The use of nonactivated iminodienophiles in the stereoselective aza-Diels-Alder reaction

Article abstract of DOI:10.1016/j.tetasy.2003.12.011

This paper describes the preparation of nitrogen-containing bicycles by the aza-Diels-Alder reaction of nonactivated iminodienophiles and cyclopentadiene. Readily available starting materials such as (S)-(-)-lactate and L-amino acids were used for the pre

Full text of DOI:10.1016/j.tetasy.2003.12.011

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 445–452
The use of nonactivated iminodienophiles in the stereoselective
aza-Diels–Alder reaction
Anna Trifonova and Pher G. Andersson*
Department of Organic Chemistry, Institute of Chemistry, Uppsala University, Box 599, SE-75124 Uppsala, Sweden
Received 19 October 2003; accepted 3 December 2003
Abstract—This paper describes the preparation of nitrogen-containing bicycles by the aza-Diels–Alder reaction of nonactivated
iminodienophiles and cyclopentadiene. Readily available startingmaterials such as ( S)-())-lactate and
the preparation of chiral aldehydes with high enantiomeric excess. The improved oxidation procedure by Dess–Martin periodinane
was employed for the synthesis of -alanine derived phthalimide protected aldehyde 14, which was difficult to obtain in high
L-amino acids were used for
L
enantiomeric excess by other methods. The influence of different Lewis acids on the stereoselectivity of the aza-Diels–Alder reaction
was also investigated: It was found that the use of a combination of BF3ÆEt2O and TFA in the cycloaddition leads to complete
racemization of the imine prepared from 14 whereas the use of TiCl4 gives the cycloaddition products 17a and 17b with high
enantioselectivity (90%).
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
and Bailey et al.,4d;e and it involves the condensation of
cyclic dienes and an electron-deficient glyoxylate imine
followed by transformation of the ester group into the
desired functionality.2 A new route based on the use of
nonactivated imine dienophiles would broaden the
scope of the synthesis considerably.
The stereoselective aza-Diels–Alder reaction is a well-
known method for the preparation of nitrogen-con-
tainingmonocyclic- and bicyclic molecules. The latter
1
compounds have been widely used as chiral ligands in
asymmetric synthesis.2;3 For example, compounds A and
B have been used for transfer hydrogenation2a of pro-
chiral ketones (Scheme 1). Compound C has been used
by Sodergren et al.2b in the lithium amide base promoted
€
2. Results and discussion
chiral rearrangement of epoxides (Scheme 1). Therefore
an efficient synthesis of these bicyclic amines as well as
related compounds should find broad application. The
reaction employed previously for the synthesis of
nitrogen-containing bicycles was described by the
groups of Stella and co-workers,4a;b Waldmann et al.4c
There are few examples in the literature describingthe
use of nonactivated imines in the aza-Diels–Alder
reaction.5 Due to the low reactivity (or poor electro-
philicity) of the imine functionality, [4+2] cycloaddition
is possible only with highly reactive dienes under Lewis
acid catalysis.6–9 In order to investigate the scope of the
reaction, a variety of optically active aldehydes was
synthesized and evaluated. Aldehyde 110 was prepared
from commercially available methyl (S)-())-lactate in
three steps11. Imine formation reaction with benzyl-
NH
NH CH
NH
3
OH
N
OH
A
B
H
C
amine in CH2Cl2 at 0 °C in the presence of MgSO4 as a
2a
2b
transfer hydrogenation
epoxide rearrangement
7b
dryingagent
yielded the iminodienophile 2, which was
used in the cycloaddition without further purification
(Scheme 2). The enantiomeric excess of aldehyde 1 was
confirmed by treatment with (S)-1-phenylethyl amine
and subsequent 13C NMR analysis of the resultingchiral
imine. It was found that no significant racemization
occurred duringoxidation and imine formation steps.
Scheme 1. Some examples of the ligands used in asymmetric trans-
formations.
* Correspondingauthor. Tel.: +46-184713801; fax: +46-185120524;
e-mail: phera@kemi.uu.se
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.12.011

446
A. Trifonova, P. G. Andersson / Tetrahedron: Asymmetry 15 (2004) 445–452
Since bicycles containinga pendant nitrogen could be
CH
CH
3
3
(i)
potentially useful as ligands in asymmetric synthesis, we
also investigated the preparation of such compounds by
the aza-Diels–Alder reaction of a nonactivated imine
with cyclopentadiene. The choice of the protecting
group for the aminoaldehyde precursor was found to be
crucial. Preliminary experiments showed that the imino-
dienophiles prepared from aminoaldehydes having
protectingrgoups such as benzyl, benzyloxycarbonyl,
and tosyl (Scheme 3) did not undergo the cycloaddition
reaction. The reason for this observation could be the
steric hindrance caused by the protectinggroups. It was
later found that the iminodienophiles prepared from less
bulky phthalimide and succinimide aldehyde derivatives
smoothly underwent aza-Diels–Alder reaction with
cyclopentadiene to give cycloadducts in excellent yields.
H
H
BnO
BnO
O
N
2
1
Ph
Scheme 2. Synthesis of imine 2. Reagents and conditions: (i) BnNH2,
MgSO4, CH2Cl2, 0 °C.
The Diels–Alder reaction of 2 with cyclopentadiene was
catalyzed by BF3ÆEt2O/TFA and gave rise to four dia-
stereomers 3a, 3b, 3c, and 3d (Table 1), which were
readily separated by silica gel chromatography or HPLC
methods (see Experimental part). The relative configu-
ration of the major bicyclic product 3a was found to be
exo by a NOESY NMR experiment, while the absolute
configuration was tentatively assigned as shown in Table
1. The enantiomeric purity of compound 3a was deter-
mined by chiral HPLC (see Experimental part). It was
found that no racemization had occurred in the last
three steps (Swern oxidation, imine formation, and
Diels–Alder reaction).
