Tandem aza-Michael additions under high pressure: a shortcut to the azanorbornyl skeleton

Article abstract of DOI:10.1016/j.tet.2006.03.070

The hyperbaric aza-Michael addition of mono- and diamines on α,β-unsaturated β,β-disubstituted mono- and diesters has been studied. While in the case of monoester, this reaction provides a β-aminoester presenting a quaternary center, a direct and efficien

Full text of DOI:10.1016/j.tet.2006.03.070

Tetrahedron 62 (2006) 5411–5416
Tandem aza-Michael additions under high pressure:
a shortcut to the azanorbornyl skeleton
y
z
*
Alexandre Yu. Rulev, Nilgun Yenil, Anthony Pesquet, Hassan Oulyadi and Jacques Maddaluno
´
´ ´
Laboratoire des Fonctions Azotees & Oxygenees Complexes de l’IRCOF, UMR 6014 CNRS,
´
Universite et INSA de Rouen, 76821 Mont St Aignan Cedex, France
Received 31 January 2006; revised 21 March 2006; accepted 22 March 2006
Available online 25 April 2006
Abstract—The hyperbaric aza-Michael addition of mono- and diamines on a,b-unsaturated b,b-disubstituted mono- and diesters has been
studied. While in the case of monoester, this reaction provides a b-aminoester presenting a quaternary center, a direct and efficient access
to diester or lactams featuring an azanorbornyl skeleton was obtained when starting from a diester, following an unprecedented double aza-
Michael addition.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
OBn
The b-lactam, which was derived directly from b-amino-
acids, and the azanorbornane skeletons are nitrogen hetero-
H
N
O
Cl
cycles sharing two characteristics. First, their biological
activity and their extensive use as fundamental building
blocks in the synthesis of pharmaceuticals and analogues of
natural products such as alkaloids and antibiotics fuels up
a permanent attention from the organic chemistry commu-
nity.1 For instance, the b-lactam nuclei featuring new charac-
teristics such as quaternary centers in a of the nitrogen
position2 or spirocyclic arrangements3 are regarded as valu-
able assets in antibiotherapy. Spiro-b-lactams exhibit other
attractive biological activities illustrated by the cholesterol
absorption inhibitor Sch 58053 (Fig. 1, left).4 It is also now
well established that the replacement of a-aminoacid resi-
dues with b-amino or a,b-diaminoacid residues at specific
positions in some peptides leads to improved biological
activity due to increased metabolic stability against pepti-
dases.5
N
N
O
F
Figure 1. Cholesterol absorption inhibitor Sch 58053 (left) and analgesic
epibatidine (right).
agonist, but its high toxicity soon prompted the development
and screening of new analogues.7
On a synthetic point of view, and this constitutes the second
common point between b-aminoacids and azanorbornanes,
the access to analogues of above structures can be envisaged
through an aza-Michael addition on simple or double acetyl-
idenic cyclohexanes (Fig. 2). The combination of this reac-
tion with a substitution–condensation sequence (tandem
aza-Michael reactions) can thus provide a short and atom-
economical route to cyclic and polycyclic complex mole-
cules including these heterocyclic moieties.
Meanwhile, the discovery of the alkaloid, epibatidine, found
in trace amounts from skin extracts of an Ecuadoran poison
frog, Epipedobates tricolor, has generated considerable in-
terest in the 7-azanorbornane nucleus.6 Indeed, epibatidine
(Fig. 1, right) was first reported to be a highly potent,
nonopioid analgesic, and nicotinic acetylcholine receptor
The aza-Michael addition on unsaturated esters is probably
the most direct method to prepare b-aminoesters.8 However,
and despite its atom-economical character, this reaction is
severely limited by steric factors such as those imposed by
the presence of a and/or b-substituent(s), as evidenced by
Pfau’s pioneering results.9 An elegant way to circumvent
this problem is to resort to the addition of enantiomerically
pure chiral lithium amides as homochiral ammonia equiva-
lents. This strategy has proved to be remarkably general
and is probably regarded as the most efficient route to these
Supplementary data associated with this article can be found in the online
version, at doi:10.1016/j.tet.2006.03.070.
* Corresponding author. Tel.: +33 235 522 446; fax: +33 235 522 971;
e-mail: jmaddalu@crihan.fr
Permanent address: A. E. Favorski Institute of Chemistry, Siberian Divi-
y
sion of the Russian Academy of Sciences, Irkutsk 664033, Russia.
Permanent address: Department of Chemistry, Science and Art Faculty,
Celal Bayar University, 45030 Muradiye, Manisa, Turkey.
z
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.03.070

5412
A. Yu. Rulev et al. / Tetrahedron 62 (2006) 5411–5416
R
N
ratio, could be separated by flash chromatography. Their
R
HN
NMR analysis showed that the major isomer 3a resulted
from an axial attack of the amine, in contrast with our own
previous observations.14a About 15% of b-methoxyester
2c, resulting from the conjugate addition of methanol on 1,
was also obtained in this case.
