhydrous 1,4-dioxane (4 mL) gave, after purifica-
tion by BiotageÒ IsoleraTM 4 [SNAP Ultra 10 g, 36 mL minꢀ1, hex-
ane:EtOAc (100:0 2 CV, 100:0 to 90:10 10 CV, 90:10 3 CV)], the
title compound 33 as an off-white crystalline solid (36 mg,
3
4
1
145.9 (N(3)SO2ArC(4)CH3), 163.7 (d, JCAF 249.7, C(2)ArC(4)F),
170.9 (C(4)@O). 19F{1H} NMR (376 MHz, CDCl3) dF: ꢀ110.8; HRMS
(NSI+) C17H17FNO4S+ [M+H]+ requires 350.0857, found 350.0859
(+0.6 ppm).
4.4.5. (2R,5R)-5-Methyl-2-(4-trifluoromethylphenyl)-3-tosyloxa-
zolidin-4-one 25
0.088 mmol, 44%); mp 128–131 °C; ½a D20
ꢂ
= +61.2 (c 1.00, CHCl3);
Using general procedure 4.4—(3R)-2-tosyl-3-(4-(trifluo-
romethyl)phenyl)-1,2-oxaziridine (3R)-21 (137 mg, 0.6 mmol),
1-oxopropan-2-yl 4-nitrobenzoate 13 (45 mg, 0.2 mmol), cesium
carbonate (71.5 mg, 0.22 mmol), N-heterocyclic carbene precata-
lyst 11 (8.4 mg, 0.02 mmol) in anhydrous 1,4-dioxane (4 mL) gave,
Chiral HPLC analysis, Chiralcel OD-H (99:1 hexane:i-PrOH, flow
rate 1.5 mL minꢀ1, 201 nm, 40 °C) tR(2S,5S): 33.4 min, tR(2R,5R):
37.0 min, >99:1 er; mmax (thin film, CHCl3) 1751 (C@O), 1375
(CAN), 1175 (ArASO2N); 1H NMR (400 MHz, CDCl3) dH: 2.40 (3H,
s, ArCH3), 3.04 (1H, dd, J 14.5, 6.0, C(5)HCHaHbAr), 3.14 (1H, dd, J
14.5, 4.4, C(5)HCHaHbAr), 4.73 (1H, ddd, J 6.0, 4.4, 1.5, C(5)H),
6.21 (1H, d, J 1.5, C(2)HPh), 7.12–7.27 (9H, m, N(3)SO2Ar(3,5)H
+ C(2)Ar(2,6)H + 5 ꢁ CH2ArH), 7.30–7.35 (2H, m, C(2)Ar(3,5)H),
7.36–7.42 (1H, m, C(2)Ar(4)H), 7.42–48 (2H, m, N(3)SO2Ar(2,6)
H); 13C NMR (101 MHz, CDCl3) dC: 21.8 (ArCH3), 37.8 (C(5)CH2Ph),
78.1 (C(5)H), 91.4 (C(2)H), 127.2 (CH2ArC(4)H), 127.3 (C(2)ArC(2,6)
H), 128.3 (N(3)SO2ArC(2,6)H), 128.6 (C(2)ArC(3,5)H), 128.7 (CH2-
ArC(3,5)H), 129.6 (N(3)SO2ArC(3,5)H), 129.8 (CH2ArC(2,6)H),
after purification by BiotageÒ IsoleraTM
4 [SNAP Ultra 10 g,
36 mL minꢀ1, hexane:EtOAc (100:0 2 CV, 100:0 to 90:10 10 CV,
90:10 3 CV)], the title compound 25 as an off-white crystalline
solid (32 mg, 0.08 mmol, 40%); mp 72–74 °C; ½a D20
ꢂ
= +17.4 (c 1.00,
CHCl3); Chiral HPLC analysis, Chiralcel OD-H (95:5 hexane:i-PrOH,
flow rate 1.5 mL minꢀ1, 201 nm, 40 °C) tR(2S,5S): 5.3 min, tR(2-
R,5R): 6.0 min, 97.5:2.5 er; mmax (thin film, CHCl3) 1753 (C@O),
1371 (CAN) 1188 (R-SO2N), 1066 (CAO); 1H NMR (400 MHz,
Please cite this article in press as: Kerr, R. W. F.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.10.012

8
R. W. F. Kerr et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
130.1 (C(2)ArC(4)H), 134.9 (N(3)SO2ArC(1)), 135.2 (CH2ArC(1)),
137.0 (C(2)ArC(1)), 145.5 (N(3)SO2ArC(4)), 169.8 (C(4)@O); HRMS
(APCI) C23H22NO4S [M+H] requires 408.1270, found 408.1272
(+0.5 ppm).