CH
CH
Ph
CH
Ph
3
3
3
H
Cbz
H
Bn
H
Bn
N
H
N
Bn
N
Ts
N
N
N
Ph
Scheme 3. Amino imines tried in the aza-Diels–Alder reaction.
The aza-Diels–Alder reaction of the imine 2 with
1,3-cyclohexadiene and isoprene was also examined.
Because of the low reactivity of these dienes, different
Lewis acids were evaluated for the activation of the
imine. Addition of BF3ÆEt2O/TFA, LiClO4, ZnCl2,
Phthalimide protected aldehyde 413 (Scheme 4) was
prepared in two steps.14 This aldehyde was then reacted
with three different amines: ethylamine, benzylamine,
and (S)-1-phenylethylamine to give the corresponding
imines 5, 7, and 9, which were used directly in the next
step. The BF3ÆEt2O/TFA catalyzed cycloaddition be-
tween the imine and cyclopentadiene resulted in for-
MgI2, Mg IÆEt2O, Et3Al, Nd(OTf)3 did not improve the
2
yield of the cyclic product and the unreacted imine re-
mained in the reaction mixture even after 7–10 days.
When the reactions were carried out at an elevated
temperature, total decomposition of the startingmate-
rial took place. The use of more potent Lewis acids such
as TiCl4 or SnCl4 as well as carryingout the reaction
in an ultrasonic bath gave a polymeric material of
unidentified structure. The procedure involvingthe
formation of iminium cation in aqueous solution in the
presence of lanthanide triflate failed as well. The best
result was obtained when isoprene was reacted with the
imine activated by an excess (2.5 equiv) of freshly pre-
pared ZnCl2ÆEt2O, but the yield was low (ꢀ20%). 1,3-
Cyclohexadiene was found to be less reactive than
isoprene and the best yield obtained was <10%.
(i)
NPht
NPht
O
N
4
R
R
1
5: R=H, R =H
1
7: R=H, R =Ph
1
9: R=CH , R =Ph
3
1
Scheme 4. Synthesis of imines 5, 7 and 9. Reagents and conditions:
ꢀ
(i) appropriate amine, 4 A molecular sieves, CH2Cl2.
Table 1. The products and the yields of aza-Diels–Alder reaction of imine 2 (the absolute stereochemistry of the products is tentatively assigned)
Entry
Imine
Lewis acid
Yield (%)a
exo/endo Selectivity Diastereoselectivityb
Major products (isol. yield)
Ph
N
CH
3
H
N
+
OBn
OBn
3b
(14%)
CH
Ph
3
H C
3
3a
1
BF3ÆEt2O/TFA
70
55:45c
60:40c
(23%)
OBn
N
2
Ph
H C
3
N
N
Ph
+
H
BnO
Ph
3c
BnO
CH
3
(15%)
3d
(18%)
a Total yield of diastereomers.
b Diastereoselectivity of the exo product.
c Determined after separation of the products.

A. Trifonova, P. G. Andersson / Tetrahedron: Asymmetry 15 (2004) 445–452
447
mation of bicycles 6a, 6b, 8, and 10 (Table 2). Com-
pounds 6a and 8 were isolated as racemic mixtures with
relative exo configuration because of the absence of a
chiral moiety in the startingmaterial. The relative con-
figuration of racemic compound 6b was determined as
endo. In the case of product 10 with exo relative con-
figuration it was not possible to detect the formation of
the other exo diastereomer by H NMR. The succin-
imide derivative 11 (Scheme 5) was obtained in two steps
by reaction of 2-aminoethanol with succinic anhy-
dride,15 followed by Dess–Martin oxidation.16b;c Com-
pound 11 was treated with (S)-1-phenylethylamine and
the resultingimine 12 was subjected to the aza-Diels–
Alder reaction with cyclopentadiene catalyzed by
BF3ÆEt2O/TFA to produce compound 13 with exo con-
figuration in good yield.
1
The preparation of the aminobicycles havingan addi-
tional stereogenic center was accomplished by employ-
ingaminoaldehydes prepared from available
D- and
Table 2. The products and the yields of the aza-Diels–Alder reaction of imines 5, 7, 9, 12, 15, and 18 (the absolute stereochemistry of the products is
tentatively assigned)
Entry
Imine
Lewis acid
Yield (%)a exo/endo Selectivity
Diastereoselectivityb Major products (isol. yield of
pure isomers)
NPht
+
N
N
1
BF3ÆEt2O/TFA
84
95
87
60:40e
85:15d
85:15d
n.a.
n.a
N
5
H
NPht
6a
(50%)
6b
(34%)
NPht
NPht
N
2
3
BF3ÆEt2O/TFA
BF3ÆEt2O/TFA
N
7
NPht
Ph
Ph
Ph
8
(81%)
NPht
N
99:1d
N
9
NPht
3
CH
Ph
H C
3
10
(74%)
O
O
N
N
N
4
BF3ÆEt2O/TFA
62
80:20f
88:12f
Ph
N
CH
3
O
13
O
12
(44%)
Ph
H C
3
CH
3
CH
3
N
NPht
NPht
5g;h
BF3ÆEt2O/TFA
89
40
72:28c
45:55f
72:28c
N
N
Ph
16
(52%)
15
Ph
CH
CH
3
3
NPht
+
NPht
6g
TiCl4
99:1f
N
N
Ph
15
PhtN CH
3
Ph
17a
17b
(18%)
Ph
(22%)
N
Bn
N
Boc
18
7h
BF3ÆEt2O/TFA
70
n.d.