O
COOR
n
n
n
COOR
COOR"
NH R'
R'
H
N
R'
n
Bielectrophiles were also expected to trigger cascade reac-
tions, of potential interest in the perspective of the synthesis
of polyheterocyclic cation-chelating molecules. We thus
turned our hands to the known16 diester 4, which was pre-
pared and reacted with primary amines (Scheme 2) as well
as with commercially available N,N- and N,O-binucleo-
philes (Scheme 3).
n
n
R
COOR"
COOR"
Figure 2. Access to spiro-b-lactams and to aza-bridged carbocyclic struc-
tures by aza-Michael additions.
compounds to date.10 Another alternative consists in resort-
ing to high pressure, which is known to help overcoming
steric barriers. It has been previously shown that this
technique indeed opens direct routes toward tertiary b-
aminoesters,11 and Jenner has measured a highly negative
(zꢀ50 mL/mol)12 activation volume associated to this re-
action, explaining its efficiency under hyperbaric conditions.
COOMe
O
K2CO3
H2O
4
+ (MeO)2P(O)CH2COOMe
(80%)
20 h, rt
MeOOC
COOMe
O
R
R-NH2
N
5a: R = Bn: 79 %
Our first results in the field led us to suggest that exo-cyclic
olefins bearing an electron-withdrawing group are substrates
for the hyperbaric (11 kbar) conjugate addition of primary
amines, provided the reaction is run in alcohols.13 Actually,
a-brominated a,b-unsaturated esters give access, in these
same conditions, to spiroaziridines in high yields and stereo-
selectivities.14 In this paper, we report developments dealing
with polyfunctional nucleophiles allowing an aza-Michael–
condensation reaction sequence.
5b: R = PMB: 40 %
11 kbar
RT
5c: R = (MeO)2CHCH2: 63 %
MeOH
MeOOC
Scheme 2. Synthesis of diester 4 and their reactions with primary amines.
HO
OH
N
6a
COOMe
NH2
COOMe
15 kbar
7a: Yd = 52%
MeOOC
Y
O
RT
2. Results and discussion
MeOH
N
NHR
MeOOC
4
6b: R = H
In a preliminary step, we checked that simple exo-cyclic
olefins such as 1 react with nucleophilic primary amines such
as benzylamine in comparable conditions. The expected
b-aminoester 2 (featuring a quaternary center) was indeed
obtained in 46% yield under 11 kbar (Scheme 1). Actually,
the nucleophilic attack of the amine on the ester group (pro-
viding the corresponding unsaturated benzylamide) is the
main competing reaction. No double 1,2- and 1,4-additions
were noted. An efficient conjugate addition was also ob-
served with a secondary amine such as morpholine.15
6c: R = Me
NH2
NH2
MeOOC
7b: Y = NH, Yd = 58%
7c: Y = NMe, Yd = 77%
7d: Y = NH, Yd = 65%
6d
NH2
Scheme 3. Reactions of diester 4 with N,N- and N,O-binucleophiles.
The diester 4 was obtained efficiently as a 1:1 mixture of (Z)-
and (E)-isomers from 1,4-cyclohexanedione resorting to the
aqueous Horner–Emons conditions described by Villieras
and Rambaud (Scheme 2).17 The room temperature hyper-
baric addition of a series of primary amines led to the bridged
structure 5 in relatively good yields. This direct access to
bridged b-aminodiesters, never described before to our
knowledge, was relatively surprising considering the low
We next moved to binucleophiles and compressed N-methyl-
ethylenediamine with 1 in identical conditions. The spirolac-
tam 3 was directly obtained in 57% yield (Scheme 1). The
two diastereomers of the resulting lactams, present in a 5:1
COOMe
2a: X = NHBn
2b: X =
X
N
O
COOMe
R1R2NH
2c: X = OMe
11 kbar
O
Me
N
RT
t-Bu
t-Bu
MeOH
H
Me
N
N
t-Bu
1
NHMe
+
H2N
t-Bu
(5 : 1)
O
N
H
3a
3b
Scheme 1. Reactions of ester 1 with N-nucleophiles.

A. Yu. Rulev et al. / Tetrahedron 62 (2006) 5411–5416
5413
N
N
NH2
H2N
COOMe
MeOOC
COOMe
11 kbar
8
COOMe
MeOOC
RT
MeOH
N
MeOOC
H
N
N
MeOOC
4
COOMe
N
O
H2N
NH2
MeOOC
9
Scheme 4. Reactions of diester 4 with N,N-binucleophiles.
reactivity of secondary amines in conjugate additions, even
underhighpressure.11a Notethatthereactionrequiresaprotic
solvent such as methanol and that only small amounts of the
corresponding amides are formed, except in the case of p-
methoxybenzylamine. Compound 5b was indeed recovered
together with 28% of its monoamide derivative.
of the two primary amines on the two double bonds was ob-
tained; (iii) in all cases, the intramolecular conjugate addi-
tion of the intermediate secondary amine on the remaining
double bond takes place efficiently while no intermolecular
addition of a secondary amine could be observed in compa-
rable conditions. Note also that resorting to 2-aminoethanol
6a led to the double addition of the amine while no lactoni-
zation was observed. The corresponding aminoalcohol 7a
was recovered in 52% yield after 24 h at 15 kbar and room
temperature.
