Stereoselective synthesis and conformational analysis of cis-5-(2-nitrophenyl)-2-azabicyclo[3.3.0]octan-6-ones

Article abstract of DOI:10.1016/S0040-4020(01)00529-4

A short route to cis-5-(2-nitrophenyl)-2-azabicyclo[3.3.0]octanes involving ozonolysis of 2-allyl-2-(2-nitrophenyl)-1,3-cyclopentanedione followed by double reductive amination is described. The preferred conformations of the azabicyclic ring system in these compounds are reported.

Full text of DOI:10.1016/S0040-4020(01)00529-4

TETRAHEDRON
Pergamon
Tetrahedron 57 )2001) 6011±6017
Stereoselective synthesis and conformational analysis
of cis-5-ꢀ2-nitrophenyl)-2-azabicyclo[3.3.0]octan-6-ones
p
Josep Bonjoch, Daniel Sole, Rosalina Carrillo, Emma Peidro and Joan Bosch
Â
Â
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, 08028 Barcelona, Spain
Received 8 November 2000; revised 25April 2001; accepted 10 May 2001
AbstractÐA short route to cis-5-)2-nitrophenyl)-2-azabicyclo[3.3.0]octanes involving ozonolysis of 2-allyl-2-)2-nitrophenyl)-1,3-cyclo-
pentanedione followed by double reductive amination is described. The preferred conformations of the azabicyclic ring system in these
compounds are reported. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The 5-aryl-2-azabicyclo[3.3.0]octane framework I1 is found
in the Melodinus quinoline alkaloids2 )e.g. meloscine), in
the vindolinine group of indole alkaloids3 )e.g. tuboxenine),
and in the structurally unique compound calebassinine-1.4
The only total synthesis for these monoterpenoid alkaloids
reported thus far is Overman's synthesis of meloscine
)Fig. 1).5,6
2.1. Synthesis of 5-ꢀ2-nitrophenyl)-2-azabicyclo[3.3.0]-
octan-6-ones
The synthetic approach to 5-)2-nitrophenyl)-2-azabicyclo-
[3.3.0]octane derivatives here described is based on an
extension of our previous work on the synthesis of 3a-)2-
nitrophenyl)octahydroindol-4-ones,11 a class of compounds
that have proved to be useful intermediates for the total
synthesis of Strychnos alkaloids12 including strychnine
itself.13
In this paper, we describe a synthetic entry to 5-)2-nitro-
phenyl)-2-azabicyclo[3.3.0]octan-6-ones, which were envis-
aged as the starting building blocks for the synthesis of the
afore-mentioned alkaloids, since they incorporate three of
their rings and possess suitable functionalities for assem-
bling the rest of the skeleton.
Our approach involves the elaboration of the pyrrolidine
ring by introduction of the amino moiety by a double
reductive amination process: ®rst, in an intermolecular
way )N2±C3 bond formed), upon the aldehyde of the tricar-
bonyl derivative resulting from the ozonolysis of 2-allyl-2-
)2-nitrophenyl)-1,3-cyclopentanedione and then, in an
Four procedures have been described for the preparation of
compounds with the framework I )Scheme 1): )i) Overman7
exploited the tandem cationic aza-Cope rearrangement/
Mannich cyclization for the preparation of this type of
compounds using 2-amino-1-)1-arylvinyl)cyclobutanols as
intermediates )last bond formed C1±C5). )ii) Remuson8
used the cyclization of an allylsilane upon an a-acyli-
minium salt )last bond formed C1±C8). )iii) Baldwin's9
key step consisted of an intramolecular nitrone/alkene
cycloaddition, followed by reduction of the labile N±O
bond and lactamization. )iv) Pearson10 formed the azabi-
cyclic system by a [312]cycloaddition promoted by a
2-azaallyl anion upon an alkene. It is noteworthy that
none of these routes incorporate a functionalization in the
aryl group which can be further elaborated into indoline or
quinoline units.
Keywords: amination; conformation; cyclopentanones; nitro compounds;
nitrogen heterocycles.
p
Corresponding author. Tel.: 134-93-402-4540; fax: 134-93-402-1896;
e-mail: bonjoch@farmacia.far.ub.es
Figure 1.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020)01)00529-4

6012
J. Bonjoch et al. / Tetrahedron 57 +2001) 6011±6017
Scheme 1. Synthetic approaches to cis-5-aryl-2-azabicyclo[3.3.0]octanes.
intramolecular manner )C1±N2 bond formed), upon one of
the two enantiotopic ketone carbonyl groups.
converted to the a,a-disubstituted cyclopentanedione 3 in
70% overall yield.
