Diastereoselective synthesis of 3-acetoxy-4-(3-aryloxiran-2-yl)azetidin-2-ones and their transformation into 3,4-oxolane-fused bicyclic β-lactams

Article abstract of DOI:10.1039/c6ob02221a

cis-3-Acetoxy-4-(3-aryloxiran-2-yl)azetidin-2-ones were prepared through a Staudinger [2+2]-cyclocondensation between acetoxyketene and the appropriate epoxyimines in a highly diastereoselective way. Subsequent potassium carbonate-mediated acetate hydrolysis, followed by intramolecular ring closure through epoxide ring opening, afforded stereodefined 3-aryl-4-hydroxy-2-oxa-6-azabicyclo[3.2.0]heptan-7-ones as a novel class of C-fused bicyclic β-lactams. Selective benzylic oxidation of bicyclic N-(4-methoxybenzyl)-β-lactams with potassium persulfate and potassium dihydrogen phosphate provided the corresponding N-aroyl derivatives as interesting leads for further β-lactamase inhibitor development.

Full text of DOI:10.1039/c6ob02221a

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Biomolecular Chemistry
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Diastereoselective synthesis of 3-acetoxy-
4-(3-aryloxiran-2-yl)azetidin-2-ones and
their transformation into 3,4-oxolane-fused
bicyclic β-lactams†
Cite this: DOI: 10.1039/c6ob02221a
Nicola Piens,a Sven De Craene,a Jorick Franceus,b Karen Mollet,a Kristof Van Hecke,c
Tom Desmetb and Matthias D’hooghe*a
cis-3-Acetoxy-4-(3-aryloxiran-2-yl)azetidin-2-ones were prepared through a Staudinger [2+2]-cyclo-
condensation between acetoxyketene and the appropriate epoxyimines in a highly diastereoselective way.
Subsequent potassium carbonate-mediated acetate hydrolysis, followed by intramolecular ring closure
through epoxide ring opening, afforded stereodefined 3-aryl-4-hydroxy-2-oxa-6-azabicyclo[3.2.0]
heptan-7-ones as a novel class of C-fused bicyclic β-lactams. Selective benzylic oxidation of bicyclic
N-(4-methoxybenzyl)-β-lactams with potassium persulfate and potassium dihydrogen phosphate provided
the corresponding N-aroyl derivatives as interesting leads for further β-lactamase inhibitor development.
Received 12th October 2016,
Accepted 4th November 2016
DOI: 10.1039/c6ob02221a
www.rsc.org/obc
Also from a synthetic point of view, the importance of
β-lactams as versatile building blocks in organic chemistry has
Introduction
In 1945, Alexander Fleming was awarded the Nobel Prize “for been universally recognized. Next to the generation of a wide
the discovery of penicillin and its curative effect in various variety of biologically interesting nitrogen-containing acyclic
infectious diseases”, together with E. Chain and H. Florey.1 and heterocyclic target compounds by selective bond-cleavage
Penicillin became available for use among the allied soldiers and ring-rearrangement protocols,5 the azetidin-2-one skeleton
during World War II, considerably reducing the overall has been widely used as a template to construct cyclic attach-
number of amputations and deaths, and ever since, β-lactam ments fused to the four-membered ring system using the
antibiotics have found widespread application in the treatment β-lactam functionalizations as (stereo)directing elements.5a,b,e–g,j,k
of infectious pathogens.2 To date, this extraordinary class of Among them, C-fused bicyclic β-lactams, in which the second
strained compounds still comprises the most extensively used ring is attached to the azetidin-2-one nucleus at the 3,4-posi-
antibacterial agents and is considered to be a cornerstone of tion, have received considerably less attention as compared to
human health care.3 However, the increasing bacterial resist- their celebrated N-fused analogues,5b,e–g,j,k rendering their con-
ance against classical β-lactam-based pharmaceuticals is truly struction and further elaboration an interesting challenge and
alarming and imposes a continued search for novel types of opportunity. A suitable strategy to access this class of hetero-
β-lactam antibiotics and β-lactamase inhibitors.4 In particular, cycles relates to the intramolecular displacement of a leaving
the development of innovative new chemical entities is of para- group present in the β-lactam C4 side chain by a nucleophile
mount importance in medicinal chemistry in order to effec- attached to the C3 position. By applying this methodology, we
tively address and eliminate microbial resistance.
have previously demonstrated the applicability of cis-3-benzyl-
oxy-4-(2-bromo/mesyloxyethyl)-β-lactams for the efficient syn-
thesis of 2-oxa-6-azabicyclo[3.2.0]heptan-7-one systems.6 In
continuation of our interest in the use of functionalized
β-lactams as building blocks in heterocyclic chemistry,5g,k the
present research is focused on the diastereoselective formation
of cis-3-acetoxy-4-(3-aryloxiran-2-yl)-β-lactams as eligible inter-
mediates for the preparation of novel and polyvalent 3-aryl-4-
hydroxy-2-oxa-6-azabicyclo[3.2.0]heptan-7-one scaffolds.
aSynBioC Research Group, Department of Sustainable Organic Chemistry and
Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653,
B-9000 Ghent, Belgium. E-mail: matthias.dhooghe@UGent.be
bDepartment of Biochemical and Microbial Technology, Faculty of Bioscience
Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
cXStruct, Department of Inorganic and Physical Chemistry, Faculty of Sciences,
Ghent University, Krijgslaan 281-S3, B-9000 Ghent, Belgium
4-Oxiranyl-substituted azetidin-2-ones have already been
proven to be convenient precursors in the synthesis of bi- and
tricyclic β-lactams, for example through reductive ring opening
†Electronic supplementary information (ESI) available. CCDC 1400949 and
1400950. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c6ob02221a
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of the strained epoxide unit with titanocene(III) monochloride cis-3-acetoxy-1-isopropyl-4-(3-phenyloxiran-2-yl)azetidin-2-ones
(Cp2TiCl) and subsequent radical intramolecular cyclization.7 4a and 5a after 90 hours at room temperature, which was puri-
However, as the reactivity of 4-oxiranylazetidin-2-ones reported fied in 83% yield by column chromatography on silica gel
in the literature is exclusively focused on the synthesis of (Scheme 1). The relative stereochemistry of the two isomeric
traditional 1,4-fused (N-fused) polycyclic β-lactams,7,8 this epoxides 4a and 5a could be easily deduced based on the
work comprises the first report on the deployment of 4-oxiranyl- vicinal coupling constants between the protons at C3 and C4
azetidin-2-ones for the preparation of synthetically relevant (of the β-lactam core), C1′ and C2′ (of the epoxide moiety), and
3,4-fused (C-fused) bicyclic β-lactams. Because of the pivotal C4 and C1′ in 1H NMR (CDCl3) (Fig. 1), which are in agreement
position of C-fused bicyclic β-lactams in the search for alter- with values reported in the literature for similar azetidin-2-
native bioactive agents against class C β-lactamases,3c,9 the ones.7a,c,d It should be noted that separation of the two
premised
3-aryl-4-hydroxy-2-oxa-6-azabicyclo[3.2.0]heptan-7- isomers 4a and 5a by column chromatography on silica
ones could also be considered as new anchor points in anti- gel proved to be impossible; nonetheless, isolation of pure
bacterial drug design and discovery.
cis-3-acetoxy-1-isopropyl-4-(3-phenyloxiran-2-yl)azetidin-2-one
5a was achieved by recrystallization from hexane/EtOAc (1/30),
albeit in a very low yield (1%), to allow unequivocal assign-
ment of its chemical structure.
