Synthesis of N,4-diaryl substituted β-lactams via Kinugasa cycloaddition/rearrangement reaction

Article abstract of DOI:10.1016/j.tet.2011.11.007

The methodology of construction of N,4-diaryl substituted β-lactam framework, based on the Kinugasa cycloaddition/rearrangement sequence is presented. The series of protected chiral propargyl alcohols was treated with diaryl nitrones to afford mainly the

Full text of DOI:10.1016/j.tet.2011.11.007

Tetrahedron 68 (2012) 10806e10817
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of N,4-diaryl substituted
b-lactams via Kinugasa
cycloaddition/rearrangement reaction
ꢀ
Micha1 Michalak, Maciej Stodulski, Sebastian Stecko, Magdalena Woznica, Olga Staszewska-Krajewska,
*
Przemys1aw Kalicki, Bart1omiej Furman, Jadwiga Frelek, Marek Chmielewski
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
The methodology of construction of N,4-diaryl substituted b-lactam framework, based on the Kinugasa
Received 2 September 2011
Received in revised form 27 October 2011
Accepted 4 November 2011
Available online 11 November 2011
cycloaddition/rearrangement sequence is presented. The series of protected chiral propargyl alcohols
was treated with diaryl nitrones to afford mainly the cis-I adduct, providing direct access to the highly-
functionalized azetitidin-2-one derivatives with a well-defined stereochemistry. Under the optimized
reaction conditions, the unprotected chiral propargylic alcohols were also found to be suitable precursors
of b-lactams. The absolute configuration of adducts was determined by CD or HPLC-CD technique, which
was shown to be reliable method of determination of the configuration at C-4 of 4-aryl-substituted
azetidin-2-ones. Epimerization of the cis adduct to the respective trans isomer could be easily done
Keywords:
2-Azetidinones
Monolactams
Kinugasa reaction
Asymmetric synthesis
Assignment of absolute configuration
Circular dichroisms
by the oxidation of hydroxyl group next to the four-membered
b
-lactam ring to the ketone, followed
by a base-mediated epimerization of the malonyl fragment.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
of R1 as a chiral auxiliary or R2 as the defined chiral fragment that
can be transformed later into desired C-3 substituent (Scheme 1).
Recently, we have reported a formal synthesis of Ezetimibe 1,18
a powerful cholesterol absorption inhibitor.1,2 The crucial step of
the reported synthesis is based on the Cu(I)-mediated Kinugasa
cycloaddition/rearrangement cascade reaction between terminal
The N,4-diaryl substituted b-lactams 1e8 represent a group of
compounds exhibiting a wide range of interesting biological ac-
tivities, such as cholesterol absorption inhibition (compounds
1e4),1e7 antifungal (compound 5),8 analgestic (compound 6),9 and
anticancer (compounds 7 and 8).10,11 All reported to-date meth-
odologies of their synthesis have been based on a construction of
acetylene derived from -glyceraldehyde acetonide 9 and suitable
L
C,N-diarylnitrone 10 (Scheme 2). The adduct 11 with (3R,4S) con-
figuration at the azetidinone ring was obtained with a high stereo-
selectivity. The diol side chain was subsequently deprotected and
subjected to the glycolic cleavage followed by the base-induced
isomerization at C-3 carbon atom to afford the (3S,4S)-aldehyde
12. The transformation of aldehyde 12 into Ezetimibe was previously
demonstrated by the Schering-Plough Process group (Scheme 2).19
The effectiveness of transformation of 9 and 10 into the alde-
hyde 12 prompted us to investigate general possibilities of appli-
cation of Kinugasa reaction as a method of the synthesis of selected
the
b-lactam ring via cyclocondensation of suitable substituted
benzylidene-anilines and ketene, ester, or amide enolates.12e17 In
many cases, compounds 1e8 have been obtained as racemic mix-
tures. Moreover, their full relative configuration has not always
been assigned.
The knowledge of an absolute configuration of chiral centers
present in biologically active compounds as well as an ability of
rational asymmetric construction of these centers are essential
preconditions for the successful exploration of future applications
of these compounds. In the case of
b-lactam syntheses via cyclo-
N,4-diaryl substituted b-lactams. Considering the structures of
condensation of esters or amides with imines, the control of stereo-
configuration of newly formed stereogenic centers in the four-
membered ring has been usually accomplished either by the use
compounds 1e8 and the possible transformations of substituents at
C-3 of synthesized azetidinones, we decided to limit the selection
of investigated compounds to acetylenes derived from L-glyceral-
dehyde (14a), (S)-malic acid (14b) and substituted propargyl
alcohols (15aee), and C,N-diaryl-nitrones: either unsubstituted or
with p-protected oxygen atom in the benzylidene fragment, or else
p-fluoroaniline (13aef).
* Corresponding author. E-mail address: chmiel@icho.edu.pl (M. Chmielewski).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.11.007

M. Michalak et al. / Tetrahedron 68 (2012) 10806e10817
10807
2. Results and discussion
aryls to corresponding hydroxylamines followed by the condensa-
tion with substituted benzaldehydes in the presence of meth-
anesulphonic acid as a catalyst. This procedure offers an advantage
over classical method, based on the condensation of an aryl hy-
droxylamine and substituted benzaldehyde in ethanol at reflux,
since it allows to easily scale-up the preparation. The optimized
conditions allowed preparation of nitrones 13bef in a 40e67% yield.
The other synthons for Kinugasa reaction, namely terminal
acetylenes 14a,b, were obtained by a one-pot procedure from
corresponding aldehydes by treatment with BestmanneOhira
reagent.24,25 Alcohol 15a was synthesized starting from
phenethylaldehyde by the known sequence of reactions involving
HornereEmmons olefination with triethyl phosphonoacetate,
reduction of the ester group to an alcohol, enantioselective epoxi-
dation, exchange of hydroxyl group into chlorine atom and finally
a rearrangement of the respective chloroepoxide to the product 15a
with 84% ee.26 Alternatively, alcohol 15a could be obtained fol-
lowing a shorter synthetic sequence based on the enantioselective
addition of 2-methyl-3-butyn-2-ol to phenethylaldehyde, medi-
ated by Zn(OTf)2/N-methylephedrine complex and subsequent
elimination of acetone in the presence of base to afford 15a with
82% ee.27 Propargylic alcohols 15b and 15c are commercially
available and were used without further purification (Chart 2).
Kinugasa reactions of nitrones 13aef and acetylenes 14 and 15
were performed under standard reaction conditions in the presence
of CuI (1 equiv) and Et3N (4 equiv) in acetonitrile at rt. Recently, we
have found that the use of N,N,N0,N0-tetramethylguanidine (TMG)
offered better selectivity and yield than that obtained with Et3N,18
Preliminary investigation of Kinugasa reaction between diaryl
nitrones and terminal acetylenes indicated that the yield of re-
action depends on the nature of both aryl substituents. This ob-
servation corresponds well with our previous work on the
FriedeleCrafts reaction between acyl-iminium cation generated
from 4-vinyloxy- or 4-acyloxy-azetidin-2-one and nucleophilic
arenes, such as anisol (Scheme 3).20 It has been shown that the
initially formed 4-anisyl-azetidinone in the presence of Lewis acid
underwent rapid opening of the four-membered ring by the
second molecule of the nucleophile to form diaryl-substituted
propionamides. Similarly, Carreira21,22 observed
opening/cyclization cascade during attempts to reduce
containing electron-rich substituent at C4. This transformation
involves the ring opening of azetidine leading to a benzylic car-
bocation as an intermediate, which is facilitated by electron-rich
substituent of arene.
To shed more light on the reaction pathway, a representative
group of C,N-diaryl-nitrones 13aef (Chart 1) was obtained utilizing
a modified literature method,23 which involved reduction of nitro-
b
-lactam ring
-lactams
b
Scheme 1.

10808
M. Michalak et al. / Tetrahedron 68 (2012) 10806e10817
Scheme 2.
Scheme 3.