We next wondered whether the combination of binucleo-
philes and bielectrophiles could afford polycyclic molecules
in a single hyperbaric step. Thus, diamines 6 and diester 4 in
methanol were put under 15 kbar at room temperature. The
tricyclic derivatives 7b–d were isolated in reasonable yields
(Scheme 3). It is worth underlining that: (i) the same reaction
can be performed under atmospheric pressure at refluxing
methanol. However, the conversion rate is only 50% after
one week; (ii) neither in the case of 6b nor in that of 6d,
any product resulting from the double aza-Michael addition
Extending this reaction to binucleophiles in which longer
tethers separate the two primary amines revealed impossible.
Actually, two separate additions take place leading to
dimeric bridged structures, a supplementary lactam ring clo-
sure occurring with diethylenetriamine (Scheme 4). How-
ever, these reactions lead to large amounts of polymeric
Figure 3. 13C (150 MHz) spectrum of 7c at variable temperature.

5414
A. Yu. Rulev et al. / Tetrahedron 62 (2006) 5411–5416
materials, adducts 8 and 9 being recovered in 10 and 16%,
respectively.
the corresponding products. The following compounds were
all prepared according to this procedure.
Some physicochemical properties of tricyclic derivatives
7b–d deserve comments. First, the floppiness of their seven-
4.2.1. Methyl 2-[1-(benzylamino)-4-(tert-butyl)cyclo-
hexyl]acetate (2a). Oil. IR (KBr, n, cmꢀ1): 1731 (C]O).
1H NMR (CDCl3): d 0.91 (s, 9H), 1.25–1.07 (m, 3H), 1.47
(br t, 2H), 1.77 (br d, 2H), 1.89 (br d, 2H), 2.67 (s, 2H),
3.73 (s, 3H), 3.79 (s, 2H), 7.82–7.24 (m, 5H). 13C NMR
(CDCl3): d 23.8 (C(CH3)3), 27.9 (C(CH3)3), 32.7, 37.1
(CH2 cycl.), 44.1 (Cq), 46.2 (CH2CO), 48.3 (CH), 51.7
(CH3O), 55.0 (NCH2), 127.9, 128.8, 129.1, 141.6 (C6H5),
172.9 (C]0). MS (CI) m/z (relative intensity): 318
(M++1), 244 (7), 106 (20), 91 (60), 57 (100). Calcd for
C20H32NO2: C, 75.67; H, 9.84; N, 4.41; found C, 75.65; H,
9.89; N, 4.49.
1
membered ring lactams is associated to poorly resolved H
and 13C NMR spectra at room temperature. At 255 K, a
dramatic improvement of the resolution was observed (see
for instance the 20–40 ppm region of the 13C NMR spectrum
of 7c in Fig. 3).
Interestingly, an elemental analysis revealed that the folded
lactamic ring traps one molecule of water. This stable clus-
ter can be dehydrated in refluxing benzene using a Dean–
Stark apparatus. The water removal could be confirmed by
a quick IR spectrum recording as well as by elemental anal-
ysis. The ability of this highly chelating ring to trap polar
molecules (and ions?) could be of interest in the perspective
of supramolecular applications.
4.2.2. Methyl 2-[4-(tert-butyl)-1-morpholinocyclohexyl]
acetate (2b). Oil. H NMR (CDCl3): d 0.77 (s, 9H), 0.90–
1
1.15 (m, 3H), 1.30 (br t, 2H), 1.63 (br d, 2H), 1.85 (br d,
2H), 2.43 (s, 2H), 2.50–2.60 (m, 4H), 3.50–3.60 (m, 4H),
3.57 (s, 3H). 13C NMR (CDCl3): d 23.62 (C(CH3)3), 27.58
(C(CH3)3), 32.32, 37.42 (CH2 cycl.), 36.82 (Cq), 45.84
(CH2CO), 47.67 (CH), 51.24 (CH3O), 58.70 (NCH2),
68.10 (OCH2), 172.70 (C]O).
3. Conclusion
In conclusion, the conjugate addition of primary amines on
a,b-unsaturated b,b-disubstituted esters can be efficient
under hyperbaric conditions, even in the case of b,b-disub-
stituted esters reacting with secondary amines. Resorting to
N,N-binucleophiles and bielectrophiles such as diester 4
leads to polycyclic lactams in reasonable yields through
a yet unknown double aza-Michael step. Extensions of
these results to other substrates, their application to the
synthesis of skeletons of biological relevance, and efforts
toward an asymmetric version18 of this tandem reaction are
in progress.
