Asymmetric Isothiourea-Catalysed Formal [3+2] Cycloadditions of Ammonium Enolates with Oxaziridines

Article abstract of DOI:10.1002/chem.201501271

A highly enantioselective Lewis base-catalysed formal [3+2] cycloaddition of ammonium enolates and oxaziridines to give stereodefined oxazolidin-4-ones in high yield is described. Employing an enantioenriched oxaziridine in this process leads to a matched/mis-matched effect with the isothiourea catalyst and allowed the synthesis of either syn- or anti-stereodefined oxazolidin-4-ones in high d.r., yield and ee. Additionally, the oxazolidin-4-one products have been derivatised to afford functionalised enantioenriched building blocks.

Full text of DOI:10.1002/chem.201501271

DOI: 10.1002/chem.201501271
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&
Organic Chemistry
Asymmetric Isothiourea-Catalysed Formal [3+2] Cycloadditions of
Ammonium Enolates with Oxaziridines
Siobhan R. Smith, Charlene Fallan, James E. Taylor, Ross McLennan, David S. B. Daniels,
Louis C. Morrill, Alexandra M. Z. Slawin, and Andrew D. Smith*[a]
Abstract: A highly enantioselective Lewis base-catalysed
formal [3+2] cycloaddition of ammonium enolates and oxa-
ziridines to give stereodefined oxazolidin-4-ones in high
yield is described. Employing an enantioenriched oxaziridine
in this process leads to a matched/mis-matched effect with
the isothiourea catalyst and allowed the synthesis of either
syn- or anti-stereodefined oxazolidin-4-ones in high d.r.,
yield and ee. Additionally, the oxazolidin-4-one products
have been derivatised to afford functionalised enantioen-
riched building blocks.
Introduction
The ubiquitous use of heterocycles in the pharmaceutical,
agrochemical as well as in the dye and fine-chemical industries
has led to the establishment of numerous strategies for their
synthesis and functionalisation.[1] Stereodefined heterocycles
are also significant components of numerous biologically
active natural products.[2] As a result of the widespread preva-
lence of heterocyclic motifs in synthetic chemistry,[3] alongside
the continued drive for efficient, selective synthetic protocols
within the chemical community, there is an ongoing require-
ment for novel asymmetric syntheses of heterocyclic scaffolds.
Oxazolidin-4-ones represent a unique heterocyclic structural
motif found within natural products and bioactive molecules.
For example, the oxazolidin-4-one core is found in the natural
products synoxazolidinone A and B which were isolated from
S. pulmonaria and exhibit antibiotic and antifungal activity at
low concentrations (Figure 1).[4] In addition, oxazolidin-4-ones
are found in lipoxazolidinones A, B, and C isolated from
a marine actinomycete strain.[5] These naturally occurring oxa-
zolidin-4-ones also exhibit antibacterial activity comparable
with the commercial antibacterial agent Linezolid (Zyvox) that
contains a structurally related oxazolidin-2-one core.[6] There-
fore, the development of a synthetic strategy for the asymmet-
ric generation of heterocyclic scaffolds of this type is a worth-
while goal. In this manuscript, we describe an isothiourea-cata-
Figure 1. Biologically active natural products and medicinal agents based
upon the oxazolidinone core.
lysed formal [3+2] cycloaddition using both racemic and enan-
tioenriched oxaziridines[7] to form stereodefined oxazolidin-4-
ones.
