Chiral Lewis Acid-Mediated Enantioselective Pictet-Spengler Reaction of Nb-Hydroxytryptamine with Aldehydes

Article abstract of DOI:10.1021/jo980810h

The first example of a reagent-controlled enantioselective Pictet-Spengler reaction is demonstrated. Using diisopinocampheylchloroborane as a chiral Lewis acid catalyst, the Pictet-Spengler reaction of N_b-hydroxytryptamine with aldehydes gave the corresponding 2-hydroxytetrahydro-β-carbolines in up to 90% ee. The enantioselective Pictet-Spengler reaction catalyzed by chiral binaphthol-derived Br?nsted acid-assisted Lewis acids, with up to 91% ee, is also demonstrated.

Full text of DOI:10.1021/jo980810h

6348
J . Org. Chem. 1998, 63, 6348-6354
Ch ir a l Lew is Acid -Med ia ted En a n tioselective P ictet-Sp en gler
Rea ction of Nb-Hyd r oxytr yp ta m in e w ith Ald eh yd es
Hideki Yamada,† Tomohiko Kawate,† Miyako Matsumizu,† Atsushi Nishida,†
Kentaro Yamaguchi,‡ and Masako Nakagawa*,†
Faculty of Pharmaceutical Sciences and Chemical Analytical Center, Chiba University,
1-33, Yayoi-cho, Inage-ku, Chiba-shi 263-8522, J apan
Received April 29, 1998
The first example of a reagent-controlled enantioselective Pictet-Spengler reaction is demonstrated.
Using diisopinocampheylchloroborane as a chiral Lewis acid catalyst, the Pictet-Spengler reaction
of Nb-hydroxytryptamine with aldehydes gave the corresponding 2-hydroxytetrahydro-â-carbolines
in up to 90% ee. The enantioselective Pictet-Spengler reaction catalyzed by chiral binaphthol-
derived Brønsted acid-assisted Lewis acids, with up to 91% ee, is also demonstrated.
In tr od u ction
group as a removable external mediator.5 In an inves-
tigation of the diastereoselective PS reaction, we found
that a chiral R-phenethyl auxiliary group attached to Nb
of tryptamine controlled the stereochemistry of the newly
formed C-1 stereogenic center in the acid-catalyzed
Pictet-Spengler reaction with up to 72% de.6 Despite
active investigation of the asymmetric PS reaction, to our
knowledge, no information is currently available on the
enantioselective PS reaction. In this paper, we report
the chiral Lewis acid-promoted enantioselective cycliza-
tion of nitrones to give optically active Nb-hydroxytet-
rahydro-â-carbolines.7
The Pictet-Spengler (PS) reaction is now established
as one of the most powerful methods for the construction
of both tetrahydro-â-carboline and tetrahydroisoquinoline
frameworks.1 Numerous naturally occurring indole and
isoquinoline alkaloids, with a wide range of important
biological and pharmaceutical properties, have been
synthesized by this method. Our interest in this area of
chemistry arose out of our earlier investigations of the
total syntheses of fumitremorgins2 and eudistomines.3
Since many indole alkaloids have a stereogenic center
at C-1 of the tetrahydro-â-carboline ring system, the
synthetic method for preparing this heterocyclic frame-
work in an enantiomerically pure form should be the
subject of widespread interest in both organic and
medicinal chemistry. Several stereoselective PS reac-
tions have been reported, in which optically active
tryptophan esters or chiral aldehydes are used as the
origin of chirality to yield optically active tetrahydro-â-
carbolines.4 Recently, Waldmann and co-workers re-
ported the diastereoselective PS reaction of achiral
imines, prepared from tryptamine and various aldehydes,
using chiral acyl chloride with a N,N-phthaloylamino
Resu lts a n d Discu ssion
We previously found that the PS reaction of Nb-
hydroxytryptamine with a chiral aldehyde such as L-
cysteinal produced the corresponding tetrahydro-â-
carboline in 97% yield with high stereoselectivity (98%
de),3f and nitrones have proven to be useful intermediates
for studying the stereoselective PS reaction. Nb-Hydroxy-
tryptamine was prepared by the reduction of 3-(2-
nitroethyl)indole. Nitrones 1-6, prepared from Nb-
hydroxytryptamine and corresponding aldehydes, were
stable and could be purified by either recrystallization
or column chromatography. Moreover, the nitrones were
confirmed to have the Z configuration by an X-ray
analysis of 7.3f A similar result was obtained by dif-
ferential NOE experiments of 1 between CHdN (δ 7.07)
and NCH2 (δ 4.18) in CDCl3, which reflected its Z
configuration.
† Faculty of Pharmaceutical Sciences.
‡ Chemical Analytical Center.
(1) (a) Whaley, W. M.; Govindachari, T. R. Organic Reactions; J ohn
Wiley & Sons: New York, 1951; Vol. 6, pp 151-190. (b) Cox, E. D.;
Cook, J . M. Chem. Rev. 1995, 95, 1797-1842.
(2) (a) Nakagawa, M.; Kodato, S.; Hongu, M.; Kawate, T.; Hino, T.
Tetrahedron Lett. 1986, 27, 6217-6220. (b) Kodato, S.; Nakagawa, M.;
Hongu, M.; Kawate, T.; Hino, T. Tetrahedron 1988, 44, 359-377. (c)
Hino, T.; Kawate, T.; Nakagawa, M. Tetrahedron 1989, 45, 1941-1944.
(d) Hino, T.; Nakagawa, M. Heterocycles 1997, 46, 673-704.
(3) (a) Nakagawa, M.; Liu, J .; Hino, T. J . Am. Chem. Soc. 1989, 111,
2721-2722. (b) Nakagawa, M.; Liu, J .; Ogata, K.; Hino, T. J . Chem.
Soc., Chem. Commun. 1988, 463-464. (c) Liu, J .; Nakagawa, M.; Hino,
T. Tetrahedron 1989, 45, 7729-7742. (d) Hino, T.; Hasegawa, A.; Liu,
J .; Nakagawa, M. Chem. Pharm. Bull. 1990, 38, 59-64. (e) Liu, J .;
Nakagawa, M.; Harada, N.; Tsuruoka, A.; Hasegawa, A.; Ma, J .; Hino,
T. Heterocycles 1990, 31, 229-232. (f) Liu, J .; Nakagawa, M.; Ogata,
K.; Hino, T. Chem. Pharm. Bull. 1991, 39, 1672-1676. (g) Hino, T.;
Nakagawa, M. J . Heterocycl. Chem. 1994, 31, 625-630.
