Development of highly stereoselective asymmetric 6π- azaelectrocyclization of conformationally flexible linear 1-azatrienes. From determination of multifunctional chiral amines, 7-alkyl cis-1-amino-2-indanols, to application as a new synthetic strategy: Formal synthesis of 20-epiuleine

Article abstract of DOI:10.1021/jo049381f

The highly stereoselective asymmetric 6π-azaelectrocyclization was achieved as a general synthetic method based on the reaction between the (E)-3-carbonyl-2,4,6-trienal compounds and the (-)-7-alkyl-cis-l-amino-2-indanol derivatives which are effective chiral amines. The 7-alkyl-substituted 2-indanol moiety of the cyclized products was efficiently removed by the novel manganese dioxide oxidation under remarkably mild conditions, and the method was successfully applied to the formal synthesis of optically active 20-epiuleine.

Full text of DOI:10.1021/jo049381f

Develop m en t of High ly Ster eoselective Asym m etr ic
6π-Aza electr ocycliza tion of Con for m a tion a lly F lexible Lin ea r
1-Aza tr ien es. F r om Deter m in a tion of Mu ltifu n ction a l Ch ir a l
Am in es, 7-Alk yl cis-1-Am in o-2-in d a n ols, to Ap p lica tion a s a New
Syn th etic Str a tegy: F or m a l Syn th esis of 20-Ep iu lein e
Katsunori Tanaka, Toyoharu Kobayashi, Hajime Mori, and Shigeo Katsumura*
School of Science and Technology, Kwansei Gakuin University, Gakuen 2-1, Sanda,
Hyogo 669-1337, J apan
katsumura@ksc.kwansei.ac.jp
Received April 13, 2004
The highly stereoselective asymmetric 6π-azaelectrocyclization was achieved as a general synthetic
method based on the reaction between the (E)-3-carbonyl-2,4,6-trienal compounds and the (-)-7-
alkyl-cis-1-amino-2-indanol derivatives which are effective chiral amines. The 7-alkyl-substituted
2-indanol moiety of the cyclized products was efficiently removed by the novel manganese dioxide
oxidation under remarkably mild conditions, and the method was successfully applied to the formal
synthesis of optically active 20-epiuleine.
In tr od u ction
LUMO of the 1-azatrienes by the combination of sub-
stituent effects, that is, the C4-carbonyl and the C6-
alkenyl or phenyl substituents of the 1-azatrienes (Scheme
1).9,10
The thermal cyclization of 1-azatrienes into 1,2-dihy-
dropyridines,1 which is the so-called 6π-azaelectrocycliza-
tion, is one of the well-known concerted pericyclic
reactions,2-4 which proceed in a disrotatory mode.5
Although a number of examples of the 6π-azaelectrocy-
clization have been reported,1,6,7 the process required a
high temperature and a long reaction time, and therefore,
the application of this reaction toward natural products
synthesis is very limited in the literature. The recent
pioneering work of Okamura and co-workers determined
that the introduction of either an electron donor or an
acceptor group at the 1-azatriene terminus moderately
accelerated the rate of the electrocyclization.5,8 Quite
recently, we independently succeeded in significantly
accelerating the azaelectrocyclization, based on the re-
markable orbital interaction between the HOMO and
Thus, we quantitatively obtained the corresponding
dihydropyridine derivatives within 5 min at room tem-
perature by the reaction of (E)-3-carbonyl-2,4,6-trienals
with primary amines. Furthermore, as a synthetic ap-
plication of this established smooth azaelectrocyclization,
we realized the novel one-pot synthesis of substituted
pyridines, and the method was successfully applied to
the synthesis of the ocular age pigment, A2E.10,11 As a
next step to develop our very fast 6π-azaelectrocycliza-
tion, we succeeded in demonstrating a general asym-
metric azaelectrocyclization using chiral amines as the
primary amines. Herein, we report in detail12 the novel
highly stereoselective asymmetric 6π-azaelectrocycliza-
tion of the conformationally flexible linear 1-azatriene
based on the reactions between the (E)-3-carbonyl-2,4,6-
trienal compounds and the new 7-alkyl substituted chiral
cis-1-amino-2-indanol derivatives by a remarkably simple
operation under quite mild conditions. The 2-indanol
chiral moiety of the cyclized products was successfully
removed by treatment with manganese dioxide under
remarkably mild conditions. The detailed mechanistic
* To whom correspondence should be addressed. Phone: 81-795-
65-8314. Fax: 81-795-65-9077.
(1) Marvell, E. N. Thermal Electrocyclic Reactions; Academic
Press: New York, 1980.
(2) (a) Marvell, E. N.; Caple, G.; Schatz, B.; Pippin, W. Tetrahedron
1973, 29, 3781. (b) Marvell, E. N.; Caple, G.; Delphey, C.; Platt, J .;
Polston, N.; Tashiro, J . Tetrahedron 1973, 29, 3797.
(3) Spangler, C. W.; J ondahl, T. P.; Spangler, B. J . Org. Chem. 1973,
38, 2478.
(4) (a) Palenzuela, J . A.; Elnagar, H. Y.; Okamura, W. H. J . Am.
Chem. Soc. 1989, 111, 1770. (b) Zhu, G.-D.; Okamura, W. H. Chem.
Rev. 1995, 95, 1877. (c) Okamura, W. H.; de Lera, A. R. In Compre-
hensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Paquette,
L. A., Volume Ed.; Pergamon Press: London, 1991; Vol. 5, Chapter
6.2, pp 699-750.
(5) Maynard, D. F.; Okamura, W. H. J . Org. Chem. 1995, 60, 1763.
(6) Schiess, P.; Chia, H. L.; Ringele, P. Tetrahedron Lett. 1972, 313.
(7) (a) Cheng, Y.-S.; Lupo, A. T., J r.; Fowler, F. W. J . Am. Chem.
Soc. 1983, 105, 7696. (b) Wyle, M. J .; Fowler, F. W. J . Org. Chem.
1984, 49, 4025.
(9) (a) Tanaka, K.; Kamatani, M.; Mori, H.; Fujii, S.; Ikeda, K.;
Hisada, M.; Itagaki, Y.; Katsumura, S. Tetrahedron Lett. 1998, 39,
1185. (b) Tanaka, K.; Kamatani, M.; Mori, H.; Fujii, S.; Ikeda, K.;
Hisada, M.; Itagaki, Y.; Katsumura, S. Tetrahedron 1999, 55, 1657.
(c) Tanaka, K.; Katsumura, S. J . Synth. Org. Chem. J pn. 1999, 57,
876.
(10) Tanaka, K.; Mori, H.; Yamamoto, M.; Katsumura, S. J . Org.
Chem. 2001, 66, 3099.
(11) Tanaka, K.; Katsumura, S. Org. Lett. 2000, 2, 373.
(12) Preliminary communication: Tanaka, K.; Katsumura, S. J . Am.
Chem. Soc. 2002, 124, 9660.
(8) de Lera, A. R.; Reischl, W.; Okamura, W. H. J . Am. Chem. Soc.
1989, 111, 4051.
10.1021/jo049381f CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/04/2004
5906
J . Org. Chem. 2004, 69, 5906-5925

Asymmetric 6π-Azaelectrocyclization
SCHEME 1
However, we later postulated that their stereochem-
istry was the same as that of (-)-1a (structure shown in
Scheme 2), which was yielded by the reaction with cis-
hydroxy-substituted aminoindanol (-)-a . Finally, it was
found that the reaction of 1 with (1S,2R)-(-)-cis-1-amino-
2-indanol a 16 quantitatively produced the pentacyclic
piperidine derivative (-)-1a , [R]24 -45.4 (c 1.1, CHCl3),
D
as a single stereoisomer (Scheme 2). The relative stereo-
chemistry was assigned based on the observation of the
NOE correlation between protons Ha and Hb and unam-
biguously determined by the X-ray crystallographic
analysis of the carboxylic acid, prepared by the treatment
of 1a with a 2 N solution of potassium hydroxide in
methanol followed by acidification (Figure 1). The 1H
NMR spectrum of the carboxylic acid was very similar
to that of 1a except for the disappearance of the methyl
ester protons, and this indicated that no epimerization
occurred during the hydrolysis of 1a (see the Experimen-
tal Section). The reaction proceeded by smooth azaelec-
trocyclization followed by aminoacetal formation between
the resulting enamine moiety of dihydropyridine and the
hydroxy group of the indanol moiety (Scheme 2).
The acetal formation was so fast in CDCl3 that the
presence of the corresponding dihydropyridine was not
observed. Since deuterated chloroform contains a small
amount of hydrochloric acid as a contaminant, the
enamine moiety of the dihydropyridine easily tautomer-
ized into the corresponding imminium ion, and then the
nucleophilic attack by the neighboring hydroxy group
would be facilitated.17 Actually, when the reaction was
analyzed in pyridine-d5, the dihydropyridine intermedi-
ary and the subsequent slow transformation into the
piperidine derivative 1a was clearly observed. Notewor-
thy is the fact that the hydroxy group of aminoindanol
is protecting the reactive enamine moiety of the chiral
dihydropyridine as its aminoacetal and contributing to
the significant stabilization of the dihydropyridine. There-
fore, this chiral dihydropyridine equivalent 1a could be
investigation of this novel phenomenon is also described.
In addition, the scale-up synthetic procedure of these
enantiomerically pure (-)-7-methyl- and isopropyl-cis-
aminoindanols is also described. Finally, the developed
method was applied toward the formal synthesis of the
indole alkaloid, 20-epiuleine.
Resu lts a n d Discu ssion
Esta blish m en t of th e Ster eoselective 6π-Aza elec-
tr ocycliza tion . Our strategy is based on controlling the
facial selectivity of the disrotatory azaelectrocyclization,
which would be affected by a chiral auxiliary on the
nitrogen13 under the established smooth azaelectrocy-
clization by the reaction of (E)-3-carbonyltrienals with
primary amines (Scheme 1). First, we selected the
reaction between trienal 1 containing the bulky 2,6,6-
trimethylcyclohexene moiety and the various commer-
cially available amines such as those shown in Table 1
and examined the diastereoselectivity of the azaelectro-
cyclization. For screening of the many chiral amines in
a short time, each reaction was directly carried out in
an NMR sample tube at 24 °C in CDCl3, and the
diastereomeric ratio of the produced 1, 2-dihydropyridine
was analyzed by observation of its characteristic 1H NMR
signals. The representative results are shown in Table
1, entries 1-6. The reactions with 1-phenylethylamine i
or 1-aminoindan iv provided the corresponding 1,2-
dihydropyridine derivatives with a 3:1 diastereoselectiv-
ity (entries 1 and 4). A complex mixture of the products
was produced by the reaction with 2-phenylglycinol ii
(entry 2), and cyclization was not observed for the
1-azatriene which was smoothly obtained by the reaction
with the bulky 2-amino-1,2-diphenylethanol iii (entry 3).
Fortunately, a 10:1 diastereoselectivity was obtained by
the reactions with v and vi, which bear an additional
methyl or methoxy substituent cis to the amino group of
1-aminoindan iv (entries 5 and 6). Unfortunately, these
generated chiral dihydropyridines14,15 were found to be
very unstable and were only treated as their solutions,
such as in ether or benzene (in CHCl3, they gradually
decomposed). Furthermore, several trials to derivatize
the dihydropyridines into stabilized compounds such as
the corresponding tetrahydropyridines by hydrogenation
led to the decomposition of the 1,2-dihydropyridines.
Therefore, the stereochemistry at the C-2 position of the
dihydropyridines produced from i and iv-vi could not
be determined at this stage.
(15) (a) Comins, D. L.; Abdullah, A. H.; Smith, R. K. Tetrahedron
Lett. 1983, 24, 2711. (b) Comins, D. L.; J oseph, S. P. In Advances in
Nitrogen Heterocycles; Moody, C. J ., Ed.; J AI Press: Greenwich, CT,
1996; Vol. 2, pp 251-294. (c) Comins, D. L.; LaMunyon, D. H.; Chen,
X. J . Org. Chem. 1997, 62, 8182. (d) Comins, D. L.; Stolze, D. A.;
Thakker, P.; McArdle, C. L. Tetrahedron Lett. 1998, 39, 5693. (e)
Comins, D. L.; Zhang, Y.; Zheng, X. J . Chem. Soc., Chem. Commun.
1998, 2509. (f) Comins, D. L.; Kuethe, J . T.; Hong, H.; Lakner, F. J . J .
Am. Chem. Soc. 1999, 121, 2651. (g) Comins, D. L.; Libby, A. H.; Al-
awar, R. S.; Foti, C. J . J . Org. Chem. 1999, 64, 2184. (h) Comins, D.
L.; Brooks, C. A.; Al-awar, R. S.; Goehring, R. R. Org. Lett. 1999, 1,
229. (i) Comins, D. L.; Zhang, Y.; J oseph, S. P. Org. Lett. 1999, 1, 657.
(j) Comins, D. L.; Green, G. M. Tetrahedron Lett. 1999, 40, 217. (k)
Comins, D. L. J . Heterocyclic Chem. 1999, 36, 1491. (l) Brooks, C. A.;
Comins, D. L. Tetrahedron Lett. 2000, 41, 3551. (m) Comins, D. L.;
Sandelier, M. J .; Grillo, T. A. J . Org. Chem. 2001, 66, 6829.
(16) For reviews on the use of cis-1-amino-2-indanol in asymmetric
synthesis, see: (a) Senanayake, C. H. Aldrichim. Acta 1998, 31, 3. (b)
Ghosh, A. K.; Fidanze, S.; Senanayake, C. H. Synthesis 1998, 937. (c)
Watson, D. J .; Lawrence, C. M.; Meyers, A. I. Tetrahedron Lett. 2000,
41, 815. (d) Mechelke, M. F.; Meyers, A. I. Tetrahedron Lett. 2000, 41,
4339. (e) Groaning, M. D.; Meyers, A. Tetrahedron 2000, 56, 9843. (f)
Thompson, C. F.; J amison, T. F.; J acobsen, E. N. J . Am. Chem. Soc.
2000, 122, 10482. (g) Palmer, M. J .; Kenny, J . A.; Walsgrove, T.;
Kawamoto, A. M.; Wills, M. J . Chem. Soc., Perkin Trans. 1 2002, 416.
(h) Gademann, K.; Chavez, D. E.; J acobsen, E. N. Angew. Chem., Int.
Ed. 2002, 41, 3059.
(13) Williams, R. M. Synthesis of Optically Active R-Amino Acids.
In The Organic Chemistry Series; Baldwin, J . E., Ed.; Pergamon
Press: Oxford, 1989.
(14) Recent examples of the chiral 1,2-dihydropyridine synthesis:
(a) Matsumura, Y.; Nakamura, Y.; Maki, T.; Onomura, O. Tetrahedron
Lett. 2000, 41, 7685. (b) Charette, A. B.; Grenon, M.; Lemire, A.;
Pourashraf, M.; Martl, J . J . Am. Chem. Soc. 2001, 123, 11829.
(17) For very similar examples of such aminoacetal formations,
see: (a) Gnecco, D.; Marazano, C.; Das, B. C. J . Chem. Soc., Chem.
Commun. 1991, 625. (b) Wong, Y.-S.; Marazano, C.; Gnecco, D.;
Genisson, Y.; Chiaroni, A.; Das, B. C. J . Org. Chem. 1997, 62, 729. (c)
Lavilla, R.; Coll, O.; Nicolas, M.; Bosch, J . Tetrahedron Lett. 1998, 39,
5089.
J . Org. Chem, Vol. 69, No. 18, 2004 5907

Tanaka et al.
TABLE 1.
a
Compounds 1-3 were reacted with 1.1 equiv of chiral amines at 24 °C in CDCl3. Each reaction was directly monitored by 1H NMR,
and the ratio of the produced 1,2-dihydropyridines was analyzed by their characteristic signals in their 1H NMR. The products were the
b
aminoacetal derivatives of the corresponding dihydropyridines.
SCHEME 2
F IGURE 1. Three-dimensional image of X-ray crystallo-
graphic analysis.
especially the cis-hydroxy group, would be important for
giving good diastereoselectivity through azaelectrocy-
clization.
We next examined the reactions of the chiral amines
with more general aldehydes 2 and 3,10 which contain
linear alkenyl or phenyl substituents, respectively (Table
1, entries 7-18). Disappointedly, almost no diastereose-
lectivity was observed even by the reactions with amines
v or vi, which showed a 10:1 selectivity by the reaction
with 1 (entries 11, 12, 17, and 18). However, it was
encouraging to find that the reaction of 2 with cis-
easily handled for further functional transformations as
shown in the following experiments. Thus, by summariz-
ing the results for the reactions of 1 with various amines,
it was suggested that the 1-aminoindan structure and
its cis-substituent with respect to the amino group,
aminoindanol a yielded the corresponding piperidine
derivatives 2a as a mixture of its four inseparable
stereoisomers (Scheme 3). The ratio of the four stereo-
isomers was established to be 15:5:3:1 based on the
integration of the characteristic vinyl protons of the
5908 J . Org. Chem., Vol. 69, No. 18, 2004