Results and discussion
Because of the lack of diastereoselectivity and the cumber-
some separation procedure associated with the latter method,
an alternative approach for the preparation of cis-3-acetoxy-4-(3-
aryloxiran-2-yl)azetidin-2-ones 4/5 was pursued. Next to the
epoxidation of 4-alkenylazetidin-2-ones, two other methodo-
logies for the synthesis of 4-oxiranylazetidin-2-ones are
available in the literature, relying on either a ketene-imine
cycloaddition13 or an ester enolate–imine condensation of
epoxyimines.14
In a first stage, the diastereoselective synthesis of cis-3-acetoxy-
4-(3-aryloxiran-2-yl)azetidin-2-ones
4
was envisaged. The
majority of literature procedures concerning the preparation of
this type of substrates relies on an epoxidation step of the
corresponding 4-alkenyl-β-lactams. In most cases, 3-chloroper-
benzoic acid (mCPBA) is used as the oxidizing agent,7a–d,f,g,8b,10
although also methods with hydrogen peroxide and sodium
hydroxide (H2O2–NaOH)8a or magnesium monoperoxy-
phthalate (MMPP)11 have been reported.
To that end, (E)-N-[trans-(3-aryloxiran-2-yl)methylidene]
In that respect, imination of (E)-cinnamaldehyde 1 with iso-
propylamine was performed, followed by reaction of the result-
ing imine 2 with acetoxyacetyl chloride in the presence of Et3N
to give cis-3-acetoxy-1-isopropyl-4-(2-phenylethenyl)azetidin-2-
one 3 in 48% yield after purification by column chromato-
graphy on silica gel (Scheme 1). The observed cis-diastereo-
selectivity in β-lactam 3 was assigned via the 1H NMR spec-
trum, as the vicinal coupling constant of 4.7 Hz (CDCl3)
between the H3 and H4 proton is in accordance with
values reported in the literature for cis-β-lactams.7a–d,f,11,12
Subsequently, epoxidation of the double bond in the latter
amines
9 were prepared in 51–68% overall yield from
Fig. 1 Vicinal coupling constants between the protons at C3 and C4,
C4 and C1’, and C1’ and C2’ of cis-3-acetoxy-4-(3-phenyloxiran-2-yl)
4-alkenylazetidin-2-one
3 using 1.5 equiv. of mCPBA in
dichloromethane afforded a 1/1 diastereomeric mixture of azetidin-2-ones 4a and 5a in 1H NMR (CDCl3).
Scheme 1 Synthesis of cis-3-acetoxy-4-(3-phenyloxiran-2-yl)azetidin-2-ones 4a and 5a via epoxidation of cis-3-acetoxy-4-(2-phenylethenyl)aze-
tidin-2-one 3.
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(E)-3-arylprop-2-en-1-ols 6 in three successive steps, including
To that end, cis-3-acetoxy-1-isopropyl-4-(3-phenyloxiran-2-yl)
(i) epoxidation with mCPBA in CH2Cl2, (ii) oxidation with SO3- azetidin-2-one 4a was used as
a model substrate for
pyridine in CH2Cl2/DMSO (7/1) in the presence of Hünig’s O-deacetylation using slightly modified literature pro-
a
base and (iii) imination in CH2Cl2 under standard conditions cedure,15 involving treatment with two equiv. of potassium
(Scheme 2). Subsequently, epoxyimines 9 were used as sub- carbonate in MeOH/H2O (1/1) at room temperature.
strates for a Staudinger β-lactam synthesis upon treatment Interestingly, next to the expected cis-3-hydroxy-1-isopropyl-4-
with 1.3 equiv. of acetoxyacetyl chloride in CH2Cl2 in the (3-phenyloxiran-2-yl)azetidin-2-one 10a, a small amount of
presence of Et3N, affording the corresponding racemic cis-3- 4-hydroxy-6-isopropyl-3-phenyl-2-oxa-6-azabicyclo[3.2.0]heptan-
acetoxy-4-(3-aryloxiran-2-yl)azetidin-2-ones 4 in high diastereo- 7-one 11a was observed in the reaction mixture after stirring
meric excess (dr = 91–94/6–9, determined by 1H NMR in for one hour without the use of a base or epoxide activator
CDCl3) and in 64–97% yield after purification by recrystalliza- (10a/11a = 86/14). Additional stirring for seven more hours
tion from hexane/EtOAc (1/30) or column chromatography proved to be sufficient to drive the reaction to completion,
on silica gel. The excellent diastereoselectivity of this giving rise to 4-hydroxy-6-isopropyl-3-phenyl-2-oxa-6-azabicyclo
reaction could be rationalized by the imposed steric [3.2.0]heptan-7-one 11a, which was eventually obtained in 62%
hindrance originating from the aryloxirane moiety during the yield and analytically pure form after additional purification
Staudinger synthesis. The coupling constants between the by preparative HPLC. Subsequently, also cis-3-acetoxy-4-(3-
protons at C4 and C1′ of the major isomers proved to be aryloxiran-2-yl)azetidin-2-ones 4b–e were smoothly converted
7.8–8.2 Hz (CDCl3), enabling its stereochemical assignment into rac-3-aryl-4-hydroxy-2-oxa-6-azabicyclo[3.2.0]heptan-7-
(Scheme 2).7a Structural diversity was introduced in these ones 11b–e as single diastereomers using similar reaction con-
4-epoxy-β-lactams 4 through variation of the N-β-lactam group ditions (except for derivative 4b, where iPrOH was used) in
(R1 = iPr, PMP, PMB) and the aryloxirane substituent (R2 = H, 35–69% yield and excellent purity after purification by prepara-
3-CF3).
tive HPLC, recrystallization or column chromatography on
With cis-3-acetoxy-4-(3-aryloxiran-2-yl)azetidin-2-ones 4 in silica gel (Scheme 3). It should be noted that complete conver-
hand, the reactivity of these new building blocks toward the sion was obtained for all derivatives, leading to ‘crude’ isolated
preparation of synthetically and biologically interesting 3,4- yields of 70–91%. The reported yields in Scheme 3 are those
fused bicyclic β-lactams was investigated. The synthetic strat- obtained after additional purification, which was performed to
egy proposed for this transformation consisted of deprotection obtain analytically pure samples for structure characterization
of the alcohol moiety in 3-acetoxyazetidin-2-ones 4 through and biological evaluation purposes.
ester hydrolysis, followed by hydroxyl group-induced intra-
To examine the influence of the relative stereochemistry of
molecular ring closure by epoxide ring opening at the benzylic cis-3-acetoxy-4-(3-aryloxiran-2-yl)azetidin-2-ones 4a and 5a on
position, whether or not with the help of an additional Lewis the kinetics of the above-described transformation, a 1/1 dia-
acid to activate the oxirane ring.
stereomeric mixture of β-lactams 4a and 5a was dissolved in
Scheme 2 Diastereoselective synthesis of cis-3-acetoxy-4-(3-aryloxiran-2-yl)azetidin-2-ones 4 via Staudinger [2+2]-cyclocondensation between
in situ prepared acetoxyketene and (E)-N-[trans-(3-aryloxiran-2-yl)methylidene]amines 9.
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Scheme 3 Synthesis of 3-aryl-4-hydroxy-2-oxa-6-azabicyclo[3.2.0]heptan-7-ones 11.