Building on Birman and Okamoto’s introduction of isothiour-
ea catalysts for kinetic resolutions[8] we have recently estab-
lished, alongside Romo,[9] isothiourea Lewis base catalysis[10] for
the preparation of a range of synthetically relevant heterocyclic
scaffolds. Substituted THFs,[11] dihydrobenzofurans and pyrroli-
dines[12] have been accessed by an asymmetric intramolecular
Michael addition/lactonisation process. In addition, stereode-
fined anti-d-lactams[13] and dihydropyranones[14] were obtained
by related intermolecular Michael addition/cyclisation proto-
cols. This methodology was extended using a strategic PhSH
elimination as part of a cascade process for the synthesis of
substituted pyrones[15] and functionalised pyridines.[16] Addi-
tionally, asymmetric formal [2+2] cycloadditions employing N-
sulfonyl imines to form anti-b-lactams have been studied.[17]
However, to date, formal [3+2] cycloaddition processes cata-
lysed by isothioureas have not been developed.[18]
[a] S. R. Smith, Dr. C. Fallan, Dr. J. E. Taylor, R. McLennan, Dr. D. S. B. Daniels,
Dr. L. C. Morrill, Prof. A. M. Z. Slawin, Prof. A. D. Smith
EaStCHEM, School of Chemistry, University of St Andrews
North Haugh, St Andrews, KY16 9ST (UK)
E-mail: ads10@st.andrews.ac.uk
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201501271.
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
This is an open access article under the terms of the Creative Commons At-
tribution License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited.
Oxaziridines have previously been reported as electrophiles
for the synthesis of oxazolidin-4-ones by Ye and co-workers
Chem. Eur. J. 2015, 21, 10530 – 10536
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Results and Discussion
Optimisation
Our investigation began with the Lewis base-catalysed reaction
of commercially available phenylacetic acid 4 with racemic ox-
aziridine 5 (Table 1, conditions A). Treatment of the acid with
pivaloyl chloride and iPr2NEt to form a mixed anhydride in situ
followed by addition of (2S,3R)-HyperBTM 3[21] and oxaziridine
5 gave high conversion into the desired [3+2] oxazolidin-4-
one product 6, with a small amount of imine 14 and b-lactam
15 (derived from a previously disclosed[17] intramolecular
formal [2+2] cycloaddition of an ammonium enolate and
imine 14) also observed by 1H NMR spectroscopy (Table 1,
entry 1). However, imine 14 was difficult to remove from the
desired product by column chromatography, resulting in con-
taminated oxazolidin-4-ones. To probe the origin of imine 14,
control experiments demonstrated that treating oxaziridine 5
in CH2Cl2 with iPr2NEt (1 equiv) led to the formation of
iPr2(Et)N-oxide and imine 14. To prevent this undesired imine
formation through oxidation of the base a number of alterna-
tive bases was examined. Disappointingly, 2,6-lutidine and
Cs2CO3 gave comparable amounts of imine 14 (entries 2 and
3). In the reaction with Cs2CO3 (entry 3), imine formation is pre-
sumably derived from reaction of oxaziridine 5 with chloride
ions[7b] generated from the reaction of phenylacetic acid 4 with
pivaloyl chloride to form the “activated” mixed anhydride. To
overcome this problem and remove the need for an activation
Scheme 1. Formal [3+2] intermolecular cycloadditions for the synthesis of
oxazolidin-4-ones catalysed by a) NHC precatalyst 1; b) bisguanidinium salt
2; c) HyperBTM 3.
Table 1. Reaction optimisation and oxaziridine scope.
using ketenes in the presence of
either N-heterocyclic carbene
(NHC) precatalyst 1 or cinchona
alkaloids.[19] The a,a-disubstitut-
ed oxazolidin-4-ones were isolat-
ed in good yield and with high
diastereo- and enantioselectivity
(Scheme 1a), although this pro-
cess is somewhat limited due to
the use of synthetically challeng-
ing ketenes and their precursors.
More recently, Feng described
chiral bisguanidinium salt 2 for
the asymmetric oxyamination of
azlactones with concurrent ki-
netic resolution of the oxaziri-
dine (Scheme 1b).[20] Building
upon these precedents, herein
we report our results on the iso-
[b]
Entry
Oxaziridine
Product
Base
Yield [%][a]
d.r.anti/syn
eeanti/syn [%][c]
Imine 14 [%]
1[d]
2[d]
3[d]
4[e]
5[e]
6[e]
7[e]
5
5
5
5
8
9
10
6
6
6
6
11
12
13
iPr2NEt
2,6-lutidine
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
64
57
72
83
78
82
73
82:18
75:25
61:39
57:43
55:45
55:45
59:41
>99:>99
–
6
8
9
–
–
–
–
thiourea-catalysed
asymmetric
formal [3+2] cycloaddition of
homoanhydrides and oxaziri-
dines to form stereodefined oxa-
zolidin-4-ones (Scheme 1c) and
their subsequent derivatisations.