55:45e
N
19
(70%)
N
Boc
Ph
a Total yield of diastereomers.
b Diastereoselectivity of the exo product.
c Determined after separation of the products.
d Determined by HPLC analysis of the crude mixture.
e Determined by 13C NMR experiment of the crude mixture.
f Determined by 1H NMR experiment of the crude mixture.
g When the combination of BF3ÆEt2O/TFA was used as a catalyst, the ee of the major product 0–80%, when TiCl4 was used as a catalyst, the ee of the
major product 90%.
h The pure isomers were not separated, the yield in brackets is given for the mixture of compounds.

448
A. Trifonova, P. G. Andersson / Tetrahedron: Asymmetry 15 (2004) 445–452
when the product was analyzed by chiral HPLC it was
O
O
O
found that total or partial racemization had taken place
duringthe cycloaddition reaction probably due to the
acidic conditions (TFA/BF3ÆEt2O). Because the presence
of labile hydrogen at the a-carbon to amino group the
protonation of imine nitrogen by TFA results in imine–
enamine equilibrium with concomitant racemization of
the a-carbon. When the trifluoroacetic acid and
BF3ÆEt2O were excluded from the reaction mixture and
TiCl4 was used as a catalyst, better results were ob-
tained. Surprisingly, in this case the configuration of the
major product of the cycloaddition 17a was determined
as endo. This product was formed with high enantio-
selectivity (90%) but in lower yield (40%) (Table 2).
HO
(i)
(ii)
N
N
N
O
N
O
O
O
11
12
H C
Ph
3
Scheme 5. Synthesis of imine 12. Reagents and conditions: (i) Dess–
ꢀ
Martin periodinane, CH2Cl2, rt; (ii) BnNH2, 4 A molecular sieves,
CH2Cl2.
L
-amino acids. To avoid racemization at the a-carbon
duringthe preparation of the phthalimide aldehyde
derivative, a convenient two-step procedure was em-
ployed (Scheme 6). First, the amino group of L-alaninol
was protected16a to give the corresponding phthalimide.
In the next step the choice of the oxidation procedure
was found to be crucial due to ready racemization at the
a-carbon. The preparation of aminoaldehyde 14 was
reported earlier16d–f but the product was obtained in
partially racemic form. The use of Swern oxidation
resulted in the complete loss of optical activity of the
product while Dess–Martin oxidation at standard con-
ditions16b;c gave a partially racemic compound (Scheme
6). However, when the oxidation by Dess–Martin peri-
odinane was performed in the presence of an excess of
NaHCO3 it was possible to obtain the aldehyde 14 with
an enantiomeric excess of 97%. In this case it was
important to keep the pH of the reaction above 5 and
carry out complete neutralization of the acid released in
the aqueous workup. The product of this modified
Dess–Martin oxidation was treated with (S)-1-phenyl-
ethylamine in CH2Cl2 in presence of MgSO4 at 0 °C16g to
give the corresponding imine 15. Its 13C NMR spectrum
was compared with the spectrum of the mixture of
diastereomeric imines produced from racemic aldehyde.
This experiment16i showed that no significant racemi-
zation had taken place duringthe oxidation and imine
preparation steps. When the enantiomerically pure
imine 15 was used in the aza-Diels–Alder reaction under
standard conditions compound 16 was formed as the
major product. Its relative configuration was determined
to be exo by a NOESY NMR experiment. However,
When the commercially available aldehyde 18 was used
in the aza-Diels–Alder reaction, a relatively high yield of
a mixture of diastereomers 19 was obtained (70%).
However, it was not possible to separate the products or
to determine the level of diastereoselectivity in this
reaction because of the complete overlap of the signals
in the NMR spectra and very similar retention times of
the products in HPLC analysis.
The extension of the present aza-Diels–Alder reaction to
other nonactivated aldehydes (for example, aldehydes
havingprotected thiol function) and further applications
of these compounds in asymmetric transformations are
under investigation.
3. Experimental section
1H, 13C, and NOESY NMR spectra were recorded in
CDCl3 solutions at 399.95/100.57 MHz. The chemical
shifts of protons are reported usingthe residual signal of
1H in CDCl3 as the internal reference (d 7.26 ppm) and
chemical shifts of carbons are reported settinga refer-
ence 76.9 ppm at the middle line of 13C signal of CDCl3.
Optical rotations were recorded on a thermostated
CH
3
H
NPht
O
racemic
Swern
Oxidation
(ii)
mod. Dess-
Martin
CH
CH
CH
CH
Ph
3
3
3
3
Oxidation
(i)
(v)
HO
HO
H
H
(iv)
NH
NPht
NPht
NPht
2
O
N
Dess-Martin
Oxidation
(iii)
97% ee
commercial alcohol 98% ee
CH
14
15
3
H
*
NPht
O
90% ee
Scheme 6. Synthesis of imine 15. Reagents and conditions: (i) phthalic anhydride, triethylamine, toluene, 130 °C; (ii) oxalyl chloride, DMSO, tri-
ethylamine, CH2Cl2, )78 °C; (iii) Dess–Martin periodinane, CH2Cl2, rt; (iv) Dess–Martin periodinane, NaHCO3, CH2Cl2, rt; (v) BnNH2, MgSO4,
CH2Cl2, 0 °C.

