An entry to the carbapenem antibiotic scaffold via the asymmetric Kinugasa reaction

Article abstract of DOI:10.1055/s-0032-1316732

The copper(I)-mediated reaction between five-membered cyclic nitrones and terminal acetylenes, leading to the assembly of the basic skeleton of carbapenem antibiotics is described. The diastereoselectivity of this cycloaddition- rearrangement cascade, a process known as the Kinugasa reaction, with respect to the structure and configuration of both substrates, as well as the reaction conditions, are discussed. Application of the described methodology to sugar-derived nitrones offers an attractive entry toward thienamycin and related compounds. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0032-1316732

FEATURE ARTICLE
▌2825
feature article
An Entry to the Carbapenem Antibiotic Scaffold via the Asymmetric
Kinugasa Reaction
Toward the Carbapenem Scaffold via Asymmetric Kinugasa Reactions
Magdalena Maciejko, Sebastian Stecko, Olga Staszewska-Krajewska, Margarita Jurczak, Bartłomiej Furman,
Marek Chmielewski*
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
Fax +48(22)6326681; E-mail: chmiel@icho.edu.pl
Received: 28.04.2012; Accepted after revision: 04.07.2012
R3
O
R2
R1
R1
O
Abstract: The copper(I)-mediated reaction between five-mem-
bered cyclic nitrones and terminal acetylenes, leading to the assem-
bly of the basic skeleton of carbapenem antibiotics is described. The
diastereoselectivity of this cycloaddition–rearrangement cascade, a
process known as the Kinugasa reaction, with respect to the struc-
ture and configuration of both substrates, as well as the reaction
conditions, are discussed. Application of the described methodolo-
gy to sugar-derived nitrones offers an attractive entry toward thien-
amycin and related compounds.
Cu(I), base
N
R3
+
R2
N
R3
CuLn
R3
[3+2]
H
R2
R3
R2
Key words: β-lactams, Kinugasa reaction, carbapenem antibiotics,
nitrones, acetylenes
N
N
Ln-1Cu
R1
R1
O
Ln-1CuO
B
A
1
Introduction
Scheme 1 Mechanism of the Kinugasa reaction
The copper(I)-mediated reaction between nitrones and
terminal acetylenes, discovered in 1972 by Kinugasa and nitrones have been utilized,5–12 whilst examples of reac-
Hashimoto,1 represents a direct and simple method for the tions involving aliphatic nitrones are scarce.4
formation of β-lactams.2 As shown in Scheme 1, the
Kinugasa reaction involves a cycloaddition–rearrange-
ment cascade process catalyzed by copper(I) ions, and
The first enantioselective intermolecular Kinugasa reac-
tion, using phenyl-substituted reactants 1 and 2 and bisox-
azoline ligands 3 as a source of chirality, was reported in
proceeds in the presence of an organic base. The initially
1995 by Miura and co-workers.8 However, the products
formed copper–alkyne π-complex undergoes deproton-
were obtained with relatively poor selectivity (cis/trans
ation. Next, the activated triple bond takes part in a 1,3-di-
>66:34, ee for the cis-diastereomer of up to 40%). Im-
polar cycloaddition with a nitrone to provide five-
proved results (up to 85% ee) were reported by Tang et
membered isoxazoline A. The rearrangement of isoxazo-
al.13 for the copper(II)–trisoxazoline ligand complex 4.
line copper complex A into copper enolate B and subse-
Promising enantioselectivity [cis/trans >95:5, ee (cis) 70–
90%) was observed by Lo and Fu for identical reactants,
quent protonation leads to the formation of a β-lactam
ring. The protonation of intermediate enolate B in the sec-
but using ferrocenyl catalyst 5.9a The same group also de-
ond step occurs from the less-shielded side of the β-lactam
scribed the first example of an intramolecular enantiose-
ring. Consequently, the major product displays the rela-
tive cis-configuration of protons in the four-membered
lective Kinugasa reaction using compound 6.9b The
corresponding tricyclic products were obtained with good
ring. There are striking similarities between the first step
stereoselectivity (74%, ee 88%).9b Other highly efficient
of the Kinugasa reaction and the well-known cycloaddi-
copper catalysts with chiral HETPHOX ligands 711 and
tion of azides to terminal acetylenes, a process known as
IndaBOX ligands 810,12 have also been described (Figure
the click reaction.3
1).
Although the first examples of the Kinugasa reaction were
In 2002, Basak and co-workers5a reported the first diaste-
described in the 1970s,1,4 almost three decades passed be-
reoselective version of the Kinugasa cascade involving re-
fore the reaction received further attention and detailed in-
actions of acetylenes with a chiral auxiliary. The reaction
vestigation. Nevertheless, the number of reports related to
between chiral oxazolidinyl propynes 9 and C,N-diarylni-
trones provided only one set of cis/trans-azetidinones 10
this particular approach toward the direct formation of 2-
azetidinones, both diastereo-5–7 and enantioselective8–12
in a moderate yield and poor cis/trans ratio, which typical-
variants, is limited. Moreover, in most cases, C,N-diaryl-
ly did not exceed 1:3 (Scheme 2). Hsung et al.,6 in 2008,
demonstrated that chiral oxazolidinone-derived ynamides
11 were efficient reagents for the diastereoselective
Kinugasa reaction involving C,N-diarylnitrones, to pro-
SYNTHESIS 2012, 44, 2825–2839
Advanced online publication: 13.08.2012
DOI: 10.1055/s-0032-1316732; Art ID: SS-2012-Z0401-FA
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

2826
M. Maciejko et al.
FEATURE ARTICLE
Biographical Sketches█
Marek Chmielewski (fourth from he obtained his doctorate under the Chmielewski at the Institute of Or-
left) is Vice President of the Polish guidance of Professor Marek ganic Chemistry in Warsaw. She is
Academy of Sciences, elected for the Chmielewski at the Institute of Or- mainly involved in the application of
term 2011–2014. He received his ganic Chemistry, Polish Academy of modern NMR techniques for deter-
M.Sc. from the Department of Chem- Sciences (Warsaw). After post-doc- mination of the structures, relative
istry, Warsaw University of Technol- toral studies with Horst Kunz (Mainz configurations and conformations of
ogy, and Ph.D. from the Institute of University), he realized Habilitation small organic molecules, in particu-
Organic Chemistry of the Polish under the direction of Marek lar, bioactive chiral β-lactams, small
Academy of Sciences (Warsaw) in Chmielewski in 2006 and was pro- heterocycles and sugars.
1972, under the supervision of Prof. moted to Associate Professor in
A. Zamojski. He received a D.Sc. 2008. He has received the Polish Sci-
Magdalena Maciejko (fifth from
left) studied organic chemistry at
(Habilitation) from the Institute of ence Award for Young Scientists
Warsaw University and the Institute
Organic Chemistry, Polish Academy (1999) and the Prime Minister Award
of Organic Chemistry, Polish Acade-
of Sciences (Warsaw) in 1981. Subse- (1999). His scientific interests in-
my of Sciences (Warsaw), under the
quently, he completed two long-term volve stereocontrolled synthesis, the
supervision of Professor Bartłomiej
Furman. In 2010, she joined the Insti-
research stays at Purdue University development of new methodologies
with R. L. Whistler (1973–74), and at and the synthesis of bioactive com-
tute of Organic Chemistry (Warsaw)
Southern Illinois University in Car- pounds.
and is currently a Ph.D. student
bondale with J. N. BeMiller (1979–
81). Since 1984 he has been a Profes-
sor at the Institute of Organic Chem-
istry, Polish Academy of Sciences
Ph.D. thesis in organic chemistry un-
Sebastian Stecko (sixth from left)
(Warsaw). He has also been a visiting
der the supervision of Professor W.
obtained his M.Sc. degree in chemi-
Professor in the U.S.A., Spain and
Sobótka at the Institute of Organic
cal technology from the Silesian Uni-
France. He is engaged in the fields of
Chemistry, Polish Academy of Sci-
Margarita Jurczak (third from left) working on the application of sugar-
studied chemistry at the University of derived nitrones in the Kinugasa re-
Warsaw. In 1977, she completed her action.
versity of Technology, Gliwice,
Poland. In 2008, he obtained his doc-
torate at the Institute of Organic
Chemistry, Polish Academy of Sci-
ences (Warsaw), under the supervi-
stereocontrolled syntheses of β-lac-
tam antibiotics and transformations
of carbohydrates into amino and imi-
no sugars with special attention di-
rected toward asymmetric addition
and cycloaddition reactions. His oth-
er fields of interest include the syn-
thesis of glycosyl hydroperoxides
with the aim of performing enantio-
selective epoxidations and solid-
phase organic synthesis.
ences (Warsaw). After a post-doctoral
stay at Louvain la Neuve University,
(Belgium, 1980–81), she again
joined the Institute of Organic Chem-
istry, Polish Academy of Sciences
(Warsaw), where she is currently in
an Assistant Research position. She
is interested in the application of ni-
trones in organic synthesis.
sion
of
Professor
Marek
Chmielewski. After post-doctoral
studies with Siegfried Blechert
(Technical University Berlin) in
2011, he commenced his independent
research at the Institute of Organic
Chemistry (Warsaw). His scientific
interests involve stereocontrolled
synthesis, the development of new
methodologies and the synthesis of
bioactive compounds.
Olga Staszewska-Krajewska (sec-
ond from left) was born in Warsaw,
Poland in 1969. She studied chemis-
try at Warsaw University. In 2000,
she obtained her doctorate under the
guidance of Professor Marek
Bartłomiej Furman (first from left)
was born in Radom, Poland in 1969.
