Catalytic enantioselective 1,3-dipolar cycloaddition reactions of cyclic nitrones: A simple approach for the formation of optically active isoquinoline derivatives

Article abstract of DOI:10.1021/jo001157c

The first highly diastereo- and enantioselective catalytic 1,3-dipolar cycloaddition reaction of cyclic nitrones activated by chiral Lewis acids with electron-rich alkenes has been developed. The nitrones, mainly 3,4-dihydroisoquinoline N-oxides, are activated by chiral 3,3′-aryl BINOL-AlMe complexes and undergo a regio-, diastereo-, and enantioselective 1,3-dipolar cycloaddition reaction with especially alkyl vinyl ethers, giving the exo diastereomer of the cycloaddition products in high yield, >90% de and up to 85% ee. The reaction has been investigated under various conditions, and it is demonstrated that the reaction is an attractive synthetic procedure for the introduction of a chiral center in the 1-position of the isoquinoline skeleton. The mechanism of the reaction is discussed on the basis of the assignment of the absolute configuration of the cycloaddition product and theoretical calculations.

Full text of DOI:10.1021/jo001157c

9080
J . Org. Chem. 2000, 65, 9080-9084
Ca ta lytic En a n tioselective 1,3-Dip ola r Cycloa d d ition Rea ction s of
Cyclic Nitr on es: A Sim p le Ap p r oa ch for th e F or m a tion of
Op tica lly Active Isoqu in olin e Der iva tives
Kim B. J ensen, Mark Roberson, and Karl Anker J ørgensen*
Center for Metal Catalyzed Reactions, Department of Chemistry, Aarhus University,
DK-8000 Aarhus C, Denmark
kaj@kemi.aau.dk
Received J uly 31, 2000
The first highly diastereo- and enantioselective catalytic 1,3-dipolar cycloaddition reaction of cyclic
nitrones activated by chiral Lewis acids with electron-rich alkenes has been developed. The nitrones,
mainly 3,4-dihydroisoquinoline N-oxides, are activated by chiral 3,3′-aryl BINOL-AlMe complexes
and undergo a regio-, diastereo-, and enantioselective 1,3-dipolar cycloaddition reaction with
especially alkyl vinyl ethers, giving the exo diastereomer of the cycloaddition products in high yield,
>90% de and up to 85% ee. The reaction has been investigated under various conditions, and it is
demonstrated that the reaction is an attractive synthetic procedure for the introduction of a chiral
center in the 1-position of the isoquinoline skeleton. The mechanism of the reaction is discussed on
the basis of the assignment of the absolute configuration of the cycloaddition product and theoretical
calculations.
In tr od u ction
the 1,3-dipolar cycloaddition reaction of nitrones, derived
from isoquinolines, and electron-rich alkenes in the
presence of a chiral catalyst.4 This paper presents the
first highly diastereo- and enantioselective 1,3-dipolar
cycloaddition reactions of cyclic nitrones with alkenes
leading to optically active isoxazolidines which easily are
converted to optically active isoquinoline derivatives. To
understand the stereoselection, we will present theoreti-
cal calculations of the nitrone-chiral catalyst intermedi-
ate which can account for both the diastereo- and
enantioselective outcome of the reaction.
The catalytic enantioselective 1,3-dipolar cycloaddition
reaction has recently been developed to be a highly
selective reaction of nitrones with electron-deficient
alkenes activated by chiral Lewis acids.5,6 However, few
synthetic methods are available for the 1,3-dipolar cyclo-
The isoquinoline skeleton constitutes a fundamental
part of numerous natural products and compounds with
physiological activity.1 As many naturally occurring
isoquinoline alkaloids and their nonnatural derivatives
have distinct properties of general interest, an intense
synthetic effort has been devoted to the development of
reactions leading to optically active isoquinoline deriva-
tives. The asymmetric synthesis of, for example, optically
active 1-substituted 1,2,3,4-tetrahydroisoquinolines has
been of considerable interest, as these compounds are
very useful compounds for the preparation of, for ex-
ample, optically active alkaloids.1,2 The synthesis of
optically active 1-substituted 1,2,3,4-tetrahydroisoquino-
lines is normally based on diastereoselective reactions
applying chiral starting material or reagents.2 An at-
tractive procedure for the preparation of optically active
compounds is asymmetric catalysis, and it has been
attempted to synthesize optically active 1-substituted
1,2,3,4-tetrahydroisoquinolines based on enantioselective
reduction of, or addition to, the CdN bond in the 3,4-
dihydroisoquinoline moiety.2f,3
(3) (a) Morimoto, T.; Suzuki, N.; Achiwa, K. Tetrahedron: Asym-
metry 1998, 9, 183. (b) Ukaji, Y.; Shimizu, Y.; Kenmoku, Y.; Ahmed,
A.; Inomata, K. Bull. Chem. Soc. J pn. 2000, 73, 447. (c) Sigman, M.
S.; Vechal, P.; J acobsen, E. N. Angew. Chem., Int. Ed. 2000, 39, 1279.