ArC(4)), 169.7 (C(4)@O); HRMS (NSI+) C24H22NO6S+ [M+H]+
requires 452.1162, found 452.1162 (ꢀ0.1 ppm).
4.4.10. (2R,5R)-5-Butyl-2-phenyl-3-tosyloxazolidin-4-one 36
Using general procedure 4.4—(3R)-3-phenyl-2-tosyl-1,2-oxazir-
idine (3R)-6 (165 mg, 0.6 mmol), 1-oxohexan-2-yl 4-nitrobenzoate
30 (55 mg, 0.2 mmol), cesium carbonate (71.5 mg, 0.22 mmol),
N-heterocyclic carbene precatalyst 11 (8.4 mg, 0.02 mmol) in
anhydrous 1,4-dioxane (4 mL) gave, after purification by BiotageÒ
IsoleraTM 4 [SNAP Ultra 10 g, 36 mL minꢀ1, hexane:EtOAc (100:0 1
CV, 100:0 to 80:20 20 CV, 80:20 3 CV)], the title compound 36 as
4.4.8. (2R,5R)-5-(4-Methoxybenzyl)-2-phenyl-3-tosyloxazolidin-
4-one 34
Using general procedure 4.4—(3R)-3-phenyl-2-tosyl-1,2-oxazir-
idine (3R)-6 (165 mg, 0.6 mmol), 1-(4-methoxyphenyl)-3-oxo-
propan-2-yl 4-nitrobenzoate 28 (66 mg, 0.2 mmol), cesium
carbonate (71.5 mg, 0.22 mmol), N-heterocyclic carbene precata-
lyst 11 (8.4 mg, 0.02 mmol) in anhydrous 1,4-dioxane (4 mL) gave,
a transparent oil (12 mg, 0.03 mmol, 16%); ½a D20
ꢂ
= +51.4 (c 0.50,
CHCl3); Chiral HPLC analysis, Chiralpak IC (80:20 hexane:i-PrOH,
flow rate 1.5 mL minꢀ1, 211 nm, 40 °C) tR(2R,5R): 6.2 min, tR(2-
S,5S): 6.6 min, >99:1 er; mmax (thin film, CHCl3) 1749 (C@O), 1373
(CAN), 1172 (R-SO2N), 1090 (CAO); 1H NMR (400 MHz, CDCl3)
dH: 0.86 (3H, t, J 7.1, CH2CH3), 1.20–1.34 (3H, m, C(5)HCH2CHaHb-
CH2CH3), 1.33–1.48 (1H, m, C(5)HCH2CHaHb), 1.65–1.76 (1H, m, C
(5)HCHaHb), 1.76–1.91 (1H, m, C(5)HCHaHb), 2.41 (3H, s, ArCH3),
4.46 (1H, ddd, J 7.1, 4.4, 1.3, C(5)HCH2), 6.52 (1H, d, J 1.3, C(2)H),
7.17–7.23 (2H, m N(3)SO2ArC(3,5)H), 7.29–7.38 (4H, m, C(2)ArC
(2,6)H + C(2)ArC(3,5)H), 7.37–7.47 (1H, m, C(2)ArC(4)H), 7.52–
7.58 (2H, m, N(3)SO2ArC(2,6)H); 13C NMR (126 MHz, CDCl3) dC:
14.0 ((CH2)3CH3), 21.8 (ArCH3), 22.5 (C(5)HCH2CH2CH2CH3), 26.6
(C(5)HCH2CH2CH2CH3), 31.4 (C(5)HCH2CH2CH2CH3), 77.4 (C(5)H),
91.1 (C(2)H), 127.2 (C(2)ArC(2,6)H), 128.3 (N(3)SO2ArC(2,6)H),
128.8 (C(2)ArC(3,5)H), 129.6 (N(3)SO2ArC(3,5)H), 130.1 (C(2)ArC
(4)H), 135.0 (N(3)SO2ArC(1)), 137.1 (C(2)ArC(1)), 145.7 (N(3)SO2-
ArC(4)), 170.8 (C(4)@O); HRMS (NSI+) C20H24NO4S+ [M+H]+
requires 374.1421, found 374.1422 (+0.4 ppm).
