The aza-Diels-Alder reaction protocol - A useful approach to chiral, sterically constrained α-amino acid derivatives

Article abstract of DOI:10.1016/S0040-4020(01)00531-2

Different types of polycyclic α-amino acid derivatives are prepared from chiral imines by using well-established aza-Diels-Alder reaction conditions. Simply by varying the diene moiety, different products such as spirocyclic compounds 8 and 9, anthracene 10, and tetrahydroquinolines 15-21 are formed.

Full text of DOI:10.1016/S0040-4020(01)00531-2

TETRAHEDRON
Pergamon
Tetrahedron 57 72001) 6399±6406
The aza-Diels±Alder reaction protocolÐa useful approach to
chiral, sterically constrained a-amino acid derivatives
Sophie K. Bertilsson, Jenny K. Ekegren, Stefan A. Modin and Pher G. Anderssonp
Department of Organic Chemistry, Institute of Chemistry, Uppsala University, P.O. Box 531, SE-751 21 Uppsala, Sweden
Received 30 January 2001; revised 23 February 2001; accepted 23 March 2001
AbstractÐDifferent types of polycyclic a-amino acid derivatives are prepared from chiral imines by using well-established aza-Diels±
Alder reaction conditions. Simply by varying the diene moiety, different products such as spirocyclic compounds 8 and 9, anthracene 10, and
tetrahydroquinolines 15±21 are formed. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
both enantiomeric forms at equal cost, either of the
enantiomers of 1 are as easily obtained.
a-Amino acids can be found almost anywhere in nature,
most evident as the building blocks of peptides and proteins
but also extensively in other natural products.1 In the area of
organic synthesis, a-amino acids are one of the most
frequently used sources of chirality. The use of both natural
and unnatural a-amino acids and their derivatives as chiral
reagents, auxiliaries, and ligands for asymmetric catalysis is
widely spread.2,3a This has resulted in the development of a
vast number of methods for the asymmetric synthesis of
nonproteinogenic a-amino acids.3 Among these, the
asymmetric aza-Diels±Alder reaction of imines provide an
effective route to optically active, sterically constrained
a-amino acid derivatives.4±6 Conformationally restricted
amino acids, precursors to b-amino alcohols, are highly
interesting synthetic targets since they are valuable as chiral
inducers in different asymmetric transformations.
Dialkyltartrate serves as precursor for the imine dienophile.
An oxidative cleavage of the tartrate produces alkyl-
glyoxylate, which is reacted with 7S)- or 7R)-1-phenylethyl-
amine to obtain the chiral imine. Aza-bicyclo-
[2.2.1]heptene derivative 1 is then formed by treating
protonated imine with a diene, here cyclopentadiene.8 The
Diels±Alder adduct 1 has, after different modi®cations,
been used with great success in a variety of reactions, e.g.
diethylzinc additions to imines and aldehydes, transfer
hydrogenation of ketones, and rearrangement of meso-
epoxides 7Fig. 1).7
The ®rst step in the modi®cation of the aza-Diels±Alder
adduct is a hydrogenation and/or a debenzylation reaction
7Scheme 2, 2 and 3). Under hydrogenation conditions,
hydrogenolytic cleavage of the strained allylic C±N bond
could occur as a side reaction to produce highly useful
a-amino esters 4 or 5 7Scheme 2). For the protocol to be
synthetically useful, reaction conditions were developed to
obtain each of the four possible amino esters as sole
products 7Scheme 2).9 The acid-catalysed allylic cleavage
is avoided by neutralising traces of acid in the reaction
medium by addition of base. At the high hydrogen pressure
needed for the preparation of 3, the ole®n hydrogenation
seem to be fast enough to suppress the allylic cleavage with-
out using base as additive. With addition of acid to the
reaction, the rate of allylic C±N cleavage increases, leading
to exclusive formation of ring-opened products 4 or 5. By
the use of iminoketones the above strategy can also be
extended to the synthesis of different optically active
a-amino ketones.
Since 1996, we have focused part of our research on the
sterically constrained 2-aza-norbornene derivative
1
7Scheme 1).7 As the chiral auxiliary 77S)-72)- or 7R)-71)-
1-phenylethylamine) used in the synthesis is available in
Scheme 1. 2-Aza-norbornene derivatives made via a Diels±Alder reaction.
Keywords: a-amino acid; aza-Diels±Alder reaction; anthracene;
tetrahydroquinoline.
Corresponding author. Tel.: 146-184713801; fax: 146-18512524;
e-mail: phera@kemi.uu.se
A broad range of imines can be used as dienophiles in the
aza-Diels±Alder reaction. Some earlier work in this area
made in our research group is summarised in Table 1.
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020701)00 531-2

6400
S. K. Bertilsson et al. / Tetrahedron 57 +2001) 6399±6406
Figure 1. Versatility of the 2-aza-norbornane structure as chiral ligand.7
Scheme 2. 7i) H2 71 atm), 1 equiv K2CO3, EtOH 72); 7ii) H2 77 atm), EtOH 73); 7iii) H2 71 atm), HOAc 74); 7iv) H2 71 atm), 10equiv HOAc, MeOH 7 5).