(4) Numerous reviews describe the formation of isoxazolidine de-
rivatives using a traditional 1,3-dipolar cycloaddition procedure, see,
e.g.: (a) Tufariello, J . J . In 1,3-Dipolar Cycloaddition Chemistry;
Padwa, A., Ed.; Wiley: New York, 1984; Vol. 2, p 83. (b) Torssell, K.
B. G. Nitrile Oxides, Nitrones and Nitronates in Organic Synthesis;
VCH: New York, 1988. (c) Huisgen, R. In 1,3-Dipolar Cycloaddition
Chemistry; Padwa, A., Ed.; Wiley: New York, 1984; Vol. 1, p 1.
(5) Recent reviews concerning 1,3-dipolar cycloaddition reactions:
(a) Gothelf, K. V.; J ørgensen, K. A. Chem. Rev. 1998, 98, 863. (b)
Frederickson, M. Tetrahedron 1997, 53, 403.
A new approach for the formation of optically active
1-substituted 1,2,3,4-tetrahydroisoquinolines would be
* To whom correspondence should be addressed. Fax: (45)-
86196199.
(1) See, e.g.: (a) Bentley, K. W. Nat. Prod. Rep. 1998, 341. (b)
Herbert, R. B. In The Chemistry and Biology of Isoquinoline Alkaloids;
Philipson, J . D., Roberts, M. F., Zenk, M. H., Eds.; Springer-Verlag:
Berlin, 1985; p 213. (c) Dyke, S. F.; Kinsman, R. G.; Kametami, T. G.;
Fukumato, K.;. McDonald, E. Isoquinolines. In Heterocyclic Com-
pounds; Grethe, G., Ed.; Wiley: New York, 1981; Vol. 38, p 1.
(2) See, e.g.: (a) Itoh, T.; Nagata, K.; Miyazaki, M.; Ohsawa, A.
Synlett 1999, 1154. (b) Wanner, K. T.; Beer, H.; Ho¨fner, G.; Ludwig,
M. Eur. J . Org. Chem. 1998, 2019. (c) Barbier, D.; Marazano, C.; Riche,
C.; Das, B. C.; Potier, P. J . Org. Chem. 1998, 63, 1767. (d) Meyers, A.
I. Tetrahedron 1992, 48, 2589. (e) Taniyama, D.; Hasegawa, M.;
Tomioka, K. Tetrahedron: Asymmetry 1999, 10, 221. (f) Monsees, A.;
Laschat, S.; Dix, I. J . Org. Chem. 1998, 63, 10018 and references cited
therein. (g) Rozwadowska, M. D. Heterocycles 1994, 39, 903.
(6) See, e.g.: (a) Gothelf, K. V.; J ørgensen, K. A. J . Org. Chem. 1994,
59, 5687. (b) Gothelf, K. V.; Thomsen, I.; J ørgensen, K. A. J . Am. Chem.
Soc. 1996, 118, 59. (c) J ensen, K. B.; Gothelf, K. V.; Hazell, R. G.;
J ørgensen, K. A. J . Org. Chem. 1997, 62, 2471. (d) J ensen, K. B.;
Gothelf, K. V.; J ørgensen, K. A. Helv. Chem. Acta 1997, 80, 2039. (e)
Hori, K.; Kodama, H.; Ohta, T.; Furukawa, I. J . Org. Chem. 1999, 64,
5017. (f) Kanemasa, S.; Oderaotoshi, Y.; Tanaka, J .; Wada, E. J . Am.
Chem. Soc. 1998, 120, 12355. (g) Kawamura, M.; Kobayashi, S.
Tetrahedron Lett. 1999, 40, 3213. (h) Kobayashi, S.; Kawamura, M. J .
Am. Chem. Soc., 1998, 120, 5840. (i) Desimoni, G.; Faita, G.; Mortoni,
A.; Righetti, P. Tetrahedron Lett. 1999, 40, 2001. (j) Crosignani, S.;
Desimoni, G.; Faita, G.; Filippone, S.; Mortoni, A.; Righetti, P.; Zema,
M. Tetrahedron Lett. 1999, 40, 7007. (k) Heckel, A.; Seebach, D. Angew.
Chem., Int. Ed. 2000, 39, 163.
10.1021/jo001157c CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/06/2000

Optically Active Isoquinoline Derivatives
J . Org. Chem., Vol. 65, No. 26, 2000 9081
Ta ble 1. Ca ta lytic Dia ster eo- a n d En a n tioselective
1,3-Dip ola r Cycloa d d ition Rea ction of 1a w ith 2a
Ca ta lyzed by Differ en t Ch ir a l Alu m in u m Com p lexesa
convb
[%]
rxn time
[h]
exo-3a /
ee exo-3a c
entry
catalyst
endo-3a b
[%]
1
2
3
4
5
6
7
8
9
5
28
88
11
76
96
74
78
30
24
20
20
42
20
46
20
20
46
>95:<5
>95:<5
20:80
85:15
92:8
89:11
98:2
87:13
78:22
0
0
0
24
66
58
82
67
50f
d
AlMe3
AlCl3
e
(R)-4a
(R)-4b
(R)-4c
(R)-4d
(R)-4e
(S)-4f
a
Reaction conditions: solvent, CH2Cl2; scale, 1a (0.1 mmol), 2a
(0.4 mmol), and 20 mol % catalyst. Determined by 1H NMR
b
spectroscopy of the crude product. c The ee of the exo-isomer was
determined by HPLC using
a Daicel Chiralcel OD column.