4.2.3. Methyl 2-[4-(tert-butyl)-1-methoxycyclohexyl]
1
acetate (2c). Oil. IR (KBr, n, cmꢀ1): 1741 (C]O). H
NMR (CDCl3): (major diastereomer): d 0.83 (s, 9H), 1.00–
1.10 (m, 2H), 1.30–1.50 (m, 2H), 1.70–1.80 (m, 2H), 1.90–
2.00 (m, 2H), 2.58 (s, 2H), 3.26 (s, 3H), 3.66 (s, 3H); (minor
diastereomer): d 0.82 (s, 9H), 1.20–1.35 (m, 7H), 1.45–1.55
(m, 2H), 1.90–2.00 (m, 2H), 2.42 (s, 2H), 3.19 (s, 3H), 3.65 (s,
3H). 13C NMR (CDCl3): (major diastereomer): d 24.31 (CH2
cycl.), 27.77 (CH3, But), 35.20 (CH2 cycl.), 37.56 (CH2CO),
47.69 (CH), 49.09 (OCH3), 51.70 (OCH3), 76.20 (C–O
cycl.), 171.76 (C]O); (minor diastereomer): d 22.26 (CH2
cycl.), 27.72 (CH3, But), 34.60 (CH2 cycl.), 43.04
(CH2CO), 47.50 (CH), 48.93 (OCH3), 51.70 (OCH3), 74.14
(C–O cycl.), 171.51 (C]O). MS (EI) m/z (relative intensity):
210 (16, M+ꢀCH3OH), 169 (49), 143 (98), 57 (100). Calcd
for C14H26O3: C, 69.38; H, 10.81; found C, 69.19; H, 10.72.
4. Experimental
4.1. General
1H NMR spectra were recorded at 300 (default) or 600 (spec-
ified) MHz and 13C NMR spectra at 75 (default) or 150 (spec-
ified) MHz; chemical shifts (d) are given in parts per million
(ppm) and the coupling constants (J) in hertz. The solvent
was deuterochloroform. IR spectra were recorded by trans-
mission. The mass spectra under electron impact conditions
(EI) were recorded at 70 eVionizing potential; ammonia was
used for chemical ionization (CI). The silica gel used for flash
chromatography was 230–400 mesh. High pressure reactions
were performed in a piston–cylinder type apparatus, de-
signed for pressures up to 20 kbar. All reagents were of re-
agent grade and were used as such or distilled prior to use.
Methyl 4-tert-butylcyclohexylidene acetate 1 and diester 4
were prepared as reported previously.13,14a
4.2.4. 4-(tert-Butyl)-10-methyl-7,10-diazaspiro[5,6]dode-
can-11-one (3a). Solid. Mp 148 ꢁC. IR (KBr, n, cmꢀ1):
1624 (C]O), 3309 (NH). H NMR (CDCl3): d 0.81 (s,
1
9H), 0.90–1.15 (m, 2H), 1.04 (dt, J¼3.0, 13.5 Hz, 2H),
1.45–1.85 (m, 5H), 2.54 (s, 2H), 2.85–2.90 (m, 2H), 2.95
(s, 3H), 3.35–3.40 (m, 2H). 13C NMR (CDCl3): d 22.02
(CH2 cycl.), 27.69 (C(CH3)3), 32.50 (C(CH3)3), 36.10
(NCH3), 42.30 (CH2 cycl.), 47.83 (C4), 50.20 (C3), 52.98
(CH2N), 53.79 (CH2N), 173.33 (C]O). MS (EI) m/z (rela-
tive intensity): 252 (38, M+), 237 (18), 153 (100). Calcd
for C15H28N2O: C, 71.38; H, 11.18; N, 11.10; found C,
71.24; H, 11.26; N, 11.08.
4.2. Typical procedure for the treatment of esters 1 and 4
with amines and binucleophiles
4.2.5. 3-(tert-Butyl)-10-methyl-7,10-diazaspiro[5,6]dode-
1
can-11-one (3b). Solid. Mp 110 ꢁC. H NMR (600 MHz,
CDCl3): d 0.79 (s, 9H), 1.01 (m, 1H), 1.32 (m, 4H), 1.74
(br s, 2H), 1.97 (br d, J¼7.3 Hz, 2H), 2.80 (s, 2H), 3.06 (s,
3H), 3.13 (t, J¼4.6 Hz, 2H), 3.55 (br s, 2H), 5.10 (br s,
1H). 13C NMR (CDCl3): d 23.28 (CH2 cycl.), 27.67
(C(CH3)3), 32.44 (C(CH3)3), 35.94 (NCH3), 42.19 (CH2
cycl.), 43.67 (C4), 47.86 (C3), 51.76 (CH2N), 53.00
A solution of the ester (1 mmol) and amine or binucleophile
(1 mmol) in methanol (1–1.5 mL) was allowed to stand
under 11–15 kbar at room temperature. After reversion to
atmospheric pressure, the solvent was evaporated. The
residue was chromatographed (CH2Cl2/MeOH 9:1) to yield

A. Yu. Rulev et al. / Tetrahedron 62 (2006) 5411–5416
5415
(CH2N), 172.14 (C]O). MS (EI) m/z (relative intensity):
252 (35, M+), 237 (18), 153 (100).