Table 1. Exploring different imines in the asymmetric aza-Diels±Alder reaction9,10
Entry
R
Yield 7%)a
exo/endo selectivityb
d.r.b,c
References
1
2
3
4
5
6
7
8
EtO2C
BnO2C
PhCO
2-Pyridyl
4-Pyridyl
2-Quinolnyl
4-Quinolnyl
2-Imidazoyl
2-Thiazoyl
Pyrrolidine-1-carbonyl
Piperidine-1-carbonyl
Morpholine-1-carbonyl
70
83
42
80
60
80
79
60
80
40
29
14
.99:2
.99:1
95:5
.99:1
.99:1
.99:1
.99:1
.99:1
.99:1
95:5
90:10
97:3
10a
10b
9
83:17
87:13
80:20
90:10
90:10
75:25
90:10
80:20
80:20
79:21
10c
10c
10c
10c
10c
10c
10d
10d
10d
9
10
11
12
96:4
95:5
a
Isolated yield.
Determined by NMR spectroscopy on the crude reaction mixture.
Diastereomeric ratio of exo-isomers.
b
c
Using this type of dienophile, the exo/endo selectivity is
generally as high as .98:2 in favour of the exo-isomer
7Table 1).4a Also the selectivity between the two exo-
isomers is high, typically about 90:10 7Table 1), and the
pure diastereomers can easily be obtained using ¯ash
chromatography.
When imines derived from aromatic amines are used in the
Diels±Alder reaction, the imine turns to act as a diene
instead of a dienophile. To induce stereoselectivity in the
reaction, an optically active glyoxylate can be used for
formation of imine. The concept of using such chiral hetero-
dienes has been much less explored than the chiral hetero-
dienophile approach.4,12 Under acidic conditions, the diene
adds to a number of electron rich dienophiles, such as cyclo-
pentadiene, cyclohexadiene, dihydrofuran, and indene, to
afford different tetrahydroquinolines.13 Trace amounts of
aza-norbornene product is obtained in some of the
reactions. The tetrahydroquinoline backbone is frequently
observed in natural products14 and is found in numerous
Access to a more extensive amount of the endo-isomer
was given as a synthetic route to invert the stereochemistry
at C-3 in the aza-norbornyl skeleton was developed.11
Deprotonation, followed by a selective electrophile addition
produce the endo-isomer in yields up to 90% and selectivity
up to .98%. A range of electrophiles 7E1, Table 2) can
be used in the reaction, e.g. water, methyl iodide, and
benzaldehyde.
commercial
products,
including
pharmaceuticals,
fragrances and dyes.15 Derivatives have been found to

S. K. Bertilsson et al. / Tetrahedron 57 +2001) 6399±6406
Table 2. Different electrophiles in the addition to aminoesters
6401
Next, we turned to dienes that would not only increase the
steric bulk but also change the electronic properties of the
bicyclic structure. Anthracene and its derivatives undergo
Diels±Alder reactions with a number of different dieno-
philes.20 Yet, this group of dienes has not, to our knowledge,
been used in combination with a chiral imine dienophile
before. Due to the rather electron-poor character of anthra-
cene, a reaction with an electron de®cient imine is likely to
be more sluggish than for cyclopentadiene. This is evident,
as only a moderate yield of 10 7Scheme 4) was isolated after
treating anthracene with 77S)-1-phenylethylimino)-acetic
acid ethyl ester and acids.8
Entry
E1
E
Selectivity 7%)
Yield 7%)
1
2
3
4
5
H2O
CH3I
C3H5Br
C6H5CHO
CH3OCOCl
H
CH3
C3H5
7090
.98
.98
.98
.98
80
67
68
75
C6H5CHOH
CH3OCO
7i) LDA, 2208C; 7ii) E1; 7iii) H2O.
The highly constrained aza-Diels±Alder adduct 10 can be
further elaborated to form the ring-opened product 11 by
treatment with Pd7OH)2 under H2.21 The weaker endo-cyclic
benzylic bond is hydrogenolysed ®rst to form N-protected
11 which is deprotected after further treatment with H2. Due
to the lower reactivity of the exo-cyclic benzylic bond in the
structure, it was not possible to isolate any N-deprotected 10
7Scheme 4).
exhibit, e.g., antitumour activities and can also act as potent
antipsycotic agents.16
2. Results and discussion
Most of our earlier research has been concentrated on how
to modify the chiral imine dienophile to extend the scope of
the aza-Diels±Alder reaction. We now focus on the diene
moiety17 in the search for rigid amino acid derivatives
suitable as building blocks in asymmetric synthesis. Our
As mentioned earlier, chiral aromatic imines are ef®cient
precursors in the synthesis of tetrahydroquinolines13Ðthe
third class of amino acid derivatives included in the study.
Our main goal in this well explored area was to apply and
evaluate ethyl lactate, ethyl mandelate and camphorsultam
as chiral auxiliaries for the synthesis of optically active
tetrahydroquinolines.22 Of these, ethyl lactate have the
great advantage of being highly accessible at low cost.
Others have used a similar strategy for making chiral
quinoline derivatives but with the help of more expensive
chiral auxiliaries, e.g. 72)-8-phenylmenthol.13d
Scheme 3. 7i) nˆ1: NaOH, 1,2-dichloroethane, tetra-n-butylammonium
iodide, rt, overnight; nˆ3: NaH, 1,4-dibromobutane, THF, rt; 7ii) 77R)- or
7S)-1-phenylethylimino)-acetic acid methyl ester, TFA, BF3´Et2O, CH2Cl2,
2788C to rt.
The imine precursors were synthesised by coupling of
fumaryl chloride with different chiral auxiliaries to form
Scheme 4. 7i) 77S)-1-phenylethylimino)-acetic acid methyl ester, TFA, BF3´Et2O, CH2Cl2, 2788C to rt, overnight; 7ii) H2 7500 psi), Pd7OH)2, EtOH, 7 days.
®rst interest was dienes having a spiro-cyclic skeleton.