–
97:97
78:78
99:95
85:80
[a] Combined isolated yield of both diastereoisomers. [b] Determined by 1H NMR spectroscopic analysis of the
crude reaction product. [c] Determined by HPLC analysis. [d] Conditions A. [e] Conditions B.
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step, homoanhydride[22] 7 was used in place of phenylacetic
acid and assessed under similar reaction conditions (Table 1,
conditions B). Pleasingly, this alternative ammonium enolate
precursor resulted in formation of oxazolidin-4-one 6 exclusive-
ly in high yield with excellent enantiocontrol, however lower
levels of diastereoselectivity were obtained (entry 4). The oxa-
zolidin-4-one diastereomeric mixture 6a and 6b was reduced
using LiAlH4 to give diol 16 in good yield maintaining stereoin-
tegrity (Scheme 2),[23] confirming that the configuration at C(5)
ing substituents in the ortho-, meta- and para-position also
participated well under the previously optimised reaction con-
ditions giving oxazolidin-4-ones 19–22 in good yields again
with excellent levels of ee for both diastereoisomers. 3-Thio-
phenylacetic anhydride led to isolation of oxazolidin-4-one 23
in 79% yield but lower levels of ee were obtained for both the
syn- and anti-diastereoisomer (87 and 81%, respectively). Pleas-
ingly, the reaction was extended beyond aromatic substitution
patterns to include alkenyl oxazolidin-4-one 24, obtained in
good yield and high ee (syn- and anti-diastereoisomer). Unex-
pectedly, p-trifluoromethyl substitution gave oxazolidin-4-one
25 in 49:51 d.r.anti/syn, with both diastereoisomers formed with
low levels of enantioselectivity (43% eeanti, 36% eesyn).
Whilst these results are synthetically relevant, their utility for
the synthesis of oxazolidin-4-ones is partially limited due to
the diastereomeric mixtures of heterocycles obtained. Al-
though this methodology is applicable to the synthesis of
enantioenriched diols (Scheme 2), further investigations sought
to investigate the cause of low diastereocontrol in this process
allowing selective access to either syn and anti diastereoiso-
mers. The conversion of (Æ)-oxaziridine 5 into product 6 under
the standard reaction conditions was monitored over time by
1H NMR spectroscopy and the ee of unreacted oxaziridine 5
and oxazolidin-4-one 6 was analysed by chiral HPLC analysis
(Table 3). Notably, over the early part of the reaction the d.r. of
6 remains fairly constant with the initial d.r. of 78:22 anti/syn at
1 min, reducing to 71:29 after 4 h at À788C. The ee of both
Scheme 2. LiAlH4 reduction of oxazolidin-4-one 6.
is equivalent in both the syn- and anti-diastereomers formed.
The absolute configuration was determined by comparison of
the specific rotation of diol 16 with literature values (see the
Supporting Information for details). To assess the effect of the
oxaziridine on the stereochemical outcome of the process, al-
ternative oxaziridines were investigated using phenylacetic an-
hydride 7 as the standard ammonium enolate precursor (en-
tries 5–7). Aromatic halogen substitution in the ortho- and
para-position was examined under the optimised conditions
and led to high yields of the de-
sired [3+2] products 11 and 12,
both in approximately 55:45 d.r.
Table 2. Investigation of homoanhydride substrate scope.
but with slightly reduced levels
of enantiocontrol for both dia-
stereoisomers. Gratifyingly, the
scope of the process could be
extended with regards to the N-
substituent. Replacing the N-
tosyl group with an N-nosyl led
to the formation of oxazolidin-4-
one 13 in high yield, however
slightly reduced ee values were
obtained for the syn- and anti-
products.