Asymmetric 6π-Azaelectrocyclization
SCHEME 3
also succeeded in the highly stereoselective azaelectro-
cyclization of their conformationally restricted 1-aza-
trienes under thermodynamically equilibrated condi-
tions.19,20 In our case, the observed diastereoselectivity
was not the result of the thermodynamic equibration,
because no equiblium between the separated diastereo-
mers could be observed under the reaction conditions of
Table 2. To the best of our knowledge, this is the first
achievement of the highly stereoselective asymmetric 6π-
azaelectrocyclization of linear 1-azatriene derivatives in
a kinetically controlled way.
Com p u ta tion a l An a lysis. To rationalize the observed
high stereoselectivity of the azaelectrocyclization on the
steric/conformational basis, the stable conformation of
1-azatriene 4 derived from compounds 3 and d was
analyzed by calculation. The stable 2,3-s-cis and 4,5-s-
cis conformation of 4, which is the likely conformation
just before the disrotatory electrocyclization (as shown
in Figure 2), was optimized by a semiempirical method
(PM3) using the software packages SPARTAN version
5.0 (Wavefunction, Inc., Irvine CA). The calculation gave
the two most stable conformers (R)-4 and (S)-4, which
would provide the experimentally produced major isomer
(-)-3d and the corresponding minor isomer via disrota-
tory azaelectrocyclization. In both conformers, the hy-
droxy group of the indan moiety is expected to participate
in the hydrogen bonding with the nitrogen of the 1-aza-
triene, and stabilizes the conformers. In conformer (S)-
4, there would be the steric interaction between the
isopropyl group of the indan moiety and the developing
dihydropyridine ring and/or the proton Ha of the aza-
triene. On the other hand, no such interaction could be
observed in conformer (R)-4, and therefore, the major
isomer (-)-3d would be preferentially produced through
the conformer (R)-4 by the disrotatory azaelectrocycliza-
tion. Thus, the above computational analysis strongly
supports the observed results that both the cis-hydroxy
group and an alkyl substituent of the aminoindanol have
contributed to improve the stereoselectivity of the aza-
electrocyclization. The poorer selectivity using t-Bu-
aminoindanol derivative e is rationalized due to the
slightly different conformational arrangement of the 1,2-
amino alcohol moiety on the five-membered ring in e from
piperidine ring in its NMR spectrum. The main isomer
of 2a was suggested to possess the same relative con-
figurations as that of 1a , by comparing their 1H NMR
spectra one another. The stereoselectivity at the 2-posi-
tion of piperidine 2a that corresponded to the diastereo-
selectivity of the azaelectrocyclization, was then eluci-
dated to be 3:1 by treating 2a with lithium aluminum
hydride and analyzing the resulting diols by its 1H NMR.
Similarly, the reaction of 3 with a gave the corresponding
piperidine 3a in the ratio of 3:1 (see Table 2, entries 1
and 2). Thus, only the cis-aminoindanol a among the
commercially available amines tested exhibited a moder-
ate selectivity by the reactions with 2 and 3.
Based on these results, we planned to increase the
bulkiness of the cis-aminoindanol a by introducing an
alkyl substituent on the benzene ring and tried to
improve the selectivity (Table 2). Unfortunately, our first
trial upon utilizing the 4-methyl- or isopropyl-substituted
cis-aminoindanols afforded a 3:1 diastereoselectivity by
the reaction with aldehyde 3, the selectivity of which was
similar to that obtained by employing the simple ami-
noindanol a (date not shown).18 In contrast, the aminoin-
danol derivatives b-e having the alkyl substituents at
the 7-position of a were successfully synthesized (vide
infra), and quite fortunately, these derivatives signifi-
cantly improved the diastereoselectivity of the azaelec-
trocyclization. Thus, the reactions of 2 and 3 with the
methyl-substituted aminoindanol (-)-b provided the cor-
responding piperidines (-)-2b and (-)-3b in the diaster-
eomeric ratio of 5:1 and 12:1 (entries 3 and 4), respec-
tively. Furthermore, the reactions with the ethyl-
substituted aminoindanol c gave the corresponding
piperidine derivatives in the ratio of 7:1 and 20:1,
respectively (entries 5 and 6). The highest selectivity was
obtained by utilizing the isopropyl-substituted aminoin-
danol (-)-d , and the corresponding piperidine derivatives
(-)-2d and (-)-3d were produced in the ratio of 10:1 and
24:1 (entries 7 and 8), respectively. Moreover, (-)-3d was
obtained as an almost single isomer at the lower tem-
perature of 13 °C (entry 9). Unexpectedly, the reactions
with the more bulky tert-butyl-substituted aminoindanol
e showed a slightly decreased selectivity (5:1 and 17:1
for 2e and 3e, entries 10 and 11, respectively). Thus, the
highly stereoselective 6π-azaelectrocyclization of the con-
formationally flexible linear 1-azatrienes was achieved
by utilizing the novel 7-alkyl-substituted cis-aminoin-
danol derivatives. Quite recently, Hsung and co-workers
1
those of a -d . This is indicated by their H NMR coupling
constants.
Syn th esis of 7-Alk yl-Su bstitu ted cis-1-Am in o-2-
in d a n ols. To work with this novel azaelectrocyclization
(19) (a) Hsung, R. P.; Wei, L.-L.; Sklenicka, H. M.; Douglas, C. J .;
McLaughlin, M. J .; Mulder, J . A.; Yao, L. J . Org. Lett. 1999, 1, 509.
(b) Sklenicka, H. M.; Hsung, R. P.; Wei, L.-L.; McLaughlin, M. J .;
Gerasyuto, A. I.; Degen, S. J . Org. Lett. 2000, 2, 1161. (c) Sklenicka,
H. M.; Hsung, R. P.; McLaughlin, M. J .; Wei, L.-l.; Gerasyuto, A. I.;
Brennessel, W. B. J . Am. Chem. Soc. 2002, 124, 10435. (d) McLaughlin,
M. J .; Hsung, R. P.; Cole, K. P.; Hahn, J . M.; Wang, J . Org. Lett. 2002,
4, 2017. (e) Luo, S.; Zificsak, C. A.; Hsung, R. P. Org. Lett. 2003, 5,
4709.
(20) Example of oxaelectrocyclization, see; (a) Hsung, R. P.; Shen,
H. C.; Douglas, C. J .; Morgan, C. D.; Degen, S. J .; Yao, L. J . J . Org.
Chem. 1999, 64, 690. (b) McLaughlin, M. J .; Hsung, R. P. J . Org. Chem.
2001, 66, 1049. (c) Zehnder, L. R.; Wei, L.-L.; Hsung, R. P.; Cole, K.
P.; McLaughlin, M. J .; Shen, H. C.; Sklenicka, H. M.; Wang, J .; Zificsak,
C. A. Org. Lett. 2001, 3, 2141. (d) Cole, K. P.; Hsung, R. P. Org. Lett.
2003, 5, 4843. (e) Kurdyumov, A. V.; Hsung, R. P.; Ihlen, K.; Wang, J .
Org. Lett. 2003, 5, 3935. (f) Shen, H. C.; Wang, J .; Cole, K. P.;
McLaughlin, M. J .; Morgan, C. D.; Douglas, C. J .; Hsung, R. P.;
Coverdale, H. A.; Gerasyuto, A. I.; Hahn, J . M.; Liu, J .; Sklenicka, H.
M.; Wei, L.-L.; Zehnder, L. R.; Zificsak, C. A. J . Org. Chem. 2003, 68,
1729.
(18) Kobayashi, T.; Tanaka, K.; Miwa, J .; Katsumura, S. Tetrahe-
dron: Asymmetry 2004, 15, 185.
J . Org. Chem, Vol. 69, No. 18, 2004 5909

Tanaka et al.
TABLE 2.a
amine
(X)
product
(major isomer)
T
(°C)
dr (at the
entry
aldehyde
2-position)c
1
2
3
2
3
2
3
2
3
2
3
3
2
3
(-)-a
(-)-a
(-)-b
(-)-b
c
2a
24
24
24
24
24
24
24
24
13
24
24
3:1d
3:1
5:1
12:1
7:1
20:1
10:1
24:1
>40:1
5:1
(-)-3a
(-)-2b
(-)-3b
2c
4
5e
6f
7
c
3c
(-)-d
(-)-d
(-)-d
e
(-)-2d
(-)-3d
(-)-3d
2e
8
9
10g
11h
e
3e
17:1
a
Unless noted, all the reactions quantitatively provided a diastereomeric mixture of two piperidine derivatives and the stereochemistry
as shown. The relative stereochemistry of the products was determined based on their 1H NMR and NOE experiments by comparison
b
with that of 1a . The stereochemistry of the 6-position of the minor isomers was not determined. CHCl3, 3 h. c Determined by 1H NMR
d
(400 MHz). An inseparable mixture of four piperidine derivatives (15:5:3:1) was obtained. The diastereomeric ratio at the 2-position
was determined after LiAlH4 reduction of the crude products. e -hThe racemic c and e were used to examine the diastereoselectivity of
the azaelectrocyclization.
F IGURE 2. Stable 2,3-s-cis, 4,5-s-cis conformation of 4, optimized by a semiempirical method (PM3) using the software package
SPARTAN version 5.0 (Wavefunction, Inc., Irvine CA).
reaction as a general method for chiral piperidine syn-
thesis, it was necessary to develop an efficient scale-up
method for the preparation of the chiral 7-substituted cis-
aminoindanol derivatives.18 The synthesis of the chiral
7-substituted cis-1-amino-2-indanols (-)-b and (-)-d was
followed by the procedure of commercially available (-)-a
developed by Merck’s group.21 The main feature of this
procedure is the Diels-Alder reaction of 1-substituted
dienes with cyclopentenone followed by the asymmetric
epoxidation of the resulting indene derivatives and then
the Ritter reaction.
Thus, 4-methylindene 6 was prepared on a 50-g scale
starting from the Diels-Alder reaction between 1,3-
pentadiene and cyclopentenone according to the method
of House and co-worker.22 Aromatization of the D-A
adduct by treatment with Pd/C at 200 °C produced
7-methylindanone 5 in 45% yield for two steps, which was
reduced by LiAlH4 and then dehydrated by treatment
with a catalytic amount of p-toluenesulfonic acid at 80
°C to give the desired 6 in 96% yield for two steps. The
indene 6 was treated with sodium hypochlorite solution
in the presence of (S,S)-(+)-N,N′-bis(3,5-di-tert-butylsali-
cylidene)-1,2-cyclohexanediaminomanganese(III) chlo-
ride and 4-phenylpyridine N-oxide at 0 °C for 7 h21b to
provide the desired indene oxide 7 in 67% yield and 85%
ee after rapid chromatography on alumina. Quite fortu-
(21) (a) Senanayake, C. H.; Roberts, F. E.; DiMichele, L. M.; Ryan,
K. M.; Liu, J .; Fredenburg, L. E.; Foster, B. S.; Douglas, A. W.; Larsen,
R. D.; Verhoeven, T. R.; Reider, P. J . Tetrahedron Lett. 1995, 36, 3993.
(b) Larrow, J . F.; Roberts, E.; Verhoeven, T. R.; Ryan, K. M.;
Senanayake, C. H.; Reider, P. J .; J acobsen, E. N. Organic Synth. 1999,
76, 46. (c) Muckensturm, B.; Diyani, F. J . Chem. Res., Synop. 1995,
442.
(22) House, H. O.; Rasmusson, C. H. J . Org. Chem. 1963, 28, 27.
5910 J . Org. Chem., Vol. 69, No. 18, 2004

Asymmetric 6π-Azaelectrocyclization
produce the phenol 11 in 72% yield.25 To remove the
phenolic hydroxy group of 11, the nickel catalyzed
reductive deoxygenation with sodium borohydride was
successfully employed.26 Thus, the tosylate, which was
prepared by treatment of the phenol 11 with p-toluene-
sulfonyl chloride and sodium hydride, was reacted with
30 equiv of sodium borohydride in the presence of 1 equiv
of nickel(II) chloride hexahydrate in methanol to give the
desired alcohol 12 in 84% yield for two steps, the product
resulting from the concomitant reduction of the ketone
group. The alcohol 12 was also quantitatively dehydrated
by a reaction with p-toluenesulfonic acid to provide the
4-isopropyl indene 13. Meanwhile, the application of the
same reaction conditions as the J acobsen’s epoxidation
for the 4-methyl derivative 6 toward the 4-isopropyl-
substituted indene 13 disappointedly gave the indene
oxide 14 in both lower chemical yield (∼50%) and
enantioselectivity (∼50% ee). Therefore, we attempted
the improved J acobsen’s epoxidation protocol under
anhydrous and lower temperature conditions.27 The in-
dene 13 was treated with 2 equiv of m-chloroperbenzoic
acid and 5 equiv of N-methylmorpholine N-oxide in the
presence of 5 mol % of (S,S)-(+)-N,N′-bis(3,5-di-tert-
butylsalicylidene)-1,2-cyclohexanediaminomanganese-
(III) chloride at -78 °C to provide the indene oxide 14 in
86% yield and 56% ee. Unfortunately, recrystallization
was not effective for isolating the enantiomerically pure
epoxide 14. Therefore, indene oxide 14 was then directly
subjected to the Ritter reaction followed by hydrolysis of
the oxazoline intermediate using the same procedure as
that utilized for the methyl derivative 7 to provide the
isopropyl substituted compound d in 77% yield for two
steps (39% yield after recrystallization). The enantio-
SCHEME 4a
a
Reagents and conditions: (a) LiAlH4, ether; (b) p-TsOH (0.1
equiv), benzene, gradually heated to 80 °C; (c) 1.8 M NaClO aq
(4.0 equiv), (S,S)-(+)-N,N′-bis(3,5-di-tert-butylsalicylidene)-1,2-
cyclohexanediaminomanganese(III) chloride (1.2 mol %), 4-phen-
ylpyridine N-oxide (6 mol %), CH2Cl2, rt; (d) fuming H2SO4,
CH3CN, rt, 30 min, then H2O, 100 °C, 2 h.
nately, the compound 7 was recrystallized from a mixture
of ether and hexane to give the enantiomerically pure
(+)-indene oxide 7, [R]24D +2.6 (c 0.9, CHCl3). The epoxide
7 was then reacted with fuming sulfuric acid (30% of SO3)
in acetonitrile21b to yield the intermediary oxazoline
derivative, which was hydrolyzed without purification in
H2O at 100 °C to provide the desired (-)-7-methyl-cis-
1-amino-2-indanol (-)-b (99% ee, [R]22 -110.8 (c 0.6,
CHCl3)] in 52% yield for two steps (Scheme 4).
D
The synthesis of 7-isopropyl-substituted aminoindanol
is as follows. Unfortunately, various attempts to prepare
a large quantity of the corresponding isopropyl-substi-
tuted 1,3-dienes were unsuccessful when using the same
method, which gave a mixture of regio- and stereoisomers
on the double bond. Therefore, we selected the corre-
sponding 2-siloxy-4-isopropyl-1,3-butadiene as a reactant
for the D-A reaction with cyclopentenone as shown in
Scheme 5. Thus, more than 200 g of isobutyraldehyde
was treated with 2.5 M solution of sodium hydroxide in
acetone to give the corresponding aldol product in 69%
yield,23 which was dehydrated by treatment with p-
toluensulfonic acid to provide the (E)-R,â-unsaturated
ketone 8 in 75% yield on a 200-g scale. The treatment of
8 with chlorotrimethylsilane and solid lithium bis(tri-
methylsilyl)amide in a mixed solvent system of THF and
toluene (1:2)24 at -78 °C provided the desired siloxydiene
9 in 79% yield. The purification of all the products so far
was successfully done by distillation that enabled us to
easily prepare the siloxydiene 9 on more than a 100-g
scale. The siloxydiene 9 was then reacted with cyclopen-
tenone in the presence of 2,5-di-tert-butylhydroquinone
in benzene at 200 °C for 72 h to give the desired
cycloadduct, which without purification was immediately
hydrolyzed by treatment with p-toluenesulfonic acid in
acetone to provide the diketone 10 in 69% yield for two
steps. The diketone consisted of two stereoisomers based
on the 1H NMR analysis. The oxidative aromatization
was successfully achieved by treatment of the diketones
10 with 10% Pd/C in p-cymene at 200 °C for 2 days to
merically homogeneous (-)-d (99% ee, [R]20 -114.2 (c
D
0.5, CHCl3)) was successfully obtained by the recrystal-
lization from toluene. The obtained enantiomeric excess
of (-)-d was analyzed by chiral HPLC (Scheme 5). Thus,
a sufficient amount of the chiral 7-methyl and 7-isopropyl
substituted cis-aminoindanol, (-)-b and (-)-d , were
prepared, respectively.
Rem ova l of In d a n ol Ch ir a l Au xilia r y by th e
Novel Ma n ga n ese Dioxid e Oxid a tion . The removal
of the indanol auxiliary of the cyclized products was
examined. The system mainly investigated for the opti-
mization of the condition was (-)-1a and its derivatives
because these compounds were relatively stable and
easily treated under a variety of conditions. Contrary to
our initial expectation, the removal of the indan auxiliary
was found to be troublesome. The conventional catalytic
hydrogenolysis (30% palladium/carbon, platinum dioxide,
or Willkinson catalyst) or Birch reduction of 1a resulted
in the recovery of the starting material. Also, the same
attempts on (-)-diol 15, [R]24 -66.9 (c 1.1, CHCl3),
D
derived from (-)-1a by the lithium aluminum hydride
reduction (Scheme 6),28 did not cleave the benzylic C-N
bond of the aminoindanol derivative, but resulted in the
decomposition of 15 due to reduction of the 2-position of
the piperidine ring, which is activated by two double
(25) (a) Anderson, A. G., J r.; Nelson, J . A. J . Am. Chem. Soc. 1951,
73, 232. (b) Turner, R. B.; Nettleton, D. E., J r.; Ferebee, R. J . Am.
Chem. Soc. 1956, 78, 5923.
(26) Wang, F.; Chiba, K.; Tada, M. J . Chem. Soc., Perkin Trans. 1
1992, 1897.
(27) Palucki, M.; Pospisil, P. J .; Zhang, W.; J acobsen, E. N. J . Am.
Chem. Soc. 1994, 116, 9333.
(23) Tishchenko, I. G.; Stanishevskii, L. S. J . Gen. Chem. USSR
1963, 33, 134.
(24) Nagata, T.; Koike, Y.; Nara, K.; Itoh, E.; Arisawa, M.; Naruto,
S.; Torisawa, Y.; Hino, T.; Nakagawa, M. Chem. Pharm. Bull. 1996,
44, 451. (b) Arisawa, M.; Torisawa, Y.; Nakagawa, M. Synthesis 1995,
1371.
J . Org. Chem, Vol. 69, No. 18, 2004 5911

Tanaka et al.
SCHEME 5a
a
Reagents and conditions: (a) 2.5 M NaOH aq acetone, 0 °C, 2.5 h (2 mol scale); (b) p-TsOH (0.005 equiv), Na2SO4, benzene, 80 °C; (c)
TMSCl, LiN(TMS)2, toluene/THF (2:1), -78 °C; (d) 2-cyclopentenone, 2,5-di-tert-butylhydroquinone, benzene, 200 °C, 72 h; (e) p-TsOH,
acetone; (f) 10% Pd/C, p-cymene, 200 °C, 48 h; (g) TsCl, NaH, THF; (h) NiCl2 (1.0 equiv), NaBH4 (30 equiv), MeOH, 0 °C; (i) p-TsOH (0.1
equiv), benzene, gradually to 80 °C; (j) m-CPBA (2 equiv), NMO (5 equiv), (S,S)-(+)-N,N′-bis(3,5-di-tert-butylsalicylidene)-1,2-
cyclohexanediaminomanganese(III) chloride (5 mol %), CH2Cl2, -78 °C; (k) fuming H2SO4, CH3CN, rt, 30 min, then H2O, 100 °C, 2 h.
TABLE 3.
SCHEME 6
yield of piperidine
alcohol (%)
entry substrate product yield of diol (%)
1
2
3
(-)-3a
(-)-3b
(-)-3d
(-)-17
(-)-17
(-)-17
76b
91
55
55
58
91c
a
The reaction was performed by treatment of the diols with
manganese dioxide (10-20 w/w, chemicals treated, Wako) in ether
for
a
few minutes at room temperature. b,c Total yield from
aldehyde 3.
bonds and nitrogen. A trial involving the oxidative
cleavage29 of the indanol moiety of 15 by utilizing Pd-
(OAc)4, KIO4, and m-CPBA also produced a complex
mixture of the products. After many trials, this task was
finally accomplished by treatment of (-)-15 with man-
ganese dioxide in ether at room temperature for three
minutes, followed by silica gel chromatography to provide
17 in 55-58% yields. Surprisingly, the cleavage of the
benzylic C-N bond proceeded under quite mild condition.
It was strongly recommended to use ether or acetone as
the solvent of the reaction. When the reaction was done
in dichloromethane, a complex mixture of products was
obtained due to the simultaneous oxidation of the allylic
alcohol to the corresponding aldehyde followed by de-
composition of the products.
To elucidate the mechanism of this interesting reac-
tion, (-)-diol 15 was treated with manganese dioxide
under the same reaction conditions described above. After
evaporation of the solvent, and without silica gel chro-
matography, very unstable N-oxide 18 was obtained
(Scheme 7). The characterization of the N-oxide deriva-
tive was conducted for the rather stable N-oxide 26
the (-)-amino alcohol 16, [R]24 -46.5 (c 0.4, CHCl3), in
D
69% yield (Scheme 6).
Similarly, the removal of the chiral indanol moiety in
(-)-3a -d was successfully achieved as shown in Table
3. Thus, (-)-3a -d were reduced with lithium aluminum
hydride to give the corresponding diols in 76-91% yields,
which were then treated with manganese dioxide in ether
at room temperature followed by silica gel chromatogra-
phy to provide the corresponding piperidine alcohol (-)-
(28) For reduction and alkylation of aminoacetal, see: (a) Yamato,
M.; Hashigaki, K.; Ishikawa, S.; Qais, N. Tetrahedron Lett. 1988, 29,
6949. (b) Higashiyama, K.; Inoue, H.; Takahashi, H. Tetrahedron Lett.
1992, 33, 235. (c) Higashiyama, K.; Inoue, H.; Takahashi, H. Tetra-
hedron 1994, 50, 1083. (d) Higashiyama, K.; Nakahata, K.; Takahashi,
H. J . Chem. Soc., Perkin. Trans. 1 1994, 351. (e) Higashiyama, K.;
Kyo, H.; Takahashi, H. Synlett 1998, 489. also see the following review;
Husson, H.-P.; Royer, J . Chem. Soc. Rev. 1999, 28, 383.
1
(structure shown in Scheme 8) by MS, IR, and H NMR
(see the Experimental Section) and compared with those
of 18. The produced N-oxide 18 was gradually trans-
formed to the (-)-piperidine alcohol 16 in deuterated
chloroform at room temperature, which was also pro-
duced when N-oxide 18 was subjected to silica gel
chromatography. On the basis of the results obtained
here, the following mechanism for the removal of the
(29) For an example of oxidative cleavage of an amino alcohol, see:
Higashiyama, K.; Inoue, H.; Yamauchi, T.; Takahashi, H. J . Chem.
Soc., Perkin. Trans. 1 1995, 111.
5912 J . Org. Chem., Vol. 69, No. 18, 2004