Direct arylation of 1,3-cyclopentanedione14 by a nucleo-
philic aromatic substitution reaction, using potassium car-
bonate as a base and 2-iodonitrobenzene as the arylating
agent in DMSO )85±908C, 3 h), afforded dione 1 in 61%
yield, the enolic form being the favoured tautomer )Scheme
2). As in the cyclohexanedione series,11 the elaboration of
the quaternary carbon center was accomplished by O-allyl-
ation and subsequent Claisen rearrangement. Thus, treat-
ment of dione 1 with allyl bromide and K2CO3 provided
allyl vinyl ether 2, which, on heating at 1908C, was
Having obtained the prochiral dione 3, we undertook the
elaboration of the pyrrolidine ring. Thus, ozonolysis of the
allyl group of dione 3, followed by reaction of the ozonide
intermediate with methylamine hydrochloride and sodium
cyanoborohydride, stereoselectively gave the cis azabicyclo
derivative 4a in 66% yield. As a minor by-product dione 5a
was isolated from the reaction of the secondary amine inter-
mediate with the formaldehyde formed during the reduction
of the ozonide. This competing process, not observed
in the 1,3-cyclohexanedione series, indicates that in the
Scheme 2. Synthesis of 5-)2-nitrophenyl)-2-azabicyclo[3.3.0]octan-6-ones.

J. Bonjoch et al. / Tetrahedron 57 +2001) 6011±6017
6013
and 4f were prepared by reaction of 7 with propargyl
bromide and )Z)-1-bromo-2-iodo-2-butene, respectively.
2.2. Spectroscopic analysis of azabicyclic derivatives
The stereochemistry of 4a was established by NMR, using
COSY and NOESY experiments, which allowed the cis
con®guration and the conformation depicted in Fig. 3 to
be determined. Strong through space interactions between
H-60 of the phenyl substituent and the N-methyl group, H-1,
H-3b and H-8b16 indicated that these groupings are all syn-
related. The half-chair cyclopentane conformation type-b17
can be deduced from the observation of H-1 as a doublet of
doublets )Jˆ5and 2 Hz) in the 1H NMR spectrum,
involving estimated dihedral angles near to 245and 75 8
between H-1 and the cis and trans H-8 hydrogens, repec-
tively. Thus, compound 4a must exist preferentially in a
conformation with the N-Me group on the b-face )trans to
C-8 and H-3a), the cis H-1 and H-3b hydrogens being
identically shielded by the syn-Me group and the anti
electron pair.18 The spectral data indicated that compound
4b as well as the propargyl derivative 4e and vinyl iodide 4f
have similar conformational characteristics )see Section 3
and Table 1).
Figure 2.
5,5-membered series the intramolecular attack of the
secondary amine upon the ketone carbonyl group is slower
than in the 6,5-membered series. Operating as above, but
using 2,2-dimethoxyethylamine as the aminocyclization
agent, azabicyclo 4b was isolated in 69% yield together
with small amounts of dione 5b.
The use of )S)-1-phenylethylamine15 in the sequence of
ozonolysis-double reductive amination from dione 3
afforded enantiopure cis azabicyclic compound 4c in 36%
yield together with minor amounts of the other cis derivative
4d, the diastereoselectivity of the process being analogous
to that observed in the 6,5-membered homoderivative.11 )for
the determination of the absolute con®guration of 4c, see
below) )Fig. 2).
The conformational behavior of enantiopure compounds 4c
and 4d was different with respect to the N-alkylderivatives
4a, 4b, 4e and 4f, since the cyclopentane ring changes
towards a preferred type-a17 half-chair conformation )dihe-
dral angles near to 45and 140 8), as can be deduced from the
coupling constants for H-1 )dd, Jˆ7.5and 5.5Hz). More-
over, the nitrogen lone pair is now located on the top face
and the bulky 1-phenylethyl substituent is on the concave,
sterically more congested, bottom face of the cis-azabi-
cyclo[3.3.0]octane ring system. The predominant conforma-
tion of 4c shown in Fig. 3 was con®rmed on the basis of 2D
NOE data, which in turn afforded diagnostic evidence for
the )1S,5R) con®guration of 4c.
The valuable secondary amine 7 was prepared from 4a by
treatment with a-)chloroethyl) chloroformate and subse-
quent heating of the resulting carbamate, 6 in a methanol
solution. Starting from enantiopure 4c, and following the
same procedure although with more drastic reaction con-
ditions, )2)-7 was obtained. Alkylation of the secondary
amine 7, introducing functionalized side chains upon the
nitrogen atom, broadens the access to 5-aryl-2-azabicyclo-
[3.3.0]octanone derivatives. For example, azabicyclos 4e
The NOESY experiment on 4c showed off-diagonal cross-
peaks connecting H-1 and H-8 with a methyl proton, thus
indicating their spatial proximity. The distance between
these protons would increase in the derivative with the
opposite con®guration at the ring junction. The NOESY
spectrum also showed interactions between the benzylic
proton and the C-3 and C-8 endo protons, thus corroborating
the absolute con®guration of 4c, which is the same as that
of alkaloids incorporating the cis-5-aryl-2-azabicyclo-
[3.3.0]octane subunit in their backbone )see Fig. 1).