Table 1
R1
13a R1: F, R2: OBn
The Kinugasa reaction of chiral acetylenes 14a,b and diaryl nitronesa
13b R1: H, R2: OBn
13c R1: F, R2: H
O
Entry Acetylene Nitrone Product dr (cis-I:trans-I):
(cis-II:trans-II)b
Yield of cis-I
N
isomer (overall
13d R1: F, R2: OTs
13e R1: H, R2: H
13f R1: F, R2: OMs
yield)c [%]
1
2
3
4
5
6
7
8
9
14a
14a
14a
14a
14a
14a
14a
14a
14b
14b
13a
13b
13c
13d
13d
13d
13e
13f
16
17
18
19
19
19
20
21
22
23
(9.7:2.7):(1:1)
41 (61)
62d (95)
55e (62)
R2
(4.1:1.0):(3.5:0)
(5.3:2.5):(1.3:1.0)
Chart 1.
(7.1:1.0):(1.0:1.6)f 45
(9.3:1.0):(1.3:1.9)
(2.9:1.4):(1.0:0)
(4.8:1):(1.1:17)
(5.0:1.0):(1.0:2.0)
(4.8:1.0):(1.2:1.8)
(6.3:1.0):(1.0:1.6)
54g
30h
48 (82)
60
R2
OR
O
O
O
O
O
13a
13c
41 (75)
R1
Ph
10
57i (62)
a
Standard conditions: nitrone (2 equiv), acetylene (1 equiv), CuI (1 equiv), TMG
(2 equiv) in MeCN at rt.
:
,
a
14
a
14b
15
1
2
R H
:
:
:
:
15b
R
R
R
Ph R
H
H
b
,
Determined by 1H NMR and HPLC.
:
15d
R TBS
1
1
e
:
c
15
M
R2
c
,
2
:
The overall yield was determined by 1H NMR of crude reaction mixture in CDCl3
e
15
Ph R TBS
in the presence of trichloroethylene as an internal standard.
d
Inseparable by chromatography mixture of 17-cis-I and 17-trans-I in ratio 3:1.
Mixture of isomers in ratio 7.3:2.5:1 (18-cis-I:18-trans-I:18-trans-II), 18-cis-II is
Chart 2.
e
more polar and was lost during the purification.
f
TMG (4 equiv) was used.
Reaction performed with 2 equiv of TMG.
Reaction performed with 4 equiv of Et3N.
Mixture of isomers in ratio 7.7:1.0:1.5 (23-cis-I:23-trans-II:23-trans-I).
and we repeated reactions in the presence of TMG. The results are
summarized in Tables 1 and 2. The absolute configuration of -lac-
g
h
b
i
tams was assigned by combination of NMR, CD, and X-ray analysis.
Since the latter methodology has a general value for assignment of
the absolute configuration for all 4-aryl-azetidin-2-ones we present
a detailed discussion in the next section (vide infra).
In comparison with the previously investigated reactions of
non-racemic acetylenes, such as 14a, with cyclic nitrones,28e30 the
Kinugasa reactions involving C,N-diaryl imine oxides offered
a lower level of stereoselectivity, reflected by the detection of four
data show that the first step of cascade, cycloaddition, exhibits the
preference of acetylene to approach to the si side of the nitrone and
therefore to yield products with the (S) configuration at C-4 of
azetidinone ring (16e27 cis-I and 16e27 trans-I, Schemes 4 and 6).
Interestingly, the protonation of (4S)-enolates proceeds with
a higher selectivity, providing mostly cis-I products, whereas pro-
tonation of corresponding (4R)-enolates tends to yield a mixture of
equal amounts of cis-II and trans-II azetidinones or with a slight
excess of latter one.
possible isomeric b-lactam products (Scheme 4). Such a result is not
entirely surprising since Kinugasa reaction is a complex reaction
cascade, which consists of cycloaddition-rearrangement followed
by the enolate protonation (Scheme 5). Nevertheless, the collected

M. Michalak et al. / Tetrahedron 68 (2012) 10806e10817
10809
Table 2
(Table 1, entry 2) in a high overall yield. For nitrone 13a both effects
are additive, therefore the reaction with this compound proceeded
stereoselectively but with a moderate yield only (Table 1, entry 1).
Next, we explored the use of unprotected chiral propargylic al-
cohols. It should be noted that such acetylenes have not been re-
ported yet as reactants in Kinugasa reaction. First, we choose
alcohol 15c and the simplest nitrone 13e. Gratifyingly, we found
The Kinugasa reaction of unprotected propargylic alcoholsa
Entry Acetylene Nitrone Product Diastereoisomers ratio
Yield [%]
cis-I:trans-I:cis-II:trans-IIb,c
1
2
3
4
15c
15b
15e
15a
13e
13e
13e
13a
24
25
26
27
42:10:26:22
45:26:18:11
d
62d
65d
n.r.
57d
42:9:26:23
that formation of
b-lactam proceeded in a good overall yield
n.r.dno reaction.
(62%) by using 2 equiv of copper iodide(I) (Table 2, entry 1). Un-
fortunately, chromatographically inseparable mixture of four pos-
sible isomers was formed. The absolute configuration of respective
adducts was confirmed by HPLC-CD technique to indicate 24-cis-I
(for stereo description see Scheme 4) adduct as a major product (for
a
Standard conditions: nitrone (2 equiv), acetylene (1 equiv), CuI (1 equiv), TMG
(2 equiv) in MeCN at rt.
b
Determined by 1H NMR and/or HPLC of crude mixture.
For cis/trans description see Scheme 4.
Isolated yield (mixture of isomers).
c
d
Scheme 4.
Scheme 5.
Scheme 6.
Additionally, as indicated by data presented in Table 1, both the
the determination of configuration vide infra). Somewhat better
diastereoselectivity was obtained using alcohol 15b with respect to
(4S):(4R) ratio. The same result, in comparison to alcohol 15c, was
obtained with alcohol 15a bearing a long side chain with nitrone
13a. However, in contrast to outcome of other reactions, the final
adducts were isolated as two mixtures: both cis diastereomers 27-
cis-I, 27-cis-II and both trans ones 27-trans-I, 27-trans-II. Rather
surprisingly, we did not observe formation of any products during
the reaction with the silyl-protected analogs 15d and 15e, probably
due to the steric reasons.
yield and the stereoselectivity of these reactions are strongly re-
lated to the electronic nature of the nitrone. This can be easily
followed comparing the results of the reaction of acetylene 14a
with nitrones 13b, 13c, and 13e (Table 1, entries 2, 3, and 7). The
reaction with nitrone bearing the p-fluorophenyl substituent at the
nitrogen atom (13c) proceeded with a higher selectivity, to afford
predominantly 18-cis-I product, but with a lower overall yield in
comparison with analogous reaction involving nitrone 13e. On the
other hand, the reaction of acetylene 14a with nitrone 13b, bearing
a nucleophilic aryl in the benzylidene fragment, proceeded with
a lack of selectivity to afford mixture of cis- and trans-azetidinones
All biologically active N,4-diaryl-b-lactams 1,3,4,8 have the trans
substituted four-membered ring, whereas Kinugasa reaction

10810
M. Michalak et al. / Tetrahedron 68 (2012) 10806e10817
stressed that, the hydroxyl group at the side chain can be restored
after epimerization by subsequent reduction of the keto function
(Scheme 9).31e39
3. Determination of an absolute configuration
Chiroptical methods, and the electronic circular dichroism
spectroscopy (ECD) in particular, appear to be convenient, sensitive,
and fast techniques for the stereochemical assignments of azetidi-
nones and their polycyclic derivatives in a solution as well as in the
solid state.40e42 Based on a broad variety of experimental data
supported by the X-ray and computational studies, several sector
and helicity rules for the correlation between the structure and
provides adducts with the cis-configuration. Epimerization of the
cis adducts to the respective trans isomers could be achieved by the
oxidation of the side-chain hydroxyl group to the ketone in 24, 25
or 27 (Scheme 7), or by deprotection of the diol in the side chain
followed by a silylation of the terminal group and oxidation of the
secondary hydroxyl (such as alcohol 29, Scheme 8). Subsequently,
Cotton effect (CE) signs of n/
ed.43e46 These rules allow to connect a negative CE associated with
the n/ * amide transition and the (4R) absolute configuration of
p* transition have been establish-
p
the base-catalyzed epimerization provided trans substituted
b-
azetidinones and a positive CE of the same excitation with their (4S)
absolute configuration. Thus, we decided to use the ECD spectros-
copy for a determination of the absolute stereochemistry at C4 car-
bon atom of compounds 16-cis-I, 16-trans-I, 16-cis-II, 20-cis-I, and
17-cis-I isolated in a pure form from the reaction mixtures. It is
important to note, however, that direct application of CIP rules for
the stereochemistry designation at C4 in investigated compounds
lactam ring. In the case of the vic-diol derived from glyceraldehyde,
glycolic cleavage led to the aldehyde, which easily epimerized in
the presence of a base. Recently, this strategy has been exploited by
us during the formal synthesis of Ezetimibe18 and presently is
demonstrated by formation of trans substituted
b
-lactams (see
Scheme 2).