He studied chemistry at the Warsaw
University of Technology. In 1998,
Synthesis 2012, 44, 2825–2839
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Toward the Carbapenem Scaffold via Asymmetric Kinugasa Reactions
2827
vide 3-amino-β-lactams 12 in good yields and with high
2
Diastereoselective Kinugasa Reactions with
stereoselectivities (Scheme 2).
Chiral Cyclic Nitrones and Achiral Acety-
lenes
Ph
N
In contrast to the examples of the diastereoselective
Kinugasa reaction described so far, we focused our atten-
tion on the reactions of chiral cyclic nitrones 13 and
14,14,15 derived from malic and tartaric acids,16 respective-
ly, with simple achiral acetylenes (Scheme 3). These stud-
ies were a continuation of our ongoing research on the
applications of nitrones in the synthesis of bioactive mol-
ecules,17 including β-lactams.18 The main reasons for the
selection of nitrones 13 and 14 were due to their availabil-
ity, stability, and ability to form products possessing the
basic skeleton of the highly active carbapenem antibiotics.
To some extent, our concept was related to the well-
known pioneering approach of Tufariello toward car-
bapenems based on the 1,3-dipolar cycloaddition of a cy-
clic nitrone to a crotonate.19 Moreover, it was intriguing
that cyclic aliphatic nitrones had been used only once in
the Kinugasa reaction, by Ding and Irwin, in 1976.4
O
Ph
1
2
O
O
N
N
O
N
N
R
R
O
O
N
3 R: i-Pr, t-Bu
4
Fe
N
N
R
R
Fe
N
Ar
O
The yields of the desired Kinugasa products (compounds
15 and 16, Scheme 3) varied from poor, for aliphatic acet-
ylenes, to moderate and good for aryl acetylenes.14a Inter-
estingly, somewhat better results were observed for
certain aliphatic acetylenes bearing oxygen atoms.14c The
effectiveness of these reactions could be further enhanced
slightly, in several cases, by the addition of hydrazine,14a
or N,N-ligands, such as 2,2′-bipyridine or 1,10-phenan-
throline.14c
5 R: H, Me
6
R
R
PPh2
O
O
R
N
O
N
N
S
8 R: H, Me, CH2Ph
7 R: i-Pr, t-Bu, Ph
All the investigated reactions with nitrones 13 and 14 pro-
vided only one set of cis/trans-azetidinones with a high
preference for the formation of the cis-isomers, cis-15 or
cis-16. On the basis of the proposed stereochemical model
of the Kinugasa reaction (Figure 2), the resulting geome-
try of the carbapenam skeleton depends strongly on the
first step of the cascade, which is the 1,3-dipolar cycload-
dition of the nitrone to the triple bond of the copper
acetylide. The approach of the reactants in the cycloaddi-
tion step is controlled by the substituent located next to the
double bond in the nitrone, whereas protonation of the in-
termediate enolate in the second step occurs from the less-
shielded side of the bicyclic skeleton. Consequently, the
major product displays the relative cis-orientation of pro-
tons in the four-membered β-lactam ring.
Figure 1 Structures of various substrates and complexes employed in
the Kinugasa reaction
R
R
Ar1
O
H
Ar1
Ar2
CuI, Et3N
DMF
N
O
O
N
+
N
O
Ar2
N
O
O
9 R: Bn, Ph
10 60–65%
cis/trans 2:3 to 1:3
R
N
R
Ar1
O
H
O
CuCl, (C6H11)2NMe
MeCN
Ar1
Ar2
N
O
O
The 5,6-cis/trans ratio depends on the structure of the
starting acetylene as well as the type of amine base
used.14a For example, the reaction of phenylacetylene (1)
with nitrone 13 in the presence of triethylamine as the
base provided a mixture of cis-15/trans-15 in a diastereo-
meric ratio of about 4:1 (Scheme 3, R = Ph). However,
when a bulkier base was utilized (e.g., DIPEA), isomer
cis-15 was obtained predominantly (dr >95:5).
+
N
O
Ar2
N
O
11 R: Bn, Ph
12 60–80%
cis/trans: 82:18 to 95:5
Scheme 2 Examples of diastereoselective Kinugasa reactions
Owing to the presence of a protected hydroxy group in the
five-membered ring, and potential for variation of the sub-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2825–2839

2828
M. Maciejko et al.
FEATURE ARTICLE
R
Ot-Bu
Ot-Bu
Ot-Bu
H
H
N
H
H
CuI (1 equiv)
Et3N (4 equiv)
R
R
4
2
6
5
3
+
N
N
MeCN
24 h
O
O
O
13
trans-15
cis-15
30–90%
dr from 4:1 up to >95:<5
R: Ph, CH(OEt)2, CH2OBn, CH2OSiPh2t-Bu
Ph
Ot-Bu
Ot-Bu
Ot-Bu
Ot-Bu
H
N
CuI (1 equiv)
Et3N (4 equiv)
H
H
N
H
Ph
Ph
+
Ot-Bu
Ot-Bu
MeCN
N
O
O
O
24 h, 64%
cis-16
trans-16
14
dr 92:8
Scheme 3 Reactions of chiral cyclic nitrones with simple achiral acetylenes
3
Diastereoselective Kinugasa Reactions of
Chiral Acetylenes with an Achiral Cyclic
Nitrone
A) Stereochemical course of the cycloaddition step
[Cu]
The reactions of chiral acetylenes, for example D-glycer-
aldehyde-derived compound 17 or acetylene 20 prepared
from L-lactic acid, with achiral nitrone 18 proceeded with
excellent diastereoselectivities to afford the correspond-
ing carbapenams 19 and 21 in moderate yields (40–46%,
Scheme 4).14b It should be noted, however, that the unsub-
stituted nitrone 18 was less stable than its substituted con-
geners 13 and 14, and therefore extension of the reaction
time may lead to the formation of side products.
si-side approach
disfavoured
O
N
O
re-side approach
[Cu]
favoured
B) Stereochemical course of the enolate-protonation step .
N
O
18
O
H
H
N
convex-side protonation
cis product
O
CuI, Et3N
MeCN
O
O
H
30 h, 46%
O
H
O
17
19
dr 90:10
N
[Cu]O
nitrone 18
BnO
H
N
H
OBn
CuI, Et3N
concave-side protonation
trans product
MeCN
H
O
48 h, 40%
20
Figure 2 Proposed stereochemical model of the Kinugasa reaction
21
dr >95:<5
Scheme 4 Reactions of chiral acetylenes with achiral nitrone 18
stituents at C-6 of the carbapenam skeleton (depending on
the acetylene used), further transformation of the initially
formed adducts, or introduction of new substituents
should be possible.
The observed direction of asymmetric induction can be ra-
tionalized using the stereochemical model presented in
Figure 3.14b During the cycloaddition step the nitrone at-
tacks from the less hindered side of the acetylene. The fi-
nal protonation of the enolate occurs to a significant
Synthesis 2012, 44, 2825–2839
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Toward the Carbapenem Scaffold via Asymmetric Kinugasa Reactions
2829
manifested by the formation of a small amount of the
trans-isomer. Nevertheless, it should be noted that since
the Kinugasa reaction proceeds in the presence of a base,
the fact that formation of the trans-isomer may occur via
subsequent base-catalyzed epimerization at C-6 (α to the
β-lactam carbonyl group) cannot be ignored.
less hindered side
O
H
N
O
[Cu]
O
H
The question of configuration of all the carbapenams ob-
tained during our studies was resolved by NMR spectros-
copy, X-ray diffraction analysis, and by chirooptical
methods. As demonstrated previously, the chirooptical
methods, and particularly electronic circular dichroism
spectroscopy (ECD), supported by time-dependent densi-
ty functional theory (TD-DFT) calculations, are conve-
nient, sensitive, and fast techniques for the stereochemical
assignment of azetidinones and their polycyclic deriva-
tives in both solution and solid states.14c,20
more hindered side
H
H
O
H
N
Figure 3 Stereochemical model of the asymmetric induction in the re-
actions depicted in Scheme 4
degree from the convex side of the intermediate (see Fig-
ure 2, B) to provide the cis-substituted β-lactam ring.
5
Structure Effect of the Acetylene on the
Kinugasa Reaction
4
Double Asymmetric Induction in Kinugasa
reactions Involving Cyclic Nitrones
During studies on the effects of the structure of the acety-
lene on the course of the Kinugasa reaction, it was found
that some acetylenes displayed enhanced reactivity pro-
viding the corresponding 2-azetidinones in high yields
and in short reaction times (Table 1, acetylenes 17 and
28).14c
Studies on the double asymmetric induction in Kinugasa
cascades with both a chiral acetylene and a cyclic nitrone
were a natural extension of our work (Scheme 5).14b For
example, in the case of matched pair 13 and 17, only cis-
carbapenam 22 was obtained, whereas for the mismatched
pair, 17 and ent-13, two diastereoisomers, cis-23 and
trans-23, were formed in a 9:1 ratio.