A. Trifonova, P. G. Andersson / Tetrahedron: Asymmetry 15 (2004) 445–452
449
polarimeter usinga 1.0 dm cell. HPLC analyses were
carried out usinga chiral column (ChiralCel OD-H or
OJ), a 254 nm UV detector and isopropanol/hexane
(1:99) as eluent with flow rate 0.5 ml/min. Flash chro-
matography was performed on silica gel (37–70 lm) and
Al2 O3 gel (0.063–0.2 mm). The TLCs were performed
on precoated plates, silica gel 60 F254. The chiral starting
materials, amines, acids, and other reagents were used as
received from commercial suppliers. Dichloromethane
was dried over CaH2 and distilled under nitrogen.
Cyclopentadiene was distilled prior to use.
3.3. The general procedure for imine preparation and the
aza-Diels–Alder reactions with aldehydes 1 and 14
The aldehyde (1 equiv) was dissolved in 20 ml of CH2Cl2
under a nitrogen atmosphere and MgSO4 (0.5 g/mmol)
was added. The reaction mixture was cooled down to
0 °C usingan ice bath and benzylamine [or ( S)-1-phen-
ylethylamine for investigation of enantiomeric purity of
the aldehydes] (1 equiv) was added. After the imine
formation was complete (ꢀ2 h by 1H and 13C NMR) the
MgSO4 was filtered off and the solvent was evaporated.
The crude imine was redissolved in CH2Cl2 and cooled
down in an acetone/dry ice bath to )78 °C followed by
the addition of BF3ÆEt2O (1 equiv) and trifluoroacetic
acid (1 equiv). The freshly distilled cyclopentadiene
(2 equiv) was added dropwise and the reaction mixture
was allowed to warm up to room temperature overnight.
3.1. 2-Succinimidoethanal 11
N-(2-Hydroxyethyl) succinimide13 (0.30 g, 2.1 mmol)
was dissolved in CH2Cl2 (21 ml, 10 ml/mmol) under a
nitrogen atmosphere and Dess–Martin periodinane
(1.42 g, 3.35 mmol) was added to the solution. After the
completion of the reaction (by TLC) the reaction mix-
ture was diluted with diethyl ether and solid K2CO3 was
added. Since the resultingaminoaldehyde 11 is water
soluble, the aqueous workup was avoided. The solids
were filtered off and washed with CH2Cl2 and the sol-
vents were evaporated giving crude aldehyde 11. The
traces of acetic acid were removed by coevaporation
with toluene (three times). The crude material was
subjected to column chromatography on silica gel using
MeOH/CH2Cl2 (0–1.5% MeOH) as eluent to yield
compound 11 (0.29 g, 2.05 mmol, 98%) as colorless oil.
Rf ¼ 0:41 (CH2Cl2/MeOH 9:1); IR (neat) m 1712, 1418,
The work up usingsaturated aqueous NaHCO was
3
followed by extraction with CH2Cl2, dryingthe organic
phase over MgSO4 and evaporation of the solvent
yieldingthe oily crude material, which was purified on a
silica gel column using MeOH/CH2Cl2 (0–2.5% MeOH)
as an eluent, and additionally purified from polymeric
byproducts on Al2O3 gel column using CH2Cl2 as an
eluent.
3.4. The general procedure for imine preparation and the
aza-Diels–Alder reactions with aldehydes 5, 11, and 18
ꢀ
To 4 A molecular sieves (0.2 g/mmol) in CH2Cl2 (2 ml/
1
1177 cmÀ1; H NMR (CDCl3) d 9.54 (s, 1H), 4.38 (s,
mmol) the aldehyde (1 equiv) was added under nitrogen
and with stirring. After that benzylamine [or (S)-1-
phenylethylamine or 2.0 M ethylamine solution in dry
THF] (1 equiv) was added. The reaction mixture was
stirred at room temperature until the imine formation
2H), 2.81 (s, 4H) ppm; 13C NMR (CDCl3) d 192.3,
176.1, 47.9, 28.15 ppm; HRMS (FABþ) (M+Hþ): calcd
for C6H8NO3 142.0504, found 142.0502.
1
was complete (usually 2–3 h accordingto H NMR). The
3.2. (2S)-2-Phthalimidopropanal 14
reaction mixture was cooled down to )78 °C usingan
acetone/dry ice bath followed by addition of BF3ÆEt2O
(1 equiv) and trifluoroacetic acid (1 equiv). The freshly
distilled cyclopentadiene (2 equiv) was added dropwise
and the reaction mixture was allowed to warm up to
room temperature overnight. Workup and purification
were performed as described for compounds 1 and 14.
Phthalimide protected (S)-alaninol16a (0.64 g, 3.1 mmol)
was dissolved in CH2Cl2 (30 ml, 10 ml/mmol) under a
nitrogen atmosphere and solid NaHCO3 (5.16 g,
61.4 mmol) was added to the solution. The Dess–Martin
periodinane (2.08 g, 4.9 mmol) was added to the mixture
and it was intensively stirred for 0.5 h. The pH of the
reaction mixture was kept ꢀ6 duringthe oxidation by
addition of solid NaHCO3. After the completion of the
reaction (by TLC) the reaction mixture was diluted with
diethyl ether and after 15 min poured into a saturated
solution of NaHCO3/Na2S2O3. The stirringwas con-
tinued until there was complete neutralization of the
released acid. The water phase was extracted with
CH2Cl2, the organic phase was dried over MgSO4, and
evaporated yieldingcompound 14 (0.62 g, 3.0 mmol,
97%) as white crystals (recrystallized from CH2Cl2/
3.5. (3R)-2-Benzyl-3-((1S)-benzyloxyethyl)-2-azabicyclo-
[2.2.1]-hept-5-ene 3a
Separated by HPLC usingisopropanol/hexane (2:98) as
an eluent. Yield: 0.94 g(2.94 mmol, 23%) (colorless oil).