OH
O
H
H
N
H
H
N
PCC, MS 4Å
CH2Cl2
R
R
O
O
single trans isomer
24 R: Me
28a R: Me, yield 73%, er 60:40
28b R: Ph, yield 82% er 68:32
28c R: CH2CH2Ph, yield 96%, er 54:46
25 R: Ph
27 R: CH2CH2Ph
Scheme 7.
Scheme 8.
Scheme 9.
The removal of a stereogenic center in the side chain of crude
mixture of Kinugasa adducts by oxidation followed by a base epi-
merization led to the partially racemized product as a consequence
of the ratio of (4R,4S) Kinugasa products (cis-Iþtrans-I:cis-IIþtrans-
II). Moreover, bearing in mind that biologically active N,4-diaryl-
may lead to a change of (R) and (S) descriptors depending on the
identity of substituents without accompanying change of the actual
stereochemical arrangement at C4 carbon atom. Therefore, for the
azetidinones studied we decided to use the D and L nomenclature
system, as defined in Fig. 1. According to this system, compounds
with a positive 240 nm CE belong to the L series (ii in Fig.1), whereas
the negative sign of this CE indicates the membership of the D series
(i in Fig.1). Thus, compounds 16-cis-I,16-trans-I, 20-cis-I, and 17-cis-
I with a negative CE, appearing at around 240 nm, were attributed to
the D series, whereas compound 16-cis-II characterized bya positive
CE at the same spectral range was assigned to the L series.
azetidinones 1,3e5,7,8 have trans substituted
b-lactam ring, the
practical selectivity of the Kinugasa reaction depends on a ratio (cis-
Iþtrans-I):(cis-IIþtrans-II) adducts because a base epimerization
transforms all adducts cis into corresponding trans ones. Conse-
quently in the case of target oriented synthesis only partial sepa-
ration of the post reaction mixture is necessary. It should be

M. Michalak et al. / Tetrahedron 68 (2012) 10806e10817
10811
Fig. 1. Definition of the D- and L-series.
Regarding the absolute configuration, the (4S) configuration can
be assigned to compounds 16-cis-I, 16-trans-I, 17-cis-I, and 20-cis-I
from the D series, whereas the (4R) absolute configuration can be
ascribed to the representative of the L series, compound 16-cis-II.
This assignment is additionally corroborated by the X-ray data of
compounds 16-cis-I, 18-cis-I, and 23-cis-I where the (4S) absolute
configuration was independently confirmed (Fig. 2).47
The stereochemical analysis of crude post-reaction mixtures
consisting of adducts with a different ratio of enantiomers or di-
astereoisomers was performed using the high-performance liquid
chromatography with a circular dichroism detection in addition to
the customary UV detection (on-line HPLC-CD). The combination of
this methodology and NMR spectroscopy allowed for the full con-
figurational assignment without the need to separate pure com-
Fig. 2. Crystal structures of compound 16-cis-I, 18-cis-I, and 23-cis-I.
To confirm that the same molecular species are present in a solid
state and in a solution, ECD spectra of 16-cis-I and 16-cis-II were
measured both in solid state as well as in the solution and then
compared. The results obtained for the solid state measurement are
in a good agreement with the respective data recorded in solution,
as can be seen in Fig. 3. This conformity indicates that the sol-
uteesolvent interactions, which may affect the ECD spectra con-
siderably due to both conformational and vicinal effects, are
negligible and strongly suggests that the observed CD is largely
a molecular property. Therefore, the analysis of the CD data for the
purpose of determination of the absolute configuration of azetidi-
nones 16e25 can be performed on the basis of chiroptical data
obtained for solutions.
ponents from reaction mixtures. In the case of compound 28a
enantiomeric resolution was performed by HPLC-CD. The chro-
matogram of 28a shows the presence of both enantiomers in the
reaction mixture (Fig. 3, left). The assignment of the absolute
configuration at C4 was made on the basis of the full LC-CD spectra
recorded in the stop-flow mode. As shown in the Fig. 3 (right), the
CD curves are almost mirror-shaped.
The positive sign of the CE at around 240 nm for the faster eluting
peakindicatesthatitisbelonging tothe L series, whereas the negative
CEinthesamespectralregionpointstothemembershipofDseriesfor
the slower eluting peak. The stereochemical assignment at C3 carbon
atom was done by comparing the coupling constants of protons (H3
and H4) located at C3 and C4 carbon atoms in the 1H NMR spectrum
(of reaction mixture). Coupling constant equal to 2.4 Hz indicates
a trans relationship of both protons. Thus, the (3R,4R) absolute con-
figuration can be attributed to the faster eluting enantiomer, whereas
(3S,4S) absolute configuration to the slower eluting enantiomer.
The same combined procedure of LC-CD and NMR when applied
to the mixture of enantiomers 28c allowed to assign the absolute
configuration at their C3 and C4 carbon atoms. The faster eluting
peak is characterized by a positive CE at 250 nm while the slower
eluting peak has a negative CE at 249 nm. Therefore, compound 28c
corresponding to the first peak could be attributed to the D series
and compound ent-28c, related to the slower eluting peak, to the L
series. The detailed ECD spectra recorded in the flow-stop mode
and 1H NMR coupling constants analysis leading to the assignment
of (3R,4R) and (3S,4S) absolute configuration, respectively, are
provided in the Supplementary data.
Much more complex and difficult was the stereochemical analysis
of diastereomeric mixtures of 18, 22, 23, and 24. All these mixtures
consisted of four components, with three-components differing in
polarity only marginally. In all studied cases, the fourth compound
has a significantly different retention time. A detailed discussion
leading to the determination of absolute stereochemistry of all four
Fig. 3. Experimental ECD spectra for 16-cis-I in acetonitrile solution (blue line) in
D 3
(Mꢀ1 cmꢀ1) and in KCl matrix (red line) in mdeg.

10812
M. Michalak et al. / Tetrahedron 68 (2012) 10806e10817
Fig. 4. Stereochemical assignment of the two enantiomers of 28a by coupling of HPLC-CD with NMR spectroscopy; left: chromatogram of the 28a mixture; right: CD spectra of 28a
(red line) and ent-28a (blue line) recorded in the stop-flow mode (ChiralpakÒ AD-H column, eluent i-PrOH/hexane 9:91 (v/v), flow 0.8 mL/min, detection at 250 nm).
components is presented here using as an example mixture 23.
For the first pass a mixture of MTBE/n-hexane 3:7 (v/v) as an
eluent was used. Under these conditions, we could separate
only the slowest component (Fig. 5, chromatogram 1). In its ECD
spectrum recorded in the stop-flow mode the positive sign of the
decisive CE at around 250 nm indicated the membership of the
L-series. In addition, the coupling constant equal to 6.1 Hz in its 1H
NMR spectrum pointed to a cis arrangement of protons at C3 and
C4. Based on the combined on-line HPLC-CD and NMR analysis
the (3S,4R) absolute configuration could be ascribed to the slowest
component of the mixture 23.
Next, the mixture of remaining three-components was sepa-
rated using an MTBE/n-hexane 15:85 (v/v) as eluant with a flow
rate of 1 mL/min and UV/CD detection at lUV,CD¼245 nm. Applying
the stop-flow mode we were also able to register their individual
ECD spectra (Fig. 5). The fastest and third consecutive components
fastest to slowest eluting as follows: (3R,4S); (3R,4R); (3S,4S);
(3S,4R), respectively. In the case of 18 and 24 the absolute config-
uration was assigned to be (3S,4R); (3R,4R); (3S,4S); and (3R,4S) in
the order of elution from fastest to slowest, respectively.
Details of HPLC-CD and NMR analysis for all compounds are
given in the experimental part and in Supplementary data.