Asymmetric 6π-Azaelectrocyclization
SCHEME 7
SCHEME 8
indan moiety was proposed (Scheme 7). Thus, the nitro-
gen atom of (-)-15 would be oxidized by manganese
dioxide to produce N-oxide 18, which would be followed
by the Polonovski-type reaction:30 the acid-catalyzed
dehydration of 18 followed by hydrolysis of the resulting
imminium ion 19.31 Time-dependent FAB-MS analysis
of the N-oxide 18 detected ion peaks corresponding to the
imminium ion 19 and the corresponding hydroxylated
intermediate, the hemiaminoacetal compound, and sup-
ported the proposed mechanism as shown in Scheme 7
(see the Experimental Section). The dehydration of
N-oxide 18 is possible from three directions: by abstract-
ing either proton Ha, Hb, or Hc. However, proton Ha is
selectively removed in this case. This can be rationalized
by considering that (1) Ha is a reactive benzylic proton
and (2) the C-Ha bond is situated in the antiperiplanar
position32 to the leaving N-O bond in the N-oxide 18.
Unfortunately, we could not isolate the cleaved R-hy-
droxyindanone moiety because it gradually decomposed
into several compounds on the basis of TLC analysis.
Furthermore, an interesting observation concerning
the mechanism of this oxidative removal of the indanol
moiety was noted by the following experiments (Scheme
8). Thus, the reaction of 20 with manganese dioxide at
(30) For a review of the Polonovski reaction for alkaloid synthesis,
see: Lounasmaa, M. Synthetic Studies in the Field of Indole Alkaloids.
In Studies in Natural Products Chemistry; Atta-ur-Rahman, Ed.;
Elsevier: Amsterdam, 1988; Vol. 1, pp 89-122.
(31) (a) Monkovic, I.; Wong, H.; Bachand, C. Synthesis 1985, 770.
(b) Chang, Z.-Y.; Coates, R. M. J . Org. Chem. 1990, 55, 3475. (c)
Blanchet, J .; Bonin, M.; Micouin, L.; Husson, H.-P. Tetrahedron Lett.
2000, 41, 8279.
(32) Fleming, I. Frontier Orbitals and Organic Chemical Reactions;
Wiley: New York, 1987.
J . Org. Chem, Vol. 69, No. 18, 2004 5913

Tanaka et al.
SCHEME 9
room temperature resulted in only the recovery of 20. The
reactions of 21-24 with manganese dioxide cleanly
produced the corresponding conjugated aldehydes. Thus,
no oxidation of nitrogen was observed with derivatives
20-24. On the other hand, the oxidation of the (-)-ester
derived from tryptophan (Scheme 9).33 Although a num-
ber of syntheses of racemic uleine derivatives were
reported in the literature,34,35 a few asymmetric syntheses
have been reported including the recent synthesis of (+)-
uleine by Ogasawara and co-workers.36 One of the com-
mon approaches toward the construction of the 2-aza-
bicyclo[3.3.1]nonane structure, which is characteristic for
the Strychnos indole alkaloids, includes the C2-C16 bond
formation of 3-(2-piperidyl)indoles as shown in Scheme
9.33 For example, Husson and co-workers succeeded in
the synthesis of (()-20-epiuleine by the acid-catalyzed
cyclization of the racemic 2,3,4-trisubstituted piperidine
derivative 29, which was prepared by the conjugate
addition of ethylmagnesium bromide to the unsaturated
ketone 30.35c Therefore, when the synthesis of the opti-
cally active Strychnos indole alkaloids is planned,37 an
efficient and stereoselective synthesis of the optically
active 2- and 4-substituted piperidine derivative such as
chiral 30 would be required, the construction method of
which has not yet been established. We envisioned the
synthesis of the optically active piperidine 30 using our
asymmetric azaelectrocyclization method as shown in
Scheme 9. The key intermediate 30 would be derived
from 31 by the functional group manupulations, and 31
was thought to be prepared by the asymmetric azaelec-
trocyclization of azatriene 32, which would be derived
from (E)-3-carbonyltrienal 33 and the developed chiral
7-alkyl-cis-aminoindanol derivatives. Thereby, the indole
ring and the ester substituent of the azatriene 32 would
alcohol 25, [R]24 -40.0 (c 1.0, CHCl3), which was
D
obtained by the sodium borohydride reduction of (-)-1a ,28
smoothly gave the corresponding N-oxide derivative 26.
However, the N-oxide 26 thus produced was found to be
stable in CDCl3 for over 24 h or on the silica gel, and
conversion of 26 to the corresponding piperidine alcohol
such as 16 in Scheme 6 was not observed. In addition,
the manganese dioxide oxidation of the compound 27, of
which the C4-hydroxymethyl group was protected as its
tert-butyldiphenylsilyl ether, produced the corresponding
N-oxide 28, which provided a complex mixture of prod-
ucts after silica gel chromatography. On the basis of these
results, it was suggested that the hydroxy group of the
cis-1-amino-2-indanol moiety would contribute to the
facile oxidation of the vicinal nitrogen, possibly by the
coordination of manganese dioxide to the cis-amino
alcohol moiety of 15 as shown in Scheme 7. Furthermore,
the hydroxymethyl group at the 4-position of the piperi-
dine would facilitate the dehydration, presumably by
participating in hydrogen bonding partially with the
N-oxide moiety, which might be also hydrogen bonded
with the vicinal hydroxy group as shown in compound
18 of Scheme 7. This additional hydrogen bonding
between the C4-hydroxymethyl group and the N-oxide
would increase the leaving ability of the N-O bond or
would make the conformation favorable to lose the Ha
proton, leading to the facile and regioselective Polonovski
reaction without any activation of N-oxide such as its
trifluoroacetate.30
(33) Bosch, J .; Bonjoch, J . Pentacyclic Strychnos Indole Alkaloids.
In Studies in Natural Products Chemistry; Atta-ur-Rahman, Ed.;
Elsevier: Amsterdam, 1988; Vol. 1, pp 31-88.
(34) Synthesis of uleine: (a) J ackson, A.; Wilson, N. D. V.; Gaskell,
A. J .; J oule, J . A. J . Chem. Soc. C 1969, 2738. (b) Buchi, G.; Gould, S.
J .; Naf, F. J . Am. Chem. Soc. 1971, 93, 2492. (c) Kametani, T.; Suzuki,
T. J . Org. Chem. 1971, 36, 129.
F or m a l Syn th esis of 20-Ep iu lein e. Finally, to apply
the thus-established method to the natural products
synthesis, we examined the asymmetric synthesis of 20-
epiuleine. Uleine, 20-epiuleine, and dasycarpidone, which
were principally isolated from Aspidosperma sp., consti-
tute a small family of Strychnos-type indole alkaloids.
These indole alkaloids lack the usual two carbon chain
(35) Synthesis of 20-epiuleine: (a) Dolby, L. J .; Biere, H. J . Org.
Chem. 1970, 35, 3843. (b) Natsume, M.; Kitagawa, Y. Tetrahedron Lett.
1980, 21, 839. (c) Harris, M.; Besselievre, R.; Grierson, D. S.; Husson,
H.-P. Tetrahedron Lett. 1981, 22, 331. (d) Grierson, D. S.; Harris, M.;
Husson, H.-P. Tetrahedron 1983, 39, 3683. see also 34.
(36) Saito, M.; Kawamura, M.; Hiroya, K.; Ogasawara, K. Chem.
Commun. 1997, 765.
(37) Enantioselective synthesis of Strychnos indole alkaloids and
related compounds: Bonjoch, J .; Sole, D. Chem. Rev. 2000, 100, 3455.
5914 J . Org. Chem., Vol. 69, No. 18, 2004

Asymmetric 6π-Azaelectrocyclization
SCHEME 10
function not only as the desirable substituents at the 2-
and 4-positions of the piperidine 30 but also as the
activating groups of the azaelectrocyclization. Trienal 33
could be prepared from (E)-vinylstannane 34 and (Z)-
vinyl halide 35 by our already-established method.10
The synthesis of (E)-vinylstannane is shown in Scheme
10. Iodide 36, which was easily prepared according to the
reported procedure,38 was reacted with TMS-acetylene
in the presence of tetrakis(triphenylphosphine)palladium-
(0), copper iodide, and triethylamine in THF to yield the
corresponding indole acetylene. After removal of the TMS
group by potassium methoxide treatment in methanol,
acetylene 37 was obtained in 85% yield in two steps.
However, a small amount of palladium and copper
reagents used for the coupling reaction could not be
completely removed from 37 by recrystallizations or
column chromatography, because of the low solubility of
the indole acetylene compounds in any solvents. There-
fore, acetylene 37 was continuously subjected to hy-
drostannylation without further purification. Contrary
to our expectation, various possible conditions for the
hydrostannylation of 37 provided only a detectable
amount of the desired (E)-stannane 39, and surprisingly,
the internal stannane 38 was produced as the major
product. We later found that a small contaminant of
palladium or copper reagents included in 37 catalyzed
the addition of SnBu3 species toward the more substi-
tuted position of acetylene.39 This phenomenon is in clear
contrast to the hydrostannylation of the ethynyl benzene
derivatives, which exclusively produced the external (E)-
stannanes.10 Unfortunately, these stannyl regioisomers
could not be separated by silica gel chromatography, and
another regioselective synthesis for (E)-vinylstannane
was required, because the pure (E)-vinylstannane was
essential for the clean Stille coupling reaction with the
vinyl halide fragment (see Scheme 11).
As another approach toward the indole-3-acetylene, the
conversion from aldehyde 40 was examined. Thus, 3-in-
dolecarbaldehyde 40 protected with an N-p-toluenesulfo-
nyl group was reacted with carbon tetrabromide (3 equiv)
and triphenylphosphine (6 equiv) at -78 °C to provide
the dibromide 41 in 93% yield on a 20-g scale, according
to the procedure developed by Corey and Fuchs.40 Com-
pound 41 was then treated with 1.2 equiv of lithium bis-
(trimethylsilyl)amide to give the intermediary bromoacet-
ylene 42, which without purification was treated with 1.5
equiv of sec-butyllithium to provide the pure acetylene
43 in 61% yield for two steps after recrystallization. The
choice of the bases such as LiN(TMS)2 and s-BuLi and
their equivalents was crucial for each reaction to be
successful. When other bases such as n-butyllithium or
LDA were used, the indole ring was decomposed due to
the simultaneous removal of the N-tosyl protecting group.
Fortunately, the reaction of the obtained pure acetylene
43 with n-Bu3SnH in the presence of AIBN at 115 °C
provided the desired (E)-vinylstannane 44 in 86% yield.
(39) Kazmaier, U.; Schauss, D.; Pohlman, M. Org. Lett. 1999, 1,
1017.
(38) Bocchi, V.; Palla, G. Synthesis 1982, 1096.
(40) Corey, E. J .; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.
J . Org. Chem, Vol. 69, No. 18, 2004 5915

Tanaka et al.
SCHEME 11
The regioselectivity is completely different from the case
of the previous attempts. It is an interesting observation
that the two regioisomeric stannanes 38 and 44 could
be respectively prepared by only changing the catalyst:
(i) AIBN for the synthesis of the external (E)-stannane
44 and (ii) the presumable complex derived from the
palladium and cuprous species for the synthesis of the
internal stannane 38.39
tivity to the temperature observed is not due to the
amine-catalyzed epimerization at the C-2 position since
the treatment of pure (-)-48b with amine bases such as
triethylamine or DBU at 33 °C did not cause the
epimerization. After separation of the minor isomer by
medium-pressure chromatography, the aminoacetal and
ester groups of (-)-48b were reduced by lithium alumi-
num hydride to give the diol 49b in 95% yield. The
removal of the indanol moiety was successfully achieved
according to the previously established method. Thus, the
treatment of 49b with manganese dioxide in ether at
room temperature for three minutes followed by silica
gel column chromatography provided the indole substi-
tuted piperidine (-)-50, [R]27D -31.1 (c 0.5, CHCl3) in 73%
yield. An aminoindanol (-)-d similarly provided (-)-50
via 48d and 49d as shown in Scheme 11. The selective
N-methylation was successfully achieved by treatment
of (-)-50 with 37% aqueous HCHO solution (6 equiv) and
sodium cyanoborohydride (2 equiv) in acetonitrile to
quantitatively give (-)-51. Finally, the conversion to the
key intermediate (-)-30 and the formal synthesis of 20-
epiuleine was successfully achieved by the conventional
functional group manipulation, which involved the oxida-
tion of the primary alcohol by manganese dioxide, me-
thylation of the aldehyde with methyllithium (55% yield
for two steps), deprotection of the indole N1-sulfonyl
group with sodium methoxide, and oxidation of the
secondary alcohol with manganese dioxide (40% yield for
two steps). The spectral characteristics of the synthesized
Unfortunately, the Stille coupling between stannane
44 and bromide 45 in the presence of Pd(PPh3)4 and LiCl
in DMF only provided the corresponding dimeric product
of 44 (Scheme 11).41 However, the reaction of 44 with the
more reactive iodide 46, which was prepared by the same
procedure as the bromide 45 (see Experimental Section),
successfully provided the coupling product in 72% yield,
which was oxidized with manganese dioxide to yield 47
in 87% yield. The next step is our asymmetric azaelec-
trocyclization as the key step of the synthesis. Thus, (E)-
3-carbonyltrienal 47 was reacted with the chiral (-)-cis-
aminoindanol b in chloroform at 24 °C to produce (-)-
48b, [R]27 -1.5 (c 0.5, CHCl3), in 96% yield as a 10:1
D
mixture of the stereoisomers at the 2-position of the
piperidine ring. The stereoselectivity was surprisingly
sensitive to the temperature, and when the reaction was
performed even at 33 °C, a 1:1 mixture of the stereoiso-
mers was produced. The quite sensitive diastereoselec-
(41) (a) Kanemoto, S.; Matsubara, S.; Oshima, K.; Utimoto, K.;
Nozaki, H. Chem. Lett. 1987, 5. (b) Liebeskind, L. S.; Riesinger, S. W.
Tetrahedron Lett. 1991, 32, 5681.
5916 J . Org. Chem., Vol. 69, No. 18, 2004