2.56 (s, 2H), 2.60 (br s, 2H), 2.77 (br s, 2H), 3.35 (br s,
2H), 3.63 (s, 3H), 6.88 (br s, 1H); (T¼255 K): d 1.50–1.90
(m, 8H, CH2-10–CH2-13), 2.37, 2.89 (2m, 2H, CH2-4),
2.54, 3.13 (2m, CH2-2), 2.64 (s, 2H, CH2-7), 3.32, 3.53
(2m, 2H, CH2-5), 3.70 (s, 3H, OCH3), 7.58 (br s, 1H). 13C
NMR (150 MHz, CDCl3, T¼298 K): d 33.35 (br s, C-10–
C-13), 38.84 (C-7), 41.69 (C-5), 42.18 (C-2), 46.03 (C-4),
51.82 (OCH3), 63.25 (C-3), 67.68 (C-6), 171.56 (C-8),
175.05 (C-1); (T¼255 K): d 29.96, 32.40, 33.77, 36.77 (C-
10–C-13), 38.68 (C-7), 41.53 (C-2), 45.69 (C-4), 41.85 (C-
5), 52.00 (OCH3), 63.01 (C-3), 67.54 (C-6), 171.62 (C-8),
175.50 (C-1). MS (EI) m/z (relative intensity): 252 (35,
M+), 224 (30), 179 (37), 165 (100). Calcd for C13H20N2O3:
C, 61.88; H, 7.99; N, 11.10; found C, 61.93; H, 8.03; N,
10.89.
4.2.6. Methyl 2-[7-benzyl-4-(2-methoxy-2-oxoethyl)-7-
azabicyclo[2.2.1]hept-1-yl]acetate (5a). Solid. Mp 65–
66 ꢁC. IR (KBr, n, cmꢀ1): 1751 (C]O). 1H NMR
(CDCl3): d 1.64–1.78 (m, 8H), 2.44 (s, 2H), 3.52 (s, 2H),
3.56 (s, 6H), 7.10–7.40 (m, 5H). 13C NMR (CDCl3):
d 33.90 (CH2 cycl.), 40.50 (CH2), 46.80 (NCH2), 51.80
(OCH3), 67.40 (C cycl.), 126.70, 128.10, 128.50, 142.10
(C6H5), 172.10 (C]O). MS (EI) m/z (relative intensity):
331 (1, M+), 272 (2), 258 (12). Calcd for C19H25NO4: C,
68.86; H, 7.60; N, 4.23; found C, 68.94; H, 7.59; N, 4.28.
4.2.7. Methyl 2-[7-(4-methoxybenzyl)-4-(2-methoxy-2-
oxoethyl)-7-azabicyclo[2.2.1]hept-1-yl]acetate (5b).
1
Solid. Mp 62–64 ꢁC. IR (KBr, n, cmꢀ1): 1742 (C]O). H
4.2.11. Methyl 2-(5-methyl-6-oxo-2,5-diazatricyclo
[6.2.2.02.8]dodec-1-yl)acetate (7c).
NMR (CDCl3): d 1.63–1.78 (m, 8H), 2.46 (s, 2H), 3.47 (s,
2H), 3.59 (s, 6H), 3.77 (s, 3H), 6.82–7.27 (dd, J¼8.7 Hz,
4H). 13C NMR (CDCl3): d 33.90 (CH2 cycl.), 40.50 (CH2),
46.20 (NCH2), 51.80 (OCH3), 55.60 (OCH3 phenyl), 67.30
(C cycl.), 113.90, 129.10 (C6H5), 172.20 (C]O). MS (EI)
m/z (relative intensity): 361 (34, M+), 330 (2), 232 (31),
121 (100). Calcd for C20H27NO5: C, 66.46; H, 7.53; N,
3.88; found: C, 66.65; H, 7.66; N, 4.02.
14
N
5
1
4
O
2
N
3
7
6
11
12
13
8
O
9
10
O
4.2.8. Methyl 2-[7-(2,2-dimethoxyethyl)-4-(2-methoxy-2-
oxoethyl)-7-azabicyclo[2.2.1]hept-1-yl]acetate (5c). Oil.
IR (KBr, n, cmꢀ1): 1747 (C]O). 1H NMR (CDCl3):
d 1.64–1.78 (m, 8H), 2.38 (d, J¼4.9 Hz, 1H), 2.64 (s, 2H),
3.37 (s, 6H), 3.65 (s, 6H), 4.22 (t, J¼4.9 Hz, 2H). 13C
NMR (CDCl3): d 33.70 (CH2 cycl.), 40.40 (CH2), 46.10
(NCH2), 51.90 (OCH3), 55.20 (OMe), 67.50 (C cycl.),
106.40 (CHO), 172.30 (C]O). MS (EI) m/z (relative inten-
sity): 298 (4, [MꢀMeO]+), 254 (100), 224 (6), 193 (15), 151
(17). Calcd for C16H27NO6: C, 58.34; H, 8.26; N, 4.25;
found C, 58.07; H, 8.31; N, 4.32.