The reaction of 1 in CH2Cl2 or CH3CN with an acid
such as TFA, AlCl3, Sn(OTf)2, GaCl3, SbCl3, or BF3‚OEt2
gave (()-9 in almost quantitative yield. However, nitrone
1 was less prone to the desired ring closure with the use
of other boron reagents such as (PhO)3B, (C6F5O)3B,
lithium or sodium cobalt-bis-dicarbollide, and ZnCl2. No
(5) (a) Waldman, H.; Schmidt, G.; Henke, H.; Burkard, M. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2402-2403. (b) Schmidt, G.; Waldman,
H.; Henke, H.; Burkard, M. Chem. Eur. J . 1996, 2, 1566-1571.
(6) (a) Than Soe; Kawate, T.; Fukui, N.; Hino, T.; Nakagawa, M.
Tetrahedron Lett. 1995, 36, 1857-1860. (b) Than Soe; Kawate, T.;
Fukui, N.; Hino, T.; Nakagawa, M. Heterocycles 1996, 42, 347-358.
(7) Part of this work has been published as a preliminary com-
munication: Kawate, T.; Yamada, H.; Than Soe; Nakagawa, M.
Tetrahedron: Asymmetry 1996, 7, 1249-1252.
(4) Recent reports: (a) Zhang, P.; Cook, J . M. Tetrahedron Lett. 1995,
36, 6999-7002 and references therein. (b) Waldmann, H.; Schmidt,
G. Tetrahedron 1994, 50, 11865-11884. (c) Bailey, P. D.; Moore, M.
H.; Morgan, K. M.; Smith, D. I.; Vernon, J . M. Tetrahedron Lett. 1994,
35, 3587-3588. (d) Melnyk, P.; Ducrot, P.; Thal, C. Tetrahedron 1993,
49, 8589-8596. (e) Piper, I. M.; MacLean, D. B.; Kvarnstro¨m, I.; Szarek,
W. A. Can. J . Chem. 1983, 61, 2721-2728.
S0022-3263(98)00810-X CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/20/1998

Pictet-Spengler Reaction of Nb-Hydroxytryptamine
J . Org. Chem., Vol. 63, No. 18, 1998 6349
Ta ble 1. P ictet-Sp en gler Rea ction of 1 w ith
Sch em e 1
Diisop in oca m p h eylh a lobor a n es
9
T
time
(h)
entry
Lewis acid
solvent (°C)
yield (%) % ee
1
2
3
4
5
6
7
8
9
(+)-Ipc2BCl
(+)-Ipc2BCl
(+)-Ipc2BCl
(+)-Ipc2BCl
(+)-Ipc2BCl
(-)-Ipc2BCl
(+)-Ipc2BCl
(+)-Ipc2BCl
(+)-Ipc2BCl
(+)-Ipc2BBr
CH2Cl2 rt
2
1
1
6
97
97
97
92
31
94
17
61
44
69
78
25 (S)
48 (S)
58 (S)
75 (S)
87 (S)
83 (R)
72 (S)
79 (S)
74 (S)
67 (S)
55 (S)
CH2Cl2
0
CH2Cl2 -20
CH2Cl2 -78
CH2Cl2 -98 12
CH2Cl2 -78
3.5
6
Et2O
THF
PhMe
-78
-78 48
-78
reaction was observed with Yb(OTf)3, Et2AlCl, or Et3Al.
The authentic racemic â-carbolines 9 and 15-19 were
prepared by the reaction with TFA in CH2Cl2, and HPLC
conditions were examined (see the Experimental Section).
9
10
11
CH2Cl2 -78 24
(+)-Ipc2BOTf CH2Cl2 -78 28
THF had little or no effect on enantioselectivity, while
the chemical yield of 9 varied from 17% to 92% (Table 1,
entries 4 and 7-9). Since replacement of the chlorine
atom of Ipc2BCl was expected to alter the Lewis acidity
of the boron, we next used (+)-Ipc2BBr or (+)-Ipc2BOTf.
However, no improvement was observed (Table 1, entries
10 and 11). Although the enantioselectivity was 85% ee,
the PS reaction of 1 gave only an 11% yield of (+)-9 with
0.5 equiv of (+)-Ipc2BCl (-78 °C, 4 days). The reaction
should proceed via an iminium ion intermediate 8, in
which the boron of Ipc2BCl is coordinated to the oxygen
of the nitrone. The stereochemical outcome can be
explained by assuming a transition state involving the
nucleophilic attack of indole to the CdN double bond from
the less hindered side (8 f 9). Preliminary calculations
for the cyclization of 8, from both the re- and si-faces of
the CdN bond attacked by the indole nucleus at the
2-position, were carried out using a semiempirical mo-
lecular orbital calculation (MOPAC, AM1),11 and the
results are shown in Figure 1. The transition-state
energy for a re-face approach (92.044 kcal/mol) to give
(S)-9 was less than that for a si-face approach (99.327
kcal/mol), which is consistent with experimental results.12
We next examined other chiral dialkylchloroboranes,
such as dialkylchloroboranes 11 and 12 prepared by
hydroboration of the corresponding chiral alkenes 1313
and 1414 with H2BCl‚SMe2,15 which were used without
purification. Compared to the reaction with (-)-Ipc2BCl,
Next, we examined the enantioselective reaction of
nitrone 1 with a chiral acid, (+)-diisopinocampheyl-
chloroborane ((+)-Ipc2BCl). When 1 was stirred in CH2-
Cl2 in the presence 1.9 molar equiv of (+)-Ipc2BCl at room
temperature for 2 h, 1 was smoothly cyclized to give (+)-9
in 97% yield after silica gel column chromatography. The
optical purity of (+)-9 was determined to be 25% ee (S)
by HPLC analysis using a chiral column (Daicel Chiral-
cel-OD). Encouraged by this result, we investigated the
effects of temperature and solvent on this reaction (Table
1). Enantioselectivity increased with a decrease in
reaction temperature. When the reaction was performed
at -78 °C, an appreciable increase in selectivity (75% ee)
was observed, while the chemical yield remained as high
as 92% (Table 1, entry 4). The highest enantioselectivity,
87% ee, was obtained at -98 °C, although cyclization
became sluggish (Table 1, entry 5). Treatment of 1 with
(-)-Ipc2BCl under the same protocol gave (-)-9 in 94%
yield with 83% ee (R) (Table 1, entry 6). The configura-
tion at the C-1 stereogenic center could be determined
by converting (-)-9 to optically active 10. Thus, (-)-9
(83% ee, Table 1, Entry 6) was refluxed with zinc in
MeOH-NH4OH in the presence of AcONH4 to give
optically active 10 in 80% yield. By comparing the
specific rotation of 10 ([R]20 +10.9 (c 0.53, EtOH)) with
D
that of authentic (S)-10 ([R]24 -16.4 (c 0.39, EtOH)),8
D
the absolute configuration of (-)-9 was determined to be
R.10 Other solvents such as CH2Cl2, Et2O, PhMe, and
(8) The authentic samples (S)-10, [R]24 -16.4 (c 0.39, EtOH), and
(11) The calculation was carried out using CAChe system Version
3.8, CAChe Scientific Inc., 1995.