Interestingly, the secondary amine 7 also adopts a type-a
half-chair conformation. Comparison of the 1H NMR
signals for H-3b )d 3.36) and H-1 )d 4.19) of secondary
amine 7 with the corresponding signals of N-methyl deriva-
tive 4a )H-3b d 2.74; H-1 d 3.35) showed that the N-methyl
group caused an up®eld shift in both of these hydrogens, as
expected from a conformational switch.
The most signi®cant differences in the 13C NMR data
)Table 1) that can be used to diagnose the preferred
conformation for azabicyclos 4)a±f), and 7 are the chemical
shifts of the carbonyl group. Compounds with type-a
Figure 3.

Table 1. 13C NMR chemical shifts of 5-)2-nitrophenyl)-2-azabicyclo[3.3.0]octan-6-ones
0
C-1
C-3
C-4
C-5C-6
C-7
C-8
C-1
C-20
C-30
C-40
C-50
C-60
4aa
4ba
4ca
4da
4ea
4fa
6a,b
7
74.1
73.4
70.9
71.2
70.7
71.6
55.3
54.3
49.534.3
49.8
51.9
35.0
35.6
63.2
62.6
217.1
216.3
21.0
215.3
216.0
217.2
36.0
21.9
22.9
133.9
134.2
149.7
149.5
132.9
148.4
149.5
149.5
125.1
125.2
130.5
125.1
125.2
125.1
127.9
127.9
132.4
132.6
130.1
130.1
36.3
136.3
36.4
36.2
35.4
.1 62.5215 36.7
34.8
35.0
1.148.5 125 127.8
62.4
62.9
62.9
61.7±62.9
64.2
22.9
23.1
22.3
136.3
134.2
134.0
127.8
127.9
127.9
133.9±134.4
128.0
132.8
132.5
132.5
128.7±1
133.2
130.3
130.1
130.4
51.5
35.3
31.4±32.4
36.1
67.8±68.546.0±46.8
70.6 46.5
210.6±212.1 .9±3536.1
215.0 37.1
26.7±27.8
26.9
133.9±134.4
135.4
147.2±147.7
148.0
126.3±126.5128.7±129.6
125.7
29.6
129.5
In ppm relative to TMS. Recorded at 50.3 MHz.
a
Substituent signals: 4a, 39.0 )NCH3); 4b, 53.2 )NCH2), 53.8 )OCH3), 103.3 )CH); 4c, 21.8 )CH3), 60.2 )NCHAr), 126.9 )CH), 128.3 )CH), 145.2 )C); 4d, 23.3 )CH3), 60.8 )NCHAr), 126.9 )CH), 128.3 )CH), 144.7 )C);
4e, 39.8 )NCH2), 73.0 )C), 78.4 )CH); 4f, 21.6 )CH3), 64.1 )N CH2), 109.1 )vCI), 131.4 )vCH); 6, 25.2±25.3 )CH3), 82.7±82.9 )OCHCl), 151.0±151.3 )NCOO).
In the description of the NMR data of this compound a hyphen is used to indicate that the spectrum is complex due to the existence of diastereomers and rotamers.
b

J. Bonjoch et al. / Tetrahedron 57 +2001) 6011±6017
6015
C-60
Table 2. 13C NMR chemical shifts of 2-)2-nitrophenyl)cyclopentanone derivatives 1±3 and 5
0
C-1
C-2
C-3
C-4
C-5C-1
C-20
C-30
126.9
C-40
131.9
128.1
128.8
C-50
131.5
132.6
134.1
1
184.0
201.3
209.6
209.7
209.6
113.5184.0
117.0
64.4
30.4
30.4
.4 125 148.4
123.7
2a
184.2
209.6
25.3
36.0
33.8
36.0
125.3
131.0
148.3
148.0
124.5
126.0
131.9
131.6
3a
5aa
5ba
63.5209.7513.05.365 35 147.5126.0
63.7 209.6 35.4
128.8
35.4
134.1
130.5
131.3
147.2
126.0
128.8
134.1
131.4
In ppm relative to TMS. Recorded at 50.3 MHz.
Substituent signals: 2, 70.7, 119.0, 131.5)OCH 2CHvCH2); 3, 36.8, 120.9, 130.0 )CH2CHvCH2); 5a, 30.3, 45.2, 53.5 )CH2CH2N)CH3)2); 5b, 29.4, 43.1,
52.0, 53.6, 58.5, 102.3 )CH2CH2N)CH3)CH2CH)OCH3)2).
a
conformation show the carbonyl carbon at a higher ®eld )d
215) than those with type-b conformation )d 216±217).