d
Performed with 10 mol % catalyst and 10 equiv of the alkene.
e Performed with 10 mol % catalyst and 2 equiv of the alkene.
f Opposite enantiomer.
addition reaction of electron-rich alkenes with nitrones
activated by chiral Lewis acids.7 In the few reports on
catalytic enantioselective 1,3-dipolar cycloaddition reac-
tion of monodentate cyclic nitrones to electron-rich al-
kenes, racemic reactions or moderate enantioselectivity
as high as 38% ee have been obtained so far.7c,d,h Fur-
thermore, some of the reactions involving 3,4-dihydroiso-
quinoline N-oxide 1a require up to 2000 bar in order to
proceed.7c
major diastereomer exo-3a are low (entry 4). The 3,3′-
aryl substituted BINOL-AlMe catalysts lead to a sig-
nificant increase in both the conversion, diastereo-, and
enantioselectivity (entries 5-9). The best results are
obtained for BINOLs having phenyl or 2,5-dimethoxy-
phenyl substituents in the 3,3′-position (entries 5 and 7).
The application of catalyst (R)-4d gave 74% conversion,
an exo-3a /endo-3a ratio of 98:2, and 82% ee of exo-3a
(entry 7). This is the first example of a highly diastereo-
and enantioselective catalytic 1,3-dipolar cycloaddition
reaction of a cyclic nitrone. The use of (R)-4e and (S)-4f
gives good diastereo- and enantioselectivity but for the
latter catalyst a somewhat lower yield (entries 8 and 9).
The reaction of 1a with 2a catalyzed by (R)-4b or (R)-
4d has been studied in different solvent compositions and
catalyst loadings. The reaction of 1a with 2a in the
presence of catalyst (R)-4b proceeds well in a variety of
solvents, e.g., CH2Cl2, toluene, CH2Cl2-pet. ether, and
CH2Cl2-t-BuOMe. In all four solvent compositions, 80-
91% isolated yield of exo-3a is obtained. The highest
selectivity for the reaction is achieved by using CH2Cl2-
pet. ether giving exo-3a in >95% de and 78% ee. Even
better enantioselectivity is found for the reaction cata-
lyzed by (R)-4d in CH2Cl2-pet. ether where 85% ee of
exo-3a is obtained. The reaction also proceeds well when
the catalyst loading is reduced to 10 mol % for both
catalyst (R)-4b and (R)-4d where similarly high dia-
stereo- and enantioselectivities are obtained.
Resu lts a n d Discu ssion
Different chiral Lewis acid complexes have been tested
for their ability to induce regio-, diastereo-, and enantio-
selectivity in the reaction of 3,4-dihydroisoquinoline
N-oxide 1a with ethyl vinyl ether 2a (eq 1). It was found
that chiral BINOL-AlX complexes gave the most prom-
ising results, and Table 1 shows some data for the
reaction of 1a with 2a catalyzed by (R)-4a -(S)-4f.
In the absence of a catalyst, only 5% conversion is
found for the reaction of 1a with 2a after 24 h (Table 1,
entry 1). The addition of AlMe3 and AlCl3 leads to a
significant increase in the reaction rate and 28% conver-
sion is observed with AlMe3 (entry 2), while a much
higher conversion of 88% is found for AlCl3 (entry 3). It
is notable that the diastereoselectivity depends on the
aluminum compound used. In the case of AlMe3, the
reaction proceeds with an exo/endo ratio of >95:<5,
whereas with AlCl3 an exo/endo ratio of 20:80 is observed.
A diastereoselective reaction is obtained when using (R)-
4a as the catalyst; however, both the yield and ee of the
(7) (a) Seerden, J .-P. G.; Scholte op Reimer, A. W. A.; Scheeren, H.
W. Tetrahedron Lett. 1994, 35, 4419. (b) Seerden, J .-P. G.; Kuypers,
M. M. M.; Scheeren, H. W. Tetrahedron: Asymmetry 1995, 6, 1441.
(c) Seerden, J .- P. G.; Boeren, M. M. M.; Scheeren, H. W. Tetrahedron
1997, 53, 11843. (d) Ellis, W. W.; Gavrilova, A.; Liable-Sands, L.;
Rheingold, A. L.; Bosnick, B. Organometallics 1999, 18, 332. (e) J ensen,
K. B.; Hazell, R. G.; J ørgensen, K. A. J . Org. Chem. 1999, 64, 2353. (f)
Simonsen, K. B.; Bayo´n, P.; Hazell, R. G.; Gothelf, K. V.; J ørgensen,
K. A. J . Am. Chem. Soc. 1999, 121, 3845. (g) Simonsen, K. B.;
J ørgensen, K. A.; Hu, Q.-S.; Pu, L. Chem. Commun. 1999, 811. (h) Hori,
K.; Ito, J .; Ohta, T.; Furukawa, I. Tetrahedron 1998, 54, 12737.
The 1,3-dipolar cycloaddition reaction of 1a with 2a
has also been studied in the presence of various 3,3′-
phenyl BINOL-derived ligands and different aluminum
Lewis acids. Table 2 gives the results of these investiga-
tions.

9082 J . Org. Chem., Vol. 65, No. 26, 2000
J ensen et al.
Ta ble 2. In flu en ce of Lew is Acid a n d Su bstition a t th e
6,6′-P osition of th e BINOL Liga n d in th e 1,3-Dip ola r
Cycloa d d ition Rea ction of 1a w ith 2a a t Room
Tem p er a tu r ea
Ta ble 3. Dia ster eo- a n d En a n tioselective 1,3-Dip ola r
Cycloa d d ition Rea ction of 1a a n d 1b w ith th e Vin yl
Eth er s 2a -c Ca ta lyzed by th e Ch ir a l Alu m in u m
Com p lexes
cat/mol
[%]
convb rxn time
exo-3a /
ee exo/endo
entry
[%]
[h]
endo-3a b
[%]c
1
2
3
4
5
(R)-4b/20
(S)-4h /20
(R)-4i/20
(R)-4j/20
(R)-4k /10
95
98
98
100
100
95/24
98/20
98/25
100/19
100/20
95:5
98:2
87:13
27:73
42:58
78/30
68d/-
48/0
66/6
13/3
a
Reaction conditions: solvent, CH2Cl2 or CH2Cl2-pet. ether;
scale, 0.1-0.2 mmol. The molar scale is defined from 1a (1 equiv),
b
2a (4 equiv). Determined by 1H NMR spectroscopy of the crude
product. c The ee was determined by HPLC using a Daicel Chiral-
d
cel OD column. Opposite enantiomer.
An introduction of bromine in the 6,6′-position of the
catalyst [(S)-4h ] gives no significant change in conversion
and diastereoselectivity; however, a small decrease in
enantioselectivity is found compared with catalyst (R)-
4b (Table 2, entries 1 and 2). An interesting change of
diastereoselectivity takes place by changing the third
substituent of the aluminum Lewis acid. An exchange of
the methyl substituent [(R)-4b] to chloride [(R)-4i] re-
duces the exo-3a /endo-3a ratio from 95:5 to 87:13, while
the ee of exo-3a is reduced from 78% to 48% (entries 1
and 3). Catalyst (R)-4j which contains the Al-I function-
ality changes the diastereoselectivity of the reaction, and
endo-3a is now formed as the major product (entry 4).
Unfortunately, the ee of endo-3a is low. The use of a
chiral aluminum catalyst substituted with triflate gives
poor diastereo- and enantioselective in the reaction (entry
5). The diastereoselectivity of the 1,3-dipolar cycloaddi-
tion of 1a with 2a is thus dependent on the X-substituent
of the BINOL-AlX catalyst. Although the ee of endo-3a
is low when using (R)-4j as the catalyst, it might be a
useful approach for controlling an endo-selective reaction
of this class of substrates. It should be noted that anions
at the Lewis acid center have previously been shown to
control the diastereoselectivity in 1,3-dipolar cycloaddi-
tion of electron-deficient alkenes with nitrones catalyzed
by TADDOL-TiX2 complexes.6b
A valuable cyclic nitrone for the 1,3-dipolar cycloaddi-
tion reaction is 6,7-dimethoxy-3,4-dihydroisoquinoline
N-oxide 1b. The cycloadducts obtained in the reactions
of this nitrone with electron-rich alkenes are potential
precursors for important natural products and com-
pounds with physiological activity.1,8 The results of the
catalytic diastereo- and enantioselective reaction of the
nitrones 1a ,b with different vinyl ethers 2a -c are pre-
sented in Table 3.
The results in Table 3 show that the catalytic 1,3-
dipolar cycloaddition reaction of 1a and 1b proceeds well
for ethyl vinyl ether 2a and tert-butyl vinyl ether 2b. The
products, exo-3a -d , are obtained in good to high isolated
yield, diastereo- and enantioselectivity (entries 1-4). It
is notable that for the reaction between 1b and 2b, the
reaction gives exclusively exo-3d in high yield and with
65% ee (entry 4). Increasing the size of the vinyl ether to
that of phenyl vinyl ether 2e leads also to a highly
cat./mol
[%]
yield
ee exo/endo
entry
1
2
3
[%]a exo/endob
[%]c
1
2
3
4
5
4d /20
4b/20
4b/10
4b/20
4b/20
1a 2a 3a
1b 2a 3b
1a 2b 3c
1b 2b 3d
1a 2c 3e
85
76
86
92
24
96:4
97:3
95:5
100:0
>95:<5
85/12
70/0
70/26
65/-
10/-
Isolated yield of exo-diastereomer. Determined by 1H NMR
spectroscopy of the crude product. c The ee was determined by
HPLC using a Daicel Chiralcel OD or OJ column.
a
b
diastereoselective reaction; unfortunately, both the yield
and ee of exo-3e are low (entry 5).
We have also performed the 1,3-dipolar cycloaddition
reaction of pyrroline-N-oxide with 2a in the presence of
the chiral BINOL-ALMe catalysts (R)-4b and (R)-4d .
The reaction proceeds with high exo-selectivity and
moderate ee (40%); however, the isolated yield of the
cycloaddition adduct was low (<40% yield).
The catalytic diastereo- and enantioselective reaction
of 6,7-dimethoxy-3,4-dihydroisoquinoline N-oxide 1b with
ethyl vinyl ether 2a leads to the formation of optically
active exo-3b. This reaction allows for a simple and
attractive approach to the introduction of a chiral center,
e.g., an ester functionality, in the 1-position of the
isoquinoline skeleton (Scheme 1). Reaction of exo-3b with
benzyl bromide followed by reduction with H2/Pd(OAc)2
gives the (-)-(1S)-amino ester 5 in high yield. This
reaction shows the potential of the present reaction and
gives a simple procedure for assignment of the absolute
configuration of the chiral center formed in the reaction.
A comparison of the optical rotation of 5 with the
literature value9 shows that catalyst (R)-4b introduces
a (1S)-configuration at the chiral center formed in the
cycloaddition step.
The absolute configuration of the new chiral center in
the 1,3-dipolar cycloaddition reaction of the cyclic ni-
trones with electron-rich alkenes was not predicted by
us because the opposite enantiomer was obtained in the
analogous reactions of acyclic nitrones with electron-rich
alkenes catalyzed by chiral BINOL-AlMe complexes.7f
The origin of this change in the absolute configuration
(8) See, e.g.: (a) Pelletier, J . C.; Cava, M. P. Synthesis 1987, 474.
(b) Fu¨lo¨p, F.; Semega, E.; Berna´th, G. J . Heterocycl. Chem. 1990, 27,
957. (c) Takeuchi, Y.; Kamada, Y.; Nishimura, K.; Nishioka, H.;
Nishikawa, M.; Hashigaki, K.; Yamato, M.; Harayama, T. Chem.
Pharm. Bull. 1994, 42, 796. (d) Fu¨lo¨p, F.; Wamhoff, H.; Soha´r, P.
Synthesis 1995, 863. (e) Ukaji, Y.; Yoshida, Y.; Inomata, K. Tetrahe-
dron: Asymmetry 2000, 11, 733.
(9) Battersby, A. R.; Bink, R.; Edwards, T. P. J . Chem. Soc. 1960,
3474.

Optically Active Isoquinoline Derivatives
J . Org. Chem., Vol. 65, No. 26, 2000 9083
Sch em e 1
upon changing the nitrone from an acyclic to a cyclic
nitrone has been the subject of theoretical calculations.
The calculations have been performed for catalyst (R)-
4b using the AM1 semiempirical method.10 Several
intermediate structures of the complex formed by coor-
dination of nitrone 1a to (R)-4b were investigated. It has
been found that the most stable intermediate 6 (Figure
1a), by theoretical calculations, is the one where the
nitrone coordinates to the chiral catalyst in a fashion that
maximizes π-π interaction between the aromatic part
of the nitrone and the naphthyl ring of the BINOL ligand.
This intermediate (6) has the re-face of the nitrone
shielded by the chiral ligand and is 3 kcal/mol more stable
than the intermediate having the re-face unshielded. The
approach of ethyl vinyl ether 2a to the si-face of the
nitrone in 6 in a diastereo- and enantioselective fashion
shown in Figure 1b is consistent with the stereochemical
outcome of the reaction.
In summary, cyclic nitrones of the 3,4-dihydroisoquino-
line N-oxide type undergo a highly diastereo- and enan-
tioselective 1,3-dipolar cycloaddition reaction with electron-
rich alkenes in the presence of chiral BINOL-AlMe
complexes as catalysts. It is shown that this reaction can
be used for the introduction of a chiral center in the
1-position of the isoquinoline skeleton. The nitrone
coordinates to the chiral BINOL-AlMe catalyst to maxi-
mize π-π interaction between the aromatic part of the
nitrone and the naphthyl ring of the BINOL ligand
leading to an exo-selective approach of the alkene to the
si-face of the activated nitrone.
F igu r e 1. (a) The most stable intermediate (6) of the nitrone
1a coordinated to (R)-4b in a fashion that maximizes the π-π
interaction between the aromatic part of the nitrone and the
naphthyl ring of the (R)-BINOL ligand. Color code: carbon,
gray; nitrogen, blue; oxygen, red; aluminum, yellow. (b)
Approach of ethyl vinyl ether 2a to the si-face of 3,4-dihydro-
isoquinoline N-oxide 1a coordinated to the chiral (R)-BINOL-
ALMe catalyst (R)-4b. Color code: carbon, gray; hydrogen,
white; nitrogen, blue; oxygen, red; aluminum, yellow.
F254 plates and visualized with blue stain. Optical rotations
were measured on a Perkin-Elmer 241 polarimeter. HPLC was
performed using 4.6 mm × 25 cm Daicel Chiracel OD or OJ
columns employing hexane/i-PrOH ratios between 98:2 and
92:8 with UV-detection at 225 nm. All glass equipment was
flame-dried under vacuum before used.
Ma ter ia ls. The chiral ligands in the catalysts 4a ,11 4b,e,12
4c,d ,13 4f,14 4h ,15 and the nitrones 3,4-dihydroisoquinoline
N-oxide 1a and 6,7-dimethoxy-3,4-dihydroisoquinoline N-oxide
1b16 were synthesized according to the literature. tert-Butyl
vinyl ether and ethyl vinyl ether and AlMe3 (2 M in hexan)
were received from Aldrich. The vinyl ethers were distilled
from sodium immediately prior to use. Millex filter units, 45
µm pore size, were received from Millipore.
Gen er a l P r oced u r e for th e Ster eoselective 1,3-Dip ola r
Cycloa d ition Rea ction s. The appropriate ligand (0.04 mmol)
was placed in a 5 mL Schlenk flask. The flask was evaporated
1 h and flushed three times with N2. A solution of CH2Cl2 (1
mL) was added with a syringe. To this solution was added a 2
Exp er im en ta l Section
Gen er a l Meth od s. The 1H and 13C NMR spectra were
recorded in CDCl3, unless otherwise stated, at 300 and 75
MHz, respectively. The chemical shifts are reported in ppm
downfield to TMS (δ ) 0) for 1H NMR and relative to the
central CDCl3 resonance (δ ) 77.0) for 13C NMR. Solvents were
dried using standard conditions and stored over molecular
sieves (4 Å). CH2Cl2 was distilled from CaH2 prior to use.
Purification of reactions products was carried out by flash
chromatography (FC) using Merck silica gel 60 (230-400
mesh). TLC was performed on Merck analytical silica gel 60
(11) Cai, D.; Hughes, D. L.; Verhoeven, T. R.; Reider, P. J . Tetra-
hedron Lett. 1995, 36, 7991.
(12) Simonsen, K. B.; Gothelf, K. V.; J ørgensen, K. A. J . Org. Chem.
1998, 63, 7536.
(10) Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Gill, P. M. W.;
J ohnson, B. G.; Robb, M. A.; Cheeseman, J . R.; Keith, T.; Petersson,
G. A.; Montgomery, J . A.; Raghavachari, K.; Al-Laham, M. A.;
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9084 J . Org. Chem., Vol. 65, No. 26, 2000
J ensen et al.
M solution of AlMe3 in hexane (20 µL, 0.04 mmol) whereupon
the solution turned yellow under the evolution of CH4.7f The
solution was stirred for 1 h, and nitrone 1 (0.2 mmol) was
added together with 4 equiv of the vinyl ethers 2 (1.6 mmol)
and pet. ether (0.5 mL). After the appropriate reaction time,
the reaction was quenched with MeOH (0.2 mL) and filtered
through a 20 mm plug of silica. The silica was washed with
5% MeOH in CH2Cl2 (5 mL), and the combined fractions were
evaporated. The crude product from 1,3-dipolar cycloaddition
reactions of 3,4-dihydroisoquinoline N-oxide 1a with vinyl
ethers 2a -c was purified by FC (silica gel, pet. ether/Et2O,
70:30) to give the single diasteromer of 3. Generally, the endo-
isomers appeared with lower Rf values than the exo-isomers
(∆Rf ) 0.1). The crude product from the 1,3-dipolar cycloaddi-
tion reactions of 6,7-dimethoxy-3,4-dihydroisoquinoline N-
oxide 1b with vinyl ethers 2a ,b was purified by FC. The ligand
was eluated out first (silica gel, pet. ether/Et2O 70:30), chang-
ing the eluent to CH2Cl2/MeOH, 98:2. The exo-isomer was
eluated out as the first of the two diastereomers (∆Rf ) 0.28).
(-)-(2S,10bS)-2-Eth oxy-1,5,6,10b-tetr a h yd r o-2H-isoxa -
zolo[3,2,-a ]isoqu in olin e (exo-3a ). Synthesized according to
the general procedure on a 0.4 mmol scale with catalyst (R)-
4b (10 mol %): yield 91%; ee ) 77%; yellow oil; [R]D ) 98.7
(c ) 1.0, CHCl3); 1H NMR δ 1.25 (t, J ) 7.1 Hz, 3H), 2.44 (ddd,
J ) 5.5, 8.8, 12.9 Hz, 1H), 2.65 (ddd, J ) 1.1, 6.9, 12.9 Hz,
1H), 2.88 (m, 2H), 3.20 (ddd, J ) 4.6, 7.4, 11.9 Hz, 1H), 3.31
(ddd, J ) 5.5, 5.7, 11.7 Hz, 1H), 3.50 (dq, J ) 7.1, 9.5 Hz, 1H),
3.88 (dq, J ) 7.1, 9.5 Hz, 1H), 4.77 (t, J ) 7.9 Hz, 1H), 5.26 (d,
J ) 5.3 Hz, 1H), 7.08-7.23 (m, 4H); 13C NMR δ 15.0, 26.7,
43.4, 49.6, 60.0, 63.1, 101.5, 126.4, 127.3, 128.1, 133.7, 135.6;
HPLC (Daicel Chiralcel OD, hexane/i-PrOH ) 98:2, flow
rate ) 1.0 mL/min) tR ) 10.5 min (minor), tR )28.7 min
(major); MS m/z 219 (M+). All structural assignments were in
agreement with the MS, 1H, and 13C NMR data available from
the literature.7c,d
1.2, 6.8, 12.4 Hz, 1H), 2.79 (m, 2H), 3.11 (ddd, J ) 4.4, 8.4,
11.2 Hz, 1H), 3.26 (ddd, J ) 4.8, 5.6, 10.4 Hz, 1H), 3.82 (s,
3H), 3.83 (s, 3H), 4.68 (t, J ) 8.4 Hz, 1H), 5.56 (d, J ) 4.8 Hz,
1H), 6.57 (s, 1H), 6.59 (s, 1H); 13C NMR δ 25.7, 27.9, 42.9, 48.5,
54.8, 54.9, 59.1, 73.5, 95.9, 108.9, 109.7, 124.7, 126.3, 146.5,
146.7; HPLC (Daicel Chiralcel OJ , hexane/i-PrOH ) 96:4,
flow rate ) 0.3 mL/min) tR ) 14.1 min (major), tR ) 16.0 min
(minor); TOF ES+ m/z 330 (M + Na)+; HRMS calcd for C17H25
-
NaNO4 330.1681, found 330.1700.