MeOH/H2O (1/1) and treated with two equiv. of potassium X-ray analysis of (1S*,3S*,4R*,5R*)-4-hydroxy-6-(4-methoxy-
carbonate. As expected, β-lactam 4a was completely converted phenyl)-3-phenyl-2-oxa-6-azabicyclo[3.2.0]heptan-7-one 11b and
into 2-oxa-6-azabicyclo[3.2.0]heptan-7-one 11a after eight (1R*,3S*,4R*,5S*)-4-hydroxy-6-isopropyl-3-phenyl-2-oxa-6-azabi-
hours stirring at room temperature (according to LC-MS ana- cyclo[3.2.0]heptan-7-one 12a (Fig. 2).
lysis). In contrast, β-lactam 5a needed 20 times more time
In an initial attempt to debenzylate 3-aryl-4-hydroxy-6-(4-
(160 h) to be rearranged into 2-oxa-6-azabicyclo[3.2.0]heptan-7- methoxybenzyl)-2-oxa-6-azabicyclo[3.2.0]heptan-7-ones 11c,e
one 12a, which is probably due to the steric hindrance exerted by means of 3.4 equiv. of potassium persulfate in the presence
by the phenyl group during intramolecular epoxide ring of 6.8 equiv. of potassium dihydrogen phosphate in CH3CN/
opening (Scheme 4). Both isomers 11a and 12a were separated H2O (2/1) at reflux temperature,16 the unprecedented selective
by preparative HPLC in 36% and 18% yield, respectively, to oxidation of the benzylic position was observed, affording
allow assessment of their structure and bioactivity.
3-aryl-4-hydroxy-6-(4-methoxybenzoyl)-2-oxa-6-azabicyclo[3.2.0]
Assuming a clean SN2-type epoxide ring opening, the pro- heptan-7-ones 13 in 46–69% yield after purification by prepara-
posed relative stereochemistry of 3-aryl-4-hydroxy-2-oxa-6-aza- tive HPLC or column chromatography on silica gel (Scheme 5).
bicyclo[3.2.0]heptan-7-ones 11 and 12 is a direct result of the Notably, benzylic oxidation of N-benzylated β-lactams, which is
relative stereochemistry secured in the starting cis-3-acetoxy- mentioned only sporadically in the literature using various
4-(3-aryloxiran-2-yl)azetidin-2-ones 4a and 5a, which was methods and reagents,17 provides a means to selectively trans-
deduced based on the vicinal coupling constants between the form the electron-donating 4-methoxybenzyl group on the
protons at C3 and C4 (of the β-lactam core), C1′ and C2′ (of the β-lactam nitrogen atom in azetidin-2-ones 11c,e into an elec-
epoxide moiety), and C4 and C1′ in 1H NMR (CDCl3) (see tron-withdrawing functional group, which is considered to be
above). Nonetheless, irrefutable proof for these relative con- beneficial in the framework of antibacterial activity studies.
figurations was eventually established by single crystal
Besides the synthetic novelty and relevance of the intra-
molecular epoxide ring opening as a valuable alternative
toward the stereoselective preparation of C-fused bicyclic
β-lactams, the new 3-aryl-4-hydroxy-2-oxa-6-azabicyclo[3.2.0]
heptan-7-ones can also be considered as useful building
blocks for e.g. the synthesis of functional oxolane β-amino
acids via amide bond hydrolysis.6,18 Indeed, the tetrahydro-
furan unit represents an important structural motif present in
bioactive natural and synthetic molecules,19 which explains
the interest in efficient strategies for its construction. As men-
tioned in the introduction, tetrahydrofuran-based azetidin-2-
ones can also be of interest as templates in the search for new
β-lactamase inhibitors. Specifically, bridged monobactams
(i.e., C-fused bicyclic β-lactams) are considered to be potent,
mechanism-based inhibitors of class C β-lactamases, which
are able to stabilize the acyl-enzyme intermediate by blocking
access of water to the enzyme-inhibitor ester bond.9a In spite
of the fact that there are a few methods available in the litera-
ture for the synthesis of the 2-oxa-6-azabicyclo[3.2.0]heptan-7-
one skeleton,6,20 no details on their bioactivity are known.
On the other hand, MK-8712, an aza-analogue of 2-oxa-6-azabi-
cyclo[3.2.0]heptan-7-ones, has recently been found to overcome
Scheme 4 Comparison of the required reaction times for the synthesis
of
(1S*,3S*,4R*,5R*)-3-aryl-4-hydroxy-2-oxa-6-azabicyclo[3.2.0]
heptan-7-one 11a and (1R*,3S*,4R*,5S*)-3-aryl-4-hydroxy-2-oxa-6-
azabicyclo[3.2.0]heptan-7-one 12a.
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Fig. 2 Molecular structure of (1S*,3S*,4R*,5R*)-4-hydroxy-6-(4-methoxyphenyl)-3-phenyl-2-oxa-6-azabicyclo[3.2.0]heptan-7-one 11b and
(1R*,3S*,4R*,5S*)-4-hydroxy-6-isopropyl-3-phenyl-2-oxa-6-azabicyclo[3.2.0]heptan-7-one 12a.
residual activity for tazobactam), revealing opportunities for
further β-lactamase inhibitor development (Table 1). These
results point to
a pronounced effect of the β-lactam
N-substituent, supporting the literature consensus on the
necessity of an electron-withdrawing group at nitrogen.23 It is
evident that additional optimization studies are required in
the future to further unravel the β-lactamase inhibitory poten-
tial of this new class of oxazabicyclic scaffolds.
Conclusions
Scheme 5 Synthesis of 3-aryl-4-hydroxy-6-(4-methoxybenzoyl)-2-
oxa-6-azabicyclo[3.2.0]heptan-7-ones 13.
In summary, two methodologies for the preparation of
4-oxiranyl-β-lactams were investigated, in which the Staudinger
[2+2]-cyclocondensation between acetoxyketene and the
appropriate epoxyimines delivered the desired cis-3-acetoxy-4-
(3-aryloxiran-2-yl)azetidin-2-ones in a highly diastereoselective
way. These β-lactams were subsequently used as eligible sub-
strates for the synthesis of the novel class of 3-aryl-4-hydroxy-
2-oxa-6-azabicyclo[3.2.0]heptan-7-ones employing an ‘intra-
molecular ring closure through epoxide ring opening’ strategy.
This protocol afforded versatile building blocks for further
elaboration and offers a valuable alternative for the prepa-
ration of 3,4-fused bicyclic β-lactams, which have received
much less attention as compared to their celebrated 1,4-fused
analogues. Finally, a selective benzylic oxidation of N-(4-meth-
oxybenzyl)-β-lactams was realized, which provided 3-aryl-4-
hydroxy-6-(4-methoxybenzoyl)-2-oxa-6-azabicyclo[3.2.0]heptan-
7-ones with potential β-lactamase inhibitory activity, revealing
opportunities for further medicinal chemistry studies toward
the development of novel antibacterial agents.
class C β-lactamase-mediated resistance and has been selected
for preclinical development.21
In order to provide some preliminary data on their
β-lactamase inhibitory potential, 3-aryl-4-hydroxy-2-oxa-6-aza-
bicyclo[3.2.0]heptan-7-ones 11a–e, 12a and 13a–b were incubated
with β-lactamase from Enterobacter cloacae, after which the
residual enzymatic activity was measured by following the rate
of nitrocefin hydrolysis, which is an excellent substrate for
class C enzymes.22 Although none of the tested compounds
showed a better activity than the reference compound tazo-
bactam, an interesting profile was observed for 3-aryl-4-hydroxy-
6-(4-methoxybenzoyl)-2-oxa-6-azabicyclo[3.2.0]heptan-7-ones
13a–b (residual activities of 58.7 12.4% and 44.3 13.8%,
respectively, after incubation with 500 µM; 16.2
10.6%
Table 1 Residual enzymatic activities after incubation of 500 µM
3-aryl-4-hydroxy-2-oxa-6-azabicyclo[3.2.0]heptan-7-ones 11a–e, 12a
and 13a–b with β-lactamase from Enterobacter cloacae
Experimental
R1
R2
Residual activitya (%)
General methods
Compd
Commercially available solvents and reagents were purchased
from common chemical suppliers and used without further
purification. Melting points were measured using a Kofler
bench, type WME Heizbank of Wagner & Munz. 1H NMR
spectra were recorded at 400 MHz (Bruker Avance III-400) in
deuterated solvents with TMS as internal standard. 19F NMR
spectra were recorded at 376 MHz (Bruker Avance III-400).