D
(S)-21, [R]26 -55.4 (c 0.41, MeOH), were synthesized from L-tryp-
D
tophan methyl ester with benzaldehyde and isovaleraldehyde, respec-
tively, according to the synthesis of (S)-20 described in the literature.9
Details of these syntheses will be reported separately. The specific
rotation of (R)-10 is also reported in ref 4b, [R]24D +15.6 (c 0.38, EtOH).
(9) Akimoto, H.; Okamura, K.; Yui, M.; Shioiri, T.; Kuramoto, H.;
Kikugawa, Y.; Yamada, S. Chem. Pharm. Bull. 1974, 22, 2614-2623.
(12) A similar result was obtained from a semiempirical molecular
orbital calculation of the cyclization of 8 from both the re- and si-faces
of the CdN bond attacked by indole nuclei at the 3-position.
(13) Greenwald, R.; Chaykovsky, M.; Corey, E. J . J . Org. Chem.
1963, 28, 1128-1129.
(14) Dimmel, D. R.; Fu, W. Y. J . Org. Chem. 1973, 38, 3778-3782.
(15) King, A. O.; Corley, E. G.; Anderson, R. K.; Larsen, R. D.;
Verhoeven, T. R.; Reider, P. J .; Xiang, Y. B.; Belley, M.; Leblanc, Y.;
Lebelle, M.; Prasit, P.; Zamboni, R. J . J . Org. Chem. 1993, 58, 3731-
3735.
(S)-20, [R]24 -52 (c 2.0, EtOH).
D
(10) The calculated optical purity of 10 suggests partial racemization
during zinc reduction of 9. A reduction procedure without racemization
is being actively investigated.

6350 J . Org. Chem., Vol. 63, No. 18, 1998
Yamada et al.
F igu r e 1. Transition-state model for 1 with (+)-Ipc2BCl.
Sch em e 2
although the reaction of 1 catalyzed by 11 or 12 proceeded
quantitatively, it gave poor enantioselectivity (less than
5% ee).
lographic structure of optically pure (S)-15 indicated a
trans configuration for the substituent at the 1-position
and the hydroxy group at the 2-position (Figure 2).16
The cyclization of p-anisyl and 1-naphthyl nitrones 2
and 4 with (+)-Ipc2BCl gave 15 and 17 with high
enantioselectivity: 90 and 86% ee, respectively. No
enantioselectivity was observed in the reaction of nitrone
3, which has an electron-withdrawing nitro group, al-
though the reaction proceeded more rapidly and gave a
high yield. Nitrones 5 and 6, which have an aliphatic
substituent, gave â-carbolines 18 and 19 in high yields
but with modest enantioselectivity. The absolute con-
figuration of these hydroxy-â-carbolines 15 and 17-19
were determined by chemical correlation and spectro-
scopic methods. Hydrogenolysis of 18 and 19 was carried
out to give the corresponding â-carbolines 20 and 21 in
yields of 93 and 57%, respectively (Scheme 2).
F igu r e 2. Crystal structure of (S)-15.
Next, we turned to the newly available Brønsted acid-
assisted Lewis acids (BLAs) that were introduced by
Yamamoto and co-workers for enantioselective PS reac-
tions. The BLAs (R)-24, (S)-24, and (R)-25 were prepared
by mixing 2 equiv of optically active 2,2′-binaphthol, (R)-
Comparison of the specific rotations of 20 and 21 with
those of authentic specimens8,9 showed that the absolute
configurations of both 20 and 21 were S. On the other
hand, the stereochemistries of 15 and 17 were deduced
to be S by comparison of the CD spectra of 15 and 17
with those of (S)- and (R)-9.
(16) Crystallographic data for (S)-15: C18H18N2O2, Mw 294.35,
orthorhombic crystal of dimensions 0.40 × 0.08 × 0.40 mm3 (space
group P212121), with unit cell a ) 8.174(2) Å, b ) 29.537(3) Å, c )
6.235(2) Å, V ) 1505.3(6) Å3, Z ) 4, Dcalcd ) 1.299 g cm-3, F000 ) 624.00.
Lattice constants and intensity data were measured using graphite-
monochromated Cu KR (λ ) 1.5418 Å) radiation on a Rigaku AFC5S
diffractometer. A total of 1638 unique reflections were obtained using
the ω-2θ scanning method with a 2θ speed of 32° min-1 to 0 < 2θ <
135.2°. The structure was solved by a direct method using SIR92 and
refined to a final R value of 0.048 and Rw ) 0.055.
The enantiomeric enrichment of â-carbolines was
achieved by simple recrystallization. The X-ray crystal-

Pictet-Spengler Reaction of Nb-Hydroxytryptamine
J . Org. Chem., Vol. 63, No. 18, 1998 6351
Ta ble 2. P ictet-Sp en gler Rea ction of Nitr on es
Ca ta lyzed by (+)-Ip c2BCl
â-carboline
entry
nitrone
time (h)
yield (%)
% ee
1
2
3
4
5
6
1
2
3
4
5
6
6
3
1
1
3
4
9 (92)
15 (65)
16 (81)
17 (94)
18 (91)
19 (75)
75 (S)
90 (S)
0.6
86 (S)
43 (S)
35 (S)
Ta ble 3. P ictet-Sp en gler Rea ction of Nitr on es
Ca ta lyzed by Br øn sted Acid -Assisted Lew is Acid s
F igu r e 3. Transition-state model for asymmetric cyclization
using BLA.