The resulting increased steric bulk at the 1-carbon bridge
in the Diels±Alder adduct would open up for a new group of
structures with potential in various ®elds of asymmetric
catalysis. Spiro-dienes 6 and 7 were synthesised by the
coupling of cyclopentadiene with a dihaloalkane 7Scheme
3).18 All attempts to synthesise spiro[3.4]octa-5,7-diene
7nˆ2, Scheme 3) and spiro[4.5]deca-1,3-diene 7nˆ4,
Scheme 3) failed, which is in accordance with results
published earlier by others.19 The spiro-dienes were used
in the aza-Diels±Alder reaction to obtain spiro-aminoesters
8 and 9 7Scheme 3).8 The yield in the cycloaddition reaction
of 6 and 7 are generally low, probably due to the high
tendency for diene polymerisation in acidic reaction
medium.
Scheme 5. 7i) 12: 7S)-72)-ethyl lactate, 1108C, overnight; 13: 7S)-71)-ethyl
mandelate, 1108C, overnight; 14: 71S,2R)-72)-2,10-camphorsultam, NaH,
toluene, rt, overnight.

6402
S. K. Bertilsson et al. / Tetrahedron 57 +2001) 6399±6406
Table 3. Synthesis of tetrahydroquinolines 15±21
Ê
7i) O3, CH2Cl2, 2788C then Me2S, 2788C to rt overnight; 7ii) amine, MS 4 A, CH2Cl2, rt, 6 h, then TFA, BF3´Et2O, and cyclopentadiene 7entry 1±6) or
cyclopentene 7entry 7), 2788C to rt overnight.
See Scheme 5.
a
b
Isolated.
Determined on the crude reaction mixture by NMR spectroscopy.
c
the diesters 12 and 13, and the diamide 14 7Scheme 5). The
fumaryl derivatives were then oxidatively cleaved by ozone
to the corresponding glyoxylates, which were converted to
imine by treatment with different aniline derivatives. With-
out isolation of the imine, using the same protocol as for the
synthesis of 1 and 8±10, the reaction mixture was acidi®ed
and cyclopentadiene or cyclopentene was added to furnish
tetrahydroquinolines 15±21 7Table 3). To verify the dia-
stereoselectivity obtained in the cycloadditions 7Table 3),
the enantiomeric excess of the corresponding amino alco-
hols was determined 7HPLC). The relative stereochemistry
of 15±21 were assigned according to the literature.13
3. Conclusion
Two new types of bicyclic aza-Diels±Alder adducts have
been synthesised. Spiro-structures 8 and 9 provide the
possibility to investigate the in¯uence of steric bulk from
the 1-carbon-bridge which has not been possible before.
Anthracene derivative 10 can be used for evaluation of
increased in steric bulk and electronic effects on, e.g., ligand
performance. We have also presented an enantioselective
route to tetrahydroquinolines using chiral auxiliaries
available at low cost.
The cycloadducts were obtained in moderate to high yields
and with diastereoselectivity ranging from 74:26 to 87:13
7Table 3). Enantioselectivity up to 92% was observed when
measured on amino alcohols from puri®ed 15±21 7¯ash
chromatography). This clearly shows the possibility of
separating the diastereomers formed by simple ¯ash
chromatography. When using 7S)-ethyl lactate as chiral
auxiliary, cyclopentadiene is acting as a better dienophile
compared to cyclopentene 7cf. entries 1 and 7, Table 3). The
addition of steric bulk to the imine seems not to affect the
reaction signi®cantly 7cf. entries 2±4). Also, no obvious
correlation between electronic properties of the diene,
reactivity, and selectivity was observed 7cf. entries 1, 5±7
with 2±4). Evident from the results is that the cheap
7S)-ethyl lactate works just as well as chiral auxiliary as
the more elaborate 71S,2R)-72)-2,10-camphorsultam struc-
ture. Even though the obtained stereoselectivity is slightly
lower than that reported using 72)-8-phenylmenthol as
chiral inducer,13d the low cost of 7S)-ethyl lactate makes
our route highly competitive.
4. Experimental
4.1. General
All reactions were run under argon or nitrogen using dry
glassware and magnetic stirring. THF was freshly distilled
from a deep-blue solution of sodium-benzophenone ketyl
under nitrogen. CH2Cl2 was distilled from powdered CaH2
under nitrogen just prior to use. Flash chromatography was
Ê
performed using Matrex silica gel 60A 737±70 mm).
Analytical TLC was carried out utilising 0.25 mm precoated
plates from Merck, silica gel 60UV
visualised by the use of UV light and ethanolic phos-
and spots were
254
phomolybdic acid followed by heating. H and 13C NMR
1
spectra were recorded on a Varian Gemini 200 or a Varian
Unity 400 spectrometer at ambient temperature for CDCl3
solutions. Chemical shifts for protons are reported using the
residual CHCl3 as internal reference 7d 7.26). Carbon
signals are referred to the shift from the 13C signal of
CDCl3 7d 77.0). Infrared spectra were recorded on a

S. K. Bertilsson et al. / Tetrahedron 57 +2001) 6399±6406
6403
Perkin±Elmer 1760FT-IR spectrometer. Optical rotations
were measured using a Perkin±Elmer 241 polarimeter.