13C NMR spectra were recorded at 100 MHz (Bruker Avance
11a
11b
11c
11d
11e
12a
13a
13b
iPr
PMP
PMB
iPr
PMB
iPr
H
H
H
3-CF3
3-CF3
H
H
3-CF3
99.3 5.8
108.8 11.3
95.1 12.9
113.7 17.7
87.1 14.6
96.6 13.3
58.7 12.4
44.3 13.8
p-Anisoyl
p-Anisoyl
a Reference compound = tazobactam (16.2 10.6% residual activity).
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III-400). IR spectra were obtained from samples in neat form however, isolation of (3S*,4R*,2′S*,3′S*)-3-acetoxy-1-isopropyl-4-(3-
with an ATR (Attenuated Total Reflectance) accessory with a phenyloxiran-2-yl)azetidin-2-one 5a could be achieved in 1%
Perkin-Elmer Spectrum BX FT-IR spectrophotometer. Electron (35 mg) yield by recrystallization from hexane/EtOAc (1/30).
spray (ES) mass spectra were obtained with an Agilent 1100
(3S*,4R*,2′S*,3′S*)-3-Acetoxy-1-isopropyl-4-(3-phenyloxiran-2-yl)
azetidin-2-one 5a
Series MS (ES, 4000V) mass spectrometer. High resolution
electron spray (ES-TOF) mass spectra were obtained with an
Agilent Technologies 6210 Series Time of Flight.
White crystals. Recrystallization from hexane/EtOAc (1/30).
Mp 110 °C. Yield 1%. H NMR (400 MHz, CDCl3): δ 1.22 (3H,
1
Synthesis of cis-3-acetoxy-1-isopropyl-4-(2-phenylethenyl)
azetidin-2-one 3
d, J = 6.7 Hz), 1.30 (3H, d, J = 6.7 Hz), 2.05 (3H, s), 3.05 (1H,
d × d, J = 6.2, 2.0 Hz), 3.83 (1H, d, J = 2.0 Hz), 3.91 (1H, septet,
J = 6.7 Hz), 3.92 (1H, d × d, J = 6.2, 4.7 Hz), 5.78 (1H, d, J =
4.7 Hz), 7.27–7.29 (2H, m), 7.34–7.39 (3H, m). 13C NMR
(100 MHz, ref = CDCl3): δ 20.0, 20.3, 21.5, 44.9, 56.2, 56.8, 59.6,
To an ice-cooled solution of (E)-N-(3-phenylprop-2-en-1-
ylidene)isopropylamine 2 (4.33 g, 25 mmol, 1 equiv.) and tri-
ethylamine (7.59 g, 75 mmol, 3 equiv.) in anhydrous CH2Cl2
(50 mL), acetoxyacetyl chloride (4.44 g, 33 mmol, 1.3 equiv.) in
anhydrous CH2Cl2 (10 mL) was added dropwise. After stirring
for 18 hours at room temperature, CH2Cl2 (30 mL) was added
and the resulting mixture was washed with a saturated
aqueous NaHCO3 solution (50 mL) and brine (50 mL). Drying
of the organic phase with MgSO4, filtration of the drying agent
and removal of the solvent in vacuo afforded crude cis-3-
acetoxy-1-isopropyl-4-(2-phenylethenyl)azetidin-2-one 3, which
was purified in 48% (3.28 g) yield by column chromatography
on silica gel (hexane/EtOAc 3/1).
74.4, 125.4, 128.7, 135.6, 164.0, 169.6. IR (ATR, cm−1): νCvO
=
1759, 1744; νmax = 1401, 1212, 1116, 1020, 892, 759, 703. MS
(70 eV): m/z (%) 290 (M+ + 1, 27). HRMS (ESI) Calcd for
C16H20NO4+ 290.1387 [M + H]+, found 290.1385.
Synthesis of (E)-N-[trans-(3-aryloxiran-2-yl)methylidene]amines 9
As a representative example, the synthesis of (E)-N-[trans-
(3-phenyloxiran-2-yl)methylidene]isopropylamine 9a is described.
To a solution of trans-(3-phenyloxiran-2-yl)formaldehyde 8a 24
(1.48 g, 10 mmol, 1 equiv.) and MgSO4 (2.41 g, 20 mmol,
2 equiv.) in anhydrous CH2Cl2 (20 mL), isopropylamine
(0.59 g, 10 mmol, 1 equiv.) was added. After stirring for
cis-3-Acetoxy-1-isopropyl-4-(2-phenylethenyl)azetidin-2-one 3
Yellow oil. Rf = 0.14 (hexane/EtOAc 3/1). Yield 48%. 1H NMR
(400 MHz, CDCl3): δ 1.24 (3H, d, J = 6.7 Hz), 1.29 (3H, d, J =
6.7 Hz), 2.05 (3H, s), 3.90 (1H, septet, J = 6.7 Hz), 4.52 (1H,
d × d, J = 8.8, 4.7 Hz), 5.73 (1H, d, J = 4.7 Hz), 6.09 (1H, d × d,
J = 16.0, 8.8 Hz), 6.69 (1H, d, J = 16.0 Hz), 7.28–7.39 (5H, m).
13C NMR (100 MHz, ref = CDCl3): δ 20.1, 20.4, 21.7, 44.8, 59.1,
76.1, 123.5, 126.6, 128.5, 128.8, 135.8, 136.3, 163.9, 169.4.
IR (ATR, cm−1): νCvO = 1742, 1711; νmax = 1372, 1222, 1105,
1043, 1021, 975, 931, 751, 693. MS (70 eV): m/z (%) 274
2
hours at room temperature, MgSO4 was removed by
filtration. Evaporation of the solvent in vacuo afforded
(E)-N-[trans-(3-phenyloxiran-2-yl)methylidene]isopropylamine 9a
in 85% (1.61 g) yield and high purity (>95% based on
1H NMR spectroscopy), which was used as such in the next
reaction step.
(E)-N-[trans-(3-Phenyloxiran-2-yl)methylidene]isopropylamine 9a
Orange oil. Yield 85%. 1H NMR (400 MHz, CDCl3): δ 1.19
(3H, d, J = 6.3 Hz), 1.22 (3H, d, J = 6.3 Hz), 3.45 (1H, septet,
J = 6.3 Hz), 3.56 (1H, d × d, J = 7.1, 1.9 Hz), 3.96 (1H, d, J =
1.9 Hz), 7.28–7.37 (6H, m). 13C NMR (100 MHz, ref = CDCl3):
δ 23.82, 23.83, 57.9, 61.2, 61.9, 125.7, 128.58, 128.61, 135.7,
158.4. IR (ATR, cm−1): νCvN = 1666; νmax = 2968, 1459,
1158, 1126, 958, 854, 753, 696, 617. MS (70 eV): m/z (%) 190
(M+ + 1, 20).