24
D
Rf ¼ 0:54 (MeOH/CH2Cl2 1:9); ½aŠ ¼ )42.5 (c 1.06,
1
CHCl3); IR (neat) m 2981, 1453, 1220, 1091 cmÀ1; H
NMR (CDCl3) d 7.38–7.23 (m, 10H), 6.49–6.47 (m, 1H),
6.11 (dd, J ¼ 5:7, 1.6 Hz, 1H), 4.72 (s, 2H), 3.90 (d,
J ¼ 12:8 Hz, 1H), 3.66 (m, 1H), 3.52–3.48 (m, 1H), 3.20
(d, J ¼ 12:8 Hz, 1H), 2.73 (d, J ¼ 1:3 Hz, 1H), 1.79 (d,
J ¼ 7:7 Hz, 1H), 1.71 (d, J ¼ 8:1 Hz, 1H), 1.28–1.23 (m,
4H) ppm; 13C NMR (CDCl3) 140.2, 139.2, 137.45,
132.1, 128.8, 128.1, 128.0, 127.5, 127.1, 126.5, 79.6, 71.7,
68.6, 62.3, 59.0, 45.5, 45.3, 17.6 ppm; HRMS (FABþ)
(M+Hþ): calcd for C22H26NO 320.2014, found
320.2012.
hexane). Rf ¼ 0.19 (ethyl acetate/pentane 2:8); mp
22
109 °C;16d ½aŠ ¼ )43 (c 1.0, C6H6);16g IR (neat) m 1960,
D
1816, 1721, 1479, 1388, 1036 cm
;
À1 16h 1H NMR (CDCl3)
d 9.67 (s, 1H), 7.87–7.85 (m, 2H); 7.84–7.73 (m, 2H),
4.73 (q, J ¼ 7:1 Hz, 1H), 1.59 (d, J ¼ 7:1 Hz, 3H) ppm;
13C NMR (CDCl3) d 196.7, 168.7, 134.2, 123.4, 53.8,
12.7 ppm; HRMS (FABþ) (M+Hþ): calcd for
C11H10NO3 204.0661, found 204.0673.

450
A. Trifonova, P. G. Andersson / Tetrahedron: Asymmetry 15 (2004) 445–452
3.6. (3S)-2-Benzyl-3-((1S)-benzyloxyethyl)-2-azabicyclo-
[2.2.1]-hept-5-ene 3b
2.0 Hz, 1H), 3.91–3.86 (m, 2H), 3.67 (dd, J ¼ 13:7,
10.0 Hz, 1H), 2.73 (m, 1H), 2.49–2.40 (m, 1H), 2.34–2.26
(m, 1H), 1.88–1.82 (m, 2H), 1.43 (m, 1H), 1.18 (t,
J ¼ 7:3 Hz, 3H) ppm; 13C NMR (CDCl3) d 168.4, 136.1,
133.8, 132.4, 132.0, 123.1, 64.4, 62.1, 48.5, 45.9, 45.1,
43.0, 14.6 ppm; HRMS (EI): calcd for C17H18N2O2
282.1368, found 282.1367.
Yield: 0.56 g(1.75 mmol, 14%) (yellow oil). Rf ¼ 0:43
24
(MeOH/CH2Cl2 1:9); ½aŠ ¼ )27 (c 1.0, CHCl3); IR
D
(neat) m 3062, 3027, 2970, 2929, 2867, 1495, 1453, 1372,
1
1333, 1166, 1091, 1028 cmÀ1; H NMR (CDCl3) d 7.49–
7.26 (m, 10H), 6.40–6.38 (m, 1H), 6.16–6.14 (m, 1H),
4.70 (s, 2H), 4.43 (d, J ¼ 13:9 Hz, 1H), 3.62 (d,
J ¼ 13:9 Hz, 1H), 3.57 (m, 1H), 3.28–3.23 (m, 1H), 3.06
(d, J ¼ 1:1 Hz), 2.73 (dd, J ¼ 9:0, 2.7 Hz, 1H), 1.85 (d,
J ¼ 8:2 Hz, 1H), 1.54 (d, J ¼ 8:2 Hz, 1H), 1.25 (d,
J ¼ 6:2 Hz, 3H) ppm; 13C NMR (CDCl3) d 143.8, 141.9,
140.7, 136.4, 131.0, 130.8, 130.7, 130.6, 130.1, 129.7,
129.0, 83.3, 74.2, 72.4, 66.3, 63.8, 48.8, 46.9, 20.3 ppm;
HRMS (FABþ) (M+Hþ): calcd for C22H26NO 320.2014,
found 320.2015.
3.10. 20-((3S)-2-Ethyl-2-azabicyclo-[2.2.1]-hept-5-ene-
3-ylmethyl)-isoindole-10,30-dione 6b
Yield: 0.71 g(2.52 mmol, 34%) (yellow oil). Rf ¼ 0:39
(MeOH/CH2Cl2 1:9); IR (neat) m 2971, 1772, 1715, 1394,
913 cmÀ1; 1H NMR (CDCl3) d 7.86–7.84 (m, 2H), 7.74–
7.71 (m, 2H), 6.53–6.47 (m, 2H), 3.64–3.59 (m, 2H), 3.38
(dd, J ¼ 13:6, 10.7 Hz, 1H), 2.89–2.87 (m, 1H), 2.78–
2.63 (m, 3H), 1.75–1.72 (m, 1H), 1.55–1.52 (m, 1H), 1.29
(t, J ¼ 7:2 Hz, 3H) ppm; 13C NMR (CDCl3) d 168.2,
137.9, 136.5, 133.8, 132.0, 123.1, 66.7, 62.4, 51.4, 45.9,
44.6, 41.8, 14.9 ppm; HRMS (EI): calcd for C17H18N2O2
282.1368, found 282.1368.