Products
Yield [%][a]
d.r.anti/syn
eeanti/eesyn [%][c]
Products
Yield [%][a]
d.r.anti/syn
eeanti/eesyn [%][c]
[b]
[b]
83
57:43
97:97
73
54:46
99:99
These reaction conditions
were next applied to a range of
homoanhydrides to assess the
scope of the reaction (Table 2).
Anhydrides with both electron-
withdrawing and -donating aro-
matic substituents were tolerat-
ed, giving a range of oxazolidin-
4-ones in high yields with ap-
proximately 50:50 d.r., but with
excellent levels of enantiocontrol
observed for each diastereoiso-
mer 6, 17 and 18 (up to
99% ee). Extended aromatic sys-
tems and aromatic groups bear-
89
55:45
97:94
48
53:47
99:99
88
53:47
97:99
79
59:41
92:94
96
53:47
99:99
79
59:41
87:81
61
54:46
99:99
68
49:51
43:36
[a] Combined isolated yield of both diastereoisomers. [b] Determined by 1H NMR spectroscopic analysis of the
crude reaction product. [c] Determined by HPLC analysis.
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1H NMR spectroscopic analysis) equating to a selectivity factor
S=4.[25]
Table 3. Investigation of enantio- and diastereoselectivity over time.
In light of these results, it was reasoned that using an enan-
tiomerically pure oxaziridine would lead to the formation of
a single diastereoisomer of the corresponding oxazolidin-4-one
product through complete chirality transfer. To assess this,
enantioenriched oxaziridine (R,R)-5 was accessed in 94% ee
(following a single recrystallisation) using a modified procedure
developed by Jørgensen and co-workers (Scheme 4).[26]
[b]
t
Conv.[a] [%]
d.r.anti/syn
6 eeanti/eesyn
[%][c]
5 ee
[%][c]
1 min
5 min
15 min
30 min
60 min
120 min
240 min
18 h
9
24
25
26
26
30
52
91
78:22
75:25
70:30
74:26
75:25
75:25
71:29
59:41
>99:99
>99:99
>99:99
>99:99
>99:99
>99:99
>99:99
>99:99
7
10
11
12
13
17
41
–
Scheme 4. Synthesis of enantioenriched oxaziridine (R,R)-5. m-CPBA=meta-
chloroperbenzoic acid.
[a] Determined by 1H NMR spectroscopic analysis. [b] Determined by
1H NMR spectroscopic analysis of the crude reaction product. [c] Deter-
mined by HPLC analysis.
Pleasingly, using enantioenriched oxaziridine (R,R)-5 with
phenylacetic anhydride 7 and (2S,3R)-HyperBTM 3 (Scheme 5a)
gave anti-oxazolidin-4-one 6a in high yield, ee and excellent
d.r. (93:7, anti/syn). This matched case arises from the ammoni-
um enolate generated with homoanhydride 7 and (2S,3R)-Hy-
perBTM 3 reacting with (R,R)-5 with excellent stereocontrol.
Using enantiomeric catalyst (2R,3S)-HyperBTM ent-3, low reac-
tivity and reduced isolated yields were observed at À788C.
However, performing the reaction at 08C allowed the desired
syn-oxazolidin-4-one 6b to be isolated in 95% yield and
80:20 d.r. (syn/anti), with the major syn product formed in ex-
cellent ee (98%) (Scheme 5b). This again suggests complete
chirality transfer from the oxaziridine with the configuration at
C(5) determined by the catalyst. In the mis-matched case the
minor anti-oxazolidin-4-one product was isolated in reduced ee
diastereoisomers of oxazolidin-4-one 6 remain consistently
high throughout the duration of the reaction. Interestingly, the
ee of the unreacted oxaziridine 5 gradually increased with con-
version up to 41% ee at 4 h, which indicates that a partial ki-
netic resolution was occurring under the reaction conditions.