A mixture of dione 1 )5g, 22.8 mmol), anhydrous K 2CO3
)6.3 g, 45.5 mmol), and allyl bromide )2.25 ml, 26 mmol) in
anhydrous acetone )100 ml) was stirred at re¯ux tempera-
ture for 3 h. The solvent was removed, and the residue was
partitioned between water and CH2Cl2. The aqueous layer
was extracted with CH2Cl2. The combined organic extracts
were washed with water, dried, and concentrated to give an
oil, which was chromatographed )CH2Cl2) affording enol
ether 2 )4.7 g, 80%). IR )CHCl3) 1687, 1625, 1600, 1526,
1381, 1352 cm21. 1H NMR )300 MHz) d 2.65)m, 2H), 2.86
)m, 2H), 4.69 )dt, Jˆ5.4 and 1.5 Hz, 2H, CH2O), 5.32 )ddt,
Jˆ10.5, 2.5, and 1.5 Hz, 1H), 5.32 )ddt, Jˆ17.2, 2.5, and
1.5Hz, 1H), 5.94 )ddt, Jˆ17.2, 10.5, and 5.4 Hz, 1H), 7.43
The same conformational behavior of the more sterically
demanding compound 4c and the secondary amine 7
suggests that the steric factor alone is not responsible for
the conformational switch, the presence of the o-nitro
substituent being an important factor in the conformational
behavior of these compounds.
3. Experimental
3.1. General
0
)ddd, Jˆ8.2, 7.3, and 1.5Hz, 1H, H-4 ), 7.49 )dd, Jˆ7.8 and
0
1.5Hz, 1H, H-6 ), 7.60 )ddd, Jˆ7.8, 7.3, and 1.2 Hz, 1H, H-
50), 7.95)dd, Jˆ8.2 and 1.2 Hz, 1H, H-30). Anal. calcd for
C14H13NO4 )259.27): C, 64.85; H, 5.05; N, 5.40. Found: C,
64.49; H, 5.01; N, 5.43.
1H- and 13C NMR spectra )Tables 1 and 2) were recorded in
CDCl3 solution, using Me4Si as internal standard. Chemical
shifts are reported in ppm down®eld )d) from Me4Si. IR
spectra were recorded on a Nicolet 205FT infrared
spectrophotometer and only noteworthy absorptions are
listed. Melting points were determined in a capillary tube
and are uncorrected. Optical rotations were measured on a
Perkin±Elmer 241 polarimeter. TLC was carried out on
SiO2 )silica gel 60 F254, Merck), and the spots were located
with UV light, iodoplatinate reagent or 1% aqueous
KMnO4. Chromatography refers to ¯ash chromatography
and was carried out on SiO2 )silica gel 60, SDS, 230±400
mesh ASTM). Drying of organic extracts during workup of
reactions was performed over anhydrous Na2SO4. Evapora-
tion of solvents was accomplished with a rotatory evapora-
tor. Microanalyses were performed by Centro de
3.1.3. 2-Allyl-2-ꢀ2-nitrophenyl)-1,3-cyclopentanedione ꢀ3).
A solution of enol ether 2 )6 g, 23.1 mmol) in anhydrous
toluene )60 ml) was stirred at 180±1908C in a sealed tube
for 12 h. After the solvent was evaporated, the residue was
crystallized )EtOAc) affording dione 3 )5.28 g, 88%); mp
145±1468C )white needles). IR )KBr) 1724, 1523,
1
1353 cm21. H NMR )200 MHz) d 2.86 )d, Jˆ7 Hz, 2H,
CH2), 2.98 )s, 4H, CH2CO), 5.24 )dd, Jˆ10 and 1 Hz, 1H),
5.29 )dd, Jˆ17 and 1 Hz, 1H), 5.71 )ddt, Jˆ17, 10, and 7 Hz,
1H), 7.52 )td, Jˆ8 and 1.5Hz, 1H), 7.66±7.78 )m, 2H), 8.13
)dd, Jˆ8 and 1.5Hz, 1H). Anal. calcd for C 14H13NO4
)259.27): C, 64.85; H, 5.05; N, 5.40. Found: C, 64.56; H,
5.11; N, 5.35.
Â
Investigacion y Desarrollo )CSIC), Barcelona.
3.1.4. cis-2-Methyl-5-ꢀ2-nitrophenyl)-2-azabicyclo[3.3.0]-
octan-6-one ꢀ4a). A stirred solution of dione 3 )2.86 g,
11 mmol, 1 equiv.) in CH2Cl2 )100 ml) at 2788C was
charged with a constant stream of ozone. After 2.5h, the
solution turned characteristic pale blue and was purged with
oxygen. The solvent was removed with a rotatory evapo-
rator without warming, and the residue was dissolved in
MeOH )40 ml). To this solution were added ®rst a solution
of methylamine hydrochloride )3 g, 44 mmol, 4 equiv.)
in MeOH )50 ml) and then sodium cyanoborohydride
)345mg, 5.5mmol, 0.5equiv.). After being stirred for
30 min, an additional portion of sodium cyanoborohydride
)345mg, 5.5mmol, 0.5equiv.) was added and stirring was
continued for 1 h. At this time, an additional portion of
sodium cyanoborohydride )1 g, 16.5mmol, 1.5equiv.)
