Stereoselective synthesis of bicyclic tetrahydrofuran-fused β-lactams and their conversion into methyl cis-3-aminotetrahydrofuran-2-carboxylates

Article abstract of DOI:10.1016/j.tet.2012.01.001

cis-3-Benzyloxy-4-(2-mesyloxyethyl)azetidin-2-ones were shown to be useful starting products for the synthesis of cis-2-oxa-6-azabicyclo[3.2.0]heptan-7- ones in high overall yields and purity upon hydrogenolysis of the benzyl ether substituent followed by

Full text of DOI:10.1016/j.tet.2012.01.001

Tetrahedron 68 (2012) 10787e10793
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereoselective synthesis of bicyclic tetrahydrofuran-fused b-lactams
and their conversion into methyl cis-3-aminotetrahydrofuran-2-
carboxylates
1
*
*
Karen Mollet , Matthias D’hooghe , Norbert De Kimpe
Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
cis-3-Benzyloxy-4-(2-mesyloxyethyl)azetidin-2-ones were shown to be useful starting products for the
synthesis of cis-2-oxa-6-azabicyclo[3.2.0]heptan-7-ones in high overall yields and purity upon hydro-
genolysis of the benzyl ether substituent followed by intramolecular nucleophilic substitution using
Received 12 September 2011
Received in revised form 21 December 2011
Accepted 2 January 2012
sodium hydride in THF. These unconventionally C-fused bicyclic b-lactams were easily converted into the
Available online 8 January 2012
corresponding methyl cis-3-aminotetrahydrofuran-2-carboxylates via acidic methanolysis. This meth-
odology constitutes a convenient alternative for the known preparation of cis-4,4-dimethyl-2-oxa-6-
azabicyclo[3.2.0]heptan-7-ones and methyl cis-3-amino-4,4-dimethyltetrahydrofuran-2-carboxylates,
as their 4,4-nor-dimethyl variants are usually considered to be more promising compounds within the
field of drug design.
Keywords:
b
-Lactams
Enamides
Oxolanes
Ó 2012 Elsevier Ltd. All rights reserved.
b
-Amino acids
Stereoselectivity
1. Introduction
g
-allenols4b,d and
1,3-dipolar cycloaddition of oxo-N-propargylamides4c comprise
regiocontrolled routes to -lactams bearing an oxygen-containing
g
-alkynols4e and the Ag-mediated intramolecular
Besides their significance as bioactive agents, the importance of
b
b
-lactams as synthetic intermediates has been widely recognized in
3,4-fused five-membered ring system. Very recently, chlorinated
tetrahydrofuro[3,2-c]azetidin-2-ones have been prepared by
a
organic synthesis. In addition to the generation of different bi-
ologically interesting nitrogen-containing (heterocyclic) systems
from azetidin-2-one derivatives by selective bond cleavage and
rearrangements,1 the azetidin-2-one skeleton has been extensively
used as a template to construct cyclic structures fused to the four-
membered ring using the functionalization of the
as a stereocontrolling element.2 Among them, 3,4-fused (C-fused)
bicyclic
-lactams have received much less attention2e4 as compared
to their celebrated N-fused analogues. However, some -lactams C-
fused with a cyclopentene,5 pyrrolidine6 or thiazolidine7 ring have
been found to possess promising -lactamase inhibitory activities
and recently, bicyclic -lactams C-fused with carbocycles and a car-
bohydrate unit have been reported to exhibit promising activities
against malaria,8a leishmaniasis,8b and several types of cancer.8c
Although the tetrahydrofuran motif is ubiquitous as a structural
feature in bioactive natural and synthetic molecules,9 relatively few
methods are available for the construction of tetrahydrofuran-
copper(I)-catalyzed atom transfer radical cyclization.4f The
radical-mediated ring closure of 3-benzyloxy-4-ethynylazetidin-2-
ones has been described toward the corresponding C-fused bicyclic
cis- -lactam
b
-lactams,4h and a cis-4-(2-fluorophenyl)-3-hydroxy-
b
b-lactam nucleus
was transformed into a tricyclic b-lactam via an (h
6-arene)tri-
carbonylchromium(0) complex through a number of reaction
steps.4g
In previous work, we have demonstrated the applicability of cis-
3-benzyloxy-4-(2-bromo-1,1-dimethylethyl)-b-lactams 1 for the
preparation of novel cis-2-oxa-6-azabicyclo[3.2.0]heptan-7-ones 2
(Scheme 1).4a Nonetheless, the incorporation of a 4,4-gem-dimethyl
group hampered the further elaboration of this synthetic meth-
odology, as the corresponding 4,4-nor-dimethyl variants 5 are
usually considered to be more effective in terms of biological ac-
tivities. In order to achieve this goal, a different synthetic route had
b
b
b
b
to be developed, as the presence of
a-protons in the N-(3-
based
b
-lactams.4bem For example, the transition metal-catalyzed
bromopropylidene)amines leads to dehydrobromination as an
undesired side reaction.
heterocyclization of azetidin-2-one-tethered methyl and phenyl
More recently, we have developed a novel synthetic route to-
ward cis-4-[2-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-ones,
which were shown to be valuable alternatives (after deprotection
and activation of the alcohol moiety) for the known cis-4-(2-bromo-
* Corresponding authors. E-mail addresses: matthias.dhooghe@UGent.be
(M. D’hooghe), norbert.dekimpe@UGent.be (N. De Kimpe).