1
Solid. IR (KBr, n, cmꢀ1): 1650, 1736 (C]O). H NMR
(600 MHz, CDCl3, T¼298 K): d 1.45–1.75 (m, 8H), 2.56
(s, 2H), 2.60 (br s, 2H), 2.82 (br s, 2H), 2.96 (s, 3H), 3.50
(br s, 2H), 3.64 (s, 3H); (T¼255 K): d 1.50–1.80 (m, 8H,
CH2-10,11,12,13), 2.40, 2.90 (2m, 2H, CH2-4), 2.65, 3.12
(2m, 2H, CH2-2), 2.67 (s, 2H, CH2-7), 2.96 (s, 3H), 3.30,
3.85 (2m, 2H, CH2-5), 3.64 (s, 3H, OCH3). 13C NMR
(150 MHz, CDCl3, T¼298 K):
d 33.37 (br s, C-
10,11,12,13), 36.04 (NCH3), 38.81 (C-7), 42.21 (C-2),
44.23 (C-4), 50.74 (C-5), 51.81 (OCH3), 63.58 (C-3), 67.46
(C-6), 171.56 (C-8), 172.03 (C-1); (T¼255 K): d 29.89,
32.40, 33.77, 36.77 (C-10,11,12,13), 36.01 (NCH3), 38.61
(C-7), 41.92 (C-2), 43.98 (C-4), 50.44 (C-5), 51.97
(OCH3), 63.34 (C-3), 67.31 (C-6), 171.59 (C-8), 172.01
(C-1). MS (EI) m/z (relative intensity): 266 (59, M+), 238
(42), 193 (63), 179 (100); (CI) m/z (relative intensity): 267
(100, MH+). Calcd for C14H22N2O3: C, 63.13; H, 8.33; N,
10.52; found C, 63.03; H, 8.39; N, 10.27.
4.2.9. Methyl 2-[7-(2-hydroxyethyl)-4-(2-methoxy-2-
oxoethyl)-7-azabicyclo[2.2.1]hept-1-yl]acetate (7a).
Oil. IR (KBr, n, cmꢀ1): 1737 (C]O), 3449 (OH). 1H NMR
(CDCl3): d 1.63 (br s, 8H), 2.45 (t, J¼5.3 Hz, 2H), 2.61 (s,
4H), 3.46 (t, J¼5.3 Hz, 2H), 3.60 (br s, 1H), 3.64 (s, 6H).
13C NMR (CDCl3): d 33.40 (CH2 cycl.), 39.48 (CH2), 43.69
(NCH2), 51.80 (OCH3), 61.36 (C cycl.), 67.29 (OCH2),
171.73 (C]O). MS (EI) m/z (relative intensity): 254 (100,
M+ꢀCH3OH), 198 (25); (CI) m/z (relative intensity): 286
(100, M+), 254 (17, M+ꢀCH3OH). Calcd for C14H23NO5:
C, 58.93; H, 8.12; N, 4.91; found C, 58.89; H, 8.16; N, 4.92.
7c$1H2O: Solid. IR (KBr, n, cmꢀ1): 1650, 1736 (C]O),
3467 (OH). 1H NMR (CD3CN, T¼298 K): d 1.45–1.75 (m,
8H), 2.20 (br s, 2H), 2.56 (s, 2H), 2.60 (br s, 2H), 2.82 (br
s, 2H), 2.96 (s, 3H), 3.50 (br s, 2H), 3.64 (s, 3H);
(T¼323 K): d 1.50–1.80 (m, 8H, CH2-10–CH2-13), 2.10
(br s, 2H), 2.40, 2.90 (2m, CH2-4), 2.62 (s, 2H, CH2-7),
2.65, 3.12 (2m, 2H, CH2-2), 2.96 (s, 3H, NCH3), 3.30,
3.85 (2m, 2H, CH2-5), 3.64 (s, 3H, OCH3); ((CD3)2CO,
T¼298 K): d 1.45–1.75 (m, 8H), 2.20 (br s, 2H), 2.56 (s,
2H), 2.60 (br s, 2H), 2.77 (br s, 2H), 2.82 (br s, 2H), 2.96
(s, 3H), 3.50 (br s, 2H), 3.64 (s, 3H); (T¼323 K): d 1.50–
1.80 (m, 8H, CH2-10–CH2-13), 2.10 (br s, 2H), 2.40, 2.90
(2m, CH2-4), 2.47 (br s, 2H), 2.62 (s, 2H, CH2-7), 2.65,
3.12 (2m, 2H, CH2-2), 2.96 (s, 3H, NCH3), 3.30, 3.85 (2m,
2H, CH2-5), 3.64 (s, 3H, OCH3). Calcd for C14H24N2O4:
C, 59.13; H, 8.51; N, 9.85; found C, 58.91; H, 8.43; N, 9.75.
4.2.10. Methyl 2-(6-oxo-2,5-diazatricyclo[6.2.2.02.8]-
dodec-1-yl)acetate (7b).