was added, and stirring was continued for 2.5h. The reac-
tion was quenched with 1N hydrochloric acid )30 ml) and
the stirring was continued for 30 min. After removal of the
3.1.1. 2-ꢀ2-Nitrophenyl)-1,3-cyclopentanedione ꢀ1). A
mixture of 1,3-cyclopentanedione )5g, 51 mmol), anhy-
drous K2CO3 )14 g, 102 mmol), and o-iodonitrobenzene19
)15.2 g, 61.2 mmol) in DMSO )50 ml) was heated to 85±
908C for 4 h. After cooling, the mixture was poured into
water. The resulting solution was acidi®ed with concen-
trated hydrochloric acid and extracted with CH2Cl2. The
combined organic extracts were washed with brine, dried,
and concentrated to give a brown foam, which was chro-
matographed )CH2Cl2 to CH2Cl2, 5% MeOH) affording
dione 1 )6.8 g, 61%). IR )KBr) 3500±2350, 1530,
1
1378 cm21. H NMR )300 MHz) d 2.64 )br, 4H, H-4 and
H-5), 7.38 )ddd, Jˆ8.1, 6.6, and 2.2 Hz, 1H), 7.52±7.63 )m,
2H), 7.90 )dd, Jˆ8.4 and 1 Hz, 1H). Anal. calcd for
C11H9NO4 )219.19): C, 61.80; H, 4.14; N, 6.39. Found: C,
61.88; H, 4.45; N, 5.97.
3.1.2. 3-Allyloxy-2-ꢀ2-nitrophenyl)-2-cyclopentenone ꢀ2).

6016
J. Bonjoch et al. / Tetrahedron 57 +2001) 6011±6017
methanol under reduced pressure, the aqueous mixture was
extracted with ether, and the organic layers were discarded.
The aqueous layer was made alkaline with solid K2CO3 and
extracted with CH2Cl2. The organic extracts were dried and
concentrated to give an oil, which was chromatographed.
Elution with CH2Cl2-1% MeOH afforded ketone 4a )1.9 g,
66%), whereas elution with CH2Cl2±3% MeOH gave
2-[2-)dimethylamino)ethyl]-2-)2-nitrophenyl)-1,3-cyclo-
pentanedione )5a, 140 mg, 5%).
)®lm) 1742, 1531, 1358 cm21. 1H NMR )500 MHz)16 d 1.34
)d, Jˆ7 Hz, 3H, CH3), 1.98 )m, 1H, H-8a), 2.12 )m, 1H,
H-8b), 2.19 )ddd, Jˆ15, 9.5, and 8 Hz, 1H, H-4), 2.42 )ddd,
Jˆ15, 8, and 4.5 Hz, 1H, H-4), 2.53 )ddd, Jˆ19, 10.5, and
7 Hz, 1H, H-7), 2.71 )ddd, Jˆ19, 10.5, and 5.5 Hz, 1H,
H-7), 2.79 )td, Jˆ9.5and 4.5Hz, 1H, H-3 a), 2.96 )dt,
Jˆ9.5and 8 Hz, 1H, H-3 b), 3.70 )q, Jˆ7 Hz, 1H,
NCHAr), 4.17 )dd, Jˆ7.5and .55Hz, 1H, H-1), 7.21±
7.33 )m, 5H, ArH), 7.44 )td, Jˆ8 and 1 Hz, 1H, H-40),
7.50 )dd, Jˆ8 and 1 Hz, 1H, H-60), 7.63 )td, Jˆ8 and
1 Hz, 1H, H-50), 7.87 )dd, Jˆ8 and 1 Hz, 1H, H-30). Anal.
calcd for C21H22N2O3 )350.04): C, 71.98; H, 6.33; N, 7.99.
Found: C, 71.74; H, 6.36; N, 7.96.
1
Ketone 4a: IR )®lm) 1738, 1530, 1363 cm21. H NMR
)500 MHz)16 d 1.95)dddd, Jˆ13.5, 9.5, 3, and 2 Hz, 1H,
H-8a), 2.02 )dddd, Jˆ14, 13.5, 9.5, and 5 Hz, 1H, H-8b),
2.36 )ddd, Jˆ19, 9.5, and 3 Hz, 1H, H-7), 2.36 )s, 3H,
NCH3), 2.36±2.40 )m, 2H, H-4), 2.61 )dt, Jˆ19 and
9.5Hz, 1H, H-7), 2.74 )q, Jˆ9 Hz, 1H, H-3b), 3.03 )ddd,
Jˆ9, 7, and 4 Hz, 1H, H-3a), 3.35)dd, Jˆ5and 2 Hz, 1H,
H-1), 7.36 )ddd, Jˆ8, 7.5, and 1.5 Hz, 1H, H-40), 7.38 )dd,
Ketone 4d: 1H NMR )300 MHz)16 d 1.39 )d, Jˆ6.6 Hz, 3H,
CH3), 2.02±2.16 )m, 2H), 2.23 )dt, Jˆ14.1 and 8.5Hz, 1 H,
H-4), 2.36±2.52 )m, 2H), 2.76 )ddd, Jˆ19, 10, and 6.6 Hz,
1H, H-7), 2.99 )td, Jˆ9.3 and 3.3 Hz, 1H, H-3a), 3.16 )dt,
Jˆ9.3 and 7.8 Hz, 1H, H-3b), 3.68 )q, Jˆ6.6 Hz, 1H,
NCHAr), 3.74 )dd, Jˆ7.5and 6 Hz, 1H, H-1), 7.18±7.65
0
Jˆ7.5and 1 Hz, 1H, H-6 ), 7.51 )ddd, Jˆ8, 7.5, and 1.5 Hz,
1H, H-50), 7.67 )dd, Jˆ7.5and 1 Hz, 1H, H-3 ). Anal. calcd
0
0
for C14H16N2O3 )260.30): C, 64.60; H, 6.20; N, 10.76.