Asymmetric 6π-Azaelectrocyclization
(c 0.3, MeOH); IR (KBr disk, cm-1) 3449, 1690, 1653, 1283; 1H
NMR (400 MHz, CDCl3) δ 1.07 (brs, 3H), 1.16 (s, 3H), 1.46-
1.63 (m, 4H), 1.83 (s, 3H), 2.03-2.10 (m, 2H), 2.64 (brs, 2H),
3.16 (d, 1H, J ) 17.8 Hz), 3.24 (dd, 1H, J ) 17.8, 5.9 Hz), 3.82
(brs, 1H), 4.38-4.39 (m, 1H), 4.85 (dd, 1H, J ) 5.6, 5.6 Hz),
4.93 (d, 1H, J ) 5.6 Hz), 6.97 (brs, 1H), 7.17-7.26 (m, 4H);
13C NMR (100 MHz, DMSO-d6) (as a mixture with its presum-
able rotamers and its corresponding dihydropyridine) δ 19.0,
20.7, 21.4, 25.3, 27.1, 28.0, 28.7, 29.2, 34.1, 34.3, 34.9, 53.7,
57.5, 59.7, 66.3, 70.6, 73.4, 74.6, 85.3, 86.6, 123.6, 124.5, 125.2,
125.3, 126.3, 126.6, 126.9, 127.5, 128.0, 134.0, 135.7, 136.1,
139.9, 140.8, 141.3, 142.9, 166.7, 167.1; EI HRMS m/e calcd
for C24H29NO3 (M+•) 379.2146, found 379.2155.
Rep r esen ta tive P r oced u r e of th e Ster eoselective 6π-
Aza electr ocycliza tion by th e Rea ction betw een (E)-3-
Eth oxyca r bon yl-2,4,6-tr ien a ls (2 a n d 3) a n d cis-Am in oin -
d a n ols (a -e) (Ta ble 2). Unless noted, all the reactions were
performed by the following representative procedure to exam-
ine the diastereoselectivity of the azaelectrocyclyzation: To a
CDCl3 (0.5 mL) solution of the aldehydes 2 or 3 (0.0267 mmol)
was added cis-aminoindanol derivatives a -e (0.0267 mmol)
at 24 °C. Each reaction was monitored by 1H NMR, and the
diastereomeric mixture of the piperidine derivatives were
quantitatively produced over 3 h. The mixture was concen-
trated in vacuo to give the crude products, from which the
major isomer was isolated by preparative thin-layer chroma-
tography on silica gel (17% ethyl acetate in hexane).
30 were in good agreement with those reported by
Husson and co-workers.
Su m m a r y
In summary, we have developed novel chiral 7-alkyl-
substituted cis-aminoindanol derivatives such as (-)-b
and (-)-d , and achieved the highly stereoselective aza-
electrocyclization by reaction with the linear trienals such
as 1-3 and 47. The cis-aminoindanol derivatives are
acting not only as a “chiral auxiliary” but also as a
“nitrogen source” for this asymmetric azaelectrocycliza-
tion. In addition, the cis-hydroxy group of the aminoin-
danol displays the following important roles: (i) it
contributes to improving the diastereoselectivity of the
azaelectrocyclization, (ii) stabilizes the notoriously un-
stable N-alkyl 1,2-dihydropyridine nucleus by its ami-
noacetal formation, and (iii) facilitates the oxidation of
the vicinal nitrogen which resulted in the removal of the
chiral indanol auxiliary under very mild conditions. It is
worthwhile mentioning that this asymmetric azaelectro-
cyclization can be quite easily carried out by simply
mixing aldehydes and the amine in chloroform at room
temperature, leaving the mixture for the completion of
the reaction, and then evaporating the solvent. This was
demonstrated by the formal synthesis of 20-epiuleine.
Further application of the developed asymmetric aza-
electrocyclization is now ongoing in our laboratory toward
achieving a new strategy for natural product synthesis.
For the reactions of entries 1-3, the crude cyclized products
prepared by the same procedure were directly reduced with
lithium aluminum hydride (1.0 equiv, in ether), purified by
column chromatography on silica gel (33% to 50% ethyl acetate
in hexane), and then the ratio of the resulting two diastereo-
meric dialcohols were analyzed by 1H NMR, respectively.
Furthermore, these diastereomers were successfully separated
by preparative thin-layer chromatography on silica gel (45%
ethyl acetate in hexane).
Exp er im en ta l Section
(-)-1,2,5,6-Tetr a h yd r op yr id in e (1a ). To a solution of
methyl (E,E)-4-oxo-2-[(2,6,6-trimethylcyclohex-1-enyl)vinyl]-
but-2-enoate 1 (1.19 g, 4.52 mmol) in chloroform (30 mL) was
added (1S,2R)-(-)-cis-1-amino-2-indanol a (742 mg, 4.97 mmol)
at room temperature, and the mixture was stirred for 1 h at
this temperature. The reaction mixture was concentrated in
vacuo to give the crude products which were purified by
column chromatography on silica gel (from 9% to 17% ethyl
acetate in hexane) to afford 1a as a single stereoisomer (1.78
Rea ction betw een 2 a n d (-)-a (En tr y 1 of Ta ble 2). The
reaction provided the four inseparable mixtures of the piperi-
dine derivatives 2a (namely, w , x, y, and z) in a ratio of 15:
1
5:3:1 (judged by H NMR) as a colorless oil: characteristic 1H
NMR signals in their vinyl protons (400 MHz, CDCl3) δ 6.73-
6.74 (m, proton w ), 6.68 (dd, proton x, J ) 2.4, 2.4 Hz), 6.79-
6.82 (m, proton y), 6.63-6.64 (m, proton z).
Dia lcoh ols P r ep a r ed fr om th e Cyclized P r od u cts of 2a
by LiAlH4 Red u ction . (Major/minor ) 3:1, determined by
both 1H NMR and their isolated yields.) Data for the major
isomer: [R]26D -41.4 (c 0.5, CHCl3); IR (neat, cm-1) 3403, 1256,
g, 100%) as a yellow oil: [R]24 -45.4 (c 1.1, CHCl3); IR (neat,
D
cm-1) 1719, 1460, 1435, 1252, 1119, 1028; 1H NMR (400 MHz,
CDCl3) δ 1.11 (brs, 3H), 1.19 (s, 3H), 1.48-1.68 (m, 4H), 1.86
(s, 3H), 2.07-2.12 (m, 2H), 2.67 (brs, 2H), 3.18 (d, 1H, J )
17.6 Hz), 3.27 (dd, 1H, J ) 18.3, 6.1 Hz), 3.76 (s, 3H), 3.82
(brs, 1H), 4.40-4.42 (m, 1H), 4.87 (dd, 1H, J ) 6.1, 6.1 Hz),
4.95 (d, 1H, J ) 5.4 Hz), 6.88 (brs, 1H), 7.21-7.26 (m, 4H);
13C NMR (100 MHz, CDCl3) δ 19.5, 21.7, 25.6, 28.4, 29.5, 34.6,
35.3, 39.6, 40.5, 51.7, 54.1, 73.9, 75.3, 87.4, 123.7, 124.6, 125.8,
127.0, 128.1, 135.4, 135.9, 141.0, 141.6, 143.0, 166.8; EI HRMS
m/e calcd for C25H31NO3 (M+•) 393.2302, found 393.2308.
(-)-Ca r boxylic Acid Der iva tive of 1a . To a solution of
(-)-1,2,5,6-tetrahydropyridine 1a (950 mg, 2.41 mmol) in
methanol (20 mL) was added a 2 N KOH solution (1.45 mL,
2.90 mmol) at room temperature. After the mixture was heated
to 80 °C and vigorously stirred for 2.5 h, a 1 N HCl solution
was added, and the resulting mixture was extracted with ethyl
acetate. The organic layers were combined, washed with brine,
dried over MgSO4, filtered, and concentrated in vacuo to give
the crude products. Rough column chromatography on silica
gel twice (33-40% ethyl acetate in hexane, and then 25-33%
ethyl acetate in hexane) gave the corresponding acid (870 mg,
88%) as a white solid, which was then recrystallized from THF,
methanol, and ethyl acetate for the X-ray crystallographic
analysis. The carboxylic acid thus obtained narrowly dissolved
in CDCl3 to analyze its 1H NMR, and the following very similar
signals to those of 1a indicated that no epimerization occurred
during the hydrolysis of (-)-1a : mp 163-164 °C; [R]24D -38.0
1
1121, 1084, 1061; H NMR (400 MHz, CDCl3) δ 0.11 (s, 3H),
0.12 (s, 3H), 0.94 (s, 9H), 1.91 (dd, 1H, J ) 17.3, 3.2 Hz), 2.14-
2.19 (m, 1H), 2.22-2.30 (m, 1H), 2.57-2.64 (m, 1H), 2.66-
2.72 (m, 1H), 3.19-3.25 (m, 1H), 3.78 (brs, 1H), 4.03 (d, 1H, J
) 16.6 Hz), 4.07 (d, 1H, J ) 13.4 Hz), 4.21-4.27 (m, 2H), 4.29-
4.38 (m, 2H), 5.59-5.60 (m, 1H), 5.72 (dt, 1H, J ) 15.4, 4.9
Hz), 5.97 (ddt, 1H, J ) 15.1, 8.8, 1.7 Hz), 7.13-7.25 (m, 3H),
7.37 (d, 1H, J ) 7.6 Hz); 13C NMR (100 MHz, CDCl3) δ-5.3,
18.4, 25.9, 26.3, 41.1, 41.7, 61.1, 62.9, 66.3, 66.8, 69.7, 123.7,
125.2, 126.4, 126.8, 128.2, 128.3, 132.4, 136.7, 139.0, 142.2;
EI HRMS m/e calcd for C24H37NO3Si (M+•) 415.2541, found
415.2551. Data for the minor isomer: [R]25 +107.1 (c 0.9,
D
CHCl3); IR (neat, cm-1) 3416, 1460, 1256, 1086, 1055, 970; 1H
NMR (400 MHz, CDCl3) δ 0.08 (s, 3H), 0.09 (s, 3H), 0.91 (s,
9H), 1.84 (brd, 1H, J ) 16.6 Hz), 2.13 (ddd, 1H, J ) 11.0, 11.0,
3.7 Hz), 2.24 (brd, 1H, J ) 14.2 Hz), 2.29-2.35 (m, 1H), 2.82
(dd, 1H, J ) 16.6, 7.1 Hz), 3.32 (dd, 1H, J ) 16.6, 8.3 Hz),
3.98 (d, 1H, J ) 13.4 Hz), 4.04 (d, 1H, J ) 13.2 Hz), 4.18-
4.27 (m, 3H), 4.39 (dd, 1H, J ) 15.4, 8.1 Hz), 4.57 (d, 1H, J )
8.3 Hz), 5.47 (brs, 1H), 5.52 (ddt, 1H, J ) 15.4, 9.0, 1.7 Hz),
5.88 (dt, 1H, J ) 15.4, 4.6 Hz), 7.17-7.31 (m, 4H); 13C NMR
(100 MHz, CDCl3) δ -5.1, 18.4, 25.9, 26.3, 41.8, 44.9, 62.8,
63.3, 64.4, 66.0, 68.9, 124.1, 125.5, 126.0, 126.4, 128.4, 131.9,
133.4, 136.8, 139.2, 141.7; EI HRMS m/e calcd for C24H37NO3-
Si (M+•) 415.2541, found 415.2537.
J . Org. Chem, Vol. 69, No. 18, 2004 5917

Tanaka et al.
R ea ct ion bet w een 3 a n d (-)-a (E n t r y 2 of Ta ble 2).
(Major/minor ) 3:1, determined by 1H NMR.) Data for the
) 6.4, 1.0 Hz), 4.50 (ddd, 1H, J ) 7.6, 7.6, 1.5 Hz), 4.86 (d,
1H, J ) 6.1 Hz), 5.52 (ddt, 1H, J ) 15.1, 10.0, 1.5 Hz), 5.86
(dt, 1H, J ) 15.4, 5.1 Hz), 6.97-7.01 (m, 3H), 7.13 (dd, 1H, J
) 7.6, 7.6 Hz).
major isomer (-)-3a : [R]21 -63.8 (c 0.5, CHCl3); IR (neat,
D
1
cm-1) 1715, 1269, 1244, 1032; H NMR (400 MHz, CDCl3) δ
1.24 (t, 3H, J ) 7.1 Hz), 2.72-2.75 (m, 2H), 3.15 (d, 1H, J )
17.8 Hz), 3.23 (dd, 1H, J ) 18.1, 6.1 Hz), 4.16 (qm, 2H, J )
7.3 Hz), 4.23 (dd, 1H, J ) 6.1, 3.7 Hz), 4.50 (dd, 1H, J ) 3.2,
3.2 Hz), 4.75 (d, 1H, J ) 5.6 Hz), 4.93 (ddd, 1H, J ) 5.9, 5.9,
1.5 Hz), 6.79 (dd, 1H, J ) 4.1, 2.0 Hz), 7.13-7.23 (m, 4H),
7.33-7.37 (m, 1H), 7.45 (ddm, 2H, J ) 7.3, 7.3 Hz), 7.58 (dm,
2H, J ) 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 14.2, 25.6, 39.5,
60.6, 61.2, 74.9, 75.4, 86.7, 124.1, 124.4, 125.5, 127.0, 127.8,
128.3, 128.4, 128.8, 138.8, 140.0, 142.3, 142.9, 166.1; EI HRMS
m/e calcd for C23H23NO3 (M+•) 361.1677, found 361.1676. Data
Dia lcoh ols P r ep a r ed fr om th e Cyclized P r od u cts of
En tr y 3 by LiAlH4 Red u ction . (Major/minor ) 5:1, deter-
mined by their isolated yields.) These dialcohols existed as
their rotamers at 24 °C in CDCl3, and most of the signals in
their 1H and 13C NMR spectra were broadened. Data for the
major isomer: [R]21D -64.3 (c 0.8, CHCl3); IR (neat, cm-1) 3387,
1470, 1381, 1256, 1121, 1092, 970; 1H NMR (400 MHz, CDCl3)
δ 0.05 (d, 6H, J ) 1.5 Hz), 0.90 (s, 9H), 2.30 (s, 3H), 2.66 (dd,
1H, J ) 15.6, 8.1 Hz), 3.11 (dd, 1H, J ) 15.6, 7.3 Hz), 4.04 (s,
2H), 4.29-4.38 (m, 2H), 5.47 (brs, 1H), 5.58 (brs, 1H), 5.73-
5.85 (brm, 1H), 6.94-7.00 (m, 2H), 7.14 (dd, 1H, J ) 7.6, 7.6
Hz); 13C NMR (100 MHz, CDCl3) δ -5.3, 18.3, 20.4, 25.9, 27.1,
29.7, 29.8, 40.9, 60.1, 63.0, 66.2, 68.2, 72.1, 122.1, 124.5, 128.0,
for the minor isomer: [R]20 +129.3 (c 0.3, CHCl3); IR (KBr
D
disk, cm-1) 1713, 1250, 1051, 1038; 1H NMR (400 MHz, CDCl3)
δ 1.22 (t, 3H, J ) 7.1 Hz), 2.36 (dddd, 1H, J ) 15.4, 8.3, 4.1,
2.7 Hz), 2.84 (ddd, 1H, J ) 16.3, 3.2, 3.2 Hz), 3.13-3.24 (m,
2H), 4.12 (dd, 1H, J ) 4.1, 4.1 Hz), 4.13 (qm, 2H, J ) 7.3 Hz),
4.73-4.75 (m, 1H), 4.86 (d, 1H, J ) 5.9 Hz), 5.11 (ddd, 1H, J
) 5.6, 5.6, 2.7 Hz), 6.70 (dd, 1H, J ) 2.4, 2.4 Hz), 7.09 (d, 1H,
J ) 7.3 Hz), 7.13-7.17 (m, 1H), 7.23-7.24 (m, 2H), 7.36 (dddd,
1H, J ) 6.8, 6.8, 1.2, 1.2 Hz), 7.46 (dd, 2H, J ) 7.3, 7.3 Hz),
7.60 (d, 2H, J ) 7.1 Hz); 13C NMR (100 MHz, CDCl3) δ 14.1,
31.0, 39.7, 59.8, 60.7, 65.9, 80.2, 85.5, 125.2, 126.2, 126.6, 127.8,
127.9, 128.5, 129.1, 129.9, 136.4, 139.8, 140.8, 143.7, 166.4;
EI HRMS m/e calcd for C23H23NO3 (M+•) 361.1677, found
361.1685.
128.6, 132.1, 136.2, 136.5, 138.4; EI HRMS m/e calcd for C25H39
-
NO3Si (M+•) 429.2697, found 429.2693. Data for the minor
isomer: [R]21 +115.9 (c 0.3, CHCl3); IR (neat, cm-1) 3412,
D
1464, 1256, 1090; 1H NMR (400 MHz, CDCl3) δ 0.09 (d, 6H, J
) 5.4 Hz), 0.91 (s, 9H), 1.84 (brd, 1H, J ) 13.4 Hz), 2.17-2.34
(m, 3H), 2.36 (s, 3H), 2.69 (dd, 1H, J ) 16.1, 8.3 Hz), 3.25 (dd,
1H, J ) 16.1, 8.1 Hz), 3.99-4.07 (m, 2H), 4.19-4.25 (m, 4H),
4.48 (d, 1H, J ) 7.8 Hz), 4.87 (brs, 1H), 5.46 (brs, 1H), 5.53
(dd, 1H, J ) 15.4, 9.0 Hz), 5.85 (dt, 1H, J ) 15.1, 4.9 Hz),
7.01-7.04 (m, 2H), 7.16 (dd, 1H, J ) 7.6, 7.6 Hz); 13C NMR
(100 MHz, CDCl3) δ -5.1, 18.4, 21.5, 25.9, 26.7, 41.9, 44.7,
63.2, 63.4, 63.8, 66.1, 69.1, 122.7, 124.4, 128.0, 128.6, 132.4,
Dia lcoh ols P r ep a r ed fr om th e Cyclized P r od u cts of
En tr y 2 by LiAlH4 Red u ction . (Major/minor ) 3:1, deter-
mined by both 1H NMR and their isolated yields.) Data for
the major isomer: mp 142-143 °C; [R]25D -82.5 (c 0.6, CHCl3);
IR (KBr disk, cm-1) 3405, 3264, 1453, 1385, 1090, 1067; 1H
NMR (400 MHz, CDCl3) δ 2.09-2.15 (m, 1H), 2.27-2.38 (m,
2H), 2.62 (dd, 1H, J ) 16.6, 6.3 Hz), 2.77-2.84 (m, 1H), 3.15
(dd, 1H, J ) 16.1, 5.9 Hz), 4.13 (brs, 2H), 4.37-4.44 (m, 3H),
5.70 (brs, 1H), 5.82 (brd, 1H, J ) 7.6 Hz), 6.90 (dd, 1H, J )
7.8, 7.8 Hz), 7.07-7.13 (m, 2H), 7.32-7.40 (m, 6H); 13C NMR
(100 MHz, CDCl3) δ 26.2, 41.1, 41.9, 62.5, 66.3, 66.6, 70.3,
123.8, 125.0, 126.1, 126.3, 127.9, 128.0, 128.6, 129.4, 136.5,
133.2, 135.6, 136.8, 139.1, 142.5; EI HRMS m/e calcd for C25H39
-
NO3Si (M+•) 429.2697, found 429.2697.
R ea ct ion bet w een 3 a n d (-)-b (E n t r y 4 of Ta b le 2).
(Major/minor ) 12:1, determined by 1H NMR.) Data for the
major isomer (-)-3b: mp 41-43 °C; [R]23D -13.5 (c 0.6, CHCl3),
IR (KBr disk, cm-1) 1717, 1671, 1456, 1265, 1242; 1H NMR
(400 MHz, CDCl3) δ 12.5 (t, 3H, J ) 7.1 Hz), 1.75 (s, 3H), 2.71
(dddd, 1H, J ) 19.3, 4.6, 4.6, 2.1 Hz), 2.78 (ddd, 1H, J ) 19.3,
2.0, 2.0 Hz), 3.14-3.24 (m, 2H), 4.11 (dd, 1H, J ) 6.1, 3.4 Hz),
4.18 (qm, 2H, J ) 7.1 Hz), 4.47 (dd, 1H, J ) 4.9, 1.2 Hz), 4.87
(d, 1H, J ) 5.4 Hz), 4.98 (ddd, 1H, J ) 5.1, 5.1, 2.7 Hz), 6.80
(dd, 1H, J ) 3.7, 2.2 Hz), 6.87 (d, 1H, J ) 7.3 Hz), 6.98 (d, 1H,
J ) 7.6 Hz), 7.08 (dd, 1H, J ) 7.6, 7.6 Hz), 7.31-7.45 (m, 5H);
13C NMR (100 MHz, CDCl3) δ 14.2, 18.3, 25.5, 39.6, 60.6, 62.1,
74.6, 75.1, 86.7, 121.6, 124.0, 127.9, 128.3, 128.37, 128.44,
129.5, 136.8, 138.3, 138.4, 141.7, 143.2, 166.2; EI HRMS m/e
calcd for C24H25NO3 (M+•) 375.1833, found 375.1845. Data for
138.9, 140.9, 141.7; EI HRMS m/e calcd for C21H23NO2 (M+•
321.1727, found 321.1733. Data for the minor isomer: [R]25
)
D
+240.2 (c 0.5, CHCl3); IR (KBr disk, cm-1) 3395, 1454, 1080;
1H NMR (400 MHz, CDCl3) δ 1.93 (brd, 1H, J ) 15.6 Hz),
2.23-2.30 (m, 1H), 2.38-2.49 (m, 2H), 2.84 (dd, 1H, J ) 16.6,
6.8 Hz), 3.24 (dd, 1H, J ) 16.6, 8.3 Hz), 3.98 (d, 1H, J ) 13.4
Hz), 4.04 (d, 1H, J ) 13.2 Hz), 4.11-4.17 (m, 1H), 4.26 (d, 1H,
J ) 8.1 Hz), 4.75 (brs, 1H), 5.53 (brs, 1H), 7.19-7.31 (m, 4H),
7.35-7.42 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 26.2, 41.7,
45.4, 64.4, 65.2, 65.9, 68.7, 125.52, 125.54, 125.9, 126.4, 127.8,
128.4, 128.9, 135.3, 139.1, 141.6, 142.5; EI HRMS m/e calcd
for C21H23NO2 (M+•) 321.1727, found 321.1731.
1
the minor isomer: representative signals in its H NMR (400
MHz, CDCl3) δ 5.06 (dd, 1H, J ) 3.9, 2.9 Hz), 6.62-6.64 (m,
1H).
Rea ction betw een 2 a n d c (En tr y 5 of Ta ble 2). (Major/
minor ) 7:1, determined by 1H NMR.) Data for the major
1
isomer 2c: IR (neat, cm-1) 1717, 1462, 1254, 1113, 1032; H
NMR (400 MHz, CDCl3) δ 0.10 (d, 6H, J ) 1.0 Hz), 0.93 (s,
9H), 1.17 (t, 3H, J ) 7.6 Hz), 1.27 (t, 3H, J ) 7.1 Hz), 2.53-
2.61 (m, 1H), 2.65-2.89 (m, 3H), 3.14 (brd, 1H, J ) 17.3 Hz),
3.21 (dd, 1H, J ) 17.8, 5.9 Hz), 3.58-3.63 (m, 1H), 4.19 (q,
2H, J ) 7.1 Hz), 4.26 (d, 2H, J ) 3.4 Hz), 4.38 (d, 1H, J ) 4.6
Hz), 4.85 (ddd, 1H, J ) 5.6, 5.6, 1.5 Hz), 4.96 (d, 1H, J ) 5.6
Hz), 5.79-5.92 (m, 2H), 6.72-6.74 (m, 1H), 7.01-7.04 (m, 2H),
7.19 (dd, 1H, J ) 7.6, 7.6 Hz); 13C NMR (100 MHz, CDCl3) δ
-5.3, 14.2, 15.1, 18.4, 25.3, 25.5, 25.9, 39.6, 59.9, 60.6, 62.9,
73.9, 75.0, 86.3, 121.8, 124.8, 126.8, 128.6, 129.9, 133.1, 137.2,
137.9, 142.9, 143.3, 166.1; EI HRMS m/e calcd for C28H41NO4-
Si (M+•) 483.2802, found 483.2810. Data for the minor iso-
R ea ct ion bet w een 2 a n d (-)-b (E n t r y 3 of Ta ble 2).
(Major/minor ) 5:1, determined by 1H NMR.) Data for the
major isomer (-)-2b: [R]21 -32.1 (c 1.2, CHCl3); IR (neat,
D
cm-1) 1717, 1464, 1254, 1113, 1034; 1H NMR (400 MHz, CDCl3)
δ 0.10 (s, 6H), 0.93 (s, 9H), 1.27 (t, 3H, J ) 7.3 Hz), 2.37 (s,
3H), 2.55-2.71 (m, 2H), 3.13 (d, 1H, J ) 17.6 Hz), 3.21 (dd,
1H, J ) 17.8, 5.9 Hz), 3.60-3.63 (m, 1H), 4.19 (q, 2H, J ) 7.3
Hz), 4.25-4.26 (m, 2H), 4.37 (d, 1H, J ) 4.4 Hz), 4.85 (ddd,
1H, J ) 5.7, 5.7, 1.5 Hz), 4.93 (d, 1H, J ) 5.6 Hz), 5.82-5.92
(m, 2H), 6.73-6.74 (m, 1H), 6.99 (d, 1H, J ) 8.3 Hz), 7.01 (d,
1H, J ) 8.3 Hz), 7.13 (dd, 1H, J ) 7.6, 7.3 Hz); 13C NMR (100
MHz, CDCl3) δ -5.3, 14.2, 18.3, 19.1, 25.5, 25.9, 39.6, 59.8,
60.5, 62.8, 74.1, 75.0, 86.3, 121.7, 124.8, 128.31, 128.35, 130.1,
132.9, 136.6, 137.8, 137.9, 143.2, 166.1; EI HRMS m/e calcd
for C27H39NO4Si (M+•) 469.2646, found 469.2649. Data for the
1
mer: representative signals in its H NMR (400 MHz, CDCl3)
δ 4.42 (dd, 1H, J ) 7.8, 1.5 Hz), 4.49 (ddd, 1H, J ) 7.3, 7.3,
1.5 Hz), 4.92 (d, 1H, J ) 6.1 Hz), 5.52 (ddt, 1H, J ) 15.4, 10.0,
1.7 Hz).
1
minor isomer: representative signals in its H NMR (400 MHz,
CDCl3) δ 0.07 (d, 6H, J ) 2.0 Hz), 0.90 (s, 9H), 1.28 (t, 3H, J
) 7.1 Hz), 2.38 (s, 3H), 2.57 (brd, 1H, J ) 20.0 Hz), 2.85 (dddd,
1H, J ) 19.3, 7.1, 1.2, 1.2 Hz), 3.08 (d, 1H, J ) 18.1 Hz), 3.21
(dd, 1H, J ) 18.1, 6.8 Hz), 4.17-4.26 (m, 5H), 4.41 (dd, 1H, J
Rea ction betw een 3 a n d c (En tr y 6 of Ta ble 2). (Major/
minor ) 20:1, determined by 1H NMR.) Data for the major
1
isomer 3c: IR (neat, cm-1) 1717, 1265, 1242, 1030; H NMR
(400 MHz, CDCl3) δ 0.73 (t, 3H, J ) 7.3 Hz), 1.25 (t, 3H, J )
5918 J . Org. Chem., Vol. 69, No. 18, 2004