after purification by BiotageÒ IsoleraTM
4 [SNAP Ultra 10 g,
36 mL minꢀ1, hexane:EtOAc (100:0 1 CV, 100:0 to 85:15 20 CV,
85:15 3 CV)], the title compound 34 as a transparent oil (21 mg,
0.05 mmol, 24%). ½a D20
ꢂ
= +60.6 (c 1.00, CHCl3); Chiral HPLC analysis,
Chiralpak IC (80:20 hexane:i-PrOH, flow rate 1.5 mL minꢀ1
,
211 nm, 40 °C) tR(2R,5R): 10.1 min, tR(2S,5S): 13.7 min, 99:1 er;
mmax (thin film) 1749 (C@O), 1371 (CAN), 1173 (R-SO2N), 1090
(CAO); 1H NMR (500 MHz, CDCl3) dH: 2.41 (3H, s, ArCH3), 3.00
(1H, dd, J 14.7, 5.6, C(5)HCHaHbAr), 3.08 (1H, dd, J 14.7, 4.4, C(5)
HCHaHbAr), 3.80 (3H, s, OCH3), 4.70 (1H, ddd, J 5.6, 4.4, 1.3, C(5)
HCHaHbAr), 6.22 (1H, d, J 1.3, C(2)HPh), 6.76–6.77 (2H, m, CH2ArC
(3,5)H), 7.08–7.13 (2H, d, J 8.6, CH2ArC(2,6)H), 7.13–7.18 (1H, m,
N(3)SO2ArC(3,5)H), 7.23–7.30 (2H, m, C(2)ArC(2,6)H), 7.30–7.35
(2H, m, C(2)ArC(3,5)H), 7.36–7.42 (1H, m, C(2)ArC(4)H), 7.42–
7.46 (2H, m, N(3)SO2ArC(2,6)H); 13C NMR (126 MHz, CDCl3) dC:
21.9 (ArCH3), 36.9 (C(5)CH2), 55.3 (ArOCH3), 78.2 (C(5)H), 91.4 (C
(2)H), 114.0 (CH2ArC(3,5)H), 127.0 (CH2ArC(1)), 127.3 (C(2)ArC
(2,6)H), 128.3 (N(3)SO2ArC(2,6)H), 128.7 (C(2)ArC(3,5)H), 129.5
(N(3)SO2ArC(3,5)H), 130.1 (C(2)ArC(4)H), 130.9 (CH2ArC(2,6)H),
134.9 (N(3)SO2ArC(1)), 137.1 (C(2)ArC(1)), 145.5 (N(3)SO2ArC(4)),
158.8 (CH2ArC(4)), 169.9 (C(4)@O); HRMS (NSI+) C24H24NO5S+ [M
+H]+ requires 438.1370, found 438.1369 (ꢀ0.2 ppm).