Found: C, 64.34; H, 6.22; N, 10.75.
)m, 8H), 7.83 )dd, Jˆ8 and 1.5Hz, 1H, H-3 ).
3.1.7. cis-2-[ꢀ1-Chloroethoxy)carbonyl]-5-ꢀ2-nitrophenyl)-
2-azabicyclo[3.3.0]octan-6-one ꢀ6). A mixture of amine 4a
)0.96 g, 3.71 mmol) and a-chloroethyl chloroformate )5ml)
was heated at re¯ux for 6 h. The mixture was diluted with
Et2O and washed with 10% hydrochloric acid. The organic
layer was dried and concentrated to give carbamate 6 )1.3 g,
quantitative). H NMR )200 MHz) d 1.80 )m, 3H, CH3),
1.86±2.98 )m, 5H), 3.15±4.98 )m, 4H), 6.53 )m, 1H,
CHCl), 7.40±7.78 )m, 3H), 8.09 )d, Jˆ7.5Hz, 1H).
1
Dione 5a: H NMR d 2.22 )s, 6H, NCH3), 2.27 )s, 4H),
2.90±3.20 )m, 4H), 7.55 )t, Jˆ8 Hz, 1H), 7.65)d, Jˆ
8 Hz, 1H), 7.80 )t, Jˆ8 Hz, 1H), 8.10 )d, Jˆ8 Hz, 1H).
3.1.5. cis-2-ꢀ2,2-Dimethoxyethyl)-5-ꢀ2-nitrophenyl)-2-aza-
bicyclo[3.3.0]octan-6-one ꢀ4b). Operating as above, from
dione 3 )0.5g, 1.9 mmol) and 2,2-dimethoxyethylamine
hydrochloride )815mg, 7.7 mmol), ketone 4b )448 mg,
69%) and 2-[2-[N-)2,2-Dimethoxyethyl)methylamino]ethyl]-
2-)2-nitrophenyl)-1,3-cyclopentanedione )5b, 63 mg, 9%)
were obtained after chromatography )CH2Cl2-1% MeOH
to CH2Cl2-4% MeOH).