Asymmetric 6π-Azaelectrocyclization
7.1 Hz), 2.05-2.27 (m, 2H), 2.70 (dddd, 1H, J ) 19.3, 6.8, 2.2,
2.2 Hz), 2.79 (dm, 1H, J ) 19.3 Hz), 3.15-3.24 (m, 2H), 4.11
(dd, 1H, J ) 6.3, 3.9 Hz), 4.18 (qm, 2H, J ) 7.1 Hz), 4.48 (dd,
1H, J ) 4.6, 1.0 Hz), 4.91 (d, 1H, J ) 5.4 Hz), 4.96-5.01 (m,
1H), 6.80 (dd, 1H, J ) 3.7, 2.0 Hz), 6.91 (d, 1H, J ) 7.3 Hz),
7.00 (d, 1H, J ) 7.1 Hz), 7.14 (dd, 1H, J ) 7.3, 7.3 Hz), 7.27-
7.45 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 14.2, 14.7, 24.8,
25.5, 39.5, 60.6, 62.1, 74.4, 75.0, 86.8, 121.7, 124.0, 126.8, 128.0,
128.5, 128.6, 129.4, 136.9, 138.4, 141.6, 143.0, 143.3, 166.3;
EI HRMS m/e calcd for C25H27NO3 (M+•) 389.1989, found
389.1983. Data for the minor isomer: representative signals
in its 1H NMR (400 MHz, CDCl3) δ 5.07 (dd, 1H, J ) 3.2, 3.2
Hz), 6.61-6.62 (m, 1H).
5.21 (d, 1H, J ) 4.4 Hz), 5.54 (ddt, 1H, J ) 15.1, 10.0, 1.5 Hz),
6.91 (ddd, 1H, J ) 5.6, 1.7, 1.7 Hz).
Rea ction betw een 3 a n d e (En tr y 11 of Ta ble 2). (Major/
minor ) 17:1, determined by 1H NMR.) Data for the major
1
isomer 3e: IR (neat, cm-1) 1717, 1263, 1244, 1036; H NMR
(400 MHz, CDCl3) δ 1.00 (s, 9H), 1.25 (t, 3H, J ) 7.3 Hz), 2.62
(dddd, 1H, J ) 19.0, 6.6, 2.4, 2.4 Hz), 2.80 (dm, 1H, J ) 18.8
Hz), 3.09 (dd, 1H, J ) 17.3, 5.6 Hz), 3.28 (d, 1H, J ) 17.6 Hz),
4.14-4.24 (m, 3H), 4.47 (dd, 1H, J ) 4.6, 1.2 Hz), 4.95 (dd,
1H, J ) 5.1, 5.1 Hz), 5.19 (d, 1H, J ) 4.6 Hz), 6.81-6.82 (m,
1H), 7.07 (d, 1H, J ) 7.1 Hz), 7.16 (dd, 1H, J ) 7.3, 7.3 Hz),
7.22 (d, 1H, J ) 7.8 Hz), 7.31-7.41 (m, 5H); 13C NMR (100
MHz, CDCl3) δ 14.2, 25.7, 30.1, 36.1, 38.7, 60.6, 62.9, 75.0,
78.1, 87.7, 122.9, 123.1, 125.2, 128.1, 128.4, 128.6, 130.1, 136.3,
R ea ct ion bet w een 2 a n d (-)-d (E n t r y 7 of Ta b le 2).
(Major/minor ) 10:1, determined by 1H NMR.) Data for the
138.7, 140.8, 144.9, 150.2, 166.3; EI HRMS m/e calcd for C27H31
-
NO3 (M+•) 417.2302, found 417.2301. Data for the minor
isomer: representative signals in its 1H NMR (400 MHz,
CDCl3) δ 5.06-5.09 (m, 1H), 5.12 (d, 1H, J ) 5.6 Hz), 6.52-
6.54 (m, 1H).
major isomer (-)-2d : [R]21 -49.6 (c 0.5, CHCl3), IR (neat,
D
1
cm-1) 1717, 1462, 1254, 1113; H NMR (400 MHz, CDCl3) δ
0.11 (d, 6H, J ) 0.7 Hz), 0.94 (s, 9H), 1.15 (d, 3H, J ) 6.8 Hz),
1.22 (d, 3H, J ) 6.8 Hz), 1.28 (t, 3H, J ) 7.3 Hz), 2.52-2.60
(m, 1H), 2.68 (dd, 1H, J ) 19.3, 3.2 Hz), 3.14 (brd, 1H, J )
17.3 Hz), 3.20 (dd, 1H, J ) 17.8, 5.6 Hz), 3.54 (qq, 1H, J )
6.8, 6.8 Hz), 3.58-3.63 (m, 1H), 4.20 (q, 2H, J ) 7.1 Hz) 4.26
(d, 2H, J ) 4.2 Hz), 4.38 (d, 1H, J ) 4.6 Hz), 4.84 (ddd, 1H, J
) 5.6, 5.6, 2.0 Hz), 4.98 (d, 1H, J ) 5.4 Hz), 5.80 (ddt, 1H, J
) 15.1, 8.8, 1.5 Hz), 5.89 (dt, 1H, J ) 15.4, 4.4 Hz), 6.72-6.73
(m, 1H), 7.02 (d, 1H, J ) 7.3 Hz), 7.13 (d, 1H, J ) 7.6 Hz),
7.22 (dd, 1H, J ) 7.6, 7.6 Hz); 13C NMR (100 MHz, CDCl3) δ
-5.3, 14.2, 18.4, 23.4, 23.5, 25.5, 26.0, 28.6, 39.6, 60.0, 60.6,
62.9, 74.0, 75.0, 86.4, 121.7, 123.5, 124.7, 128.7, 129.8, 133.2,
4-Meth ylin d en e (6). To a solution of lithium aluminum
hydride (2.60 g, 68.4 mmol) in ether (240 mL) was slowly added
a solution of 7-methyl-1-indanone 5 (10.0 g) in ether (50 mL)
at 0 °C. After the mixture was warmed to room temperature
and stirred for an additional 10 min, H2O was carefully added
over 30 min. The resulting mixture was filtered and concen-
trated in vacuo to give the crude alcohol which was dehydrated
without further purification.
To a solution of the crude alcohol obtained above in benzene
(200 mL) was added p-toluenesulfonic acid monohydrate (1.30
g, 6.84 mmol) at room temperature. After the mixture was
gradually heated to 100 °C with vigorous stirring over 30 min,
saturated aqueous NaHCO3 solution was added, and the
resulting mixture was extracted with ether. The organic layers
were combined, washed with brine, dried over MgSO4, filtered,
and concentrated in vacuo to give the crude products. Column
chromatography on silica gel (gradually 2% to 3% ethyl acetate
in hexane) gave the corresponding indene 6 (8.56 g, 96%) as a
colorless oil: IR (neat, cm-1) 1603, 1476, 1458, 1393, 1312,
1202, 1071, 947; 1H NMR (400 MHz, CDCl3) δ 2.45 (s, 3H),
3.39-3.40 (m, 2H), 6.54 (ddd, 1H, J ) 5.6, 2.1, 2.1 Hz), 6.98
(dm, 1H, J ) 5.6 Hz), 7.05-7.11 (m, 2H), 7.30 (dd, 1H, J )
6.8, 0.5 Hz); 13C NMR (100 MHz, CDCl3) δ 18.6, 39.3, 121.1,
124.6, 127.2, 130.2, 133.5, 143.5, 143.7.
136.6, 137.9, 143.2, 147.6, 166.2; EI HRMS m/e calcd for C29H43
-
NO4Si (M+•) 497.2959, found 497.2952. Data for the minor
isomer: representative signals in its 1H NMR (400 MHz,
CDCl3) δ 4.42 (dd, 1H, J ) 7.3, 1.0 Hz), 4.47 (ddd, 1H, J )
7.6, 7.6, 1.5 Hz), 4.95 (d, 1H, J ) 6.1 Hz), 5.52 (ddt, 1H, J )
15.1, 10.0, 1.5 Hz).
Rea ction betw een 3 a n d (-)-d (En tr ies 8 a n d 9 of
Ta ble 2). (Major/minor ) 24:1 at 24 °C and >40:1 at 13 °C,
determined by 1H NMR.) Data for the major isomer (-)-3d :
[R]19 -58.7 (c 0.3, CHCl3); IR (neat, cm-1) 1717, 1267, 1242,
D
1
1032; H NMR (400 MHz, CDCl3) δ 0.59 (d, 3H, J ) 7.1 Hz),
1.01 (d, 3H, J ) 6.8 Hz), 1.25 (t, 3H, J ) 7.1 Hz), 2.62 (qq, 1H,
J ) 6.8, 6.8 Hz), 2.70 (dddd, 1H, J ) 19.3, 6.6, 2.2, 2.2 Hz),
2.79 (dm, 1H, J ) 19.3 Hz), 3.15-3.25 (m, 2H), 4.12 (dd, 1H,
J ) 6.1, 3.7 Hz), 4.18 (qm, 2H, J ) 7.3 Hz), 4.48 (d, 1H, J )
4.4 Hz), 4.92 (d, 1H, J ) 5.6 Hz), 4.96-5.01 (m, 1H), 6.80 (brs,
1H), 6.99 (d, 1H, J ) 8.1 Hz), 7.01 (d, 1H, J ) 8.8 Hz), 7.17
(dd, 1H, J ) 7.6, 7.6 Hz), 7.33-7.43 (m, 5H); 13C NMR (100
MHz, CDCl3) δ 14.2, 22.8, 23.5, 25.5, 28.0, 39.6, 60.6, 62.2,
74.4, 75.0, 86.7, 121.6, 123.5, 124.0, 128.0, 128.4, 128.8, 129.4,
136.3, 138.3, 141.5, 143.1, 147.8, 166.3; EI HRMS m/e calcd
for C26H29NO3 (M+•) 403.2146, found 403.2137. Data for the
(+)-7-Meth ylin d en e Oxid e (7). To a dichloromethane (5
mL) solution of 4-methylindene 6 (1.0 g, 7.68 mmol), (S,S)-
(+)-N,N′-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanedi-
aminomanganese(III) chloride (58.5 mg, 0.0922 mmol), and
4-phenylpyridine N-oxide (78.9 mg, 0.461 mmol) was added
dropwise a cold sodium hypochlorite (NaOCl) solution (18.7
mL, 9.99 mmol, 1.6 M, 0.2 M in sodium hydroxide) at 0 °C
over 30 min. After the mixture was gradually warmed to room
temperature and stirred for an additional 5 h, H2O was added,
and the resulting mixture was extracted with CHCl3. The
organic layers were combined, washed with H2O, brine, dried
over MgSO4, filtered, and concentrated in vacuo to give the
crude products. Column chromatography on aluminum oxide
(gradually from 1% to 4% ethyl acetate in hexane) gave the
corresponding epoxides (750 mg, 67%, 85% ee). The enantio-
meric excess of the epoxide was determined by HPLC analysis
using a Chiracel OD column (25 cm × 4.6 mm, Daicel) eluted
with 2-propanol/hexanes (5:95) at 1 mL/min, while monitoring
at 254 nm. The retention times of the epoxide enantiomers
are 6.9 (major isomer 7) and 7.4 (minor isomer) min. The
products were further recrystallized from ether and hexane
to provide the enantiomerically pure 7 as a colorless needle:
mp 53 °C; [R]24D +2.6 (c 0.9, CHCl3); IR (neat, cm-1) 1597, 1478,
1
minor isomer: representative signals in its H NMR (400 MHz,
CDCl3) δ 4.85 (d, 1H, J ) 6.0 Hz), 5.12 (dd, 1H, J ) 3.2, 3.2
Hz), 6.60 (brs, 1H).
Rea ction betw een 2 a n d e (En tr y 10 of Ta ble 2). (Major/
minor ) 5:1, determined by 1H NMR.) Data for the major
1
isomer 2e: IR (neat, cm-1) 1717, 1464, 1256, 1113; H NMR
(400 MHz, CDCl3) δ 0.10 (d, 6H, J ) 1.7 Hz), 0.93 (s, 9H),
1.27 (t, 3H, J ) 7.1 Hz), 1.46 (s, 9H), 2.44-2.52 (m, 1H), 2.69
(brdd, 1H, J ) 19.0, 2.9 Hz), 3.07 (dd, 1H, J ) 17.3, 5.6 Hz),
3.23 (d, 1H, J ) 17.6 Hz), 3.65-3.70 (m, 1H), 4.19 (q, 2H, J )
7.1 Hz), 4.24 (d, 2H, J ) 2.7 Hz), 4.37 (dd, 1H, J ) 4.9, 1.0
Hz), 4.79 (dd, 1H, J ) 5.4, 5.4 Hz), 5.22 (d, 1H, J ) 4.9 Hz),
5.79-5.88 (m, 2H), 6.70-6.71 (m, 1H), 7.08 (d, 1H, J ) 7.3
Hz), 7.20 (dd, 1H, J ) 7.6, 7.6 Hz), 7.30 (d, 1H, J ) 7.8 Hz);
13C NMR (100 MHz, CDCl3) δ -5.3, 14.2, 18.4, 25.7, 26.0, 31.1,
36.5, 38.8, 60.58, 60.60, 62.9, 75.0, 77.3, 87.2, 122.9, 124.3,
125.3, 128.4, 130.4, 133.0, 136.6, 138.2, 145.0, 150.0, 166.2;
EI HRMS m/e calcd for C30H45NO4Si (M+•) 511.3116, found
511.3117. Data for the minor isomer: representative signals
in its 1H NMR (400 MHz, CDCl3) δ 4.39 (d, 1H, J ) 5.9 Hz),
1
1460, 1233, 1028, 988; H NMR (400 MHz, CDCl3) δ 2.47 (s,
3H), 2.96 (dd, 1H, J ) 18.1, 2.9 Hz), 3.19 (d, 1H, J ) 18.1 Hz),
4.08-4.09 (m, 1H), 4.33-4.34 (m, 1H), 6.98 (dd, 1H, J ) 7.6,
0.5 Hz), 7.04 (d, 1H, J ) 7.3 Hz), 7.13 (dd, 1H, J ) 7.6, 7.3
Hz); 13C NMR (100 MHz, CDCl3) δ 18.3, 34.7, 57.2, 57.6, 123.3,
127.4, 128.5, 135.1, 139.5, 143.4.
J . Org. Chem, Vol. 69, No. 18, 2004 5919