1
Aspirant of the Research Foundation-Flanders (FWO-Vlaanderen).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.01.001

10788
K. Mollet et al. / Tetrahedron 68 (2012) 10787e10793
O
O
O
BnO
Br
H
H
MeO
MeO
R
R
HN
HN
N
N
N
N
Ref. 4a
Ref. 4a
O
R
O
R
R
1
2
3
O
O
BnO
OMs
H
H
this work
this work
O
O
R
O
4
5
6
Scheme 1.
1,1-dimethylethyl)azetidin-2-ones 1 in the synthesis of 5,5-nor-
dimethylpiperidines as biologically interesting analogues of their
5,5-dimethyl variants.1f Encouraged by these results, the present
research will focus on the synthesis of cis-2-oxa-6-azabicyclo[3.2.0]
heptan-7-ones 5, as the absence of a 4,4-dimethyl group might open
up interesting possibilities for the development of biologically and
pharmaceutically relevant compounds.
2. Results and discussion
The starting materials, i.e., (E)-N-[3-(tert-butyldimethylsilyloxy)
propylidene]alkylamines 7, were easily prepared from 1,3-
propanediol in a three-step procedure1f involving (i) monop-
rotection of the diol as its tert-butyldimethylsilyl ether upon
treatment with NaH and tert-butyldimethylsilyl chloride
(TBDSMCl) in THF, (ii) oxidation of the free hydroxyl group by
means of a Swern oxidation using oxalyl chloride, DMSO and Et3N
in CH2Cl2, and (iii) imination of 3-(tert-butyldimethylsilyloxy)
propanal with different primary amines in dichloromethane in the
presence of MgSO4 as a drying agent. Subsequently, in order to
evaluate the Staudinger synthesis of cis-4-[2-(tert-butyldime-
thylsilyloxy)ethyl]azetidin-2-ones 8, N-isopropylimine 7a was
selected as a model substrate and was subjected to different re-
action conditions, involving variation of the solvent, base, tem-
perature, and reaction time (Scheme 2, Table 1). In almost all
cases, mixtures of cis-4-[2-(tert-butyldimethylsilyloxy)ethyl]-1-
In view of the continuous quest for new lead compounds in
the pharmaceutical industry, the synthesis of new (cyclic)
b-
amino acid derivatives comprises an important research field in
modern synthetic chemistry. The selective synthesis of b-amino
acids10 has been the subject of tremendous effort principally due
to their important biological activities10c,11 as, for example, en-
zyme inhibitors or
peptides possessing unique conformational properties (
des).10c,12 Furthermore, cyclic
-amino acids in which the amino
a
-amino acid surrogates in the construction of
b
-pepti-
b
group and the acid functionality are vicinally attached to a ring
system represent an important challenge due to their biological
1.3 equiv
O
PhOCH2COCl
OTBDMS
O
O
O
N
3 equiv base
N
+
N
see Table 1
H
OTBDMS
OTBDMS
(25-85/15-75)
7a
8a
9a
Scheme 2.
utility.13,14 In that respect, acidic methanolysis of cis-2-oxa-6-
azabicyclo[3.2.0]heptan-7-ones 5 is evaluated in the present re-
port in order to provide a convenient entry into the biologically
interesting class of 3-aminotetrahydrofuran-2-carboxylates 6 as
Table 1
Staudinger reaction of (E)-N-[3-(tert-butyldimethylsilyloxy)propylidene]isopropyl-
amine 7a under different reaction conditions
valuable analogues of cyclic
b
-amino acids 3 (Scheme 1).15 In
-amino acid de-
b-amino esters are also known to possess
Entry Solvent Base
Acid chloride Reaction
Resulta
addition to their relevance as constrained
b
added at
temperature
rivatives, oxolane
and time
antimycotic activities.16
1
2
C6H6
C6H6
Et3N
Reflux
Reflux, 1 h;
rt, 15 h
8a/9a¼25/75
In continuation of our interest in the application of b-lactams as
versatile synthons toward diversely functionalized biologically
relevant nitrogen-containing target compounds, the stereo-
selective synthesis of novel cis-2-oxa-6-azabicyclo[3.2.0]heptan-7-
ones 5 and cis-3-aminotetrahydrofuran-2-carboxylates 6 from cis-
4-[2-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-ones is described
here. This approach constitutes a convenient alternative for the
2,6-Lutidine Reflux
Reflux, 15 h
Complex
mixture
3
4
C6H6
CH2Cl2
Et3N
PPh3
Reflux
0
Reflux, 15 h
rt, 15 h
8a/9a¼30/70
ꢀC
Complex
mixture
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et3N
Et3N
Et3N
Et3N
0
0
ꢀC
ꢀC
rt, 15 h
8a/9a¼83/17
8a/9a¼80/20
8a/9a¼81/19
8a/9a¼85/15
Reflux, 15 h
Reflux, 15 h
Reflux, 1 h;
rt, 15 h
Reflux
Reflux
known preparation of bicyclic b-lactams 2 and oxaheterocyclic b-
amino esters 3 (Scheme 1), thus providing an easy access to the 4,4-
nor-dimethyl variants as valuable templates in medicinal
chemistry.
a
Based on 1H NMR analysis of the reaction mixture.