1
3.1.8. cis-5-ꢀ2-Nitrophenyl)-2-azabicyclo[3.3.0]octan-6-
one ꢀ7). A solution of carbamate 6 )1.3 g, 3.71 mmol) in
MeOH )15ml) was heated at re¯ux for 3 h. The solvent was
evaporated, and the residue partitioned between dichloro-
methane and saturated aqueous K2CO3. The organic layer
was dried and concentrated, and the residue was chroma-
tographed )CH2Cl2-2% MeOH) to give amine 7 )826 mg,
1
Ketone 4b: IR )®lm) 1737, 1529, 1360 cm21. H NMR
)500 MHz)16 d 1.97 )dddd, Jˆ13, 10, 3, and 2 Hz, 1H,
H-8a), 2.11 )m, 1H, H-8b), 2.32±2.47 )m, 3H, H-4 and
H-7), 2.63±2.72 )m, 2H, H-7 and CH2N), 2.85)dd, Jˆ13
and 5.5 Hz, 1H, CH2N), 2.92 )q, Jˆ8.5Hz, 1H, H-3 b), 3.18
)td, Jˆ8.5and 3 Hz, 1H, H-3 a), 3.35)s, 6H, OCH 3), 3.66 )br
d, Jˆ5Hz, 1H, H-1), 4.42 )t, Jˆ5.5 Hz, 1H, CH)OMe)2),
1
91%). H NMR )500 MHz)16 d 1.78 )dddd, Jˆ13.5, 10.5,
7.5, and 6.5 Hz, 1H, H-8a), 2.18 )ddd, Jˆ15, 9.5, and
7.5Hz, 1H, H-4), 2.40±2.48 )m, 2H, H-4 and H-8 b), 2.54
)ddd, Jˆ19, 10.5, and 7.5 Hz, 1H, H-7), 2.69 )ddd, Jˆ19,
10.5, and 4.5 Hz, 1H, H-7), 3.36 )m, 2H, H-3), 4.19 )dd, Jˆ8
and 6.5Hz, 1H, H-1), 7.34 )dd, Jˆ8 and 1 Hz, 1H, H-60),
7.41 )td, Jˆ8 and 1 Hz, 1H, H-40), 7.58 )td, Jˆ8 and 1 Hz,
1H, H-50), 7.87 )dd, Jˆ8 and 1 Hz, 1H, H-30). Anal. calcd
for C13H14N2O3 )246.27). 1/2H2O: C, 61.17; H, 5.92; N,
10.97. Found: C, 61.01; H, 5.71; N, 10.84.
0
0
7.40 )t, Jˆ7.5Hz, 1H, H-4 ), 7.43 )d, Jˆ7.5Hz, 1H, H-6 ),
0
0
7.55 )t, Jˆ7.5Hz, 1H, H-5 ), 7.75)d, Jˆ7.5Hz, 1H, H-3 ).
Anal. calcd for C17H22N2O5 )334.24): C, 61.07; H, 6.63; N,
8.37. Found: C, 60.78; H, 6.81; N, 8.20.
Dione 5b: 1H NMR )200 MHz) d 2.35)s, 3H, NCH 3), 2.40±
2.70 )m, 4H), 2.90±3.25)m, 4H), 3.30±3.50 )m, 2H), 3.37
)s, 6H, )OMe)2), 4.45)t, Jˆ5.5 Hz, 1H, CH)OMe)2), 7.52 )t,
Jˆ8 Hz, 1H), 7.62 )d, Jˆ8 Hz, 1H), 7.75)t, Jˆ8 Hz, 1H),
8.09 )d, Jˆ8 Hz, 1H).
3.1.9. ꢀ1S,5R)-5-ꢀ2-Nitrophenyl)-2-azabicyclo[3.3.0]octan-
6-one [ꢀ2)7]. Using a procedure similar to that described
for the preparation of )^)-7 from 6, compound 4c )100 mg,
0.28 mmol) was heated with a-chloroethyl chloroformate
)5ml) and then with MeOH )3 ml) to give ) 2)-7 )30 mg,
45%) as an oil. [a]Dˆ2203 )c 0.4, MeOH).
3.1.6. ꢀ1S,5R)-2-[ꢀS)-2-ꢀ1-Phenylethyl)]-5-ꢀ2-nitrophenyl)-
2-azabicyclo[3.3.0]octan-6-one ꢀ4c). Operating as above,
from dione 3 )0.9 g, 3.4 mmol) and )S)-a-methylbenzyl-
amine hydrochloride )570 mg, 3.6 mmol), using i-PrOH as
the solvent in the reductive amination step, ketone 4c
)425mg, 36%) and the )1 R,5S)-isomer )4d, 47 mg, 4%) were
obtained after chromatography )hexane to 8:2 hexane±EtOAc).
3.1.10. cis-5-ꢀ2-Nitrophenyl)-2-propargyl-2-azabicyclo-
[3.3.0]octan-6-one ꢀ4e). To a solution of 7 )150 mg,
0.6 mmol) in CH3CN )10 ml) were added propargyl bro-
mide )0.14 ml, 1.2 mmol) and K2CO3 )168 mg, 1.2 mmol).
After stirring at 508C for 3 h, the solvent was evaporated,
and the residue was partitioned between water and CH2Cl2.
Ketone 4c: [a]Dˆ2107 )c 0.3, MeOH). mp 93±958C. IR

J. Bonjoch et al. / Tetrahedron 57 +2001) 6011±6017
6017
3. Hemisynthesis: )a) Cartier, D.; Ouahrani, M.; Huguel, G.;
Â
Levy, J. Heterocycles 1988, 27, 657±661. )b) Huguel, G.;
The organic extract was concentrated and chromatographed
)0.5% MeOH in CH2Cl2) to give 4e )134 mg, 77%) as an oil.
1H NMR )200 MHz) 1.85±2.05 )m, 1H), 2.05±2.20 )m,
2H), 2.20±2.50 )m, 3H), 2.70 )dt, Jˆ19 and 9.5Hz, 1H,
H-7), 3.02±3.20 )m, 2H), 3.52 )d, Jˆ2.6 Hz, NCH2), 3.75
Â
Cartier, D.; Levy, J. Tetrahedron Lett. 1989, 30, 4513±4516.
4. Hemisynthesis: Palmisano, G.; Danieli, B.; Lesma, G.; Mauro,
M. J. Chem. Soc., Chem. Commun. 1986, 1564±1565.
5. Overman, L. E.; Robertson, G. M.; Robichaud, A. J. Am.
Chem. Soc. 1991, 113, 2598±2610.
)d, Jˆ5Hz, 1H, H-1), 7.35±7.45)m, 2H), 7.55)t,
Jˆ8 Hz,
1H), 7.75)d, Jˆ8 Hz, 1H). Anal. calcd for C16H16N2O3
)284.29): C, 67.59; H, 5.67; N, 9.85. Found: C, 67.25; H,
5.73: N, 9.76.