(M+ + 1, 13). HRMS (ESI) Calcd for C16H20NO3 274.1438
+
[M + H]+, found 274.1439.
Synthesis of (3S*,4R*,2′S*,3′S*)-3-acetoxy-1-isopropyl-
4-(3-phenyloxiran-2-yl)azetidin-2-one 5a
To an ice-cooled solution of cis-3-acetoxy-1-isopropyl-4-
(2-phenylethenyl)azetidin-2-one 3 (3.11 g, 12 mmol, 1 equiv.)
in anhydrous CH2Cl2 (40 mL), 3-chloroperbenzoic acid (3.55 g,
18 mmol, 1.5 equiv.) was added in small portions. The result- (E)-N-[trans-(3-Phenyloxiran-2-yl)methylidene]-
ing mixture was stirred for 90 hours at room temperature, after 4-methoxyphenylamine 9b 13,25
which a saturated aqueous Na2SO3 solution (40 mL) was
(E)-N-[trans-(3-phenyloxiran-2-yl)methylidene]-4-
methoxybenzylamine 9c
added. After additionally stirring for 15 minutes at room temp-
erature, the reaction mixture was washed with a saturated
1
aqueous NaHCO3 solution (30 mL) and brine (30 mL). Drying Orange oil. Yield 82%. H NMR (400 MHz, CDCl3): δ 3.61 (1H,
of the organic phase with MgSO4, filtration of the drying agent d × d, J = 7.0, 1.9 Hz), 3.80 (3H, s), 3.98 (1H, d, J = 1.9 Hz), 4.61
and removal of the solvent in vacuo afforded an equimolar (1H, d, J = 13.9 Hz), 4.63 (1H, d, J = 13.9 Hz), 6.87–6.90
mixture of (3S*,4R*,2′R*,3′R*)-3-acetoxy-1-isopropyl-4-(3-phenyl- (2H, m), 7.19–7.40 (7H, m). 13C NMR (100 MHz, ref = CDCl3):
oxiran-2-yl)azetidin-2-one 4a and (3S*,4R*,2′S*,3′S*)-3-acetoxy-1- δ 55.3, 57.9, 62.0, 64.3, 114.1, 125.7, 128.60, 128.63, 129.4,
isopropyl-4-(3-phenyloxiran-2-yl)azetidin-2-one 5a, which was pur- 130.3, 135.7, 158.9, 161.6. IR (ATR, cm−1): νCvN = 1666; νmax
=
ified in 83% (2.88 g) yield by column chromatography on silica 1509, 1240, 1180, 1031, 856, 844, 810, 760, 697. MS (70 eV):
gel (hexane/EtOAc 3/1). Separation of the two isomers 4a and 5a m/z (%) 268 (M+ + 1, 42). HRMS (ESI) Calcd for C17H18NO2
+
by column chromatography on silica gel proved to be impossible, 268.1332 [M + H]+, found 268.1330.
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(E)-N-{trans-{3-[3-(Trifluoromethyl)phenyl]oxiran-2-yl}
methylidene}isopropylamine 9d
3.68 (1H, d, J = 2.0 Hz), 4.07 (1H, septet, J = 6.7 Hz), 5.67 (1H,
d, J = 4.8 Hz), 7.23–7.25 (2H, m), 7.29–7.38 (3H, m). 13C NMR
(100 MHz, ref = CDCl3): δ 19.9, 20.0, 21.5, 44.3, 56.8, 59.2, 61.3,
74.8, 125.3, 128.61, 128.63, 135.6, 163.3, 170.0. IR (ATR, cm−1):
νCvO = 1747, 1711; νmax = 1400, 1216, 1130, 1107, 1024, 923,
895, 797, 761, 701. MS (70 eV): m/z (%) 290 (M+ + 1, 15). HRMS
(ESI) Calcd for C16H20NO4+ 290.1387 [M + H]+, found 290.1385.
Orange oil. Yield 87%. 1H NMR (400 MHz, CDCl3): δ 1.19
(3H, d, J = 6.3 Hz), 1.22 (3H, d, J = 6.3 Hz), 3.46 (1H, septet, J =
6.3 Hz), 3.54 (1H, d × d, J = 7.0, 1.9 Hz), 4.03 (1H, d, J =
1.9 Hz), 7.34 (1H, d, J = 7.0 Hz), 7.47–7.49 (2H, m), 7.56–7.59
(2H, m). 19F NMR (376 MHz, CDCl3): δ −62.82 (s). 13C NMR
(100 MHz, ref = CDCl3): δ 23.8, 57.2, 61.3, 62.1, 122.7 (q, J =
3.8 Hz), 123.9 (q, J = 272.3 Hz), 125.4 (q, J = 3.7 Hz), 128.9,
129.2, 131.1 (q, J = 31.7 Hz), 137.0, 157.7. IR (ATR, cm−1):
νCvN = 1665; νmax = 1327, 1163, 1121, 1071, 801, 700. MS
(70 eV): m/z (%) 258 (M+ + 1, 100). HRMS (ESI) Calcd for
C13H15F3NO+ 258.1100 [M + H]+, found 258.1102.
(3S*,4R*,2′R*,3′R*)-3-Acetoxy-1-(4-methoxyphenyl)-4-
(3-phenyloxiran-2-yl)azetidin-2-one 4b
White crystals. Recrystallization from hexane/EtOAc (1/30). Mp
1
147 °C. Yield 85%. H NMR (400 MHz, CDCl3): δ 1.78 (3H, s),
3.11 (1H, d × d, J = 7.8, 1.9 Hz), 3.78 (1H, d, J = 1.9 Hz), 3.82
(3H, s), 4.00 (1H, d × d, J = 7.8, 5.0 Hz), 5.89 (1H, d, J = 5.0 Hz),
6.94 (2H, d, J = 9.0 Hz), 7.23–7.26 (2H, m), 7.32–7.38 (3H, m),
7.60 (2H, d, J = 9.0 Hz). 13C NMR (100 MHz, ref = CDCl3):
δ 20.1, 55.5, 56.2, 60.5, 61.0, 75.0, 114.6, 118.8, 125.4, 128.7,
(E)-N-{trans-{3-[3-(Trifluoromethyl)phenyl]oxiran-2-yl}
methylidene}-4-methoxybenzylamine 9e
Orange oil. Yield 99%. 1H NMR (400 MHz, CDCl3): δ 3.58–3.60
(1H, m), 3.80 (3H, s), 4.05 (1H, s(broad)), 4.62 (1H, d, J =
13.8 Hz), 4.65 (1H, d, J = 13.8 Hz), 6.86–6.90 (2H, m), 7.20–7.24
(2H, m), 7.39 (1H, d, J = 6,9 Hz), 7.47–7.50 (2H, m), 7.55–7.59
(2H, m). 19F NMR (376 MHz, CDCl3): δ −62.79 (s). 13C NMR
(100 MHz, ref = CDCl3): δ 55.3, 57.2, 62.1, 64.2, 114.1, 122.7
(q, J = 3.7 Hz), 123.9 (q, J = 273.0 Hz), 125.4 (q, J = 3.7 Hz),
128.8, 129.2, 129.4, 130.1, 131.1 (q, J = 32.7 Hz), 136.9, 158.9,
160.8. IR (ATR, cm−1): νCvN = 1666; νmax = 1511, 1328, 1246,
1164, 1121, 1119, 1070, 1034, 802, 700. MS (70 eV): m/z (%) 336
128.8, 130.5, 135.3, 157.0, 160.5, 170.0. IR (ATR, cm−1): νCvO
=
1745, 1704; νmax = 1514, 1246, 1216, 1195, 1108, 1096, 826,
760. MS (70 eV): m/z (%) 354 (M+ + 1, 100). HRMS (ESI) Calcd
for C20H20NO5+ 354.1336 [M + H]+, found 354.1337.