4.4.11. (2R,5R)-5-(2-(Benzyloxy)ethyl)-2-phenyl-3-tosyloxazolidin-
4-one 37
Using general procedure 4.4—(3R)-3-phenyl-2-tosyl-1,2-oxazir-
idine (3R)-6 (165 mg, 0.6 mmol), 4-(benzyloxy)-1-oxobutan-2-yl
4-nitrobenzoate 31 (69 mg, 0.2 mmol), cesium carbonate
(71.5 mg, 0.22 mmol), N-heterocyclic carbene precatalyst 11
(8.4 mg, 0.02 mmol) in anhydrous 1,4-dioxane (4 mL) gave, after
4.4.9. (2R,5R)-5-(Benzo[d][1,3]dioxol-5-ylmethyl)-2-phenyl-3-
tosyloxazolidin-4-one 35
purification by BiotageÒ IsoleraTM 4 [SNAP Ultra 10 g, 36 mL minꢀ1
,
Using general procedure 4.4—(3R)-3-phenyl-2-tosyl-1,2-
oxaziridine (3R)-6 (165 mg, 0.6 mmol), 1-(benzo[d][1,3]dioxol-5-
yl)-3-oxopropan-2-yl 4-nitrobenzoate 29 (69 mg, 0.2 mmol),
cesium carbonate (71.5 mg, 0.22 mmol), N-heterocyclic carbene
precatalyst 11 (8.4 mg, 0.02 mmol) in anhydrous 1,4-dioxane
(4 mL) gave, after purification by BiotageÒ IsoleraTM 4 [SNAP Ultra
10 g, 36 mL minꢀ1, hexane:EtOAc (100:0 1 CV, 100:0 to 93:7 20
CV, 93:7 5 CV, 93:7 to 90:10 12 CV)] to give the title compound
hexane:EtOAc (100:0 1 CV, 100:0 to 80:20 20 CV, 80:20 3 CV)] to
give the title compound 37 as a transparent oil (13 mg, 0.03 mmol,
14%). ½a 2D0
ꢂ
= +47.6 (c 1.00, CHCl3); Chiral HPLC analysis, Chiralpak
IC (80:20 hexane:i-PrOH, flow rate 1.5 mL minꢀ1, 211 nm, 40 °C)
tR(2R,5R): 10.1 min, tR(2S,5S): 12.4 min, >99:1 er; mmax (thin film)
1751 (C@O), 1371 (CAN), 1173 (R-SO2N), 1088 (CAO); 1H NMR
(400 MHz, CDCl3) dH: 2.02 (1H, dddd, J 14.5, 7.4, 6.4, 5.3, C(5)HCHa-
HbCH2OBn), 2.15 (1H, dddd, J 14.5, 7.2, 5.6, 4.6, C(5)HCHaHbCH2),
2.39 (3H, s, ArCH3), 3.52–3.70 (2H, m, CH2OBn), 4.45 (2H, s, OCH2-
Ph), 4.65 (1H, ddd, J 7.4, 4.6, 1.3, C(5)H), 6.50 (1H, d, J 1.3, C(2)H),
7.15–7.21 (2H, m, N(3)SO2ArC(3,5)H), 7.23–7.38 (9H, m, ArH),
7.39–7.47 (1H, m, ArH), 7.50–7.56 (2H, m, N(3)SO2ArC(2,6)H); 13C
NMR (101 MHz, CDCl3) dC: 21.8 (ArCH3), 31.8 (C(5)CH2), 65.0 (CH2-
OBn), 73.1 (OCH2Ph), 74.6 (C(5)H), 91.2 (C(2)H), 127.3 (C(2)ArC
(2,6)H), 127.8 (OCH2ArC(4)H), 127.9 (OCH2ArC(2,6)H), 128.3 (N
(3)SO2ArC(2,6)H), 128.5 (OCH2ArC(3,5)H), 128.8 (C(2)ArC(3,5)H),
129.6 (N(3)SO2ArC(3,5)H), 130.1 (C(2)ArC(4)H), 135.0 (N(3)SO2-
ArC(1)), 137.0 (C(4)ArC(1)), 138.2 (OCH2ArC(1)), 145.6 (N(3)SO2-
ArC(4)), 170.7 (C(4)@O); HRMS (NSI+) C25H26NO5S+ [M+H]+
requires 452.1532, found 452.1531 (ꢀ0.2 ppm).
