Asymmetric Kinugasa reaction involving six-membered cyclic nitrones

Article abstract of DOI:10.1016/j.tet.2012.09.031

Kinugasa reactions between terminal acetylenes and six-membered ring nitrones when one or both components are chiral, proceed in a low to moderate yield and with a high diastereoselectivity affording mostly one, dominant β-lactam product. The first step of the reaction is controlled by the configuration of the nitrone, whereas the protonation of the C-7 center of the carbacepham skeleton in the second step depends on: a) the configuration of the bridgehead carbon atom formed in the first step, b) epimerization process in the presence of a base, and c) on the configuration of the stereogenic center in the acetylenic partner. In the case of the nitrone derived from dihydroisoquinoline, the reaction proceeds in a more complex way affording not only β-lactams, but also products derived from the alternative regio-1,3-cycloaddition, or nucleophilic addition of the acetylene to the double bond of the nitrone.

Full text of DOI:10.1016/j.tet.2012.09.031

Tetrahedron 68 (2012) 10633e10639
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric Kinugasa reaction involving six-membered
cyclic nitrones
Barbara Grzeszczyk a, Kamila Po1awska a, Yasser M. Shaker b, Sebastian Stecko a,
a
a
a
a,
*
ꢀ
Adam Mames , Magdalena Woznica , Marek Chmielewski , Bart1omiej Furman
a Institute of Organic Chemistry of Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
b Department of Chemistry of Natural and Microbal Products, National Research Center, Tahrir St., Dokki, Cairo 12622, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 August 2012
Received in revised form 29 August 2012
Accepted 4 September 2012
Available online 12 September 2012
Kinugasa reactions between terminal acetylenes and six-membered ring nitrones when one or both
components are chiral, proceed in a low to moderate yield and with a high diastereoselectivity
affording mostly one, dominant b-lactam product. The first step of the reaction is controlled by the
configuration of the nitrone, whereas the protonation of the C-7 center of the carbacepham skeleton in
the second step depends on: a) the configuration of the bridgehead carbon atom formed in the first
step, b) epimerization process in the presence of a base, and c) on the configuration of the stereogenic
center in the acetylenic partner. In the case of the nitrone derived from dihydroisoquinoline, the
reaction proceeds in a more complex way affording not only b-lactams, but also products derived from
the alternative regio-1,3-cycloaddition, or nucleophilic addition of the acetylene to the double bond of
the nitrone.
Keywords:
Kinugasa reaction
b
-Lactams
Nitrones
Cascade reactions
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
antibiotics. As a reactants for these reactions the non-racemic cyclic
nitrones, derived from malic acid,6aec tartaric acid,6aec and pento-
The carba-analogs of penicillins and cephalosporins, which are
furanoses6d,9 and simple acetylenes have been used, which open an
easy access to side chains present in carbapenem antibiotics. Re-
actions displayed the high diastereoselectivity leading to one dom-
inant product. The addition was controlled by the substituent
present in the nitrone, whereas the protonation of intermediate
enolate in the second step occurred from the less-shielded side of
carbapenam skeleton.6a Consequently, the major product displayed
found to be relatively resistant to b-lactamase enzymes, represent
a powerful tool against bacterial infections.1e3
Although the former onesdcarbapenemsdare more popular,
the latterdcarbacephem antibioticsdlike Loracarbef (1) have also
found a proper place in modern therapy.4,5
the relative cis-orientation of protons in the four-membered b-lac-
tam ring. Kinugasa reaction involving six-membered ring nitrones is
the logic continuation of our earlier studies. It should be noted,
however, that the six-membered ring nitrones are less stable10 than
their five-membered congeners, therefore extension of the reaction
time may lead to the formation of decomposition products.
2. Results and discussion
Recently,6 we have reported an application of diastereoselective
version of copper(I)-mediated reaction between nitrones and ter-
minal acetylenes, discovered in 1972 by Kinugasa and Hashimoto,7,8
for direct and simple formation of the basic skeleton of carbapenem
For the present study we selected three different nitrones, two
nonchiral, 2 and 3, and one chiral 4, which after the Kinugasa re-
action should provide carbacepham skeletons. As acetylenes we
selected representative nonchiral compounds 5, 6 and chiral ones
derived from D- and L
-glyceraldehyde 7,6b 7ent,11 which are known
to provide products in a relatively good yield.6b,c Except commer-
cially available acetylenes 5 and 6 other substrates 2,12 3,13 414
and 7,6b 7ent11 were obtained following the known procedures.
* Corresponding author. E-mail address: bartlomiej.furman@icho.edu.pl
(B. Furman).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.09.031

10634
B. Grzeszczyk et al. / Tetrahedron 68 (2012) 10633e10639
Compound 3, derived from dihydroisoquinoline, showed dif-
ferent reactivity than previously investigated cyclic nitrones.
Acetylene 5 did not afford any defined product, whereas more re-
active compound 6 gave expected b-lactams 10a and 10b in a ratio
of about 2:1, respectively, accompanied by adduct 11 originated
from the opposite regiochemistry of the first 1,3-dipolar cycload-
dition step of the reaction (intermediate 13). In addition, occa-
sionally a minute amount of N-acyl-tetrahydroisoquinoline 12 was
also isolated, which is probably formed as a result of a redox re-
action involving copper acetylide and the nitrone. (Scheme 2).