6- and 6′-positions of binaphthol had little effect on either
the chemical yield or enantioselectivity (Table 3, entry
8). In all of the reactions, binaphthol was recovered in
70-80% yield.
results
Lewis
acid
recovery of
nitrone (%)
entry
nitrone
yield (%)
% eea
1
2
3
4
5
6
7
8
1
2
3
4
5
6
1
1
(R)-24
(R)-24
(R)-24
(R)-24
(R)-24
(R)-24
(S)-24
(R)-25
9 (81)
15 (39)
16 (75)
17 (59)
18 (94)
19 (68)
9 (82)
73 (S)
91 (S)
74 (S)
31 (S)
15 (R)
50 (S)
78 (R)
77 (S)
18
44
8
26
14
7
9 (84)
The stereochemical outcome can be explained by as-
suming a model in which the oxygen of nitrone is
coordinated to the boron of BLA, as shown in Figure 3.
Transition state A, which shows a si-face approach of
indole nuclei to the CdN double bond, would be preferred
over transition state B due to steric hindrance between
the indole ring of the nitrone and the naphthyl ring of
the Lewis acid in transition state B.
In summary, a reagent-controlled enantioselective PS
reaction was developed in the reaction of nitrones,
prepared from Nb-hydroxytryptamine with various alde-
hydes, catalyzed by diisopinocampheylchloroborane and
binaphthol-based Brønsted acid-assisted Lewis acid. The
availability of both enantiomers of diisopinocampheyl-
chloroborane as well as binaphthol is an advantage of
our findings, and we hope theses results will provide a
new strategy for the synthesis of optically active â-car-
boline alkaloids. Application of these results to natural
product synthesis and further improvement of the enan-
tioselectivity is in progress.
a
Enantiomeric excess and absolute configuration were deter-
mined by HPLC using a chiral column (Daicel, Chiralcel-OD).
22, (S)-22, and (R)-23, respectively, with (PhO)3B follow-
ing Yamamoto’s procedure.17 The PS reactions of ni-
trones 1-6 were performed with (R)-24, (S)-24, and (R)-
25 in CH2Cl2 at room temperature for 48 h under an
argon atmosphere. Thus, 1 was treated with 2 equiv of
(R)-24 to give (S)-9 in 81% yield with 73% ee (Table 3,
entry 1). (R)-9 was obtained with (S)-24 in similar
selectivity (Table 3, entry 7). These conditions were also
useful for the enantioselective cyclization of 2 and gave
enantioselectivity of up to 91% ee (Table 3, entry 2). In
particular, the enantioselectivity for the reaction of 3 was
greatly improved compared with that using (+)-Ipc2BCl,
which did not show any selectivity (Table 3, entry 3 vs
Table 2, entry 3).18 The introduction of bromine at the
(17) Ishihara, K.; Miyata, M.; Hattori, K.; Toda, T.; Yamamoto, H.
J . Am. Chem. Soc. 1994, 116, 10520-10524.
(18) 16 (74% ee) was treated with (+)-Ipc2BCl under these reaction
conditions in CH2Cl2 for 1 h. After quenching followed by silica gel
column chromatography, 16 was recovered in 94% yield with 73% ee.
This indicates that 16 did not undergo racemization by (+)-Ipc2BCl
during the PS reaction of 3 with (+)-Ipc2BCl.
Exp er im en ta l Section
Syn th esis of Nitr on es. Syn th esis of N-Ben zylid en e-
N-[2-(3-in d olyl)eth yl]a m in e Oxid e (1) (Typ ica l P r oce-

6352 J . Org. Chem., Vol. 63, No. 18, 1998
Yamada et al.
d u r e). Zinc powder (8.0 g, 122.3 mmol) was added to a stirred
solution of 3-(2-nitroethyl)indole (4.0 g, 21.3 mmol) and NH4-
Cl (2.3 g, 42.9 mmol) in THF (100 mL)-H2O (40 mL) at room
temperature over a period of 10 min. After being stirred at
room temperature for 1.3 h, the mixture was filtered through
a Celite pad. The organic layer was separated, washed with
brine (40 mL), and dried over Na2SO4. Evaporation of the
solvent gave crude hydroxytryptamine as a yellow solid, which
was used for the next reaction without further purification.
Benzaldehyde (3.2 mL, 31.4 mmol) was added to a stirred
solution of the hydroxytryptamine (21.3 mmol) in dry THF (40
mL) at room temperature over a period of 5 min under an
argon atmosphere. The whole was stirred at room tempera-
ture for 3 h and then concentrated. The resulting brown oil
was chromatographed on silica gel with AcOEt/n-hexane
(1/1-4/1) to give 1 as a yellow solid. Recrystallization from
benzene gave nitrone 1 (3.4 g, 61% yield) as yellow prisms:
mp 128-129 °C (benzene). This compound was spectroscopi-
cally identical to the authentic sample.3d
perature for 2 h, and the reaction was quenched with saturated
NaHCO3 (10 mL) at 0 °C. The mixture was diluted with CHCl3
(10 mL), and the organic layer was separated, washed with
brine (10 mL), and dried over Na2SO4. Evaporation of the
solvent gave a yellow solid, which was recrystallized from
AcOEt/n-hexane to give the hydroxytetrahydro-â-carboline (()-
17 (130.7 mg, 76% yield) as colorless prisms: mp 160.0-161.0
°C (AcOEt/n-hexane); HPLC (eluent; n-hexane/2-propanol )
1
90/10, flow rate 1.0 mL/min) tR (min) 25.06 (S), 30.75 (R); H
NMR (CDCl3) δ 3.02 (d, J ) 5.1 Hz, 1H), 3.17 (brs, 1H), 3.30
(m, 1H), 3.61 (brs, 1H), 5.36 (m, 2H), 7.07-7.21 (m, 3H), 7.24
(m, 1H), 7.43-7.54 (m, 5H), 7.88 (m, 2H), 8.22 (brs, 1H); 13C
NMR (DMSO-d6) δ 19.25, 79.19, 106.86, 111.19, 117.68, 118.33,
120.50, 125.21, 125.38, 125.53, 126.25, 128.24, 131.97, 133.78,
136.14, 136.53; LREIMS m/z 314 (M+). Anal. Calcd for
C
21H18N2O: C, 80.23; H, 5.77; N, 8.91. Found: C, 80.09; H,
6.07; N, 8.60.
(()-2-H yd r oxy-1-p h e n yl-1,2,3,4-t e t r a h yd r o-â-ca r b o-
lin e ((()-9): yield 83% (rt, 2 h). This compound was spectro-
scopically identical to the authentic sample:3d HPLC (eluent;
n-hexane/2-propanol ) 90/10, flow rate 1.0 mL/min) tR (min)
12.48 (S), 22.60 (R).