It can be postulated that the high reactivities observed for
compounds 17 and 28 correlate with the specific struc-
tures of these molecules. The copper(I) complexes of ter-
minal acetylenes are usually highly aggregated species,
engaging in a range of σ- and π-interactions.21,22 Although
the precise nature of the reactive alkynyl copper species is
still not clear, some recent experimental and computation-
al results have revealed that dinuclear copper(I) acetylides
display enhanced reactivity in 1,3-dipolar cycloaddition
reactions (e.g., copper-mediated azide–alkene cycloaddi-
tion).3,23,24
The stereochemical outcome of the reactions in which
both the reactants (acetylene and nitrone) were chiral, can
be rationalized on the basis of previous observations (Fig-
ure 2).14b The most important feature is that the first 1,3-
dipolar cycloaddition step proceeds almost exclusively
anti to the tert-butoxy group of the nitrone. The influence
of the stereogenic center of the acetylene can be disre-
garded in this step. It also had an insignificant effect on
the protonation step, and only in the case of mismatched
pairs was the influence of the acetylene stereogenic center
O
O
t-BuO
(R)
Ot-Bu
17
(S)
N
N
O
O
CuI, Et3N
MeCN
CuI, Et3N
MeCN
ent-13
13
O
Ot-Bu
O
Ot-Bu
O
Ot-Bu
H
N
H
H
H
N
H
H
O
O
O
+
N
O
O
O
trans-23
cis-23
22
dr >95:<5
CuI (100 mol%) 94%, 24 h
CuI (100 mol%) 80%, 2 h
dr 92:8
24 h, 53%
CuI (5 mol%), 78%, 20 h
Scheme 5 Double asymmetric induction in Kinugasa cascades with both a chiral acetylene and a chiral nitrone
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2825–2839

2830
M. Maciejko et al.
FEATURE ARTICLE
The enhancement of the Kinugasa reaction rate for acety-
lenes derived from glyceraldehyde 17, and propargyl al-
dehyde acetal 28, is probably the result of formation of a
highly reactive rigid dinuclear copper(I) complex in
which each copper ion is coordinated to one or both oxy-
gen atoms of the acetylene molecule, and to both triple
bonds (Figure 4).14c
Table 1 Structure Effect of Acetylenes on the Kinugasa Reaction
Acetylene
CuI (mol%)
Time (h) Yield (%)
100
100
5
24
2
24
2
94 (60)a
80 (47)a
78
O
O
5
80
H
17
A)
O
O
O
100
100
5
24
2
24
75
46
30
MeO
Cu
Ln
24
Cu
Ln
O
100
100
5
24
2
24
41
nd
nd
EtO
O
H
O
O
25
O
MeO
100
100
5
24
2
24
40
nd
nd
B)
H
O
26
100
100
5
24
2
24
2
45 (55)a
12
nd
MeO
Ln
27
5
nd
Cu
Ln
OEt
EtO
100
100
5
24
2
24
2
72 (94)a
62 (68)a
58 (97)a
60a
O
H
O
5
28
OMe
MeO
31 (36)a
10
nd
Figure 4 Possible structures of the rigid dinuclear copper(I) complex-
es formed from acetylenes 17 and 28
100
100
5
24
2
24
2
MeO
5
nd
29
The rigid structure of the dioxolane ring stabilizes the
acetylide conformation and enables optimum interaction
between the oxygen atoms and the copper ion. Such coor-
dination is less effective in the case of more flexible struc-
tures (Table 1, compounds 24–26). It has been
demonstrated that a phenyl ring can replace one of the ox-
ygen atoms to provide coordination of the copper ion by
the aromatic sextet.14c However, it should be noted that
two nucleophilic centers are necessary for the effective
coordination of the copper ion, and thus to activate the tri-
ple bond for the cycloaddition reaction with nitrones (cf.
acetylenes 17 and 28).14c
100
100
5
24
2
24
2
55 (52)a
55
O
O
35 (36)a
36
5
30
OMe
O
100
100
5
24
2
24
2
56 (30)a
57
MeO
O
49 (31)a
31
5
31
a In the presence of 1,10-phenanthroline (100 or 5 mol%); nd = not
determined.
The existence of a specific coordination effect of the cop-
per(I) ion would appear to be confirmed by reactions with
an external ligand, for example, 1,10-phenanthroline. The
significant increase in the reaction yield in the case of
acetylene 28 may indicate the occurrence of synergistic
effects of both oxygen atoms and the N,N-ligand. In con-
trast, addition of 1,10-phenanthroline to the reaction of ni-
trone 13 and acetylene 27 resulted in only a slight
enhancement in the yield. The opposite effect imparted by
Bearing in mind these previous reports23,24 and our own
experimental observations,14c it can be concluded that in
the case of acetylenes 17 and 28, some additional coordi-
nation effect might occur that disables their deactivating
high aggregation ability, which consequently enhances
their reactivity toward the Kinugasa cascade.
Synthesis 2012, 44, 2825–2839
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Toward the Carbapenem Scaffold via Asymmetric Kinugasa Reactions
2831
1,10-phenanthroline in the case of acetylene 17 could pos-
sibly be explained assuming interference with the 1,3-di-
oxolane ring effect, probably due to competitive
coordination of the metal ion. A similar situation, that is,
competitive coordination of copper(I) can occur if an ad-
ditional oxygen atom is introduced to the acetylene mole-
cule (compare substrates 28 and 29). This result further
confirms the important role of the oxygen atoms and their
location in the acetylene molecule.
HO
NH2
NH2
H
H
N
H
N
H
S
S
O
O
COOH
COOH
35
thienamycyn (34)
NH2
H
H
The general message from the above results is that suc-
cessful Kinugasa reactions require the use of highly active
acetylenes. This ensures that formation of the 2-azetidi-
none is fast enough to inhibit other possible side reactions.
Consequently, in such cases, the catalyst loading can be
decreased to 5 mol% to afford the desired products in ac-
ceptable yields without any decrease in the diastereoselec-
tivity (Table 1).14c On the other hand, the low-active
acetylenes require extended reaction times, which can
promote side processes. We also observed deoxygenation
of the nitrones mediated by the copper(I) complex and
acetylene coupling to give diacetylenes. Accordingly, the
yields were lower and the reactions could not be per-
formed effectively in a catalytic manner.
S
N
O
COOH
36
Figure 6 Carbapenem antibiotics
Bearing in mind the therapeutic value of compounds 34–
36, we focused our attention on acetylenes 17, 28, and 37–
42, which should allow easy access to the side chains
present in carbapenem antibiotics, and to nitrones avail-
able from L- and D-arabinose, and 2-deoxy-D-ribose (Fig-
ure 7).30–32 Several of our attempts to reproduce the
published procedure33 for the synthesis of sugar-derived
cyclic nitrones did not lead to the desired products.
Based on our observations, as well as the reported cases of
copper-mediated acetylene–azide cycloaddition proposed
by Sharpless,25 we have suggested a plausible catalytic cy-
cle for the investigated cascade process.14c
O
BnO
The encouraging obtained results for the glyceraldehyde-
derived acetylene 1714c prompted further studies on the
synthetic potential of this compound as a precursor for
ezetimibe (32),26–29 a strong cholesterol absorption inhib-
itor that reduces the levels of low-density lipoprotein
(LDL) in the plasma. Consequently, we focused our atten-
tion on the Kinugasa reactions involving readily available
C,N-diarylnitrone 33 (Figure 5) and related compounds.27,29
38
37
39
O
O
OR
OR
41 R = H
42 R = TBDPS
ent-41 R = H
ent-42 R = TBDPS
40
OH
OBn
OBn
BnO
BnO
OBn
OBn
OH
H
H
N
N
N
O
N
O
N
O
OBn
OBn
OBn
O
F
O
F
43
44
45
F
ezetimibe (32)
33
Figure 5 Structures of ezetimibe (32) and C,N-diarylnitrone 33
O
O
OBn
BnO
OBn
BnO
O
N
N
O
N
O
6
Kinugasa Reactions Involving Sugar-
Derived Nitrones toward the Synthesis of
Carbapenems
OBn
O
OBn
O
ent-43
46
47
Figure 7 Structures of acetylenes 37–42 and nitrones 43–47
The good stereoselectivities afforded by Kinugasa reac-
tions with simple five-membered nitrones enabled an at-
tractive entry into the carbapenem antibiotic skeleton (see
structures 34–36, Figure 6), notwithstanding the moderate
yields realized at the time.2
Nitrones 43-47 were selected in order to achieve high dia-
stereoselectivity in the Kinugasa reaction, and to obtain
compounds that could be easily transformed into the five-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2825–2839

2832
M. Maciejko et al.
FEATURE ARTICLE
membered 2-carboxypyrrolidine ring present in carbapen- The benzyloxymethyl group at C-5 is responsible for de-
ems. Very recently, Kinugasa reactions involving nitrones termining the diastereoselectivity only when there is no
43, 44, 46, and 47 with sugar-derived acetylenes were re- substituent at C-3 on the nitrone, as for example in com-
ported by Khangarot and Kaliappan.7
pound 45, derived from 2-deoxyribose. Its reaction with
acetylene 28 afforded carbapenam 51 preferentially, how-
ever, a trace amount of the corresponding trans-product
52 was also isolated (Scheme 6).
The structures and configurations of all the synthesized
carbapenams were assigned using 1H NMR spectroscopy.
In addition to the standard correlations and NOE effects,
characteristic features including the upfield shifts of the A similar situation was apparent with acetylene 37, ob-
protons located on carbon atoms next to the nitrogen atom tained from propargyl alcohol. Addition of 37 to nitrone
and syn to the unshared electron pair were evident.34
ent-43 gave the cis-adduct 53. The same outcome was ob-
served for the reaction between nitrone 45 and acetylene
37, which provided carbapenam 54, exclusively (Scheme
7).
The stereoselectivities of the Kinugasa reactions involv-
ing sugar-derived nitrones 43–47 and achiral acetylenes
(e.g. 28, 37, and 38) depend on the substitution pattern in
the former. In contrast to the simple nitrones 13 and 14,
the outcome of the process is governed not only by the
substituent next to the double bond (position C-3), but can
also be influenced by the group attached to the C-5 atom.