Mass spectra were recorded using a Finnigan MAT GCQ
PLUS system 7EI; 70eV).
procedure described for 8 was followed, using dimethyl
7l)-tartrate 70.92 g, 5.17 mmol), 7S)-1-phenylethylamine
71.32 mL, 10.3 mmol), and 7 71.50g, 12.5 mmol), which
gave 9 as a mixture of diastereomers 7major exo/minor
exo/endo, 70:20:10). Puri®cation was performed using
¯ash chromatography 7silica gel deactivated with Et3N, pen-
tane/EtOAc, 95:5) to obtain the major exo-isomer as a white
4.1.1. Spiro[2.4]hepta-4,6-diene 26). Diene 6 was synthe-
sised using a slightly modi®ed literature procedure.18a
NaOH 725.9 g, 648 mmol), tetra-n-butylammonium iodide
71.40g, 3.83 mmol), cyclopentadiene 715 mL, 181 mmol),
and 1,2-dichloroethane 713 mL, 165 mmol) were stirred for
8 h. A solution of THF and H2O 71/1, 50mL) was added and
the resulting mixture was poured onto an ice/water slurry.
The organic layer was separated and the aqueous phase
extracted with pentane 72£200 mL). The combined organic
layers were washed with 0.5 M HCl 750 mL), water
72£50mL) and dried 7MgSO 4). After distillation 735±
408C, 10mmHg), 6 was obtained 73.5 g, 23%). Spectro-
scopic and physical data were in complete agreement with
those published.23
25
solid in 34% yield 71.1 g). 9: mp 94±958C; [a]D ˆ178.4
1
7cˆ0.92, CH2Cl2); IR 7KBr, cm21) 3045, 2978, 1710; H
NMR 7400 MHz) d 7.36 72H, dd, Jˆ7.1, 1.4 Hz), 7.24 72H,
dt, Jˆ7.1, 1.6 Hz), 7.17 71H, m), 6.46 71H, m), 6.2071H,
m), 3.75 71H, m), 3.33 73H, s), 3.27 71H, q, Jˆ6.6 Hz), 2.77
71H, m), 2.43 71H, m), 2.20±2.12 71H, m), 1.62±1.21 76H,
m), 1.39 73H, d, Jˆ6.6 Hz), 1.12 71H, dt, Jˆ13.7, 8.5 Hz);
13C NMR 7100.4 MHz) d 173.1, 144.0, 136.9, 133.6, 128.7,
127.5, 126.9, 69.6, 66.4, 56.5, 51.1, 46.9, 33.4, 31.4, 26.4,
25.1, 21.0, 18.9; MS 7GC) m/z 7rel. intensity) 312 7M1H, 5),
296 73), 252 772), 206 77), 148 7100); Anal. Calcd for
C20H25NO2: C, 77.14; H, 8.09; N, 4.50. Found: C, 76.96;
H, 8.12; N, 4.32.
4.1.2. Spiro[4.4]nona-1,3-diene 27). Diene 7 was synthe-
sised using a literature method.18b Physical and spectro-
scopic data were in complete agreement with those
published.24
4.1.5. Cycloadduct with anthracene 210). The procedure
described for 8 was followed using diethyl-7l)-tartrate
71.50g, 7.30mmol), 7 S)-1-phenylethylamine 71.87 mL,
14.6 mmol) and anthracene 73.25 g, 18.2 mmol, added as
solid), which gave 10 as a mixture of two diastereomers
757:43, 6.7 g). The crude product was puri®ed by ¯ash chro-
matography 7silica, pentane/EtOAc, 90:10) to afford pure
major diastereomer in 37% yield 72.1 g, 5.3 mmol). 10: Rf
4.1.3. Cycloadduct with spiro[2.4]hepta-4,6-diene 28). To
dimethyl-7l)-tartrate 76.03 g, 33.7 mmol) in Et2O 780mL)
at 08C was added periodic acid 77.65 g, 33.7 mmol) in small
portions during 20min. The reaction mixture was then stir-
red at room temperature for 1 h. After drying 7MgSO4), the
ether solution was ®ltered through Celitee, and concen-
trated in vacuo. The residual was dissolved in CH2Cl2
25
0.25 7pentane/EtOAc 9:1); mp 105±1068C; [a]D ˆ123.1
1
7cˆ1.06, CHCl3); IR 7®lm, cm21) 3425, 1752, 1718; H
NMR 7300 MHz) d 7.32±7.44 73H, m), 7.05±7.24 710H,
m), 5.39 71H, s), 4.42 71H, d, Jˆ2.5 Hz), 3.74 72H, q,
Jˆ7.1 Hz), 3.11 71H, d, Jˆ2.5 Hz), 2.97 71H, q,
Jˆ6.5 Hz), 1.52 73H, d, Jˆ6.5 Hz), 0.90 73H, t,
Jˆ7.1 Hz); 13C NMR 775.3 MHz) d 172.3, 144.5, 142.6,
141.0, 140.0, 128.1, 128.0, 127.0, 126.4, 126.35, 126.27,
126.0, 124.0, 123.9, 123.8, 66.2, 64.1, 60.2, 59.5, 47.8,
21.6, 14.0; Anal. Calcd for C26H25NO2: C, 81.43; H, 6.57;
N, 3.65. Found: C, 81.28; H, 6.41; N, 3.51.
Ê
7100 mL), activated MS 4 A was added and the reaction
mixture was cooled to 08C. 7R)-1-Phenylethylamine
78.62 mL, 67.3 mmol) was added dropwise via syringe.
After stirring for 30min, the reaction was cooled further
to 2788C and TFA 75.10mL, 67.3 mmol), BF 3´OEt2
78.53 mL, 67.3 mmol) and 6 76.20g, 67.3 mmol) were
added dropwise. The reaction mixture was then stirred
over night while the temperature was allowed to rise slowly
to rt. To quench the reaction, NaHCO3 7aq. sat., 100 mL)
was added. The organic layer was separated and subse-
quently washed with brine 7100 mL) and dried 7MgSO4).
