The first catalytic enantioselective Diels-Alder reactions of 1,2-dihydropyridine: Efficient syntheses of optically active 2-azabicyclo[2.2.2]octanes with chiral BINAM derived Cr(III) salen complexes

Article abstract of DOI:10.1016/S0040-4020(02)00980-8

We have synthesized a new family of enantiomerically enriched BINAM-derived Schiff base Cr(III) complexes and evaluated them as catalysts for Diels-Alder reactions. These complexes effectively catalyze, for the first time, the enantioselective Diels-Alder reactions between 1,2-dihydropyridine and N-acryloyloxazolidinone to afford 2-azabicyclo[2.2.2]octanes in high yields (89-99%) and with moderate to good enantioselectivities (79-85%).

Full text of DOI:10.1016/S0040-4020(02)00980-8

Tetrahedron 58 (2002) 8299–8305
The first catalytic enantioselective Diels–Alder reactions of
1,2-dihydropyridine: efficient syntheses of optically active
2-azabicyclo[2.2.2]octanes with chiral BINAM derived Cr(III)
salen complexes
*
Norito Takenaka, Yong Huang and Viresh H. Rawal
Department of Chemistry, University of Chicago, 5735 South Ellis Avenue, Chicago, IL 60637, USA
Received 14 May 2002; accepted 23 May 2002
Abstract—We have synthesized a new family of enantiomerically enriched BINAM-derived Schiff base Cr(III) complexes and evaluated
them as catalysts for Diels–Alder reactions. These complexes effectively catalyze, for the first time, the enantioselective Diels–Alder
reactions between 1,2-dihydropyridine and N-acryloyloxazolidinone to afford 2-azabicyclo[2.2.2]octanes in high yields (89–99%) and with
moderate to good enantioselectivities (79–85%). q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
A well-established route to the 2-azabicyclo[2.2.2]octane
skeleton is through the Diels–Alder reaction of a suitably
protected dihydropyridine with a dienophile (Eq. (1)).1,5,6
Although such cycloadditions provide the most direct and
efficient access to the desired isoquinuclidine system, there
has been little work on the asymmetric variants of this
process.5 All reported examples of asymmetric Diels–Alder
reactions of dihydropyridines are diastereoselective pro-
cesses: stoichiometric chirality, whether in the diene or the
dienophile, induces asymmetry in the cycloaddition step.
The variations that have been investigated are those in
The 2-azabicyclo[2.2.2]octane skeleton is found widely in
natural products, particularly among the Iboga family of
alkaloids, members of which have varied and interesting
biological properties.1–3 Of particular interest to us are the
pharmacologically important Vinca alkaloids, such as
vinblastine and vincristine (3, 4).2,3 These alkaloids arise
from coupling of catharanthine (1), which possesses the
2-azabicyclo[2.2.2]octane skeleton, with the Aspidosperma
portion (Scheme 1).2,4
Scheme 1.
Keywords: Diels–Alder reaction; enantioselective; alkaloids; asymmetric catalysis; 2-azabicyclo[2.2.2]octane.
*
Corresponding author. Tel.: þ773-702-2194; fax: þ773-702-0805; e-mail: vrawal@uchicago.edu
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00980-8

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N. Takenaka et al. / Tetrahedron 58 (2002) 8299–8305
which (a) the 1,2-dihydropyridine possesses a chiral
centre,5a (b) the dihydropyridine nitrogen is attached to a
chiral auxiliary,5b,c or (c) the dienophile has a chiral
auxiliary.5d,e Despite its obvious advantages, to the best of
our knowledge, there are no reports of asymmetric Diels–
Alder reactions of dihydropyridines catalysed by a sub-
stoichiometric amount of a Lewis acid. Indeed, because 1,2-
dihydropyridines are unstable to many Lewis acids, the
reported cycloadditions of this diene are generally carried
out under thermal (uncatalysed) conditions, often with poor
endo–exo selectivity. A further problem with the use of
Lewis acids is its expected complexation with the Diels–
Alder products, which would impede catalyst turnover.7
type salen complexes for the Diels–Alder reaction between
1,2-dihydropyridines and common dienophiles. The reac-
tion between diene 5 and methacrolein was carried out in the
presence of 10 mol% of Cr(III) salen complex 6 (Eq. (2)).