6. For an asymmetric entry to the tricyclic core of Melodinus
alkaloids, see: Schultz, A. G.; Dai, N. Tetrahedron Lett. 1999,
40, 645±648.
3.1.11. cis-2-[ꢀZ)-2-iodo-2-butenyl]-5-ꢀ2-nitrophenyl)-2-
azabicyclo[3.3.0]octan-6-one ꢀ4f). To a solution of 7
)740 mg, 3 mmol) in CH3CN )10 ml) were added )Z)-1-
bromo-2-iodo-2-butene )1.5g, 6 mmol) and K 2CO3
)829 mg, 6 mmol). After stirring at room temperature for
3 h, the solvent was evaporated, and the residue was par-
titioned between water and CH2Cl2. The dried organic
extract was concentrated and chromatographed )1:1, hex-
ane±CH2Cl2) to give 769 mg )60%) of 4f as an oil. IR
7. Overman, L. E.; Okazaki, M. E.; Jacobsen, E. J. J. Org. Chem.
1985, 50, 2403±2405.
8. Gramain, J.-C.; Remuson, R. Heterocycles 1989, 29, 1263±
1273.
Â
9. Baldwin, S. W.; Aube, J.; McPhail, A. T. J. Org. Chem. 1991,
56, 6546±6550.
10. )a) Pearson, W. H.; Walters, M. A.; Oswell, K. D. J. Am.
Chem. Soc. 1986, 108, 2769±2771. )b) Pearson, W. H.;
Szura, D. P.; Harter, W. G. Tetrahedron Lett. 1988, 29,
761±764. )c) Pearson, W. H.; Szura, D. P.; Postich, M. J.
J. Am. Chem. Soc. 1992, 114, 1329±1345.
)®lm) 1745, 1534, 1363 cm21
;
1H NMR d 1.77 )d,
Jˆ6.4 Hz, 3H, CH3), 1.94±2.10 )m, 2H), 2.30±2.50 )m,
2H), 2.65±2.90 )m, 2H), 3.03 )m, 1H), 3.26 and 3.56 )2d,
Jˆ14 Hz, 1H each, NCH2), 3.66 )t, Jˆ3.6 Hz, 1H, H-1),
5.83 )q, Jˆ6.4 Hz, 1H, vCH), 7.24±7.60 )m, 3H), 7.71
)d, Jˆ8 Hz, 1H). Anal. calcd for C17H19IN2O3 )426.25):
C, 47.90; H, 4.49, N, 6.57. Found: C, 47.80; H, 4.41; N,
6.59.
Â
11. Sole, D.; Bosch, J.; Bonjoch, J. Tetrahedron 1996, 52, 4013±
4028.
12. Bonjoch, J.; Sole, D.; Garcõa-Rubio, S.; Bosch, J. J. Am.
Chem. Soc. 1997, 119, 7230±7240.
Â
Â
 Â
13. )a) Sole, D.; Bonjoch, J.; Garcõa-Rubio, S.; Peidro, E.; Bosch,
Â
Â
J. Angew. Chem., Int. Ed. Engl. 1999, 38, 395±397. )b) Sole,
 Â
D.; Bonjoch, J.; Garcõa-Rubio, S.; Peidro, E.; Bosch, J. Chem.
Eur. J. 2000, 6, 655±665.
Acknowledgements
14. This expensive starting material was prepared in our initial
studies from norbornene following the Schank protocol:
Lick, C.; Schank, K. Chem. Ber. 1978, 111, 2461±2464.
15. For recent pyrrolidine ring formation by means of a double
reductive amination using chiral amines, see: )a) Manescalchi,
F.; Nardi, A. R.; Savoia, D. Tetrahedron Lett. 1994, 35, 2775±
2778. )b) Loh, T.-P.; Zhou, J.-R.; Li, X.-R.; Sim, K.-Y.
Tetrahedron Lett. 1999, 40, 7847±7850. )c) Degnan, A. P.;
Meyers, A. I. J. Org. Chem. 2000, 65, 3503±3512. See also
Ref. 11.
Financial support for this research was provided by DGES
)Spain) through Grants PB94-0214 and PB97-0877. Support
for DURSI, Catalonia )1999SGR-00078 and 1999SGR-
00079) is also acknowledged. R. C. was on leave from the
Â
University of Zacatecas )Mexico) with a fellowship.
References
16. See Fig. 3 for the notation a and b.
17. For the analysis of cyclopentanes by H NMR, see: Constan-
1
1. Cyclopenta[b]pyrrole, octahydro-3a-phenyl, cis- is the name
used in the Chemical Abstracts.
Â
2. Hemisynthesis: )a) Huguel, G.; Levy, J. J. Org. Chem. 1984,
tino, M. G.; da Silva, G. V. J. Tetrahedron 1998, 54, 11363±
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49, 3275±3277. )b) Palmisano, D.; Danieli, B.; Lesma, G.;
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Â
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19. Using the cheaper bromonitrobenzene the yield decreases to
50% yield.