OBn
H
N
H
37, CuI, Et3N
ent-43
BnO
OBn
MeCN
50%
O
With nitrones 43 and ent-43, bearing both 3-OBn and 5-
CH2OBn groups on the same face of the dipole, the
Kinugasa cascade provides single diastereoisomers 48
and ent-48, respectively, as a result of the anti approach of
the acetylide of 28 to both substituents (Scheme 6). How-
ever, when the substituents occupied opposite sides of the
nitrone plane, as in nitrone 44, an antagonistic effect of
both groups on the asymmetric induction would be ex-
pected. Indeed, such an internal mismatch effect was ob-
served in the reaction of nitrone 44 with acetylene 28,
which provided a mixture of two cis-carbapenams, 49 and
50. The benzyloxy substituent next to the double bond (C-
3) of the nitrone played a significant role in the stereocon-
trol and the cis-isomer 49, resulting from the anti ap-
proach of the acetylide, was the major product (Scheme 6).
OBn
53
H
N
H
37, CuI, Et3N
45
BnO
OBn
MeCN
37%
O
OBn
54
Scheme 7 Synthesis of carbapenams 53 and 54
The reaction of commercially available acetylene 38 with
2-deoxyribose-derived nitrone 45 provided the expected
product 55 along with the double bond migration product
56 (Scheme 8), which was the major component follow-
ing work-up. This partial shift of the double bond can be
OBn
OBn
EtO
28, CuI, Et3N
H
N
H
43
MeCN
57%
EtO
O
H
OBn
48
OBn
EtO
EtO
OBn
EtO
EtO
H
N
H
28, CuI, Et3N
H
44
MeCN
54%
OBn
OBn
+
N
O
O
OBn
OBn
49
50
3:1
EtO
EtO
EtO
EtO
H
N
H
H
N
H
28, Cu(MeCN)4PF6, Et3N
OBn
45
OBn
+
MeCN
80%
O
O
OBn
OBn
51
52
7:1
Scheme 6 Stereoselectivities of the Kinugasa reactions involving sugar-derived nitrones 43–45
Synthesis 2012, 44, 2825–2839
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Toward the Carbapenem Scaffold via Asymmetric Kinugasa Reactions
2833
ascribed to the basic conditions of Kinugasa reaction. It
should be noted that an exo double bond can be easily
transformed into a hydroxy, amino or isopropyl group via
a sequence of reactions involving cis-hydroxylation, fol-
lowed by glycolic cleavage and standard transformation
of the keto group, or hydrogenation of the double
bond.35,36 Unfortunately, commercially available acetyl-
ene 39 did not provide any defined product under Kinugasa
reaction conditions.
H
N
H
N
H
38 (3 equiv)
CuI, Et3N, MeCN
53%
OBn
OBn
OBn
+
45
O
O
OBn
55
56
ratio
1:3
Scheme 8 Synthesis of carbapenams 55 and 56
Reactions in which both the acetylenes (17/ent-17, 41/ent-
41 and 42/ent-42) and nitrones (43/ent-43, 44 and 45)
were chiral, demonstrate interesting cases of double
asymmetric induction (Scheme 9). Since the stereochem-
ical pathway all of these reactions proceeded in a similar
fashion, we have discussed in detail only those involving
acetylenes 17/ent-17, with the exception of the reactions
of acetylenes 41/ent-41 and 42/ent-42 with nitrone 45, be-
cause the latter substrates enable access to the basic skel-
eton of the carbapenem antibiotics. The results of other
reactions can be found in the Supporting Information.
O
H
N
H
17, CuI, Et3N
O
45
OBn
MeCN
45%
O
OBn
57
OBn
OBn
OBn
O
O
O
H
H
N
H
H
H
H
N
17, CuI, Et3N
O
O
O
43
+
OBn
OBn
OBn
+
MeCN
78%
N
O
O
O
OBn
OBn
OBn
60
59
61
dr 11:1:1
OBn
O
H
N
H
17, CuI, Et3N
O
44
45
OBn
MeCN
52%
O
OBn
64
O
H
H
ent-17, CuI, Et3N
O
MeCN
44%
OBn
N
O
OBn
58
OBn
OBn
O
O
H
H
H
H
N
ent-17, CuI, Et3N
O
O
43
OBn
OBn
MeCN
75%
+
N
O
O
OBn
OBn
63
62
dr 6.5:1
OBn
O
H
N
H
ent-17, CuI, Et3N
O
44
OBn
MeCN
34%
O
OBn
65
Scheme 9 Kinugasa reactions of chiral acetylenes and nitrones
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2825–2839

2834
M. Maciejko et al.
FEATURE ARTICLE
As was demonstrated previously,14b in cases in which both 60 and alternative cis-isomer 61. The formation of these
substrates were chiral, the configuration of the stereogenic trace products could be due to the influence of the stereo-
center present in the acetylene molecule played only a genic center of the dioxolane fragment. In the case of ent-
secondary role. The stereoselectivity depends mostly on 17 and nitrone 43, the configurations of all the stereogenic
the nature of the substituents and configurations of the ni- centers influenced asymmetric induction toward the same
trones at C-3 and C-5 . The case in which the nitrone did outcome, and therefore anti/cis adduct 62 was formed
not possess a benzyloxymethyl group is similar to the sit- along with a trace amount of the epimerized product 63.
uation discussed above for nitrones 13 and 14 having a 3-
tert-butoxy substituent. When the nitrone does not have a
large substituent at C-3 (e.g., nitrone 45), the benzyloxy-
O
O
O
N
methyl substituent at C-5 determines the stereoselectivity
of the reaction. The acetylene approaches the nitrone anti
to that group regardless of the configuration of the nitrone
stereogenic center. This was observed when nitrone 45 re-
acted with acetylenes 17 and ent-17 to afford compounds
57 and 58 as the only products (Scheme 9).
O
BnO
H
H
N
40, CuI, Et3N
H
H
45
MeCN
OBn
BnO
OBn
66
A more complicated situation arises when the nitrone pos-
sesses substituents at both C-3 and C-5 (as in 43 and 44).
Matched and mismatched relationships between the con-
figurations of both substituents on the five-membered ring
of the nitrone (benzyloxymethyl and benzyloxy groups)
need be taken into consideration. If both substituents are
on the same side of the ring (43/ent-43 – matched situa-
tion) the product of anti addition is formed with a high
preference. However, when both substituents are on oppo-
site sides of the ring (mismatched situation), the stereo-
chemistry of the acetylene fragment can influence the
composition of the isomeric products since it fits with
both configurations at C-3 and C-5 of the nitrone. It
should be recalled that the preferred cis-product can al-
ways be accompanied by the trans-isomer, which can be
assigned to base-mediated epimerization at the position α
to the β-lactam carbonyl group. The tendency for epimer-
ization to occur depends on the base used, but can also be
attributed to the structure and configuration of the acety-
lene fragment. However, the latter process cannot be rea-
sonably or adequately rationalized. The above-mentioned
observations were manifested in the reactions of 17/ent-17,
41/ent-41, and 42/ent-42 with nitrones 43/ent-43 and 44.
Scheme 10 Formation of bis-adduct 66
Interesting double addition was observed in the case of
acetylene 40 derived from D-tartaric acid (Scheme 10).
The bis-substituted product 66 was formed with high ste-
reoselectivity via reaction of two of the same matched
pairs. A similar double addition involving diaryl nitrone
33 and 40 was investigated previously with the aim of de-
veloping an attractive entry to ezetimibe (32), but without
success.27
The reaction of the chiral acetylene 41 (derived from L-
lactic acid) with nitrone 45 led to the cis-diastereomeric
product 67 in a low yield (27%), accompanied by a trace
amount of the trans isomer 68 (Scheme 11). A much im-
proved result was obtained for the reaction of O-protected
acetylene 42 with the same nitrone (45). Carbapenam 69
along with a small amount of the trans isomer 70 were ob-
tained in 74% overall yield (69:70, dr = 7:1).
Different results were obtained from the reactions of acet-
ylene ent-41, derived from D-lactic acid. The mismatched
situation of nitrone 45 and the acetylene led to the forma-
tion of isomers cis-71 and trans-72 in a ratio of about 2:1,
and an overall yield of 30%. In contrast to the reaction of
the O-silyl protected acetylene derived from L-lactic acid,
In the reaction of chiral acetylene 17 and nitrone 43,
anti/cis-59 was obtained as the major product. It was,
however, accompanied by trace amounts of adduct trans-
RO
H
RO
H
N
H
H
N
OR
45, CuI, Et3N
OBn
OBn
+
MeCN
O
O
OBn
41 R = H
42 R = TBDPS
OBn
67 R = H
68 R = H
69 R = TBDPS
70 R = TBDPS
RO
OR
RO
H
H
H
N
H
45, CuI, Et3N
+
OBn
OBn
MeCN
N
O
O
ent-41 R = H
ent-42 R = TBDPS
OBn
OBn
71 R = H
73 R = TBDPS
72 R = H
74 R = TBDPS
Scheme 11 Kinugasa reactions of chiral acetylenes 41/ent-41, 42/ent-42 and nitrone 45
Synthesis 2012, 44, 2825–2839
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Toward the Carbapenem Scaffold via Asymmetric Kinugasa Reactions
2835
42, the reaction of ent-42 with nitrone 45 proceeded in a tion on the pyrrolidine ring, which enables the introduc-
lower yield (17%) compared to that of the free alcohol tion of side chains in subsequent reaction steps, as well as
ent-41 to afford a mixture of diastereoisomers 73 and 74 the correct configurations at the bridgehead carbon atom.
in a ratio of about 3.3:1 (Scheme 11).
It was demonstrated that epimerization (cis into trans) at
C-6 of the carbapenam skeleton could be easily achieved
in the presence of potassium hexamethyldisilazide.