We were delighted to find that the catalyst not only greatly
accelerated the reaction, ultimately giving the product (7) in
92% yield, but that it promoted the exclusive formation of
the endo-cycloadduct (by NMR). Importantly, the catalytic
cycle (turnover) was efficient, despite the potential for the
catalyst to coordinate strongly to the Lewis basic carbamate
carbonyl in the product.
ð1Þ
ð2Þ
In connection with our interest in the development of an
efficient asymmetric synthesis of Vinca alkaloids, we had
previously investigated the catalysed enantioselective
Diels–Alder reactions of amino dienes with dienophiles.
Our studies had revealed that weakly Lewis acidic Cr(III)
salen complexes, of the type used by Jacobsen, promoted
the Diels–Alder reactions through an efficient catalytic
cycle, and afforded cycloadducts in high yields, and
excellent ee’s.8 Given the success of these asymmetric
Diels–Alder reactions, we decided to utilise similar
catalysis for the cycloadditions with 1,2-dihydropyridines.
The determination of the cycloadduct enantioselectivity
proved challenging. The aldehyde group was reduced using
NaBH4 and the resulting alcohol was converted to its
Mosher ester. Although accurate determination of the
diastereomeric ratio by NMR was difficult, due to the
presence of carbamate rotomers, it was immediately clear
that the cycloaddition had proceeded with poor enantio-
selectivity (ca. 10% ee). The poor enantioselectivity
obtained with 6 prompted us to consider the use of salens
that were structurally quite dissimilar.
2. Results and discussion
The initial investigations focused on the use of Jacobsen-
Scheme 2.

N. Takenaka et al. / Tetrahedron 58 (2002) 8299–8305
Table 1. Effect of solvent on yield and enantioselectivity of 13
8301
After considering several different chiral diamines, we
decided to examine salens prepared from 1,10-bi-2-
naphthylamine (BINAM) 8, which has received consider-
ably less attention than trans-1,2-cyclohexanediamine.
Schiff bases of BINAM have, however, been prepared, as
have some metal complexes thereof.9 The Cr(III) complex
required for Diels–Alder catalysis was prepared as shown in
Scheme 2. An ethanolic solution of BINAM and 3,5-di-tert-
butylsalicylaldehyde, both available commercially, was
heated to reflux overnight and then diluted with water.9
The resulting precipitate was isolated in good yield by
simple filtration of the reaction mixture. The BINAM Schiff
base (10) was mixed with CrCl2 in THF and stirred under N2
overnight and then under an air atmosphere for another 12 h
to produce the Cr(III) complex, 11.10 The chloride ion was
exchanged using silver salts of the desired counter ion. The
catalyst preparation method employed here is operationally
simple and does not require the use of a dry box.
Entrya
Solvent
Yield
Cat
Cat
(%)b (S)-11b %ee of 13 (R)-11b %ee of ent-13
1
2
3
4
5
6
7
8
CH2Cl2
THF
THP
Et2O
Acetone
EtOAc
2-Butanone 85
DMA
NDc
86
90
83
63
99
97
74
84
73
53
74
85
79
75
ND
a
All reactions were carried out for 24 h, except for entry 8, which was a 3
day reaction.
The yields refer to isolated, purified products.