(3S*,4R*,2′R*,3′R*)-3-Acetoxy-1-(4-methoxybenzyl)-4-
(3-phenyloxiran-2-yl)azetidin-2-one 4c
Yellow oil. Rf = 0.17 (hexane/EtOAc 2/1). Yield 97%. 1H NMR
(400 MHz, CDCl3): δ 1.76 (3H, s), 2.90 (1H, d × d, J = 8.0,
2.0 Hz), 3.45 (1H, d × d, J = 8.0, 4.8 Hz), 3.55 (1H, d, J =
2.0 Hz), 3.82 (3H, s), 4.33 (1H, d, J = 14.7 Hz), 4.66 (1H, d, J =
14.7 Hz), 5.68 (1H, d, J = 4.8 Hz), 6.89–6.93 (2H, m), 7.16–7.19
(2H, m), 7.30–7.35 (5H, m). 13C NMR (100 MHz, ref = CDCl3):
δ 20.0, 45.1, 55.3, 55.5, 59.9, 60.5, 75.8, 114.3, 125.3, 126.8,
128.57, 128.61, 130.2, 135.5, 159.5, 163.6, 169.9. IR (ATR,
cm−1): νCvO = 1762, 1747; νmax = 1512, 1239, 1218, 1176, 1028,
754, 698. MS (70 eV): m/z (%) 368 (M+ + 1, 51). HRMS (ESI)
Calcd for C21H22NO5+ 368.1492 [M + H]+, found 368.1499.
(M+ + 1, 22). HRMS (ESI) Calcd for C18H17F3NO2 336.1206
+
[M + H]+, found 336.1207.
Synthesis of (3S*,4R*,2′R*,3′R*)-3-acetoxy-4-(3-aryloxiran-2-yl)
azetidin-2-ones 4
As a representative example, the synthesis of (3S*,4R*,2′R*,3′R*)-
3-acetoxy-4-{3-[3-(trifluoromethyl)phenyl]oxiran-2-yl}-1-(4-methoxy-
benzyl)azetidin-2-one 4e is described. To an ice-cooled solu-
tion of (E)-N-{trans-{3-[3-(trifluoromethyl)phenyl]oxiran-2-yl}
(3S*,4R*,2′R*,3′R*)-3-Acetoxy-4-{3-[3-(trifluoromethyl)phenyl]
methylidene}-4-methoxybenzylamine 9e (1.68 g,
5 mmol,
oxiran-2-yl}-1-isopropylazetidin-2-one 4d
1 equiv.) and triethylamine (1.52 g, 15 mmol, 3 equiv.) in an-
hydrous CH2Cl2 (20 mL), acetoxyacetyl chloride (0.89 g, 7 mmol,
1.3 equiv.) in anhydrous CH2Cl2 (5 mL) was added dropwise.
After stirring for 18 hours at room temperature, CH2Cl2
(15 mL) was added and the resulting mixture was washed
with a saturated aqueous NaHCO3 solution (20 mL) and
brine (20 mL). Drying of the organic phase with MgSO4,
filtration of the drying agent and removal of the solvent
in vacuo afforded crude (3S*,4R*,2′R*,3′R*)-3-acetoxy-4-{3-
[3-(trifluoromethyl)phenyl]oxiran-2-yl}-1-(4-methoxybenzyl)aze-
tidin-2-one 4e, which was purified in 79% (1.72 g) yield by
column chromatography on silica gel (hexane/EtOAc 2/1).
Yellow oil. Rf = 0.37 (hexane/EtOAc 1/1). Yield 64%. 1H NMR
(400 MHz, CDCl3): δ 1.31 (3H, d, J = 6.7 Hz), 1.40 (3H, d, J =
6.7 Hz), 1.78 (3H, s), 2.92 (1H, d × d, J = 8.2, 1.8 Hz), 3.60 (1H,
d × d, J = 8.2, 4.8 Hz), 3.77 (1H, d, J = 1.8 Hz), 4.07 (1H, septet,
J = 6.7 Hz), 5.66 (1H, d, J = 4.8 Hz), 7.46–7.51 (3H, m),
7.58–7.60 (1H, m). 19F NMR (376 MHz, CDCl3): δ −62.78 (s).
13C NMR (100 MHz, ref = CDCl3): δ 19.9, 20.0, 21.5, 44.4, 56.2,
59.1, 61.4, 74.9, 122.1 (q, J = 3.7 Hz), 123.8 (q, J = 271.9 Hz),
125.3 (q, J = 3.7 Hz), 128.6, 129.2, 131.3 (q, J = 32.3 Hz), 137.0,
163.1, 170.1. IR (ATR, cm−1): νCvO = 1764, 1748; νmax = 1329,
1220, 1193, 1166, 1109, 1089, 1068, 1026, 894, 804. MS (70 eV):
m/z (%) 358 (M+ + 1, 100). HRMS (ESI) Calcd for C17H19F3NO4
+
(3S*,4R*,2′R*,3′R*)-3-Acetoxy-1-isopropyl-4-(3-phenyloxiran-
2-yl)azetidin-2-one 4a
358.1261 [M + H]+, found 358.1249.
(3S*,4R*,2′R*,3′R*)-3-Acetoxy-4-{3-[3-(trifluoromethyl)phenyl]
oxiran-2-yl}-1-(4-methoxybenzyl)azetidin-2-one 4e
J = 6.7 Hz), 1.40 (3H, d, J = 6.7 Hz), 1.74 (3H, s, CH3CvO), 2.95 Yellow oil. Rf = 0.13 (hexane/EtOAc 2/1). Yield 79%. 1H NMR
(1H, d × d, J = 8.1, 2.0 Hz), 3.59 (1H, d × d, J = 8.1, 4.8 Hz), (400 MHz, CDCl3): δ 1.80 (3H, s), 2.84 (1H, d × d, J = 8.0,
White crystals. Recrystallization from hexane/EtOAc (1/30). Mp
110 °C. Yield 77%. H NMR (400 MHz, CDCl3): δ 1.31 (3H, d,
1
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1.9 Hz), 3.46 (1H, d × d, J = 8.0, 4.8 Hz), 3.64 (1H, d, J = δ 55.5, 64.7, 75.4, 86.5, 91.7, 114.4, 118.4, 124.8, 127.7, 128.4,
1.9 Hz), 3.82 (3H, s), 4.34 (1H, d, J = 14.7 Hz), 4.65 (1H, d, J = 129.8, 137.5, 156.6, 162.7. IR (ATR, cm−1): νOH = 3415; νCvO
=
14.7 Hz), 5.66 (1H, d, J = 4.8 Hz), 6.90–6.93 (2H, m), 7.29–7.33 1722; νmax = 1507, 1244, 1065, 1029, 827, 733, 697. MS (70 eV):
+
(2H, m), 7.37–7.39 (1H, m), 7.44–7.49 (2H, m), 7.56–7.58 (1H, m/z (%) 312 (M+ + 1, 100). HRMS (ESI) Calcd for C18H18NO4
m). 19F NMR (376 MHz, CDCl3): δ −62.83 (s). 13C NMR 312.1230 [M + H]+, found 312.1233.