Even more convoluted reaction pathway was found for nitrone 3
and acetylene 7ent. Enamino-ketone 15, the main component of
the reaction mixture, was obtained in 25.5% yield. Expected Kinu-
gasa products 14a, 14b, 14c, and racemic product 16 consisting of
two molecules of the nitrone and one acetylene, were obtained in
29.3% yield and a ratio of about 5:7:1:2, respectively (Scheme 3,
Fig. 1). The mixture of 14a, 14b, 14c, and 16 was separated into in-
dividual pure components by HPLC chromatography. The configu-
Reactions between nitrone 2 and the non-chiral acetylenes 5
and proceeded with relatively good diastereoselectivity,
6
a
affording the corresponding racemic carbacephams 8a and 9a in
a very low yield, 20% and 10%, respectively (Scheme 1). The ac-
companying isomer 9b was not isolated, only noticed in 1H NMR
spectra of crude post reaction mixtures. The relative configuration
of H-6 and H-7 protons in both products 8a and 9a were established
analyzing the 3JH6eH7 coupling constants and was found to be cis for
both compounds.
ration of b-lactam products 14a, 14b, and 14c were assigned using
1H NMR and CD spectroscopy. Structure of 16 was established by
the crystal structure analysis (Fig. 1).
The plausible reaction pathway leading to 16 involves known
alkylation of the nitrone by cooper acetylide10,15 followed by rear-
rangement of the triple bond to the cooper salt of allene 17 and
subsequently alkylation of the second molecule of the nitrone. The
intermediate 18 underwent oxidation of one hydroxylamine frag-
ment to nitrone 19, which was followed by the rapid intramolecular
1,3-dipolar cycloaddition. The final step involves intramolecular
addition of the free N-hydroxy group to the vinyl ether double bond,
followed by the cleavage of the NeO bond to afford compound 16
(Scheme 3). The control of absolute configuration of the final mol-
ecule is lost, leading consequently racemate 16, owed to either the
presence of plane of symmetry in allene 18, or to the possible oxi-
dation of enantiotopic hydroxylamine fragments in nitrone 19.
Scheme 1.
Scheme 2.
Scheme 3.

B. Grzeszczyk et al. / Tetrahedron 68 (2012) 10633e10639
10635
Fig. 1. X-ray structure of compound 16 (with inclusion of solventd
dichloromethane).17
Reactions of nitrone 4 with acetylenes 5e7/7ent under standard
conditions followed a typical pathway for the Kinugasa process
(Scheme 4). b-Lactam products were obtained in a low to moderate
Fig. 2. X-ray structure of compound 22a.17
yield. In the case of acetylene 5, one cis product 20 was obtained.
Acetal 6 afforded two products: cis 21a and trans 21b in a ratio of
about 2:1, respectively, both of them had the same configuration at
the bridgehead carbon atom as a result of anti addition to the
benzyloxy group of the nitrone. Formation of trans isomer could be
attributed to the base catalyzed epimerization at the carbon atom
next to the carbonyl group.
isolated in a pure form. When, however, the reaction was per-
formed in methylene chloride, the -lactams 23a and 23b were
b
accompanied by the product 24, which, plausibly, results from the
acid promoted deprotection of the diol moiety followed by elimi-
nation of water molecule.
In the case of both chiral substrates, mixtures of isomeric
products were obtained. Bearing in mind our earlier findings,6
compounds 4 and 7 constitute the matched pair, whereas com-
pounds 4 and 7ent constitute the mismatched pair. In both cases,
domination of the nitrone stereogenic center was observed. Acet-
ylene 4 and nitrone 7 afforded two products 22a and 22b in a ratio
of about 2:1, respectively. Both products had the same configura-
tion at the bridgehead carbon atom, as a result of anti addition to
the benzyloxy group in the nitrone. The structure and configuration
of both products were established by the 1H NMR, and, in the case
of 22a, was corroborated also by the X-ray (Fig. 2). In the case of the
mismatched pair 4 and 7ent, the main product 23a was accom-
panied by the trace amount of the other isomer 23b, which was not
2.1. Determination of absolute configuration at C6
Our previous studies on the structuredchiroptical properties of
penicillin and cephalosporin analogs have shown that the absolute
configuration at the bridgehead carbon can be easily determined by
application of simple
developed for the bicyclic
mophore, correlates the sign of Cotton effect (CE) of amide n/
transition with the absolute stereochemistry at the ring junction.
According to this rule, the bicyclic -lactams belong to the series
(or, alternatively to the series) when in their CD spectra the pos-
itive (or negative) sign of CE is present (Fig. 3).
b
-lactam helicity rule.16 This rule, originally
b
-lactams with nonplanar amide chro-
p*
b
D
L
Scheme 4.

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B. Grzeszczyk et al. / Tetrahedron 68 (2012) 10633e10639
Fig. 3. (a) Definition of D- and L-series, (b) CD spectra of compounds 14a and 23a recorded in acetonitrile.
Since the amide chromophore in studied compounds is twisted
(X-ray data of compound 22a, the angle O]C8eN1eC2 equals to
15.7ꢀ, Fig. 2)17 the
-lactam helicity rule can be applied for the
reported as
in hertz. The proton assignment was done based on COSY experi-
ments. Infrared spectra were recorded on FTIR-1600 Per-
d values in parts per million, and coupling constants are
b
a
absolute configuration assignment at C6. According to the rule,
compounds that displayed the positive sign at 220e230 nm were
kineElmer spectrophotometer. CD spectra were recorded on Jasco
J-815 spectropolarimeter. Optical rotation was recorded on Jasco P-
2000 polarimeter. High-resolution mass spectra were recorded on
ESI-TOF Mariner Spectrometer (Perspective Biosystem) or Synapt
G2-S Waters Spectrometer for electrospray ionization. Thin layer
chromatography was performed on Merck aluminum sheet Silica
Gel 60 F254. Column chromatography was carried out using Merck
silica gel (230e400 mesh), zones were detected visually by ultra-
violet irradiation (254 nm) or spraying with H2MoO4$H2O/
Ce(SO4)2$4H2O in 15% H2SO4, followed by heating at 100 ꢀC. All
reactions were performed under argon in pre-dried glassware. All
solvents were purified by standard techniques. Diastereomeric ra-
tios of cephams obtained were determined for the crude post re-
action mixtures by 1H NMR or HPLC.
assigned as belonging to the
D series, and the negative sign was
characteristic for compounds from the L series (Fig. 3).