Tanaka et al.
(1S,2R)-(-)-cis-1-Am in o-7-m eth ylin d a n -2-ol ((-)-b). To
a solution of fuming sulfuric acid (0.729 mL, 13.7 mmol, 30%
SO3) in acetonitrile (5 mL) was added dropwise a solution of
epoxide (+)-7 (1.0 g, 6.84 mmol) in hexane (10 mL) and
acetonitrile (2 mL) at 0 °C. After the biphasic mixture was
warmed to room temperature and stirred for an additional 1
h, H2O was carefully added, and the resulting mixture was
stirred for 30 min at this temperature. The lower aqueous
phase was separated and diluted with H2O (5 mL), and
acetonitrile was removed by distillation at atmospheric pres-
sure to a head temperature of 100 °C. The resulting mixture
was heated to reflux for 2 h, and 50% aqueous NaOH solution
was added until the reaction mixture reached pH 12 and the
white solid of aminoindanol free base precipitated. After the
precipitate was completely dissolved in CHCl3, the resulting
mixture was extracted with CHCl3. The organic layers were
combined, washed with brine, dried over MgSO4, filtered, and
concentrated in vacuo to give the crude products. The obtained
white solid was dissolved in hot toluene (6 mL), and the
resulting solution was allowed to cool to room temperature and
then further cooled to 0 °C. The resulting white solid was
collected by vacuum filtration, washed with cold toluene, and
dried under reduced pressure to provide the desired (-)-b (585
distillation under reduced pressure (65-79 °C/10.0 mmHg) to
afford the corresponding trimethylsilyl enol ether (78.4 g, 79%)
as a colorless oil: IR (neat, cm-1) 1655, 1593, 1464, 1334, 1308,
1
1253; H NMR (400 MHz, CDCl3) δ 0.23 (s, 9H), 1.02 (d, 6H,
J ) 6.8 Hz), 2.35 (qd, 1H, J ) 6.6, 6.6 Hz), 4.23-4.24 (m, 2H),
5.66 (dd, 1H, J ) 15.4, 1.0 Hz), 5.92 (dd, 1H, J ) 15.4, 6.4
Hz); 13C NMR (100 MHz, CDCl3) δ 0.0, 22.2, 30.5, 94.2, 124.7,
138.6, 155.1.
5-Hyd r oxy-7-isop r op yl-1-in d a n on e (11). The benzene
solution (58 mL) of the silyl enol ether 9 (85.2 g, 376 mmol),
2-cyclopenenone (30.9 g, 376 mmol), and 2,5-di-tert-butylhy-
droquinone (3.95 g) in a sealed tube was heated at 200 °C for
56 h. The resulting mixture was concentrated in vacuo to give
the crude products which were hydrolyzed without any puri-
fication.
To an acetone (1.5 L) solution of the crude Diels-Alder
adducts obtained above was added p-toluenesulfonic acid
monohydrate (7.16 g, 37.6 mmol) at room temperature. After
the mixture was stirred at room temperature for 30 min, the
bulk of the methanol was removed in vacuo, saturated aqueous
NaHCO3 solution was added, and the resulting mixture was
extracted with ethyl acetate. The organic layers were com-
bined, washed with brine, dried over MgSO4, filtered, and
concentrated in vacuo to precipitate one diastereomer of
diketone 10 (14.2 g) as a white crystal. Then, column chro-
matography of the residues on silica gel (gradually 9% to 33%
ethyl acetate in hexane) provided the other diastereomer as a
white solid (29.6 g, total 60% for two steps).
mg, 52%) as a white solid: mp 101-102 °C; [R]22 -110.8 (c
D
0.6, CHCl3); IR (KBr disk, cm-1) 3314-2571 (br), 1593, 1474,
1346, 1098; 1H NMR (400 MHz, CDCl3) δ 2.39 (s, 3H), 2.81
(dd, 1H, J ) 15.9, 7.6 Hz), 3.13 (dd, 1H, J ) 15.9, 7.3 Hz),
4.22 (d, 1H, J ) 6.6 Hz), 4.35 (ddd, 1H, J ) 7.1, 7.1, 7.1 Hz),
7.00-7.03 (m, 2H), 7.14 (dd, 1H, J ) 7.6, 7.3 Hz); 13C NMR
(100 MHz, CDCl3) δ 18.4, 39.3, 55.6, 71.2, 122.7, 128.26,
128.32, 134.5, 140.7, 142.6; EI HRMS m/e calcd for C10H13NO
(M+•) 163.0996, found 163.1001.
To a solution of a mixture of the diketone diastereomers 10
obtained above (5.64 g, 29.0 mmol) in p-cymene (140 mL) was
added 30% palladium carbon (1.20 g) at room temperature,
and the mixture was stirred for 45 h at 200 °C. The precipitate
was dissolved in acetone, and palladium carbon was filtered
off. Concentration of the residues in vacuo to precipitate the
5-Meth ylh ex-3-en -2-on e (8). To a solution of acetone (270
mL) and 2.5 M aqueous NaOH solution (100 mL) was added a
solution of isobutyraldehyde (138 mL, 1.52 mol) in acetone (270
mL) at an inner temperature of 8.5 °C over 1.5 h. After the
mixture was stirred at room temperature for an additional 1
h, 6 N aqueous HCl solution (40 mL) was added, and the pH
of the solution was adjusted toward 7. After the bulk of acetone
was removed in vacuo to 300 mL, the resulting mixture was
extracted with ether. The organic layers were combined,
washed with brine, dried over MgSO4, filtered, and concen-
trated in vacuo to give the crude products. Distillation under
reduced pressure (75-89 °C/7.0 mmHg) gave the correspond-
ing â-hydroxy ketone (316 g, 69%) which was used without
further purification.
To a benzene (350 mL) solution of the â-hydroxyketone
obtained above (147 g, 1.13 mol) were added p-toluenesulfonic
acid monohydrate (1.07 g, 5.64 mmol) and Na2SO4 (75.0 g) at
room temperature. After the mixture was stirred for 5 h at 90
°C, saturated aqueous NaHCO3 solution was added, and the
resulting mixture was extracted with ether. The organic layers
were combined, washed with brine, dried over MgSO4, filtered,
and concentrated in vacuo to give the crude products. Distil-
lation under reduced pressure (54-68 °C/20 mmHg) gave the
corresponding R,â-unsaturated ketone 8 (89.3 g, 71%) as a
colorless oil: IR (neat, cm-1) 1676, 1626, 1362, 1260; 1H NMR
(400 MHz, CDCl3) δ 1.08 (d, 6H, J ) 6.8 Hz), 2.25 (s, 3H),
2.48 (qdm, 1H, J ) 6.8, 6.8 Hz), 6.03 (dd, 1H, J ) 15.9, 1.2
Hz), 6.77 (dd, 1H, J ) 16.1, 6.8 Hz); 13C NMR (100 MHz,
CDCl3) δ 21.3, 26.9, 31.1, 128.5, 154.5, 199.1.
phenol 11 (4.12 g, 75%) as a brown solid: IR (KBr disk, cm-1
)
2965, 1651, 1607, 1566, 1312, 1273; 1H NMR (400 MHz,
acetone-d6) δ 1.16 (d, 6H, J ) 6.8 Hz), 2.49-2.53 (m, 2H), 2.95-
2.98 (m, 2H), 4.11 (qm, 1H, J ) 6.8 Hz), 6.72 (brs, 1H), 6.76
(brs, 1H); 13C NMR (100 MHz, acetone-d6) δ 23.1, 25.7, 27.7,
37.5, 110.6, 112.6, 126.5, 152.6, 160.4, 164.0, 205.1.
5-p-Tolu en esu lfon oxy-7-isop r op yl-1-in d a n on e. To a so-
lution of the phenol 11 (7.78 g, 40.9 mmol) in THF (400 mL)
was added sodium hydride (1.88 g, 49.1 mmol, 62.5%) at room
temperature. The mixture was stirred for 20 min, and p-
toluenesulfonyl chloride (8.57 g, 45.0 mmol) was added at this
temperature. After the resulting mixture was stirred for an
additional 2.5 h, H2O was added, and the resulting mixture
was extracted with ethyl acetate. The organic layers were
combined, washed with brine, dried over MgSO4, filtered, and
concentrated in vacuo to give the crude products. Column
chromatography on silica gel (5% to 25% ethyl acetate in
hexane) gave the corresponding tosylate (13.7 g, 97%) as a
yellow solid: IR (KBr disk, cm-1) 1701, 1593, 1377, 1192, 1179;
1H NMR (400 MHz, CDCl3) δ1.05 (d, 6H, J ) 6.8 Hz), 2.46 (s,
3H), 2.66-2.69 (m, 2H), 3.04-3.07 (m, 2H), 4.08 (qq, 1H, J )
6.8, 6.8 Hz), 6.63-6.64 (m, 1H), 7.06-7.07 (m, 1H), 7.34 (dd,
2H, J ) 8.5, 0.5 Hz), 7.73 (d, 2H, J ) 8.3 Hz); 13C NMR (100
MHz, CDCl3) δ 21.7, 22.6, 25.4, 26.9, 37.2, 117.8, 118.3, 128.6,
129.8, 131.7, 132.2, 145.7, 152.3, 154.0, 158.1, 206.1.
7-Isop r op ylin d a n ol (12). To a methanol solution (15 mL)
of the tosylate obtained above (500 mg, 1.45 mmol) and nickel-
(II) chloride hexahydrate (345 mg, 1.45 mmol) was slowly
added sodium borohydride (1.65 g, 43.6 mmol) at 0 °C over 2
h. After the mixture was stirred at room temperature for an
additional 1 h, the bulk of methanol was removed in vacuo, 2
N HCl solution was added, and the resulting mixture was
extracted with ether. The organic layers were combined,
washed with brine, dried over MgSO4, filtered, and concen-
trated in vacuo to give the crude products. Column chroma-
tography on silica gel (5% to 9% ethyl acetate in hexane)
provided the corresponding alcohol 12 (221 mg, 87%) as a white
solid: IR (KBr disk, cm-1) 3331, 3243, 1047, 783; 1H NMR (400
5-Meth yl-2-tr im eth ylsiloxyh exa -1,3-d ien e (9). To a solu-
tion of R,â-unsaturated ketone 8 (60.0 g, 535 mmol) and
chlorotrimethylsilane (74.7 mL, 588 mmol) in toluene (520 mL)
and THF (260 mL) was slowly added lithium bis(trimethylsi-
lyl)amide (116 g, 695 mmol) at -78 °C, and the resulting
solution was stirred for 30 min at this temperature. After the
mixture was gradually warmed to room temperature and
stirred for an additional 40 min, H2O was added, and the
resulting mixture was extracted with ether. The organic layers
were combined, dried over MgSO4, filtered, and concentrated
in vacuo to give the crude products which were purified by
5920 J . Org. Chem., Vol. 69, No. 18, 2004

Asymmetric 6π-Azaelectrocyclization
MHz, CDCl3) δ 1.25 (d, 3H, J ) 6.8 Hz), 1.30 (d, 3H, J ) 6.8
Hz), 1.64 (brs, 1H), 2.06 (dddd, 1H, J ) 13.7, 7.8, 2.7, 2.0 Hz),
2.28-2.37 (m, 1H), 2.81 (ddd, 1H, J ) 16.1, 9.0, 2.7 Hz), 3.15
(ddd, 1H, J ) 16.3, 8.3, 8.3 Hz), 3.33 (qq, 1H, J ) 6.8, 6.8 Hz),
5.36 (brd, 1H, J ) 6.3 Hz), 7.09 (d, 1H, J ) 7.8 Hz), 7.15 (d,
1H, J ) 7.8 Hz), 7.26 (dd, 1H, J ) 7.3, 7.3 Hz); 13C NMR (100
MHz, CDCl3) δ 23.9, 24.1, 29.8, 30.1, 35.2, 74.9, 122.3, 123.2,
129.2, 141.7, 144.0, 146.3.
tography on silica gel (gradually from 5% to 9% methanol in
chloroform) gave the corresponding d (796 mg, 74%) as a white
solid. The mixture of stereoisomers of d was dissolved in hot
toluene (1.5 mL), the resulting solution was allowed to cool to
room temperature and then further cooled to 0 °C. The
resulting white solid was collected by vacuum filtration,
washed with cold toluene, and dried under reduced pressure
to provide the optically pure (-)-d as a colorless crystal: mp
90-91 °C; [R]20 -114.2 (c 0.5, CHCl3); IR (KBr disk, cm-1
)
D
4-Isop r op ylin d en e (13). To a solution of the alcohol 12
(1.98 g, 11.2 mmol) prepared above in benzene (110 mL) was
added p-toluenesulfonic acid monohydrate (213 mg, 1.12 mmol)
at room temperature. After the mixture was gradually heated
to 100 °C with vigorous stirring over 40 min, saturated
aqueous NaHCO3 solution was added, and the resulting
mixture was extracted with ether. The organic layers were
combined, washed with brine, dried over MgSO4, filtered, and
concentrated in vacuo to give the crude products. Column
chromatography on silica gel (2% ethyl acetate in hexane) gave
the corresponding indene 13 (1.87 g, 100%) as a colorless oil:
IR (neat, cm-1) 1476, 1431, 1391, 953; 1H NMR (400 MHz,
CDCl3) δ 1.31 (d, 6H, J ) 6.8 Hz), 3.27 (qq, 1H, J ) 6.8, 6.8
Hz), 3.40 (brs, 2H), 6.55 (ddd, 1H, J ) 5.6, 2.0, 2.0 Hz), 7.06
(dm, 1H, J ) 5.6 Hz), 7.16-7.17 (m, 2H), 7.31-7.33 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 23.4, 30.8, 39.3, 121.3, 122.5,
124.9, 130.0, 133.5, 141.1, 142.5, 143.7.
1
3194 (br), 1586, 1480, 1451, 1383, 1333, 1094; H NMR (400
MHz, CDCl3) δ 1.25 (d, 3H, J ) 6.8 Hz), 1.31 (d, 3H, J ) 6.8
Hz), 2.31 (brs, 3H), 2.80 (dd, 1H, J ) 15.9, 8.3 Hz), 3.14 (dd,
1H, J ) 15.6, 7.3 Hz), 3.13-3.21 (m, 1H), 4.29 (brd, 1H, J )
6.1 Hz), 4.34-4.38 (m, 1H), 7.03 (d, 1H, J ) 7.3 Hz), 7.14 (d,
1H, J ) 7.8 Hz), 7.23 (dd, 1H, J ) 7.6, 7.6 Hz); 13C NMR (100
MHz, CDCl3) δ 23.9, 24.2, 30.0, 39.3, 55.0, 71.4, 122.7, 123.6,
128.8, 140.6, 141.3, 145.8; CI HRMS m/z calcd for C12H18NO
(M + H)+ 192.1387, found 192.1383.
(()-cis-1-Am in o-7-eth ylin d a n -2-ol (c): mp 118-119 °C;
IR (KBr disk, cm-1) 3316-2753 (br), 1591, 1478, 1451, 1345,
1
1100; H NMR (400 MHz, CDCl3) δ 1.28 (t, 3H, J ) 7.8 Hz),
2.12 (brs, 3H), 2.74 (qm, 2H, J ) 7.6 Hz), 2.80 (dd, 1H, J )
15.6, 7.8 Hz), 3.14 (dd, 1H, J ) 15.6, 7.3 Hz), 4.26 (brd, 1H, J
) 6.3 Hz), 4.36 (brddd, 1H, J ) 7.1, 7.1, 7.1 Hz), 7.04 (d, 1H,
J ) 7.6 Hz), 7.07 (d, 1H, J ) 7.6 Hz), 7.20 (dd, 1H, J ) 7.6,
7.3 Hz); 13C NMR (100 MHz, CDCl3) δ 15.1, 25.3, 39.3, 55.2,
71.4, 122.8, 126.4, 128.6, 140.7, 140.8, 142.1; CI HRMS m/e
calcd for C11H16NO (M + H)+ 178.1231, found 178.1234.
7-Isop r op ylin d en e Oxid e (14). To a dichloromethane (6.0
mL) solution of 4-isopropylindene 13 (100 mg, 0.63 mmol),
(S,S)-(+)-N,N′-bis(3,5-di-tert-butylsalicylidene)-1,2cyclohex-
anediaminomanganese(III) chloride (20.1 mg, 0.032 mmol),
and 4-methylmorpholine N-oxide (370.2 mg, 3.16 mmol) was
added 3-chloroperoxybenzoic acid (218 mg 1.26 mmpl), at -78
°C. After the mixture was stirred for 1 h at -78 °C, dimethyl
sulfide (0.3 mL) in CH2Cl2 (1.5 mL) and NaOH solution (6 mL)
were added, and the resulting mixture was extracted with
CHCl3. The organic layers were combined, washed with H2O
and brine, dried over MgSO4, filtered, and concentrated in
vacuo to give the crude products. Column chromatography on
aluminum oxide (gradually from 2% to 3% ethyl acetate in
hexane) gave the corresponding epoxide 14 (95 mg, 86%, 56%
ee) as a colorless oil which was used for the next reaction
without further purification. The enantiomeric excess of the
epoxide was determined by HPLC analysis using a Chiracel
OD column (25 cm × 4.6 mm, Daicel) eluted with 2-propanol/
hexanes (3:97) at 1 mL/min, while monitoring at 254 nm. The
retention times of the epoxide enantiomers are 6.3 (major
isomer 14) and 6.7 (minor isomer) min: IR (neat, cm-1) 1753,
(()-cis-1-Am in o-7-ter t-bu tyl-in d a n -2-ol (e): mp 61-62
°C; IR (neat, cm-1) 3341 (br), 1580, 1480, 1364, 1206, 1092;
1H NMR (400 MHz, CDCl3) δ 1.43 (s, 9H), 2.28 (brs, 3H), 2.79
(dd, 1H, J ) 15.1, 9.3 Hz), 3.02 (dd, 1H, J ) 15.4, 7.3 Hz),
4.31 (brddd, 1H, J ) 7.1, 7.1, 7.1 Hz), 4.42 (brd, 1H, J ) 5.9
Hz), 7.07 (d, 1H, J ) 7.1 Hz), 7.18 (dd, 1H, J ) 7.8, 7.3 Hz),
7.24 (d, 1H, J ) 7.8 Hz); 13C NMR (100 MHz, CDCl3) δ 31.7,
32.2, 37.8, 57.0, 72.5, 123.5, 124.8, 128.3, 142.1, 147.4; EI
HRMS m/e calcd for C13H19NO (M+•) 205.1466, found 205.1460.
(1S,2R)-(-)-cis-1-[(2R)-4-H yd r oxym et h yl-2-(2,6,6-t r i-
methylcyclohex-1-enyl)-1,2,5,6-tetrahydropyridin-1-yl]indan-
2-ol ((-)-15). To a solution of the ester (-)-1a prepared in
Scheme 2 (119 mg, 0.302 mmol) in ether (3.0 mL) was added
lithium aluminum hydride (11.5 mg, 0.302 mmol) at 0 °C. After
the mixture was warmed to room temperature and stirred for
an additional 5 min, H2O was carefully added over 30 min.
The resulting mixture was filtered and concentrated in vacuo
to give the crude products which were purified by column
chromatography on silica gel (40% ethyl acetate in hexane) to
afford the corresponding (-)-dialcohol 15 (112 mg, 100%) as a
white foam: mp 70-71 °C; [R]24D -66.9 (c 1.1, CHCl3); IR (KBr
disk, cm-1) 3387, 1460, 1047; 1H NMR (400 MHz, CDCl3) δ
1.12 (s, 3H), 1.20 (s, 3H), 1.41-1.55 (m, 4H), 1.90 (s, 3H), 1.90-
1.92 (m, 3H), 2.21-2.29 (m, 1H), 2.83 (dd, 1H, J ) 16.3, 2.4
Hz), 3.03-3.10 (m, 2H), 3.17 (dd, 1H, J ) 11.5, 4.6 Hz), 4.01
(d, 1H, J ) 12.9 Hz), 4.05 (d, 1H, J ) 12.9 Hz), 4.41 (d, 1H, J
) 5.1 Hz), 4.48 (brs, 1H), 4.86 (brs, 1H), 5.54 (s, 1H), 7.19-
7.26 (m, 3H), 7.32 (d, 1H, J ) 6.6 Hz); 13C NMR (100 MHz,
CDCl3) δ 19.5, 21.1, 27.4, 28.2, 29.3, 34.7, 35.5, 40.9, 41.2, 45.1,
58.0, 65.4, 66.9, 77.6, 125.1, 125.5, 126.4, 126.8, 127.1, 133.8,
134.3, 135.3, 139.6, 142.9; EI HRMS m/e calcd for C24H33NO2
(M+•) 367.2510, found 367.2514.
1
1460, 1447, 1084, 1036, 1009; H NMR (400 MHz, CDCl3) δ
1.32 (d, 3H, J ) 7.1 Hz), 1.33 (d, 3H, J ) 7.1 Hz), 2.97 (dm,
1H, J ) 18.1 Hz), 3.20 (d, 1H, J ) 18.1 Hz), 3.29 (qq, 1H, J )
7.1, 7.1 Hz), 4.09-4.11 (m, 1H), 4.40-4.41 (m, 1H), 7.05 (d,
1H, J ) 7.3 Hz), 7.09 (d, 1H, J ) 7.6 Hz), 7.20 (dd, 1H, J )
7.6, 7.6 Hz); 13C NMR (100 MHz, CDCl3) δ 23.5, 23.9, 30.7,
34.7, 57.4, 57.5, 122.8, 123.4, 128.8, 138.4, 143.5, 146.2.
(1S,2R)-(-)-cis-1-Am in o-7-isop r op ylin d a n -2-ol ((-)-d ).
To a solution of fuming sulfuric acid (0.601 mL, 11.3 mmol,
30% SO3) in acetonitrile (11 mL) was added dropwise a solution
of the epoxide 14 (983 mg, 5.64 mmol) in hexane (11 mL) at 0
°C. After the biphasic mixture was warmed to room temper-
ature and stirred for an additional 1 h, H2O (11 mL) was
carefully added, and the resulting mixture was stirred for 30
min at this temperature. The lower aqueous phase was
separated and diluted with H2O (11 mL), and acetonitrile was
removed by distillation at atmospheric pressure to a head
temperature of 100 °C. The resulting mixture was heated to
reflux for 2 h, and 50% aqueous NaOH solution was added
until the reaction mixture reached pH 12 and the white solid
of aminoindanol free base precipitated. After the precipitate
was completely dissolved in CHCl3, the resulting mixture was
extracted with CHCl3. The organic layers were combined,
washed with brine, dried over MgSO4, filtered, and concen-
trated in vacuo to give the crude products. Column chroma-
(2R)-(-)-4-Hyd r oxym eth yl-2-(2,6,6-tr im eth ylcycloh ex-
1-en yl)-1,2,5,6-tetr a h yd r op yr id in e ((-)-16). To a solution
of the (-)-alcohol 15 prepared from (-)-1a as mentioned above
(100 mg, 0.271 mmol) in ether (3.0 mL) was added manganese
dioxide (1.0 g) at room temperature, and the resulting mixture
was stirred for 3 min. The reaction mixture was filtered and
concentrated in vacuo to give the corresponding unstable
N-oxide (major isomer/minor isomer ) 3:1): representative
1
signals in their H NMR (400 MHz, CDCl3) δ 4.40 (brs, major)
and 4.34 (brs, minor), 5.55 (brs, major) and 5.53 (brs, minor),
5.58 (brs, major) and 5.74 (brs, minor), 5.12 (dd, major, J )
8.4, 2.4 Hz) and 5.58-5.60 (m, minor).
J . Org. Chem, Vol. 69, No. 18, 2004 5921