(100 MHz, ref = CDCl3): δ 20.0, 45.1, 54.9, 55.3, 59.7, 60.7, 75.9,
114.3, 122.1 (q, J = 3.7 Hz), 123.8 (q, J = 273.7 Hz), 125.3 (q, J = (1S*,3S*,4R*,5R*)-4-Hydroxy-6-(4-methoxybenzyl)-3-phenyl-
3.9 Hz), 126.7, 128.6, 129.2, 130.2, 131.2 (q, J = 32.5 Hz), 137.0, 2-oxa-6-azabicyclo[3.2.0]heptan-7-one 11c
159.6, 163.3, 169.9. IR (ATR, cm−1): νCvO = 1768, 1750; νmax
1513, 1328, 1245, 1221, 1165, 1122, 1089, 1070, 1030, 806. MS
(70 eV): m/z (%) 436 (M+ + 1, 76). HRMS (ESI) Calcd for
C22H21F3NO5+ 436.1366 [M + H]+, found 436.1376.
=
White crystals. Rf = 0.12 (hexane/EtOAc 1/1). Recrystallization
from hexane/EtOAc (1/30). Mp 158 °C. Yield 39%. 1H NMR
(400 MHz, CDCl3): δ 1.86 (1H, d, J = 6.0 Hz), 3.79 (3H, s), 3.82
(1H, d, J = 14.9 Hz), 3.985 (1H, d, J = 14.9 Hz), 3.988 (1H, d,
J = 3.6 Hz), 4.31 (1H, d, J = 6.0 Hz), 5.37 (1H, d, J = 3.6 Hz),
5.46 (1H, s(broad)), 6.74–6.76 (2H, m), 6.80–6.84 (2H, m),
7.28–7.30 (1H, m), 7.32–7.38 (4H). 13C NMR (100 MHz, ref =
CDCl3): δ 44.5, 55.3, 65.2, 76.2, 87.9, 92.2, 114.3, 124.4,
126.4, 127.5, 128.5, 129.8, 138.3, 159.2, 165.9. IR (ATR, cm−1):
νOH = 3332; νC=O = 1720; νmax = 1512, 1246, 1176, 1121, 1097,
1070, 1036, 809, 736. MS (70 eV): m/z (%) 326 (M+ + 1, 100).
Synthesis of (1S*,3S*,4R*,5R*)-3-aryl-4-hydroxy-2-oxa-
6-azabicyclo[3.2.0]heptan-7-ones 11 and (1S*,3R*,4S*,5R*)-
3-aryl-4-hydroxy-2-oxa-6-azabicyclo[3.2.0]heptan-7-one 12
As a representative example, the synthesis of (1S*,3S*,4R*,5R*)-
4-hydroxy-6-(4-methoxybenzyl)-3-[3-(trifluoromethyl)phenyl]-2-
oxa-6-azabicyclo[3.2.0]heptan-7-one 11e is described. To a solu-
tion of (3S*,4R*,2′R*,3′R*)-3-acetoxy-4-{3-[3-(trifluoromethyl)
phenyl]oxiran-2-yl}-1-(4-methoxybenzyl)azetidin-2-one 4e (0.44 g,
1 mmol, 1 equiv.) in MeOH/H2O (1/1, 20 mL), potassium
carbonate (0.28 g, 2 mmol, 2 equiv.) was added. After stirring
for 24 hours at room temperature, the solvent was evaporated
in vacuo and the residue was dissolved in CH2Cl2 (20 mL). The
resulting mixture was washed with H2O (3 × 10 mL), after
which the combined aqueous phases were extracted again with
CH2Cl2 (3 × 10 mL). Drying of the combined organic phases
with MgSO4, filtration of the drying agent and removal of the
solvent in vacuo afforded crude (1S*,3S*,4R*,5R*)-4-hydroxy-
6-(4-methoxybenzyl)-3-[3-(trifluoromethyl)phenyl]-2-oxa-6-azabi-
cyclo[3.2.0]heptan-7-one 11e, which was purified in 69%
(0.27 g) yield by column chromatography on silica gel (hexane/
EtOAc 1/1).
HRMS (ESI) Calcd for C19H20NO4 326.1387 [M + H]+, found
+
326.1388.
(1S*,3S*,4R*,5R*)-4-Hydroxy-6-isopropyl-3-[3-(trifluoromethyl)
phenyl]-2-oxa-6-azabicyclo[3.2.0]heptan-7-one 11d
Colorless oil. Rf = 0.15 (hexane/EtOAc 1/1). Yield 35%. 1H NMR
(400 MHz, CDCl3): δ 0.69 (3H, d, J = 6.7 Hz), 0.97 (3H, d, J =
6.7 Hz), 3.44 (1H, septet, J = 6.7 Hz), 3.77 (1H, s(broad)), 4.18
(1H, d, J = 3.6 Hz), 4.67 (1H, s(broad)), 5.31 (1H, d, J = 3.6 Hz),
5.59 (1H, s(broad)), 7.45–7.52 (2H, m), 7.68–7.70 (2H, m).
19F NMR (376 MHz, CDCl3): δ −62.71 (s). 13C NMR (100 MHz,
ref = CDCl3): δ 19.6, 20.6, 44.3, 63.7, 77.6, 86.7, 91.5, 121.4
(q, J = 3.6 Hz), 124.0 (q, J = 276.9 Hz), 124.2 (q, J = 3.8 Hz),
127.9, 129.0, 130.7 (q, J = 32.4 Hz), 140.2, 165.9. IR (ATR,
cm−1): νOH = 3324; νCvO = 1748; νmax = 2975, 1389, 1331, 1233,
1196, 1163, 1122, 1075, 1025, 1008, 940, 805, 788, 704, 670. MS
(70 eV): m/z (%) 316 (M+ + 1, 100).
(1S*,3S*,4R*,5R*)-4-Hydroxy-6-isopropyl-3-phenyl-2-oxa-
6-azabicyclo[3.2.0]heptan-7-one 11a
Colorless oil. Rf = 0.07 (hexane/EtOAc 1/1). Yield 62%. 1H NMR
(1S*,3S*,4R*,5R*)-4-Hydroxy-6-(4-methoxybenzyl)-
3-[3-(trifluoromethyl)phenyl]-2-oxa-6-azabicyclo[3.2.0]heptan-
7-one 11e
(400 MHz, CDCl3): δ 0.71 (3H, d, J = 6.7 Hz, (CH3 2
(3H, d, J = 6.7 Hz, (CH3)2CH), 3.02 (1H, s(broad)), 3.45 (1H,
septet, J = 6.7 Hz), 4.14 (1H, d, J = 3.6 Hz), 4.66 (1H, s(broad)),
̲ ) CH), 0.98
̲
5.29 (1H, d, J = 3.6 Hz), 5.56 (1H, s(broad)), 7.21–7.25 (1H, m), White crystals. Rf = 0.15 (hexane/EtOAc 1/1). Mp 132 °C. Yield
7.31–7.35 (2H, m), 7.42–7.44 (2H, m). 13C NMR (100 MHz, ref = 69%. 1H NMR (400 MHz, CDCl3): δ 1.86 (1H, s(broad)), 3.79
CDCl3): δ 19.8, 20.7, 44.2, 63.7, 77.7, 86.7, 92.2, 124.4, 127.4, (3H, s), 3.91 (1H, d, J = 14.7 Hz), 3.96 (1H, d, J = 14.7 Hz), 4.01
128.4, 138.8, 165.8. IR (ATR, cm−1): νOH = 3377; νCvO = 1724; (1H, d, J = 3.6 Hz), 4.23 (1H, s(broad)), 5.40 (1H, d, J = 3.6 Hz),
νmax = 1390, 1235, 1102, 1071, 1018, 785, 736, 699. MS (70 eV): 5.46 (1H, s(broad)), 6.73–6.75 (2H, m), 6.79–6.81 (2H, m),
m/z (%) 248 (M+ + 1, 100). HRMS (ESI) Calcd for C14H18NO3
7.48–7.51 (2H, m), 7.55–7.56 (1H, m), 7.61–7.63 (1H, m).