3. Conclusions
We have shown that the diastereoselective Kinugasa reaction
involving six-membered nitrones proceeds in a lower yield but
with a similar diastereoselectivity to the reactions involving five-
membered congeners, very likely resulting from the lower stabil-
ity of dipole components. Based on the known mechanism, it is
possible to rationalize the stereochemical pathway of the reaction
and to predict the geometry of synthesized products. The first step
of Kinugasa reaction, the 1,3-dipolar cycloaddition, is controlled
predominantly by the configuration of the nitrone. The protonation
of the intermediate enolate in the second step depends mostly on
the configuration at the bridgehead carbon atom formed in the first
step. As a result, the reaction is leading to the cis substituted car-
bacepham as the main diastereoisomer, except for the reactions
involving nitrones derived from the dihydro-isoquinoline.
In the case of latter, the reaction pathway is more complicated
owing to the influence of the rigid aromatic ring coupled with the
nitrone double bond. The flat geometry of the dipole molecule causes
that the carbon atom of the C]N double bond is more electrophilic
than the corresponding one in the other investigated nitrones. Con-
sequently, the nucleophilic terminal of the copper acetylide has the
tendency to be added to the electrophilic center of the nitrone. This
attractive force is manifested by formation of side products originated
from the opposite regiochemistry of 1,3-dipolar cycloaddition step, as
well as, products derived from addition of acetylide to the nitrone
double bond.
Nitrones 2,12 3,13 and 414 were obtained according known pro-
cedures. Acetylenes 5 and 6 were purchased from Aldrich, whereas
acetylenes 76b and 7ent11 were obtained following our protocols.
4.2. Reaction of nitrones with acetylenes. General procedure
To a suspension of CuI (190 mg, 1 mmol) in dry, degassed MeCN
(5 mL) were added 0.56 mL (4.0 mmol) of Et3N and acetylene
(1 mmol) and the mixture was cooled to 0 ꢀC. After 15 min, a so-
lution of nitrone (2 mmol) in MeCN (5 mL) was added slowly, and
the mixture was kept at 0 ꢀC for an additional 15 min. After that
time the cooling bath was removed, and the reaction mixture was
stirred at room temperature under argon atmosphere. The progress
of the reaction was monitored by TLC. Subsequently, the solvent
was removed under reduced pressure, and the residue was purified
by column chromatography on silica gel. The diastereoisomeric
ratio was assigned by HPLC or 1H NMR.
In all cases, formation of trans isomer should be assigned to the
4.2.1. Compound 8. Compound 8 was obtained from 2 and 5 in 20%
yield.
base catalyzed epimerization at the carbon atom next to the
lactam carbonyl group.
b-
4.2.1.1. (6R*,7S*)-7-Phenyl-1-azabicyclo[4.2.0]octan-8-one
4. Experimental section
4.1. General
(8). Oil; 1H NMR (500 MHz, CDCl3)
d: 7.34e7.23 (m, 5H), 4.61 (1H, d,
J 5.1, 1.1 Hz), 3.92 (1H, dd, J 13.5, 5.2 Hz), 3.69 (1H, m, J 11.0, 5.1,
4.6 Hz), 2.80e2.72 (1H, m), 1.86e1.77 (1H, m), 1.67e1.61 (1H, m),
1.52e1.34 (3H, m), 0.95e0.84 (1H, m); 13C NMR (125 MHz, CDCl3)
d:
1H and 13C NMR spectra were recorded on Varian VN MRS
Spectrometer at 600 MHz and 150 MHz, respectively, in CDCl3 or
C6D6. TMS was used as an internal standard. Chemical shifts are
166.7, 133.6, 128.5(2ꢁ), 128.4(2ꢁ), 127.1, 58.3, 52.6, 38.7, 26.9, 24.9,
21.8; IR (film)
C13H15NONa 224.1051; found 224.1048.
n
: 1743 cmꢂ1; HRMS (ESI) m/z calcd for [MþNa]þ

B. Grzeszczyk et al. / Tetrahedron 68 (2012) 10633e10639
10637
4.2.2. Compound 9a. Compound 9a was obtained from 2 and 6 in
10% yield.
from 3 and 7ent. Their ratio was assigned by HPLC (LiChrosorbÒ
m, 10% Et2O in CH2Cl2, 1 mL/min, 254 nm; re-
tention times: 7.9 min (16), 12.0 min (14a), 13.23 min (14b), 14.05
(14c)). Preliminary separation of 15 (25.5%) was done using 40%
Si60 250ꢁ4.6, 5
m
4.2.2.1. (6R*,7R*)-7-(Diethoxymethyl)-1-azabicyclo[4.2.0]octan-
8-one (9a/9b). A mixture of diastereomers in a ratio of about 4.6:1,
AcOEt in hexane. Subsequently compound 16 and b-lactams 14a,
respectively; isomer 9a: oil; 1H NMR (500 MHz, CDCl3)
d: 4.82 (1H,
14b, 14c (29%) in a ratio of about 5:7:1:2, respectively, were sepa-
rated by preparative HPLC using 10% diethyl ether in CH2Cl2 (2ꢁ
d, J 7.4 Hz), 3.7 (1H, dd, J 13.4, 5.3 Hz), 3.7e3.49 (4H, m), 3.47 (1H,
ddd, J 7.4, 5.0, 1.8 Hz), 3.42 (1H, m), 2.67 (1H, m), 1.9e1.3 (6H, m),
1.21 (3H, t), 1.17 (3H, t); HRMS (ESI) m/z calcd for C12H21NO3Na
Nucleosil Si60 10ꢁ250, 5
mm, 6 mL/min, 254 nm).