K. Mollet et al. / Tetrahedron 68 (2012) 10787e10793
10789
isopropyl-3-phenoxyazetidin-2-one 8a and N-[3-(tert-butyldime-
thylsilyloxy)prop-1-en-1-yl]-N-isopropyl-2-phenoxyacetamide 9a
were obtained (8a/9a 25e85/15e75), next to negligible amounts of
unidentified side products. Furthermore, different attempts to tune
substituent in imines 7 has a pronounced influence on the ratio of
-lactams 8 and N-acyl enamines 9, as the presence of an isobutyl,
allyl or benzyl group favors the formation of the corresponding N-
acyl enamines 9, while an isopropyl group leads to the corre-
b
the reaction selectivity toward
b
-lactam 8a by applying more harsh
sponding b-lactams 8. The Staudinger synthesis of b-lactams 8
reaction conditions were not successful, as the ratio of compounds
8a and 9a remained unaffected independent of the reaction tem-
perature and the temperature of acid chloride addition (Table 1,
entries 6e8).
proceeded in a highly diastereoselective way, which can be at-
tributed to the electron-donating benzyloxy or phenoxy group
present in the BooseeEvans ketenes, favoring direct conrotatory
ring closure of the Zwitterionic intermediates toward cis-b-lac-
Subsequently, the synthesis of a number of cis-4-[2-(tert-
tams.17 The stereochemical outcome of the Staudinger reaction
toward azetidin-2-ones 8 was shown to be cis based on the cou-
pling constants between the protons at C3 and C4 in 1H NMR
(4.1e5.2 Hz, CDCl3).18
butyldimethylsilyloxy)ethyl]azetidin-2-ones
8
was evaluated
according to the optimal reaction conditions as described in Table 1,
entry 5. Thus, treatment of (E)-N-[3-(tert-butyldimethylsilyloxy)
propylidene]alkylamines 71f with 1.3 equiv of phenoxy- or benzy-
loxyacetyl chloride in dichloromethane in the presence of 3 equiv of
The presence of N-acyl enamines 9 can be explained as follows.
Nucleophilic addition of imines 7 across the acid chloride and
Et3N resulted in the corresponding mixtures of
b
-lactams 8 and N-
subsequent a-deprotonation with respect to the in situ formed
acyl enamines 9 (22/78e83/17) after 15 h at room temperature
(Scheme 3, Table 2). It should be noted that the specific N-
iminium moiety 10 can account for the formation of the observed
enamides 9 (Scheme 4). It is known that N-(alkylmethylidene)
O
O
R2O
R1
H
R2O
R1
1.3 equiv
OTBDMS
R2O
O
Cl
N
N
+
OTBDMS
N
3 equiv Et3N
R1
CH2Cl2, r.t., 15 h
OTBDMS
(22/78 - 83/17)
8a (R1 = iPr, R2 = Ph, 47%)
8b (R1 = iPr, R2 = Bn, 35%)
8c (R1 = cHex, R2 = Bn, 55%)
8d (R1 = iBu, R2 = Bn, 5%)
7
9d (R1 = iBu, R2 = Bn, 66%)
Scheme 3.
amines are less reactive toward [2þ2]-cyclocondensation reactions
as compared to N-(arylmethylidene)amines, sometimes resulting
in the full and selective formation of enamides instead of azetidin-
2-ones.19 The E-stereochemistry assigned to the olefinic moiety in
enamides 9 is supported by the observed vicinal coupling constants
between both olefinic protons (J¼13.8 Hz, 1H NMR, CDCl3).
Table 2
Synthesis of cis-4-[2-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-ones 8 and N-[3-
(tert-butyldimethylsilyloxy)prop-1-en-1-yl]acetamides 9
Entry
R1
R2
Resulta
1
2
3
4
5
6
7
8
9
iPr
iPr
cHex
iBu
Allyl
cHex
nPr
nBu
Bn
Ph
Bn
Bn
Bn
Bn
Ph
Ph
Bn
Ph
Bn
8a/9a¼83/17
8b/9b¼75/25
8c/9c¼67/33
In the next part of this work, the potential of 3-benzyloxy-b-
8d/9d¼40/60
8e/9e¼22/78
lactams 8b,c as selected synthons in the synthesis of bicyclic azeti-
din-2-ones was investigated. Thus, deprotection of the silyl ether in
8f/9f¼33/67
b-lactams 8b,c using 1.1 equiv of tetra-n-butylammonium fluoride
Complex mixture
Complex mixture
8g/9g¼33/67
Complex mixture
(TBAF) in THF, followed by treatment with 1.05 equiv of mesyl
chloride (MsCl) in the presence of a base and a catalytic amount of 4-
(dimethylamino)pyridine (DMAP) in dichloromethane at 0 ꢀC for 3 h
furnished the corresponding cis-3-benzyloxy-4-(2-mesyloxyethyl)
10
Ph
a
Based on 1H NMR analysis of the reaction mixture.
azetidin-2-ones 12 in good yields (Scheme 5). The latter b-lactams
O
O
R2O
R1
N
1.3 equiv
R2O
R1
Cl
N
H
OTBDMS
3 equiv Et3N
CH2Cl2, r.t., 15 h
OTBDMS
7
9
O
R2O
R1
N
H
OTBDMS
H
B
10
Scheme 4.