3.7. (3R)-2-Benzyl-3-((1S)-benzyloxyethyl)-2-azabicyclo-
[2.2.1]-hept-5-ene 3c
Yield: 0.62 g(1.94 mmol, 15%) (yellow oil). Rf ¼ 0:77
24
(MeOH/CH2 Cl2 1:9); ½aŠ ¼ +76 (c 1.15, CHCl3); IR
3.11. 20-((3R)-2-Benzyl-2-azabicyclo-[2.2.1]-hept-5-ene-
D
(neat) m 2982, 2868, 1495, 1453, 1368, 1107, 1028 cmÀ1
;
3-ylmethyl)-isoindole-10,30-dione 8
1H NMR (CDCl3) d 7.45–7.29 (m, 10H), 6.56–6.54 (m,
1H), 6.20 (dd, J ¼ 5:5, 1.5 Hz, 1H), 4.75 (d, J ¼ 11:6 Hz,
1H), 4.57 (d, J ¼ 11:6 Hz, 1H), 3.74 (d, J ¼ 13:3 Hz,
1H), 3.65 (m, 1H), 3.52–3.45 (m, 1H), 3.28 (d,
J ¼ 13:3 Hz, 1H), 1.76–1.74 (m, 2H), 1.47 (d,
J ¼ 6:2 Hz, 3H), 1.30 (d, J ¼ 8:2 Hz, 1H) ppm; 13C
NMR (CDCl3) d 139.8, 138.7, 137.4, 132.5, 128.5, 128.1,
128.0, 127.6, 79.1, 70.7, 68.2, 62.2, 58.6, 45.4, 45.1,
17.9 ppm; HRMS (FABþ) (M+Hþ): calcd for
C22H26NO 320.2014, found 320.2018.
Yield: 0.28 g(0.86 mmol, 81%) (lhigt-yellow oil).
Rf ¼ 0:59 (ethyl acetate/pentane 1:1); IR (neat) m 2984,
1
1773, 1715, 1392, 913 cmÀ1; H NMR (CDCl3) d 7.82–
7.91 (m, 2H), 7.71–7.68 (m, 2H), 7.32–7.25 (m, 4H),
7.19–7.15 (m, 1H), 6.38–6.35 (m, 1H), 6.15 (dd, J ¼ 5:6,
1.9 Hz, 1H), 3.74 (d, J ¼ 1:2 Hz, 1H), 3.74–3.61 (m, 2H),
3.42 (dd, J ¼ 12:9 Hz, 2H), 2.74 (d, J ¼ 1:5 Hz), 2.12
(dd, J ¼ 8:2, 5.6 Hz, 1H), 1.88 (d, J ¼ 8:5 Hz, 1H), 1.40
(d, J ¼ 8:5 Hz, 1H) ppm; 13C NMR (CDCl3) d 168.4,
139.7, 136.6, 133.7, 132.7, 131.9, 128.9, 128.1, 123.1,
64.0, 62.1, 58.5, 46.1, 45.2, 42.5 ppm; HRMS (EI): calcd
for C22H20N2O2 344.1525, found 344.1525.
3.8. (3S)-2-Benzyl-3-((1S)-benzyloxyethyl)-2-azabicyclo-
[2.2.1]-hept-5-ene 3d
3.12. 20-((3R)-2-((1S)-Phenylethylamino)-2-azabicyclo-
Separated by HPLC usingisopropanol/hexane (2:98) as
an eluent. Yield: 0.71 g(2.22 mmol, 18%) (light-yellow
[2.2.1]-hept-5-ene-3-ylmethyl)-isoindole-10,30-dione 10
24
D
oil). Rf ¼ 0:52 (MeOH/CH2Cl2 1:9); ½aŠ ¼ +135 (c 0.80,
1
CHCl3); IR (neat) m 2870, 1452, 1219, 1096 cmÀ1; H
Yield: 0.33 g(0.91 mmol, 74%) (lhigt-yellow oil).
22
D
NMR (CDCl3) d 7.38–7.24 (m, 10H), 6.20–6.18 (m, 1H),
5.91–5.89 (m, 1H), 4.64 (d, J ¼ 11:6 Hz, 1H), 4.37 (d,
J ¼ 11:6 Hz, 1H), 4.00 (d, J ¼ 14:0 Hz, 1H), 3.52 (d,
J ¼ 14:0 Hz, 1H); 3.44 (m, 1H), 3.30 (m, 1H), 3.07–3.02
(m, 1H), 2.53 (dd, J ¼ 9:4, 2.9 Hz), 1.80–1.77 (m, 1H),
1.49–1.46 (m, 1H), 1.29 (d, J ¼ 6:0 Hz) ppm; 13C NMR
(CDCl3) d 140.5, 138.8, 136.9, 135.9, 128.2, 128.1, 128.0,
127.8, 127.3, 126.6, 78.1, 70.2, 69.1, 64.0, 61.2, 46.0,
43.9, 17.8 ppm; HRMS (FABþ) (M+Hþ): calcd for
C22H26NO 320.2014, found 320.2015.