Bearing in mind the configuration of the antibiotic, thien-
amycin (34) and related compounds 35 and 36, the trans-
isomer 72 had the desired configuration of the stereogenic
centers in the four-membered ring and hydroxyethyl side
chain. Thus, the reactions of nitrones 43–45 provide most-
ly cis-azetidinones, and we decided to explore a method
for the epimerization at C-3 to afford the corresponding
trans-product bearing the same absolute configurations at
C-5, C-6 and C-1′ as those found in active antibiotics, for
example, carbapenems 34–36. After screening various
bases, we found that in the presence of two equivalents of
potassium hexamethyldisilazide (KHMDS), the cis-iso-
mer 71 could be epimerized at C-6 of the carbapenam
skeleton to provide the desired isomer 72 (Scheme 12) in
55% yield. On the other hand, base-mediated epimeriza-
tion of the corresponding silyl-protected compound 73
yielded a 1:1 (E/Z) mixture of elimination products 75.
Thin-layer chromatography was performed on Merck silica gel 60
F254 (20 cm × 20 cm, × 0.2 cm) aluminum sheets. Column chroma-
tography was carried out using Merck silica gel (230–400 mesh).
Optical rotations were measured using a JASCO P-2000 digital po-
larimeter. Infrared spectra were recorded on an FT-IR-1600 Perkin-
Elmer spectrophotometer. 1H and 13C NMR spectra were recorded
on a Varian-NMR-vnmrs 600 spectrometer using deuterated sol-
vents and TMS as the internal standard. Chemical shifts are reported
as δ values in ppm and coupling constants are quoted in Hz. High-
resolution mass spectra were recorded on an ESI-TOF Mariner
Spectrometer (Perspective Biosystem). HPLC was carried out on an
Hitachi Chromatograph with a DAD detector equipped with an Li-
Chrospher® Si60 analytical column (250 × 4.6, 5 μm). Detailed
characterization data of selected carbapenams is provided below.
Full data for all other newly synthesized compounds can be found
in the Supporting Information.
Kinugasa Reaction; General Procedure
HO
To a suspension of CuI (0.5 mmol, 95 mg) in degassed anhyd
MeCN (3 mL) was added Et3N (280 μL, 2.0 mmol). After cooling
to 0 °C, a soln of acetylene (0.5 mmol) in MeCN (1 mL) was added
and the obtained mixture was stirred for 15 min. Next, a soln of ni-
trone (1 mmol) in MeCN (1–2 mL) was added slowly and the mix-
ture was kept at 0 °C for an additional 15 min. The cooling bath was
removed and the mixture stirred at r.t. under an N2 atm. The prog-
ress of the reaction was monitored by TLC. Upon completion of the
reaction the solvent was removed under reduced pressure and the
residue was purified by column chromatography on silica gel. The
diastereoisomeric ratio was determined by HPLC or 1H NMR spec-
troscopy of the crude reaction mixture
H
H
N
HO
H
H
N
OBn
KHMDS (2 equiv)
OBn
THF, –50 °C
55%
O
O
OBn
OBn
71
72
OTBDPS
H
H
H
N
OBn
KHMDS (2 equiv)
N
OBn
THF, –50 °C
64%
O
O
OBn
OBn
73
(2S,3S,4S,5S,6R)-3,4-Bis(benzyloxy)-2-[(benzyloxy)methyl]-6-
(diethoxymethyl)-1-azabicyclo[3.2.0]heptan-7-one (48)
Reaction of acetylene 28 with nitrone 43 afforded compound 48 in
57% yield.
E/Z 1:1
75
Scheme 12 Successful epimerization of carbapenam 71 and forma-
tion of elimination products 75
Colorless oil; [α]D +33 (c 1, CH2Cl2); Rf = 0.52 (hexanes–EtOAc,
2:1).
IR (film): 2975, 2868, 1773, 1100 cm–1.
1H NMR (600 MHz, C6D6): δ = 0.92 (t, J = 7.1 Hz, 3 H, CH2CH3),
1.07 (t, J = 7.1 Hz, 3 H, CH2CH3), 3.18–3.23 (m, 1 H, CHHCH3),
3.34–3.51 (m, 5 H, CH2OBn, CHHCH3, CH2CH3), 3.66 (dd, J = 6.1,
2.7 Hz, 1 H, H-5), 3.75 (dd, J = 8.2, 6.1 Hz, 1 H, H-6), 4.22–4.30
(m, 3 H, 3 × CHHPh), 4.33–4.42 (m, 5 H, H-3, H-4, 3 × CHHPh),
4.52 (m, 1 H, H-2), 4.83 [d, J = 8.1 Hz, 1 H, CH(OEt)2], 7.00–7.30
(15 H, ArH).
13C NMR (150 MHz, CDCl3): δ = 15.5, 15.7, 55.5, 56.2, 58.3, 62.1,
63.0, 67.8, 72.5, 73.7, 74.3, 80.5, 86.1, 98.3, 127.1, 127.3, 127.5 (×
2), 127.6 (× 2), 127.7, 127.8, 127.9, 128.1, 128.2, 137.8, 138.4,
138.5, 177.2.
7
Conclusion
In conclusion, we have shown that the diastereoselective
Kinugasa reaction involving five-membered cyclic ni-
trones derived from pentofuranoses, and simple non-
chiral and chiral acetylenes provides an interesting entry
into carbapenam antibiotics. The reactions proceeded in
moderate to good yields and displayed high levels of dia-
stereoselectivity affording mostly one predominant cis-
product. It should be noted that the configuration at the
bridgehead carbon atom, which is essential for the biolog-
ical activity of the target antibiotic, can be easily con-
trolled by the substituents and the configurations of the
groups next to the double bond of the nitrone. Bearing in
mind the structures and configurations of carbapenem an-
tibiotics, the nitrone derived from 2-deoxyribose provided
the most attractive products having appropriate substitu-
HRMS (ESI): m/z [M + Na]+ calcd for C33H39NO6Na: 568.2670;
found: 568.2719.
(2S,3R,4R,5R,6S)-3,4-Bis(benzyloxy)-2-[(benzyloxy)methyl]-6-
(diethoxymethyl)-1-azabicyclo[3.2.0]heptan-7-one (49) and
(2S,3R,4R,5S,6R)-3,4-Bis(benzyloxy)-2-[(benzyloxy)methyl]-6-
(diethoxymethyl)-1-azabicyclo[3.2.0]heptan-7-one (50)
Reaction of acetylene 28 with nitrone 44 afforded compounds 49
and 50 in 54% combined yield in a ratio of ~3:1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2825–2839

2836
M. Maciejko et al.
FEATURE ARTICLE
Compound 49
Compound 52
Colorless oil; [α]D –46 (c 1, CH2Cl2); Rf = 0.73 (hexanes–EtOAc,
Colorless oil; [α]D +4.4 (c 1, CH2Cl2); Rf = 0.31 (hexanes–EtOAc,
2:1).
2:1).
IR (film): 2928, 2870, 1770, 1103 cm–1.
IR (film): 2975, 2868, 1764, 1095 cm–1.
1H NMR (600 MHz, C6D6): δ = 0.91 (t, 3 H, J = 7.1 Hz, CH2CH3),
1.06 (t, 3 H, J = 7.1 Hz, CH2CH3), 3.16–3.24 (m, 1 H, CH2CH3),
3.30 (m, 3 H, CH2CH3), 3.51 (dd, J = 6.2, 2.5 Hz, 1 H, H-5), 3.60
(dd, J = 9.0, 6.2 Hz, 1 H, H-6), 3.61–3.65 (m, 1 H, H-2), 4.05 (dd,
J = 4.2, 2.2 Hz, 1 H, H-3), 4.11 (dd, J = 9.7, 4.4 Hz, 1 H, CHHOBn),
4.25–4.28 (m, 1 H, H-4), 4.31–4.42 (m, 7 H, 3 × CH2Ph, CHHOBn),
4.81 [d, J = 9.0 Hz, 1 H, CH(OEt)2], 7.00–7.21 (15 H, ArH).
13C NMR (150 MHz, CDCl3): δ = 15.0, 15.2, 55.7, 58.7, 59.6, 63.0,
63.8, 64.6, 71.4, 71.9, 73.1, 80.3, 85.8, 99.1, 127.2, 127.3, 127.4,
127.5, 127.6 (× 2), 127.7, 127.8, 127.9, 128.1, 128.2, 137.8, 138.2,
138.5, 174.1.
1H NMR (600 MHz, C6D6): δ = 1.01 (t, J = 7.2 Hz, 3 H, OCH2CH3),
1.06 (t, J = 7.2 Hz, 3 H, OCH2CH3), 1.33–1.36 (m, 1 H), 1.92 (ddd,
J = 13.2, 5.8, 2.8 Hz, 1 H, CHH, H-4b), 3.02 (dd, J = 5.5, 2.2 Hz, 1
H, H-5), 3.30–3.41 (m, 2 H, OCH2CH3), 3.48–3.57 (m, 2 H,
OCH2CH3), 3.60 (dd, J = 9.4, 5.6 Hz, 1 H, CHHOBn), 3.66 (dd, J =
9.3, 7.4 Hz, 1 H, CHHOBn), 3.89 (m, 1 H, H-2), 3.92 (ddd, J = 8.1,
5.9, 2.2 Hz, 1 H, H-5), 4.02–4.13 (m, 3 H, 2 × CH2Ph, H-3), 4.23–
4.32 (m, 2 H, CH2Ph), 4.67 [d, J = 5.4 Hz, 1 H, CH(OEt)2], 7.00–
7.24 (10 H, ArH).
13C NMR (150 MHz, C6D6): δ = 15.2, 15.3, 36.2, 53.4, 60.1, 61.6,
62.1, 62.7, 67.8, 72.3, 73.2, 83.9, 99.8, 127.4, 127.5, 127.6, 127.7,
128.3, 128.4, 137.8, 138.3, 175.5.
HRMS (ESI): m/z [M + Na]+ calcd for C33H39NO6Na: 568.2669;
found: 568.2661.