10790
K. Mollet et al. / Tetrahedron 68 (2012) 10787e10793
1.05 equiv MsCl
1.1 equiv Et3N
OTBDMS
OH
OMs
BnO
O
BnO
O
BnO
O
1.1 equiv TBAF
0.1 equiv DMAP
N
THF, 0 °C r.t., 5 h
N
N
CH2Cl2, 0 °C, 3 h
R1
R1
R1
11a (R1 = iPr, 49%)
12a (R1 = iPr, 89%)
8b,c
11b (R1 = cHex, 60%)
12b (R1 = cHex, 86%)
1)
2)
20% Pd/C, H2
5 bar, MeOH, r.t., 60 h
5 equiv
O
O
1 equiv NaH
THF, Δ, 15 h
HCl/MeOH (3 M)
H
H
O
R1
HN
N
MeOH, Δ, 24 h
O
R1
OMe
6a (R1 = iPr, 66%)
5a (R1 = iPr, 52%)
6b (R1 = cHex, 70%)
5b (R1 = cHex, 62%)
Scheme 5.
hold interesting potential for further elaboration due tothe presence
of a strained four-membered ring and an oxygenated carbon center
in the side chain. Indeed, the corresponding 2-(2-mesyloxyethyl)
structures.12 Since the use of
thesis of -amino acids with a pre-determined stereochemistry is
well known in the literature,20 hydrolysis of the amide function-
ality in bicyclic -lactams can lead to the selective formation of
(hetero)cyclic -amino acids. In that respect, the reactivity of bi-
cyclic -lactams 5 toward methanolic hydrogen chloride was
b-lactams as synthons for the syn-
b
azetidines, obtained after monochloroalane reduction of
b
-lactams
b
12, have already been proven to be very useful intermediates in the
b
ring enlargement of
b
-lactams 8 toward a variety of highly func-
b
tionalized piperidines via transient 1-azoniabicyclo[2.2.0]hexanes.1f
In previous work, the synthesis of cis-4,4-dimethyl-2-oxa-6-
azabicyclo[3.2.0]heptan-7-ones 2 (Scheme 1) has been described
evaluated with the intention to develop an efficient and
straightforward route toward the biologically relevant class of 3-
aminotetrahydrofuran-2-carboxylates 6. Treatment of
b-lactams
as a novel class of C-fused bicyclic
b
-lactams starting from cis-4-(2-
5 with 5 equiv of HCl in MeOH (3 M) under reflux for 24 h resulted
in the selective formation of novel methyl cis-3-
aminotetrahydrofuran-2-carboxylates 6 in good yields and purity
(Scheme 5). The observed coupling constants between the protons
bromo-1,1-dimethylethyl)-3-hydroxyazetidin-2-ones
through
intramolecular nucleophilic substitution.4a However, in light of
structureeactivity relationship studies, our interest was directed
toward the synthesis of analogues of bicyclic
b
-lactams 2 in which
at C2 and C3 in b
-amino esters 6 (5.5e6.6 Hz, 1H NMR, CDCl3)
no 4,4-dimethyl unit is present, since these 4,4-nor-dimethyl
variants are usually considered to be more effective in terms of
pharmacological properties. In that respect, hydrogenolysis of the
benzyl ether substituent of the former cis-3-benzyloxy-4-(2-
mesyloxyethyl)azetidin-2-ones 12 using 20% (w/w) palladium on
activated carbon in methanol at room temperature for 60 h
were in good accordance with those reported for their 4,4-
dimethyl variants.4a In this way, the transfer of the stereochemi-
cal information, introduced by the stereoselective Staudinger
synthesis of cis-b-lactams 8, through the reaction pathway enables
the selective preparation of cis-3-aminotetrahydrofuran-2-
carboxylates 6.
afforded the corresponding cis-3-hydroxy-
(>90%, 1H NMR), which were used as such for further elaboration.
Indeed, the latter 3-hydroxy- -lactams were subjected to ring
b-lactams in high purity
b
3. Conclusion
closure via intramolecular substitution of the mesyloxy function-
ality upon treatment with 1 equiv of NaH in THF under reflux for
15 h, yielding the premised new cis-2-oxa-6-azabicyclo[3.2.0]
heptan-7-ones 5 in high yields after purification by column chro-
In summary, the Staudinger reaction between different (E)-N-
[3-(tert-butyldimethylsilyloxy)propylidene]alkylamines and phe-
noxy- or benzyloxyacetyl chloride was evaluated, resulting in the
diastereoselective formation of cis-1-alkyl-4-[2-(tert-butyldime-
thylsilyloxy)ethyl]azetidin-2-ones, together with small to high
amounts of N-alkyl-N-[3-(tert-butyldimethylsilyloxy)prop-1-en-1-
yl]acetamides depending on the reaction conditions. The ob-
tained 3-benzyloxy-b-lactams were selectively transformed into
novel cis-2-oxa-6-azabicyclo[3.2.0]heptan-7-ones in high yields
and purity upon subsequent hydrogenolysis of the benzyl ether
substituent and intramolecular substitution using NaH in THF.
matography on silica gel. The cis-stereochemistry of bicyclic
b-
lactams 5, which is a direct consequence of the relative stereo-
chemistry defined during the Staudinger synthesis of the starting
b
-lactams 8, was unambiguously assigned based on the coupling
constants between the protons at C1 and C5 (3.3 Hz, 1H NMR,
CDCl3), pointing to a cis-configuration of the bicyclic frame-
work.4a,h It has to be mentioned that this is the first report re-
garding b-lactams C-fused with an unsubstituted tetrahydrofuran
unit, in which the oxygen atom is connected to the C3
carbon atom.