In summary, the presented on-line HPLC-CD methodology,
supported by 1H NMR spectroscopy, proved to be a very valuable
tool to determine the absolute configuration of the individual
constituents of complex multi-component mixtures. One of the
main advantages of such an approach is that it does allow to per-
form the full structural analysis without the need to isolate in a pure
form the individual components of the mixture. It is particularly
useful in cases where a separation or a purification of a multi-
component mixture by traditional chromatography is very diffi-
cult or impossible. In addition, this methodology can be considered
as a method of choice for fast assignment of the three dimensional
structure when tested compounds are not sufficiently stable. For
these reasons, it seems that the on-line HPLC-CD detection with the
stop-flow mode will find an increased use both in the laboratories of
modern organic chemistry and pharmaceutical chemistry as well.
both had a negative CD in the n/p* b-lactam amide transition
spectral range, which allowed the assignment of both constituents
to the D-series. The second fastest peak belonged to the component
with a positive CE in the crucial spectral range thus indicating its
membership in the L-series. The NMR coupling constant value
equal to 2.4 and 2.6 Hz, measured for the fastest and the second
fastest peaks of chromatogram, respectively, was indicative of the
trans arrangement of protons at carbon atoms C3 and C4. On this
basis, the (3S,4S) and (3R,4R) can be ascribed to the fastest and the
second fastest peaks, respectively. The slowest peak was charac-
terized by a cis orientation of protons at carbons C3 and C4, as in-
dicated by the coupling constant of 5.6 Hz in its NMR spectrum.
Accordingly, the (3R,4S) absolute configuration was assigned to this
component of the reaction mixture. Thus, using HPLC-CD meth-
odology combined with 1H NMR analysis we could assign the ab-
solute configuration of all four components of the reaction mixture
without separation of individual components in a pure form.
Applying a similar combined HPLC-CD/NMR methodology we
were able to fully characterize stereochemically all components of
the other reaction mixtures. The analysis of 22 allowed to establish
the absolute configuration of its four components in order from
4. Summary
The presented methodology enables an easy access to N,4-diaryl
b-lactams with the defined configuration of C3 and C4 stereogenic
centers, starting from readily available, inexpensive chiral acety-
lenes. All reactions are characterized by a moderate to good dia-
stereoselectivity, and it could be further modulated by changing the
electronic properties of the nitrone. The best results, from the point
of selectivity, were obtained for nitrones bearing electron-
withdrawing group (e.g., Ts or Ms). Bearing in mind that in-
teresting N,4-diaryl-azetidinones have trans substituted b-lactam
ring, the practical selectivity of the Kinugasa reaction depends on
a ratio (cis-Iþtrans-I):(cis-IIþtrans-II) adducts. It was also demon-
strated for the first time that the unprotected chiral propargylic
alcohol could be utilized in the Kinugasa reaction. The respective

M. Michalak et al. / Tetrahedron 68 (2012) 10806e10817
10813
Fig. 5. Stereochemical assignment of the four diastereoisomers of 23 by coupling of HPLC-CD with NMR spectroscopy; top: two chromatograms of the 23 mixture; bottom: CD
spectra of 23-trans-I (red line), 23-trans-II (blue line), 23-cis-I (green line), and 23-cis-II (violet line) recorded in the stop-flow mode (LiChrospherÒ Si60 column and mixtures of
MTBE/n-hexane as the mobile phase with a flow rate of 1 mL/min).
adducts were subsequently oxidized/epimerized by treatment with
PCC affording pure derivatives of trans azetidinone, which is
a common framework of many antibiotics.
Jasco P-2000 polarimeter. Melting points were determined on
a hot-stage apparatus and are uncorrected.
HPLC-CD measurements were performed with the Jasco HPLC
system equipped with a PU-2089 quaternary gradient pump, the
UV-2075 UV-detector and Jasco J-815 spectropolarimeter as a CD-
detector. The 1 mg sample was dissolved in 1 mL of mobile phase
5. Experimental procedures
5.1. General
and filtered through a 0.45
mm Nylon syringe filter. Injection vol-
umes for all samples were 20
m
L. Separations were performed with
LiChrospherÒ Si60 column (5
mm, 250ꢁ4.6) using mixtures of MTBE
The NMR spectra were recorded on Varian VNMRS 500 MHz and
Varian VNMRS 600 MHz spectrometers. Chemical shifts are re-
and hexane as a mobile phase with a flow rate in range 0.8e1.0 mL/
min or with Daicel ChiralpakÒ AD-H or Daicel ChiracelÒ OD-H chiral
ported in d units and coupling constants are reported in hertz. High
column (5
m
m, 250ꢁ4.6) using mixtures of i-PrOH and hexane as
resolution mass spectra (HRMS) were taken using AMD-604 spec-
trometer (for electron ionization, 70 eV) or on Mariner spectrom-
eter (for electrospray ionization). Infrared spectra were recorded on
Jasco-V670 spectrophotometer. Optical rotatory was recorded on
a mobile phase with a flow rate in range 0.6e0.8 mL/min.
All solvents were dried and purified by known techniques.48
N,N,N0,N0-tetramethylguanidine (TMG) was purchased from

10814
M. Michalak et al. / Tetrahedron 68 (2012) 10806e10817
SigmaeAldrich and used without further purification. Nitrones 13a18
and 13e49 were prepared following literature procedures. Merck
silica gel, 230e400 mesh was usedfor flash columnchromatography.
cannulated into suspension of nitrone. After stirring for 20 h at rt
under argon atmosphere, the reaction mixture was diluted with
AcOEt (10 mL) and H2O (10 mL). Aqueous phase was separated and
washed with AcOEt (2ꢁ50 mL). Combined organic phases were
washed with brine, dried (Na2SO4), and concentrated. The di-
5.1.1. N-Phenyl-a-(4-benzyloxyphenyl)nitrone (13b). Nitrone 13b
was synthesized following literature procedure18 starting from
N-phenylhydroxylamine (5.46 g, 50.0 mmol), p-benzyloxybenzal-
dehyde (10.61 g, 50.0 mmol), CH3SO3H (4 drops), and acetone
(100 mL). Nitrone 13b was obtained as a off-white solid (6.1 g, 40ꢀ%1).
astereoisomer ratio of b
-lactamic products was assigned by 1H NMR
and HPLC of crude reaction mixture. The products was isolated by
column chromatography on silica gel (hexane/AcOEt mixtures).
Pure cis-I isomers were obtained by recrystallization from EtOH.
Mp 157e159 ꢂC (acetone); IR (film): 3050, 3035, 1603, 1550 cm
;
1H NMR (600 MHz, CDCl3) 8.42e8.38 (m, 2H), 7.84 (s,1H), 7.78e7.74
(m, 2H), 7.48e7.31 (m, 8H), 7.08e7.04 (m, 2H), 5.13 (s, 2H); 13C NMR
(150 MHz, CDCl3) 160.7, 149.0, 136.4, 134.1, 131.1, 129.6, 129.1, 128.7,
128.2, 127.5, 124.0, 121.7, 114.9, 70.1; HRMS (EI) m/z calcd for
C20H17NO2: 303.1259; found: 303.1252.
5.2.1. Azetidinone 16-cis-I. Mp 150e152 ꢂC (EtOH); ½a D25
ꢀ74 (c 0.6,
ꢃ
CH2Cl2); 1H NMR (500 MHz, C6D6)
d: 7.20 (m, 2H), 7.12 (m, 2H), 7.06
(m, 2H), 7.01 (m,1H), 7.86 (d, J 14 Hz, 2H), 6.69 (d, J 14 Hz, 2H), 6.61 (m,
2H), 4.55 (m, 2H), 4.45 (d, J 5.8 Hz,1H), 4.13 (dd, J 8.5, 6.5 Hz,1H), 3.94
(dd, J 8.5, 6.1 Hz, 1H), 3.81 (dt, J 9.4, 6.1 Hz, 1H), 3.33 (dd, J 9.4, 5.8 Hz,
1H),1.30 (s, 3H), 0.93 (s, 3H); 13C NMR (125 MHz, C6D6)
d: 162.9,159.7,
5.1.2. N-(4-Fluorophenyl)-
a
-phenylnitrone (13c). Nitrone 13c was
158.8 (d, JCF 241.5 Hz), 158.1, 136.9, 134.2 (d, JCF 2.6 Hz), 128.3, 128.0,
126.3, 118.4 (d, JCF 7.6 Hz),115.6 (d, JCF 22.5 Hz),115.3,114.8,108.5, 71.0,
synthesized following literature procedure18 starting from N-(p-
fluorophenyl)-hydroxylamine (5.95 g, 46.8 mmol), benzaldehyde
(4.7 mL, 46.8 mmol), CH3SO3H (3 drops), and acetone (70 mL).