HRMS (ESI): m/z [M + Na]+ calcd for C26H33NO5Na: 462.2251;
found: 462.2271.
Compound 50
Colorless oil; [α]D +30 (c 1, CH2Cl2); Rf = 0.53 (hexanes–EtOAc,
(2S,3S,5R,6R)-3-(Benzyloxy)-2-[(benzyloxy)methyl]-6-[(S)-
2′,2′-dimethyl-1′,3′-dioxolan-4′-yl]-1-azabicyclo[3.2.0]heptan-
7-one (57)
Reaction of acetylene 17 with nitrone 45 afforded compound 57 in
45% yield.
2:1).
IR (film): 2928, 2869, 1769, 1100 cm–1.
1H NMR (600 MHz, C6D6): δ = 1.12–1.17 (m, 6 H, 2 × CH2CH3),
3.21–3.23 (m, 1 H, 1 × CH2CH3), 3.49–3.58 (m, 2 H, CH2CH3),
3.60–3.67 (m, 4 H, CHHCH3, CH2OBn, H-6), 3.89 (dd, J = 5.8, 3.3
Hz, 1 H, H-5), 4.00–4.04 (m, 1 H, H-4), 4.07–4.09 (m, 1 H, H-2),
4.22–4.26 (m, 1 H, H-3), 4.39–4.58 (m, 6 H, CH2Ph), 5.03 [d, J =
8.1 Hz, 1 H, CH(OEt)2], 7.20–7.35 (15 H, ArH).
13C NMR (150 MHz, C6D6): δ = 15.3, 15.5, 53.5, 57.2, 59.3, 61.1,
63.0, 67.8, 71.5, 72.7, 73.3, 80.5, 85.1, 98.3, 127.1, 127.3, 127.5 (×
2), 127.6 (× 2), 127.7, 127.8, 127.9, 128.1, 128.2, 137.8, 138.4,
138.5, 177.2.
Colorless oil; [α]D +56.0 (c 1, CH2Cl2); Rf = 0.41 (hexanes–EtOAc,
2:1).
IR (film): 2931, 2870, 1751, 1062 cm–1.
1H NMR (600 MHz, CDCl3): δ = 1.29 (d, J = 8.3 Hz, 6 H, 2 × CH3),
2.06–2.08 (m, 1 H, H-4a), 2.25–2.29 (m, 1 H, H-4b), 3.48 (dd, J =
3.6, 3.4 Hz, 1 H, H-6), 3.63–3.65 (m, 2 H, CH2OBn), 3.89–3.97 (m,
2 H, H-5, H-5′a), 4.00 (dd, J = 8.1, 6.1 Hz, 1 H, H-5′b), 4.08 (dd,
J = 11.3, 5.6 Hz, 1 H, H-2), 4.22 (ddd, J = 9.4, 6.1, 3.7 Hz, 1 H, H-
4′), 4.38 (dd, J = 11.7, 5.8 Hz, 1 H, H-3), 4.51–4.57 (m, 4 H, 2 ×
CH2Ph), 7.28–7.34 (10 H, ArH).
13C NMR (150 MHz, CDCl3): δ = 26.0, 26.3, 31.6, 52.7, 53.7, 60.2,
67.6, 67.8, 72.2, 72.3, 73.3, 82.2, 110.3, 127.5, 127.6, 127.7, 128.3,
128.4, 138.0, 138.3, 176.4.
HRMS (ESI): m/z [M + Na]+ calcd for C33H39NO6Na: 568.2675;
found: 568.2661.
(2S,3S,5R,6R)-3-(Benzyloxy)-2-[(benzyloxy)methyl]-6-
(diethoxymethyl)-1-azabicyclo[3.2.0]heptan-7-one (51) and
(2S,3S,5R,6S)-3-(Benzyloxy)-2-[(benzyloxy)methyl]-6-
(diethoxymethyl)-1-azabicyclo[3.2.0]heptan-7-one (52)
Reaction of acetylene 28 with nitrone 45 afforded compounds 51
and 52 in 55% combined yield and in a ratio of ~ 4:1. When the re-
action was performed in the presence of Cu(MeCN)4PF6 instead of
CuI, the dr was 7:1 and the yield was 80%.
HRMS (ESI): m/z [M + Na]+ calcd for C26H31NO5Na: 460.2095;
found: 460.2095.
(2S,3S,5R,6R)-3-(Benzyloxy)-2-[(benzyloxy)methyl]-6-[(R)-
2′,2′-dimethyl-1′,3′-dioxolan-4′-yl]-1-azabicyclo[3.2.0]heptan-
7-one (58)
Reaction of acetylene ent-17 with nitrone 45 afforded compound 58
in 44% yield.
Compound 51
Colorless oil; [α]D +10 (c 1, CH2Cl2); Rf = 0.68 (hexanes–EtOAc,
2:1).
Colorless oil; [α]D +130 (c 1, CH2Cl2); Rf = 0.53 (hexanes–EtOAc,
2:1).
IR (film): 2971, 2867, 1764, 1098 cm–1.
IR (KBr): 2942, 2857, 1767, 1062 cm–1.
1H NMR (600 MHz, C6D6): δ = 0.99 (t, J = 7.1 Hz, 3 H, OCH2CH3),
1.05 (t, J = 7.1 Hz, 3 H, OCH2CH3), 1.87 (ddd, J = 13.5, 7.5, 5.5
Hz, 1 H, H-4b), 1.98 (ddd, J = 13.5, 6.7, 3.6 Hz, 1 H, H-4a), 3.31–
3.50 (m, 5 H, 2 × OCH2CH3, H-6), 3.60 (dd, J = 9.5, 5.4 Hz, 1 H,
CHHOBn), 3.64 (d, J = 9.5, 6.3 Hz, 1 H, CHHOBn), 3.71–3.75 (m,
1 H, H-5), 4.07–4.12 (m, 2 H, H-2, H-3), 4.17 (d, J = 12.0 Hz, 1 H,
OCHHPh), 4.21 (d, J = 12.0 Hz, 1 H, OCHHPh), 4.28 (d, J = 12.0
Hz, 1 H, OCHHPh), 4.33 (d, J = 12.0 Hz, 1 H, OCHHPh), 4.53 [d,
J = 6.2 Hz, 1 H, CH(OEt)2], 6.98–7.30 (10 H, ArH).
1H NMR (600 MHz, CDCl3): δ = 1.32 (s, 3 H, CH3), 1.40 (s, 3 H,
CH3), 1.94 (ddd, J = 13.6, 7.2, 5.8 Hz, 1 H, H-4a), 2.29 (ddd, J =
6.5, 4.3, 1.6 Hz, 1 H, H-4b), 3.47 (dd, J = 9.5, 5.4 Hz, 1 H, H-6),
3.62–3.68 (m, 2 H, CH2OBn), 3.85 (dd, J = 8.3, 3.8 Hz, 1 H, H-5′a),
4.02–4.07 (m, 2 H, H-2, H-5), 4.15–4.17 (m, 2 H, H-4′, H-5′b), 4.35
(dd, J = 10.2, 5.5 Hz, 1 H, H-3), 4.49–4.59 (m, 4 H, 2 × CH2Ph),
7.26–7.32 (10 H, ArH).
13C NMR (150 MHz, CDCl3): δ = 25.4, 26.8, 31.9, 54.0, 54.3, 60.9,
67.7, 68.2, 71.4, 72.3, 73.3, 83.1, 109.2, 127.5 (× 2), 127.6, 127.8,
128.3, 128.4, 137.8, 138.2, 176.4.
13C NMR (150 MHz, C6D6): δ = 15.07, 15.09, 32.3, 53.5, 54.9, 60.8,
61.7, 62.4, 68.3, 71.9, 72.9, 82.9, 99.3, 127.4, 127.5, 127.6, 127.7,
128.3, 128.4, 137.9, 138.3, 175.5.
HRMS (ESI): m/z [M + Na]+ calcd for C26H31NO5Na: 460.2095;
found: 460.2112.
HRMS (ESI): m/z [M + Na]+ calcd for C26H33NO5Na: 462.2251;
found: 462.2273.
Synthesis 2012, 44, 2825–2839
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Toward the Carbapenem Scaffold via Asymmetric Kinugasa Reactions
2837
(2S,3S,4S,5S,6R)-3,4-Bis(benzyloxy)-2-[(benzyloxy)methyl]-6-
[(S)-2′,2′-dimethyl-1′,3′-dioxolan-4′-yl]-1-azabicyclo[3.2.0]hep-
tan-7-one (59), (2S,3S,4S,5S,6S)-3,4-Bis(benzyloxy)-2-[(benzyl-
oxy)methyl]-6-[(S)-2′,2′-dimethyl-1′,3′-dioxolan-4′-yl]-1-
azabicyclo[3.2.0]heptan-7-one (60) and (2S,3S,4S,5R,6S)-3,4-
Bis(benzyloxy)-2-[(benzyloxy)methyl]-6-[(S)-2′,2′-dimethyl-
1′,3′-dioxolan-4′-yl]-1-azabicyclo[3.2.0]heptan-7-one (61)
Reaction of acetylene 17 with nitrone 43 afforded compounds 59,
60 and 61 in 78% combined yield in a ratio of ~ 11:1:1.
(2S,3S,4S,5S,6R)-3,4-Bis(benzyloxy)-2-[(benzyloxy)methyl]-6-
[(R)-2′,2′-dimethyl-1′,3′-dioxolan-4′-yl]-1-azabicyclo[3.2.0]hep-
tan-7-one (62) and (2S,3S,4S,5S,6S)-3,4-Bis(benzyloxy)-2-[(ben-
zyloxy)methyl]-6-[(R)-2′,2′-dimethyl-1′,3′-dioxolan-4′-yl]-1-
azabicyclo[3.2.0]heptan-7-one (63)
Reaction of acetylene ent-17 with nitrone 43 afforded compounds
62 and 63 in 75% combined yield in a ratio of ~ 6.5:1.