b
-lactam
Furthermore, these C-fused bicyclic
the corresponding methyl
b
-lactams were converted into
cis-3-aminotetrahydrofuran-2-
As mentioned before, (cyclic)
constituents of biologically active natural products and pharma-
ceutical agents.11 In addition, oligomers of
-amino acids, for ex-
ample, -peptides, have attracted considerable attention as useful
peptidomimetics because of their proteolytic stability relative to
natural -peptides and their propensity to adopt stable secondary
b
-amino acids are important
carboxylates upon treatment with HCl in MeOH. This approach
constitutes a convenient alternative for the known preparation of
b
cis-4,4-dimethyl-2-oxa-6-azabicyclo[3.2.0]heptan-7-ones
and
b
methyl cis-3-amino-4,4-dimethyltetrahydrofuran-2-carboxylates,
thus providing an easy access to their novel 4,4-nor-dimethyl var-
iants as valuable templates in medicinal chemistry.
a

K. Mollet et al. / Tetrahedron 68 (2012) 10787e10793
10791
4. Experimental
4.1. General
12:1, Rf¼0.05. Yield 5%, colorless oil. HRMS (ESI) calcd for
C22H38NO3Si 392.2621 [MþH]þ, found 392.2632.
4.2.2.2. 2-Benzyloxy-N-[3-(tert-butyldimethylsilyloxy)prop-1-en-
1H NMR spectra were recorded at 300 MHz (JEOL ECLIPSEþ)
with CDCl3 as solvent and tetramethylsilane as internal standard.
13C NMR spectra were recorded at 75 MHz (JEOL ECLIPSEþ) with
CDCl3 as solvent and tetramethylsilane as internal standard. Mass
spectra were obtained with a mass spectrometer Agilent 1100,
70 eV. IR spectra were measured with a Spectrum One FT-IR
spectrophotometer. Elemental analyses were performed with
a PerkineElmer series II CHNS/O analyzer 2400. High resolution
electron spray (ES) mass spectra were obtained with an Agilent
Technologies 6210 Series Time-of-Flight. Dichloromethane was
distilled over calcium hydride, while diethyl ether was dried over
sodium benzophenone ketyl. Other solvents were used as received
from the supplier. Melting points of crystalline compounds were
1-yl]-N-isobutylacetamide 9d. 1H NMR (CDCl3, 300 MHz):
d
¼0.06 (s,
6H), 0.90 (d, 6H, J¼6.1 Hz), 0.90 (s, 9H), 2.01e2.10 (m, 1H), 3.51 (d,
2H, J¼7.7 Hz), 4.19 (d, 2H, J¼5.3 Hz), 4.29 and 4.62 (2ꢁ s, 2ꢁ 2H),
5.15 (dꢁdꢁd, 1H, J¼13.8, 5.3, 5.3 Hz), 6.70 (d, 1H, J¼13.8 Hz),
7.28e7.37 (m, 5H); 13C NMR (ref¼CDCl3, 75 MHz):
¼ꢂ5.2, 18.3,
d
20.2, 25.9, 26.0, 49.6, 62.1, 69.0, 73.0, 110.9, 127.6, 127.8, 128.0, 128.3,
137.3, 168.0; IR (ATR):
n
¼1686, 1649 (C]C, C]O); MS (ESþ): m/
z¼392 (MHþ). Column chromatography (SiO2), petroleum ether/
ethyl acetate 12:1, Rf¼0.07. Yield 66%, yellow oil. HRMS (ESI) calcd
for C22H38NO3Si 392.2621 [MþH]þ, found 392.2634.
4.2.3. Synthesis of cis-1-alkyl-4-(2-hydroxyethyl)azetidin-2-ones
11. To an ice-cooled solution of cis-4-[2-(tert-butyldimethylsily-
loxy)ethyl]azetidin-2-ones 8 (2 mmol) in tetrahydrofuran (20 mL)
was added tetra-n-butylammonium fluoride (2.2 mmol), and the
resulting solution was stirred at room temperature for 5 h. Sub-
sequently, the reaction mixture was poured into brine (20 mL) and
extracted with CH2Cl2 (3ꢁ20 mL), after which the organic fraction
was dried (MgSO4), followed by removal of the drying agent and
evaporation of the solvent in vacuo. Purification by means of col-
€
measured with a Buchi 540 apparatus.
4.2. Synthetic procedures
4.2.1. Synthesis of (E)-N-[3-(tert-butyldimethylsilyloxy)propylidene]
alkylamines 7.1f To a solution of 3-(tert-butyldimethylsilyloxy)
propanal1f (10 mmol) in anhydrous CH2Cl2 (40 mL) were added
MgSO4 (20 mmol) and a primary amine (10 mmol). After stirring for
2 h at room temperature, MgSO4 was removed by filtration. After
evaporation of the solvent in vacuo, (E)-N-[3-(tert-butyldime-
thylsilyloxy)propylidene]alkylamines 7 were obtained in high pu-
rity (>95% based on 1H NMR) and used as such in the next reaction
step due to their hydrolytic instability.
umn chromatography on silica gel gave pure b-lactams 11.