Tanaka et al.
1
The unstable N-oxide thus obtained were immediately
(otherwise decomposed) subjected to column chromatography
on silica gel (11% methanol in chloroform) to afford (-)-16 (44
1051, 1032; H NMR (400 MHz, CDCl3) δ 2.10 (brd, 1H, J )
17.3 Hz), 2.20-2.28 (m, 1H), 2.68 (brs, 2H), 2.95 (ddd, 1H, J
) 13.2, 8.3, 4.9 Hz), 3.14 (ddd, 1H, J ) 12.2, 5.1, 5.1 Hz), 4.07
(brs, 2H), 4.50 (brs, 1H), 5.72 (brs, 1H), 7.24-7.36 (m, 5H);
13C NMR (100 MHz, CDCl3) δ 25.6, 41.3, 57.9, 66.4, 123.6,
mg, 69%) as a colorless oil: [R]24 -46.5 (c 0.4, CHCl3); IR
D
(neat, cm-1) 3329, 1454, 1427, 1024; 1H NMR (400 MHz,
CDCl3) δ 1.00 (s, 3H), 1.07 (s, 3H), 1.38-1.48 (m, 2H), 1.52-
1.58 (m, 2H), 1.69 (s, 3H), 1.84-1.96 (m, 2H), 2.00 (brd, 1H, J
) 16.6 Hz), 2.18-2.27 (m, 1H), 2.44 (brs, 2H), 2.91 (ddd, 1H,
J ) 11.7, 11.7, 4.4 Hz), 3.30 (ddd, 1H, J ) 12.2, 5.6, 1.0 Hz),
3.96-4.03 (m, 3H), 5.58 (brs, 1H); 13C NMR (100 MHz, CDCl3)
δ 19.3, 20.6, 25.4, 27.9, 28.2, 34.0, 35.3, 39.7, 44.1, 54.0, 66.6,
127.2, 132.2, 134.4, 138.3; EI HRMS m/e calcd for C15H25NO
(M+•) 235.1935, found 235.1933.
127.5, 127.8, 128.5, 137.6, 142.7; EI HRMS m/e calcd for C12H15
-
NO (M+•) 189.1153, found 189.1160.
(1S ,2R )-(-)-cis-1-[(2R )-4-H yd r oxym e t h yl-2-p h e n yl-
1,2,5,6-tetr a h yd r op yr id in -1-yl]-7-m eth ylin d a n -2-ol (Ex-
p er im en ta l P r oced u r e of En tr y 2 of Ta ble 3). To a solution
of the ester (-)-3b prepared in entry 4 of Table 2 (370 mg,
0.985 mmol) in ether (4.0 mL) and THF (2.0 mL) was added
lithium aluminum hydride (56.1 mg, 1.48 mmol) at 0 °C. After
the mixture was warmed to room temperature and stirred for
5 min, H2O was carefully added over 30 min. The resulting
mixture was filtered and concentrated in vacuo to give the
crude products which were purified by column chromatography
on silica gel (from 33% to 50% ethyl acetate in hexane) to
produce the corresponding (-)-dialcohol (300 mg, 91%) as a
white foam: mp 83-85 °C; [R]19D -1.8 (c 0.6, CHCl3); IR (KBr
disk, cm-1) 3410, 1468, 1456, 1399, 1159, 1030; EI HRMS m/e
calcd for C22H25NO2 (M+•) 335.1884, found 335.1892. The
obtained dialcohol existed as its rotamers at 24 °C in CDCl3,
and all the signals in its 1H and 13C NMR spectra were
broadened.
(2R)-(-)-4-Hyd r oxym eth yl-2-p h en yl-1,2,5,6-tetr a h yd r o-
p yr id in e ((-)-17). To a solution of the (-)-dialcohol prepared
from (-)-3b as mentioned above (80 mg, 0.238 mmol) in ether
(2.0 mL), THF (0.5 mL), and acetone (0.1 mL) was added
manganese dioxide (2.0 g) at room temperature, and the
mixture was stirred for 1 min. The reaction mixture was
filtered and concentrated in vacuo to give the crude products
which were purified by preparative thin-layer chromatography
on silica gel (13% methanol in chloroform) to afford (-)-17 (25
mg, 55%) as a colorless oil, whose spectral data were good
agreement with those obtained from (-)-3a .
Ch a r a cter iza tion of th e N-Oxid e Der iva tive a n d th e
Mech a n istic In sigh t Con cer n in g th e Rem ova l of th e
In d a n Au xilia r y by Ma n ga n ese Dioxid e Oxid a tion . In the
oxidative removal of the indan auxiliary by the reaction with
manganese dioxide (Scheme 6 and Table 3), the N-oxide
intermediate was characterized by the following experiment
and spectroscopic data of rather stable N-oxide 26: To a
solution of the (-)-ester alcohol 25 (20 mg, 0.0506 mmol)
derived from (-)-1a by sodium borohydride reduction (see
below) in dichloromethane (2.0 mL) was added manganese
dioxide (200 mg) at room temperature, and the mixture was
stirred for 5 min. The reaction mixture was filtered and
concentrated in vacuo to give the corresponding N-oxide 26
as a yellow oil (major isomer/minor isomer ) 3:1). IR (KBr
1
disk, cm-1) 3451, 1717, 972; representative signals in their H
NMR (400 MHz, CDCl3) δ 4.52 (brs, major) and 4.45 (brs,
minor), 6.79 (brs, major) and 6.77 (brs, minor), 5.59 (brs, major)
and 5.74 (brs, minor), 5.12 (dd, major, J ) 8.4, 3.2 Hz) and
5.59-5.61 (m, minor); 13C NMR (100 MHz, CDCl3) δ 15.2, 19.3,
21.45, 21.50, 25.1, 26.3, 27.6, 29.2, 29.3, 34.4, 34.5, 34.6, 35.8,
35.9, 36.5, 40.4, 40.5, 42.3, 42.4, 51.6, 56.56, 56.65, 82.0, 86.8,
91.9, 92.0, 125.5, 125.9, 126.56, 126.63, 126.8, 127.4, 127.6,
128.8, 129.0, 132.7, 134.1, 134.16, 134.23, 135.3, 135.4, 135.8,
142.36, 142.41, 144.3, 167.57, 167.60; EI HRMS m/e calcd for
(1S ,2R )-(-)-cis-1-[(2R )-4-H yd r oxym e t h yl-2-p h e n yl-
1,2,5,6-tetr ah ydr opyr idin -1-yl]-7-isopr opylin dan -2-ol (Ex-
p er im en ta l P r oced u r e for En tr y 3 of Ta ble 3). To a
solution of the crude ester (-)-3d prepared in entry 9 of Table
2 (theoretical; 3.37 mmol) in ether (15 mL) and THF (15 mL)
was added lithium aluminum hydride (256 mg, 6.75 mmol) at
0 °C. After the mixture was warmed to room temperature and
stirred for further 10 min, H2O was carefully added over 30
min. The resulting mixture was filtered and concentrated in
vacuo to give the crude products which were purified by
column chromatography on silica gel (from 33% to 50% ethyl
acetate in hexane) to afford the corresponding (-)-dialcohol
C
25H33NO4 (M+•) 411.2408, found 411.2410.
Furthermore, the time-dependent EIMS analyses of thus
obtained N-oxide 26 detected the ion peaks corresponding to
the imminium ion [(M - H)+• ) 393] and its hydroxylated
product (M+• ) 411) under the MS-measurement condition.
(-)-Ester 25. To a solution of the ester (-)-1a (200 mg,
0.508 mmol) in methanol (5.0 mL) was added sodium borohy-
dride (28.8 mg, 0.762 mmol) at 0 °C. After the mixture was
stirred for an additional 15 min at this temperature, the
resulting mixture was concentrated in vacuo to give the crude
products which were purified by column chromatography on
silica gel (gradually from 4% to 12% ethyl acetate in hexane)
to afford (-)-ester alcohol 25 (159 mg, 79%) as a white solid:
(1.12 g, 91% for 2 steps) as a white foam: mp 40-42 °C; [R]20
D
-162.9 (c 0.5, CHCl3); IR (KBr disk, cm-1) 3393, 1454, 1383,
1080; EI HRMS m/e calcd for C24H29NO2 (M+•) 363.2196, found
363.2195. The dialcohol thus obtained existed in a mixture of
rotamers at 24 °C in CDCl3, and all the signals of its 1H and
13C NMR spectra were broadened.
[R]24 -40.0 (c 1.0, CHCl3); IR (KBr disk, cm-1) 3486, 1701,
D
1260; 1H NMR (400 MHz, CDCl3) δ 1.17 (s, 3H), 1.23 (s, 3H),
1.48-1.63 (m, 4H), 1.88 (s, 3H), 1.94-1.95 (m, 2H), 2.31-2.37
(m, 2H), 2.86 (dd, 1H, J ) 16.3, 2.9 Hz), 3.01-3.06 (m, 1H),
3.10 (dd, 1H, J ) 16.6, 6.1 Hz), 3.13-3.18 (m, 1H), 3.75 (s,
3H), 4.42 (d, 1H, J ) 5.1 Hz), 4.65 (brs, 1H), 4.86 (brs, 1H),
6.79 (s, 1H), 7.24-7.30 (m, 4H); 13C NMR (100 MHz, CDCl3)
δ 19.4, 21.1, 26.1, 28.0, 29.2, 34.7, 35.6, 40.7, 41.4, 44.6, 51.6,
58.4, 65.0, 77.4, 125.1, 125.5, 126.7, 127.0, 127.3, 133.7, 135.4,
139.6, 142.0, 142.5, 167.8; EI HRMS m/e calcd for C25H33NO3
(M+•) 395.2459, found 395.2462.
(2R)-(-)-4-Hyd r oxym eth yl-2-p h en yl-1,2,5,6-tetr a h yd r o-
p yr id in e ((-)-17). To a solution of the (-)-dialcohol prepared
from (-)-3d as mentioned above (80 mg, 0.220 mmol) in ether
(3.0 mL) was added manganese dioxide (2.0 g) at room
temperature, and the mixture was stirred for 1 min. The
reaction mixture was filtered and concentrated in vacuo to give
the crude products which were purified by column chroma-
tography on silica gel (gradually from 0% to 33% methanol in
chloroform) to afford (-)-17 (24 mg, 58%) as a colorless oil,
whose spectral data were good agreement with those obtained
from (-)-3a and (-)-3b.
3-(2,2-Dibr om ovin yl)-N-p-tolu en esu lfon ylin d ole (41).
To a solution of triphenylphosphine (52.6 g, 200 mmol) in CH2-
Cl2 (200 mL) was added carbon tetrabromide (33.2 g, 100
mmol) at -20 °C. After the mixture was stirred for 10 min at
-20 °C, a solution of N-p-toluenesulfonylindole-3-carboxalde-
hyde 40 (10.0 g, 33.4 mmol) in CH2Cl2 (60 mL) was slowly
added at -78 °C, and stirring was continued for an additional
(2R)-(-)-4-Hyd r oxym eth yl-2-p h en yl-1,2,5,6-tetr a h yd r o-
p yr id in e ((-)-17) (Exp er im en ta l P r oced u r e for En tr y 1
of Ta ble 3). To a solution of the dialcohol prepared from (-)-
3a (see entry 2 of Table 2) (80 mg, 0.249 mmol) in ether (4.0
mL) and THF (1.0 mL) was added manganese dioxide (1.0 g)
at room temperature, and the mixture was stirred for 5 min.
The reaction mixture was filtered and concentrated in vacuo
to give the crude products which were purified by column
chromatography on silica gel (gradually from 0% to 33%
methanol in chloroform) to afford (-)-17 (26 mg, 55%) as a
colorless oil: [R]19D -67.4 (c 0.8, CHCl3); IR (neat, cm-1) 3424,
5922 J . Org. Chem., Vol. 69, No. 18, 2004

Asymmetric 6π-Azaelectrocyclization
5 min. After the reaction mixture was gradually warmed to
room temperature, a bulk of hexane (200 mL) was added. The
resulting precipitate was filtered, and the filtrate was con-
centrated in vacuo to give the crude solids, which were then
completely dissolved in chloroform. The resulting black solu-
tion was again concentrated in vacuo to give the crude products
as an oil which were rapidly purified by column chromatog-
raphy on silica gel (gradually 25% to 50% ethyl acetate in
hexane) to provide the corresponding dibromide 41 (14.1 g,
for 12 h, the bulk of dichloromethane was removed in vacuo,
H2O was added, and the resulting mixture was extracted with
ether. The organic layers were combined, washed with brine,
dried over MgSO4, filtered, and concentrated in vacuo to give
the crude products. Column chromatography on silica gel (17%
ethyl acetate in hexane) gave an inseparable 10:1 mixture of
(Z)- and (E)-conjugated ester derivatives (5.69 g, 65%) as an
orange oil, which was used for the next step without further
purification.
To a methanol (100 mL) solution of a (Z)- and (E)-mixture
of the conjugated ester obtained above (7.78 g, 22.9 mmol) was
added p-toluenesulfonic acid monohydrate (435 mg, 2.29 mmol)
at room temperature. After the mixture was stirred at room
temperature for 40 min, saturated aqueous NaHCO3 solution
was added, and the resulting mixture was extracted with
ether. The organic layers were combined, washed with brine,
dried over MgSO4, filtered, and concentrated in vacuo to give
the crude products. Column chromatography on silica gel
(gradually from 9% to 29% ethyl acetate in hexane) gave (Z)-
93%) as a white solid: mp 129-130 °C; IR (KBr disk, cm-1
)
1
1447, 1372, 1173, 1138, 1123, 1094, 972; H NMR (400 MHz,
CDCl3) δ 2.34 (s, 3H), 7.22-7.24 (m, 2H), 7.27 (dd, 1H, J )
8.1, 8.1 Hz), 7.35 (dd, 1H, J ) 7.3, 7.3 Hz), 7.51 (d, 1H, J )
8.1 Hz), 7.53 (s, 1H), 7.77-7.80 (m, 2H), 7.98 (d, 1H, J ) 8.3
Hz), 8.29 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 21.6, 90.3,
113.6, 117.3, 118.8, 123.6, 124.9, 125.4, 126.8, 126.9, 129.4,
130.0, 134.0, 134.8, 145.3; EI HRMS m/e calcd for C17H13Br2-
NO2S (M+•) 452.9033, found 452.9040.
3-Eth yn yl-N-p-tolu en esu lfon ylin d ole (43). To a solution
of the dibromide prepared above (4.5 g, 9.89 mmol) in THF
(80 mL) was added lithium bis(trimethylsilyl)amide (1.0 M in
THF, 21.8 mL, 21.8 mmol) at -78 °C. After the reaction
mixture was stirred for 20 min at this temperature, saturated
aqueous NH4Cl solution was rapidly added, and the resulting
mixture was extracted with ethyl acetate. The organic layers
were combined, dried over MgSO4, filtered, and concentrated
in vacuo to give the corresponding crude ethynyl bromide 42
as a white solid which was subjected to the next reaction
without any purification.
vinyl iodide 46 (4.94 g, 84%) as an orange oil: IR (neat, cm-1
)
3447, 1717, 1618, 1256; 1H NMR (400 MHz, CDCl3) δ 1.33 (t,
3H, J ) 7.1 Hz), 4.28 (q, 2H, J ) 7.1 Hz), 4.36 (d, 2H, J ) 5.1
Hz), 7.50 (t, 1H, J ) 5.1 Hz); 13C NMR (100 MHz, CDCl3) δ
14.1, 63.0, 67.4, 144.8, 151.6, 162.3; EI HRMS m/e calcd for
C6H9IO3 (M+•) 255.9596, found 255.9601.
Eth yl (E,E)-4-Oxo-2-[(N-p-tolu en esu lfon ylin d ol-3-yl)-
vin yl]bu t-2-en oa te (47). To a solution of the (E)-stannane
44 (11.0 g, 18.8 mmol) and the vinyl iodide 46 (4.94 g, 19.3
mmol) in DMF (160 mL) were added tetrakis(triphenylphos-
phine)palladium(0) (1.08 g, 0.938 mmol) and lithium chloride
(1.59 g, 37.5 mmol) at room temperature. After the reaction
mixture was stirred at 115 °C for 30 min, 10% aqueous NH3
solution was added, and the resulting mixture was extracted
with ether. The organic layers were combined, washed with
brine, dried over MgSO4, filtered and concentrated in vacuo
to give the crude products. Rough purification by column
chromatography on silica gel (from 25% to 50% ethyl acetate
in hexane) gave the corresponding alcohol (5.14 g, 64%) as a
yellow oil which was oxidized without further purification.
To a solution of the crude ethynyl bromide 42 in THF (80
mL) was added sec-butyllithium (1.0 M in cyclohexane, 14.8
mL, 14.8 mmol) at -78 °C. After the reaction mixture was
stirred for 5 min at this temperature, saturated aqueous NH4-
Cl solution was rapidly added, and the resulting mixture was
extracted with ethyl acetate. The organic layers were com-
bined, dried over MgSO4, filtered, and concentrated in vacuo
to give the crude products which were purified by recrystal-
lization from hexane and ethyl acetate to afford the corre-
sponding acetylene derivative 43 (1.79 g, 61% in two steps) as
a white solid: mp 161-162 °C; IR (KBr disk, cm-1) 3266, 3131,
To a solution of the crude alcohol thus obtained (750 mg,
1.76 mmol) in dichloromethane (20 mL) was added manganese
dioxide (20 g) at room temperature, and the mixture was
stirred for 13 min. The reaction mixture was filtered and
concentrated in vacuo to give the crude products which were
purified by column chromatography on silica gel (gradually
from 17% to 25% ethyl acetate in hexane) to afford the desired
1
1595, 1449, 1375, 1175, 1138, 1094, 966; H NMR (400 MHz,
CDCl3) δ 2.34 (s, 3H), 3.26 (s, 1H), 7.22-7.34 (m, 3H), 7.36
(dd, 1H, J ) 7.3, 7.3 Hz), 7.64 (d, 1H, J ) 7.8 Hz), 7.76-7.79
(m, 3H), 7.97 (d, 1H, J ) 8.1 Hz); 13C NMR (100 MHz, CDCl3)
δ 21.6, 74.9, 81.5, 104.0, 113.5, 120.5, 123.8, 125.5, 126.9, 129.9,
130.0, 130.7, 134.0, 134.8, 145.4; EI HRMS m/e calcd for C17H13
-
NO2S (M+•) 295.0666, found 295.0654.
aldehyde 47 (500 mg, 67%) as a yellow oil: IR (neat, cm-1
)
1
(E)-(N-p-Tolu en esu lfon ylin d ol-3-yl)-tr ibu tyltin (44). To
a solution of 3-ethynyl-N-p-toluenesulfonylindole 43 (1.45 g,
4.91 mmol) and tri-n-butyltin hydride (1.42 mL, 5.40 mmol)
in benzene (50 mL) was added 2,2′-azobisisobutyronitrile
(AIBN) (32 mg, 0.196 mmol) at room temperature. After being
stirred at 115 °C for 3 h, the reaction mixture was concentrated
in vacuo to give the crude products which were purified by
column chromatography on aluminum oxide (gradually from
1% to 4% ethyl acetate in hexane) to give (E)-vinylstannane
44 (2.88 g, 84%) as a colorless oil: IR (KBr, cm-1) 1599, 1447,
1375, 1130; 1H NMR (400 MHz, CDCl3) δ 7.98 (d, 1H, J ) 8.1
Hz), 7.80 (d, 1H, J ) 8.3 Hz), 7.70 (d, 2H, J ) 8.3 Hz), 7.58 (s,
1H), 7.32 (ddd, 1H, J ) 7.8, 1.0, 1.0 Hz), 7.26 (ddd, 1H, J )
7.4, 1.0, 1.0 Hz) 7.21 (d, 1H, J ) 8.1 Hz), 6.94 (d, 1H, J ) 19.8
Hz), 6.83 (d, 1H, J ) 19.8 Hz), 2.33 (s, 1H), 1.52-1.59 (m, 6H),
1723, 1672, 1613, 1447, 1373, 1175, 1127, 976; H NMR (400
MHz, CDCl3) δ 1.39 (t, 3H, J ) 7.1 Hz), 2.35 (s, 3H), 4.37 (q,
2H, J ) 7.3 Hz), 6.67 (d, 1H, J ) 6.8 Hz), 7.22-7.27 (m, 3H),
7.32-7.41 (m, 2H), 7.54 (d, 1H, J ) 16.1 Hz), 7.79-7.82 (m,
4H), 8.02 (d, 1H, J ) 8.1 Hz), 10.17 (d, 1H, J ) 6.8 Hz); 13C
NMR (100 MHz, CDCl3) δ 14.1, 21.6, 62.1, 113.9, 119.6, 119.9,
120.5, 124.1, 125.5, 127.0, 127.2, 128.0, 130.1, 130.4, 132.7,
134.7, 135.6, 145.5, 145.7, 166.3, 191.2; EI HRMS m/e calcd
for C23H21NO5S (M+•) 423.1139, found 423.1144.
(-)-1,2,5,6-Tetr a h yd r op yr id in e d er iva tive ((-)-48b). To
a solution of the aldehyde 47 (500 mg, 1.18 mmol) in chloro-
form (10 mL) was added (1S,2R)-(-)-cis-1-amino-7-methylin-
dan-2-ol, (-)-b (193 mg, 1.18 mmol) at 23 °C, and the mixture
was stirred for 12 h at this temperature. The reaction mixture
was concentrated in vacuo to give the crude products which
were purified by column chromatography on silica gel (from
5% to 25% ethyl acetate in hexane) to afford a 10:1 mixture of
(-)-48b and its stereoisomer (643 mg, 96%) as a yellow oil.
The major stereoisomer (-)-48b was then successfully isolated
by medium-pressure liquid chromatography (14% ethyl acetate
1.30-1.39 (m, 6H), 0.96-1.00 (m, 6H), 0.89-0.93 (m, 9H); 13
C
NMR (100 MHz, CDCl3) δ 144.9, 136.5, 135.5, 135.2, 131.7,
129.9, 129.0, 126.8, 124.8, 123.5, 123.4, 122.7, 120.4, 113.7,
29.1, 27.3, 21.5, 13.7, 9.60; EI HRMS m/e calcd for C29H40
-
NO2S119Sn (M - H)+• 585.1811, found 585.1816.
Eth yl (Z)-4-Hydr oxy-2-iodo-2-bu ten oate (46). To a dichlo-
romethane (140 mL) solution of tetrahydropyranyloxyethanal
(3.74 g, 25.9 mmol) was added triphenylcarbethoxyiodometh-
ylenephosphorane (14.8 g, 31.1 mmol) at room temperature.
After the reaction mixture was stirred at room temperature
in hexane): [R]27 -1.5 (c 0.5, CHCl3); IR (KBr disk, cm-1
)
D
1
1715, 1447, 1372, 1258, 1175; H NMR (400 MHz, CDCl3) δ
1.17 (s, 3H), 1.24 (t, 3H, J ) 7.1 Hz), 2.29 (s, 3H), 2.76 (dm,
1H, J ) 19.3 Hz), 2.85 (dm, 1H, J ) 19.3 Hz), 3.16 (d, 1H, J
) 17.6 Hz), 3.23 (dd, 1H, J ) 18.1, 5.9 Hz), 4.17 (qm, 2H, J )
J . Org. Chem, Vol. 69, No. 18, 2004 5923