Nitrone 13c was obtained as a off-white solid (4.8 g, 50%). Mp
69.6, 67.3, 58.7, 57.0, 26.8, 25.1; 19F NMR (470 MHz)
d: ꢀ117.4 (m); IR
(film): 1748, 1510 cmꢀ1; HRMS (ESI): m/z calcd for C27H26NO4FNa
[MþNaþ] 470.1738; found: 470.1754; El. Anal. calcd for C27H26NO4F, C
72.47, H 5.86, N 3.13, F 4.25; found: C 72.39, H 5.78, N 3.15, F 4.32.
170e171 ꢂC (EtOH); 1H NMR (500 MHz, CDCl3)
d
: 8.45e8.36 (m,
2H), 7.88 (s, 1H), 7.84e7.76 (m, 2H), 7.56e7.45 (m, 3H), 7.20e7.12
(m, 2H), 5.13 (s, 2H); 13C NMR (125 MHz, CDCl3)
: 163.0 (JCF
d
5.2.2. Azetidinone 17-cis-I. Mp 142 ꢂC (EtOH); ½a D25
ꢀ94.5 (c 0.62,
ꢃ
248.8 Hz), 145.3, 134.5, 131.1, 128.8 (JCF 40.0 Hz), 123.7 (JCF 8.8 Hz),
116.0 (JCF 22.5 Hz); HRMS (EI) m/z calcd for C13H10FNO: 215.0746;
found: 215.0737; El. Anal. calcd for C13H10FNO: C 72.55; H 4.68, F
8.83, N 6.51. Found: C 72.68, H 4.54, N 6.63, F 8.74.
CHCl3); IR (film): 2989, 1747, 1612, 1599 cmꢀ1 1H NMR (600 MHz,
;
CDCl3) d: 7.44e7.36 (m, 4H), 7.35e7.25 (m, 5H), 7.24e7.19 (m, 2H),
7.09e7.04 (m, 1H), 6.99e6.94 (m, 2H), 5.29 (d, J 5.4 Hz, 1H),
4.01e3.93 (m, 2H), 3.89e3.83 (m, 1H), (dd, J 9.0, 6.0 Hz, 1H), 1.36 (s,
3H), 1.05 (s, 3H); 13C NMR (125 MHz, CDCl3)
d: 163.8, 158.7, 137.4,
5.1.3. N-(4-Fluorophenyl)-
a
-(4-tosyloxyphenyl)nitrone
136.7, 129.1, 128.6, 128.4, 128.0, 124.0, 117.2, 114.9, 108.6, 70.1, 70.0,
67.3, 58.1, 57.1, 26.8, 25.4; HRMS (EI) m/z calcd for C27H27NO4:
429.1940; found: 429.1934.
(13d). Nitrone 13d was synthesized following literature pro-
cedure18 starting from N-(p-fluorophenyl)-hydroxylamine (2.75 g,
21.6 mmol), p-tosyloxybenzaldehyde (5.96 g, 21.6 mmol), CH3SO3H
(1 drop), and acetone (50 mL). Nitrone 13d was obtained as a white
solid (5.58 g, 67%). Mp 172e174 ꢂC (acetone); IR (film): 3097, 3060,
5.2.3. Azetidinone 18-cis-I. ½a D25
ꢃ
þ77.9 (c 0.66, CH2Cl2); mp
: 7.40e7.24 (m, 7H),
113e115 ꢂC (EtOH); 1H NMR (600 MHz, CDCl3)
d
1596, 1504, 1380 cmꢀ1
;
1H NMR (600 MHz, DMSO-d6) 8.51 (s, 1H),
7.00e6.92 (m, 2H), 5.30 (d, J 5.5 Hz, 1H), 3.97 (dd, J 8.4, 5.8 Hz, 1H),
3.93 (dd, J 8.4, 6.6 Hz,1H), 3.84 (ddd, J 9.2, 6.6, 5.8 Hz,1H), 3.79 (dd, J
9.2, 5.5 Hz, 1H), 1.34 (s, 3H), 1.01 (s, 3H); 13C NMR (150 MHz, CDCl3)
8.48e8.44 (m, 2H), 7.98e7.94 (m, 2H), 7.77e7.74 (m, 2H), 7.49e7.46
(m, 2H), 7.42e7.36 (m, 2H), 7.18e7.14 (m, 2H), 2.42 (s, 3H); 13C NMR
(125 MHz, DMSO-d6) 162.4 (d, JCF 205.0 Hz), 149.6, 146.0, 144.7 (d,
JCF 2.4 Hz), 132.5, 131.2, 130.4, 130.3, 130.1, 128.3, 123.8 (d, JCF 7.5 Hz),
d: 163.4, 159.1 (d, JCF 243.8 Hz), 133.8, 133.6, 128.6, 128.4, 127.1, 118.6
(d, JCF 7.9 Hz), 115.9 (d, JCF 22.7 Hz), 108.6, 70.8, 67.3, 58.2, 57.6, 26.8,
122.1, 115.9 (d, JCF 19.3 Hz), 21.2; 19F NMR (470 MHz, DMSO-d6)
d:
25.2; 19F NMR (470 MHz, CDCl3)
d
: ꢀ117.6 (m); IR (film) v: 1750,
ꢀ111.3 (m); El. Anal. calcd for C20H16FNO4S C, 62.33; H, 4.18; F, 4.93;
1511 cmꢀ1; HRMS (ESI) m/z calcd for C20H20NO3FNa [MþNaþ]
N, 3.63; S, 8.32. Found: C, 61.93; H, 4.32; F, 5.13; N, 3.52.
364.1325; found 364.1330.
5.1.4. N-(4-Fluorophenyl)-
a
-(4-mesyloxyphenyl)nitrone (13f). Nitr-
5.2.4. Azetidinone 19-cis-I. Mp 157e159 ꢂC (EtOH/hexane);
½ ꢃ
a 2D5
one 13f was synthesized following literature procedure18 starting
from N-(p-fluorophenyl)-hydroxylamine (3.18 g, 25.0 mmol), p-
mesyloxybenzaldehyde (5.00 g, 25.0 mmol), CH3SO3H (1 drop), and
acetone (50 mL). Nitrone 13f was obtained as a white solid (3.18 g,
41%). Mp 158e160 ꢂC (acetone); IR 1603, 1506, 1373 cmꢀ1; 1H NMR
(600 MHz, DMSO-d6) 8.61e8.57 (m, 2H) overlapping 8.59 (s, 1H),
8.02e7.97 (m, 2H), 7.51e7.47 (m, 2H), 7.43e7.37 (m, 2H), 3.44 (s,
3H); 13C NMR (125 MHz, DMSO-d6) 162.4 (d, JCF 205.1 Hz), 149.8,
144.8, 132.5, 130.6, 130.1, 123.8 (d, JCF 7.5 Hz), 122.3, 115.9 (d, JCF
19.3 Hz); 19F NMR (376 MHz, DMSO-d6) ꢀ111.7 (m); HRMS (EI) m/z
calcd for C14H12FNO4S: 309.0471; found: 309.0472.