4.2.3.1. cis-3-Benzyloxy-4-(2-hydroxyethyl)-1-isopropylazetidin-
2-one 11a. 1H NMR (CDCl3, 300 MHz):
d
¼1.24 and 1.28 (2ꢁ d, 2ꢁ
3H, J¼6.9 Hz), 1.96e2.18 (m, 2H), 2.26 (t, 1H, J¼5.0 Hz), 3.64e3.85
(m, 3H), 3.91 (dꢁdꢁd, 1H, J¼9.2, 4.7, 4.5 Hz), 4.62 (d, 1H, J¼4.7 Hz),
4.73 and 4.99 (2ꢁ d, 2ꢁ 1H, J¼11.3 Hz), 7.28e7.40 (m, 5H); 13C NMR
(ref¼CDCl3, 75 MHz,): ¼20.2, 21.8, 32.3, 44.3, 55.3, 59.4, 72.9, 80.5,
d
4.2.1.1. (E)-N-[3-(tert-Butyldimethylsilyloxy)propylidene]iso-
128.05, 128.12, 128.6, 137.0, 167.2; IR (ATR):
n
¼1726 (C]O), ¼3418
n
butylamine 7c. 1H NMR (CDCl3, 300 MHz):
d
¼0.05 (s, 6H), 0.88 (s,
(OH); MS (ESþ): m/z¼264 (MHþ). Column chromatography (SiO2),
petroleum ether/ethyl acetate 1:1, Rf¼0.49. Yield 49%, yellow oil.
HRMS (ESI) calcd for C15H22NO3 264.1600 [MþH]þ, found 264.1598.
9H), 0.89 and 0.90 (2ꢁ d, 2ꢁ 3H, J¼6.8 Hz), 1.90 (nonet, 1H,
J¼6.8 Hz), 2.47 (q, 2H, J¼5.7 Hz), 3.19 (d, 2H, J¼6.8 Hz), 3.85 (t, 2H,
J¼5.7 Hz), 7.61 (t, 1H, J¼5.7 Hz); 13C NMR (CDCl3, 75 MHz):
d
¼ꢂ5.4,
18.3, 20.6, 25.9, 29.0, 38.9, 60.6, 69.6, 163.6; IR (ATR):
n
¼1671 (C]
4.2.3.2. cis-3-Benzyloxy-1-cyclohexyl-4-(2-hydroxyethyl)azeti-
N); MS (ESþ): m/z¼244 (MHþ). Yield 68%, yellow oil.
din-2-one 11b. 1H NMR (CDCl3, 300 MHz):
d
¼1.06e1.48, 1.52e1.65
and 1.73e1.95 (3ꢁ m, 4H, 2H, 4H), 1.97e2.15 (m, 2H), 2.37 (d, 1H,
J¼2.8 Hz), 3.36e3.46 (m, 1H), 3.63e3.77 (m, 2H), 3.91 (dꢁdꢁd, 1H,
J¼9.1, 4.7, 4.4 Hz), 4.61 (d, 1H, J¼4.7 Hz), 4.72 and 4.98 (2ꢁ d, 2ꢁ 1H,
J¼11.6 Hz), 7.29e7.36 (m, 5H); 13C NMR (ref¼CDCl3, 75 MHz):
4.2.2. Synthesis of cis-1-alkyl-4-[2-(tert-butyldimethylsilyloxy)ethyl]
azetidin-2-ones 8 and N-alkyl-N-[3-(tert-butyldimethylsilyloxy)prop-
1-en-1-yl]acetamides 9.1f To an ice-cooled solution of (E)-N-[3-
(tert-butyldimethylsilyloxy)propylidene]alkylamines 7 (3.6 mmol)
and Et3N (10.8 mmol) in anhydrous CH2Cl2 (25 mL) was added
dropwise a solution of benzyloxy- or phenoxyacetyl chloride
(4.7 mmol) in CH2Cl2. The reaction mixture was stirred for 15 h at
room temperature and was then washed with water (25 mL).
Subsequently, the aqueous phase was extracted with CH2Cl2
(3ꢁ25 mL), after which the combined organic fractions were dried
over MgSO4. After removal of the solvent in vacuo, mixtures of cis-
d
¼25.25, 25.28, 25.4, 30.6, 32.0, 32.3, 52.2, 55.4, 59.4, 72.8, 80.5,
128.06, 128.12, 128.6, 137.0, 167.1; IR (ATR):
n
¼1735 (C]O), ¼3238
n
(OH); MS (ESþ): m/z¼304 (MHþ). Mp¼70 ꢀC (column chromatog-
raphy (SiO2), petroleum ether/ethyl acetate 1:1, Rf¼0.18). Yield 60%,
white crystals. Anal. Calcd for C18H25NO3: C 71.26, H 8.31, N 4.62.
Found: C 71.13, H 8.50, N 4.63.
4.2.4. Synthesis of cis-1-alkyl-4-(2-mesyloxyethyl)azetidin-2-ones
12. To an ice-cooled solution of cis-4-(2-hydroxyethyl)azetidin-2-
ones 11 (5 mmol) in CH2Cl2 (30 mL) was added 4-(dimethyla-
mino)pyridine (0.5 mmol), Et3N (5.5 mmol), and mesyl chloride
(5.25 mmol), after which the mixture was stirred for 3 h at 0 ꢀC.