19F NMR (376 MHz, CDCl3): δ −62.51 (s). 13C NMR (100 MHz,
ref = CDCl3): δ 44.7, 55.2, 65.4, 76.4, 88.0, 91.7, 114.3,
121.4 (q, J = 3.9 Hz), 124.1 (q, J = 272.4 Hz), 124.3 (q, J =
3.6 Hz), 126.1, 127.9, 129.1, 129.7, 130.7 (q, J = 32.3 Hz);
+
248.1281 [M + H]+, found 248.1282.
(1S*,3S*,4R*,5R*)-4-Hydroxy-6-(4-methoxyphenyl)-3-phenyl-
2-oxa-6-azabicyclo[3.2.0]heptan-7-one 11b
Colorless oil. Rf = 0.17 (hexane/EtOAc 1/1). Yield 57%. 1H NMR 139.7, 159.3, 165.8. IR (ATR, cm−1): νOH = 3359; νCvO = 1724;
(400 MHz, CDCl3): δ 2.60 (1H, s(broad)), 3.74 (3H, s), 4.56 (1H, νmax = 1513, 1329, 1310, 1251, 1157, 1119, 1095, 1067,
d, J = 3.7 Hz), 4.76 (1H, s(broad)), 5.42 (1H, d, J = 3.7 Hz), 5.49 1036, 702. MS (70 eV): m/z (%) 394 (M+ + 1, 100). HRMS
(1H, s(broad)), 6.73–6.77 (2H, m), 6.97–7.01 (2H, m), 7.17–7.26 (ESI) Calcd for C20H18F3NO4Cl− 428.0882 [M + Cl−], found
(3H, m), 7.31–7.32 (2H, m). 13C NMR (100 MHz, ref = CDCl3): 428.0885.
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(1S*,3R*,4S*,5R*)-4-Hydroxy-6-isopropyl-3-phenyl-2-oxa-
6-azabicyclo[3.2.0]heptan-7-one 12a
4.79 (1H, d, J = 4.4 Hz), 4.96 (1H, s(broad)), 5.41 (1H, d, J =
4.4 Hz), 5.60 (1H, s(broad)), 6.75 (2H, d, J = 8.9 Hz), 7.29 (2H,
d, J = 8.9 Hz), 7.42–7.46 (1H, m), 7.52–7.54 (1H, m), 7.60–7.62
(1H, m), 7.78 (1H, m). 19F NMR (376 MHz, CDCl3): δ −62.77
(s). 13C NMR (100 MHz, ref = CDCl3): δ 55.5, 63.3, 77.3, 84.9,
90.1, 113.4, 121.7 (q, J = 3.8 Hz), 123.9 (q, J = 272.6 Hz), 122.7,
124.7 (q, J = 3.7 Hz), 128.3, 129.3, 131.1 (q, J = 32.5 Hz), 131.9,
139.4, 161.8, 164.1, 165.7. MS (70 eV): m/z (%) 430 (M+ + Na,
70), 408 (M+ + 1, 12), 380 (M+ − CO, 100). HRMS (ESI) Calcd
for C20H17F3NO5+ 408.1053 [M + H]+, found 408.1049.
White crystals. Rf = 0.29 (hexane/EtOAc 1/1). Mp 150 °C. Yield
18%. 1H NMR (400 MHz, CDCl3): δ 1.34 (3H, d, J = 6.7 Hz),
1.38 (3H, d, J = 6.7 Hz), 2.20 (1H, s(broad)), 3.88 (1H, d × d, J =
8.6, 5.0 Hz), 3.90 (1H, septet, J = 6.7 Hz), 4.19–4.21 (1H, m),
4.70 (1H, d, J = 8.6 Hz), 5.07 (1H, d, J = 3.6 Hz), 7.33–7.40 (5H,
m). 13C NMR (100 MHz, ref = CDCl3): δ 19.8, 21.6, 45.8, 58.1,
78.3, 81.5, 83.6, 126.5, 128.6, 128.7, 137.4, 165.6. IR (ATR,
cm−1): νOH = 3384; νCvO = 1719; νmax = 1348, 1306, 1100, 1085,
1007, 968, 780, 759, 705. MS (70 eV): m/z (%) 248 (M+ + 1, 100).
β-Lactamase inhibition assay
HRMS (ESI) Calcd for C14H18NO3 248.1281 [M + H]+, found
+
Each compound (500 µM) was incubated with β-lactamase
248.1279.
from Enterobacter cloacae (0.25 mg L−1
) at 35 °C for
Synthesis of (1S*,3S*,4R*,5R*)-3-aryl-4-hydroxy-6-
(4-methoxybenzoyl)-2-oxa-6-azabicyclo[3.2.0]heptan-7-ones 13
10 minutes, after which the residual enzymatic activity was
measured by following the rate of nitrocefin (150 µM) hydro-
lysis at 480 nm in 100 mM phosphate buffer, pH 7.0, and 10%
(v/v) DMSO. Each reaction was performed in triplicate.
As a representative example, the synthesis of (1S*,3S*,4R*,5R*)-
4-hydroxy-6-(4-methoxybenzoyl)-3-phenyl-2-oxa-6-azabicyclo
[3.2.0]heptan-7-one 13a is described. To
(1S*,3S*,4R*,5R*)-4-hydroxy-6-(4-methoxybenzyl)-3-phenyl-2-
oxa-6-azabicyclo[3.2.0]heptan-7-one 11c (0.33 g, mmol,
a solution of
Acknowledgements
1
1 equiv.) in CH3CN/H2O (2/1, 10 mL), potassium persulfate
(0.92 g, 3.4 mmol, 3.4 equiv.) and potassium dihydrogen phos-
phate (0.93 g, 6.8 mmol, 6.8 equiv.) were added. After stirring
for 4 hours at reflux, the solvent was evaporated in vacuo and
the residue was dissolved in CH2Cl2 (10 mL). The resulting
mixture was washed with H2O (2 × 5 mL), a saturated aqueous
NaHCO3 solution (5 mL) and brine (5 mL), after which the
combined aqueous phases were extracted again with CH2Cl2
(3 × 10 mL). Drying of the combined organic phases with MgSO4,
filtration of the drying agent and removal of the solvent in vacuo
afforded crude (1S*,3S*,4R*,5R*)-4-hydroxy-6-(4-methoxybenzoyl)-
3-phenyl-2-oxa-6-azabicyclo[3.2.0]heptan-7-one 13a, which was
purified in 46% (0.16 g) yield by preparative HPLC.
The authors are indebted to Ghent University – Belgium (BOF)
for financial support. KVH thanks the Hercules Foundation
(project AUGE/11/029 “3D-SPACE: 3D Structural Platform
Aiming for Chemical Excellence”) and the Research
Foundation – Flanders (FWO) for funding.
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(1S*,3S*,4R*,5R*)-4-Hydroxy-6-(4-methoxybenzoyl)-
3-[3-(trifluoromethyl)phenyl]-2-oxa-6-azabicyclo[3.2.0]heptan-
7-one 13b
Colorless oil. Rf = 0.30 (hexane/EtOAc 19/1). Yield 69%.
1H NMR (400 MHz, CDCl3): δ 3.17 (1H, s(broad)), 3.81 (3H, s),
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