[MþNa]þ: 250.1419; found 250.1414; IR (film)
n
: 1748 cmꢂ1; Com-
4.2.4.1. (1R,9bS)-1-[(4R)-2,2-Dimethyl-1,3-dioxolan-4yl]-1,4,5,9b-
20
pound 9b: oil; 1H NMR (500 MHz, CDCl3)
d
: selected signals taken
tetrahydro-2H-azeto[2,1-a]isoquinolin-2-one (14a). Oil; [
a]
ꢂ154
D
from the spectrum of 9a: 4.78 (d, J 4.5 Hz), 3.06 (d, J 4.5, 1.6 Hz).
(c 0.88, CH2Cl2); 1H NMR (600 MHz, CDCl3)
d
: 7.25e6.60 (4H, m),
4.20 (1H, d, J 5.2 Hz), 3.98 (1H, dd, J 8.5, 6.9 Hz), 3.85 (1H, dd, J 8.5,
6.1 Hz), 3.66e3.61 (2H, m), 3.38 (1H, dd, J 9.7, 5.2 Hz), 2.61 (1H, ddd,
J 16.8, 11.3, 7.0 Hz), 2.26 (1H, ddd, J 13.4, 11.3, 4.5 Hz), 1.94 (1H, dd, J
4.2.3. Compounds 10a, 10b, 11 and 12. Compounds 10a, 10b, 11 and
12 were obtained following general procedure, from 6 and nitrone
3. The 10a/10b ratio was assigned by HPLC (LiChrosorbÒ Si60
16.0, 4.2 Hz), 1.03 (3H, s), 1.33 (3H, s); 13C NMR (150 MHz, C6D6)
d:
250ꢁ4.6, 5
m
m, 10% i-PrOH in hexane, 1 mL/min, 226 nm; retention
167.9, 134.6, 132.2, 129.3, 128.2, 127.0, 126.1, 108.4, 71.5, 67.5, 58.1,
times: 7.2 min (10b), 8.6 min (10a)). Preliminary separation of 11
(6.5%) was made using 40% AcOEt in hexane, subsequently 10a and
10b (58%) in a ratio of about 2:1 were separated by preparative
HPLC using 2.5% i-PrOH in hexane (preparative LiChrosorbÒ Si60
51.4, 36.7, 28.6, 26.8, 25.3; IR (film) n: 2934, 1751, 1370, 1218, 1062,
838, 752 cmꢂ1; HRMS (EI) m/z calcd for [M] C16H19O3 N 273.1365
found 273.1357.
column, 5
mixture of 10a and 10b.
m
m); a minute amount of 12 was found to accompany the
4.2.4.2. (1S,9bS)-1-[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]-1,4,5,9b-
20
tetrahydro-2H-azeto[2,1-a]isoquinolin-2-one (14b). Oil;
[
a]
ꢂ58
D
(c 0.94, CH2Cl2); 1H NMR (600 MHz, C6D6)
d
: 7.20e6.60 (4H, m),
4.2.3.1. (1R*,9bS*)-1-Diethoxymethyl-1,4,5,9b-tetrahydro-azeto
4.31 (1H, bs), 4.18 (1H, ddd, J 7.5, 6.4, 3.6 Hz), 4.06 (1H, dd, J 8.4,
7.5 Hz), 3.73 (1H, dd, J 8.4, 6.4 Hz), 3.56 (1H, m), 2.79 (1H, dd, J 3.6,
2.4 Hz), 2.51e2.42 (2H, m), 1.95 (1H, m), 1.46 (3H, s), 1.29 (3H, s); 13C
[2,1-a]isoquinolin-2-one (10a). Oil 1H NMR (600 MHz, CDCl3)
d:
7.30e7.10 (4H, Ar), 4.69 (1H, d, J 5.4 Hz), 4.27 (1H, d, J 5.3 Hz), 4.08
(1H, ddd, J 13.5, 5.7, 0.6 Hz), 3.81 (1H, dt, J 5.3, 0.6 Hz), 3.62 (1H, m,
CHHCH3), 3.41 (1H, m, CHHCH3), 3.30 (1H, m, CHHCH3), 3.07 (1H,
m), 2.96 (1H, m, CHHCH3), 2.90 (1H, m), 2.63 (1H, dd, J 15.7, 3.8 Hz),
1.14 (3H, t, J 7.1 Hz, CH2CH3), 0.89 (3H, t, J 7.1 Hz, CH2CH3); 13C NMR
NMR (150 MHz, C6D6) d: 167.3, 135.5, 134.0, 129.2, 126.8, 126.5,
126.0, 109.4, 72.6, 66.1, 60.5, 50.3, 37.2, 27.8, 26.4, 25.5; IR (film) n:
2936, 1751, 1370, 1218, 1061, 847, 745 cmꢂ1; HRMS (EI) m/z calcd for
[M] C16H19O3 N 273.1365 found 273.1353.