Afterward, the reaction mixture was washed with brine (2ꢁ30 mL)
and a saturated NaHCO3-solution (2ꢁ30 mL). The aqueous phase
was extracted with CH2Cl2 (2ꢁ30 mL), after which the organic
fraction was dried (MgSO4), followed by removal of the drying
1-alkyl-4-[2-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-ones
8
and N-acyl enamines 9 were obtained (22/78e83/17). Further pu-
rification by column chromatography on silica gel gave pure
lactams 8 and N-acyl enamines 9.
b-
4.2.2.1. cis-3-Benzyloxy-4-[2-(tert-butyldimethylsilyloxy)ethyl]-
1-isobutylazetidin-2-one 8d. 1H NMR (CDCl3, 300 MHz):
d
¼0.04 (s,
6H), 0.88 (d, 3H, J¼6.1 Hz), 0.89 (s, 9H), 0.92 (d, 3H, J¼6.1 Hz),
1.82e2.00 (m, 3H), 2.83 and 3.19 (2ꢁ (dꢁd), 2ꢁ 1H, J¼14.1, 8.3,
6.0 Hz), 3.64e3.78 (m, 2H), 3.88 (dꢁdꢁd, 1H, J¼7.0, 5.4, 5.2 Hz),
4.66 (d, 1H, J¼5.2 Hz), 4.69 and 4.90 (2ꢁ d, 2ꢁ 1H, J¼11.6 Hz),
agent and evaporation of the solvent in vacuo. b-Lactams 12 were
obtained in high purity (>95% based on 1H NMR) and used as such
in the next reaction step.
7.29e7.36 (m, 5H); 13C NMR (ref¼CDCl3, 75 MHz):
¼ꢂ5.3, 18.4,
d
20.3, 20.5, 26.0, 27.3, 31.5, 48.0, 55.5, 60.0, 72.8, 81.3, 127.9, 128.5,
4.2.4.1. cis-3-Benzyloxy-1-isopropyl-4-(2-mesyloxyethyl)azeti-
137.5, 168.3; IR (ATR):
Column chromatography (SiO2), petroleum ether/ethyl acetate
n
¼1750 (C]O); MS (ESþ): m/z¼392 (MHþ).
din-2-one 12a. 1H NMR (CDCl3, 300 MHz):
2ꢁ 3H, J¼6.3 Hz), 2.14e2.23 (m, 2H), 2.93 (s, 3H), 3.80 (septet, 1H,
d
¼1.23 and 1.27 (2ꢁ d,

10792
K. Mollet et al. / Tetrahedron 68 (2012) 10787e10793
J¼6.3 Hz), 3.91 (dꢁdꢁd, 1H, J¼8.5, 4.6, 4.1 Hz), 4.24e4.37 (m, 2H),
4.62 (d, 1H, J¼4.6 Hz), 4.68 and 4.93 (2ꢁ d, 2ꢁ 1H, J¼11.8 Hz),
(4.88 mmol). Subsequently, the resulting mixture was heated under
reflux for 4 h, after which the solvent was removed under reduced
pressure. Addition of dry diethyl ether, filtration of the precipitated
triethylamine hydrochloride, drying of the filtrate (MgSO4), filtra-
tion of the drying agent and removal of the solvent in vacuo yielded
the crude methyl cis-3-aminotetrahydrofuran-2-carboxylates 6,
which were further purified by means of column chromatography
on silica gel to provide an analytically pure sample.
7.28e7.36 (m, 5H); 13C NMR (ref¼CDCl3, 75 MHz):
¼20.2, 21.8,
d
29.6, 37.2, 44.4, 53.1, 66.9, 73.0, 80.6, 128.1, 128.2, 128.6, 137.2, 167.0;
IR (ATR):
n
¼1741 (C]O); MS (ESþ): m/z¼342 (MHþ). Yield 89%,
yellow oil. HRMS (ESI) calcd for C16H24NO5S 342.1375 [MþH]þ,
found 342.1381.
4.2.4.2. cis-3-Benzyloxy-1-cyclohexyl-4-(2-mesyloxyethyl)azeti-
din-2-one 12b. 1H NMR (CDCl3, 300 MHz):
d¼1.08e1.46, 1.51e1.66
4.2.6.1. Methyl cis-3-(isopropylamino)tetrahydrofuran-2-
and 1.75e1.93 (3ꢁ m, 4H, 2H, 4H), 2.11e2.29 (m, 2H), 2.94 (s, 3H),
3.37e3.47 (m, 1H), 3.92 (dꢁdꢁd, 1H, J¼8.8, 4.7, 4.4 Hz), 4.26e4.38
(m, 2H), 4.62 (d, 1H, J¼4.7 Hz), 4.68 and 4.95 (2ꢁ d, 2ꢁ 1H,
J¼11.5 Hz), 7.28e7.38 (m, 5H); 13C NMR (ref¼CDCl3, 75 MHz):
carboxylate 6a. 1H NMR (CDCl3, 300 MHz):
d
¼1.00 and 1.04 (2ꢁ
d, 2ꢁ 3H, J¼6.3 Hz), 1.83e1.95 and 2.10e2.21 (2ꢁ m, 2ꢁ 1H), 2.83
(septet, 1H, J¼6.3 Hz), 3.67 (wq, 1H, J¼6.6 Hz), 3.75 (s, 3H), 3.92
(dꢁdꢁd, 1H, J¼8.3, 8.3, 7.5 Hz), 4.18 (dꢁdꢁd, 1H, J¼8.3, 8.3, 5.5 Hz),
d
¼25.2, 25.3, 29.6, 30.6, 32.0, 37.2, 52.2, 53.3, 67.0, 72.9, 80.7, 128.0,
4.47 (d, 1H, J¼6.6 Hz); 13C NMR (ref¼CDCl3, 75 MHz):
¼23.1, 23.4,
d
128.1, 128.6, 137.2, 166.9; IR (ATR):
n
¼1740 (C]O); MS (ESþ): m/
32.6, 47.3, 51.7, 58.4, 67.7, 80.4, 171.9; IR (ATR):
n
¼1742 (C]O); MS
z¼382 (MHþ). Yield 86%, yellow oil. HRMS (ESI) calcd for
C19H28NO5S 382.1688 [MþH]þ, found 382.1695.