Rf ¼ 0:56 (ethyl acetate/pentane 1:1); ½aŠ ¼ )84 (c 3.0,
1
CHCl3); IR (neat) m 2979, 1774, 1715, 1392 cmÀ1; H
NMR (CDCl3) d 7.75–7.72 (m, 2H), 7.67–7.63 (m, 2H),
7.42–7.35 (m, 4H), 7.28–7.24 (m, 1H), 6.29–6.26 (m, 1H),
6.20 (dd, J ¼ 5:7, 1.8 Hz, 1H), 4.22 (d, J ¼ 1:5 Hz, 1H),
3.37 (dd, J ¼ 13:6, 10.4 Hz, 1H), 3.10 (q, J ¼ 6:6 Hz,
1H), 2.97 (dd, J ¼ 13:6, 4.4 Hz, 1H), 2.56 (d, J ¼ 1:5 Hz),
2.11 (dd, J ¼ 10:4, 4.4 Hz, 1H), 1.92 (d, J ¼ 8:6 Hz, 1H),
1.44–1.39 (m, 4H) ppm; 13C NMR (CDCl3) d 168.1,
145.6, 135.9, 133.5, 132.3, 131.8, 128.1, 127.9, 126.9,
122.8, 63.2, 63.0, 61.1, 45.0, 44.2, 42.5, 22.1 ppm; HRMS
(EI): calcd for C23H22N2O2 358.1681. found 358.1682.
3.9. 20-((3R)-2-Ethyl-2-azabicyclo-[2.2.1]-hept-5-ene-3-
ylmethyl)-isoindole-10,30-dione 6a
3.13. 20-((3R)-2-((1S)-Phenylethylamino)-2-azabicyclo-
[2.2.1]-hept-5-ene-3-ylmethyl)-pyrrolidine-10,30-dione 13
Yield: 1.07 g(3.78 mmol, 50%) (yellow oil). Rf ¼ 0:51
(MeOH/CH2Cl2 1:9); IR (neat) m 2970, 1773, 1715, 1394,
913 cmÀ1; 1H NMR (CDCl3) d 7.87–7.83 (m, 1H), 7.74–
7.70 (m, 1H), 6.26–6.23 (m, 1H), 6.08 (dd, J ¼ 5:6,
Yield: 0.27 g(0.87 mmol, 43.5%) (white crystals, from
hexane). Rf ¼ 0:59 (MeOH/CH2Cl2 1:9); mp 116 °C;

A. Trifonova, P. G. Andersson / Tetrahedron: Asymmetry 15 (2004) 445–452
451
22
D
½aŠ ¼ )33.5 (c 1.0, CHCl3); IR (neat) m 1702, 1398, 1166
(d, J ¼ 14:2 Hz, 1H), 3.41–3.40 (m, 1H), 3.18–3.17 (m,
1H), 1.84–1.82 (m, 1H), 1.57–1.55 (m, 1H), 1.44 (d,
J ¼ 7:1 Hz, 3H) ppm; 13C NMR (CDCl3) d 168.7, 140.5,
138.5, 134.1, 133.4, 131.7, 127.79, 127.78, 126.1, 122.75,
65.63, 65.60, 61.1, 52.1, 46.6, 45.0, 15.9 ppm; HRMS
(FABþ) (M+Hþ): calcd for C23H23N2O2 359.1759,
found 359.1757.
cmÀ1; 1H NMR (CDCl3) d 7.34–7.23 (m, 5H), 6.30–6.27
(m, 1H), 6.17 (dd, J ¼ 5:6, 1.7 Hz, 1H); 4.18–4.17 (m,
1H), 3.21 (dd, J ¼ 13:2, 8.4 Hz, 1H), 3.06 (q, J ¼ 6:5 Hz,
1H), 2.83 (dd, J ¼ 13:2, 4.4 Hz, 1H), 2.53 (s, 1H), 2.47–
2.46 (m, 1H), 1.99 (m, 1H), 1.84–1.82 (m, 1H), 1.41–1.39
(m, 1H), 1.36 (d, J ¼ 6:5 Hz, 3H) ppm; 13C NMR
(CDCl3) d 177.0, 145.6, 135.8, 132.55, 128.15, 128.0,
127.0, 63.2, 63.1, 69.5, 45.1, 44.4, 43.5, 27.9, 22.2 ppm;
HRMS (FABþ) (M+Hþ): calcd for C19H23N2O2
311.1759, found 311.1756.
3.17. 20-((1S)-((3S)-2-Benzyl-2-azabicyclo-[2.2.1]-hept-
5-ene-3-yl)-ethyl)-isoindole-10,30-dione 17b
Yield: 0.19 g(0.53 mmol, 18%) (lhigt-yellow oil).
22
D
3.14. 20-((3R)-2-Benzyl-2-azabicyclo-[2.2.1]-hept-5-ene-
Rf ¼ 0:56 (ethyl acetate/pentane 2:8); ½aŠ ¼ +2.5 (c 1.0,
3-ylethyl)-isoindole-10,30-dione 16
CHCl3); IR (neat) m 2925, 2254, 1078, 1468, 1382 cmÀ1
;
1H NMR (CDCl3) d 7.74–7.72 (m, 2H), 7.62–7.59 (m,
2H), 7.04–6.93 (m, 5H), 6.50–6.47 (m, 1H), 6.16 (dd,
J ¼ 5:7, 2.0 Hz, 1H); 4.27 (dq, J ¼ 10:1, 7.1 Hz, 1H),
3.57–3.56 (m, 1H), 3.29 (d, J ¼ 14:2 Hz, 1H), 3.14
(d, J ¼ 14:2 Hz, 1H), 2.91–2.90 (m, 1H), 2.47 (d,
J ¼ 10:1 Hz, 1H), 1.92–1.90 (m, 1H), 1.56 (d,
J ¼ 7:1 Hz, 3H), 1.39–1.36 (m, 1H) ppm; 13C NMR
(CDCl3) d 168.7, 139.8, 136.6, 134.0, 133.5, 131.8, 127.8,
127.7, 126.1, 122.8, 66.2, 63.1, 58.4, 52.5, 46.7, 45.4,
16.1 ppm; HRMS (FABþ) (M+Hþ): calcd for
C23H23N2O2 359.1759, found 359.1762.