N -(4-Me t h o x y b e n zy lid e n e )-N -[2-(3-in d o ly l)e t h y l]-
a m in e oxid e (2): yield 69% (rt, 0.5 h); colorless needles; mp
157.5-158.0 °C (AcOEt/n-hexane); 1H NMR (CDCl3) δ 3.47 (t,
J ) 6.8 Hz, 2H), 3.84 (s, 3H), 4.15 (t, J ) 6.8 Hz, 2H), 6.90 (dt,
J ) 2.4, 9.9 Hz, 2H), 7.01 (s, 1H), 7.03 (d, J ) 2.2 Hz, 1H),
7.13 (ddd, J ) 0.9, 7.0, 7.9 Hz, 1H), 7.20 (ddd, J ) 1.2, 7.0, 8.2
Hz, 1H), 7.36 (d, J ) 8.2 Hz, 1H), 7.64 (d, J ) 8.1 Hz, 1H),
8.05 (brs, 1H), 8.14 (dt, J ) 2.3, 9.4 Hz, 2H); 13C NMR (CDCl3)
δ 23.71, 55.26, 67.09, 111.30, 111.36, 113.73, 118.28, 119.34,
121.95, 122.96, 123.28, 126.86, 130.52, 134.52, 136.26, 160.94;
LRFABMS m/z 295 (M+ + H). Anal. Calcd for C18H18N2O2:
C, 73.45; H, 6.16; N, 9.52. Found: C, 73.60; H, 6.09; N, 9.54.
N-(4-Nitr oben zyliden e)-N-[2-(3-in dolyl)eth yl]am in e ox-
id e (3): yield 68% (rt, 0.5 h); orange prisms; mp 196.0-197.0
(()-2-Hydr oxy-1-(4-m eth oxyph en yl)-1,2,3,4-tetr ah ydr o-
â-ca r bolin e ((()-15): yield 54% (rt, 1 h); colorless prisms; mp
202.0-203.0 °C (AcOEt/n-hexane); HPLC (eluent; n-hexane/
2-propanol/Et2NH ) 800/200/0.1, flow rate 0.5 mL/min) tR
(min) 21.46 (S), 38.27 (R); 1H NMR (CDCl3) δ 2.93 (m, 1H),
3.08 (m, 1H), 3.21 (m, 1H), 3.52 (m, 1H), 3.80 (s, 3H), 4.82
(brs, 1H), 6.10 (brs, 1H), 6.88 (m, 2H), 7.07-7.14 (m, 2H), 7.17
(m, 1H), 7.23 (m, 2H), 7.32 (brs, 1H), 7.50 (m, 1H); 13C NMR
(DMSO-d6) δ 20.03, 54.70, 55.07, 68.43, 106.76, 111.24, 113.37,
117.64, 118.34, 120.52, 126.12, 130.49, 133.02, 134.48, 136.67,
158.69; LRFABMS m/z 295 (M+ + H). Anal. Calcd for
1
°C (AcOEt/n-hexane); H NMR (CDCl3) δ 3.49 (t, J ) 6.4 Hz,
C18H18N2O2: C, 73.45; H, 6.16; N, 9.52. Found: C, 73.17; H,
6.08; N, 9.39.
2H), 4.25 (t, J ) 6.7 Hz, 2H), 7.04 (d, J ) 2.2 Hz, 1H), 7.12
(ddd, J ) 0.9, 7.0, 7.9 Hz, 1H), 7.16 (s, 1H), 7.21 (ddd, J ) 1.2,
7.0, 8.2 Hz, 1H), 7.37 (d, J ) 8.1 Hz, 1H), 7.62 (d, J ) 8.0 Hz,
1H), 8.00 (brs, 1H), 8.21 (dt, J ) 2.0, 9.1 Hz, 2H), 8.27 (dt, J
) 2.0, 8.9 Hz, 2H); 13C NMR (DMSO-d6) δ 23.44, 67.42, 110.11,
110.37, 118.20, 118.36, 121.04, 123.15, 123.70, 127.00, 128.47,
132.43, 136.10, 136.75, 146.84; LRFABMS m/z 310 (M+ + H).
Anal. Calcd for C17H15N3O3: C, 66.01; H, 4.89; N, 13.59.
Found: C, 66.06; H, 4.73; N, 13.71.
(()-2-Hyd r oxy-1-(4-n itr op h en yl)-1,2,3,4-tetr a h yd r o-â-
ca r bolin e ((()-16): yield 45% (rt, 3 h); colorless prisms; mp
184.0-185.0 °C (AcOEt/n-hexane); HPLC (eluent; n-hexane/
2-propanol/Et2NH ) 800/200/0.1, flow rate 1.0 mL/min) tR
1
(min) 11.28 (S), 25.59 (R); H NMR (CD3OD) δ 2.92 (m, 1H),
3.09 (m, 1H), 3.20 (m, 1H), 3.56 (m, 1H), 4.99 (brs, 1H), 6.98
(dt, J ) 1.2, 7.3 Hz, 1H), 7.02 (dt, J ) 1.4, 7.5 Hz, 1H), 7.17
(d, J ) 8.1 Hz, 1H), 7.43 (d, J ) 7.9 Hz, 1H), 7.61 (dt, J ) 2.2,
9.3 Hz, 2H), 8.23 (dt, J ) 2.2, 9.0 Hz, 2H); 13C NMR (DMSO-
d6) δ 20.34, 55.42, 59.75, 68.53, 107.14, 111.28, 117.86, 118.57,
120.90, 123.17, 125.88, 130.69, 133.11, 136.85, 146.99, 148.90;
LRFABMS m/z 310 (M+ + H). Anal. Calcd for C17H15N3O3:
C, 66.01; H, 4.89; N, 13.59. Found: C, 65.86; H, 4.71; N, 13.69.
(()-2-H yd r oxy-1-m e t h yl-1,2,3,4-t e t r a h yd r o-â-ca r b o-
lin e ((()-18): yield 54% (rt, 0.5 h); colorless prisms; mp 191.0-
192.0 °C (AcOEt/n-hexane); HPLC (eluent; n-hexane/2-pro-
panol ) 95/5, flow rate 1.2 mL/min) tR (min) 52.67 (S), 61.42
(R); 1H NMR (CDCl3) δ 1.58 (d, J ) 6.6 Hz, 3H), 2.88 (m, 2H),
3.17 (m, 1H), 3.58 (m, 1H), 3.98 (m, 1H), 6.30 (brs, 1H), 7.10
(t, J ) 7.3 Hz, 1H), 7.16 (t, J ) 7.1 Hz, 1H), 7.31 (d, J ) 8.1
Hz, 1H), 7.46 (d, J ) 7.6 Hz, 1H), 7.71 (brs, 1H); 13C NMR
(DMSO-d6) δ 18.01, 20.23, 55.43, 59.91, 105.63, 110.94, 117.50,
118.31, 120.33, 126.25, 136.01, 136.31; LRFABMS m/z 203 (M+
+ H). Anal. Calcd for C12H14N2O: C, 71.26; H, 6.98; N, 13.85.