After concentration in vacuo, the crude product was
obtained as a 4:3 mixture of the two exo-isomers 795%,
18.0g, 63.6 mmol). Puri®cation was performed using ¯ash
chromatography 7silica gel deactivated with Et3N, pentane/
EtOAc, 9:1 to 4:1) to afford the major exo-isomer in 32%
yield from dimethyl-7l)-tartrate 76.0g, 21 mmol). 8: Rf 0.50
4.1.6. 21R)-Amino-29,10-dihydro-anthracen-9-yl)-acetic
acid ethyl ester 211). Dry Pd7OH)2/C 720%, 0.40 g wet
weight) was added to 10 70.50 g, 1.30 mmol), dissolved in
EtOH 725 mL). The mixture was stirred under H2 at 500 psi
at room temperature for 7 days. The catalyst was removed
by ®ltration through Celitee, and the ®ltrate was evaporated
in vacuo. The crude product was puri®ed by ¯ash chromato-
graphy 7silica, Et2O) to afford 11 70.3 g, 81%) as a white
solid. All spectroscopic and physical data were in complete
agreement with the reported for the racemic compound.21
23
7pentane/Et2O 5:1); [a]D ˆ159.9 7cˆ3.83, CH2Cl2); IR
1
7®lm, cm21) 3065, 3026, 2963, 1737; H NMR 7400 MHz)
25
d 7.36±7.24 75H, m), 6.43 71H, dd, Jˆ5.2, 2.4 Hz), 6.39
71H, m), 6.07 71H, dd, Jˆ5.2, 1.7 Hz), 3.74 73H, s), 3.66
71H, q, Jˆ6.6 Hz), 3.3071H, m), 2.05 71H, m), 1.70±1.64
71H, m), 1.60±1.45 72H, m), 1.35 73H, d, Jˆ6.6 Hz), 1.33±
1.28 71H, m); 13C NMR 7100.4 MHz) d 174.1, 145.3, 144.4,
140.0, 128.5, 127.8, 127.3, 127.1, 127.0, 56.9, 55.4, 51.9,
37.7, 24.7, 13.5, 13.2; MS 7GC) m/z 7rel. intensity) 284
7M1H1, 19), 224 7100), 163 76), 120 769), 105 796), 93
769), 77 728); Anal. Calcd for C18H21NO2: C, 76.30; H,
7.47; N, 4.94. Found: C, 76.02; H, 7.27; N, 5.03.
[a]D ˆ135.2 7cˆ1.22, CHCl3).
4.1.7. Bis[2S)-1-2ethoxycarbonyl)ethyl] fumarate 212).
Fumarate 12 was prepared from 7S)-ethyl lactate and
fumaryl chloride according to a literature procedure.25 All
spectroscopic and physical data were in agreement with the
data for the commercial available compound.
4.1.8.
Bis[2S)-1-2ethoxycarbonyl)-1-2phenyl)methyl]
fumarate 213). Compound 13 was prepared from 7S)-ethyl
mandelate and fumaryl chloride according to a literature
procedure.25 13: IR 7KBr, cm21) 3067, 2983, 1719, 1646;
4.1.4. Cycloadduct with spiro[4.4]nona-1,3-diene 29). The

6404
S. K. Bertilsson et al. / Tetrahedron 57 +2001) 6399±6406
1H NMR 7200 MHz) d 7.59±7.31 7m, 10H), 7.07 7s, 2H),
6.02 7s, 2H), 4.20 7q, 4H, Jˆ7.0Hz), 1.23 76H, t, Jˆ7.0Hz);
13C NMR 750.2 MHz) d 168.1, 163.9, 133.6, 133.3, 129.4,
128.8, 127.6, 75.3, 61.9, 13.9; MS 7GC) m/z 7rel. intensity)
4407M , ,1), 216 735), 164 798), 163 7100), 135 748), 91
731); Anal. Calcd for C24H24O8: C, 65.45; H, 5.49. Found: C,
65.46; H, 5.50.
2.507m, 2H), 1.55 7d, 3H, Jˆ7.0Hz), 1.30 7t, 3H,
Jˆ7.0Hz); 13C NMR 750.2 MHz) d 171.2, 170.0, 143.5,
133.6, 129.9, 128.4, 126.1, 125.6, 119.0, 115.5, 68.9, 61.2,
56.0, 46.1, 40.7, 32.3, 16.7, 13.9; MS 7GC) m/z 7rel. inten-
sity) 315 7M1, 36), 171 746), 170 7100), 169 723), 168 730);
Anal. Calcd for C18H21NO4: C, 68.55; H, 6.71; N, 4.44.
Found: C, 68.40; H, 6.67; N, 4.28.