(2,10b)-2-P h en yloxy-1,5,6,10b-tetr ah ydr o-2H-isoxazolo-
[3,2,-a ]isoqu in olin e (exo-3e). Synthesized according to the
general procedure on a 0.4 mmol scale employing catalyst (R)-
1
4b (20 mol %): yield 24%; ee ) 10%; colorless oil; H NMR δ
2.60 (ddd, J ) 5.8, 8.4, 13.6 Hz, 1H), 2.78 (ddd, J ) 5.2, 7.6,
12.8 Hz, 1H), 2.89 (m, 2H), 3.27 (m,32H), 4.83 (t, J ) 6.4 Hz,
1H), 5.82 (d, J ) 4.8 Hz, 1H), 6.90-7.23 (m, 9H); 13C NMR δ
26.3, 43.9, 49.6, 60.1, 100.1, 116.8, 122.0, 126.6, 127.4, 128.3,
129.4, 133.8, 135.3, 156.8; HPLC (Daicel Chiralcel OJ , hexane/
i-PrOH ) 92:8, flow rate ) 0.3 mL/min) tR ) 44.6 min (major),
tR ) 90.3 min (minor). TOF ES+ m/z: 330 (M + Na)+; HRMS
calcd for C18H19NaNO2 290.1157, found 290.1174.
F or m a tion of (1S)-2-Ben zyl-1-eth oxyca r bon ylm eth yl-
6,7-d im eth oxy-1,2,3,4-tetr a h yd r oisoqu in olin e. To a solu-
tion of exo-3b (58% ee, 73.8 mg, 0.264 mmol) in toluene (1 mL)
was added 1.05 equiv of BnBr (33 µL, 0.277 mmol); the flask
was capped and stirred overnight. The reaction was quenched
with saturated NaHCO3 and extracted with Et2O (3 × 2 mL).
The organic layer was dried and the solvent evaporated. The
crude product was purified by FC (silica gel, pet. ether/Et2O,
1
40:60): yield 61%; yellow oil; H NMR δ 1.18 (t, J ) 7.2 Hz,
3H), 2.36 (dd, J ) 3.3, 14.7 Hz, 1H), 2.55 (dd, J ) 5.4, 14.4
Hz, 1H), 2.73-2.9 (m, 3H), 3.10 (ddd, J ) 1.8, 4.8, 13.2 Hz,
1H), 3.65 (d, J ) 13.2 Hz, 1H), 3.72 (d, J ) 13.0, 1H), 3.79 (s,
3H), 3.80 (s, 3H), 4.03 (dq, J ) 7.2, 11.1 Hz, 1H), 4.14 (dq,
J ) 7.2, 10.5 Hz, 1H), 6.53 (s, 1H), 6.54 (s, 1H), 7.18-7.29 (m,
5H); 13C NMR δ 14.1, 23.1, 41.7, 42.0, 55.7, 55.8, 57.4, 58.3,
60.3, 110.1, 111.5, 126.0, 126,9, 128.0, 128.7, 128.8, 139.2,
147.3, 147.6, 171.9; MS m/z 369 (M+).