Found: C, 70.97; H, 7.03; N, 13.63.
N-[(1-Na p h t h yl)m et h ylid en e]-N-[2-(3-in d olyl)et h yl]-
a m in e oxid e (4): yield 72% (rt, 1.7 h); colorless prisms; mp
156.0-156.5 °C (benzene); 1H NMR (CDCl3) δ 3.50 (t, J ) 6.6
Hz, 2H), 4.34 (t, J ) 6.6 Hz, 2H), 6.98 (d, J ) 2.1 Hz, 1H),
7.16-7.26 (m, 3H), 7.31-7.45 (m, 3H), 7.52 (t, J ) 8.0 Hz, 1H),
7.64 (s, 1H), 7.69-7.85 (m, 3H), 8.07 (brs, 1H), 9.39 (d, J )
9.5 Hz, 1H); 13C NMR (DMSO-d6) δ 23.66, 67.15, 110.42,
111.37, 118.37, 118.41, 121.02, 122.64, 123.19, 125.33, 125.43,
125.93, 126.23, 126.59, 127.09, 128.79, 129.60, 130.02, 130.13,
133.04, 136.18; LREIMS m/z 314 (M+). Anal. Calcd for
C
21H18N2O: C, 80.23; H, 5.77; N, 8.91. Found: C, 80.13; H,
5.75; N, 8.66.
N-Eth ylid en e-N-[2-(3-in d olyl)eth yl]a m in e oxid e (5):
yield 96% (rt, 0.1 h); brown amorphous solid; 1H NMR (CDCl3)
δ 1.90 (d, J ) 5.8 Hz, 3H), 3.39 (t, J ) 6.7 Hz, 2H), 4.03 (t, J
) 6.7 Hz, 2H), 6.46 (q, J ) 5.8 Hz, 1H), 7.05 (d, J ) 2.4 Hz,
1H), 7.13 (ddd, J ) 1.1, 7.1, 8.2 Hz, 1H), 7.21 (ddd, J ) 1.3,
7.0, 8.3 Hz, 1H), 7.38 (dd, J ) 1.0, 8.0 Hz, 1H), 7.61 (d, J )
8.0 Hz, 1H), 8.25 (brs, 1H); 13C NMR (CDCl3) δ 12.47, 23.38,
65.64, 110.57, 111.42, 118.00, 118.96, 121.62, 122.96, 126.76,
135.95, 136.27; LRFABMS m/z 203 (M+ + H); HRFABMS calcd
for C12H14N2O + H 203.1184, found 203.1189.
(()-2-H yd r oxy-1-isob u t yl-1,2,3,4-t et r a h yd r o-â-ca r b o-
lin e ((()-19): yield 89% (rt, 0.4 h). This product was spec-
troscopically identical to the authentic sample:3d HPLC (eluent;
n-hexane/2-propanol ) 95/5, flow rate 1.0 mL/min) tR (min)
32.27 (S), 66.54 (R).
N-(3-Meth ylbu tyliden e)-N-[2-(3-in dolyl)eth yl]am in e ox-
id e (6): yield 86% (rt, 0.4 h); brown oil. This compound was
spectroscopically identical to the authentic sample.3d
Syn th esis of (()-2-Hyd r oxy-1-su bstitu ted -1,2,3,4-tet-
r a h yd r o-â-ca r bolin es. Syn th esis of (()-2-Hyd r oxy-1-(1-
n a p h th yl)-1,2,3,4-tetr a h yd r o-â-ca r bolin e ((()-17) (Typ i-
ca l P r oced u r e). Trifluoroacetic acid (0.12 mL, 1.5 mmol) was
added dropwise to a stirred solution of nitrone 4 (171.9 mg,
0.54 mmol) in CH2Cl2 (10 mL) at 0 °C under an argon
atmosphere. The reaction mixture was stirred at room tem-
Asym m etr ic P ictet-Sp en gler Rea ction of Nitr on es
w it h Diisop in oca m p h eylch lor ob or a n e. Syn t h esis of
2-H yd r oxy-1-p h en yl-1,2,3,4-t et r a h yd r o-â-ca r b olin e (9)
(Typ ica l P r oced u r e: Ta ble 1, En tr y 4). A solution of (+)-
Ipc2BCl (259.4 mg, 0.8 mmol) in dry CH2Cl2 (10 mL) was added
dropwise to a stirred solution of nitrone 1 (110.5 mg, 0.41
mmol) in dry CH2Cl2 (10 mL) at -78 °C under an argon
atmosphere over a period of 10 min. The reaction mixture was
stirred at -78 °C for 6 h, and the reaction was then quenched
with saturated NaHCO3 (10 mL). The mixture was diluted

Pictet-Spengler Reaction of Nb-Hydroxytryptamine
J . Org. Chem., Vol. 63, No. 18, 1998 6353
with CHCl3 (10 mL), and the organic layer was separated,
washed with brine (10 mL), and dried over Na2SO4. After
removal of the solvent, the resulting yellow oil was subjected
to column chromatography on silica gel with AcOEt/n-hexane
(1/8-1/2). Eluted product was further purified with silica gel
preparative TLC with Et2O/CHCl3 (1/2) to give 9 (101.1 mg,
92% yield) as a colorless solid. The enantiomeric excess of this
compound was determined to be 75% ee (S) by HPLC analysis.
This product was spectroscopically identical to racemic 9.
Recrystallization from AcOEt/n-hexane gave (S)-9 (100% ee)
as colorless prisms. Optically pure (S)-9: mp 191.5-192.5 °C
209.7 (0), 214.2 (-1.52), 221.6 (0), 230.0 (1.14), 239.5 (0), 253.0
(-0.19), 259.0 (0), 263.6 (0.18), 279.2 (0.13) nm.
2-Hydr oxy-1-isobu tyl-1,2,3,4-tetr ah ydr o-â-car bolin e (19):
yield 75%, 35% ee (S) (with (+)-Ipc2BCl, -78 °C, 4 h), 68%,
50% ee (S) (with (R)-24). This product was spectroscopically
identical to racemic 19: CD (25% ee (R), MeOH, 2.86 × 10-4
M, 25 °C, 0.2 cm) λ (∆ꢀ) 212.8 (1.35), 217.9 (0), 224.8 (-2.63),
229.1 (0), 235.6 (4.06), 258.8 (0), 272.8 (-0.35), 277.5 (-0.26),
284.8 (-0.37), 291.6 (-0.26) nm.
P r ep a r a tion of Ch ir a l Dia lk ylch lor obor a n es. P r ep a -
r a t ion of 11 (Typ ica l p r oced u r e).15 Monochloroborane-
dimethyl sulfide complex (0.10 mL, 0.96 mmol) was added
dropwise to a stirred solution of 13 (331 mg, 2.20 mmol) in
dry n-hexane (0.25 mL) at -10 °C under an argon atmosphere.
After being stirred at 30 °C for 3 h, the resulting mixture was
used as 11 (0.96 mmol) without further purification.
(AcOEt/n-hexane); [R]25 +49.5 (c 0.25, CHCl3); CD (91% ee
D
(S), MeOH, 4.1 × 10-4 M, 28 °C, 0.2 cm) λ (∆ꢀ) 206.6 (7.89),
215.8 (0), 227.8 (-12.41), 252.9 (0), 272.0 (2.68), 286.0 (1.85),
292.1 (1.16), 295.4 (1.29) nm; CD (83% ee (R), prepared in
Table 1, entry 6, MeOH, 1.13 × 10-4 M, 26 °C, 0.1 cm) λ (∆ꢀ)
205.4 (-17.20), 215.1 (0), 227.6 (29.62), 254.4 (0), 270.6 (-5.48),
288.0 (-3.26), 292.1 (-1.99), 296.2 (-2.60) nm.
Syn t h esis of 1-P h en yl-1,2,3,4-t et r a h yd r o-â-ca r b olin e
(10). A mixture of 9 (70.1 mg, 0.26 mmol, 83% ee (R)) and
AcONH4 (50.0 mg) in aqueous 28% ammonia (2 mL), methanol
(10 mL), and H2O (5 mL) was heated at reflux temperature.
Zinc powder (300.0 mg) was added to the refluxing mixture,
and the mixture was refluxed for 0.5 h. Zinc powder (300.0
mg) was added to the reaction mixture, and the whole was
refluxed for an additional 3.5 h. The mixture was filtered
through a Celite pad, and the filtrate was concentrated in
vacuo. The residue was diluted with AcOEt (20 mL), and 3 N
sodium hydroxide was added (∼pH 10). The organic layer was
separated, washed with brine (10 mL), and dried over Na2-
SO4. Evaporation of the solvent gave a colorless solid, which
was chromatographed on silica gel with AcOEt/n-hexane (1/
1)-AcOEt to give the tetrahydro-â-carboline 10 (52.5 mg, 80%)
as a colorless solid. This product was spectroscopically identi-
cal to known 10.3d,19 The enantiomeric excess of this compound
was determined by measuring the optical rotation, which
Asym m etr ic P ictet-Sp en gler Rea ction of Nitr on es
w ith Ch ir a l Br øn sted Acid -Assisted Lew is Acid . Syn -
th esis of 2-Hyd r oxy-1-p h en yl-1,2,3,4-tetr a h yd r o-â-ca r -
bolin e (9) (Typ ica l P r oced u r e: Ta ble 3, En tr y 7).
A
solution of (PhO)3B (232.4 mg, 0.8 mmol) in dry CH2Cl2 (5 mL)
was added to a stirred suspension of (S)-22 (458.4 mg, 1.6
mmol) and powdered MS-4A (2.0 g) in dry CH2Cl2 (15 mL) at
room temperature under an argon atmosphere. The reaction
mixture was stirred at room temperature for 1 h, and the
resulting suspension was used as Brønsted acid-assisted chiral
Lewis acid (S)-24 (0.8 mmol). A solution of nitrone 1 (104.3
mg, 0.39 mmol) in dry CH2Cl2 (10 mL) was added to a stirred
suspension of Brønsted acid-assisted chiral Lewis acid (S)-24
(0.8 mmol) and the mixture was stirred at room temperature
for 48 h. The mixture was filtered through a Celite pad, and
the filtrate was washed with saturated NaHCO3 (10 mL) and
brine (10 mL) and dried over Na2SO4. Evaporation of the
solvent gave a yellow solid, which was chromatographed on
silica gel with AcOEt/n-hexane (1/6-1/2-1/0) to give the
hydroxytetrahydro-â-carboline 9 (85.7 mg, 82%) as a colorless
solid. This product was spectroscopically identical to racemic
9. Binaphthol (S)-22 (436.0 mg) and nitrone 1 (6.8 mg, 7%)
were recovered. The enantiomeric excess of 9 (78% ee, R) was
determined by a chiral HPLC analysis.
indicated 66% ee (R). Compound 10: [R]20 +10.9 (c 0.53,
D
EtOH), 66% ee (R); CD (66% ee (R), MeOH, 2.82 × 10-4 M, 25
°C, 0.2 cm) λ (∆ꢀ) 205.0 (-9.88), 213.6 (0), 229.2 (18.08), 253.6
(0), 271.6 (-4.84), 286.6 (-3.17), 292.2 (-1.40), 296.4 (-2.35)
nm; CD (43% ee (S), MeOH, 2.82 × 10-4 M, 25 °C, 0.2 cm) λ
(∆ꢀ) 206.8 (11.80), 215.1 (0), 229.0 (-18.90), 252,9 (0), 271.0
(4.15), 286.4 (3.15), 292.1 (1.89), 295.4 (2.28) nm.
Hyd r ogen olysis of 2-Hyd r oxytetr a h yd r o-â-ca r bolin e.