The ee values of 5 obtained experimentally in Table 3 correlate
with the predicted values based upon the given conversion
and d.r., within error. Significantly, high conversion was only
achieved after an extended reaction time and upon warming
to room temperature, which indicates that one enantiomer of
the oxaziridine requires increased temperature to react effi-
ciently with the ammonium enolate. This experiment also pro-
vided evidence that chirality transfer from (Æ)-oxaziridine 5 to
product 6 was the cause of the low diastereocontrol in this
process, which has implications with regard to the mechanism
of this isothiourea-catalysed formal [3+2] process.
To further investigate and utilise the chirality transfer in this
process the use of an excess of (Æ)-oxaziridine 5 (2 equiv with
respect to homoanhydride 7) was trialled (Scheme 3).[24] In this
case, oxazolidin-4-one 6 was isolated in 71% yield with an im-
proved 75:25 d.r., with both diastereoisomers again formed
with excellent enantioselectivity. The remaining oxaziridine 5
was isolated in 42% ee, with the (S,S)-enantiomer in excess.
This formally represents a kinetic resolution of (Æ)-5 with 49%
conversion with respect to the oxaziridine (as judged by crude
Scheme 5. Investigation of a) matched and b) mis-matched effects between
Scheme 3. Use of excess (Æ)-oxaziridine 5.
ammonium enolate and enantiomerically enriched oxaziridine.
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The significance of the matched/mis-matched effect was fur-
ther demonstrated through reaction of a range of homoanhy-
drides with (R,R)-oxaziridine 5 (94% ee) using HyperBTM 3
(Table 4). Under the previously optimised conditions, electron-
donating and -withdrawing aromatic substituents were easily
incorporated resulting in high yields, enantioselectivities and,
importantly, high d.r. of oxazolidin-4-ones 17a and 18a, re-
spectively. Substitution in either the ortho- or meta-positions of
the aryl ring was also well tolerated, forming oxazolidin-4-ones
19a, 21a and 22a as single diastereoisomers with excellent
levels of enantioselectivity. Alkenyl and heteroaryl homoanhy-
dride substituents were also successfully incorporated to give
30a and 31a respectively, with high levels of stereocontrol.
However, the introduction of a p-trifluoromethyl substituent
gave oxazolidin-4-one 25 in a reduced 60:40 d.r.anti/syn, with
both diastereoisomers formed in high enantioselectivity
(>99% ee). This suggests that major product anti-25a is
formed with high levels of enantioselectivity but undergoes
base-mediated epimerisation at C(5) into syn-25b. This result
also provides a plausible explanation for the unexpected result
using the p-trifluoromethyl-substituted homoanhydride with
(Æ)-oxaziridine 5, with epimerisation at C(5) in combination
with the expected mixture at C(2) leading to the observed
drop in ee of both diastereoisomers of 25 (Table 2).
Scheme 6. Proposed mechanism for Lewis base catalysed formal [3+2] cy-
cloaddition of ammonium enolates with oxaziridines.
(67%), presumably as a result of a competitive uncatalysed
background reaction for this catalytically unfavoured process.
The results described in Scheme 5 lead us to propose a cata-
lytic cycle for the synthesis of oxazolidin-4-ones, shown in
Scheme 6. Firstly, homoanhydride 26 acylates HyperBTM 3 to
give acyl ammonium 27. Subsequent deprotonation of 27 to
give (Z)-ammonium enolate 28, stabilised by a favourable no to
s*CÀS interaction,[8h,9d,27] followed by intermolecular stereoselec-
tive a-oxidation[28] leads to acyl ammonium 29. Finally, lactami-
sation gives the oxazolidin-4-one
To demonstrate the synthetic utility of this [3+2] process,
additional product derivatisations have been investigated
(Scheme 7). Removal of the N-tosyl protecting group on oxazo-
lidin-4-ones 6a and 17a–18a was achieved with SmI2 at low
temperature to give the parent heterocycles 32–34 in high
yields, with complete retention of ee. Further hydrolysis of oxa-
zolidin-4-one 32 with HCl led to formation of (R)-mandelic acid
35 in quantitative yield.