ꢀ81.6 (c 0.53, CHCl3); IR (CHCl3): 2986, 2935, 1752, 1511, 1373 cmꢀ1
;
1H NMR (600 MHz, CDCl3)
d: 7.68 (br d, J 7.8 Hz, 2H), 7.28 (br d, J 7.8 Hz,
2H), 7.24e7.19 (m, 4H), 7.02e6.94 (m, 4H), 3.77e3.70 (m, 2H), 2.44 (s,
3H),1.33 (s, 3H),1.02 (s, 3H); 13C NMR (125 MHz, CDCl3)
: 161.3 (d, JCF
202.4 Hz), 136.7 (d, JCF 13.6 Hz), 129.8 (d, JCF 30.8 Hz), 115.2 (d, JCF
85.6 Hz), 84.5, 73.4, 61.4, 39.1, 30.4; 19F NMR (376 MHz)
ꢀ117.8 (m);
HRMS (EI) m/z calcd for C27H26O6NFS: 511.1465; found: 511.1443.
d
d
5.2.5. Azetidinone 20-cis-I. Mp 153e155 ꢂC (EtOH); ½a D25
ꢀ125.1 (c
ꢃ
0.57, CHCl3); IR (film): 1749, 1599 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
: 7.36e7.19 (m, 9H), 7.06e6.98 (m, 1H), 5.29 (d, J 5.2 Hz, 1H),
3.97e3.87 (m, 2H), 3.83e3.71 (m, 2H), 1.31 (s, 3H), 0.97 (s, 3H); 13C
NMR (100 MHz, CDCl3) : 163.7, 137.4, 134.1, 129.1, 128.5, 128.3,
5.2. Kinugasa reactiondgeneral procedure
d
127.2, 124.1, 117.1, 108.6, 70.9, 67.3, 57.9, 57.4, 26.8, 25.3; HRMS (EI)
The Schlenk flask was charged with copper(I) iodide (1 mmol),
purged with argon and degassed MeCN (5 mL), followed by
N,N,N0,N0-tetramethylguanidine (2 mmol) were added. After cool-
ing to 0 ꢂC, acetylene (1 mmol) was added and the yellow mixture
was stirred for 15 min. The second Schlenk flask was charged with
nitrone (1.5e2 mmol), purged with argon and degassed MeCN was
added (5 mL). Subsequently, solution of copper acetylide was
m/z calcd for C20H21O3N: 323.1521; found: 323.1536.
5.2.6. Azetidinone 21-cis-I. Mp 148e151 ꢂC (EtOH); ½a D25
ꢀ81.7 (c
ꢃ
0.83, CHCl3); IR (CHCl3): 2987, 2938,1750, 1510,1371 cmꢀ1; 1H NMR
(600 MHz, CDCl3) d: 7.38e7.33 (m, 2H), 7.32e7.22 (m, 4H), 5.33 (d, J
4.8 Hz, 1H), 4.05e4.01 (m, 1H), 3.94e3.89 (m, 1H), 3.81e3.75 (m,
2H), 3.16 (s, 3H), 1.34 (s, 3H), 1.01 (s, 3H); 13C NMR (125 MHz, CDCl3)

M. Michalak et al. / Tetrahedron 68 (2012) 10806e10817
10815
d: 163.0, 159.2 (d, JCF 202.3 Hz), 148.9, 133.4, 133.3 (d, JCF 2.1 Hz),
four diastereoisomer in
a
ratio cis-I:cis-II:trans-I:trans-II
128.9, 122.2, 118.5 (d, JCF 6.5 Hz), 116.1 (d, JCF 18.9 Hz), 108.0, 70.7,
67.3, 58.3, 56.9, 37.6, 26.8, 25.2; HRMS (ESI) m/z calcd for
C21H22NO6FS: 458.1044; found: 458.1056.
0.52:0.12:0.31:0.05). The configuration of a mixture of di-
astereoisomers was confirmed by UV-CD HPLC analysis:
LiChrospherÒ Si60 column, 30% MTBE in hexane, 1 mL/min; tR 11.5,
13.4, 15.5, and 60.2 min; 1H NMR (600 MHz, CDCl3)
d: 7.48e6.65 (m,
5.2.7. Azetidinone 22-cis-I. ½a D25
ꢃ
ꢀ76 (c 0.38, CH2Cl2); mp
: 7.43e7.15 (m, 9H),
15H), 5.38 (d, J 4.0 Hz, 0.31ꢁ1H), 5.34 (d, J 5.8 Hz, 0.12ꢁ1H), 5.16 (d, J
2.5 Hz, 0.31ꢁ1H), 5.13 (d, J 7.2 Hz, 0.05ꢁ1H), 5.09 (d, J 6.0 Hz,
0.52ꢁ1H), 4.81 (d, J 2.5 Hz, 0.05ꢁ1H), 4.69 (d, J 10.0 Hz, 0.12ꢁ1H),
4.67 (d, J 9.0 Hz, 0.52ꢁ1H), 4.01 (dd, J 10.0, 5.8 Hz, 0.12ꢁ1H), 3.99 (dd,
J 9.0, 6.0 Hz, 0.52ꢁ1H), 3.44 (dd, J 7.2, 2.5 Hz, 0.05ꢁ1H), 3.43 (dd, J 4.0,
128e130 ꢂC; 1H NMR (600 MHz, CDCl3)
d
6.97e6.88 (m, 4H), 5.17 (d, J 5.5 Hz, 1H), 5.06 (s, 2H), 3.82e3.74 (m,
3H), 3.57 (dd, J 10.6, 5.6 Hz, 1H), 1.82e1.73 (m, 2H), 1.10 (s, 3H), 0.54
(s, 3H); 13C NMR (151 MHz, CDCl3)
d: 163.9, 158.9 (d, JCF 243.5 Hz),
158.6, 136.7, 133.7, 128.6, 128.0, 127.3, 126.3, 118.6 (d, JCF 7.8 Hz),
115.8 (d, JCF 22.7 Hz), 114.6, 98.0, 69.9, 64.7, 59.5, 59.4, 57.3, 29.7,
2.5 Hz, 0.31ꢁ1H); 13C NMR (151 MHz, CDCl3)
d: 166.3, 165.5, 141.1,
140.1, 137.6, 137.5, 137.1, 134.7, 134.5, 133.7, 130.9, 130.6, 129.9, 129.2,
129.1,129.1,129.0,129.0,128.9,128.8,128.6,128.6,128.6,128.5,128.4,
128.2,128.1,127.9,127.9,127.4,126.8,126.6,125.7,125.5,124.1,123.9,
121.7, 117.3, 117.2, 117.10, 117.07, 71.4, 70.1, 69.7, 66.9, 61.6, 59.7, 58.3,
57.6, 55.7, 46.0, 31.9, 29.7, 29.3, 22.7, 14.2; HRMS (ESI) m/z calcd for
C22H19NO2Na [MþNaþ] 352.1308; found 352.1318.
29.4, 17.7; 19F NMR (470 MHz, CDCl3)
d
: ꢀ117.9 (m); IR (CH2Cl2) v:
1751, 1511 cmꢀ1; HRMS (ESI) m/z calcd for C28H28FNO4Na [MþNaþ]
484.1900; found 484.1896.
5.2.8. Azetidinone 23-cis-I. ½a D25
ꢃ
ꢀ108.6 (c 0.55, CH2Cl2); mp
: 7.37e7.24 (m, 7H),
180e182 ꢂC; 1H NMR (500 MHz, CDCl3)
d
6.97e6.91 (m, 2H), 5.23 (d, J 5.6 Hz, 1H), 3.83e3.74 (m, 3H), 3.63
(dd, J 10.6, 5.6 Hz, 1H), 1.85e1.73 (m, 2H), 1.12 (s, 3H), 0.51 (s, 3H);
5.2.11. Azetidinones 27. To a suspension of CuI (380.9 mg,
2.0 mmol) in anhydrous CH3CN (2 mL), TMG (0.25 mL, 2.0 mmol)
was added followed by solution of (S)-5-phenylpent-1-yn-3-ol
(160.2 mg, 1.0 mmol) in CH3CN (2 mL) at 0 ꢂC. After 15 min at this
temp, nitrone 13e (417.8 mg, 1.3 mmol) was added and stirred for
16 h at rt. Then reaction mixture was diluted with water (40 mL)
and extracted with EtOAc (2ꢁ15 mL). The combined organic ex-
tracts were washed with 10% solution of citric acid (2ꢁ10 mL), brine
(1ꢁ20 mL), dried over MgSO4, and evaporated. The residue was
chromatographed on silica (30e40% MTBE/hexane) to give a mix-
ture of azetidinones 27-cis-I and 27-cis-II in ratio 67:33 (180.3 mg;
based on 1H NMR) and 27-trans-I and 27-trans-II in ratio 46:54
(90.3 mg; after crystallization from EtOH/hexanes; based on 1H
NMR); total yield 56%). The configuration of a mixture of di-
astereoisomers was confirmed by UV-CD HPLC analysis:
LiChrospherÒ Si60 column, 30% MTBE in hexane, 0.8 mL/min; tR
27.7 (27-trans-I), 29.5 (27-trans-II), 57.1 (27-cis-II), and 74.7 (27-cis-
I) min; Mixture of azetidinones 27-trans-I and 27-trans-II IR (film):
3443, 3029, 2930, 1743, 1510 cmꢀ1; 1H NMR (500 MHz, benzene-d6)
13C NMR (125 MHz, CDCl3)
d: 163.8, 159.0 (d, JCF 243.7 Hz), 134.2,
133.6 (d, JCF 2.8 Hz), 128.2, 127.5, 118.6 (d, JCF 7.8 Hz), 115.8 (d, JCF
22.7 Hz), 98.0, 64.7, 59.5, 59.4, 57.7, 29.7, 29.4, 17.6; 19F NMR
(470 MHz, CDCl3)
d
: ꢀ117.8 (m); IR (film): 1754, 1509 cmꢀ1; HRMS
m/z calcd for C21H22NO3FNa [MþNaþ] 378.1476; found 378.1489.