1
4.1.9. 22)-N,N0-Fumaroylbis[22R)-bornane-2, 10-sultam]
214). Compound 14 was prepared from 71S)-72)-2,10-
camphorsultam and fumaryl chloride according to a litera-
ture procedure.26 All spectroscopic and physical data were
in complete agreement with the reported.27
4.1.12. 23aR,4S,9bR)-6-Ethyl-3a,4,5,9b-tetrahydro-3H-
cyclopenta[c]quinoline-4-carboxylic acid 21S)-1-ethoxy-
carbonyl-ethyl ester 217). Following the same procedure
as reported for 15 using 12 71.47 g, 4.66 mmol), 2-ethyl-
aniline 70.86 mL, 6.99 mmol) and cyclopentadiene
70.69 mL, 8.38 mmol), yielded 17 as a pale yellow oil
71.4 g, 44% from 12). 17: IR 7CH2Cl2, cm21) 3420, 2965,
2939, 1745; 1H NMR 7200 MHz) d 6.97 7app. d, 2H,
Jˆ7.6 Hz), 6.77 7app. t, 1H, Jˆ7.6 Hz), 5.86±5.66 7m,
2H), 5.24 7q, 1H, Jˆ7.0Hz), 4.38±4.13 7m, 5H), 3.62±
3.37 7m, 1H), 2.75±2.407m, 4H), 1.62 7d, 3H, Jˆ7.0Hz),
1.42±1.25 7m, 6H); 13C NMR 750.2 MHz) d 171.5, 170.0,
141.1, 134.0, 129.8, 128.2, 126.2, 125.3, 125.2, 118.5, 69.0,
61.3, 56.0, 46.6, 40.7, 32.3, 23.3, 16.7, 13.9, 12.8; MS 7GC)
m/z 7rel. intensity) 343 7M1, 54), 199 752), 198 7100), 170
731), 169 745); Anal. Calcd for C20H25NO4: C, 69.95; H,
7.34; N, 4.08. Found: C, 69.82; H, 7.44; N, 4.26.
4.1.10. 23aR,4S,9bR)-8-Methoxy-3a,4,5,9b-tetrahydro-
3H-cyclopenta[c]quinoline-4-carboxylic acid 21S)-1-
ethoxycarbonyl ethyl ester 215). Fumarate 12 72.40g,
7.60mmol) was dissolved in CH 2Cl2 7120mL). After cool-
ing to 2788C, O3 was bubbled through the solution until a
blue colour persisted 72 h). The reaction was quenched via
dropwise addition of Me2S 73.35 mL, 45.6 mmol) in CH2Cl2
74.0mL). The mixture was allowed to warm up to room
temperature over night and then evaporated. The product
formed was used without further puri®cation. p-Anisidine
72.02 g, 16.4 mmol) was dissolved in CH2Cl2 725 mL), MS
Ê
3 A were added and the atmosphere was changed to N2. The
product from the ozonolysis was added via syringe as a
solution in CH2Cl2 725 mL). The reaction mixture was
stirred in room temperature for 6 h and then cooled to
2788C. TFA 71.26 mL, 16.3 mmol), BF3´OEt2 72.07 mL,
16.3 mmol) and cyclopentadiene 71.62 mL, 19.6 mmol)
were added via syringe. The temperature was kept at
2788C for 3 h and then allowed to reach room temperature
overnight. NaHCO3 7aq. sat.) was added until the water
phase was slightly basic. The reaction mixture was ®ltrated
through Celitee whereafter the organic phase was dried
7MgSO4), ®ltered and evaporated to dryness. The diastereo-
meric ratio of the crude product was determined by integra-
tion of 13C NMR spectral lines. Puri®cation by ¯ash
chromatography 7silica gel deactivated with Et3N, pen-
tane/EtOAc, 6:1) gave 15 as a yellow oil 73.1 g, 59% from
12). 15: IR 7CH2Cl2, cm21) 3389, 1755, 1727, 1095, 1041;
1H NMR 7200 MHz) d 6.63±6.57 7m, 3H), 5.78±5.65 7m,
2H), 5.18 7q, 1H, Jˆ7.0Hz), 4.23 7q, 2H, Jˆ7.0Hz), 4.16±
4.08 7m, 1H), 4.08±4.01 7m, 1H), 3.95 7br s, 1H), 3.73 7s,
3H), 3.48±3.26 7m, 1H), 2.52 7dd, 2H, Jˆ1.5, 8.9 Hz), 1.54
7d, 3H, Jˆ7.0Hz), 1.30 7t, 3H, Jˆ7.0Hz), 13C NMR
750.2 MHz) d 171.1, 169.9, 152.7, 137.2, 133.2, 130.0,
126.7, 116.4, 113.3, 111.9, 68.7, 61.0, 56.3, 55.1, 46.4,
40.3, 32.1, 16.5, 13.7; MS 7GC) m/z 7rel. intensity) 345
7M1, 48), 201 738), 200 7100), 185 712), 169 714); Anal.
Calcd for C19H23NO5: C, 66.07; H, 6.71; N, 4.06. Found: C,
66.91; H, 6.75; N, 4.05.
4.1.13. 23aR,4S,9bR)-6-Isopropyl-3a,4,5,9b-tetrahydro-
3H-cyclopenta[c]quinoline-4-carboxylic acid 21S)-1-
ethoxycarbonyl-ethyl ester 218). Following the procedure
reported for 15 using 12 71.50g, 4.74 mmol), 2-isopropyl-
aniline 71.57 mL, 11.1 mmol) and cyclopentadiene
71.11 mL, 13.4 mmol), gave 18 as a pale yellow solid
72.2 g, 64% from 12). 18: IR 7CH2Cl2, cm21) 3425, 1755,
1744, 1098; 1H NMR 7200 MHz) d 7.08±6.90 7m, 2H), 6.79
7app. t, 1H, Jˆ7.6 Hz), 5.83±5.65 7m, 2H), 5.23 7q, 1H,
Jˆ7.0Hz), 4.47±4.08 7m, 5H), 3.58±3.36 7m, 1H), 3.12±
2.86 7m, 1H), 2.62 7app. d, 2H, Jˆ8.5 Hz), 1.59 7d, 3H,
Jˆ7.0Hz), 1.40±1.24 7m, 9H); 13C NMR 750.2 MHz) d
171.4, 169.9, 140.5, 134.0, 132.8, 129.8, 126.0, 125.6,
122.2, 118.5, 68.9, 61.1, 56.1, 46.8, 40.6, 32.3, 26.9, 22.3,
21.9, 16.6, 13.9, 13.8; MS 7GC) m/z 7rel. intensity) 357 7M1,
37), 213 748), 212 7100), 171 731), 170 766); Anal. Calcd for
C21H27NO4´0.6 H2O: C, 68.49; H, 7.72; N, 3.80. Found: C,
68.35; H, 7.53; N, 3.90.