Tanaka et al.
7.1 Hz), 4.35 (dd, 1H, J ) 6.1, 3.4 Hz), 4.47 (d, 1H, J ) 4.4
Hz), 4.87 (d, 1H, J ) 5.4 Hz), 4.99 (ddd, 1H, J ) 5.9, 5.9, 1.2
Hz), 6.72 (d, 1H, J ) 7.3 Hz), 6.80 (brs, 1H), 6.97 (d, 1H, J )
7.3 Hz), 7.05 (dd, 1H, J ) 7.3, 7.3 Hz), 7.16-7.20 (m, 3H), 7.34
(dd, 1H, J ) 7.8, 7.8 Hz), 7.53 (d, 1H, J ) 8.1 Hz), 7.65 (s,
1H), 7.78-7.81 (m, 2H), 8.03 (d, 1H, J ) 8.5 Hz); 13C NMR
(100 MHz, CDCl3) δ 14.2, 17.4, 21.5, 25.5, 39.6, 54.4, 60.7, 74.7,
75.0, 86.4, 113.8, 121.3, 121.6, 122.6, 123.2, 124.7, 125.0, 125.1,
126.8, 128.1, 128.4, 129.8, 129.9, 135.1, 135.8, 136.5, 137.2,
137.3, 143.1, 145.1, 166.0; EI HRMS m/e calcd for C33H32N2O5S
(M+•) 568.2030, found 568.2028.
(2S)-(-)-4-Hydr oxym eth yl-2-(N-p-tolu en esu lfon ylin dol-
3-yl)-1,2,5,6-tetr a h yd r op yr id in e ((-)-50). To a solution of
the ester (-)-48b (1.10 g, 1.93 mmol) in ether (15 mL) and
THF (5 mL) was added lithium aluminum hydride (100 mg,
2.64 mmol) at 0 °C over 10 min. After the mixture was warmed
to room temperature and stirred for an additional 5 min, H2O
was carefully added over 30 min. The resulting mixture was
filtered and concentrated in vacuo to give the crude products
which were roughly purified by column chromatography on
silica gel (from 40% to 67% ethyl acetate in hexane) to afford
the corresponding diol (969 mg, 95%) as a white foam, which
was oxidized without further purification.
THF (2.0 mL) was added lithium aluminum hydride (30.0 mg,
0.792 mmol) at 0 °C over 10 min. After the mixture was
warmed to room temperature and stirred for an additional 5
min, H2O was carefully added over 30 min. The resulting
mixture was filtered and concentrated in vacuo to give the
crude products which were roughly purified by column chro-
matography on silica gel (from 33% to 50% ethyl acetate in
hexane) to afford the corresponding dialcohol (244 mg, 83%)
as a white foam, which was oxidized without further purifica-
tion.
To a solution of the crude alcohol thus obtained (200 mg,
0.359 mmol) in ether (6.0 mL) was added manganese dioxide
(2.3 g) at room temperature, and the mixture was stirred for
3 min. The reaction mixture was filtered and concentrated in
vacuo to give the crude products which were purified by
column chromatography on silica gel twice (gradually from 5%
to 14% methanol in chloroform) to afford (-)-50 (102 mg, 74%),
whose spectral data were good agreement with those obtained
from (-)-48b.
(2S)-(-)-4-H yd r oxym et h yl-N-m et h yl-2-(N-p -t olu en e-
su lfon ylin d ol-3-yl)-1,2,5,6-tetr a h yd r op yr id in e (51). To a
solution of (-)-50 (154 mg, 0.403 mmol) and 37% aqueous
formaldehyde (0.16 mL, 2.01 mmol) in acetonitrile (4.0 mL)
was added sodium cyanoborohydride (50.3 mg, 0.805 mmol)
at room temperature. After the reaction mixture was stirred
for 5 min, saturated aqueous NH4Cl solution was added, and
the resulting mixture was extracted with chloroform. The
organic layers were combined, washed with brine, dried over
MgSO4, filtered, and concentrated in vacuo to give the crude
products which were purified by column chromatography on
silica gel (gradually from 5% to 11% methanol in chloroform)
to afford the corresponding (-)-N-methyl derivative 51 (159
To a solution of the crude alcohol thus obtained (150 mg,
0.284 mmol) in ether (5.0 mL) was added manganese dioxide
(2.0 g) at room temperature, and the mixture was stirred for
3 min. The reaction mixture was filtered and concentrated in
vacuo to give the crude products which were purified by
column chromatography on silica gel (gradually from 5% to
14% methanol in chloroform) to afford (-)-50 (79 mg, 73%) as
a white foam: mp 79-80 °C; [R]27 -31.1 (c 0.5, CHCl3); IR
D
(KBr disk, cm-1) 3320, 3131, 3052, 2920, 1449, 1370, 1173,
1
1123; H NMR (400 MHz, CDCl3) δ 2.07 (brs, 2H), 2.15 (brs,
mg, 100%) as a colorless oil: [R]26 -82.4 (c 0.3, CHCl3); IR
D
1
2H), 2.33 (s, 3H), 2.91-2.97 (m, 1H), 3.01-3.07 (m, 1H), 4.10
(brs, 2H), 4.75 (brs, 1H), 5.82 (brs, 1H), 7.19-7.33 (m, 4H),
7.45 (s, 1H), 7.60 (d, 1H, J ) 7.6 Hz), 7.74-7.77 (m, 2H), 7.96
(d, 1H, J ) 8.3 Hz); 13C NMR (100 MHz, CDCl3) δ 21.5, 26.0,
40.7, 49.7, 66.4, 113.7, 119.9, 122.2, 123.2, 123.9, 124.1, 124.8,
126.8, 129.4, 129.8, 135.2, 135.5, 138.3, 144.9; EI HRMS m/e
calcd for C21H22N2O3S (M+•) 382.1350, found 382.1354.
(KBr disk, cm-1) 3399, 1447, 1368, 1175, 1121; H NMR (400
MHz, CDCl3) δ 2.08-2.12 (m, 1H), 2.17 (s, 3H), 2.32 (s, 3H),
2.43-2.52 (m, 2H), 2.95-3.02 (m, 1H), 3.94 (brs, 1H), 4.01-
4.17 (m, 2H), 5.52 (brs, 1H), 7.16-7.21 (m, 3H), 7.26-7.30 (m,
1H), 7.48 (s, 1H), 7.63 (d, 1H, J ) 7.8 Hz), 7.73-7.75 (m, 2H),
7.95 (d, 1H, J ) 8.3 Hz); 13C NMR (100 MHz, CDCl3) δ 21.5,
26.0, 43.6, 51.4, 59.4, 66.0, 113.6, 120.9, 123.0, 123.1, 123.4,
124.5, 124.6, 126.7, 126.9, 129.8, 135.1, 135.6, 136.3, 144.8;
EI HRMS m/e calcd for C22H24N2O3S (M+•) 396.1506, found
396.1511.
(2S)-(-)-4-(1-Hyd r oxyeth yl)-N-m eth yl-2-(N-p-tolu en e-
su lfon ylin d ol-3-yl)-1,2,5,6-tetr a h yd r op yr id in e. To a solu-
tion of the (-)-N-methyl derivative 51 obtained above (60 mg,
0.151 mmol) in dichloromethane (2 mL) was added manganese
dioxide (1.2 g) at room temperature, and the mixture was
stirred for 5 min. The reaction mixture was filtered and
concentrated in vacuo to give the crude aldehyde which was
reacted with methyllithium without any purification.
(-)-1,2,5,6-Tetr a h yd r op yr id in e d er iva tive ((-)-48d ). To
a solution of the aldehyde 47 (600 mg, 1.42 mmol) in chloro-
form (20 mL) was added (1S,2R)-(-)-7-cis-1-amino-7-isopro-
pylindan-2-ol, (-)-d (271 mg, 1.42 mmol), at 12 °C, and the
mixture was stirred for 8.5 h at this temperature. The
resulting mixture was concentrated in vacuo to give the crude
products which were purified by column chromatography on
silica gel (33% ethyl acetate in hexane) to afford a 10:1 mixture
of (-)-48d and its stereoisomer (840 mg, 99%) as a yellow oil.
The major stereoisomer (-)-48d was then successfully isolated
by column chromatography on silica gel (gradually from 17%
to 29% ethyl acetate in hexane): [R]16 -87.0 (c 0.7, CHCl3);
D
To a solution of the crude aldehyde thus obtained in ether
(2 mL) and THF (1 mL) was added methyllithium (1.5 M
solution in ether, 0.20 mL, 0.303 mmol) at 0 °C. After the
reaction mixture was stirred for 5 min at 0 °C, saturated
aqueous NH4Cl solution was added, and the resulting mixture
was extracted with chloroform. The organic layers were
combined, washed with brine, dried over MgSO4, filtered, and
concentrated in vacuo to give the crude products which were
purified by column chromatography on silica gel (gradually
from 5% to 9% methanol in chloroform) to afford the corre-
sponding (-)-secondary alcohol as a 1:1 mixture of stereoiso-
mers (34 mg, 55% in two steps) as a colorless oil: [R]24D -68.8
(c 0.4, CHCl3); IR (neat, cm-1) 3391, 1447, 1372, 1175, 1121;
1H NMR (400 MHz, CDCl3) δ 1.29 (d, 3H, J ) 6.3 Hz), 2.10-
2.17 (m, 1H), 2.17 (s, 3H), 2.33 (s, 3H), 2.44-2.49 (m, 2H),
2.97-3.05 (m, 1H), 3.91-3.93 (m, 1H), 4.19-4.27 (m, 1H), 5.51
(brd, 1H, J ) 11.0), 7.16-7.21 (m, 3H), 7.25-7.30 (m, 1H),
7.47 (s, 1H), 7.63 (dd, 1H, J ) 9.0, 9.0 Hz), 7.73-7.75 (m, 2H),
7.95 (d, 1H, J ) 8.3 Hz); 13C NMR (100 MHz, CDCl3) δ 21.4,
21.5, 21.8, 24.1, 25.3, 43.67, 43.73, 51.7, 51.9, 59.7, 59.8, 70.7,
70.9, 113.7, 120.9, 121.0, 121.7, 123.0, 123.6, 124.5, 124.6,
IR (KBr disk, cm-1) 1715, 1447, 1373, 1260, 1175, 1123, 1030;
1H NMR (400 MHz, CDCl3) δ 0.05 (d, 3H, J ) 7.1 Hz), 0.52 (d,
3H, J ) 6.6 Hz), 1.24 (t, 3H, J ) 7.1 Hz), 2.32 (s, 3H), 2.52
(qq, 1H, J ) 6.8, 6.8 Hz), 2.77 (dddd, 1H, J ) 19.5, 4.4, 4.4,
2.0 Hz), 2.84 (dm, 1H, J ) 19.5 Hz), 3.17 (d, 1H, J ) 17.1 Hz),
3.23 (dd, 1H, J ) 18.1, 5.9 Hz), 4.17 (qm, 2H, J ) 7.1 Hz),
4.34 (dd, 1H, J ) 6.3, 3.9 Hz), 4.52 (dd, 1H, J ) 4.6, 1.2 Hz),
4.94-5.00 (m, 2H), 6.80 (dd, 1H, J ) 3.7, 2.0 Hz), 6.89 (d, 1H,
J ) 7.6 Hz), 6.98 (d, 1H, J ) 7.6 Hz), 7.13 (dd, 1H, J ) 7.6,
7.6 Hz), 7.18-7.28 (m, 3H), 7.35 (ddm, 1H, J ) 7.3, 7.3 Hz),
7.55 (d, 1H, J ) 7.8 Hz), 7.66 (s, 1H), 7.84 (ddd, 2H, J ) 8.8,
2.0, 2.0 Hz), 8.02 (d, 1H, J ) 8.5 Hz); 13C NMR (100 MHz,
CDCl3) δ 14.2, 21.5, 22.2, 22.5, 25.6, 27.6, 39.5, 54.4, 60.7, 74.3,
74.9, 86.6, 113.4, 121.6, 121.8, 123.0, 123.3, 124.4, 125.0, 125.4,
126.9, 128.8, 129.5, 130.0, 135.2, 135.6, 136.0, 137.4, 143.1,
145.1, 147.6, 166.0; EI HRMS m/e calcd for C35H36N2O5S (M+•
)
596.2343, found 596.2345.
(2S)-(-)-4-Hydr oxym eth yl-2-(N-p-tolu en esu lfon ylin dol-
3-yl)-1,2,5,6-tetr a h yd r op yr id in e ((-)-50). To a solution of
the ester (-)-48d (315 mg, 0.528 mmol) in ether (3.0 mL) and
5924 J . Org. Chem., Vol. 69, No. 18, 2004

Asymmetric 6π-Azaelectrocyclization
126.8, 129.79, 129.84, 135.2, 135.7, 140.1, 144.8; EI HRMS m/e
calcd for C23H26N2O3S (M+•) 410.1662, found 410.1662.
(2S)-(-)-2-(In d ol-3-yl)-N-m et h yl-4-m et h yloxo-1,2,5,6-
tetr a h yd r op yr id in e ((-)-30). To a solution of the (-)-
secondary alcohol obtained above (21.5 mg, 0.0524 mmol) in
methanol (1.5 mL) was added an 50% aqueous NaOH solution
(0.3 mL) at room temperature, and the mixture was stirred
for 7 h at 80 °C. The reaction mixture was directly concen-
trated in vacuo to give the crude products which were roughly
purified by column chromatography on silica gel (gradually
from 13% to 25% methanol in chloroform) to afford the
corresponding indole N-H derivative. It was oxidized without
further purification.
4.26 (brs, 1H), 6.74-6.76 (m, 1H), 7.12 (ddd, 1H, J ) 8.1, 8.1,
1.0 Hz), 7.158-7.163 (m, 1H), 7.22 (ddd, 1H, J ) 8.1, 8.1, 1.0
Hz), 7.40 (d, 1H, J ) 8.3 Hz), 7.67 (d, 1H, J ) 8.1 Hz), 8.20
(brs, 1H); 13C NMR (100 MHz, CDCl3) δ 24.0, 25.2, 43.6, 51.4,
59.8, 111.2, 111.3, 119.6, 119.8, 122.4, 123.2, 123.4, 126.7,
136.4, 141.6, 198.9; EI HRMS m/e calcd for C16H18N2O (M+•
)
254.1418, found.
Ack n ow led gm en t. We thank Dr. Kayoko Saiki at
the Kobe Pharmaceutical University for her high-
resolution mass spectra measurements. We also thank
Mr. Tamotsu Yamamoto at the Institute for Life Science
Research at Asahi Chemical Industry Co., Ltd., for his
X-ray crystallographic measurements. This study was
supported by a Grant-in-Aid for Scientific Research
09480145 from the Ministry of Education, Science,
Sports and Culture of J apan. K.T. is grateful to the
J SPS for a Research Fellowship for Young Scientists.
To a solution of the roughly purified indole N-H derivative
thus obtained in dichloromethane (2.0 mL) was added man-
ganese dioxide (800 mg) at room temperature, and the mixture
was stirred for 30 min. The reaction mixture was filtered and
concentrated in vacuo to give the crude products which were
purified by column chromatography on silica gel (gradually
from 3% to 9% methanol in chloroform) to afford (-)-30 (5.3
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
mg, 40% for two steps) as a yellow oil: [R]24 -3.8 (c 0.3,
D
CHCl3); IR (neat, cm-1) 3355, 1665, 1254, 1236, 1094; 1H NMR
(400 MHz, CDCl3) δ 2.25 (s, 3H), 2.28 (s, 3H), 2.45-2.51 (m,
1H), 2.55-2.59 (m, 2H), 3.07 (ddd, 1H, J ) 11.2, 4.4, 4.4 Hz),
J O049381F
J . Org. Chem, Vol. 69, No. 18, 2004 5925