The yield was not determined (ND), since very little of the cycloadduct
was present.
b
c
Table 2. Effects of counter ion (X2) of 11 on yield and ee
BINAM–salen complex 11c effectively catalysed the
cycloaddition between 1,2-dihydropyridine (5) and metha-
crolein. Although the desired product was obtained in good
yield and with moderately good enantioselectivity (60% ee),
determination of the product’s ee was difficult, as mentioned
previously. On the other hand, N-acryloyloxazolidinone
(12) proved to be a very effective dienophile for these
cycloadditions, and it was used for most of the subsequent
investigations (Eq. (3)). The cycloadducts were not only
formed in higher ee, but the enantioselectivity determi-
nation was also simpler, since the two enantiomers were
nicely separated by HPLC using a chiral stationary phase.11
Entrya
Counter ion (X)
Yield (%)b
%ee of 13
Rxn time (h)
1
2
3
4
5
Cl
ND
99
99
ND
93
0
72
24
24
72
24
BF4
SbF6
PF6
OTf
70
74
NDc
79
a
All reactions were carried out in acetone at room temperature.
The yields refer to isolated, purified products.
Not determined (ND).
b
c
(DMA), presumably because the highly polarised carbonyl
group of DMA coordinates strongly with Cr(III) and
prohibits it from catalysing the cycloaddition. Although
THF and acetone were equally effective in terms of
enantioselectivity, the reaction was faster in acetone, as
reflected in the yield.13,14 The role of Lewis basic solvents in
increasing both yield and ee remains unclear.
ð3Þ
Our work on the Diels–Alder reaction of amino dienes had
shown that highly dissociated counter ions yielded products
with the highest ee’s. The same trend was observed for the
cycloaddition with 1,2-dihydropyridine, shown in Eq. (3)
(Table 2). The reactions were performed at room tempera-
ture in acetone, since this solvent gave the best results for
the cycloaddition. The complex with the chloride counter
ion (11a) was an ineffective catalyst (entry 1). Only a small
amount of the product had formed after 3 days at room
temperature, and, even then, the product was racemic. For
reasons that are not clear, the complex having PF26 as the
counter ion was also a poor catalyst for this cycloaddition.
Among the fluorinated counter ions, the complex having
SbF26 (11c) was the best catalyst for the reaction, albeit by
only a small margin over BF24 (entries 2 and 3). The
superior enantioselectivity observed for the antimonate
counter ion parallels the reactivity profile observed for
different salens for the Diels–Alder reactions of acyclic
amino dienes.8a The complex having trifluoromethane-
We examined the above Diels–Alder reaction in several
different solvents in order to see how the coordinating
properties of the solvent would affect yield and enantio-
selectivity (Table 1). The reaction of diene 5 (1.0 equiv.)
and dienophile 12 (2.0 equiv.) was carried out at ambient
temperature in CH2Cl2 in the presence of 10 mol% of
˚
Cr(III) catalyst (R)-11 and 4 A molecular sieves. A clean
reaction ensued, affording exclusively (by NMR) the endo-
cycloadduct (13) in 86% yield with 74% ee. An interesting
and somewhat surprising trend can be gleaned from the
solvent survey, shown in Table 1. The preferred solvents for
this cycloaddition—in term of rate, yield, and enantio-
selectivity—were the more Lewis basic ones. Cyclic ether
solvents, THF and THP, gave similar yields but higher ee’s
than did CH2Cl2. The best results were obtained in solvents
having a carbonyl group, especially acetone and EtOAc.12
Practically no reaction occurred in dimethylacetamide
sulfonate
enantioselectivity.
counter
ion
afforded
the
highest
In order to assess the influence of the salen scaffold structure
on enantioselectivity, we prepared and evaluated the
effectiveness of BINAM derived Cr(III) complexes in

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N. Takenaka et al. / Tetrahedron 58 (2002) 8299–8305
Table 3. Effectiveness of other salen complexes
Entry
Cr(III)a
R1
R2
Yield (%)b
Product
ee (%)
Rxn time (h)
1
2
3
4
5
6
7
8
(R-11
tBu
Me
OMe
Cl
Me
tBu
tBu
tBu
tBu
Cl
ade
SPh
99
99
93
54
86
61
96
78
ent-13
ent-13
ent-13
NDc
13
ent-13
13
13
85
70
81
NDc
65
23
28
9
24
24
48
72
24
72
24
48
(R)-14
(R)-15
(R)-16
(S)-17d
(S)-18d
(S)-19
(S)-20
a
All reactions were carried out in acetone at room temperature.