product and regenerates the cat-
Table 4. Investigation of the substrate scope with enantioenriched oxaziridine 5.
alyst. This mechanism provides
an alternative to that proposed
by Ye and co-workers who sug-
gest that for their related NHC-
catalysed formal [3+2] process
the azolium enolate generated is
oxidised by an oxaziridine to
form a transient epoxide species
and an imine, with subsequent
collapse of the epoxide and nu-
cleophilic attack onto the imine
generating an acyl azolium spe-
cies that can cyclise into an oxa-
zolidin-4-one. Our observation of
Major Product
Yield [%][a]
d.r.anti/syn
eeanti [%][c]
Major product
Yield [%][a]
[b]
[b]
d.r.anti/syn
eeanti [%][c]
81
94:6
99
87
95:5
97
60
95:5
>99
87
>95:5
>99
a
matched/mis-matched effect
95
71
using enantioenriched oxaziri-
dine suggests the formation of
a transient planar imine inter-
mediate in this process is unlike-
ly. However, the possibility of an
alternative mechanistic pathway
operating in the mis-matched
case cannot be ruled out.
>95:5
>99
96:4
>99
61
94:6
>99
49
60:40
>99:99
[a] Isolated yield. [b] Determined by 1H NMR spectroscopic analysis of the crude reaction product. [c] Deter-
mined by HPLC analysis.
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2007—2013), ERC Grant Agreement No. 279850 (C.F. and J.E.T.),
GSK (CASE award to S.R.S.) and EPSRC grant No. EP/J018139/
1 (D.S.B.D.) for funding. We also thank the EPSRC UK National
Mass Spectrometry Facility at Swansea University.
Keywords: asymmetric synthesis · heterocycles · Lewis base ·
organocatalysis · oxaziridines
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Conclusion
The asymmetric formal [3+2] cycloaddition of ammonium eno-
lates with both (Æ)-oxaziridines and (R,R)-oxaziridines has been
developed using a range of 2-aryl and 2-alkenylacetic anhy-
drides with the commercially available isothiourea catalyst Hy-
perBTM 3. This process allows access to stereodefined oxazoli-
din-4-ones that can be readily deprotected or reduced to give
enantioenriched building blocks in high yield. Further studies
using enantioenriched oxaziridines led to the observation of
a matched/mis-matched effect with isothiourea HyperBTM 3,
which has been utilised to obtain oxazolidin-4-ones in high d.r.
with excellent ee. Ongoing studies within this laboratory are
focused upon the continued development of Lewis base catal-
ysis.
Experimental Section
General
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For general experimental details, full characterisation data, NMR
spectra, and HPLC traces, see the Supporting Information.
General procedure for the asymmetric organocatalytic for-
mation of oxazolidin-4-ones
The appropriate oxaziridine (1 equiv) and (2S,3R)-HyperBTM 3
(10 mol%) were added to a solution of the appropriate homoanhy-
dride (1.5 equiv) and cesium carbonate (2 equiv) in CH2Cl2 (0.2m)
at À788C. The reaction mixture was stirred at À788C then warmed
slowly to room temperature over 16 h before being quenched
with HCl (1.0m). The reaction mixture was extracted with CH2Cl2 (”
2), the combined organics dried over MgSO4, filtered and concen-
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Acknowledgements
We thank Prof. K. A. Jørgensen and L. Lykke for helpful advice
regarding the preparation of enantiomerically enriched oxaziri-
dines. We thank the Royal Society for a University Research Fel-
lowship (A.D.S.) and the European Research Council under the
European Union’s Seventh Framework Programme (FP7/
Chem. Eur. J. 2015, 21, 10530 – 10536
www.chemeurj.org
10535 ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
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Received: March 31, 2015
[21] (2S,3R)-HyperBTM 3 was previously called HBTM 2.1 and is commercially
available from Strem or TCI via SynthAndrews.
Published online on June 12, 2015
Chem. Eur. J. 2015, 21, 10530 – 10536
www.chemeurj.org
10536 ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim