Synthesis of 2-azabicyclo[4.1.0]heptanes through stereoselective cyclopropanation reactions

Article abstract of DOI:10.1002/ejoc.201000863

Unsaturated δ-lactams are cyclopropanated with the aid of diazo compound decomposition catalysed by metal complexes. A study of the reaction conditions, stereochemical outcome and group protection is reported. The resulting bicyclic products are related to bioactive compounds. Transformation into thiolactams facilitates the separation of the different isomers obtained and the removal of the protecting group. The cyclopropanation reaction works with diverse diazo compounds. Unsaturated δ-lactams are cyclopropanated with the aid of diazo compound decomposition catalysed by metal complexes. A study of the reaction conditions, stereochemical outcome and group protection isreported. Transformation into thiolactams assists in separation of the different isomers obtained and removal of the protecting group.

Full text of DOI:10.1002/ejoc.201000863

FULL PAPER
DOI: 10.1002/ejoc.201000863
Synthesis of 2-Azabicyclo[4.1.0]heptanes through Stereoselective
Cyclopropanation Reactions
Irene Suárez del Villar,[a] Ana Gradillas,[a] and Javier Pérez-Castells*[a]
Keywords: Nitrogen heterocycles / Cyclopropanation / Polycycles / Lactams / Diastereoselectivity
Unsaturated δ-lactams are cyclopropanated with the aid of
diazo compound decomposition catalysed by metal com-
plexes. A study of the reaction conditions, stereochemical
outcome and group protection is reported. The resulting bi-
cyclic products are related to bioactive compounds. Transfor-
mation into thiolactams facilitates the separation of the dif-
ferent isomers obtained and the removal of the protecting
group. The cyclopropanation reaction works with diverse di-
azo compounds.
the key cyclopropanation step we chose transition-metal-
catalysed decomposition of diazo compounds. Inter-
molecular cyclopropanation mediated by Rh2(OAc)4 or
Cu(OAc)2 continues to provide a powerful tool for the con-
struction of constrained systems from diazo precursors,
with high levels of diastereoselectivity. Many related chiral
metal complexes are able to give high enantioselectivities.[10]
In a previous paper we presented our preliminary results
on cyclopropanation of unsaturated lactams, based on the
use of a number of metal catalysts to decompose diazo
compounds.[11] Initial attempts, however, were thwarted by
our inability to cleave the protecting group from the lactam
efficiently.
Introduction
The synthesis of highly functionalized chiral cyclopro-
panes is of interest because many biologically active com-
pounds contain cyclopropane moieties.[1,2] These units are
also present in important synthetic intermediates, especially
for the synthesis of condensed polycycles and molecules of
higher complexity, and have attracted considerable interest
in medicinal chemistry, due to their potential to control
conformation by restricting the number of rotational de-
grees of freedom. Most recent synthetic efforts have focused
on stereoselective cyclopropanation reactions.[3]
On the other hand, the syntheses of many 2-pyridine-
containing compounds[4] have been developed because these
moieties are contained in potent antitumor,[5] antiviral[6]
and antimicrobial[7] agents. We envisioned that 2-pyridones
fused with cyclopropane rings might present interesting bio-
logical activities or be useful intermediates in syntheses of
bioactive products.[8] In particular, certain amidines derived
from tetrahydro-2-pyridones have shown high inhibitory ac-
tivities against nitric oxide synthase (NOS). Identification
of potent and selective inhibitors of iNOS (the inducible
isoform of NOS) has been the subject of intense interest
because of their therapeutic potential in the treatment of
diseases mediated by overexpression of nitric oxide (NO).
This need has been met through the design of a rigid ligand
bearing a cyclopropane unit fused to a cyclic amidine. A
good example of such a system is ONO-1714, a selective
iNOS inhibitor currently undergoing evaluation in a
Phase II clinical trial.[9]
We now present all the synthetic details for the developed
highly stereoselective intermolecular cyclopropanation and
describe its scope and limitations, together with the effects
of varying the catalyst and the protecting group.
Results and Discussion
In order to conduct an extended study of the cyclopro-
panation of compounds 2, we optimised the supply of these
materials by means of the route shown in Scheme 1. Our
aim was to study the influence of the protecting group on
We therefore set out to develop efficient synthetic strate-
gies for the construction of 2-azabicyclo[4.1.0]heptanes. For
[a] Departamento de Química, Facultad de Farmacia,
Universidad San Pablo-CEU, Urb. Montepríncipe,
28668 Boadilla del Monte, Madrid, Spain
Fax: +34-913510496
E-mail: jpercas@ceu.es
Scheme 1. Synthesis of substrates 2a–e.
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Stereoselective Cyclopropanation
the yield and selectivity of the cyclopropanation step, as addition periods were tested and 4 h were fixed as the best
well as the feasibility of the deprotection step.
option, with longer addition periods not producing any im-
The compounds 2a–e were prepared by a procedure de- provement (Entry 8). At this point we had achieved a good
scribed by Kawanaka,[12] with certain modifications. After diastereomeric ratio, although chemical yields were still not
aminolysis of glutaric anhydride and formation of the satisfactory. In all the reactions, the major compound was
imides 1a–e we carried out the reduction of 1a–e with trans-3a; stereochemical assignment was carried out by me-
DIBAL-H.[13] For the subsequent dehydration step we ans of n.O.e. experiments.[14]
treated the intermediates with mesyl chloride in the pres-
The conditions shown in Entry 1 were then used with a
ence of triethylamine as the base, which resulted in the for- selection of chiral catalysts. When using chiral complexes
mation of compounds 2 in 73–87% overall yields from glut- we were pleased to observe a general improvement in the
aric anhydride.
yields. In particular, copper complexes gave good results,
We next examined a set of conditions for cyclopropan- maintaining high diastereomeric ratios. These catalysts were
ation with ethyl diazoacetate (EDA, Table 1). Firstly, some prepared in situ by treatment of CuOTf with the ligands 5–
conventional achiral catalysts were used. In all reactions 7 depicted in Figure 1.[15] In addition, two rhodium cata-
with compound 2a, the two diastereomeric cyclopropanes lysts were used (Entries 12–13),[16] but these gave worse re-
trans-3a and cis-3a were isolated together with unreacted sults than those obtained with copper in terms of global
starting material and a minor compound which was as- yield, dr and ee. The enantiomeric excesses were measured
signed as the insertion product 4. Temperature, solvent, cat- by chiral HPLC (see Exp. Sect.). As shown in Entries 10
alyst loading and reagent ratios were examined. Catalyst and 11, these ee values are low, although it is interesting
loading produced only slight variation in yields, and was that the major enantiomers are different in the reactions of
fixed at 4% because no significant improvement was ob- Entries 10 and 11.
served on increasing this value (Entries 1–3). Use of rho-
The conditions listed in Entry 11 were selected for reac-
dium acetate gave better results than that of other metal tions with substrates 2b–e (Entries 14 and 16–18). With
acetates such as palladium or copper (Entries 2 and 4–5). compound 2b the chemical yields of cyclopropane 3b were
Solvent and reaction temperature were chosen according to slightly lower than for 2a, with a decrease in diastereoselec-
conventional reaction conditions described in the litera- tivity also being observed (Entry 14). We therefore tried a
ture.[10] CH2Cl2 gave the best results, and levels of conver- different CuI complex, with ligand 6 (Entry 15), but ob-
sion were not improved by increasing temperature (En- tained a lower level of conversion. These conditions, how-
tries 6–7). EDA was added slowly by pump syringe. Several ever gave trans-3b with a moderate ee (33%), whereas the
Table 1. Reaction conditions for the cyclopropanation of enamides 2a–e.
Entry[a]
R
Substrate Catalyst
mol-% Solvent
cat.
Time
addition
Yield [%][b]
% dr[c]
trans/cis
% ee
2
trans-3
cis-3
4
trans-3[d]
1
2
3
4
PMB
PMB
PMB
PMB
PMB
PMB
PMB
PMB
PMB
PMB
PMB
PMB
PMB
Dmob
Dmob
Bn
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2c
2d
2e
Rh2(OAc)4
1
4
8
4
4
4
4
4
1:1
1:1
1:1
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
pentane
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
2 h
4 h
4 h
4 h
4 h
4 h
4 h
8 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
27
25
26
32
75
29
24
29
20
28
18
29
31
20
57
40
30
18
25
45
32
19
Ͼ5
35
27
25
59
52
62
25
28
47
26
25
25
55
15
5
20
10
–
11
15
19
6
6
5
5
8
–
8
6
5
6
7
5
7
8
5
7
–
–
–
66:33
90:10
57:43
67:33
–
–
–
–
Rh2(OAc)4
Rh2(OAc)4
Cu(OAc)2
Pd2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
CuOTf/5
CuOTf/6
CuOTf/7
Rh2[2S-DOSP]4
Rh2[2S-TBSP]4
CuOTf/7
5
6[e]
7
71:29
61:39
60:40
82:18
87:13
78:22
56:44
60:40
62:38
73:27
81:19
75:25
85:15
–
–
–
40
75
–55
0
0
8
9
10
11
12
13
14
15
16
17
18
4
10
20
14
25
9
Ͻ5
Ͻ5
Ͻ5
[13]
[13]
1
1:1
1:1
1:1
1:1
1:1
15
33
CuOTf/6
CuOTf/7
CuOTf/7
CuOTf/7
n.c.[f]
n.c.[f]
n.c.[f]
o-tBuPh
PMP
[a] The reactions were carried out under argon, with EDA (2 equiv.) slowly added by syringe pump. [b] Of pure product, with correct
1
analytical and spectroscopic data. [c] % dr was determined by H NMR examination of the crude mixture. [d] % ee was determined by
HPLC analysis with a CHIRAL-AGP (100ϫ4.0 mm) column. [e] All reactions were carried out at room temp. except for that of Entry 6,
which was performed under reflux. [f] n.c.: not calculated.
Eur. J. Org. Chem. 2010, 5850–5862
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5851

I. Suárez del Villar, A. Gradillas, J. Pérez-Castells
Table 2. Deprotection reactions of 3a–e.
FULL PAPER
Entry
R
Reagent
TFA
Conditions
Yield [%]
20
1
2
3
4
5
6
7
8
PMB
PMB
PMB
PMB
PMB
PMB
Dmob
Bn
80 °C, 48 h
H2, Pd/C AcOEt/MeOH, 50 °C, 94 h n.r.[a]
AlCl3
anisole, r.t.
n.r.[a]
dec.[b]
dec.
BF3·OEt2 anisole, 100 °C, 35 h
CAN[c]
DDQ[d]
TFA
CH3CN/H2O (7:3)
CH2Cl2/H2O
80 °C, 16 h
n.r.[a]
36
H2, Pd/C AcOH/EtOH, r.t.
AlCl3
Na/NH3
n.r.[a]
n.r.[a]
n.r.[a]
dec.[b]
dec.[b]
9
Bn
Bn
benzene, r.t.
THF, r.t.
CH3CN/H2O (7:3), r.t.
CH3CN/H2O (7:3), r.t.
10
11
12
o-tBuPh CAN[c]
PMP
CAN[c]
Figure 1. Chiral catalytic systems used.
[a] n.r.: no reaction. [b] dec.: decomposition. [c] CAN: ceric(IV)
ammonium nitrate. [d] DDQ: 2,3-dichloro-5,6-dicyanobenzoqui-
none.
reaction of Entry 14 had given only 15% ee. Cyclopropan-
ation of 2c and 2d proceeded with low levels of conversion,
with large amounts of starting materials being recovered.
Compounds trans-3c and trans-3d were isolated in low
yields (Entries 16–17). Finally, the PMP-protected product
trans-3e was obtained with a good yield and diastereoselec-
tivity (Entry 18). From these results we can conclude that
PMB and Dmob are the groups that give better chemical
yields, with PMB being the one that gives better selectivity.
We next checked the feasibility of removing the protect-
ing group (Table 2). Many experimental procedures for the
removal of the PMB group have been reported in the litera-
ture. We started by treating trans-3a with TFA at 80 °C (En-
try 1), which sluggishly gave a crude product from which
only a 20% yield of the desired product trans-8 could be
isolated (Entry 1). Attempted hydrogenolysis or treatment
with AlCl3 produced no observable reaction (Entries 2 and
3). On the other hand, use of BF3·OEt2 or CAN resulted
in extensive decomposition of the starting compound (En-
tries 4 and 5). A final attempt with DDQ failed to produce
any deprotection (Entry 6). We next subjected compound
trans-3b to treatment with TFA and observed a much
cleaner reaction that gave trans-8 in 36% yield (Entry 7).
We then examined the elimination of the benzyl group from
trans-3c. Unfortunately none of the conditions tested (at-
tempted hydrogenolysis, treatment with AlCl3 or reductive
NH3/Na conditions, Entries 8–10) provided any conversion
into the unprotected lactam. Finally both trans-3d and
trans-3e were treated with CAN, which led to complex reac-
tion mixtures (Entries 11 and 12). We therefore selected
logical activity.[9] We prepared the two starting lactams with
PMB and Dmob as protecting groups by a methodology
similar to that used for the substrates 2. In addition we
prepared the enantiomerically pure substrate (–)-10b from
methyl (3R)-5-hydroxy-3-methylpentanoate, which was sub-
jected to aminolysis to yield the compound (–)-11 (72%).[11]
Oxidation of the hydroxy group formed the cyclic hemiami-
nal 12 as a mixture of diastereomers, which upon dehy-
dration gave the desired lactam (–)-10b in 59% yield.
Scheme 2. Synthesis of the substrates 10a, 10b and (–)-10b.
We carried out cyclopropanations of these unsaturated
Dmob as the best protecting group, although without yet lactams under the previously determined best reaction con-
having achieved a satisfactory result in the deprotection ditions (Table 1, Entry 2). Use of the chiral catalysts with
step.
the racemic substrates resulted in the observation of slight
Our following target was the cyclopropanation of 4-sub- kinetic resolution. Compound (Ϯ)-10a was thus treated un-
stituted lactams. As a model system we selected the sub- der the conditions indicated in Table 3, giving mixtures of
strates 10a and 10b (Scheme 2), because these lactams bear the four possible diastereomers 13a, with the anti-trans iso-
methyl substituents as present in ONO-1714.[9] The methyl mer in all cases being the major one. A small amount of
group at the 4-position is thought to be important for bio- the insertion compound 14 was also obtained. This time,
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Stereoselective Cyclopropanation
Table 3. Reaction conditions for cyclopropanations of the enamides (Ϯ)-10a, (Ϯ)-10b and (–)-10b.
Entry Substrate
R
Catalyst
mol-% Yield [%][a]
% dr[b]
% ee
cat.
10
13 combined anti-trans-13 anti-cis-13
14/15
anti-trans[c]
1
2
3
4
5
6
7
8
9
10
(Ϯ)-10a
(Ϯ)-10a
(Ϯ)-10a
(Ϯ)-10a
(Ϯ)-10a
(Ϯ)-10a
(Ϯ)-10b
(Ϯ)-10b
(–)-10b
(–)-10b
PMB
PMB
PMB
PMB
PMB
PMB
Dmob
Dmob
Dmob
Dmob
Rh2(OAc)4
Cu(OAc)2
CuOTf/6
4
4
30
22
30
18
28
31
72
33
38
28
60
72
41
72
70
66
–
–
–
–
36
41
25
50
30
32
12
54
23
52
18
16
10
10
36
29
4
6
12
Ͼ5
8
6
2
7
5
5
12
7
Ͼ5
4
57:28:8:7
63:13:18:6
80:12:0:0
57:25:12:6
39:52:9:0
49:35:13:3
71:29:0:0
90:10:0:0
65:35:0:0
95:05:0:0
–
–
18
14
9
18
16
0
Ͼ99
Ͼ99
1:1
1:1
1:1
1:1
1:1
1:1
4
CuOTf/7
Rh2[(4S)-MEOX]4
Rh2[(5S)-MEPY]4
CuOTf/6
CuOTf/7
Rh2(OAc)4
CuOTf/7
1:1
[a] Of pure product, with correct analytical and spectroscopic data. [b] % dr was determined by 1H NMR examination of the crude
mixture. [c] % ee was determined by HPLC analysis with a CHIRAL-AGP (100ϫ4.0 mm) column.
insertion of EDA occurred in the 5-position of the ring. Rh2(OAc)4 as the catalyst and moderate conversion into a
This surprising change in the regiochemistry of the inser- mixture of the two (–)-13b anti isomers was observed (En-
tion product is evident from the chemical shift value of the try 9), with recovery of starting material (38%). The reac-
remaining olefinic proton. We do not have an explanation tion in the presence of CuOTf/7 gave (–)-anti-trans-13b in
for this result because the presence of a methyl group 52% yield with the anti-cis isomer also being detectable in
should have favoured the same result as for 2a [i.e., insertion the crude mixture (Entry 10). The insertion byproduct in all
at C–H(6)]. Good results in terms of global yield were ob- the reactions with substrate 10b was 15, involving a C–H
tained with Cu(OAc)2 (Entry 2), although still with poor insertion at the 6-position.
diastereoselectivity.
One possible solution to achieving efficient deprotection
When using chiral catalysts, we observed good levels of of the bicyclic compounds synthesized above was to carry
conversion. The best result, in terms both of total yield and out a functional group transformation; this might, in ad-
of diastereoselectivity, was achieved with the complex Cu- dition, also favour a cleaner isomer separation. We decided
OTf/7 (Entry 4, Table 3). The major product, anti-trans-13a, to convert the lactam group into a thiolactam, because this
was isolated in 50% yield as a pure scalemic compound group allows many further modifications. The synthesis of
(14% ee). The overall yield of this reaction was 72%. All possibly active products such as amidines[11] or iminosugar-
the isomers could be separated and independently charac- derived compounds could therefore be envisioned. The mix-
terized by use of n.O.e. experiments to assign relative stereo- ture of anti-trans-13b and anti-cis-13b (9:1) obtained in the
chemistry.[17] Two chiral rhodium catalysts, selected from reaction of Entry 8, Table 3, was thus transformed into the
the most frequently used in the literature, and different from corresponding thioamido derivatives by treatment with
those tested with previous substrates, because those had Lawesson’s reagent (Scheme 3). We were pleased to obtain
given unsatisfactory results, were used with (Ϯ)-10a. the corresponding mixture of isomeric thiolactams, which
[18]
[19]
Rh2[(4S)-MEOX]4
and Rh2[(5S)-MEPY]4
(Entries 5 could be separated to give a 73% yield of anti-trans-16 and
and 6) gave cyclopropanes in similar chemical yields, al- an 8% yield of anti-cis-16. In addition, removal of the
though the diastereoselectivity was lower than for copper Dmob group with TFA gave anti-trans-17 in 82% yield. In
catalysts. Interestingly, in the reaction in the presence of view of this pleasing result we subjected the corresponding
Rh2[(4S)-MEOX]4 the major product was anti-cis-13a. On mixture of enantiomerically pure (–)-anti-trans-13b and its
the other hand cyclopropanation of (Ϯ)-10b gave similar anti-cis isomer to the same transformation and obtained
results in terms of chemical yield but with good diastereose- (–)-anti-trans-16 and (–)-anti-cis-16 in high yields. The
lection. Only anti products could be detected under the two first isomer was deprotected efficiently to give (–)-anti-
sets of reaction conditions used (Entries 7 and 8), and com- trans-17.
pound anti-trans-13b was strongly predominant in the crude
Our next goal was to explore different substitution at the
mixtures, especially with CuOTf/7 as the catalyst. One 7-position in the bicyclic system. The first idea was to re-
problem in these two reactions was the separation of the duce the ester group selectively. Unfortunately, treatment
two 13b isomers, which could not be completely achieved. of anti-trans-13b with DIBAL-H (1 equiv.) resulted in the
The major product anti-trans-13b was isolated in 54% yield formation of compound anti-trans-18 (Scheme 4) in 42%
(Entry 8), whereas anti-cis-13b was obtained as a 5:2 mix- yield with recovery of starting material. We thus studied the
ture with the major isomer. Finally (–)-10b was treated with reduction of the corresponding thioamide. With this sub-
Eur. J. Org. Chem. 2010, 5850–5862
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5853

I. Suárez del Villar, A. Gradillas, J. Pérez-Castells
FULL PAPER
ment with 2-chlorodiazoethane produced no cyclopropanes
but a low yield of the insertion product 22 (Scheme 5). On
the other hand, on treatment with the trifluoromethyl-con-
taining diazo compound, we were pleased to obtain a mix-
ture of the cyclopropanes anti-trans-23 and anti-cis-23 to-
gether with a small amount of the corresponding insertion
product 24. Separation of the isomers allowed the isolation
of a 65% yield of anti-trans-23 as a scalemic product with
ee = 40%. The minor isomer anti-cis-23 could not be com-
pletely separated, so we proceeded as in the previous cases,
transforming the mixture of isomers as obtained from the
cyclopropanation reaction into the corresponding thiolac-
tams. These could be efficiently separated to give anti-trans-
25 (70%) and anti-cis-25 (10%).[22] The major isomer was
further deprotected to give anti-trans-26 in good yield
(60%).
Scheme 3. Conversion to compounds 17.
strate we were able to isolate three different products, de-
pending on the amount of DIBAL-H used. With 1.5 equiv.
the only product formed, albeit in low yield, was the alde-
hyde anti-trans-19. An increase to 3 equiv. did not improve
the result, and when the mixture was allowed to come room
temp. after the addition of the reagent we obtained a mix-
ture of anti-trans-20 and anti-trans-21, meaning competi-
tion from the thiolactam group, which is reduced at higher
temperatures. Finally, use of DIBAL-H (4 equiv.) at low
temperature allowed the isolation of anti-trans-20 as the
only reaction product in good yield (70%).
Scheme 5. Synthesis of trifluoromethyl-substituted cyclopropanes.
Scheme 4. Reduction of anti-trans-13b and anti-trans-16.
Conclusions
In conclusion, an efficient and highly diastereoselective
One interesting extension of this work was a study of the intermolecular cyclopropanation reaction has allowed the
cyclopropanation reaction with other diazo compounds. We synthesis of new potentially active bicyclo[4.1.0] com-
thus subjected the substrate (Ϯ)-10b to treatment with 2- pounds. The transformation of the lactam group into the
chlorodiazoethane and 1,1,1-trifluorodiazoethane, both thiolactam system has revealed a convenient way to im-
reagents prepared in situ from the corresponding ethyl- prove isomer separation and deprotection efficiency. The re-
amine hydrochlorides by reported methodology.[21] Treat- sulting structures are related to active compounds and can
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Stereoselective Cyclopropanation
1-(2-tert-Butylphenyl)piperidine-2,6-dione (1d): This compound was
obtained as a colourless oil (1.990 g, 93%, hexane/EtOAc 3:7) by
the General Procedure for the formation of imides, from glutaric
anhydride (1.000 g, 8.76 mmol) and 2-tert-butylphenylamine
(1.22 mL, 9.26 mmol). 1H NMR (300 MHz, CDCl3): δ = 1.30 (s, 9
further be easily functionalised. Investigation of the bio-
logical activities of the newly synthesized compounds is cur-
rently underway.
H), 2.07–2.16 (m, 2 H), 2.83 (t, J = 6.6 Hz, 4 H), 6.82 (dd, J1
=
Experimental Section
7.7, J2 = 1.6 Hz, 1 H), 7.29 (dt, J1 = 7.7, J2 = 1.6 Hz, 1 H), 7.37
(dt, J1 = 7.7, J2 = 1.6 Hz, 1 H), 7.58 (dd, J1 = 7.7, J2 = 1.6 Hz, 1
Syntheses of compounds 9a and (Ϯ)-10a are described in the litera-
ture.[9,12]
H) ppm. IR (film): ν = 3380, 2965, 1734, 1655, 1598, 1580 cm–1.
˜
General Procedure for the Formation of the Imides 1a–e: The appro-
priate amine (37.00 mmol) was added at room temperature to a
stirred solution of glutaric anhydride (35.00 mmol) in THF
(60 mL) and the system was stirred for 30 min. After completion
of the reaction, the mixture was concentrated under reduced pres-
sure and the residue was diluted with EtOAc (25 mL). The resulting
mixture was treated with HCl (1 , 20 mL) and extracted with
EtOAc (3ϫ30 mL). The organic layer was washed with brine
(30 mL), dried with anhydrous magnesium sulfate and concen-
trated to afford a residue, which was used for the subsequent reac-
tion without further purification.
1-(4-Methoxyphenyl)piperidine-2,6-dione (1e): This compound was
obtained as a colourless oil (1.800 g, 93%, hexane/EtOAc 3:7) by
the General Procedure for the formation of imides, from glutaric
anhydride (1.000 g, 8.76 mmol) and 4-methoxyphenylamine
(1.10 mL, 9.26 mmol). 1H NMR (300 MHz, CDCl3): δ = 2.02–2.11
(m, 2 H), 2.78 (t, J = 6.6 Hz, 4 H), 3.79 (s, 3 H), 6.93–7.00 (m, 4
H) ppm. IR (film): ν = 3380, 2965, 1734, 1655, 1598, 1580 cm–1.
˜
1-(2,4-Dimethoxybenzyl)-4-methylpiperidine-2,6-dione (9b): This
compound was obtained as a white solid (3.200 g, 77%, hexane/
EtOAc 3:1) by the General Procedure for the formation of imides,
from glutaric anhydride (2.000 g, 15.74 mmol) and 2,4-dimethoxy-
benzylamine (2.54 mL, 16.50 mmol); m.p. 80–85 °C (EtOH). 1H
NMR (300 MHz, CDCl3): δ = 1.06 (d, J = 6.6 Hz, 3 H), 2.26–2.35
(m, 3 H), 2.77 (dd, J1 = 14.3, J2 = 3.0 Hz, 2 H), 3.74 (s, 3 H), 3.77
(s, 3 H), 4.88 (s, 2 H), 6.34–6.39 (m, 2 H), 6.85 (d, J = 8.1 Hz, 1
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 20.3, 24.4, 24.5, 37.9,
40.7, 55.3, 55.4, 98.4, 103.8, 117.4, 128.3, 158.0, 159.9, 172.0 ppm.
Et3N (51.00 mmol) was added at room temperature to a stirred
solution of the compound obtained above in Ac2O (10 mL). The
reaction mixture was heated at 80 °C for 1 h. After completion of
the reaction, the mixture was allowed to cool to room temperature
and the solvents were evaporated. The residue was diluted with
EtOAc (10 mL). The organic layer was washed with aqueous HCl
(1 , 30 mL), saturated aqueous sodium hydrogen carbonate
(30 mL) and brine (30 mL), dried with anhydrous magnesium sul-
fate and concentrated under reduced pressure. The crude residue
was purified by flash chromatography on silica gel (hexane/EtOAc
mixtures).
IR (film): ν = 3390, 2920, 2810, 1720, 1660, 1600, 1580 cm–1.
˜
C15H19NO4 (277.13): calcd. C 64.80, H 6.72, N 5.15; found C
63.93, H 6.50, N 5.28.
(3R)-N-(2,4-Dimethoxybenzyl)-5-hydroxy-3-methylpentanamide
[(–)-11]: 2,4-Dimethoxybenzylamine (5.4 mL, 36.64 mmol) was
added to a stirred solution of methyl (3R)-5-hydroxy-3-methyl-
pentanoate[11] (5.000 g, 34.22 mmol) in toluene (60 mL) and the
system was heated at reflux for 3 h. After cooling to room tempera-
ture, the reaction mixture was concentrated under reduced pressure.
The resulting residue was purified by flash column chromatography
(EtOAc/hexane 3:2) to afford (–)-11 (5.400 g, 79%) as a pale yellow
1-(4-Methoxybenzyl)piperidine-2,6-dione (1a): This compound was
obtained as a yellow pale oil (7.100 g, 90%, hexane/EtOAc 7:3) by
the General Procedure for the formation of imides, from glutaric
anhydride (4.000 g, 35.38 mmol) and 4-methoxybenzylamine
(5.36 mL, 37.39 mmol). 1H NMR (300 MHz, CDCl3): δ = 1.84–
1.92 (m, 2 H), 2.66 (t, J = 6.6 Hz, 4 H), 3.78 (s, 3 H), 4.88 (s, 2 H),
6.80–6.83 (m, 2 H), 7.34 (d, J = 8.8 Hz, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 16.7, 32.5, 41.7, 54.9, 113.4, 129.3, 130.0,
oil. [α]2D5 = –4.10 (c = 1.14, CHCl3). H NMR (300 MHz, CDCl3):
1
δ = 0.94 (d, J = 6.0 Hz, 3 H), 1.22 (d, J = 7.1 Hz, 1 H), 1.43–1.54
(m, 2 H), 2.07–2.11 (m, 2 H), 3.58–3.64 (m, 2 H), 3.76 (s, 3 H),
3.79 (s, 3 H), 4.33 (d, J = 5.5 Hz, 1 H), 5.90–5.93 (m, 2 H), 6.43
(d, J = 8.2 Hz, 2 H), 7.14 (d, J = 8.2 Hz, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 20.6, 27.0, 38.9, 39.5, 43.7, 55.3, 55.4, 60.3,
158.5, 172.8 ppm. IR (film): ν = 3440, 2970, 2.880, 1730, 1660,
˜
1576, 1510 cm–1. MS (ESI): m/z = 255.92 [M + Na]+. C13H15NO3
(233.27): calcd. C. 66.94, H 6.48, N 6.00; found C 66.84, H 6.41,
N 6.21.
98.5, 103.8, 118.6, 130.6, 158.5, 160.5, 172.4 ppm. IR (film): ν =
˜
1-(2,4-Dimethoxybenzyl)piperidine-2,6-dione (1b): This compound
was obtained as a white solid (7.100 g, 89%, hexane/EtOAc 3:7) by
the General Procedure for the formation of imides, from glutaric
anhydride (4.000 g, 35.38 mmol) and 2,4-dimethoxybenzylamine
(5.60 mL, 37.39 mmol); m.p. 115–123 °C (EtOH). 1H NMR
(300 MHz, CDCl3): δ = 1.91–1.96 (m, 2 H), 2.66 (t, J = 6.6 Hz, 4
H), 3.74 (s, 3 H), 3.77 (s, 3 H), 4.9 (s, 2 H), 6.35–6.39 (m, 2 H),
6.87 (d, J = 8.2 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
17.1, 30.9, 32.92, 37.8, 55.2, 55.3, 98.4, 103.8, 117.3, 128.0, 158.0,
3358, 2146, 1730, 1660, 1598, 1576 cm–1. C15H23NO4 (281.16):
calcd. C 64.03, H 8.24, N 4.98; found C 64.13, H 8.34, N 4.93.
(4R)-1-(2,4-Dimethoxybenzyl)-6-hydroxy-4-methylpiperidin-2-one
(12): Et3N (5.56 mL, 40.20 mmol) and sulfur trioxide pyridine com-
plex (6.940 g, 43.60 mmol) were added at 0 °C under argon to a
stirred solution of (–)-11 (2.300 g, 8.18 mmol) in DMSO (15 mL).
After stirring for 5 h at room temperature the reaction mixture was
quenched with water (4 mL). The mixture was then treated with
HCl (1 , 7 mL) and extracted with EtAcO (3ϫ20 mL). The or-
ganic layer was washed with brine, dried with magnesium sulfate
and concentrated under reduced pressure. The residue was purified
by column chromatography on silica gel (EtOAc/hexane 1:1) to af-
ford (–)-12 (1.370 g, 55%) as a colourless oil. 1H NMR (300 MHz,
CDCl3): δ = 0.96 (d, J = 6.0 Hz, 3 H), 1.58–1.62 (m, 2 H), 1.96–
1.98 (m, 2 H), 2.51–2.58 (m, 1 H), 3.77 (s, 3 H), 3.79 (s, 3 H), 4.20
159.8, 172.4, 172.8 ppm. IR (film): ν = 3394, 2980, 1722, 1660,
˜
1598, 1576 cm–1. C14H17NO4 (263.12): calcd. C 63.87, H 6.51, N
5.32; found C 63.93, H 6.50, N 5.28.
1-Benzylpiperidine-2,6-dione (1c): This compound was obtained as
a colourless oil (1.610 g, 91%, hexane/EtOAc 3:7) by the General
Procedure for the formation of imides, from glutaric anhydride
(1.000 g, 8.76 mmol) and benzylamine (1.16 mL, 9.26 mmol). 1H
NMR (300 MHz, CDCl3): δ = 1.87–1.96 (m, 2 H), 2.68 (t, J = (d, J = 14.8 Hz, 1 H), 4.35 (d, J = 2.7 Hz, 1 H), 5.15 (d, J =
6.0 Hz, 4 H), 4.93 (s, 2 H), 7.21–7.35 (m, 5 H) ppm. IR (film): ν =
14.8 Hz, 1 H), 6.43 (m, 2 H), 7.17 (d, J = 8.8 Hz, 1 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 15.2, 23.9, 37.5, 40.4, 42.2, 55.3, 55.4,
˜
3365, 2962, 1734, 1655, 1598, 1580 cm–1.
Eur. J. Org. Chem. 2010, 5850–5862
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5855

I. Suárez del Villar, A. Gradillas, J. Pérez-Castells
FULL PAPER
79.3, 98.4, 104.1, 117.7, 130.8, 158.7, 160.2, 169.5 ppm. IR (film): (0.82 g, 92%, hexane/EtOAc 7:3) by the General Procedure for the
ν = 3258, 2951, 2810, 1734, 1580, 1500, 1479, 1439, 1413, 1312, dehydration. 1H NMR (300 MHz, CDCl3): δ = 2.33–2.38 (m, 2 H),
˜
1297, 1281, 1249, 1182, 1170, 1100, 1065, 1026, 974, 931 cm–1
.
2.61 (t, J = 7.7 Hz, 2 H), 4.70 (s, 2 H), 5.13–5.17 (m, 1 H), 6.00–
C15H21NO4 (279.15): calcd. C 64.50, H 7.58, N 5.01; found C
64.43, H 7.50, N 5.17.
6.04 (m, 1 H), 7.23–7.36 (m, 5 H) ppm. IR (film): ν = 2290, 2845,
˜
1650, 1590, 1405, 1390 cm–1.
General Procedure for the Formation of the Enamides 2a-e: DIBAL-
H (12.50 mmol, 1  solution in toluene) was added dropwise at
–78 °C to a stirred solution of the appropriate imide 1 (6.40 mmol)
in CH2Cl2 (22.66 mL) After the mixture had been stirred for 1 h
at –78 °C, H2O (12 mL), followed by NaOH (2 , 3.7 mL) were
cautiously added and the reaction mixture was poured into a satu-
rated solution of Rochelle’s salt (90 mL). The mixture was then
extracted with CH2Cl2 (4ϫ30 mL). The combined extracts were
then washed with brine (35 mL), dried with anhydrous magnesium
sulfate and concentrated under reduced pressure to yield a crude
residue, which was purified by flash chromatography on silica gel
(hexane/EtOAc mixtures).
1-(2-tert-Butylphenyl)-3,4-dihydropyridin-2(1H)-one (2d): The corre-
sponding hydroxyamide was obtained from the imide 1d (1.000 g,
4.08 mmol) and DIBAL-H (8.16 mL, 8.16 mmol) as an orange oil
(0.760 g, 76%, hexane/EtOAc 1:1) by the General Procedure for the
reduction with DIBAL-H. Compound 2d was obtained from the
previous intermediate (1.000 g, 4.04 mmol) as a colourless oil
(0.740 g, 80%, hexane/EtOAc 7:3) by the General Procedure for the
dehydration. 1H NMR (300 MHz, CDCl3): δ = 1.37 (s, 9 H), 2.43–
2.49 (m, 2 H), 2.65–2.71 (m, 2 H), 5.21–5.31 (m, 1 H), 6.04–6.09
(m, 1 H), 6.99 (dd, J1 = 7.7, J2 = 1.6 Hz, 1 H), 7.25–7.28 (m, 2 H),
7.56 (dd, J1 = 7.7, J2 = 1.6 Hz, 1 H) ppm. IR (film): ν = 2290,
˜
2845, 1650, 1590, 1405, 1390 cm–1.
Et3N (22.71 mmol) was added at 0 °C to a solution of the pre-
viously obtained hydroxyamide (7.50 mmol) in CH2Cl2 (7.5 mL),
followed by methanesulfonyl chloride (mesyl chloride, 8.06 mmol).
The reaction mixture was stirred at room temperature for 2 h, then
washed with H2O (7.5 mL), a saturated solution of NaHCO3
(7.5 mL) and brine (7.5 mL), dried with anhydrous magnesium sul-
fate and concentrated under reduced pressure to yield a crude resi-
due, which was purified by flash chromatography on silica gel (hex-
ane/EtOAc mixtures).
1-(4-Methoxyphenyl)-3,4-dihydropyridin-2(1H)-one (2e): The corre-
sponding hydroxyamide was obtained from the imide 1d (1.000 g,
4.56 mmol) and DIBAL-H (9.12 mL, 9.12 mmol) as an orange oil
(0.730 g, 73%, hexane/EtOAc 1:1) by the General Procedure for the
reduction with DIBAL-H. Compound 2e was obtained from the
previous intermediate (1.000 g, 4.52 mmol) as a colourless oil
(0.840 g, 92%, hexane/EtOAc 7:3) by the General Procedure for the
dehydration. 1H NMR (300 MHz, CDCl3): δ = 1.37 (s, 9 H), 2.43–
2.49 (m, 2 H), 2.65–2.71 (m, 2 H), 5.21–5.31 (m, 1 H), 6.04–6.09
(m, 1 H), 6.99 (dd, J1 = 7.7, J2 = 1.6 Hz, 1 H), 7.25–7.28 (m, 2 H),
1-(4-Methoxybenzyl)-3,4-dihydropyridin-2(1H)-one (2a): The corre-
sponding hydroxyamide was obtained from the imide 1a (1.000 g,
4.28 mmol) and DIBAL-H (8.36 mL, 8.4 mmol) as an orange oil
(0.850 g, 85%, hexane/EtOAc 1:1) by the General Procedure for the
reduction with DIBAL-H. Compound 2a was obtained from the
previous intermediate (2.260 g, 9.6 mmol) as a colourless oil
(1.810 g, 87%, hexane/EtOAc 7:3) by the General Procedure for the
dehydration. 1H NMR (300 MHz, CDCl3): δ = 2.27–2.53 (m, 2 H),
2.55 (t, J = 7.7 Hz, 2 H), 3.77 (s, 3 H), 4.60 (s, 2 H), 5.08–5.13 (m,
1 H), 5.98–6.02 (m, 1 H), 6.83 (d, J = 8.8 Hz, 2 H), 7.34 (d, J =
8.8 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 20.3, 31.2,
48.2, 55.2, 106.4, 114.0, 129.0, 129.2, 129.3, 158.9, 169.3 ppm. IR
7.56 (dd, J1 = 7.7, J2 = 1.6 Hz, 1 H) ppm. IR (film): ν = 2290,
˜
2845, 1650, 1590, 1405, 1390 cm–1.
(؎)-1-(2,4-Dimethoxybenzyl)-4-methyl-3,4-dihydropyridin-2(1H)-
one [(؎)-10b]: The corresponding hydroxyamide was obtained from
the imide 9b (3.500 g, 13.40 mmol) and DIBAL-H (13.40 mL,
13.40 mmol) as a colourless oil (3.100 g, 74%) and as an insepa-
rable mixture of diastereomers (4:1, hexane/EtOAc 3:2) by the Ge-
neral Procedure for the reduction with DIBAL-H. Compound (Ϯ)-
10b was obtained from the previous intermediate (1.000 g,
3.58 mmol) as a colourless oil (0.700 g, 69%, hexane/EtOAc 3:1)
by the General Procedure for the dehydration. 1H NMR (300 MHz,
CDCl3): δ = 1.01 (d, J = 6.7 Hz, 3 H), 2.21–2.28 (m, 1 H), 2.55–
2.60 (m, 2 H), 3.76 (s, 3 H), 3.77 (s, 3 H), 4.55 (d, J = 15.1 Hz, 1
H), 4.62 (d, J = 15.1 Hz, 1 H), 4.93–4.97 (m, 1 H), 6.02 (dd, J1 =
7.8, J2 = 1.5 Hz, 1 H), 6.39–6.42 (m, 2 H), 7.11 (d, J = 8.8 Hz, 1
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 20.2, 26.9, 39.7, 43.3,
55.3, 55.3, 98.3, 104.0, 112.2, 117.8, 128.7, 130.3, 158.3, 160.3,
(film): ν = 2290, 2815, 1655, 1605, 1590, 1405 cm–1. MS (ESI): m/z
˜
= 239.94 [M + Na]+. C13H15NO2 (217.11): calcd. C 71.87, H 6.96,
N 6.45; found C 71.90, H 7.11, N 6.28.
1-(2,4-Dimethoxybenzyl)-3,4-dihydropyridin-2(1H)-one (2b): The
corresponding hydroxyamide was obtained as an orange oil
(5.540 g, 59%, hexane/EtOAc 1:1) by the General Procedure for the
reduction with DIBAL-H, from the imide 1b (1.700 g, 6.46 mmol)
and DIBAL-H (12.50 mL, 6.46 mmol). Compound 2b was ob-
tained from the previous intermediate (0.200 g, 0.75 mmol) as a
colourless oil (0.810 g, 98 %, hexane/EtOAc 3:1) by the General
169.2 ppm. IR (film): ν = 3060, 2930, 2710, 1730, 1610, 1580,
˜
1500 cm–1. C15H19NO3 (261.14): calcd. C 68.94, H 7.33, N 5.36;
found C 67.00, H 7.27, N 5.46.
(4S)-1-(2,4-Dimethoxybenzyl)-4-methyl-3,4-dihydropyridin-2(1H)-
one [(–)-10b]: Et3N (5.42 mmol) was added at 0 °C to a solution of
12 (0.500 g, 1.79 mmol) in CH2Cl2 (1.8 mL), followed by meth-
anesulfonyl chloride (mesyl chloride, 1.82 mmol). The reaction
mixture was stirred at room temperature for 2 h, washed with H2O
(1.8 mL), a saturated solution of NaHCO3 (1.8 mL) and brine
(1.8 mL), dried with anhydrous magnesium sulfate and concen-
trated under reduced pressure to yield an oil. The crude residue
was purified by column chromatography on silica gel (EtOAc/hex-
1
Procedure for the dehydration. H NMR (300 MHz, CDCl3): δ =
2.24–2.28 (m, 2 H), 2.51 (t, J = 7.7 Hz, 2 H), 3.74 (s, 3 H), 3.76 (s,
3 H), 4.58 (s, 2 H), 5.01–5.06 (m, 1 H), 6.06 (m, 1 H), 6.38–6.40 (m,
2 H), 7.12 (d, J = 8.8 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 20.3, 31.4, 43.4, 55.2, 55.3, 98.3, 104.0, 105.5, 117.7, 130.0, 130.3,
158.3, 160.2, 169.4 ppm. IR (film): ν = 3050, 3010, 2999, 1612,
˜
1552, 1503, 1452 cm–1. C14H17NO3 (247.12): calcd. C 68.00, H 6.93,
N 5.66; found C 68.32, H 7.11, N 5.70.
1-Benzyl-3,4-dihydropyridin-2(1H)-one (2c): The corresponding hy-
droxyamide was obtained from the imide 1c (1.000 g, 4.92 mmol)
and DIBAL-H (9.84 mL, 9.84 mmol), as a pale yellow pale oil
(0.830 g, 82%, hexane/EtOAc 1:2), by the General Procedure for
the reduction with DIBAL-H. Compound 2c was obtained from
the previous intermediate (1.000 g, 4.87 mmol) as a colourless oil
ane 3:1) to afford (–)-10b (0.240 g, 59%) as a colourless oil. [α]2D5
=
1
–152.00 (c = 0.50, CHCl3). H NMR (300 MHz, CDCl3): δ = 1.01
(d, J = 6.7 Hz, 3 H), 2.23–2.29 (m, 1 H), 2.53–2.59 (m, 2 H), 3.76
(s, 3 H), 3.77 (s, 3 H), 4.54 (d, J = 14.6 Hz, 1 H), 4.61 (d, J =
14.6 Hz, 1 H), 4.93–4.97 (m, 1 H), 6.02 (dd, J1 = 7.9, J2 = 1.2 Hz,
1 H), 6.39–6.41 (m, 2 H), 7.11 (d, J = 9.3 Hz, 1 H) ppm. 13C NMR
5856
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5850–5862

Stereoselective Cyclopropanation
(75 MHz, CDCl3): δ = 20.1, 26.9, 39.7, 43.3, 55.2, 55.3, 98.3, 103.9,
H), 2.15–2.23 (m, 1 H, 6-H), 2.37–2.43 (m, 2 H, CH2), 3.03 (dd, J1
112.2, 117.8, 128.7, 130.3, 158.3, 160.2, 169.2 ppm. IR (film): ν = = 8.2, J2 = 6.3 Hz, 1 H, 1-H), 3.60 (d, J = 14.3 Hz, 1 H, CH2),
˜
2990, 2220, 1750, 1600, 1505, 1450 cm–1. C15H19NO3 (261.14): 3.83 (s, 3 H, OCH3), 4.11 (q, J = 7.1 Hz, 2 H, CH2), 5.32 (d, J =
calcd. C 68.94, H 7.33, N 5.36; found C 69.00, H 7.15, N 5.21.
14.3 Hz, 1 H, CH2), 6.88 (d, J = 8.8 Hz, 2 H, ArH), 7.23–7.27 (m,
2 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.2, 20.7, 21.7,
30.7, 31.0, 40.5, 48.6, 55.2, 60.7, 113.9, 128.8, 130.1, 158.9, 169.0,
171.7 ppm. MS (ESI): m/z = 326.21 [M + Na]+. C17H21NO4
(303.15): calcd. C 67.31, H 6.98, N 4.62; found C 67.22, H 6.93, N
4.70.
General Procedures for Cyclopropanation Reactions
Method A – General Procedure for Cyclopropanation Reactions with
Rhodium(II) Acetate: A solution of rhodium(II) acetate (4 mol-%)
in anhydrous CH2Cl2 (3 mL) was added under argon to a stirred
solution of the appropriate enamide 2 (1.60 mmol) in anhydrous
CH2Cl2 (4 mL). An anhydrous CH2Cl2 solution (10 mL) of ethyl
diazoacetate (3.80 mmol) was then added to the reaction mixture
by syringe pump, at 30 °C under argon, over the course of 4 h at
room temperature. The mixture was stirred for an additional 8 h,
filtered through celite and concentrated under reduced pressure to
yield a crude residue that was purified by flash chromatography on
silica gel (hexane/EtOAc mixtures).
Ethyl 2-[1-(4-Methoxybenzyl)-6-oxo-1,4,5,6-tetrahydropyridin-2-yl]-
1
acetate (4a): H NMR (300 MHz, CDCl3): δ = 1.22 (t, J = 7.1 Hz,
3 H), 1.52–1.63 (m, 2 H), 1.93–2.00 (m, 2 H), 3.30–3.51 (m, 2 H),
3.77 (s, 3 H), 3.90 (d, J = 14.3 Hz, 1 H), 4.09 (q, J = 7.1 Hz, 2 H),
4.10–4.13 (m 1 H), 4.42 (d, J = 14.3 Hz, 1 H), 6.84 (d, J = 8.8 Hz,
2 H), 7.16 (d, J = 8.8 Hz, 2 H) ppm. IR (film): ν = 2999, 2910,
˜
1720, 1651, 1610, 1510, 1420, 1280 cm–1. C17H21NO4 (303.15):
calcd. C 67.31, H 6.98, N 4.62; found C 67.26, H 7.02, N 4.56.
Method B – General Procedure for Cyclopropanation Reactions with
Copper(I) Complexes: Copper(I) trifluoromethanesulfonate ben-
zene (0.029 mmol, 1 mol-%) and the corresponding chiral bis-ox-
azolidine ligand (0.027 mmol, 1 mol-%) were combined under ar-
gon in a dry box with addition of anhydrous CH2Cl2 (3 mL). The
solution was stirred for 1 h at room temperature. The reaction mix-
ture was filtered through a 0.2 mm filter, and the filtrate was added
to a solution of 2 (1.60 mmol) in anhydrous CH2Cl2 (4 mL). The
reaction flask was stoppered with a septum. An anhydrous CH2Cl2
solution (10 mL) of ethyl diazoacetate (2 equiv.) was added to the
reaction mixture by syringe pump, under argon at room tempera-
ture, over the course of 4 h. The mixture was stirred for an ad-
ditional 1 h, filtered through celite and concentrated under reduced
pressure to yield a crude residue that was purified by flash
chromatography on silica gel (hexane/EtOAc mixtures).
Cyclopropanation of 2b with EDA: A crude residue containing a
mixture of isomers (62:38) was obtained (Table 1, Entry 14) by cy-
clopropanation Method B from the enamide 2b (0.400 g,
1.6 mmol), the copper(I) complex formed by the bis-oxazolidine
7 (0.016 mmol) and CuOTf (0.016 mmol) and ethyl diazoacetate
(3.2 mmol), with an addition time of 4 h. Compounds trans-3b
(0.250 g, 47%), cis-3b (0.150 g, 25%) and 4b (0.027 g, 5%) were all
obtained (hexane/EtOAc 3:1) as colourless oils.
Ethyl (1S*,6S*,7S*)-2-(2,4-Dimethoxybenzyl)-3-oxo-2-azabicy-
clo[4.1.0]heptane-7-carboxylate (trans-3b): [α]2D5 = –3.32 (c = 0.054,
CHCl3, scalemic, ee = 15%). 1H NMR (300 MHz, CDCl3): δ =
1.19 (t, J = 7.1 Hz, 3 H, CH3), 1.44 (dd, J1 = 5.0, J2 = 2.7 Hz, 1
H, 7-H), 1.61–1.69 (m, 1 H, CH2), 1.89–1.92 (m, 1 H, 6-H), 2.14–
2.18 (m, 1 H, CH2), 2.29–2.38 (m, 2 H, CH2), 3.02 (dd, J1 = 8.8,
J2 = 2.2 Hz, 1 H, 1-H), 3.74 (s, 3 H, OCH3), 3.77 (s, 3 H, OCH3),
4.02 (q, J = 7.1 Hz, 2 H, CH2), 4.63 (d, J = 14.3 Hz, 1 H, CH2),
4.56 (d, J = 14.3 Hz, 1 H, CH2), 6.40–6.41 (m, 2 H, ArH), 7.17 (d,
J = 8.8 Hz, 1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.2,
21.0, 21.7, 30.7, 30.9, 40.8, 43.3, 55.1, 55.3, 60.5, 98.2, 104.1, 117.1,
Cyclopropanation of 2a with EDA: A crude residue containing a
mixture of isomers (78:22) was obtained (Table 1, Entry 11) by cy-
clopropanation Method B from the enamide 2a (0.200 g,
0.90 mmol), the copper(I) complex formed by the bis-oxazolidine
7 (0.09 mmol) and CuOTf (0.09 mmol) and ethyl diazoacetate
(1.8 mmol), with an addition time of 4 h. Compounds trans-3a
(0.170 g, 62%), cis-3a (0.028 g, 10%) and 4a (0.014 g, 5%) were all
obtained as colourless oils (hexane/EtOAc 3:1) .
131.1, 158.7, 160.5, 170.5, 171.2 ppm. IR (film): ν = 2900, 2820,
˜
1740, 1650, 1600, 1580, 1520 cm–1. C18H23NO5 (333.16): calcd. C
64.85, H 6.95, N 4.20; found C 65.00, H 6.89, N 4.32. The ee was
determined by HPLC with a CHIRAL-AP (100ϫ4.0 mm) column
and 9% propan-2-ol/sodium phosphate buffer (pH 7.0. 10 m) as
mobile phase; flow rate = 0.9 mLmin–1; retention time for trans-3b:
3.02 min for first enantiomer and 3.85 min for second enantiomer.
Ethyl (1S*,6S*,7S*)-2-(4-Methoxybenzyl)-3-oxo-2-azabicy-
clo[4.1.0]heptane-7-carboxylate (trans-3a): [α]2D5 = +9.90 (c = 0.14,
CHCl3, scalemic, ee = 55%). 1H NMR (300 MHz, CDCl3): δ =
1.22 (t, J = 7.1 Hz, 3 H, CH3), 1.44–1.47 (m, 1 H, 7-H), 1.61–1.73
(m, 1 H, CH2), 1.92–1.97 (m, 1 H, 6-H), 2.19–2.22 (m, 1 H, CH2),
2.24–2.48 (m, 2 H, CH2, CH2), 2.97 (dd, J1 = 8.8, J2 = 2.7 Hz, 1
H, 1-H), 3.77 (s, 3 H, OCH3), 4.05 (q, J = 7.1 Hz, 2 H, CH2), 4.42
(d, J = 14.3 Hz, 1 H, CH2), 4.69 (d, J = 14.3 Hz, 1 H, CH2), 6.82
(d, J = 8.8 Hz, 2 H, ArH), 7.18 (d, J = 8.8 Hz, 2 H, ArH) ppm.
13C NMR (75 MHz, CDCl3): δ = 14.1, 20.6, 21.7, 30.7, 30.8, 40.4,
48.5, 55.1, 60.6, 113.8, 128.6, 129.9, 158.9, 170.3, 170.9 ppm. IR
Ethyl (1S*,6S*,7R*)-2-(2,4-Dimethoxybenzyl)-3-oxo-2-azabicy-
clo[4.1.0]heptane-7-carboxylate (cis- 3b): [α]2D5 = +9.90 (c = 0.06,
CHCl3, scalemic). 1H NMR (300 MHz, CDCl3): δ = 1.19 (t, J =
7.1 Hz, 3 H, CH3), 1.62 (dd, J = 8.8, J2 = 6.6 Hz, 1 H, 7-H), 1.79–
1.83 (m, 1 H, 6-H), 2.14–2.18 (m, 2 H, CH2), 2.31–2.34 (m, 2 H,
CH2), 3.02 (dd, J1 = 7.7, J2 = 6.6 Hz, 1 H, 1-H), 3.74 (s, 3 H,
OCH3), 3.77 (s, 3 H, OCH3), 3.86 (d, J = 14.3 Hz, 1 H, CH2), 4.08
(q, J = 7.1 Hz, 2 H, CH2), 4.96 (d, J = 14.3 Hz, 1 H, CH2), 6.39–
6.40 (m, 2 H, ArH), 7.17 (d, J = 8.8 Hz, 1 H, ArH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 13.9, 20.4, 21.3, 30.2, 30.4, 40.3, 42.8, 54.5,
54.6, 60.0, 97.7, 103.8, 116.6, 131.8, 158.2, 160.0, 170.0, 170.7 ppm.
(film): ν = 2999, 2910, 1720, 1651, 1610, 1510 cm–1. MS (ESI): m/z
˜
= [M + Na]+: 326.10. C17H21NO4 (303.15): calcd. C 67.31, H 6.98,
N 4.62; found C 68.00, H 6.93, N 4.70. The ee was determined by
HPLC with a CHIRAL-AP (100ϫ4.0 mm) column and 9% pro-
pan-2-ol/sodium phosphate buffer (pH 7.0, 10 m) as mobile
phase; flow rate = 0.9 mL min–1; retention time for trans-3a:
2.45 min for first enantiomer and 3.15 min for second enantiomer.
IR (film): ν = 2900, 2820, 1740, 1650, 1600, 1580, 1520 cm–1
.
˜
C18H23NO5 (333.16): calcd. C 64.85, H 6.95, N 4.20; found C
64.76, H 6.87, N 4.31.
Ethyl 2-[1-(2,4-Dimethoxybenzyl)-6-oxo-1,4,5,6-tetrahydropyridin-2-
yl]acetate (4b): 1H NMR (300 MHz, CDCl3): δ = 1.20 (t, J =
7.1 Hz, 3 H), 1.92–2.01 (m, 2 H), 2.25–2.38 (m, 1 H), 2.47–2.51 (m,
Ethyl (1S*,6S*,7R*)-2-(4-Methoxybenzyl)-3-oxo-2-azabicy-
clo[4.1.0]heptane-7-carboxylate (cis-3a): [α]2D5 = +10.90 (c = 0.12,
CHCl3, scalemic). 1H NMR (300 MHz, CDCl3): δ = 1.30 (t, J = 1 H), 3.36–3.48 (m, 2 H), 3.76 (s, 3 H), 3.77 (s, 3 H), 4.09 (q, J =
7.1 Hz, 3 H, CH3), 1.73–1.78 (m, 2 H, CH2), 1.88–1.93 (m, 1 H, 7-
7.1 Hz, 2 H), 4.15 (d, J = 14.8 Hz, 1 H), 4.54 (t, J = 4.9 Hz, 1 H),
Eur. J. Org. Chem. 2010, 5850–5862
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5857

I. Suárez del Villar, A. Gradillas, J. Pérez-Castells
5.03 (d, J = 14.8 Hz, 1 H), 6.38–6.42 (m, 2 H), 7.15 (d, J = 8.8 Hz, J = 7.1 Hz, 2 H, CH2), 4.37 (d, J = 14.3 Hz, 1 H, CH2), 4.72 (d, J
FULL PAPER
1 H) ppm. IR (film): ν = 2900, 2820, 1740, 1650, 1600, 1580, = 14.3 Hz, 1 H, CH2), 6.79–6.82 (m, 2 H, ArH), 7.15 (d, J = 8.8 Hz,
˜
1520 cm–1. MS (ESI): m/z = 356.38 [M + Na]+. C18H23NO5
(333.16): calcd. C 64.85, H 6.95, N 4.20; found C 64.76, H 6.88, N
4.13.
2 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.1, 21.2, 27.6,
30.1, 31.3, 39.4, 40.4, 48.3, 55.2, 60.7, 113.9, 128.7, 129.9, 159.0,
170.6, 171.1 ppm. IR (film): ν = 3010, 2990, 1720, 1670, 1550 cm–1.
˜
MS (ESI): m/z = 340.41 [M + Na]+. C18H23NO4 (317.16): calcd. C
Ethyl (1S*,6S*,7S*)-2-Benzyl-3-oxo-2-azabicyclo[4.1.0]heptane-7-
carboxylate (trans-3c): This compound was obtained as a mixture
of isomers (81:19) by cyclopropanation Method B (Table 1, En-
try 16) from the enamide 2c (0.200 g, 1.1 mmol), the copper(I) com-
plex formed by the bis-oxazolidine 7 (0.016 mmol) and CuOTf
(0.016 mmol) and ethyl diazoacetate (2.1 mmol), with a time of ad-
dition of 4 h. The crude residue contained trans-3c (0.072 g, 25%)
as a colourless oil (hexane/EtOAc 3:1). 1H NMR (300 MHz,
CDCl3): δ = 1.22 (t, J = 7.1 Hz, 3 H), 1.47–1.48 (m, 1 H), 1.65–
1.73 (m, 1 H), 1.92–2.02 (m, 1 H), 2.21–2.30 (m, 1 H), 2.32–2.50
(m, 2 H), 3.37 (dd, J1 = 8.8, J2 = 2.1 Hz, 1 H, 1-H), 4.05 (q, J =
7.1 Hz, 2 H, CH2), 4.08 (d, J = 14.3 Hz, 1 H), 4.72 (d, J = 14.3 Hz,
68.12, H 7.30, N 4.41; found C 68.07, H 7.25, N 4.53.
Ethyl (1S*,5S*,6S*,7R*)-2-(4-Methoxybenzyl)-5-methyl-3-oxo-2-
azabicyclo[4.1.0]heptane-7-carboxylate (anti-cis-13a): [α]2D5 = +9.51
(c = 0.10, CHCl3, scalemic). 1H NMR (300 MHz, CDCl3): δ = 1.13
(d, J = 6.6 Hz, 3 H, CH3), 1.24 (t, J = 7.1 Hz, 3 H, CH3), 1.39–
1.46 (m, 1 H, 6-H), 1.74 (dd, J1 = 9.1, J2 = 6.6 Hz, 1 H, 7-H), 2.12
(dd, J1 = 12.6, J2 = 2.7 Hz, 1 H, CH2), 2.35 (dd, J1 = 15.4, J2 =
4.4 Hz, 1 H, CH2), 2.55–2.65 (m, 1 H, CH), 2.94 (dd, J1 = 8.5, J2
= 6.6 Hz, 1 H, 1-H), 3.50 (d, J = 14.3 Hz, 1 H, CH2), 3.79 (s, 3 H,
OCH3), 4.07 (q, J = 7.1 Hz, 2 H, CH2), 5.26 (d, J = 14.3 Hz, 1 H,
CH2), 6.80–6.83 (m, 2 H, ArH), 7.25 (d, J = 8.8 Hz, 2 H,
ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.2, 22.1, 23.3, 24.2,
25.8, 38.0, 40.4, 48.2, 55.3, 60.7, 113.8, 128.9, 130.0, 159.0, 169.1,
1 H), 7.26–7.30 (m, 5 H) ppm. IR (film): ν = 2999, 2910, 1720,
˜
1651, 1610, 1510 cm–1.
171.7 ppm. IR (film): ν = 3010, 2990, 1720, 1670, 1550 cm–1. MS
˜
Ethyl (1S*,6S*,7S*)-2-(2-tert-Butylphenyl)-3-oxo-2-azabicy-
clo[4.1.0]heptane-7-carboxylate (trans-3d): This compound was ob-
tained as a mixture of isomers (75:25) by cyclopropanation
Method B (Table 1, Entry 17) from the enamide 2d (0.210 g,
0.9 mmol), the copper(I) complex formed by the bis-oxazolidine
7 (0.091 mmol) and CuOTf (0.091 mmol) and ethyl diazoacetate
(1.8 mmol), with a time of addition of 4 h, The crude residue con-
tained trans-3d (0.070 g, 25%) as a pale yellow oil (hexane/EtOAc
(ESI): m/z = 340.02 [M + Na]+. C18H23NO4 (317.16): calcd. C
68.12, H 7.30, N 4.41; found C 68.09, H 7.21, N 4.32.
Ethyl (1S*,5R*,6S*,7S*)-2-(4-Methoxybenzyl)-5-methyl-3-oxo-2-
azabicyclo[4.1.0]heptane-7-carboxylate (syn-trans-13a): [α]2D5 = –6.32
(c = 0.10, CHCl3, scalemic). 1H NMR (300 MHz, CDCl3): δ = 1.03
(d, J = 6.6 Hz, 3 H, CH3), 1.20 (t, J = 7.1 Hz, 3 H, CH3), 1.65 (dd,
J1 = 5.5, J2 = 2.7 Hz, 1 H, 7-H), 1.71–1.79 (m, 1 H, CH), 1.83–
1.94 (m, 1 H, 6-H), 2.42–2.51 (m, 2 H, CH2), 3.03 (dd, J1 = 8.8, J2
= 2.7 Hz, 1 H, 1-H), 3.77 (s, 3 H, OCH3), 4.05 (q, J = 7.1 Hz, 2
H, CH2), 4.59 (s, 2 H, CH2), 6.83–6.86 (m, 2 H, ArH), 7.18 (d, J
= 8.8 Hz, 2 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.0,
20.2, 22.6, 23.1, 24.3, 36.7, 39.0, 49.8, 55.2, 60.6, 113.8, 129.7,
1
3:1). H NMR (300 MHz, CDCl3): δ = 1.22 (t, J = 7.1 Hz, 3 H),
1.41 (s, 9 H), 2.14–2.22 (m, 3 H), 2.29–4.41 (m, 2 H), 2.52–2.57 (m,
1 H), 3.30 (dd, J1 = 7.1, J2 = 4.9 Hz, 1 H), 4.08 (q, J = 7.1 Hz, 2
H), 7.02 (dd, J1 = 7.7, J2 = 1.6 Hz, 1 H), 7.23–7.29 (m, 2 H), 7.56
(dd, J1 = 7.7, J2 = 1.6 Hz, 1 H) ppm. IR (film): ν = 3010, 2934,
˜
1720, 1651, 1620, 1510 cm–1.
130.2, 159.0, 169.6, 169.7 ppm. IR (film): ν = 3010, 2990, 1720,
˜
1670, 1550 cm–1. MS (ESI): m/z = 340.21 [M + Na]+. C18H23NO4
(317.16): calcd. C 68.12, H 7.30, N 4.41; found C 68.16, H 7.28, N
4.51.
Ethyl (1S*,6S*,7S*)-2-(4-Methoxyphenyl)-3-oxo-2-azabicy-
clo[4.1.0]heptane-7-carboxylate (trans-3e): This compound was ob-
tained as a mixture of isomers (85:15) by cyclopropanation
Method B (Table 1, Entry 18), from the enamide 2e (0.210 g,
1.0 mmol), the copper(I) complex formed by the bis-oxazolidine
7 (0.098 mmol) and CuOTf (0.098 mmol) and ethyl diazoacetate
(1.8 mmol), with a time of addition of 4 h. The crude residue con-
tained trans-3e (0.150 g, 55%) as a yellow pale oil (hexane/EtOAc
Ethyl (1S*,5R*,6S*,7R*)-2-(4-Methoxybenzyl)-5-methyl-3-oxo-2-
azabicyclo[4.1.0]heptane-7-carboxylate (syn-cis-13a): [α]2D5 = +15.81
(c = 0.07, CHCl3, scalemic). 1H NMR (300 MHz, CDCl3): δ = 1.12
(d, J = 6.6 Hz, 3 H, CH3), 1.19 (t, J = 7.1 Hz, 3 H, CH3), 1.64 (dd,
J1 = 7.2, J2 = 7.1 Hz, 1 H, 7-H), 2.36–2.43 (m, 2 H, CH, CH2),
2.53–2.57 (m, 2 H, CH2, 6-H), 3.11 (dd, J1 = 7.2, J2 = 7.1 Hz, 1 H,
1-H), 3.79 (s, 3 H, OCH3), 4.03 (q, J = 7.1 Hz, 2 H, CH2), 4.45 (d,
J = 14.3 Hz, 1 H, CH2), 4.82 (d, J = 14.3 Hz, 1 H, CH2), 6.84 (d,
J = 8.8 Hz, 2 H, ArH), 7.25 (d, J = 8.8 Hz, 2 H, ArH) ppm. 13C
NMR (75 MHz, CDCl3): δ = 14.0, 20.2, 22.5, 23.0, 24.2, 36.7, 39.0,
49.7, 55.2, 60.5, 113.7, 129.0, 130.2, 159.0, 169.5, 169.6 ppm. IR
1
3:1). H NMR (300 MHz, CDCl3): δ = 1.22 (t, J = 7.1 Hz, 3 H),
1.84–1.92 (m, 2 H), 2.08–2.13 (m, 1 H), 2.29–2.49 (m, 1 H), 2.51–
2.61 (m, 2 H), 3.37 (dd, J1 = 8.8, J2 = 2.7 Hz, 1 H), 3.79 (s, 3 H),
4.05 (q, J = 7.1 Hz, 2 H), 6.88–6.91 (m, 2 H), 7.20 (d, J = 9.3 Hz,
2 H) ppm. IR (film): ν = 2999, 2910, 1720, 1651, 1610, 1510 cm–1.
˜
Cyclopropanation of (؎)-10a with EDA: A crude residue containing
a mixture of isomers (57:25:12:6) was obtained (Table 2, Entry 4)
by cyclopropanation Method B from the enamide (Ϯ)-10a (0.200 g,
0.9 mmol), the copper(I) complex formed by the bis-oxazolidine
7 (0.086 mmol) and CuOTf (0.086 mmol) and ethyl diazoacetate
(1.73 mmol), with a time of addition of 4 h. Compounds anti-trans-
13a (0.130 g, 50 %), anti-cis-13a (0.027 g, 10 %), syn-trans-13a
(0.016 g, 8%), syn-cis-13a (0.008 g, 4%) and 14 (0.019 g, 7%) were
all obtained as colourless oils (hexane/EtOAc 3:1).
(film): ν = 3010, 2990, 1720, 1670, 1550 cm–1. MS (ESI): m/z =
˜
340.62 [M + Na]+. C18H23NO4 (317.16): calcd. C 68.12, H 7.30, N
4.41; found C 68.10, H 7.18, N 4.35.
Ethyl 2-[1-(4-Methoxybenzyl)-4-methyl-6-oxo-1,4,5,6-tetrahydropyr-
1
idin-3-yl]acetate (14): H NMR (300 MHz, CDCl3): δ = 0.96 (t, J
= 6.6 Hz, 3 H), 1.22 (t, J = 7.1 Hz, 3 H), 2.33 (dd, J1 = 16.0, J2 =
4.4 Hz, 1 H), 2.44–2.69 (m, 1 H), 2.76 (dd, J1 = 16.0, J2 = 6.6 Hz,
1 H), 2.94 (d, J = 16.5 Hz, 1 H), 3.02 (d, J = 16.5 Hz, 1 H), 3.79
(s, 3 H), 4.12 (q, J = 7.1 Hz, 2 H), 4.45 (d, J = 14.8 Hz, 1 H), 4.75
(d, J = 14.8 Hz, 1 H), 5.85 (s, 1 H), 6.83–6.86 (m, 2 H), 7.16 (d, J
= 8.8 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.1, 17.4,
Ethyl (1S*,5S*,6S*,7S*)-2-(4-Methoxybenzyl)-5-methyl-3-oxo-2-
azabicyclo[4.1.0]heptane-7-carboxylate (anti-trans-13a): [α]2D5
+12.60 (c = 0.34, CHCl3, scalemic, 14% ee). H NMR (300 MHz,
=
1
CDCl3): δ = 1.15 (d, J = 6.6 Hz, 3 H, CH3), 1.24 (t, J = 7.1 Hz, 3 29.7, 37.4, 38.9, 48.2, 55.2, 60.9, 114.0, 117.8, 126.2, 129.1, 159.0,
H, CH3), 1.45 (dd, J1 = 5.0, J2 = 2.7 Hz, 1 H, 7-H), 1.57–1.64 (m, 168.5, 171.4 ppm. IR (film): ν = 2999, 2910, 1720, 1651, 1610, 1510,
˜
1 H, 6-H), 1.81–1.98 (m, 1 H, CH), 2.13–2.26 (m, 2 H, CH2), 2.93
(dd, J1 = 8.3, J2 = 2.7 Hz, 1 H, 1-H), 3.78 (s, 3 H, OCH3), 4.09 (q,
1420, 1300 cm–1. C18H23NO4 (317.16): calcd. C 68.12, H 7.30, N
4.41; found C 68.23, H 7.19, N 4.44.
5858
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5850–5862

Stereoselective Cyclopropanation
Cyclopropanation of (؎)-10b with EDA: A crude residue containing
a mixture of isomers (90:10:0:0) was obtained (Table 2, Entry 8) by
cyclopropanation Method B from the enamide (Ϯ)-10b (0.500 g,
1.9 mmol), the copper(I) complex formed by the bis-oxazolidine
7 (0.019 mmol) and CuOTf (0.019 mmol) and ethyl diazoacetate
(3.80 mmol), with time of addition of 4 h. Compound anti-trans-
13b (0.360 g, 54%), a mixture (5:2, 0.040 g, 6%) of anti-cis-13b with
anti-trans-13b and compound 15 (0.046 g, 7%) were all obtained
(hexane/EtOAc 4:1–1:2) as colourless oils.
117.1, 131.5, 158.7, 160.5, 171.7, 171.3 ppm. IR (film): ν = 2970,
˜
2810, 2220, 1740, 1605, 1580, 1360 cm–1. C19H25NO5 (347.17):
calcd. C 65.69, H 7.25, N 4.03; found C 65.55, H 7.09, N 4.1.
Ethyl (4R)-2-[1-(2,4-Dimethoxybenzyl)-4-methyl-6-oxo-1,4,5,6-
tetrahydropyridin-2-yl]acetate [(–)-15]: [α]2D5 = –10.00 (c = 0.02,
1
CHCl3). H NMR (300 MHz, CDCl3): δ = 0.94 (d, J = 6.6 Hz, 3
H), 1.19 (t, J = 7.4 Hz, 3 H), 1.86–1.96 (m, 1 H), 2.21–2.31 (m, 1
H), 2.50–2.57 (m, 1 H), 3.28–3.52 (m, 2 H), 3.75 (s, 3 H), 3.76 (s,
3 H), 4.11–4.23 (m, 3 H), 4.51 (s, 1 H), 5.02 (d, J = 15.4 Hz, 1 H),
6.39–6.41 (m, 2 H), 7.15 (d, J = 8.8 Hz, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 15.1, 21.0, 22.3, 35.0, 40.6, 41.3, 55.0, 55.1,
61.5, 97.9, 103.7, 103.9, 117.9, 130.3, 130.5, 158.2, 159.8, 169.8,
Ethyl (1S*,5S*,6S*,7S*)-2-(2,4-Dimethoxybenzyl)-5-methyl-3-oxo-
2-azabicyclo[4.1.0]heptane-7-carboxylate (anti-trans-13b): [α]2D5
=
1
+6.25 (c = 0.08, CHCl3, scalemic). H NMR (300 MHz, CDCl3):
δ = 1.13 (d, J = 6.6 Hz, 3 H, CH3), 1.20 (t, J = 7.3 Hz, 3 H, CH3),
1.42 (dd, J1 = 5.0, J2 = 3.3 Hz, 1 H, 7-H), 1.53–1.60 (m, 1 H, 6-
H), 1.81–1.86 (m, 1 H, CH), 2.14–2.18 (m, 2 H, CH2), 2.98 (dd, J1
= 8.8, J2 = 2.7 Hz, 1 H, 1-H), 3.70 (s, 3 H, OCH3), 3.72 (s, 3 H,
OCH3), 4.07 (q, J = 7.3 Hz, 2 H, CH2), 4.50 (d, J = 14.0 Hz, 1 H,
CH2), 4.62 (d, J = 14.0 Hz, 1 H, CH2), 6.37–6.40 (m, 2 H, ArH),
7.14 (d, J = 8.8 Hz, 1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3):
δ = 14.1, 21.1, 27.8, 30.0, 31.2, 39.4, 40.6, 42.9, 55.1, 55.2, 60.5,
98.1, 104.0, 117.0, 131.5, 158.6, 160.4, 171.2, 182.6 ppm. IR (film):
169.9 ppm. IR (film): ν = 2810, 2230, 2070, 1740, 1651, 1492,
˜
1460 cm–1. C19H25NO5 (347.17): calcd. C 65.69, H 7.25, N 4.03;
found C 65.57, H 7.31, N 3.97.
6-(2-Chloroethyl)-1-(2,4-dimethoxybenzyl)-4-methyl-3,4-dihydropyr-
idin-2(1H)-one (22): This compound (0.142 g, 22%) was obtained
by cyclopropanation Method B from the enamide (Ϯ)-10b (0.500 g,
1.9 mmol), the copper(I) complex formed by the bis-oxazolidine 7
(0.019 mmol) and CuOTf (0.019 mmol) and 2-chlorodiazoe-
thane[21] (19.0 mmol, 0.3  solution in Et2O), with a time of ad-
dition of 8 h, as a yellow pale oil (hexane/EtOAc 7:3). 1H NMR
(300 MHz, CDCl3): δ = 0.94 (d, J = 6.8 Hz, 3 H), 1.16–1.32 (m, 1
H), 1.86–1.96 (m, 2 H), 2.25–2.31 (m, 1 H), 2.54 (d, J = 1.7 Hz, 1
H), 3.60–3.65 (m, 2 H), 3.76 (s, 3 H), 3.77 (s, 3 H), 4.15 (d, J =
14.6 Hz, 1 H), 4.58 (s, 1 H), 5.04 (d, J = 14.6 Hz, 1 H), 6.39–6.41
(m, 2 H), 7.15–7.19 (m, J = 8.8 Hz, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 21.2, 35.2, 40.7, 41.7, 42.8, 55.2, 55.3, 64.4, 98.3, 104.2,
ν = 2975, 1730, 1706, 1661, 1602, 1576, 1500, 1455 cm–1
.
˜
C19H25NO5 (347.17): calcd. C 65.69, H 7.25, N 4.03; found C
65.77, H 7.13, N 4.01.
Ethyl 2-[1-(2,4-Dimethoxybenzyl)-4-methyl-6-oxo-1,4,5,6-tetra-
hydropyridin-2-yl]acetate (15): 1H NMR (300 MHz, CDCl3): δ =
0.94 (d, J = 6.6 Hz, 3 H), 1.23 (t, J = 7.1 Hz, 3 H), 1.87–1.97 (m,
1 H), 2.23–2.28 (m, 1 H), 2.50–2.57 (m, 1 H), 3.35–3.50 (m, 2 H),
3.76 (s, 3 H), 3.77 (s, 3 H), 4.05–4.12 (m, 3 H), 4.50 (d, J = 7.1 Hz,
1 H), 5.02 (d, J = 14.8 Hz, 1 H), 6.39–6.40 (m, 2 H), 7.15 (d, J =
8.8 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 15.1, 21.0,
22.3, 35.0, 40.6, 41.3, 55.0, 55.1, 61.5, 97.9, 103.7, 103.9, 117.9,
104.3, 118.0, 129.5, 131.0, 158.5, 160.1, 170.1 ppm. IR (film): ν =
˜
3317, 2949, 1648, 1609, 1507, 1456, 1340, 1266, 1255, 1153,
1039 cm–1. C17H22ClNO3 (323.13): calcd. C 63.06, H 6.85, N 4.33;
found C 63.03, H 6.71, N 4.27.
130.3, 130.5 ppm. 158.2, 159.8, 169.8, 169.9 ppm. IR (film): ν =
˜
(1S*,5S*,6S*,7S*)-2-(2,4-Dimethoxybenzyl)-5-methyl-7-(trifluoro-
methyl)-2-azabicyclo[4.1.0]heptan-3-one (anti-trans-23): A crude res-
idue containing a mixture of isomers (87:130:0:0) was obtained by
cyclopropanation Method B from the enamide (Ϯ)-10b (0.500 g,
1.9 mmol), the copper(I) complex formed by the bis-oxazolidine 7
(0.019 mmol) and CuOTf (0.019 mmol) and 1,1,1-trifluorodiazoe-
thane[21] (3.8 mmol, 0.25  solution in Et2O), with a time of ad-
dition of 4 h. Compound anti-trans-23 (0.510 g, 65%) and a mix-
ture (3:2) of anti-cis-23/anti-trans-23 (0.220 g, 23%) were obtained
as colourless oils (hexane/EtOAc 3:1). anti-trans-23: [α]2D5 = +20.02
(c = 0.07, CHCl3, scalemic, ee = 40 %). 1H NMR (300 MHz,
CDCl3): δ = 1.20 (d, J = 6.8 Hz, 3 H, CH3), 1.36–1.41 (m, 1 H, 6-
H), 1.43–1.48 (m, 1 H, 7-H), 1.87–1.94 (m, 1 H, CH), 2.17–2.30
(m, 2 H, CH2), 2.94 (dd, J1 = 8.8, J2 = 2.9 Hz, 1 H, 1-H), 3.79 (s,
3 H, OCH3), 3.81 (s, 3 H, OCH3), 4.41 (d, J = 14.1 Hz, 1 H, CH2),
4.83 (d, J = 14.1 Hz, 1 H, CH2), 6.43–6.46 (m, 2 H, ArH), 7.22 (d,
J = 9.8 Hz, 1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.2,
22.0 (q, J = 2.8 Hz), 29.9, 30.2 (q, J = 36 Hz), 34.8 (q, J = 3.8 Hz),
39.5, 42.5, 55.1, 55.4, 98.2, 104.2, 117.2, 123.4 (q, J = 270 Hz),
2900, 2820, 1740, 1650, 1600, 1470, 1500, 980 cm–1. MS (ESI): m/z
= 348.13 [M + H]+. C19H25NO5 (347.17): calcd. C 65.69, H 7.25,
N 4.03; found C 65.72, H 7.31, N 3.98.
Cyclopropanation of (–)-10b with EDA: a) A crude residue contain-
ing a mixture of isomers (95:5:0:0) was obtained (Table 2, Entry 10)
by cyclopropanation Method B from the enamide (–)-10b (0.400 g,
1.5 mmol), the copper(I) complex formed by the bis-oxazolidine
7 (0.015 mmol) and CuOTf (0.015 mmol) and ethyl diazoacetate
(3.06 mmol), with a time of addition of 4 h. Compounds (–)-anti-
trans-13b (0.160 g, 52%) and (–)-15 (0.021 g, 4%) were obtained
(hexane/EtOAc 3:1) as yellow oils. b) A crude residue containing a
mixture of isomers (65:35:0:0) was obtained (Table 2, Entry 9) by
cyclopropanation Method A from the enamide (–)-10b (0.400 g,
1.5 mmol), rhodium(II) acetate (0.06 mmol) and ethyl diazoacetate
(3.06 mmol), with a time of addition of 4 h. Compound (–)-anti-
trans-13b (0.073 g, 23%) and a mixture (5:2) of anti-cis-13b with
(–)-anti-trans-13b (0.037 g,12%) were obtained (hexane/EtOAc 3:1)
as yellow oils.
131.7, 158.7, 160.5, 170.7 ppm. IR (film): ν = 2975, 1730, 1706,
˜
Ethyl (1S,5S,6S,7S)-2-(2,4-Dimethoxybenzyl)-5-methyl-3-oxo-2-
1661, 1602, 1576, 1500, 1455 cm–1. C17H20F3NO3 (343.34): calcd.
C 59.47, H 5.87, N 4.08; found C 59.36, H 6.01, N 4.14.
azabicyclo[4.1.0]heptane-7-carboxylate [(–)-anti-trans-13b]: [α]2D5
–25.20 (c = 0.06, CHCl3). H NMR (300 MHz, CDCl3): δ = 1.15
(d, J = 6.7 Hz, 3 H, CH3), 1.22 (t, J = 7.3 Hz, 3 H, CH3), 1.43 (dd,
=
1
Reduction of Ethoxycarbonylcyclopropanes
J1 = 4.9, J2 = 3.1 Hz, 1 H, 7-H), 1.55–1.69 (m, 1 H, 6-H), 1.80– [(1S*,5S*,6S*,7S*)-2-(2,4-Dimethoxybenzyl)-5-methyl-2-azabi-
1.90 (m, 1 H, CH), 2.14–2.20 (m, 2 H, CH2), 2.99 (dd, J1 = 9.1, J2 cyclo[4.1.0]hept-3-en-7-yl]methanol (anti-trans-18): Compound anti-
= 3.1 Hz, 1 H, 1-H), 3.73 (s, 3 H, OCH3), 3.77 (s, 3 H, OCH3), trans-18 (0.017 g, 42%) was obtained (hexane/EtOAc 3:2) as a pale
4.06 (q, J = 7.3 Hz, 2 H, CH2), 4.52 (d, J = 14.0 Hz, 1 H, CH2),
4.64 (d, J = 14.0 Hz, 1 H, CH2), 6.39–6.42 (m, 2 H, ArH), 7.16 (d, H from anti-trans-13b (0.050 g, 0.14 mmol) and DIBAL-H
J = 9.1 Hz, 1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.1,
(0.15 mL, 0.15 mmol), reaction time, temperature: 30 min, –78 °C.
21.2, 27.9, 30.1, 31.2, 39.5, 40.7, 42.9, 55.1, 55.3, 60.5, 98.2, 104.1, 1H NMR (300 MHz, CDCl3): δ = 0.94 (d, J = 7.4 Hz, 3 H), 1.21–
yellow oil by the General Procedure for the reduction with DIBAL-
Eur. J. Org. Chem. 2010, 5850–5862
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5859

I. Suárez del Villar, A. Gradillas, J. Pérez-Castells
FULL PAPER
1.23 (m, 1 H), 1.50–1.53 (m, 1 H), 1.98–2.01 (m, 1 H), 2.12 (dd, J1 General Procedure for the Formation of Thioamides: Lawesson’s rea-
= 15.9, J2 = 5 Hz, 1 H), 2.62 (dd, J1 = 15.9, J2 = 4.4 Hz, 1 H), gent (0.80 mmol) was added to a stirred solution of the appropriate
2.83 (d, J = 8.8 Hz, 1 H), 3.77 (s, 3 H), 3.78 (s, 3 H), 4.13 (d, J = lactam (1.10 mmol) in benzene (10 mL). The reaction mixture was
14.8 Hz, 1 H), 4.83–4.86 (m, 1 H), 5.11 (d, J = 14.8 Hz, 1 H), 5.60
(d, J = 9.3 Hz, 1 H), 6.36–6.45 (m, 2 H), 7.21–7.24 (m, 1 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 18.5, 23.6, 30.4, 46.0, 46.3, 50.0,
55.3, 55.4, 68.1, 98.4, 103.4, 104.0, 115.8, 128.8, 131.5, 158.7,
stirred at 80 °C for 2 h, concentrated under reduced pressure and
purified by flash chromatography on silica gel (hexane/EtOAc mix-
tures).
Synthesis of 16: Isomers anti-trans-16 (0.350 g, 73%) and anti-cis-
16 (0.037 g, 8%) were obtained as yellow pale oils (hexane/EtOAc
3:1) by the General Procedure for the formation of thioamides,
from a mixture (9:1) of anti-trans-13b and anti-cis-13b (0.380 g,
1.13 mmol).
160.5 ppm. IR (film): ν = 2960, 1730, 1706, 1500, 1455, 1256,
˜
1113 cm–1. MS (ESI): m/z = 312.17 [M + Na]+. C17H23NO3
(289.17): calcd. C 70.56, H 8.01, N 4.84; found C 70.44, H 7.94, N
4.96.
(1S*,5S*,6S*,7S*)-2-(2,4-Dimethoxybenzyl)-5-methyl-3-thioxo-2-
azabicyclo[4.1.0]heptane-7-carbaldehyde (anti-trans-19): Compound
anti-trans-19 (0.010 g, 39%) was obtained (hexane/EtOAc 1:1) as a
yellow pale oil by the General Procedure for the reduction with
DIBAL-H from anti-trans-16 (0.050 g, 0.14 mmol) and DIBAL-H
(0.21 mL, 0.21 mmol), reaction time, temperature: 45 min, –78 °C.
1H NMR (300 MHz, CDCl3): δ = 1.13 (d, J = 6.7 Hz, 3 H), 1.20–
1.23 (m, 1 H), 1.80–1.83 (m, 1 H), 1.88–1.91 (m, 1 H), 2.63 (dd, J1
= 15.9, J2 = 10.4 Hz, 1 H), 2.98 (dd, J1 = 15.9, J2 = 3.6 Hz, 1 H),
3.19 (dd, J1 = 7.9, J2 = 3.0 Hz, 1 H), 3.73 (s, 3 H), 3.78 (s, 3 H),
5.19 (d, J = 14.0 Hz, 1 H), 5.30 (d, J = 14.0 Hz, 1 H), 6.41–6.45
(m, 2 H), 7.35 (d, J = 7.9 Hz, 1 H), 9.33 (d, J = 2.4 Hz) ppm. 13C
NMR (75 MHz, CDCl3): δ = 20.6, 29.3, 30.1, 39.9, 44.2, 49.7, 49.9,
55.3, 55.4, 98.3, 104.4, 115.8, 132.0, 157.9, 160.8, 197.1, 200.1 ppm.
Ethyl (1S*,5S*,6S*,7S*)-2-(2,4-Dimethoxybenzyl)-5-methyl-3-thi-
oxo-2-azabicyclo[4.1.0]heptane-7-carboxylate (anti-trans-16): 1H
NMR (300 MHz, CDCl3): δ = 1.13 (d, J = 6.6 Hz, 3 H), 1.19 (t, J
= 7.1 Hz, 3 H), 1.52–1.54 (m, 1 H), 1.67–1.74 (m, 1 H), 1.75–1.80
(m, 1 H), 2.62 (dd, J1 = 15.9, J2 = 10.4 Hz, 1 H), 2.97 (dd, J1 =
16.4, J2 = 3.8 Hz, 1 H), 3.08 (dd, J1 = 8.2; J2 = 2.2 Hz, 1 H), 3.74
(s, 3 H), 3.77 (s, 3 H), 3.95 (q, J = 7.1 Hz, 2 H), 5.11 (d, J =
14.1 Hz, 1 H), 5.30 (d, J = 14.1 Hz, 1 H), 6.41–6.43 (m, 2 H), 7.31
(d, J = 8.8 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.1,
20.6, 28.7, 29.3, 30.9, 41.7, 49.7, 50.4, 55.2, 55.3, 60.8, 98.3, 104.2,
115.6, 131.8, 158.7, 160.9, 172.1, 200.9 ppm. IR (film): ν = 2930,
˜
2820, 1730, 1610, 1585, 1410, 1205 cm–1. MS (ESI): m/z = 386.50
[M + Na]+. C19H25NO4S (363.15): calcd. C 62.78, H 6.93, N 3.85;
found C 62.56, H 7.13, N 4.04.
IR (film): ν = 3010, 2980, 1724, 1706, 1661, 1602, 1500, 1455 cm–1.
˜
MS (ESI): m/z = 342.31 [M + Na]+. C17H21NO3S (319.12): calcd.
Ethyl (1S*,5S*,6S*,7R*)-2-(2,4-Dimethoxybenzyl)-5-methyl-3-thi-
oxo-2-azabicyclo[4.1.0]heptane-7-carboxylate (anti-cis-16): 1H
NMR (300 MHz, CDCl3): δ = 1.11 (d, J = 6.6 Hz, 3 H, CH3), 1.19
(t, J = 7.3 Hz, 3 H, CH3), 1.51–1.62 (m, 1 H, 7-H), 1.72 (dd, J1 =
9.1, J2 = 6.7 Hz, 1 H, 6-H), 2.41–2.53 (m, 2 H, CH2, CH), 3.07
(dd, J1 = 7.9, J2 = 6.7 Hz, 1 H, 1-H), 3.13 (d, J = 11.6 Hz, 1 H,
CH2), 3.77 (s, 3 H, OCH3), 3.78 (s, 3 H, OCH3), 4.07 (q, J = 7.3 Hz,
2 H, CH2), 4.30 (d, J = 14.6 Hz, 1 H, CH2), 5.86 (d, J = 14.6 Hz,
1 H, CH2), 6.40–6.43 (m, 2 H, ArH), 7.25 (d, J = 8.5 Hz, 1 H,
ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.3, 21.4, 23.1, 25.3,
27.1, 39.31, 50.2, 51.0, 55.3, 55.4, 60.7, 98.3, 104.0, 115.6, 131.5,
C 63.92, H 6.63, N 4.39; found C 63.76, H 6.43, N 4.57.
(1S*,5S*,6S*,7S*)-2-(2,4-Dimethoxybenzyl)-7-(hydroxymethyl)-5-
methyl-2-azabicyclo[4.1.0]heptane-3-thione (anti-trans-20): Com-
pound anti-trans-20 (0.061 g 70%) was obtained (hexane/EtOAc
1:1) as a yellow pale oil by the General Procedure for the reduction
with DIBAL-H, from anti-trans-16 (0.010 g, 0.27 mmol) and DI-
BAL-H (1.1 mL, 1.08 mmol), reaction time, temperature: 2 h,
–78 °C. 1H NMR (300 MHz, CDCl3): δ = 1.09 (d, J = 6.7 Hz, 3
H), 1.20–1.22 (m, 1 H), 1.70–1.79 (m, 2 H), 2.44–2.48 (m, 1 H),
2.51–2.60 (m, 1 H), 2.95 (dd, J1 = 15.2, J2 = 3.6 Hz, 1 H), 3.07
(dd, J1 = 11.6; J2 = 7.3 Hz, 1 H), 3.43 (dd, J1 = 11.6, J2 = 4.9 Hz,
1 H), 3.77 (s, 3 H), 3.79 (s, 3 H), 4.97 (d, J = 14.0 Hz, 1 H), 5.56
(d, J = 14.0 Hz, 1 H), 6.43–6.46 (m, 2 H), 7.39 (d, J = 9.1 Hz, 1
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.0, 24.6, 30.4, 32.7,
38.4, 49.7, 50.3, 55.3, 55.7, 63.1, 98.7, 104.8, 116.4, 131.5, 158.4,
158.8, 160.6, 168.8, 203.1 ppm. IR (film): ν = 2930, 2820, 1730,
˜
1610, 1585, 1410, 1205 cm–1. C19H25NO4S (363.15): calcd. C 62.78,
H 6.93, N 3.85; found C 62.89, H 6.98, N 3.98.
Synthesis of (–)-16: Isomers (–)-anti-trans-16 (0.071 g, 58%) and
(–)-anti-cis-16 (0.031 g, 27 %) were obtained as yellow pale oils
(hexane/EtOAc 3:1) by the General Procedure for the formation of
thioamides from a mixture (6:4) of (–)-anti-trans-13b and anti-cis-
13b (0.120 g, 0.38 mmol).
160.7, 201.0 ppm. IR (film): ν = 3440, 2950, 1860, 1590, 1500,
˜
1210 cm–1. C17H23NO3S (321.14): calcd. C 63.52, H 7.21, N 4.36;
found C 63.56, H 7.43, N 4.58.
Ethyl (1S*,5S*,6S*,7S*)-2-(2,4-Dimethoxybenzyl)-5-methyl-2-aza-
bicyclo[4.1.0]heptane-7-carboxylate (anti-trans-21): Compound
anti-trans-21 (0.057 g, 71%) was obtained as a yellow pale oil, to-
gether with anti-trans-20 (0.021 g, 23%) (hexane/EtOAc 1:1) by the
General Procedure for the reduction with DIBAL-H, from anti-
trans-16 (0.010 g, 0.27 mmol) and DIBAL-H (0.83 mL,
0.83 mmol), reaction time, temperature: 3 h, –78 °C. 1H NMR
(300 MHz, CDCl3): δ = 1.15 (d, J = 6.7 Hz, 3 H), 1.20 (t, J =
6.6 Hz, 3 H), 1.42–1.45 (m, 1 H), 1.56–1.57 (m, 1 H), 1.78–1.81 (m,
2 H), 2.16–2.21 (m, 1 H), 2.46–2.51 (m, 1 H), 3.00 (dd, J1 = 8.5,
J2 = 2.4 Hz, 1 H), 3.61–3.73 (m, 1 H), 3.73 (s, 3 H), 3.77 (s, 3 H),
4.05 (q, J = 6.6 Hz, 2 H), 4.52 (d, J = 14.3 Hz, 1 H), 4.65 (d, J =
14.3 Hz, 1 H), 6.40–6.42 (m, 2 H), 7.16 (d, J = 8.5 Hz, 1 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 14.2, 21.2, 27.9, 28.0, 30.1, 31.2,
39.6, 40.7, 42.9, 55.2, 55.3, 60.6, 98.2, 104.1, 117.1, 131.6, 158.7,
(1S,5S,6S,7S)-Ethyl-2-(2,4-dimethoxybenzyl)-5-methyl-3-thioxo-2-
azabicyclo[4.1.0]heptane-7-carboxylate [(–)-anti-trans-16]: [α]2D5
=
1
–184.00 (c = 0.03, CHCl3). H NMR (300 MHz, CDCl3): δ = 1.13
(d, J = 6.7 Hz, 3 H), 1.20 (t, J = 7.3 Hz, 3 H), 1.52–1.54 (m, 1 H),
1.69–1.73 (m, 1 H), 1.76–1.80 (m, 1 H), 2.64 (dd, J1 = 15.8, J2 =
10.3 Hz, 1 H), 2.95 (dd, J1 = 15.8, J2 = 3.6 Hz, 1 H), 3.08 (dd, J1
= 7.9, J2 = 2.4 Hz, 1 H), 3.74 (s, 3 H), 3.77 (s, 3 H), 3.98 (q, J =
7.3 Hz, 2 H), 5.14 (d, J = 14.0 Hz, 1 H), 5.31 (d, J = 14.0 Hz, 1
H), 6.40–6.43 (m, 2 H), 7.31 (d, J = 8.5 Hz, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 14.1, 20.6, 28.7, 29.3, 30.8, 41.7, 49.7, 50.4,
55.2, 55.3, 60.8, 98.3, 104.2, 115.6, 131.8, 158.7, 160.9, 170.6,
200.8 ppm. IR (film): ν = 2910, 2830, 1720, 1610, 1580, 1405, 1205,
˜
1035 cm–1. C19H25NO4S (363.15): calcd. C 62.78, H 6.93, N 3.85;
found C 62.77, H 6.86, N 3.91.
160.5, 170.6 ppm. IR (film): ν = 3330, 2830, 2810, 1530, 1510, 1400,
(1S,5S,6S,7R)-Ethyl-2-(2,4-dimethoxybenzyl)-5-methyl-3-thioxo-2-
˜
1120 cm–1. C19H27NO4 (333.19): calcd. C 68.44, H 8.16, N 4.20; azabicyclo[4.1.0]heptane-7-carboxylate [(–)-anti-cis-16]: [α]2D5
=
1
found C 68.35, H 8.10, N 4.07. 4.58.
5860
–48.00 (c = 0.07, CHCl3). H NMR (300 MHz, CDCl3): δ = 1.10
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5850–5862

Stereoselective Cyclopropanation
(d, J = 6.1 Hz, 3 H, CH3), 1.25 (t, J = 7.3 Hz, 3 H, CH3), 1.51– (film): ν = 1940, 1745, 1630, 1550, 1430, 1300, 1290 cm–1. MS
˜
1.59 (m, 1 H, 7-H), 1.72 (dd, J1 = 9.1, J2 = 6.7 Hz, 1 H, 6-H),
(ESI): m/z = 214.05 [M + H]+. C10H15NO2S (213.08): calcd. C
2.40–2.53 (m, 2 H, CH2, CH), 3.07 (dd, J1 = 7.9, J2 = 6.7 Hz, 1 H, 56.31, H 7.09, N 6.57; found C 56.27, H 7.01, N 6.43.
1-H), 3.13 (d, J = 11.6 Hz, 1 H, CH2), 3.74 (s, 3 H, OCH3), 3.77 (s,
Ethyl (1S,5S,6S,7S)-5-Methyl-3-thioxo-2-azabicyclo[4.1.0]heptane-
3 H, OCH3), 4.12 (q, J = 7.3 Hz, 2 H, CH2), 4.27 (d, J = 14.6 Hz, 1
7-carboxylate [(–)-anti-trans-17]: Compound (–)-anti-trans-17
H, CH2), 5.83 (d, J = 14.6 Hz, 1 H, CH2), 6.39–6.42 (m, 2 H, ArH),
(0.040 g, 65%) was obtained as a pale yellow oil (hexane/EtOAc
7.23 (d, J = 9.1 Hz, 1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3):
4:1) by the General Procedure from (–)-anti-trans-16 (0.100 g,
1
0.3 mmol). [α]2D5 = –30.43 (c = 0.03, CHCl3). H NMR (300 MHz,
CDCl3): δ = 1.17 (d, J = 6.6 Hz, 3 H), 1.21 (t, J = 7.3 Hz, 3 H),
1.76–1.80 (m, 1 H), 1.82–1.85 (m, 1 H), 1.96–2.08 (m, 1 H), 2.55
(dd, J1 = 16.5, J2 = 7.3 Hz, 1 H), 2.75 (dd, J1 = 17.1, J2 = 5.5 Hz,
1 H), 3.18–3.23 (m, 1 H), 4.13 (q, J = 7.3 Hz, 2 H), 8.45 [s(a), 1
H] ppm. 13C NMR (75 MHz, CDCl3): δ = 14.1, 20.8, 25.7, 27.7,
δ = 14.3, 21.4, 23.13, 25.3, 27.0, 39.3, 50.2, 51.1, 55.3, 55.4, 60.7,
98.3, 104.1, 115.6, 131.6, 158.8, 160.6, 168.8, 203.1 ppm. IR (film):
ν = 2960, 2910, 1720, 1610, 1590, 1410, 1290, 1260, 1210,
˜
1060 cm–1. C19H25NO4S (363.15): calcd. C 62.78, H 6.93, N 3.85;
found C 62.66, H 7.10, N 3.79.