The yields refer to isolated, purified products.
Not determined (ND).
The counter ion for entries 5–8 was TfO2.
ad¼adamantyl.
b
c
d
e
which the salicylaldehyde component, especially sub-
stituents R1 and R2, are varied (Table 3). Complex 14,
with the sterically less demanding methyl group instead of
the tert-butyl group for position R1, gave lower enantio-
selectivity in the Diels–Alder reaction (entries 1 and 2). On
the other hand, the analogous complex in which the tert-
butyl group is replaced with a methoxy, gave only slightly
lower enantioselectivity than the tert-butyl complex (entry
3). The observed decrease in reaction rate with complex 15
can be understood if the electron donating property of the
methoxy substituent reduces the Lewis acidity of the metal.
Curiously, rather than being more reactive, dichloro-
substituted complex 16 was a poor catalyst for the
cycloaddition. The reaction was quite slow, and even after
3 days considerable starting material remained. The slow
turnover for this catalyst may be attributable to a strong
interaction between the metal and the reaction product,
which would diminish the reaction rate as product
concentration increased. The complex having methyl/
adamantly substituents (17, entry 5) was comparable in
efficacy to the methyl/tert-butyl complex (14). The phenyl
sulfide containing complex, 18, provided a surprise.
Although a poor catalyst, in terms of product yield and ee,
complex 18 favoured the formation of ent-13 as the major
product, opposite of what one might have expected based on
entries 1–5. The lower reactivity of 18 can be attributed to
the presence of the thiophenyl group, but further studies are
needed to understand the factors responsible for enantio-
selectivity reversal.
cycloaddition, but with poor enantioselectivity. The results
in Table 3 highlight the importance of large aliphatic
substituents on the effectiveness of the BINAM salen
catalysts for the Diels–Alder reaction with dihydropyridine.
In order to broaden the utility of this enantioselective
Diels–Alder reaction, we examined the cycloaddition
reactions with two other dienophiles, methacrolyloxa-
zolidinone (21) and methacrolein, both possessing sub-
stituent at the a-position (Scheme 3). Unfortunately,
dienophile 21 was completely unreactive, even under the
optimised conditions. On the other hand, the cycloaddition
with methacrolein proceeded well and afforded the
cycloadduct (22) with higher ee than under the conditions
In addition to the salicylaldehyde derived BINAM com-
plexes, two isomeric hydroxynaphthaldehyde (i.e. benzo-
salicylaldehyde) derived complexes, 19 and 20, were also
prepared. Both of these complexes catalysed the desired
Scheme 3.

N. Takenaka et al. / Tetrahedron 58 (2002) 8299–8305
8303
originally used (vide supra). The poor reactivity of 21, while
disappointing, is not surprising given the combined steric
effects of the methyl group and oxazolidinone unit.
3.2.1. (R)-2,20-Bis(3-0tert-butyl-5-methyl-2-hydroxy-
chloroform-d) d 12.70 (br s, 2H), 8.50 (s, 2H), 8.04 (d,
J¼8.0 Hz, 2H), 7.95 (d, J¼8.0 Hz, 2H), 7.53 (d, J¼8.0 Hz,
2H), 7.44 (t, J¼8.0 Hz, 2H), 7.33 (d, J¼8.0 Hz, 2H), 7.28 (t,
J¼4.0 Hz, 2H), 6.99 (d, J¼2 Hz, 2H), 6.77 (d, J¼2 Hz, 2H),
2.18 (s, 6H), 1.20 (s, 18H).
1
benzylideneamino)-1,1 -binaphthyl. H NMR (400 MHz,
In summary, we have described the first catalysed
enantioselective Diels–Alder reactions of 1,2-dihydro-
pyridine. A family of BINAM based Cr(III) salen
complexes were developed specifically for these cyclo-
additions. Under optimised reaction conditions, the cyclo-
addition between the dihydropyridine and N-
acryloyloxazolidinone (12) proceeded in excellent yield
(99%) and good ee (up to 85%). The BINAM catalysts
described here should prove useful not only for other Diels–
Alder reactions but also for other asymmetric processes.15
3.2.2. (R)-2,20-Bis(3-t0ert-butyl-5-methoxy-2-hydroxy-
1
benzylideneamino)-1,1 -binaphthyl. H NMR (400 MHz,
chloroform-d) d 12.50 (br s, 2H), 8.52 (s, 2H), 8.05 (d,
J¼8.0 Hz, 2H), 7.96 (d, J¼8.0 Hz, 2H), 7.55 (d, J¼8.0 Hz,
2H), 7.45 (t, J¼8.0 Hz, 2H), 7.34 (d, J¼8.0 Hz, 2H), 7.30 (t,
J¼4.0 Hz, 2H), 6.85 (d, J¼3.2 Hz, 2H), 6.45 (d, J¼3.2 Hz,
2H), 3.68 (s, 6H), 1.20 (s, 18H).
3.2.3. (S)-2,20-Bis(3-adamantyl-5-methyl-2-hydroxy-
0
1
3. Experimental
benzylideneamino)-1,1 -binaphthyl. H NMR (400 MHz,
chloroform-d) d 8.57 (s, 2H), 8.04 (d, J¼8.8 Hz, 2H), 7.94
(d, J¼8.0 Hz, 2H), 7.57 (d, J¼8.0 Hz, 2H), 7.39–7.44 (m,
4H), 7.32 (t, J¼1.2 Hz, 2H), 6.91 (d, J¼2 Hz, 2H), 6.77 (d,
J¼1.4 Hz, 2H), 2.17 (s, 6H), 2.02 (br s, 6H), 1.88 (br s,
12H), 1.75 (br s, 12H).
3.1. General information
All reactions were carried out under a nitrogen atmosphere
unless otherwise indicated. All commercial reagents were
used as received from commercial suppliers unless other-
wise indicated. All known compounds were prepared
according to the literature. Tetrahydrofuran (THF) and
diethyl ether (Et2O) were distilled from sodium-benzo-
phenone ketyl prior to use. Dichloromethane (CH2Cl2) was
distilled from calcium hydride. 2-Butanone was distilled
from and stored over CaSO4. N,N-Dimethylacetamide
(DMA), tetrahydropyran (THP), and ethyl acetate (EtOAc)
3.3. General procedure for Cr(III) chloride complex
To an oven-dried round-bottom flask containing a magnetic
stir bar and anhydrous CrCl2 (235.97 mg, 1.92 mmol) was
added a solution of (S)-2,20-bis(3,5-di-tert-butyl-2-hydroxy-
benzylideneamino)-1,10-binaphthyl (1.25 g, 1.74 mmol) in
THF (50 mL). The reaction mixture was stirred for 12 h
under a nitrogen atmosphere and another 12 h under air at
ambient temperature (the reaction mixture was brought to
reflux for 12 h in the cases of (S)-5, and (S)-6). The reaction
mixture was then diluted with reagent grade diethyl ether
(50 mL) and washed with saturated, aqueous NH4Cl, brine,
dried (Na2SO4) and concentrated in vacuo to afford 1.38 g
(1.72 mmol, 99%) of (S)-2,20-bis(3,5-di-tert-butyl-2-hydro-
˚
were stored over activated 4 A molecular sieve and used
without distillation. Acetone was stored over CaSO4 and
used without distillation. Reactions were monitored by thin
layer chromatography (TLC) using 250 mm Whatman
precoated silica gel plates. Flash column chromatography
was performed over EM Science Laboratories silica gel
(230–400 mesh). Proton and carbon NMR spectra were
xybenzylideneamino)-1,10-binaphthyl
chromium(III)
1
recorded on Bru¨ker DRX-500 and 400 spectrometers. H
NMR chemical shifts are reported as d values (ppm) relative
to internal tetramethylsilane in chloroform-d or the residual
proton solvent signals. Splitting patterns are designated as:
s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet.