Compound 62
Colorless oil; [α]D +55.5 (c 1, CH2Cl2); Rf = 0.55 (hexanes–EtOAc,
Compound 59
2:1).
Colorless oil; [α]D +11 (c 1, CH2Cl2); Rf = 0.30 (hexanes–EtOAc,
IR (film): 2934, 2868, 1767, 1097 cm–1.
2:1).
1H NMR (600 MHz, CDCl3): δ = 1.25 (s, 3 H, CH3), 1.31 (s, 3 H,
CH3), 3.47–3.51 (m, 2 H, CH2OBn), 3.58 (dd, J = 10.7, 5.5 Hz, 1 H,
H-6), 3.83–3.88 (m, 2 H, H-5, H-5′a), 4.05 (dd, J = 8.7, 6.0 Hz, 1 H,
H-5′b), 4.19–4.25 (m, 2 H, H-2, H-4), 4.29–4.32 (m, 1 H, H-3), 4.36
(m, 1 H, H-4′), 4.43–4.62 (m, 6 H, CH2Ph), 7.00–7.23 (15 H, ArH).
13C NMR (600 MHz, C6D6): δ = 26.9, 56.8, 60.4, 62.4, 68.2, 68.3,
71.2, 71.7, 71.8, 72.8, 82.5, 88.1, 108.6, 127.3, 127.4, 127.5, 127.6,
127.7, 127.8, 127.9, 128.1, 128.2, 128.3, 137.6, 138.3, 174.9.
IR (film): 2934, 2867, 1769, 1098 cm–1.
1H NMR (600 MHz, C6D6): δ = 1.17 (s, 3 H, CH3), 1.40 (s, 3 H,
CH3), 2.92 (dd, J = 5.5, 3.9 Hz, 1 H, H-6), 3.27 (dd, J = 9.9, 4.5 Hz,
1 H, CHHOBn), 3.36 (dd, J = 9.7, 5.7 Hz, 1 H, CHHOBn), 3.42–
3.45 (m, 1 H, H-5), 3.56 (dd, J = 7.9, 5.9 Hz, 1 H, H-5′a), 3.84 (dd,
J = 7.9, 4.0 Hz, 1 H, H-5′b), 3.94 (ddd, J = 9.8, 5.9, 4.0 Hz, 1 H, H-
4′), 4.12–4.16 (m, 1 H, H-2), 4.16–4.24 (m, 2 H, CH2Ph), 4.32–4.51
(m, 5 H, 2 × CH2Ph, H-3), 4.63–4.67 (m, 1 H, H-4), 7.02–7.25 (15
H, ArH).
HRMS (ESI): m/z [M + Na]+ calcd for C33H37NO6Na: 566.2519;
found: 566.2533.
13C NMR (600 MHz, CDCl3): δ = 26.4, 54.2, 58.6, 60.3, 60.7, 67.5,
68.9, 72.1, 72.2, 72.4, 73.1, 82.7, 88.2, 110.3, 127.5, 127.6, 127.8,
127.9, 128.1, 128.3, 128.4, 128.5, 137.5, 137.6, 137.9, 174.8.
Compound 63
Compound 63 was not isolated in pure form; Rf = 0.58 (hexanes–
HRMS (ESI): m/z [M + Na]+ calcd for C33H37NO6Na: 566.2530;
EtOAc, 2:1).
1H NMR (600 MHz, CDCl3): δ (selected signals from a diastereo-
isomeric mixture) = 3.35 (dd, J = 4.2, 2.9 Hz, 1 H), 3.65 (dd, J =
6.4, 2.9 Hz, 1 H).
found: 566.2513.
Compound 60
Colorless oil; [α]D +24 (c 1, CH2Cl2); Rf = 0.41 (hexanes–EtOAc,
2:1).
HRMS (ESI): m/z [M + Na]+ calcd for C33H37NO6Na: 566.2519;
found: 566.2525.
IR (film): 2924, 2858, 1767, 1092 cm–1.
1H NMR (600 MHz, CDCl3): δ = 1.35 (s, 3 H, CH3), 1.43 (s, 3 H,
CH3), 3.23 (dd, J = 7.4, 2.3 Hz, 1 H, H-6), 3.47 (d, J = 6.4 Hz, 2 H,
CH2OBn), 3.69 (dd, J = 3.8, 2.6 Hz, 1 H, H-5), 3.74 (dd, J = 8.4,
6.2 Hz, 1 H, H-5′a), 3.81–3.83 (m, 1 H, H-4), 4.08 (dd, J = 8.4, 6.3
Hz, 1 H, H-5′b), 4.17 (ddd, J = 13.0, 6.5, 3.2 Hz, 1 H, H-2), 4.27–
4.33 (m, 1 H, H-3), 4.38 (dd, J = 13.4, 6.3 Hz, 1 H, H-4′), 4.47–4.60
(m, 6 H, 3 × CH2Ph), 7.21–7.40 (15 H, ArH).
(2S,3R,4R,5R,6S)-3,4-Bis(benzyloxy)-2-[(benzyloxy)methyl]-6-
[(S)-2′,2′-dimethyl-1′,3′-dioxolan-4′-yl]-1-azabicyclo[3.2.0]hep-
tan-7-one (64)
Reaction of acetylene 17 with nitrone 44 afforded compound 64 in
52% yield.
Colorless oil; [α]D +25.0 (c 1, CH2Cl2); Rf = 0.48 (hexanes–EtOAc,
2:1).
13C NMR (150 MHz, CDCl3): δ = 25.3, 26.8, 59.2, 59.7, 62.7, 67.5,
68.5, 71.9, 72.0, 73.2, 73.5, 85.6, 87.9, 109.5, 127.5, 127.6, 127.7,
127.8, 127.9, 128.0, 128.3, 128.4, 128.5, 137.3, 137.5, 137.9, 174.9.
HRMS (ESI): m/z [M + Na]+ calcd for C33H37NO6Na: 566.2513;
found: 566.2533.
IR (film): 2921, 2854, 1765, 1099 cm–1.
1H NMR (600 MHz, CDCl3): δ = 1.12 (s, 3 H, CH3), 1.37 (s, 3 H,
CH3), 3.40 (dd, J = 10.8, 5.4 Hz, 1 H, H-6), 3.61–3.65 (m, 1 H, H-
2), 3.70 (dd, J = 5.4, 3.8 Hz, 1 H, H-5), 3.76 (dd, J = 8.5, 5.7 Hz, 1
H, H-5′a), 3.84 (dd, J = 8.5, 6.1 Hz, 1 H, H-5′b), 4.00 (dd, J = 9.7,
4.3 Hz, 1 H, CHHOBn), 4.08 (dd, J = 9.8, 5.9 Hz, 1 H, CHHOBn),
4.15–4.18 (m, 1 H, H-4′), 4.20 (dd, J = 5.1, 3.6 Hz, 1 H, H-3), 4.33–
4.34 (m, 1 H, H-4), 4.46–4.65 (m, 6 H, 3 × CH2Ph), 7.23–7.35 (15
H, ArH).
13C NMR (150 MHz, CDCl3): δ = 25.2, 27.0, 55.6, 58.8, 62.8, 64.2,
68.2, 71.8, 72.1, 72.2, 73.3, 79.8, 86.0, 108.8, 127.4, 127.6, 127.7,
127.8 (× 2), 127.9, 128.34, 128.36, 128.4, 137.6, 137.9, 138.0,
174.0.
Compound 61
Colorless oil; [α]D +19.6 (c 1, CH2Cl2); Rf = 0.60 (hexanes–EtOAc,
2:1).
IR (film): 2925, 2859, 1767, 1096 cm–1.
1H NMR (600 MHz, CDCl3): δ = 1.23 (s, 3 H, CH3), 1.40 (s, 3 H,
CH3), 3.44–3.50 (m, 2 H, CH2OBn), 3.56 (dd, J = 10.7, 5.6 Hz, 1 H,
H-6), 3.82–3.86 (m, 2 H, H-5′a, H-5), 4.04 (dd, J = 8.8, 6.1 Hz, 1 H,
H-5′b), 4.16–4.20 (m, 1 H, H-2), 4.21–4.22 (m, 1 H, H-4), 4.28–
4.31 (m, 1 H, H-3), 4.33–4.35 (m, 1 H, H-4′), 4.42–4.62 (m, 6 H,
CH2Ph), 7.20–7.36 (15 H, ArH).
HRMS (ESI): m/z [M + Na]+ calcd for C33H37NO6Na: 566.2519;
found: 566.2520.
13C NMR (150 MHz, CDCl3): δ = 25.3, 27.0, 56.3, 60.2, 62.4, 68.2,
68.3, 71.5, 71.6, 72.2, 73.1, 82.4, 88.1, 108.9, 127.6 (× 2), 127.7 (×
2), 127.8, 127.9, 128.2, 128.3, 128.4, 137.3, 137.6, 137.9, 175.4.
HRMS (ESI): m/z [M + Na]+ calcd for C33H37NO6Na: 566.2513;
found: 566.2513.
(2S,3R,4R,5S,6R)-3,4-Bis(benzyloxy)-2-[(benzyloxy)methyl]-6-
[(R)-2′,2′-dimethyl-1′,3′-dioxolan-4′-yl]-1-azabicyclo[3.2.0]hep-
tan-7-one (65)
Reaction of acetylene ent-17 with nitrone 44 afforded compound 65
in 34% yield.
Colorless oil; [α]D +43 (c 1, CH2Cl2); Rf = 0.53 (hexanes–EtOAc,
2:1).