5.2.9. Azetidinones 24. To
a suspension of CuI (723.7 mg,
3.80 mmol, 2.0 equiv) in CH3CN (19 mL), (S)-but-3-yn-2-ol
(133.2 mg, 1.90 mmol) was added dropwise at 0 ꢂC. After 15 min,
nitrone 13e (449.7 mg, 2.28 mmol) was added as a solid at this
temp, and stirring was continued for 16 h at rt. The reaction mix-
ture was diluted with water (40 mL) and aq ammonia (40 mL), and
extracted with EtOAc (2ꢁ30 mL). The combined extracts were
washed with brine (2ꢁ10 mL), dried over MgSO4, and evaporated.
The reside was purified by chromatography on silica (10% EtOAc/
DCM) to give a product as a white solid (314.7 mg, 62%, mixture of
four disatereoisomer in
a
ratio cis-I:cis-II:trans-I:trans-II
4.2:2.6:2.2:1). The configuration of a mixture of diastereoisomers
was confirmed by UV-CD HPLC analysis: LiChrospherÒ Si60 20%
MTBE in hexane, 1 mL/min; tR 143.5 min (24-cis-I), 154.8 min (24-
trans-II), 176.0 min (24-trans-I), 191.0 min (24-cis-II); IR (film):
3456, 3063, 2970, 2927,1746,1599 cmꢀ1; 1H NMR (600 MHz, CDCl3)
d: 7.32e7.23 (m, 2H), 7.18e6.99 (m, 10H), 6.94e6.89 (m, 1H),
6.84e6.80 (m, 1H), 6.72e6.67 (m, 2H), 6.62e6.56 (m, 2H), 4.82 (d, J
2.6 Hz, 0.46ꢁ1H), 4.64e4.55 (m, 1H), 4.47 (d, J 2.6 Hz, 0.54ꢁ1H),
3.89e3.80 (m, 0.54ꢁ1H), 3.71e3.64 (m, 0.46ꢁ1H), 2.89 (dd, J 5.6,
2.4 Hz, 0.46ꢁ1H), 2.84 (dd, J 4.6, 2.4 Hz, 0.54ꢁ1H), 2.70e2.39 (m,
2H), 2.13 (d, J 5.2 Hz, 0.54ꢁ1H), 1.99e1.86 (m, 0.46ꢁ1H þ1H),
d: 7.43e7.37 (m, 1H), 7.35e7.11 (m, 6H), 7.00e6.92 (m, 1H), 5.19 (d, J
5.4 Hz, 0.32ꢁ1H), 5.12 (d, J 6.0 Hz, 0.18ꢁ1H), 5.03 (d, J 2.4 Hz,
0.16ꢁ1H), 4.82 (d, J 2.4 Hz, 0.08ꢁ1H), 4.31e4.24 (m, 0.20ꢁ1H),
4.21e4.13 (m, 0.13ꢁ1H), 3.79e3.70 (m, 0.52ꢁ1H), 3.51 (dd, J 10.2,
6.0 Hz, 0.32ꢁ1H), 3.42 (dd, J 7.8, 5.4 Hz, 0.18ꢁ1H), 3.07 (dd, J 6.0,
2.4 Hz, 0.08ꢁ1H), 3.05 (dd, J 4.8, 2.4 Hz, 0.16ꢁ1H), 1.33 (d, J 6.0,
0.12ꢁ3H), 1.28e1.27 (m, 0.63ꢁ3H), 0.83 (d, J 6.0 Hz, 0.25ꢁ3H); 13C
NMR (150 MHz): 166.6, 165.9, 165.7, 164.6, 138.0, 137.6, 137.4, 137.4,
137.3, 137.1, 134.7,134.5, 134.4, 134.0, 131.0,130.6, 129.9, 129.7, 129.2,
129.1, 129.0, 129.0, 129.0, 129.0, 128.8, 128.7, 128.6, 128.5, 128.2,
127.0, 127.0, 125.9, 125.9, 67.2, 66.3, 66.0, 65.1, 64.9, 63.9, 62.1, 60.3,
57. 7, 57.5, 56.8, 29.6, 22.6, 21.6, 21.3, 20.9; HRMS (EI) m/z calcd for
C23H27NO5: 267.1259; found: 267.1265.
1.75e1.64 (m, 2H); 13C NMR (125 MHz, benzene-d6)
d: 165.3, 165.1,
159.9, 159.0, 158.9, 157.9, 141.6, 141.5, 136.9, 136.8, 134.3, 134.2,
130.2, 129.7, 128.5, 128.4, 128.4, 128.4, 127.9, 127.7, 127.56, 127.2,
127.2, 125.9, 118.3, 118.3, 115.7, 115.5, 115.4, 115.4, 69.7, 68.7, 67.8,
66.5, 65.9, 57.2, 56.3, 37.1, 36.8, 31.8, 31.7; HRMS (ESI) m/z calcd for
C31H28NO3FNa [MþNaþ] 504.1945; found 504.1946. Mixture of
azetidinones 27-cis-I and 27-cis-II IR (film): 3463, 3028, 2923,
1744 cmꢀ1; 1H NMR (600 MHz, benzene-d6)
d: 7.21e6.95 (m, 14H),
6.83e6.79 (m, 2H), 6.67e6.56 (m 4H), 4.63e4.54 (m, 2H), 4.43 (d, J
5.7 Hz, 0.67ꢁ1H), 4.19 (d, J 5.8 Hz, 0.33ꢁ1H), 3.63e3.57 (m,
0.67ꢁ1H), 3.53e3.48 (m, 0.33ꢁ1H), 3.26 (dd, J 10.4, 5.7 Hz,
0.67ꢁ1H), 3.26 (dd, J 10.4, 5.7 Hz, 0.33ꢁ1H), 2.80e2.74 (m,
0.67ꢁ1H), 2.65e2.59 (m, 2.57e2.50 (m, 1H), 2.44e2.33 (m, 1H),
1.92e1.85 (m, 0.67ꢁ1H), 1.53e1.46 (m, 0.33ꢁ1H), 1.24e1.15 (m, 1H);
5.2.10. Azetidinones 25. To a suspension of CuI (190 mg, 1 mmol)
and TMG (250
mL, 2 mmol) in MeCN (5 mL), (R)-1-phenylprop-2-yn-
13C NMR (150 MHz, benzene-d6)
d: 166.1, 163.8, 159.6, 159.0, 159.0,
1-ol (132 mg, 1 mmol) was added dropwise at 0 ꢂC. After 15 min,
a solution of nitrone 13e (394 mg, 2 mmol) in MeCN (5 mL) was
added at this temp, and stirring was continued for 20 h at rt. The
reaction mixture was diluted with water (10 mL) and aq ammonia
(10 mL), and extractedwith EtOAc(2ꢁ15 mL). Thecombined extracts
were washed with brine (10 mL), dried over MgSO4, and evaporated.
The reside was purified by chromatography on silica (20% AcOEt/
hexane) to give a product as a yellow solid (214 mg, 65%, mixture of
158.0, 141.9, 141.6, 136.8, 136.7, 134.2, 133.9, 128.5, 128.4, 128.2,
128.2, 128.0, 127.3, 126.4, 125.8, 125.7, 125.5, 118.4, 118.4, 118.3,
118.2, 115.7, 115.5, 115.2, 114.9, 69.8, 69.7, 67.2, 66.8, 61.2, 59.4, 57.2,
56.9, 36.9, 36.4, 31.6, 31.2, 31.2; HRMS (ESI) m/z calcd for [MþNaþ]
C31H28FNO3Na: 501.1945; found 501.1959.