(150 MHz, CDCl3) d: 168.3, 135.4, 132.0, 129.5, 127.6, 127.1, 126.1,
98.5, 62.1, 61.2, 58.0, 50.7, 37.3, 29.3, 15.2, 14.7; IR (film)
n
: 2974,
4.2.4.3. (1R,9bR)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-1,4,5,9b-
22
1759, 1357, 1060, 753 cmꢂ1; HRMS (ESI) m/z calcd for [MþNa]þ
tetrahydro-2H-azeto[2,1-a]isoquinolin-2-one (14c). Oil;
[
a
]
þ27
D
C16H21NO3Na 298.1414; found 298.1428.
(c 0.16, CH2Cl2); 1H NMR (600 MHz, C6D6)
d: 7.23e6.68 (4H, m), 4.22
(1H, bs), 4.16 (1H, dt, J 7.5 and 6.2 Hz) 3.87 (1H, dd, J 8.5, 6.2 Hz),
3.79 (1H, dd, J 8.5, 6.2 Hz), 3.55 (1H, ddd, J 12.8, 6.6, 3.8 Hz), 2.73
(1H, dd, J 7.5, 2.1 Hz), 2.48 (1H, m), 2.46 (1H, m), 1.97 (1H, m), 1.33
4.2.3.2. (1S*, 9bS*)-1-Diethoxymethyl-1,4,5,9b-tetrahydro-azeto
[2,1-a]isoquinolin-2-one (10b). Oil 1H NMR (600 MHz, CDCl3)
d:
7.30e7.10 (4H, m), 4.90 (1H, d, J 4.4 Hz), 4.60 (1H, bs), 3.93 (1H, ddd,
J 12.9, 6.6, 4.1 Hz), 3.29 (1H, dd, J 4.4, 2.3 Hz), 3.83 (1H, m, CHHCH3),
3.75 (1H, m CHHCH3), 3.67 (1H, m CHHCH3), 3.62 (1H, m CHHCH3),
3.14 (1H, ddd, J 13.0, 9.3, 5.2 Hz), 3.02 (1H, ddd, J 15.7, 9.1, 6.7 Hz),
2.74 (1H, dt, J 15.6, 4.4 Hz), 1.272 (3H, t, J 7.0 Hz, CH2CH3), 1.266 (3H,
(3H, s), 1.22 (3H, s); 13C NMR (150 MHz, C6D6)
d
: 167.1, 135.3, 133.9,
129.2, 126.9, 126.6, 126.3, 108.9, 74.0, 67.7, 62.2, 51.4, 37.1, 27.8, 26.7,
25.2; IR (film)
: 2936, 1751, 1370, 1218, 1061, 847, 745 cmꢂ1; HRMS
n
(EI) m/z calcd for [M] C16H19O3 N 273.1365 found 273.1362.
t, J 7.0 Hz, CH2CH3); 13C NMR (150 MHz, CDCl3)
d: 167.9, 135.3, 133.8,
4.2.4.4. (2Z)-2-(3.4-Dihydroisoquinolin-1(2H)-ylidene)-1-(2,2-
129.2, 127.2, 126.9, 126.4, 99.80, 63.9, 63.0, 62.5, 49.7, 37.7, 28.2,
dimethyl-1,3-dioxolan-4-yl)-ethanone (15). Oil; 1H NMR (600 MHz,
15.31, 15.29; IR (film)
(ESI) m/z calcd for [MþNa] C16H21NO3Na 298.1414 found 298.1413.
n
: 2þ975, 1755, 1371, 1061, 746 cmꢂ1; HRMS
CDCl3) d: 11.4 (1H, s), 7.80e7.19 (4H, m), 6.09 (1H, s), 4.54 (1H, dd, J
6.9, 6.4 Hz), 4.31 (1H, dd, J 8.1, 7.5 Hz), 4.04 (1H, dd, J 8.1, 6.4 Hz),
3.51 (2H, ddd, J 6.9, 6.4, 3.5 Hz), 2.96e2.92 (2H, m), 1.54 (3H, s), 1.45
4.2.3.3. (3Z)-3-(3,4-Dihydroisoquinolin-1(2H)-ylidene)-1,1-
(3H, s); 1H NMR (600 MHz, C6D6)
d: 11.6 (1H, s), 7.70e6.58 (4H, Ar),
diethoxypropan-2-one (11). Oil 1H NMR (600 MHz, CDCl3)
d: 11.40
6.46 (1H, s), 4.69 (1H, dd, J 7.4, 6.2 Hz), 4.35 (1H, dd, J 8.2, 6.0 Hz),
4.25 (1H, dd, J 8.2, 7.5 Hz), 2.54e2.45 (2H, m), 2.07e1.98 (2H, m),
(1H, s), 7.80e7.15 (4H, m), 6.04 (1H,s), 4.73 (1H,s), 3.76e3.70 (2H, m,
CH2CH3), 3.66e3.60 (2H, m, CH2CH3), 3.51e3.47 (2H, m), 2.92 (2H,
dd, J 6.6, 6.5 Hz), 1.26 (6H, 2ꢁ t, J 7.1 Hz 2ꢁ CH2CH3); 13C NMR
1.54 (3H, s), 1.34 (3H, s); 13C NMR (150 MHz, CDCl3)
d: 195.3, 158.9,
136.7, 131.4, 128.9, 128.3, 127.2, 125.8, 110.3, 85.3, 79.3, 68.3, 38.6,
(150 MHz, CDCl3)
d: 191.7, 159.3, 136.6, 131.3, 129.0, 128.2, 127.1,
28.2, 26.3, 25.6; IR (film) n: 2984, 1751, 1635, 1557, 1445, 1370, 1220,
126.0, 102.6, 85.9, 62.4 (2ꢁ), 38.6, 28.2, 15.3 (2ꢁ); IR (film)
n
: 2974,
1061, 856 cmꢂ1; HRMS (ESI) m/z calcd for [MþNa]þ C16H19NO3Na
1727, 1618, 1561, 1309, 1103, 1061, 757 cmꢂ1; HRMS (ESI) m/z calcd
for [MþNa]þ C16H21NO3Na 298.1414 found 298.1408.