13C NMR chemical shifts are reported as d values (ppm)
relative to CDCl3 or DMSO-d. High performance liquid
chromatography (HPLC) was performed using the
CHIRALPAKw AD (25 cm).
chloride as a dark green solid which was used without
further purification.
3.4. General procedure for Cr(III) trifluoromethane-
sulfonate complex
To an oven-dried round-bottom flask containing a magnetic
stir bar and (S)-2,20-bis(3,5-di-tert-butyl-2-hydroxybenzyl-
ideneamino)-1,10-binaphthyl chromium(III) chloride
(95.5 mg, 0.12 mmol) was added AgOTf (62.0 mg,
0.24 mmol). The flask was charged with CH2Cl2 (4 mL)
and stirred for 12 h in the dark. The reaction mixture was
filtered through a short pad of Celitew and concentrated i0n
vacuo to afford 108.8 mg (0.12 mmol, quant.) of (S)-2,2 -
bis(3,5-di-tert-butyl-2-hydroxybenzylideneamino)-1,10-
binaphthyl chromium(III) trifluoromethanesulfonate as a
dark brown solid which was used without further
purification.
3.2. General procedure for binaphthyl Schiff base9,12a,16
To an oven-dried round-bottom flask fitted with a magnetic
stir bar and a water-jacketed condenser were added (S)-1,10-
binaphthyl-2,20-diamine (1.00 g, 3.52 mmol) and 3,5-di-
tert-butyl-salicylaldehyde (1.65 g, 7.04 mmol). The flask
was charged with absolute ethanol (117 mL) and brought to
reflux for 24 h. Enough water was added to the refluxing
reaction mixture to ensure some precipitation, and the
reaction mixture was cooled down to ambient temperature.
The yellow precipitate was collected by filtration and drie0d
in vacuo to give 1.84 g (2.57 mmol, 73%) of (S)-2,2 -
bis(3,5-di-tert-butyl-2-hydroxybenzylideneamino)-1,10-
binaphthyl which was used without further purification.
Spectral data matched literature values.9n
3.4.1. General procedure for 7-(2-oxo-oxazolidine-3-
carbonyl)-2-aza-bicyclo[2.2.2]oct-5-ene-2-carboxylic
acid phenyl ester. An oven-dried round-bottom flask
containing a stir bar was charged with 1,2-dihydropyridine17
(46.5 mg,
0.23 mmol),
N-acryloyloxazolidinone18

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N. Takenaka et al. / Tetrahedron 58 (2002) 8299–8305
˚
999–1005. (e) Marazano, C.; LeGoff, M.; Fourrey, J.; Das,
B. C. J. Chem. Soc., Chem. Commun. 1981, 389–391.
(f) Raucher, S.; Bray, B. L. J. Org. Chem. 1985, 50,
3236–3237. (g) Kuehne, M. E.; Bornmann, W. G.; Earley,
W. G.; Marko, I. J. Org. Chem. 1986, 51, 2913–2927.
(h) Raucher, S.; Bray, B. L.; Lawrence, R. F. J. Am. Chem.
Soc. 1987, 109, 442–446. (i) Reding, M. T.; Fukuyama, T.