4.1.14. 23aR,4S,9bR)-8-Methoxy-3a,4,5,9b-tetrahydro-
3H-cyclopenta[c]quinoline-4-carboxylic acid 21S)-1-
ethoxycarbonyl-phenyl-methyl ester 219). By following
the same procedure as reported for 15 using 13 74.81 g,
10.9 mmol), p-anisidine 72.49 g, 20.2 mmol), and cyclo-
pentadiene 72.01 mL, 24.3 mmol), 19 was afforded as a
yellow oil 75.7 g, 64% from 13). 19: IR 7CH2Cl2, cm21
)
3375, 1746, 1505, 1229, 1042; 1H NMR 7200 MHz) d
7.62±7.25 7m, 5H), 6.70±6.51 7m, 3H), 6.05 7s, 1H),
5.82±5.66 7m, 2H), 4.33±4.01 7m, 5H), 3.64 7s, 3H),
3.59±3.28 7m, 1H), 2.86±2.61 7m, 2H), 1.21 7t, 3H,
Jˆ7.0Hz); 13C NMR 750.2 MHz) d 171.1, 167.9, 152.6,
137.2, 133.2, 133.1, 129.9, 128.8, 128.3, 127.9, 127.1,
126.5, 126.1, 116.3, 113.3, 111.8, 74.4, 61.2, 56.3, 54.9,
46.3, 40.3, 32.2, 13.4; MS 7GC) m/z 7rel. intensity) 255
787), 227 7100), 192 757), 165 754); Anal. Calcd for
C24H25NO5: C, 70.75; H, 6.18; N, 3.44. Found: C, 70.59;
H, 6.25; N, 3.28.
4.1.11. 23aR,4S,9bR)-3a,4,5,9b-Tetrahydro-H-cyclopen-
ta[c]quinoline-4-carboxylic acid 21S)-1-ethoxycarbonyl-
ethyl ester 216). By following the procedure reported for 15
using 12 71.51 g, 4.80mmol), aniline 71.03 mL, 11.3 mmol)
and cyclopentadiene 71.12 mL, 13.5 mmol), afforded 16 as a
pale yellow solid 71.9 g, 62% from 12). 16: IR 7CH2Cl2,
1
cm21) 3399, 1755, 1730, 1097; H NMR 7200 MHz) d
7.07±6.93 7m, 2H), 6.79±6.56 7m, 2H), 5.82±5.61 7m,
2H), 5.19 7q, 1H, Jˆ7.0Hz), 3.52±3.30 7m, 1H), 2.62±

S. K. Bertilsson et al. / Tetrahedron 57 +2001) 6399±6406
6405
4.1.15. 23aR,4S,9bR)-210,10-Dimethyl-3,3-dioxo-3l6-thia-
4-aza-tricyclo[5.2.1.01,5]dec-4-yl)-28-methoxy-3a,4,5,9b-
tetrahydro-3H-cyclopenta[c]quinoline-4-yl)methanone
220). Following the procedure reported for 15 using 14
71.70g, 3.33 mmol), p-anisidine 70.87 g, 7.07 mmol), and
cyclopentadiene 70.69 mL, 8.39 mmol), yielded 20 as a
pale yellow solid 71.4 g, 49% from 14). 20: IR 7CH2Cl2,
1539±1650. 7d) Duthaler, R. O. Tetrahedron 1994, 50,
1539±1650.
4. Weinreb, S. M. Comprehensive Organic Synthesis; Trost,
B. M., Flemming, I., Eds.; Pergamon: Oxford, 1991; Vol. 5,
pp 401±415.
5. For asymmetric aza-Diels±Alder reactions: 7a) Waldmann, H.
Synthesis 1994, 535±551. 7b) Hattori, K.; Yamamoto, H.
Tetrahedron 1993, 49, 1749±1760. 7c) Ishihara, K.; Miyata,
M.; Hattori, K.; Tada, T.; Yamamoto, H. J. Am. Chem. Soc.
1994, 116, 10520±10524. 7d) KuÈndig, E. P.; Xu, L. H.;
Romanens, P.; Bernardinelli, G. Synlett 1996, 270±272.
6. For catalytic asymmetric aza-Diels±Alder reactions, see:
7a) Ishitani, H.; Kobayashi, S. Tetrahedron Lett. 1996, 37,
7357±7360. 7b) Yao, S.; Saaby, S.; Hazell, R. G.; Jùrgensen,
K. A. Chem. Eur. J. 2000, 6, 2435±2448.
1
cm21) 3376, 2887, 1710, 1343, 1039; H NMR 7200 MHz)
d 6.65±6.53 7m, 3H), 5.81±5.64 7m, 1H), 5.63±5.57 7m,
1H), 4.65 7app. d, 1H, Jˆ3.05 Hz), 4.20±4.02 7m, 1H),
4.00±3.87 7m, 1H), 3.69 7s, 3H), 3.58±3.25 7s, 4H), 2.74±
2.507m, 2H), 2.22±1.607m, 5H), 1.42±1.19 7m, 2H), 1.14
7s, 3H), 0.91 7s, 3H); 13C NMR 750.2 MHz) d 172.0, 152.6,
137.0, 133.6, 129.1, 126.7, 116.9, 113.1, 112.0, 64.6, 58.0,
55.1, 52.4, 48.1, 47.3, 46.5, 44.0, 41.3, 37.8, 31.9, 31.3,
26.0, 20.1, 19.3; MS 7GC) m/z 7rel. intensity) 441
7M12H, 1), 256 742), 149 7100), 134 742), 123 719);
Anal. Calcd for C24H30N2O4S: C, 65.13; H, 6.83; N, 6.33;
S, 7.24. Found: C, 64.95; H, 7.00; N, 6.38; S, 7.38.