(+)-(2S,10bS)-2-Eth oxy-8,9-dim eth oxy-1,5,6,10b-tetr ah y-
d r o-2H-isoxa zolo[3,2,-a ]isoqu in olin e (exo-3b). Synthesized
according to the general procedure on a 0.4 mmol scale
employing catalyst (R)-4b (20 mol %): yield 76%; ee ) 70%;
F or m a t ion of (-)-(1S)-1-E t h oxyca r bon ylm et h yl-6,7-
d im eth oxy-1,2,3,4-tetr a h yd r oisoqu in olin e (5). (1S)-2-Ben-
zyl-1-ethoxycarbonylmethyl-6,7-dimethoxy-1,2,3,4-tetrahydroiso-
quinoline (59.5 mg, 0.161 mmol) obtained in the previous
reaction was dissolved in EtOH (3 mL). The reaction vessel
was set under vacuum and flushed with N2. This procedure
was repeated (3×), and 0.75 equiv of Pd(OAc)2 (27 mg, 0.122
mmol) was added. Vacuum was applied, and subsequently the
reaction vessel was flushed with H2 and the mixture was
sonicated for 3 h and filtered through a glass fiber filter and
the residual Pd(OAc)2 washed with EtOH and pyridine. The
combined fractions were concentrated in vacuo and coevapo-
rated with toluene (3×). The residue was purified by FC
(deactivated silica gel, CH2Cl2/MeOH, 90:10): yield 90%;
ee ) 58%; oil [R]D ) -10.2 (c ) 1.0, CHCl3); 1H NMR δ 1.24 (t,
J ) 6.9 Hz, 3H), 2.96-3.20 (m, 2H), 3.33 (ddd, J ) 6.3, 6.3,
12.6 Hz, 1H), 3.45 (ddd, J ) 5.4, 6.0, 11.4 Hz, 1H), 3.83 (s,
3H), 3.85 (s, 3H), 4.19 (q, J ) 7.2 Hz, 2H), 4.80 (t, J ) 6.6 Hz,
1H), 6.60 (s, 2H); 13C NMR δ 14.1, 26.5, 39.3, 40.1, 51.6, 55.9,
56.0, 61.4, 108.6, 111.6, 124.7, 125.1, 148.0, 148.6, 171.1; HPLC
(Daicel Chiralcel OD, hexane/i-PrOH ) 95:5, flow rate ) 1.0
mL/min) tR ) 30.2 min (major), tR ) 44.1 min (minor); MS m/z
279 (M+).
1
yellow oil; [R]D ) +47.4 (c ) 1.0, CHCl3); H NMR δ 1.21 (t,
J ) 7.2 Hz, 3H), 2.40 (ddd, J ) 5.4, 8.7, 12.9 Hz, 1H), 2.58
(ddd, J ) 1.2, 7.8, 13.2 Hz, 1H), 2.77 (m, 2H), 3.15 (ddd, J )
5.4, 6.3, 11.7 Hz, 1H), 3.26 (ddd, J ) 5.4, 6.3, 11.7 Hz, 1H),
3.45 (dq, J ) 6.9, 9.3 Hz, 1H), 3.81 (s, 3H), 3.82 (s, 3H), 3.84
(dq, J ) 7.2, 9.5 Hz, 1H), 4.66 (t, J ) 7.2 Hz, 1H), 5.23 (d, J )
4.8 Hz, 1H), 6.56 (s, 1H), 6.57 (s, 1H); 13C NMR δ 15.1, 26.4,
43.4, 49.7, 55.8, 55.9, 59.8, 63.2, 101.7, 109.9, 110.8, 125.7,
127.1, 147.6, 147.8; HPLC (Daicel Chiralcel OJ , hexane/i-
PrOH ) 96:4, flow rate ) 1.0 mL/min) tR ) 27.7 min (major),
tR ) 44.2 min (minor); TOF ES+ m/z 302 (M + Na)+; HRMS
calcd for C15H21NaNO4 302.1368, found 302.1360.
(+)-(2S,10b S)-2-ter t-Bu t oxy-1,5,6,10b -t et r a h yd r o-2H
isoxa zolo[3,2,-a ]isoqu in olin e (exo-3c). Synthesized accord-
ing to the general procedure on a 0.4 mmol scale with catalyst
(R)-4b (10 mol %): yield 86%; ee ) 70%; yellow oil; [R]D ) 81.7
1
(c ) 1.0, CHCl3); H NMR δ 1.28 (s, 9H), 2.43 (ddd, J ) 5.5,
8.8, 12.7 Hz, 1H), 2.53 (ddd, J ) 0.9, 6.6, 12.6 Hz, 1H), 2.87
(m, 2H), 3.13 (ddd, J ) 5.1, 6.5, 11.5 Hz, 1H), 3.28 (ddd, J )
4.9, 5.4, 10.4 Hz, 1H), 4.75 (t, J ) 8.2 Hz, 1H), 5.57 (d, J ) 4.4
Hz, 1H), 7.08-7.19 (m, 4H); 13C NMR δ 27.1, 28.9, 44.1, 49.5,
60.4, 74.5, 96.9, 126.3, 126.4, 127.4, 128.2, 133.8, 135.9; HPLC
(Daicel Chiralcel OD, hexane/i-PrOH ) 98:2, flow rate ) 1.0
mL/min) tR ) 7.4 min (minor), tR )10.2 min (major); MS m/z
247 (M+). All structural assignments were in agreement with
the 1H NMR data available from the literature.7d
Ack n ow led gm en t. This work was made possible by
a grant from the Danish National Research Foundation.
(+)-(2S,10b S)-2-ter t-Bu t oxy-8,9-d im et h oxy-1,5,6,10b -
tetr ah ydr o-2H-isoxazolo[3,2,-a ]isoqu in olin e (exo-3d). Syn-
thesized according to the general procedure on a 0.4 mmol
scale employing catalyst (R)-4b (20 mol %): yield 92%; ee )
65%; yellow oil; [R]D ) +52.1 (c ) 1.0, CHCl3); 1H NMR δ 1.27
(s, 9H), 2.41 (ddd, J ) 6.0, 8.8, 12.8 Hz, 1H), 2.49 (ddd, J )
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
and MS spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
J O001157C