Org. Lett. 1999, 1, 973–976. Synthesis of (þ)-catharanthine
(65.0 mg, 0.46 mmol), dry powdered 4 A molecular sieve
(138.0 mg), and (S)-02,20-bis(3,5-di-tert-butyl-2-hydroxy-
benzylideneamino)-1,1 -binaphthyl chromium(III) trifluoro-
methanesulfonate (21.0 mg, 0.023 mmol). Acetone
(0.5 mL) was added to the flask and the reaction mixture
was stirred for 24 h at ambient temperature. The reaction
mixture was filtered through a short pad of silica gel and the
pad was rinsed with ethyl acetate. The crude reaction
mixture was concentrated in vacuo and then purified by
flash chromatography on silica gel (50% ethyl acetate in
hexanes) to give 77.9 mg (quant.) of the title compound, a
light yellow foam. 1H NMR (400 MHz, DMSO-d6, 1208C) d
(7.35, J¼16.0, 8.0 Hz, 2H), 7.18 (t, J¼8.0 Hz, 1H), 7.13 (d,
J¼8.0 Hz, 2H), 6.49 (dd, J¼16.0, 8.0 Hz, 1H), 6.41 (dd,
J¼12.0, 8.0 Hz, 1H), 5.03 (br s, 1H), 4.39 (m, 2H), 4.14 (m,
1H), 3.88 (m, 2H), 3.42 (br d, J¼8.0 Hz, 1H), 3.06 (br d,
J¼8.0 Hz, 1H), 2.91 (br s, 1H), 2.12 (t, J¼8 Hz, 1H), 1.68
(m, 1H); 13C NMR (100 MHz, DMSO-d6, 1208C) d 171.3,
152.3, 151.7, 150.9, 133.6, 130.2, 128.2, 124.0, 120.7, 61.7,
46.8, 46.4, 43.1, 42.0, 29.7, 26.6; HPLC analysis
(CHIRALPAKw AD, 75% iPrOH/hexanes, 1.0 mL/min,
254 nm; tr (minor)¼8.29, tr (major)¼12.51, 79% ee).
´
´
¨
via resolution: (j) Szantay, C.; Bolcskei, H.; Gacs-Baitz, E.
Tetrahedron 1990, 46, 1711–1732, and references cited
therein.
´
2. (a) Kuehne, M. E.; Marko, I. In Syntheses of Vinblastine-type
Alkaloids. The Alkaloids. Antitumor Bisindole Alkaloids from
Catharanthus roseus (L.); Brossi, A., Suffness, M., Eds.;
Academic: San Diego, 1990; Vol. 37, pp 77–131.
(b) Takayama, H.; Sakai, S. In Monoterpenoid Indole Alkaloid
Syntheses Utilizing Biomimetic Reactions. The alkaloids.
Chemistry and Biology; Cordell, G. A., Ed.; Academic: San
Diego, 1998; Vol. 50, pp 415–452.
3. (a) The Alkaloids. Antitumor Bisindole Alkaloids from
Catharanthus roseus (L.); Brossi, A., Suffness, M., Eds.;
Academic: San Diego, 1990; Vol. 37. (b) Popik, P.; Skolnick,
P. In Pharmacology of Ibogaine and Ibogaine-related
Alkaloids. The Alkaloids. Chemistry and Biology; Cordell,
G. A., Ed.; Academic: San Diego, 1999; Vol. 52, pp 197–231.
(c) Glick, S. D.; Maisonneuve, I. M.; Szumlinski, K. K. In
Mechanisms of Action of Ibogaine: Relevance to Putative
Therapeutic Effects and Development of a Safer Iboga
Alkaloid Congener. The Alkaloids; Alper, K. R., Glick, S. D.,
Cordell, G. A., Eds.; Academic: San Diego, 2001; Vol. 56,
pp 39–53.
3.4.2. General procedure for 7-formyl-7-methyl-2-aza-
bicyclo[2.2.2]oct-5-ene-2-carboxylic acid phenyl ester.