Syn th esis of 1-Meth yl-1,2,3,4-tetr a h yd r o-â-ca r bolin e (20)
(Typ ica l P r oced u r e). A mixture of 18 (54 mg, 0.26 mmol,
43% ee (S)) and 20% Pd(OH)2 on carbon (16 mg) in methanol
(5 mL) was stirred under a hydrogen atmosphere at room
temperature for 24 h. The catalyst was filtered through a
Celite pad, and the pad was washed with AcOEt. The
combined filtrate was concentrated under reduced pressure
to give a residue, which was chromatographed on silica gel
with AcOEt-AcOEt/methanol/Et3N (20:2:1) to give 20 (46 mg,
93% yield) as a yellow solid. This product was spectroscopi-
cally identical to known 20.19 The enantiomeric excess of 20
was determined by measuring the optical rotation, which
2-Hyd r oxy-1-(4-m eth oxyp h en yl)-1,2,3,4-tetr a h yd r o-â-
ca r bolin e (15): yield 65%, 90% ee (S) (with (+)-Ipc2BCl, -78
°C, 3 h), 39%, 91% ee (S) (with (R)-24). This product was
spectroscopically identical to racemic 15. After removal of
racemic crystals by crystallization of 15 (80% ee) from AcOEt
as the first and second crop, enantiomerically pure 15 was
obtained from the third crop and its mother liquor. Recrys-
tallization from AcOEt gave (S)-15 (100% ee) as colorless
prisms: mp 186.0-186.5 °C (AcOEt); [R]27.5 +33.6 (c 1.04,
D
THF) for 100% ee (S); CD (100% ee (S), MeOH, 1.7 × 10-4 M,
26 °C, 0.1 cm) λ (∆ꢀ) 209.6 (22.42), 220.4 (44.02), 225.1 (0),
233.2 (-116.88), 252.3 (0), 285.2 (12.49), 295.4 (6.72) nm.
indicated 26% ee (S). Compound 20: [R]24 -13.6 (c 0.46,
D
2-Hyd r oxy-1-(4-n itr op h en yl)-1,2,3,4-tetr a h yd r o-â-ca r -
bolin e (16): yield 81%, 0.6% ee (with (+)-Ipc2BCl, -78 °C, 1
h), 75%, 74% ee (S) (with (R)-24). This product was spectro-
scopically identical to racemic 16: CD (71% ee (S), MeOH, 3.2
× 10-4 M, 22 °C, 0.2 cm) λ (∆ꢀ) 205.2 (3.00), 210.2 (0), 217.4
(-4.77), 220.1 (0), 227.6 (15.04), 239.4 (-7.27), 252.8 (-7.52),
268.5 (0), 281.8 (5.80), 301.0 (0), 309.8 (-0.69) nm.
EtOH), 26% ee (S); CD (50% ee (S), MeOH, 4.29 × 10-4 M, 25
°C, 0.2 cm) λ (∆ꢀ) 210.2 (-4.56), 212.6 (-4.35), 217.0 (-5.33),
219.4 (0), 232.6 (5.85), 243.2 (0), 246.6 (-0.13), 253.6 (0), 261.6
(0.31), 291.2 (0), 296.2 (0.25) nm.
1-Isobu tyl-1,2,3,4-tetr ah ydr o-â-car bolin e (21): yield 57%,
30% ee (S) from 18 of 34% ee (S) (rt, 38 h); [R]20 -16.6 (c
D
1
0.96, MeOH), 30% ee (S); H NMR (CDCl3) δ 1.00 (d, J ) 6.6
2-Hyd r oxy-1-(1-n a p h t h yl)-1,2,3,4-t et r a h yd r o-â-ca r b o-
lin e (17): yield 94%, 86% ee (S) (with (+)-Ipc2BCl, -78 °C, 1
h), 59%, 31% ee (S) (with (R)-24). This product was spectro-
scopically identical to racemic 17: [R]23D +62.6 (c 1.20, CHCl3)
for 86% ee (S); CD (86% ee (S), MeOH, 2.86 × 10-4 M, 20 °C,
0.1 cm) λ (∆ꢀ) 213.4 (7.01), 210.6 (0), 224.8 (-11.95), 227.9 (0),
230.8 (7.26), 233.2 (0), 236.6 (-2.87), 242,4 (-1.58), 245.3
(-1.70), 267.9 (0), 283.0 (2.14), 292.1 (0.92), 297.2 (1.44) nm.
2-Hydr oxy-1-m eth yl-1,2,3,4-tetr ah ydr o-â-car bolin e (18):
yield 91%, 43% ee (S) (with (+)-Ipc2BCl, -78 °C, 3 h), 94%,
15% ee (R) (with (R)-24). This product was spectroscopically
identical to racemic 18: CD (15% ee (R), MeOH, 1.98 × 10-4
M, 25 °C, 0.2 cm) λ (∆ꢀ) 202.2 (-1.54), 207.5 (0), 209.0 (0.07),
Hz, 3H), 1.03 (d, J ) 6.4 Hz, 3H), 1.62 (m, 2H), 1.87-2.04 (m,
2H), 2.74 (m, 2H), 3.03 (ddd, J ) 5.4, 7.9, 13.3 Hz, 1H), 3.35
(dt, J ) 4.6, 12.9 Hz, 1H), 4.11 (m, 1H), 7.09 (ddd, J ) 1.1,
6.1, 8.3 Hz, 1H), 7.14 (ddd, J ) 1.2, 7.6, 8.8 Hz, 1H), 7.30 (d,
J ) 7.9 Hz, 1H), 7.48 (d, J ) 7.6 Hz, 1H), 7.73 (brs, 1H);
LREIMS m/z 228 (M+); CD (30% ee (S), MeOH, 4.38 × 10-4
M, 25 °C, 0.2 cm) λ (∆ꢀ) 203.0 (-1.39), 205.2 (-1.09), 213.4
(-1.81), 215.6 (-1.52), 219.4 (-2.05), 226.8 (0), 231.2 (1.04),
241.7 (0), 245.4 (-0.11), 255.1 (0), 275.4 (0.22), 290.1 (0.05),
296.2 (0.17) nm.
(19) Nakagawa, M.; Kawate, T.; Kakikawa, T.; Yamada, H.; Matsui,
T.; Hino, T. Tetrahedron 1993, 49, 1739-1748.

6354 J . Org. Chem., Vol. 63, No. 18, 1998
Yamada et al.
Su p p or tin g In for m a tion Ava ila ble: Copies of the 1H
NMR spectra of compounds 1-6, 9, 10, and 15-21, copy of
the 13C NMR spectrum of 5, IR and UV data for compounds
2-5, (()-15-18, and 21, and X-ray material for (S)-15 (26
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
Ack n ow led gm en t. This study was supported in
part by a Grant-in-Aid for Scientific Research from the
Ministry of Science, Education, Sports and Culture.
Financial support from the Research Foundation of
Optically Active Compounds, J apan Tabacco, Inc., and
Toso Co., Inc., is gratefully acknowledged. The authors
thank Dr. Hiroko Seki and Ms. Ritsuko Hara of the
Chemical Analytical Center of Chiba University for
performing the microanalyses and measuring mass
spectra.
J O980810H