296.1257 found 296.1249.
4.2.4.5. (10Z)-10-(3,4-Dihydroisoquinolin-1(2H)-ylidene)-2,2-
dimethyl-10,60,70,11b0-tetrahydro-20H-spiro[1,3]dioxolane-4,30-[1,2]ox-
azino[3,2-a]isoquinolin]-20-one (16). Colorless crystals; 179e182 ꢀC;
4.2.3.4. 3,3-Diethoxy-N-(1,2,3,4-tetrahydroizoquinoline)propioa-
mide (12). A mixture of rotamers: IR (film) nmax: 1640, 1060 cmꢂ1
;
1H NMR (600 MHz, CDCl3)
d: 7.20e7.00 (4H, m), 4.95 (1H, m), 4.74
1H NMR (600 MHz, C6D6)
d: 13.4 (1H, s), 7.66e6.40 (8H, m), 4.96
(1H, s), 4.66 (1H, s), 3.82 (1H, m), 3.78e3.54 (5H, m), 2.90e2.74 (4H,
(1H, s), 4.80 (1H, d, J 8.4 Hz), 4.62 (1H, d, J 8.4 Hz), 3.29 (1H, ddd, J
13.9, 7.3, 3.7 Hz), 3.01 (1H, m), 2.96 (1H, m), 2.60e2.50 (2H, m), 2.23
(1H, ddd, J 16.4, 7.3, 4.0 Hz), 2.11 (1H, m), 1.84 (1H, dt, J 15.0, 3.1 Hz),
m), 1.22e1.09 (6H, m); LR MS (ESI) m/z 300.16 [MþNa]þ
4.2.4. Compounds 14a, 14b, 14c, 15, and 16. Compounds 14a, 14b,
14c, 15, and 16 were obtained according to the general procedure
1.67 (3H, s), 1.45 (3H, s); 13C NMR (150 MHz, C6D6)
d: 189.7, 157.0,
138.9, 138.6, 134.7, 130.0, 129.0, 128.6, 128.2, 126.8, 126.2, 125.9,

10638
B. Grzeszczyk et al. / Tetrahedron 68 (2012) 10633e10639
(two aromatic carbons are shielded by C6D6 signals)
d
: 113.1, 107.3,
37.7, 28.5, 26.8, 25.6, 24.1; IR (film) n: 2936, 1749, 1370, 1104, 1066,
101.1, 75.3, 61.4, 51.5, 38.3, 29.5, 27.4, 25.3, 24.5; IR (film)
n: 2929,
699 cmꢂ1; HRMS (EI) m/z calcd for [M]þ C19H25NO4 331.1784;
1726, 1608, 1576, 1552, 1466, 1257, 1098, 1044, 1019, 839, 763 cmꢂ1
;
found: 331.1799.
HRMS (ESI) m/z calcd for [MþNa]þ C25H26N2O4Na 441.1785 found
441.1785.
4.2.7.2. (5S,6R,7S,4’S)-5-Benzyloxy-7-(20,20-dimethyl-10,30-dioxo-
lan-40-yl)-1-aza-bicyclo[4.2.0]octan-8-one (22b). 1H NMR (600 MHz,
4.2.5. (5S,6R,7R)-5-(Benzyloxy)-7-phenyl-1-azabicyclo[4.2.0]octan-
CDCl3, signals was taken from the spectrum of crude 22a) d: 4.62
8-one (20). Yield 65%; [
a
]
20 þ1.9 (c 1.1, CH2Cl2); 1H NMR (600 MHz,
(1H, d, J 11.6 Hz), 4.58 (1H, d, J 11.6 Hz), 4.38 (1H, m, J 7.0, 6.3, 4.1 Hz),
4.02 (1H, dd, J 8.3, 6.3 Hz), 3.93 (1H, dd, J 8.3, 7.0 Hz), 3.71 (1H, m),
3.27 (1H, dd, J 8.5, 1.0 Hz), 3.25 (1H, dd, J 8.5, 3.3 Hz), 3.09 (1H, dd,
J 4.1, 1.0 Hz), 2.60 (1H, m), 2.16 (1H, m), 1.78 (1H, m), 1.40 (2H, m),
D
CDCl3)
d
: 7.36e724 (8H, m), 7.03 (2H, m), 4.69 (1H, dd, J 5.0, 1.7 Hz),
3.97 (1H, d, J 10.8 Hz), 3.84 (1H, dd, J 13.2, 5.5 Hz), 3.62 (1H, d, J 8.6,
5.0 Hz), 3.60 (1H, d, J 10.8 Hz), 3.02 (1H, ddd, J 11.3, 8.6, 4.1 Hz),
2.69e2.61 (1H, m), 2.15e2.09 (1H, m), 1.79e1.74 (1H, m), 1.52e1.48
1.41 (3H, s), 1.37 (3H, s); 13C NMR (150 MHz, CDCl3)
d: 165.0, 138.0,
(1H, m), 1.41e1.33 (1H, m); 13C NMR (150 MHz, CDCl3)
d
: 166.6,
128.5, 127.9, 127.8, 127.6, 109.8, 77.9, 72.6, 70.8, 66.3, 59.5, 55.5, 37.8,
28.8, 26.4, 25.5, 24.5.