NH
5
1
4
O
2
N
3
7
6
11
12
13
8
O
9
10
O
Solid. Mp 151 ꢁC. IR (KBr, n, cmꢀ1): 1660, 1732 (C]O). 1H
NMR (600 MHz, CDCl3, T¼298 K): d 1.50–1.80 (m, 8H),

5416
A. Yu. Rulev et al. / Tetrahedron 62 (2006) 5411–5416
2. (a) Ponsford, R. J.; Roberts, P. M.; Southgate, R. J. Chem.
Soc., Chem. Commun. 1979, 846–847; (b) Nagao, Y.;
Kumagai, T.; Tamai, S.; Matsunaga, H.; Abe, T.; Inoue, Y.
Heterocycles 1996, 42, 849–859; (c) Bossio, R.; Marcos,
C. F.; Marcaccini, S.; Pepino, R. Tetrahedron Lett. 1997, 38,
2519–2520; (d) Palomo, C.; Aizpurua, J. M.; Ganboa, I.;
Odriozola, B.; Urchegui, R.; Goerls, H. Chem. Commun.
1996, 1269–1271.
3. (a) Manhas, M. S.; Chib, J. S.; Chiang, Y. H.; Bose, A. K. Tet-
rahedron 1969, 25, 4421–4426; (b) Ishibashi, H.; Higuchi, M.;
Ohba, M.; Ikeda, M. Tetrahedron 1983, 39, 75–82; (c) Ikeda,
M.; Ohtani, S.; Yamamoto, T.; Sato, T.; Ishibashi, H.
J. Chem. Soc., Perkin Trans. 1 1998, 1763–1768.
4.2.12. Methyl 2-(4,4-dimethyl-7-oxo-2,6-diazatricyclo-
[7.2.2.02.9]tridec-1-yl)acetate (7d).
1
2
4
3
H
O
N
5
16
8
14
N
13
12
O
15
O
6
7
10
9
11
Solid. Mp 179 ꢁC. IR (KBr, n, cmꢀ1): 1661, 1736 (C]O),
31.98, 32.91 (NH). 1H NMR (600 MHz, CDCl3, T¼260 K)
major isomer: d 0.80 (s, 3H), 0.90 (s, 3H), 1.45–1.75 (m,
8H, CH2-9–CH2-12), 1.83 (A-part of AB system,
J¼14.8 Hz, 1H), 2.04 (B-part of AB system, J¼14.8 Hz,
1H), 2.40 (A-part of AB system, J¼13.2 Hz, 1H), 2.56 (m,
2H), 2.60 (d, J¼4.4 Hz, 1H), 2.88 (B-part of AB system,
J¼13.2 Hz, 1H), 3.38 (dd, J¼14.8, 11.1 Hz, 1H), 3.67 (s,
3H), 6.62 (br s, 1H); minor isomer: d 0.78 (s, 3H), 0.98 (s,
3H), 1.45–1.75 (m, 8H, CH2-9–CH2-12), 2.06 (A-part of
AB system, J¼14.8 Hz, 1H), 2.24 (B-part of AB system,
J¼14.8 Hz, 1H), 2.29 (A-part of AB system, J¼13.0 Hz,
1H), 2.54 (m, 2H), 2.72 (d, J¼7.2 Hz, 1H), 2.75 (B-part of
AB system, J¼13.0 Hz, 1H), 3.20 (dd, J¼13.5, 7.2 Hz,
1H), 3.67 (s, 3H), 6.70 (br s, 1H). 13C NMR (150 MHz,
CDCl3, T¼298 K) major isomer: d 23.16, 24.01 (C-1, C-2),
30.54 (C-9 or C-11), 32.73 (C-10 or C-12), 33.70 (C-10 or
C-12), 36.57 (C-3), 38.08 (C-9 or C-11), 39.99 (C-14),
40.15 (C-6), 48.79 (C-8), 50.51 (C-4), 51.40 (C-16), 67.46
(C-7), 68.11 (C-13), 171.75 (C-15), 174.93 (C-5); minor iso-
mer: d 22.05, 27.03 (C-1, C-2), 32.18, 33.31, 33.87, 34.58 (C-
9–C-11), 35.33 (C-3), 36.57 (C-6), 39.99 (C-14), 51.40
(C-16), 53.53 (C-8), 54.76 (C-4), 67.16 (C-13), 67.86 (C-7),
171.82 (C-15), 174.33 (C-5). MS (EI) m/z (relative intensity):
294 (11, M+), 265 (42), 221 (100). Calcd for C16H26N2O3: C,
65.28; H, 8.90; N, 9.52; found C, 65.02; H, 8.97; N, 9.48.
4. For an elegant enantioselective synthesis of this compound,
see: Kambara, T.; Tomioka, K. J. Org. Chem. 1999, 64,
9282–9285.
5. Review about b-aminoesters as peptido mimetics: Steer, D. L.;
Lew, R. A.; Perlmutter, P.; Smith, A. I.; Aguilar, M.-I. Curr.
Med. Chem. 2002, 9, 811–822; About a,b-diamino acids:
´
Viso, A.; Fernandez de la Pradilla, R.; Garcıa, A.; Flores, A.
Chem. Rev. 2005, 105, 3167–3196.