Synthesis of 25: Isomers anti-trans-25 (0.290 g, 70%) and anti-cis-
25 (0.029 g, 10%) were obtained as yellow pale oils (hexane/EtOAc
4:1) by the General Procedure for the formation of thioamides,
from a mixture (87:13) of anti-trans-23 and anti-cis-23 (0.400 g,
1.20 mmol).
29.1, 37.7, 45.4, 61.1, 170.6, 199.7 ppm. IR (film): ν = 1940, 1745,
˜
1630, 1550, 1430, 1300, 1290 cm–1. MS (ESI): m/z = 214.05 [M +
H]+. C10H15NO2S (213.08): calcd. C 56.31, H 7.09, N 6.57; found
C 56.33, H 6.96, N 6.44.
(1S*,5S*,6S*,7S*)-5-Methyl-7-(trifluoromethyl)-2-azabicyclo-
[4.1.0]heptane-3-thione (anti-trans-26): Compound anti-trans-26
(0.840 g, 60%) was obtained as a pale yellow oil (hexane/EtOAc
9:1) by the General Procedure from anti-trans-25 (0.240 g,
0.7 mmol). H NMR (300 MHz, CDCl3): δ = 1.18 (d, J = 6.8 Hz,
3 H), 1.55–1.59 (m, 1 H), 1.72–1.75 (m, 1 H), 1.89–2.00 (m, 1 H),
(1S*,5S*,6S*,7S*)-2-(2,4-Dimethoxybenzyl)-5-methyl-7-(trifluoro-
methyl)-2-azabicyclo[4.1.0]heptan-3-one (anti-trans-25): H NMR
(300 MHz, CDCl3): δ = 1.15 (d, J = 6.8 Hz, 3 H), 1.51–1.57 (m, 2
H), 1.82–1.87 (m, 1 H), 2.62 (dd, J1 = 16.1; J2 = 10.3 Hz, 2 H),
1
1
2.94 (dd, J1 = 15.6, J2 = 3.9 Hz, 1 H), 3.12 (dd, J1 = 8.8, J2
=
3.5 Hz, 1 H), 3.77 (s, 3 H), 3.78 (s, 3 H), 4.93 (d, J = 14.1 Hz, 1
H), 4.63 (d, J = 14.1 Hz, 1 H), 6.42–6.44 (m, 2 H), 7.43 (d, J =
9.2 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 20.7, 23.1 (q,
J = 2.3 Hz), 28.8, 29.5 (q, J = 36 Hz), 36.5 (q, J = 3.8 Hz), 49.5,
49.7, 55.2, 55.3, 98.3, 104.3, 115.7, 125.9 (q, J = 270 Hz), 131.7,
2.54 (dd, J1 = 16.6, J2 = 7.8 Hz, 1 H), 2.74 (dd, J1 = 16.6, J2
=
4.9 Hz, 1 H), 3.07 (d, J = 8.8 Hz, 1 H), 8.80 [s(a), 1 H] ppm. 13C
NMR (75 MHz, CDCl3): δ = 19.8 (q, J = 2.8 Hz), 20.0, 27.5, 28.2
(q, J = 36.0 Hz), 32.0 (q, J = 3.8 Hz), 45.3, 124.2 (q, J = 270.0 Hz),
203.1 ppm. IR (film): ν = 3110, 3000, 1533, 1445, 1390, 1330, 1274,
˜
158.7, 160.9, 201.0 ppm. IR (film): ν = 2931, 2810, 1688, 1600,
˜
1070 cm–1. MS (ESI): m/z = 209.91 [M + H]+. C8H10F3NS (209.05):
calcd. C 45.92, H 4.82, N 6.69, S 15.33; found C 46.01, H 4.67, N
6.74, S 15.27.
1597, 1500, 1465, 1380, 1355, 1250 cm–1. C17H20F3NO2S (359.12):
calcd. C 56.81, H 5.61, N 3.90, S 8.92; found C 56.69, H 5.56, N
3.98, S 8.97.
(1S*,5S*,6S*,7R*)-2-(2,4-Dimethoxybenzyl)-5-methyl-7-(trifluoro-
methyl)-2-azabicyclo[4.1.0]heptan-3-one (anti-cis-25): 1H NMR
(300 MHz, CDCl3): δ = 1.16 (d, J = 6.8 Hz, 3 H, CH3), 1.43–1.51
(m, 1 H, 6-H), 1.57–1.66 (m, 1 H, 7-H), 2.11–2.14 (m, 1 H, CH),
2.50 (dd, J1 = 15.5, J2 = 12.7 Hz, 1 H, CH2), 3.03 (dd, J1 = 7.3, J2
= 2.5 Hz, 1 H, 1-H), 3.12 (dd, J1 = 15.6, J2 = 3.4 Hz, 1 H, CH2),
3.77 (s, 3 H, OCH3), 3.78 (s, 3 H, OCH3), 4.22 (d, J = 14.6 Hz, 1
H, CH2), 6.13 (d, J = 14.6 Hz, 1 H, CH2), 6.42–6.44 (m, 2 H, ArH),
7.30 (d, J = 9.2 Hz, 1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3):
δ = 21.4, 23.8 (q, J = 2.8 Hz), 25.3 (q, J = 34.6 Hz), 30.2 (q, J =
3.8 Hz), 36.2, 50.0, 50.9, 55.3, 55.4, 98.3, 104.1, 115.4, 131.1, 134.3
Acknowledgments
Funding of this project by the Spanish Ministerio de Educación y
Ciencia (MEC), (Project No. CTQ2009-07738/BQU) is gratefully
acknowledged. I.S.-V. thanks the Fundación San Pablo-CEU for
predoctoral fellowships.
[1] W. A. Donalson, Tetrahedron 2001, 57, 8589–8628.
[2] a) J. Salaün, Top. Curr. Chem. 2000, 207, 1–67; b) R. Faust,
Angew. Chem. Int. Ed. 2001, 40, 2251–2253.
[3] For a review, see: H. Lebel, J.-F. Marcoux, C. Molinaro, A. B.
Charrette, Chem. Rev. 2003, 103, 977–1050.
[4] See: a) E. D. de Silva, A.-S. Geiermann, M. I. Mitova, P.
Kuegler, J. W. Blunt, A. L. J. Cole, M. H. G. Munro, J. Nat.
Prod. 2009, 72, 477–479; b) L. M. Halo, M. N. Heneghan,
A. A. Yakasai, Z. Song, K. Williams, A. M. Bailey, R. J. Cox,
C. M. Lazarus, T. J. Simpson, J. Am. Chem. Soc. 2008, 130,
17988–17996.
[5] a) T. Kelly, S. Bell, N. Osashi, J. Armstrong-Chong, J. Am.
Chem. Soc. 1988, 110, 6471–6480; b) D. Curran, H. Liu, J. Am.
Chem. Soc. 1992, 114, 586–5864.
(q, J = 272.0 Hz), 158.7, 160.6, 202.8 ppm. IR (film): ν = 2925,
˜
2810, 1690, 1608, 1580, 1500, 1450, 1380, 1352, 1250 cm–1
.
C17H20F3NO2S (359.12): calcd. C 56.81, H 5.61, N 3.90, S 8.92;
found C 56.62, H 5.58, N 3.97, S 8.88.
General Procedure for Removal of the 2,4-Dimethoxybenzyl (Dmob)
Group: A solution of the appropriate thioamide (0.33 mmol) in tri-
fluoroacetic acid (0.60 mmol) was heated at reflux for 16 h. The
reaction mixture was concentrated under reduced pressure and
purified by flash column chromatography (EtOAc/hexane mix-
tures).
Ethyl (1S*,5S*,6S*,7S*)-5-Methyl-3-thioxo-2-azabicyclo[4.1.0]hep-
tane-7-carboxylate (anti-trans-17): Compound anti-trans-17
(0.580 g, 82%) was obtained as a pale yellow oil (hexane/EtOAc
4:1) by the General Procedure, from anti-trans-16 (0.120 g,
[6] D. Williams, P. Lowder, Y.-G. Gu, Tetrahedron Lett. 1997, 38,
327–320.
[7] J. A. Meulbroek, A. Oleksijew, S. K. Tanaka, J. D. Alder, J.
Antimic. Chem. 1996, 38, 641–653; for a review, see: Q. Li,
M. A. Mitschner, L. L. Shen, Med. Chem. Rev. 2000, 20, 231–
293.
[8] For an example of a cyclopropane-2-pyridone as a starting ma-
terial for the synthesis of actinophylic acid, see: R. G. Vaswani,
J. J. Day, J. L. Wood, Org. Lett. 2009, 11, 4532–4535.
[9] B. J. Whittle, IDrugs 2002, 5, 590–593; for a selective iNOS
inhibitor with a 2-azabicyclo[4.1.0]heptane structure see ONO-
1
0.3 mmol). H NMR (300 MHz, CDCl3): δ = 1.17 (d, J = 6.6 Hz,
3 H), 1.21 (t, J = 7.3 Hz, 3 H), 1.76–1.80 (m, 1 H), 1.82–1.85 (m,
1 H), 1.96–2.08 (m, 1 H), 2.55 (dd, J1 = 16.5, J2 = 7.3 Hz, 1 H),
2.75 (dd, J1 = 17.1, J2 = 5.5 Hz, 1 H), 3.18–3.23 (m, 1 H), 4.13 (q, J
= 7.3 Hz, 2 H), 8.45 [s(a), 1 H] ppm. 13C NMR (75 MHz, CDCl3): δ
= 14.1, 20.8, 25.7, 27.7, 29.1, 37.7, 45.4, 61.1, 170.6, 199.7 ppm. IR
Eur. J. Org. Chem. 2010, 5850–5862
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5861

I. Suárez del Villar, A. Gradillas, J. Pérez-Castells
FULL PAPER
1714: Y. Kawanaka, K. Kobayashi, S. Kusuda, T. Tatsumi, M. [16]
Murota, T. Nishiyama, K. Hisaichi, A. Fujii, K. Hirai, M.
H. M. L. Davies, D. K. Hutcheson, Tetrahedron Lett. 1993,34,
7243–7246.
Stereochemical assignment for 13a:
Naka, M. Komeno, H. Nakai, M. Toda, Eur. J. Med. Chem.
2003, 38, 277–288.
[17]
[10] a) M. P. Doyle, A. B. Dyatkin, A. V. Kalinin, D. A. Ruppar, J.
Am. Chem. Soc. 1995, 117, 11021–11022; b) H. M. L. Davies,
P. R. Bruzinski, D. H. Lake, N. Kong, M. J. Fall, J. Am. Chem.
Soc. 1996, 118, 6897–6907; c) M. P. Doyle, M. A. McKervey,
T. Ye, Modern Catalytic Methods for Organic Synthesis with
Diazo Compounds, John Wiley & Sons, New York, 1998; d)
M. P. Doyle, D. C. Forbes, Chem. Rev. 1998, 98, 911–936; e)
M. P. Doyle, in: Catalytic Asymmetric Synthesis, 2nd ed. (Ed.:
I. Ojima), Wiley-VCH, New York, 2000, pp. 191–228; f) T. A.
Kirkland, J. Colucci, L. S. Geraci, M. A. Marx, M. Schneider,
D. E. Kaelin Jr., S. F. Martin, J. Am. Chem. Soc. 2001, 123,
12432–12433; g) M. Barris, J. Pérez-Prieto, S.-E. Stiriba, P. La-
huerta, Org. Lett. 2001, 3, 3317–3319; h) A. Caballero, A. Pri-
eto, M. M. Diaz-Requejo, P. J. Pérez, Eur. J. Inorg. Chem. 2009,
1137–1144; i) H. Pellissier, Tetrahedron 2008, 64, 7041–7095; j)
Z. Zhang, J. Wang, Tetrahedron 2008, 64, 6577–6605; k)
H. M. L. Davies, S. J. Hedley, Chem. Soc. Rev. 2007, 36, 1109–
1119.
[11] For a preliminary communication containing parts of this
work, see: I. Suárez del Villar, A. Gradillas, A. Gómez-Ovalles,
R. Martínez-Murillo, A. Martínez, J. Pérez-Castells, Chem.
Lett. 2008, 37, 1222–1223.
[12] Y. Kawanaka, K. Kobayashi, S. Kusuda, T. Tatsumi, M. Mur-
ota, T. Nishiyama, K. Hisaichi, A. Fujii, K. Hirai, M. Naka,
M. Komeno, Y. Odagaki, H. Nakai, M. Toda, Bioorg. Med.
Chem. 2003, 11, 1723–1743.
[18]
M. P. Doyle, W. R. Winchester, M. N. Protopopova, P. Müller,
G. Bernardinelli, D. Ene, S. Motallebi, Helv. Chim. Acta 1993,
76, 2227–2235.
M. P. Doyle, W. R. Winchester, J. A. A. Hoorn, V. Lynch, S. H.
Simonsen, R. Ghosh, J. Am. Chem. Soc. 1993, 115, 9968–9978.
[19]
[20]
Stereochemical assignment of anti-trans-13b and anti-cis-16:
[13] D. J. Bennett, A. J. Blake, P. A. Cooke, C. R. A. Godfrey, P. L.
Pickering, N. S. Simpkins, M. D. Walker, C. Wilson, Tetrahe-
dron 2004, 60, 4491–4511.
[14] Stereochemical assignment for 3a and 3b:
[21] H. Gilman, R. G. Jones, J. Am. Chem. Soc. 1943, 65, 1458–
1460.
[22] Stereochemical assignment of anti-trans-23 and anti-cis-25:
Received: June 16, 2010
Published Online: September 6, 2010
[15] See: a) D. A. Evans, K. A. Whoerpel, M. M. Hinman, M. M.
Faul, J. Am. Chem. Soc. 1991, 113, 726–728; b) R. E. Lowen-
thal, S. Masamune, Tetrahedron Lett. 1991, 32, 7373–7376.
5862
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5850–5862