35 as a transparent oil (22 mg, 0.05 mmol, 24%); ½a D20
ꢂ
= +124.0 (c
0.5, CHCl3); Chiral HPLC analysis, Chiralcel OD-H (95:5 hexane:i-
PrOH, flow rate 1.5 mL minꢀ1, 201 nm, 40 °C) tR(2S,5S): 16.1 min,
tR(2R,5R): 18.0 min, >99:1 er; mmax (thin film, CHCl3) 1749 (C@O),
1369 (CAN), 1173 (R-SO2N), 1090 (CAO); 1H NMR (500 MHz,
CDCl3) dH: 2.41 (3H, s, ArCH3), 2.96 (1H, dd, J 14.7, 5.8, C(5)HCHaHb-
Ar), 3.06 (1H, dd, J 14.7, 4.3, C(5)HCHaHbAr), 4.68 (1H, ddd, J 5.8,
4.3, 1.4, C(5)HCHaHbAr), 5.92–5.95 (2H, m, ArOCHaHbOAr), 6.29
(1H, d, J 1.4, C(2)HPh), 6.65 (1H, dd, J 7.9, 1.7, C(5)CH2Ar(6)H),
6.67 (1H, d, J 7.9, C(5)CH2Ar(5)H), 6.70 (1H, d, J 1.7, C(5)CH2Ar(2)
H), 7.13–7.19 (2H, m, N(3)SO2Ar(3,5)H), 7.27–7.31 (2H, m, C(2)Ar
(2,6)H), 7.31–7.36 (2H, m, C(2)Ar(3,5)H), 7.37–7.42 (1H, m, C(2)
Ar(4)H), 7.44–7.51 (2H, m, N(3)SO2Ar(2,6)H); 13C NMR (126 MHz,
CDCl3) dC: 21.9 (ArCH3), 37.4 (C(5)CH2Ar), 78.1 (C(5)H), 91.3 (C(2)
H), 101.0 (ArOCOAr), 108.4 (CH2ArC(5)H), 110.1 (CH2ArC(1)),
110.3 (CH2ArC(2)H), 123.0 (CH2ArC(6)H), 127.3 (C(2)ArC(2,6)H),
128.3 (N(3)SO2ArC(2,6)H), 128.7 (CH2ArC(3)), 128.8 (C(2)ArC(3,5)
H), 129.5 (N(3)SO2ArC(3,5)H), 129.5 (CH2ArC(4)), 130.1 (C(2)ArC
(4)H), 134.9 (N(3)SO2ArC(1)), 137.1 (C(2)ArC(1)), 145.6 (N(3)SO2-
4.4.12. 2-(2-((2R,5R)-4-Oxo-2-phenyl-3-tosyloxazolidin-5-yl)
ethyl)isoindoline-1,3-dione 38
Using general procedure 4.4—(3R)-3-phenyl-2-tosyl-1,2-oxazir-
idine (3R)-6 (165 mg, 0.6 mmol), 4-(1,3-dioxoisoindolin-2-yl)-
1-oxobutan-2-yl 4-nitrobenzoate 32 (76 mg, 0.2 mmol), cesium
Please cite this article in press as: Kerr, R. W. F.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.10.012

R. W. F. Kerr et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
9
carbonate (71.5 mg, 0.22 mmol), N-heterocyclic carbene precata-
lyst 11 (8.4 mg, 0.02 mmol) in anhydrous 1,4-dioxane (4 mL) gave,
Acknowledgments
after purification by BiotageÒ IsoleraTM
4 [SNAP Ultra 10 g,
We thank the EPSRC Centre for Doctoral Training in Critical
Resource Catalysis (CRITICAT, grant code EP/L016419/1) (R.W.F.
K.) for funding. The European Research Council under the European
Union’s Seventh Framework Programme (FP7/2007–2013) ERC
Grant Agreement No. 279850 is also acknowledged. A.D.S. thanks
the Royal Society for a Wolfson Research Merit Award. We also
thank the EPSRC UK National Mass Spectrometry Facility at Swan-
sea University.