137.8, 133.1, 129.1(ꢁ2), 128.5, 128.3(ꢁ2), 127.7(ꢁ2), 127.6(ꢁ2), 127.5,
74.5, 70.6, 58.6, 57.7, 37.8, 28.1, 24.6; IR (film) n
: 1748 cmꢂ1; HRMS
(ESI) m/z calcd for [MþNa]þ C20H21NO2Na 330.1465; found:
4.2.8. Compounds 23a, 23b. Compounds 23a, 23b were obtained
according to the general procedure, using acetylene 7ent. The post
reaction mixture was separated by chromatography using 5% ace-
tone in CH2Cl2 to provide pure 23a in 33% yield and a mixture of 23a
and 23b (12%).
330.1470.
4.2.6. Compounds 21a and 21b. Compounds 21a and 21b were
obtained according from 4 and 6 following the general procedure.
Products were separated by chromatography using 10% acetone in
CH2Cl2. Yield 21a 19% and 21b 9%. The diastereoisomeric ratio
assigned by 1H NMR 21a:21b¼2:1.
4.2.8.1. (5S,6R,7R,4’R)-5-benzyloxy-7-(20,20-dimethyl-10,30-dioxo-
20
lan-40-yl)-1-aza-bicyclo[4.2.0]octan-8-one (23a). Oil;
[
a
]
þ145
D
(c 1.6, CH2Cl2); 1H NMR (600 MHz, C6D6)
d: 7.25e7.05 (5H, m), 4.40
4.2.6.1. (5S,6R,7S)-5-(Benzyloxy)-7-(diethoxymethyl)-
(1H, d, J 11.5 Hz), 4.28 (1H, d, J 11.5 Hz), 4.14e4.10 (2H, m), 3.93
(1H, ddd J 11.3, 8.6, 4.0 Hz), 3.65 (1H, m), 3.43 (1H, dd, J 13.1,
5.5 Hz), 2.97 (1H, dd, J 8.6, 5.0 Hz), 2.78 (1H, dt, J 5.0, 1.4 Hz); 1.96
(1H, m), 1.78 (1H, m), 1.51 (3H, s), 1.31 (3H, s), 1.10 (1H, m), 1.00
1eazabicyclo[4.2.0]octan-8-one (21a). Oil; [
a
]
20 þ98 (c 1.1, CH2Cl2);
D
1H NMR (600 MHz, C6D6)
d: 7.00e7.30 (5H, m), 4.86 (1H, d, J 3.8 Hz),
4.39 (1H, d, J 11.6 Hz), 4.34 (1H, d, J 11.6 Hz), 3.74 (1H, ddd, J 11.0, 8.5,
4.2 Hz), 3.43 (1H, m), 3.71e3.53 (3H, m, 3ꢁ CHHCH3), 3.38 (1H, ddd,
J 5.0, 3.8, 1.7 Hz), 3.25 (1H, m, 1ꢁ CHHCH3), 3.08 (1H, dd, J 8.5,
5.0 Hz), 1.96 (1H, m), 1.65 (1H, m), 1.06 ( 3H, t, J 7.1 Hz), 1.03 (3H, t, J
7.1 Hz), 0.89e0.81 (2H, m), 1.04 (1H, m); 13C NMR (150 MHz, C6D6)
(1H, m), 0.86 (1H, m); 13C NMR (150 MHz, C6D6)
d: 164.0, 138.9,
128.2, 127.9, 127.7, 127.6 (one aromatic carbon was shielded by
C6D6 signals) 110.0, 74.9, 72.3, 70.2, 67.7, 55.5, 54.2, 37.1, 26.2, 26.8,
26.2, 23.9; IR (film) n
: 2934, 1751, 1370, 1061, 699 cmꢂ1; HRMS
d
: 163.4, 139.1, 128.2, 128.1, 127.9, 127.3(2ꢁ), 98.9, 73.9, 70.1, 62.4,
(ESI) m/z calcd for [MþNa]þ C19H25NO4Na 354.1681; found
60.9, 57.8, 55.0, 37.2, 37.1, 28.3, 15.3, 15.1; IR (film)
n
: 2928, 1753,
354.1680.
1454, 1057, 698 cmꢂ1
;
HRMS (ESI) m/z calcd for [MþNa]þ
C19H27NO4Na 356.1836 found 356.1838.
4.2.8.2. (5S,6R,7S,4’R)-5-Benzyloxy-7-(20,20-dimethyl-10,30-dioxo-
lan-40-yl)-1-aza-bicyclo[4.2.0]octan-8-one (23b). 1H NMR (600 MHz,
CDCl3, selected signals taken from the spectrum of crude 23a)
4.2.6.2. (5S,6R,7R)-5-(Benzyloxy)-7-(diethoxymethyl)-
20
1eazabicyclo [4.2.0] octan-8-one (21b). Oil; [
a
]
þ14 (c 0.95,
d: 4.54 (1H, d, J 11.7 Hz), 4.30 (1H, d, J 11.7 Hz), 4.08 (1H, m, J 8.0,
D
CH2Cl2); 1H NMR (600 MHz, C6D6)
d
: 7.35e7.00 (5H, m), 4.71 (1H, d,
6.7, 6.2 Hz), 3.97 (1H, dd J 8.4, 6.2 Hz), 3.93 (1H, dd, J 8.4, 6.7 Hz),
3.04 (1H, dd, J 8.2, 1.5 Hz), 2.82 (1H, dd, J 8.0, 1.5 Hz), 1.33 (3H, s),
1.20 (3H, s).