An oven-dried round-bottom flask containing a stir bar was
charged with 1,2-dihydropyridine (46.5 mg, 0.23 mmol),
0
˚
dry powdered 4 A molecular sieve (138.0 mg), (S)-2,20-
bis(3,5-di-tert-butyl-2-hydroxybenzylideneamino)-1,1 -
binaphthyl chromium(III) SbF6 (23.0 mg, 0.023 mmol), and
acetone (0.5 mL). Methacrolein (38 mL, 0.46 mmol) was
added to the flask and the reaction mixture was stirred for
24 h at ambient temperature. The reaction mixture was
filtered through a short pad of silica gel and the pad
was rinsed with ethyl acetate. The crude reaction mixture
was concentrated in vacuo and then purified by flash
chromatography on silica gel (20% ethyl acetate in hexanes)
to give 55.5 mg (0.20 mmol, 89%) of the product as a light
4. For our work on the synthesis of the Aspidosperma portion,
see: (a) Kozmin, S. A.; Rawal, V. H. J. Am. Chem. Soc. 1998,
120, 13523–13524. (b) Kozmin, S. A.; Iwama, T.; Huang, Y.;
Rawal, V. H. J. Am. Chem. Soc. 2002, 124, 4628–4641. For
other papers on the chemistry of amino siloxy dienes, see:
(c) Kozmin, S. A.; Rawal, V. H. J. Org. Chem. 1997, 62,
5252–5253. (d) Kozmin, S. A.; Rawal, V. H. J. Am. Chem.
Soc. 1997, 119, 7165–7166. (e) Kozmin, S. A.; Janey, J. M.;
Rawal, V. H. J. Org. Chem. 1999, 64, 3039–3052. (f) Kozmin,
S. A.; Green, M. T.; Rawal, V. H. J. Org. Chem. 1999, 64,
8045–8047. (g) Kozmin, S. A.; Rawal, V. H. J. Am. Chem.
Soc. 1999, 121, 9562–9573. (h) Kozmin, S. A.; He, S.; Rawal,
V. H. Org. Synth. 2000, 78, 152. (i) Kozmin, S. A.; He, S.;
Rawal, V. H. Org. Synth. 2000, 78, 160. (j) Janey, J. M.;
Iwama, T.; Kozmin, S. A.; Rawal, V. H. J. Org. Chem. 2000,
65, 9059–9068. (k) Huang, Y.; Rawal, V. H. Org. Lett. 2000,
2, 3321–3323.
1
yellow oil. H NMR (400 MHz, DMSO-d6, 1208C) d (???,
J¼16.0, 8.0 Hz, 2H), 7.19 (t, J¼8.0 Hz, 1H), 7.12 (d,
J¼8.0 Hz, 2H), 6.47 (m, 2H), 4.76 (br d, J¼4 Hz, 1H), 3.45
(br d, J¼8.0 Hz, 1H), 3.06 (br d, J¼8.0 Hz, 1H), 2.92 (m,
1H), 2.09 (dt, J¼12.0, 2.8 Hz, 1H), 1.38 (dd, J¼12.0,
4.0 Hz, 1H), 1.25 (s, 3H); 13C NMR (100 MHz, DMSO-d6,
1208C) d 202.3, 150.9, 134.8, 130.7, 128.3, 124.1, 120.6,
52.1, 50.7, 46.9, 31.3, 30.1, 20.1; enantiomeric excess of the
title compound was determined to be 67% by the Mosher
ester analysis of the corresponding alcohol prepared by
NaBH4 reduction.
5. For 1,2-dihydropyridine possessing a chiral centre:
(a) Matsumura, Y.; Nakamura, Y.; Maki, T.; Onomura, O.
Tetrahedron Lett. 2000, 41, 7685–7689. Dihydropyridine
having
a chiral auxiliary attached to the nitrogen:
(b) Mehmandoust, M.; Marazano, C.; Singh, R.; Gillet, B.;
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