5.2.12. Azetidinone 28a. To a solution of a mixture of alcohols 24
ꢁ
(185.8 mg, 0.70 mmol) in DCM (10 mL), molecular sieves 4 A

10816
M. Michalak et al. / Tetrahedron 68 (2012) 10806e10817
(224.8 mg) and PCC (224.8 mg, 0.70 mmol) were added and stirred
for 4.5 h at rt. Then reaction mixture was passed through pad of
Florisil (10 mL), washed with 20% EtOAc/hexanes (20 mL) and
evaporated. The crude product was chromatographed on silica (10 g,
10%EtOAc/hexanes)togiveketone28a a colorlessoil(135.2mg, 73%).
Er 3:2 by HPLC, Daicel ChiralpakÒ AD-H column, 2% i-PrOH in hexane,
1.0 mL/min (Fig. 4); IR (film): 3065, 3033, 1754, 1716, 1501 cmꢀ1; 1H
on silica (20% EtOAc/hexanes) to give alcohol 29 as a colorless oil
(189 mg, 71%). ½a D25
ꢃ
ꢀ70.8 (c 0.25, CHCl3); IR (CHCl3) v: 3483, 1748,
1511, 1249, 1248, 834 cmꢀ1; 1H NMR (600 MHz, CDCl3)
d
: 7.51e7.18
(m, 9H), 7.08e6.88 (m, 4H), 5.24 (d, J 5.6 Hz, 1H), 5.06 (s, 2H),
3.96e3.84 (m, 2H), 3.83e3.75 (m, 1H), 3.73e3.62 (m, 1H), 2.79 (br s,
2H), 2.22e2.09 (m, 1H), 1.84e1.71 (m, 1H), 0.88 (s, 9H), 0.02 (s, 6H);
13C NMR (150 MHz, CDCl3)
d: 164.6, 158.9, 159 (d, JCF 243.4 Hz),
NMR (400 MHz, CDCl3)
7.09e7.02 (m, 1H), 5.48 (d, J 2.4 Hz, 1H), 4.14 (d, J 2.4 Hz, 1H), 2.38 (s,
3H); 13C NMR (100 MHz, CDCl3)
: 198.8, 160.2, 137.1, 136.5, 129.2,
129.1, 128.7, 126.1, 117.0, 71.8, 55.5, 29.9; HRMS (ESI) m/z calcd for
C17H15NO2Na [MþNaþ]: 265.3065; found: 265.3069.
d
: 7.40e7.30 (m, 5H), 7.29e7.21 (m, 4H),
136.7, 133.7 (d, JCF 2.6 Hz), 128.6, 128.5, 128.1, 127.5, 126.3, 118.6 (d,
JCF 7.8 Hz), 115.8 (d, JCF 22.6 Hz), 115.0, 70.1, 67.0, 61.7, 60.8, 57.8,
36.2, 25.8, 18.1, ꢀ5.5, ꢀ5.6; HRMS (ESI) m/z calcd for [MþNaþ]
C31H38FNO4NaSi: 558.2446; found: 558.2468.
d
5.2.16. Azetidinone 30. To a suspension of PCC (65 mg, 0.3 mmol)
ꢁ
5.2.13. Azetidinone 28b. To a solution of a mixture of alcohols 25
and MS 4 A (1 mg per 1 mg, 65 mg) in DCM (1 mL), alcohol 29
ꢁ
(100 mg, 0.30 mmol) in CH2Cl2 (5 mL), molecularsieves4 A (200 mg),
(53.6 mg, 0.1 mmol) was added and the mixture was stirred for 3 h.
Then reaction mixture was diluted with Et2O (5 mL), stirred for ad-
ditional 30 min, filtrated through Celite, and evaporated. The residue
was chromatographed on silica (10% EtOAc/hexanes) to give keto-
and PCC (196 mg, 0.91 mmol) were added and stirred for 3 h at rt.
Then reaction mixture was diluted with Et2O and passed through
pad of Celite and evaporated to give ketone 28b as a yellowish oil
(81 mg, 82%). Er 69:31 by HPLC: Daicel ChiracelÒ OD-H column, el-
uent 10% i-PrOH/hexane, 1.0 mL/min; tR 8.4 and 9.6 min 1H NMR
lactam 30 as a colorless oil (47.0 mg, 88%). ½a D25
þ10.6 (c 0.44, CHCl3);
ꢃ
1H NMR (500 MHz, CDCl3)
d: 7.47e7.17 (m, 9H), 7.04e6.89 (m, 4H),
(600 MHz, CDCl3)
d
: 7.60 (t, J 7.4 Hz, 1H), 7.51 (t, J 7.8 Hz, 2H),
5.40 (d, J 2.5 Hz,1H), 5.03 (s, 2H), 4.23 (d, J 2.5 Hz,1H), 4.04e3.86 (m,
7.46e7.42 (m, 2H), 7.39 (t, J 7.4 Hz, 2H), 7.36e7.22 (m, 5H), 7.06 (t, J
2H), 2.97e2.75 (m, 2H), 0.79 (s, 9H), 0.01 (s, 3H), ꢀ0.02 (s, 3H); 13C
7.4 Hz, 1H), 5.77 (d, J 2.5 Hz, 1H), 4.83 (d, J 2.6 Hz, 1H); 13C NMR
NMR (125 MHz, CDCl3) d: 200.4, 160.2, 159.2 (d, JCF 244.0 Hz), 159.1,
(151 MHz, CDCl3)
d
: 190.5, 160.0, 137.3, 136.8, 135.7, 134.0, 129.4,
136.6,133.5 (d, JCF 2.7 Hz),128.6,128.4,128.1,127.5,127.4,118.6 (d, JCF
7.9 Hz),115.9 (d, JCF 22.8 Hz),115.57, 72.05, 70.08, 58.36, 55.30, 45.56,
25.75, 18.12, ꢀ5.54, ꢀ5.56; HRMS (ESI) m/z calcd for [MþNaþ]
C31H36FNO4NaSi: 556.2290; found: 556.2281.
129.3, 129.1, 128.8, 128.74, 126.2, 124.3, 117.1, 68.9, 55.8, 29.7; HRMS
(ESI) m/z calcd for C22H17NO2Na [MþNaþ] 350.1152; found 350.1162.
5.2.14. Azetidinone 28c. To a solution of alcohol 27 (282.2 mg,
ꢁ
0.59 mmol) in dichloromethane (10 mL), molecular sieves 4 A
Acknowledgements
(380 mg) and PCC (380.0 mg, 0.56 mmol) were added, and stirred
for 3 h at rt. Then reaction mixture was passed through pad of
Florisil (5 g), washed with 20% EtOAc/hexanes (20 mL) and evap-
orated to give ketolactam 28c as a colorless oil (270.1 mg, 96%). IR
Financial support for this work was provided through the Polish
Ministry of Science and Higher Education Grant N N204 156036.
(film): 3063, 3030, 2931, 1754, 1713 cmꢀ1
CDCl3)
;
1H NMR (600 MHz,
Supplementary data
d
: 7.43e7.36 (m, 4H), 7.35e7.31 (m, 1H), 7.28e7.17 (m, 9H), 6,
98e6.92 (m, 4H), 5.37 (d, J 2.4 Hz, 1H), 5.05 (s, 2H), 4.08 (d, J 2.4 Hz,
The CD spectra and chromatograms of presented in this work
azetidinones can be found. Supplementary data associated with
this article can be found, in the online version, at doi:10.1016/
j.tet.2011.11.007. These data include MOL files and InChiKeys of the
most important compounds described in this article.
1H), 3.15e3.08 (m, 1H), 3.00e2.92 (m, 2H), 2.91e2.83 (m, 1H); 13C
NMR (125 MHz)
d 200.3, 160.1, 159.2, 159.2 (d, JCF 242.7 Hz), 140.4,
136.6, 133.4, 128.7, 128.5, 128.4, 128.3, 128.1, 127.5, 127.5, 126.3, 118.6
(d, JCF 8.0 Hz), 116.3 (d, JCF 22.7 Hz), 115.6 71.4, 70.1, 55.4, 44.2, 29.1;
HRMS (EI) m/z calcd for C31H26NO3FNa: 502.1789; found: 502.1783.
UV-CD HPLC Daicel ChiralpakÒ AD-H, 30% i-PrOH in hexane,
0.6 mL/min, tR 31.3 min (3R,4R), 74.8 min (3S,4S).
References and notes
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