´
6. See for instance: Gonzalez, J.; Koontz, J. I.; Hodges, L. M.;
Nilsson, K. R.; Neely, L. K.; Myers, W. H.; Sabat, M.; Harman,
W. D. J. Am. Chem. Soc. 1995, 117, 3405–3421.
7. See for instance: (a) Ellis, J. L.; Harman, D.; Gonzalez, J.;
Spera, M. L.; Liu, R.; Shen, T. Y.; Wypij, D. M.; Zuo, F.
J. Pharmacol. Exp. Ther. 1999, 288, 1143–1150; (b) Boyce,
S.; Webb, J. K.; Shepheard, S. L.; Russell, M. G. N.; Hill,
R. G.; Rupniak, N. M. J. Pain 2000, 85, 443–450; (c) Kassiou,
M.; Bottlaender, M.; Loc’h, C.; Dolle, F.; Musachio, J. L.;
Coulon, C.; Ottaviani, M.; Dannals, R. F.; Maziere, B.
Synapse 2002, 45, 95–104.
8. (a) Xu, L.-W.; Xia, C.-G. Eur. J. Org. Chem. 2005, 633–639;
(b) Ma, J.-A. Angew. Chem., Int. Ed. 2003, 42, 4290–4299;
(c) Gorobets, E. N.; Miftakhov, M. S.; Valeev, F. A. Russ.
Chem. Rev. 2000, 69, 1001–1019; (d) Volontiero, A.; Bravo, P.;
Zanda, M. Org. Lett. 2000, 2, 1827–1830.
9. Pfau, M. Bull. Soc. Chim. Fr. 1967, 1117–1125.
10. For an extensive and recent review, see: Davies, S. G.; Smith,
A. D.; Price, P. D. Tetrahedron: Asymmetry 2005, 16, 2833–
2891.
11. (a) D’Angelo, J.; Maddaluno, J. J. Am. Chem. Soc. 1986, 108,
8112–8114; (b) Jenner, G. Tetrahedron 1996, 52, 13557–
13568.
1
Compound 8: Solid. IR (KBr, n, cmꢀ1): 1738 (C]O). H
NMR (CDCl3): d 1.55–1.80 (m, 16H), 2.39 (s, 8H), 3.47
(AB system, 4H), 3.52 (s, 12H), 7.10–7.25 (m, 4H). 13C
NMR (CDCl3): d 33.70 (CH2 cycl.), 40.34 (CH2), 46.70
(NCH2), 51.60 (OCH3), 67.12 (C cycl.), 126.19, 127.11,
128.12, 141.64 (C6H4), 171.98 (C]O). MS (EI) m/z (rela-
tive intensity): 584 (100, M+), 553 (43), 511 (32).
12. Jenner, G. New J. Chem. 1995, 19, 173–178.
13. Rulev, A. Y.; Maddaluno, J. J. Phys. Org. Chem. 2002, 15,
590–598.
Compound 9: Solid. IR (KBr, n, cmꢀ1): 1650, 1736 (C]O).
1H NMR (CDCl3): d 1.51–1.70 (m, 16H), 2.36 (t, J¼2.6 Hz,
2H), 2.59 (br s, 2H), 2.68 (br s, 6H), 2.75–2.85 (m, 2H),
3.25–3.35 (m, 2H), 3.55–3.65 (m, 2H), 3.65 (s, 6H), 3.66
(s, 3H). 13C NMR (CDCl3): d 33.51 (br s, C-10–C-13),
38.75, 39.70 (CH2C(O)O), 40.23 (CH2CON), 42.31, 45.12,
50.23, 51.00 (CH2N), 51.71, 51.83 (OCH3), 63.61, 67.27,
67.56 (Cq), 171.53, 171.83, 171.88 (C]O). MS (EI) m/z
(relative intensity): 519 (5, M+), 488 (10), 254 (100).
´
14. (a) Rulev, A. Y.; Maddaluno, J.; Ple, G.; Plaquevent, J.-C.;
Duhamel, L. J. Chem. Soc., Perkin Trans. 1 1998, 1397–1401;
(b) Rulev, A. Y.; Maddaluno, J. Eur. J. Org. Chem. 2001,
2569–2576.
15. Rulev, A. Y.; Maddaluno, J. Unpublished results.
16. Bryce, M. R.; Coates, H. M.; Cooper, J.; Murphy, L. C. J. Org.
Chem. 1984, 49, 3399–3401.
17. Villieras, J.; Rambaud, M. Synthesis 1983, 300–303.
18. For reviews on the asymmetric aza-Michael addition on
esters and amides, see Refs. 1 and 11, as well as: (a) Cole,
D. C. Tetrahedron 1994, 50, 9517–9582; (b) Enantioselec-
tive Synthesis of b-aminoacids, 2nd ed.; Juaristi, E.,
Soloshonok, V. A., Eds.; Wiley-VCH: Hoboken, NJ, USA,
2005; (c) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56,
8033–8061.
References and notes
1. Cardillo, G.; Tomasini, C. Chem. Soc. Rev. 1996, 25, 117–128
and references therein.