(ESþ): m/z¼188 (MHþ). Column chromatography (SiO2), petroleum
ether/ethyl acetate 4:1, Rf¼0.08. Yield 66%, light-yellow oil. HRMS
(ESI) calcd for C9H18NO3 188.1287 [MþH]þ, found 188.1289.
4.2.5. Synthesis of cis-2-oxa-6-azabicyclo[3.2.0]heptan-7-ones
5. Palladium on activated carbon (20% w/w) was added to a solu-
tion of cis-3-benzyloxy-4-(2-mesyloxyethyl)azetidin-2-ones 12
(4.5 mmol) in methanol (30 mL), and the resulting mixture was
placed in a Parr apparatus. The inside of the Parr apparatus was
then degassed and filled with hydrogen gas, after which the mix-
ture was stirred for 60 h at room temperature while applying 5 bar
of hydrogen gas. Filtration of the heterogeneous mixture through
CeliteÒ and evaporation of the solvent in vacuo afforded cis-3-
hydroxy-4-(2-mesyloxyethyl)azetidin-2-ones in high purity
(>90%, 1H NMR), which were used as such in the next reaction step.
4.2.6.2. Methyl cis-3-(cyclohexylamino)tetrahydrofuran-2-
carboxylate 6b. 1H NMR (CDCl3, 300 MHz):
d¼0.96e1.30,
1.57e1.61 and 1.68e1.94 (3ꢁ m, 5H, 1H, 5H), 2.09e2.19 (m, 1H),
2.40e2.49 (m, 1H), 3.75 (s, 3H), 3.73 (dꢁdꢁd, 1H, J¼10.3, 5.5,
5.4 Hz), 3.91 (wq, 1H, J¼7.5 Hz), 4.18 (wq, 1H, J¼7.5 Hz), 4.46 (d, 1H,
J¼5.5 Hz); 13C NMR (CDCl3, 75 MHz):
¼24.9, 25.0, 26.2, 32.7, 33.6,
d
34.2, 51.5, 55.1, 58.0, 67.6, 80.6, 171.8; IR (ATR):
n
¼1742 (C]O); MS
(ESþ): m/z¼228 (MHþ). Column chromatography (SiO2), petroleum
ether/ethyl acetate 6:1, Rf¼0.07. Yield 70%, colorless oil. HRMS (ESI)
calcd for C12H22NO3 228.1600 [MþH]þ, found 228.1603.
To an ice-cold solution of the latter b-lactams (4.5 mmol) in tetra-
hydrofuran (30 mL) was added sodium hydride (4.5 mmol), after
which the mixture was heated under reflux for 15 h. The reaction
mixture was poured into brine (1ꢁ30 mL) and extracted with ethyl
acetate (3ꢁ30 mL), after which the organic fraction was dried
(MgSO4), followed by removal of the drying agent and evaporation
of the solvent in vacuo. Purification by means of column chroma-
tography on silica gel afforded cis-2-oxa-6-azabicyclo[3.2.0]hep-
tan-7-ones 5 in pure form.
Acknowledgements
The authors are indebted to Ghent University (GOA) and the
Research Foundation – Flanders (FWO-Vlaanderen) for financial
support.
References and notes
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4.2.5.1. cis-6-Isopropyl-2-oxa-6-azabicyclo[3.2.0.]heptan-7-one
5a. 1H NMR (CDCl3, 300 MHz):
d
¼1.26 and 1.28 (2ꢁ d, 2ꢁ 3H,
J¼6.6 Hz), 1.60e1.73 (m, 1H), 2.07 (w(dꢁd), 1H, J¼13.8, 5.0 Hz),
3.86e3.98 (m, 2H), 4.20e4.29 (m, 2H), 5.03 (d, 1H, J¼3.3 Hz); 13C
NMR (CDCl3, 75 MHz):
d
¼20.4, 21.9, 29.7, 43.9, 56.9, 67.2, 85.7,
165.6; IR (ATR):
n
¼1732 (C]O); MS (ESþ): m/z¼156 (MHþ). Column
chromatography (SiO2), petroleum ether/ethyl acetate 1:1, Rf¼0.10.
Yield 52%, colorless oil. HRMS (ESI) calcd for C8H14NO2 156.1025
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d
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n
¼1736 (C]O); MS (ESþ): m/z¼196
(MHþ). Column chromatography (SiO2), petroleum ether/ethyl ac-
etate 3:1, Rf¼0.05. Yield 62%, colorless oil. HRMS (ESI) calcd for
C11H18NO2 196.1338 [MþH]þ, found 196.1335.
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