Yield: 0.25 g(0.68 mmol, 52%) (colorless oil). Rf ¼ 0:40
(ethyl acetate/pentane 2:8); IR (neat) m 2985, 1773, 1708,
1
1386, 1332, 1024 cmÀ1; H NMR (CDCl3) d 7.86–7.83
(m, 2H), 7.75–7.71 (m, 2H), 7.42–7.33 (m, 4H), 7.28–
7.25 (m, 1H), 6.37–6.35 (m, 1H), 6.18 (dd, J ¼ 5:7,
1.8 Hz, 1H), 4.37–4.29 (m, 1H), 3.86 (d, J ¼ 13:4 Hz,
1H), 3.63 (d, J ¼ 1:1 Hz, 1H), 3.27 (d, J ¼ 13:4 Hz, 1H),
2.58 (d, J ¼ 1:6 Hz, 1H), 2.48 (d, J ¼ 10:1 Hz, 1H), 1.83
(d, J ¼ 8:4 Hz, 1H), 1.70 (d, J ¼ 7:1 Hz, 3H), 1.30 (d,
J ¼ 8:4 Hz, 1H) ppm; 13C NMR (CDCl3) d 168.4, 139.7,
136.7, 133.7, 133.6, 131.8, 128.4, 128.1, 126.7, 123.0,
64.5, 62.4, 58.5, 52.7, 45.9, 45.1, 16.8 ppm; HRMS (EI):
calcd for C23H22N2O2 358.1681, found 358.1682.
3.18. 20-(2-Benzyl-2-azabicyclo-[2.2.1]-hept-6-ene-3-yl)-
pyrrolidine-10-carboxylic acid tert-butyl ester 19
(mixture of diastereomers)
3.15. 20-((1S)-(2-Benzyl-2-azabicyclo-[2.2.1]-hept-5-ene-
3-yl)-ethyl)-isoindole-10,30-dione 17a and 17b
Yield: 0.28 mg(0.79 mmol, 70%) (yellow oil). Rf ¼ 0:62
(MeOH/CH2Cl2 1:9); IR (neat) m 2975, 2936, 1683, 1393,
1
The aldehyde 14 (0.62 g, 3.0 mmol) was dissolved in
ꢀ20 ml of CH2Cl2 under a nitrogen atmosphere and
MgSO4 (1.5 g, 0.5 g/mmol) was added. The reaction
mixture was cooled down to 0 °C usingan ice bath and
benzylamine (0.33 ml, 3.0 mmol) was added. After the
imine formation was complete (ꢀ2 h by 1H and 13C
NMR) the MgSO4 was filtered off and the solvent was
evaporated. The crude imine was redissolved in CH2Cl2
(ꢀ20 ml) and cooled down in an acetone/dry ice bath to
)78 °C followed by addition of TiCl4 (0.33 ml,
3.0 mmol). The freshly distilled cyclopentadiene
(0.50 ml, 6.0 mmol) was added dropwise and the reaction
mixture was allowed to warm up to room temperature
overnight. The work up and purification were performed
as described above. Compounds 17a and 17b were
obtained in total yield 0.43 g(1.2 mmol, 40%) after
purification.
1365, 1170, 1103, 911 cmÀ1; H NMR (CDCl3) d 7.37–
7.23 (m), 6.45–6.43 (m), 6.08–6.03 (m), 4.10 (br s), 3.90
(br s), 3.69–3.09 (m), 2.70–2.66 (m), 2.00–1.75 (m), 1.47
(s), 1.26 (s) ppm; HRMS (EI): calcd for C22H30N2O2
354.2307, found 354.2306.
Acknowledgement
This work was supported by grants from The Swedish
Research Council.
References and notes
1. Hetero Diels–Alder Methodology in Organic Synthesis;
Academic: London, 1987; Chapter 2.
2. (a) Alonso, D. A.; Guijarro, D.; Pinho, P.; Temme, O.;
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3.16. 20-((1S)-((3R)-2-Benzyl-2-azabicyclo-[2.2.1]-hept-
5-ene-3-yl)-ethyl)-isoindole-10,30-dione 17a
€
Sodergren, M. J.; Bertilsson, S. K.; Andersson, P. G.
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Yield: 0.24 g(0.67 mmol, 22%) (lhigt-yellow oil).
22
D
Rf ¼ 0:45 (ethyl acetate/pentane 2:8); ½aŠ ¼ +24 (c 1.0,
CHCl3); IR (neat) m 2924, 2254, 1706, 1381 cmÀ1; H
1
NMR (CDCl3) d 7.80–7.66 (m, 2H), 7.60–7.56 (m, 2H),
7.03–6.92 (m, 5H); 6.42–6.40 (m, 1H), 6.28–6.26 (m,
1H), 3.97 (dq, J ¼ 10:1, 7.1 Hz, 1H), 3.61 (d,
J ¼ 14:2 Hz, 1H), 3.47 (dd, J ¼ 10:1, 3.0 Hz, 1H), 3.43

452
A. Trifonova, P. G. Andersson / Tetrahedron: Asymmetry 15 (2004) 445–452
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D
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D
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