36 mL minꢀ1, hexane:EtOAc (90:10 1 CV, 90:10 to 75:25 15 CV,
75:25 6 CV)], the title compound 38 as a transparent oil (24 mg,
0.05 mmol, 24%). ½a D20
ꢂ
= +31.0 (c 1.00, CHCl3); Chiral HPLC analysis,
Chiralpak IB (90:10 hexane:i-PrOH, flow rate 1 mL minꢀ1, 211 nm,
40 °C) tR(2S,5S): 31.9 min, tR(2R,5R): 42.0 min, >99:1 er; mmax (thin
film, CHCl3) 1749 (C@O), 1712 (C@O), 1373 (CAN), 1175 (R-SO2N),
1090 (CAO); 1H NMR (400 MHz, CDCl3) dH: 2.07–2.26 (2H, m, C(5)
CH2), 2.39 (3H, s, ArCH3), 3.68–3.80 (1H, m, NCHaHb), 3.83–3.95
(1H, m, NCHaHb), 4.53 (1H, ddd, J 7.6, 4.2, 1.2, C(5)H), 6.53 (1H, d,
J 1.2, C(2)HPh), 7.15–7.21 (2H, m, N(3)SO2ArC(3,5)H), 7.22–7.27
(2H, m, C(2)ArC(2,6)H), 7.28–7.39 (2H, m, C(2)ArC(3,5)H), 7.37–
7.43 (1H, m, C(2)ArC(4)H), 7.51–7.57 (2H, m, N(3)SO2ArC(2,6)H),
7.70 (2H, m, PhthC(5,6)H), 7.82 (2H, m, PhthC(4,7)H); 13C NMR
(101 MHz, CDCl3) dC: 21.8 (C(5)CH2), 30.2 (ArCH3), 34.1 (CH2N),
75.4 (C(5)H), 91.1 (C(2)H), 123.5 (PhthC(4,7)H), 127.1 (C(2)ArC
(2,6)H), 128.8 (N(3)SO2ArC(2,6)H), 128.8 (C(2)ArC(3,5)H), 129.6
(N(3)SO2ArC(3,5)H), 130.1 (C(2)ArC(4)H), 132.2 (PhthC(3a,7a)),
134.1 (PhthC(5,6)H), 134.8 (N(3)SO2ArC(1)), 136.7 (C(2)ArC(1)),
145.7 (N(3)SO2ArC(4)), 168.3 (PhthC(1,3)@O), 169.6 (C(4)@O);
HRMS (NSI+) C26H26N3O6S+ [M+NH4]+ requires 508.1537, found
508.1529 (ꢀ1.5 ppm).
A. Supplementary data30
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetasy.2016.10.
012.
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0.12 mmol, 20%). ½a D20
ꢂ
= +35.0 (c 0.20, CHCl3); Chiral HPLC analysis,
Chiralcel OD-H (98:2 hexane:i-PrOH, flow rate 1.5 mL minꢀ1
,
201 nm, 40 °C) tR(2R,9bS): 24.6 min, tR(2S,9bR): 53.9 min, 88:12
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s, C(9b)CH3), 4.74 (1H, q, J 6.8, C(2)HCH3), 7.62 (1H, app. d, J 7.8,
C(9)H), 7.67 (1H, app. td, J 7.7, 1.0, C(7)H), 7.73–7.82 (2H, m, C
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(9b)CH3), 75.5 (C(2)H), 96.1 (C(9b)), 121.8 (ArC(6)H), 123.6 (ArC
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4.4.14. (2R,5R)-5-Methyl-2-phenyloxazolidin-4-one 41
Anhydrous THF was sparged with argon for 30 mins, and then
1.3 mL transferred to
a flame-dried Schlenk flask containing
(2R,5R)-5-methyl-2-phenyl-3-tosyloxazolidin-4-one 14 (43 mg,
0.13 mmol). The flask was cooled to ꢀ78 °C and SmI2 (2.6 mL,
ꢄ0.1 M in anhydrous THF, 0.26 mmol, 2 equiv) was added drop-
wise. The blue solution was warmed to rt and monitored by TLC.
After 15 min the solution turned yellow and the reaction was
diluted with EtOAc (20 mL) and washed with aq satd NH4Cl
(20 mL) and brine (20 mL). The organic fraction was dried (MgSO4),
filtered and concentrated under vacuum to give the title compound
41 as a colourless oil in accordance with literature29 (13 mg,
0.07 mmol, 57%); ½a D20
= ꢀ6.8 (c 1.00, CHCl3); Chiral HPLC analysis,
ꢂ
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qd, J 6.8, 2.1, C(5)H), 6.45 (1H, d, J 2.1, C(2)H), 7.10 (1H, br. s, N
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Please cite this article in press as: Kerr, R. W. F.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.10.012

10
R. W. F. Kerr et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
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50:50 er), 4-Br-C6H4 (48%, 52:48 er), 1-napthyl (0%), 2-naphthyl (5%, 50:50 er),
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Please cite this article in press as: Kerr, R. W. F.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.10.012