7. Brandt, P.; Andersson, P. G. Synlett 2000, 1092±1106 and
references cited therein.
8. 7a) Stella, L.; Abraham, H.; Feneau-Dupont, J.; Tinant, B.;
Declercq, J. P. Tetrahedron Lett. 1990, 31, 2603±2606.
7b) Waldmann, H.; Braun, M. Liebigs Ann. Chem. 1991,
1045±1048. 7c) Bailey, P. D.; Wilson, R. D.; Brown, G. R.
J. Chem. Soc., Perkin Trans. 1 1991, 1337±1340.
9. Alonso, D. A.; Bertilsson, S. K.; Johnsson, S. Y.; Nordin,
4.1.16. 23aR,4S,9bS)-8-Methoxy-2,3,3a,4,5,9b-hexahydro-
1H-cyclopenta[c]quinoline-4-carboxylic acid 1-ethoxy-
carbonyl-ethyl ester 221). Following the same procedure
as reported for 15 using 12 72.14 g, 6.77 mmol), p-anisidine
71.73 g, 14.0mmol) and cyclopentene 71.53 mL,
17.4 mmol), 21 was afforded as a yellow oil 71.8 g, 38%
from 12). 21: IR 7CH2Cl2, cm21) 3397, 1755, 1728, 1096,
1042; 1H NMR 7200 MHz) d 6.68±6.46 7m, 3H), 5.15 71H,
q, Jˆ7.2 Hz), 4.4071H, br s), 4.19 72H, q, Jˆ7.2 Hz), 4.02
71H, d, Jˆ3.2 Hz), 3.69 73H, s), 3.39 71H, dt, Jˆ3.2 and
7.3 Hz), 2.99±2.76 72H, m), 2.21±1.96 72H, m), 1.92±1.68
72H, m) 1.51 73H, d, Jˆ7.2 Hz), 1.26 73H, t, Jˆ7.2 Hz); 13C
NMR 750.2 MHz) d 171.8, 170.2, 152.8, 137.3, 127.6,
115.8, 113.7, 112.2, 68.9, 61.3, 56.1, 55.4, 41.3, 40.6,
35.3, 24.7, 24.0, 16.8, 13.9; MS 7GC) m/z 7rel. intensity)
347 7M1, 35), 203 732), 202 7100), 161 714), 160 720);
Anal. Calcd for C19H25NO5: C, 65.69; H, 7.25; N, 4.03.
Found: C, 65.66; H, 7.13; N, 4.19.
È
S. J. M.; Sodergren, M. J.; Andersson, P. G. J. Org. Chem.
1999, 64, 2276±2280.
10. 7a) Abraham, H.; Stella, L. Tetrahedron 1992, 48, 9707±9718.
7b) Guijarro, D.; Pinho, P.; Andersson, P. G. J. Org. Chem.
È
1998, 63, 2530±2535. 7c) Sodergren, M. J.; Andersson, P. G.
Tetrahedron Lett. 1996, 37, 7577±7580. 7d) Hedberg, C.;
Pinho, P.; Roth, P.; Andersson, P. G. J. Org. Chem. 2000,
65, 2810±2812. 7e) Modin, S. A.; Andersson, P. G. J. Org.
Chem. 2000, 65, 6736±6738.
11. Alonso, D. A.; Nordin, S. J. M.; Andersson, P. G. Org. Lett.
1999, 1, 1595±1597.
12. 7a) Tietze, L.-F.; GluÈsenkamp, K.-H. Angew. Chem., Int. Ed.
Engl. 1983, 22, 887±888. 7b) Kober, R.; Papadopoulos, K.;
Miltz, W.; Enders, D.; Steglich, W. Tetrahedron 1985, 41,
1693±1701.
13. 7a) Lucchini, V.; Prato, M.; Quintily, U.; Scorrano, G.
J. Chem. Soc., Chem. Commun. 1984, 48±50. 7b) Lucchini,
V.; Prato, M.; Scorrano, G.; Tecilla, P. J. Org. Chem. 1988, 53,
2251±2258. 7c) Borrione, E.; Prato, M.; Scorrano, G.;
Stivanello, M. J. Heterocycl. Chem. 1988, 25, 1831±1835.
7d) Borrione, E.; Prato, M.; Scorrano, G.; Stivanello, M.
Acknowledgements
We thank the Swedish Natural Research Council 7NFR),
The Swedish Foundation for Strategic Research 7SSF),
Solvias AG and The Swedish Research Council for
Engineering Sciences 7TFR) for generous ®nancial support.
J. Chem. Soc., Perkin Trans.
1 1989, 2245±2250.
7e) Lucchini, V.; Prato, M.; Scorrano, G.; Stivanello, M.;
Valle, G. J. Chem. Soc., Perkin Trans. 2 1992, 259±266.
7f) Babu, G.; Perumal, P. T. Tetrahedron 1998, 54, 1627±
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1995, 1195±1202. 7h) Loh, T.-P.; Koh, K. S.-V.; Sim, K.-Y.;
Leong, W.-K. Tetrahedron Lett. 1999, 40, 8447±8451.
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Ê
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