J 4.4 Hz), 4.63 (1H, d, J 11.9 Hz, CHHPh), 4.36 (1H, d, J 11.9 Hz,
CHHPh), 3.62 (1H, m, CHHCH3), 3.56 (1H, m, CHHCH3), 3.44e3.38
(2H, m, 2ꢁ CHHCH3) 3.37e3.31 (2H, m) 3.23 ( 1H, dd, J 4.4, 1.6 Hz),
2.87 (1H, ddd, J 11.3, 8.4, 3.9 Hz), 1.96 (1H, dt, J 12.6, 4.4 Hz); 1.66
(1H, m), 1.05 (3H, t, J 7.0 Hz CH2CH3); 1.04 (3H, t, J 7.0 Hz CH2CH3);
4.2.9. Compounds 23a, 23b, and 24. Compounds 23a, 23b, and 24
were obtained in the similar reaction perform in dichloromethane
according to the general procedure, using acetylene 7ent. The post
reaction mixture was separated by chromatography using 5% ace-
tone in CH2Cl2 to provide pure 23a in 17.5% yield and a mixture of
23a and 23b (14%), and 24 (15%).
1.00 (1H, m), 0.94e0.81 (2H, m); 13C NMR (150 MHz, C6D6)
d: 163.5,
139.0, 128.2(2ꢁ), 128.1, 127.6, 127.3, 100.4, 77.6, 70.1, 63.5, 62.7, 62.2,
55.0, 37.2, 29.1, 24.0, 15.1, 15.1; IR (film) n: 2929, 1751, 1454, 1058,
698 cmꢂ1; HRMS (ESI) m/z calcd for [MþNa]þ C19H27NO4Na
356.1836 found 356.1837.
4.2.9.1. (5S)-5-Benzyloxy-7-(2-hydroxy-ethylidene)-1eazabicyclo
21
4.2.7. Compounds 22a, 22b. Compounds 22a, 22b were obtained
according to the general procedure, using 7. Solvent for chroma-
tography 10% acetone in CH2Cl2 Yield 22a and 22b 45% The di-
astereoisomeric ratio assigned by 1H NMR 22a:22b 2.5:1.
[4.2.0] octan-8-one (24). Oil; [
(600 MHz, C6D6)
a]
þ61 (c 0.4, CH2Cl2); 1H NMR
D
d
: 7.25e7.00 (5H, m), 5.99 (br t, 1H, J 3.4 Hz), 4.14
(1H, d, J 11.5 Hz), 3.96 (2H, m), 3.93 (1H, d, J 11.5 Hz), 3.73 (1H, d, J
8.5 Hz), 3.56 (1H, br s), 3.45 (1H, dd, J 13.5, 5.7 Hz), 2.84 (1H, ddd J
11.2, 8.5, 3.5 Hz), 2.03 (1H, dt, J 13.0, 4.5 Hz), 1.51 (1H, m), 0.90 (1H,
4.2.7.1. (5S,6R,7R,40S)-5-benzyloxy-7-(20,20-dimethyl-10,30-dioxo-
lan-40-yl)-1-aza-bicyclo[4.2.0]octan-8-one (22a). Mp 98e100 ꢀC;
m), 0.83 (1H, m), 0.66 (1H, m); 13C NMR (150 MHz, C6D6)
d
: 161.7,
141.4, 137.1, 128.4, 127.9(ꢁ2), 127.6, 126.1, 78.7, 69.8, 60.2, 58.8, 37.2,
25
[
a]
þ75 (c 1.0, CH2Cl2); 1H NMR (600 MHz, CDCl3)
d
: 7.40e7.27
26.4, 24.3; IR (film) n ;
: 3425, 2928, 1744, 1715, 1386, 1090, 700 cmꢂ1
D
(5H, m), 4.64 (1H, d, J 10.9 Hz), 4.58 (1H, d, J 10.9 Hz), 4.37 (1H,
m), 4.19 (1H, dd, J 8.5, 6.3 Hz), 3.93 (1H, dd, J 8.5, 7.0 Hz), 3.70
(1H, bdd, J 13.3, 5.3 Hz), 3.60 (1H, ddd, J 10.6, 8.7, 4.1 Hz), 3.50
(1H, dd, J 8.7, 4.6 Hz), 3.45 (1H, ddd, J 9.7, 4.6, 1.7 Hz), 2.60 (1H,
m), 2.28 (1H, m), 1.77 (1H, m) 1.49 (1H, m), 1.38 (1H, m), 1.43 (3H,
HRMS (ESI) m/z calcd for [MþNa]þ C16H19NO3Na 296.1263 found
296.1263.
Acknowledgements
s), 1.36 (3H, s); 13C NMR (150 MHz, CDCl3)
d
: 164.8, 138.2,
Financial support for this work was provided through the Polish
Ministry of Science and Higher Education Grant N N204 156036.
128.3(2ꢁ), 128.0, 127.9, 127.8, 109.1, 74.2, 71.3, 71.1, 68.2, 57.1, 55.7,

B. Grzeszczyk et al. / Tetrahedron 68 (2012) 10633e10639
10639
Moellering, R. C.; Jacobs, N. F. Am. J. Med.1992, 92, S1; (i) Therasse, D. G. Am. J. Med.
1992, 92, S20eS25; (j) Zeckel, M. L. Am. J. Med. 1992, 92, S58eS64.
Supplementary data
6. (a) Chmielewski, M.; Stecko, S.; Mames, A.; Furman, B. J. Org. Chem. 2008, 73,
7402e7404; (b) Chmielewski, M.; Stecko, S.; Mames, A.; Furman, B. J. Org. Chem.
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Synthesis 2012, 2825e2839.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2012.09.031.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
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17. Crystallographic data for the structures reported in this paper have been de-
posited with the Cambridge Crystallographic Data Center, Cambridge, UK, as
a supplementary publications: 16 (CCDC 898221), 22a (CCDC 898220).