IR (film): 2933, 2869, 1765, 1098 cm–1.
1H NMR (600 MHz, CDCl3): δ = 1.24 (s, 3 H, CH3), 1.40 (s, 3 H,
CH3), 3.49 (dd, J = 9.8, 5.6 Hz, 1 H, H-6), 3.62–3.68 (m, 2 H,
CH2OBn), 3.76 (dd, J = 8.7, 5.7 Hz, 1 H, H-5′a), 3.92 (dd, J = 5.6,
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2825–2839

2838
M. Maciejko et al.
FEATURE ARTICLE
3.7 Hz, 1 H, H-5), 4.04–4.10 (m, 2 H, H-5′b, H-2), 4.22–4.24 (m, 2
H, H-3, H-4), 4.49–4.56 (m, 6 H, 3 × CH2Ph), 4.76–4.79 (m, 1 H,
H-4′), 7.27–7.37 (m, 15 H, ArH).
13C NMR (150 MHz, C6D6): δ = 21.4, 31.0, 53.9, 56.7, 60.4, 64.6,
68.1, 71.9, 72.9, 83.3, 127.4, 127.5, 127.6, 127.7, 127.8, 127.9,
128.0, 128.1, 128.2, 128.3, 178.9.
13C NMR (150 MHz, CDCl3): δ = 25.4, 27.1, 53.4, 56.5, 59.1, 67.6,
69.1, 71.0, 71.7, 73.0, 73.3, 80.6, 85.7, 108.6, 127.0, 127.6, 127.7,
127.8, 127.9, 128.4, 128.5, 128.6, 137.3, 137.6, 138.1, 176.5.
HRMS (ESI): m/z [M + Na]+ calcd for C33H37NO6Na: 566.2513;
found: 566.2520.
HRMS (ESI): m/z [M + Na]+ calcd for C23H27NO4Na: 404.1838;
found: 404.1845.
Compound 72
Colorless oil; [α]D +34 (c 1, CH2Cl2); Rf = 0.26 (hexanes–acetone,
2:1).
IR (film): 2924, 2859, 1756, 1099 cm–1.
(2S,3S,5R,6R)-3-(Benzyloxy)-2-[(benzyloxy)methyl]-6-[(S)-1′-
hydroxyethyl]-1-azabicyclo[3.2.0]heptan-7-one (67) and
(2S,3S,5R,6S)-3-(Βenzyloxy)-2-[(benzyloxy)methyl]-6-[(S)-1′-
hydroxyethyl]-1-azabicyclo[3.2.0]heptan-7-one (68)
Reaction of acetylene 41 with nitrone 45 afforded compounds 67
and 68 in 27% combined yield in a ratio of about 8:1.
1H NMR (600 MHz, CDCl3): δ = 1.33 (d, J = 6.3 Hz, 3 H, CH3),
1.61 (ddd, J = 13.2, 8.1, 5.1 Hz, 1 H, H-4a), 2.39 (ddd, J = 13.3, 5.7,
2.8 Hz, 1 H, H-4a), 2.86 (dd, J = 6.9, 1.9 Hz, 1 H, H-6), 3.62 (dd,
J = 9.5, 6.1 Hz, 1 H, CHHOBn), 3.69 (dd, J = 9.7, 6.9 Hz, 1 H,
CHHOBn), 3.88 (ddd, J = 9.9, 5.7, 1.9 Hz, 1 H, H-5), 4.08–4.12 (m,
1 H, H-2), 4.14–4.18 (m, 1 H, H-1′), 4.39–4.41 (m, 1 H, H-3), 4.44–
4.66 (m, 4 H, CH2Ph), 7.26–7.38 (10 H, ArH).
Compound 67
Colorless oil; [α]D +115 (c 1, CH2Cl2); Rf = 0.3 (hexanes–acetone,
2:1).
13C NMR (150 MHz, CDCl3): δ = 21.9, 36.4, 54.3, 61.6, 63.7, 66.3,
67.9, 72.3, 73.3, 84.2, 127.4, 127.5, 127.7, 127.8, 128.3, 128.4,
137.8, 138.2, 176.7.
HRMS (ESI): m/z [M + Na]+ calcd for C23H27NO4Na: 404.1838;
found: 404.1832.
IR (film): 2929, 2866, 1755, 1096 cm–1.
1Η ΝΜR (600 ΜΗz, CDCl3): δ = 1.14 (d, J = 6.0 Ηz, 3 Η, CΗ3),
1.69 (ddd, J = 13.3, 8.0, 5.0 Ηz, 1 Η, Η-4a), 1.95 (ddd, J = 13.5, 6.2,
3.0 Ηz, 1 Η, Η-4b), 2.89 (dd, J = 9.1, 5.4 Ηz, 1 Η, Η-6), 3.60 (dd,
J = 9.2, 5.0 Ηz, 1 Η, CΗΗΟΒn), 3.65–3.70 (m, 2 Η, CΗΗΟΒn, Η-
1′), 3.74–3.76 (m, 1 Η, Η-5), 3.98–4.02 (m, 2 Η, Η-2, Η-3), 4.10–
4.21 (m, 2 Η, CΗ2ΟΒn), 4.25–4.35 (m, 2 Η, CΗ2ΟPh), 7.01–7.30
(10 Η, ArH).
13C NMR (150 MHz, CDCl3): δ = 21.8, 31.9, 54.6, 57.7, 60.8, 63.8,
68.3, 71.8, 73.0, 83.5, 127.2, 127.3, 127.4, 127.5 (× 2), 127.8, 128.0,
128.1, 128.2, 177.2.
Epimerization; Typical Procedure
A soln of cis-2-azetidinone 71 (100 mg, 0.26 mmol) in anhyd THF
(10 mL) was cooled to –55 °C and treated with a soln of KHMDS
(520 μL, 0.52 mmol, 1 M in THF). The progress of the reaction was
monitored by TLC. After stirring for 5 h, the resulting mixture was
diluted with Et2O (25 mL) followed by the addition of H2O (10 mL).
The organic phase was dried over Na2SO4, evaporated and the resi-
due chromatographed on silica gel (hexane–i-PrOH, 9:1) to afford
trans-azetidinone 72 (54 mg, 55%).
HRMS (ESI): m/z [M + Na]+ calcd for C23H27NO4Na: 404.1832;
found: 404.1830.
Compound 68
Colorless oil; [α]D +85 (c 1, CH2Cl2); Rf = 0.32 (hexanes–acetone,
Acknowledgment
2:1).
This research was financed by the European Union within the
European Regional Development Fund, Project POIG.01.01.02.-
14-102/09.
IR (film): 2934, 2865, 1754, 1098 cm–1.
1H NMR (600 MHz, CD3CN): δ = 0.92 (ddd, J = 13.2, 8.1, 5.1 Hz,
1 H, H-4a), 1.05 (d, J = 6.5 Hz, 3 H, CH3), 1.83 (ddd, J = 13.2, 6.0,
2.9 Hz, 1 H, H-4b), 2.51 (dd, J = 5.5, 2.1 Hz, 1 H, H-6), 3.55–3.61
(m, 2 H, H-5, CHHOBn), 3.65 (dd, J = 9.5, 7.6 Hz, 1 H, CHHOBn),
3.69–3.72 (m, 1 H, H-1′), 3.88–3.91 (m, 1 H, H-2), 4.00–4.02 (m, 1
H, H-3), 4.08–4.36 (m, 4 H, 2 × CH2Ph), 7.21–7.35 (10 H, ArΗ).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
13C NMR (150 MHz, CDCl3): δ = 19.9, 34.7, 52.6, 61.4, 62.4, 68.3,
71.5, 72.0, 73.2, 79.2, 127.5, 127.6, 127.7, 128.4, 138.22, 138.23,
138.3, 169.9.
HRMS (ESI): m/z [M + Na]+ calcd for C23H27NO4Na: 404.1832;
found: 404.1831.
References
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Figueroa, R. Org. Lett. 2008, 10, 3477.
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(2S,3S,5R,6R)-3-(Benzyloxy)-2-[(benzyloxy)methyl)]-6-[(R)-1′-
hydroxyethyl]-1-azabicyclo[3.2.0]heptan-7-one (71) and
(2S,3S,5R,6S)-3-(Benzyloxy)-2-[(benzyloxy)methyl]-6-[(R)-1′-
hydroxyethyl]-1-azabicyclo[3.2.0]heptan-7-one (72)
Reaction of acetylene ent-41 with nitrone 45 afforded compounds
71 and 72 in 30% combined yield in a ratio of ~ 2:1.
Compound 71
Colorless oil; [α]D +25 (c 1, CH2Cl2); Rf = 0.35 (hexanes–acetone,
2:1).
IR (film): 2929, 2865, 1753, 1092 cm–1.
1H NMR (600 MHz, C6D6): δ = 0.94 (d, J = 6.3 Hz, 3 H, CH3), 1.38
(ddd, J = 12.7, 7.7, 5.3 Hz, 1 H, H-4a), 1.61 (ddd, J = 13.3, 6.6. 3.6
Hz, 1 H, H-4b), 2.83 (dd, J = 8.0, 5.6 Hz, 1 H, H-6), 3.47–3.52 (m,
1 H, H-5), 3.56 (dd, J = 9.1, 5.0 Hz, 1 H, CHHOBn), 3.58–3.67 (m,
2 H, CHHOBn, H-1′), 3.95–4.01 (m, 2 H, H-2, H-3), 4.10–4.18 (m,
2 H, CH2Ph), 4.25–4.33 (m, 2 H, CH2Ph), 7.00–7.26 (10 H, ArH).
Synthesis 2012, 44, 2825–2839
© Georg Thieme Verlag Stuttgart · New York

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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2825–2839