A synthesis of chiral 1,1,3-trisubstituted 1,2,3,4-tetrahydro-β- carbolines by the Pictet-Spengler reaction of tryptophan and ketones: Conversion of (1R,3S)-diastereomers into their (1S,3S)-counterparts by scission of the C(1)-N(2) bond

Article abstract of DOI:10.1248/cpb.51.1368

The Pictet-Spengler cyclization of the imines (3) prepared by the condensation of L-tryptophan methyl ester (1) and aryl methyl ketones (2), using titanium(IV) isopropoxide as an iminating reagent, quantitatively proceeded, when treated with trifluoroacetic acid (TFA) or formic acid, to provide two diastereomers, that is (1S,3S)-1-aryl-3-isopropoxycarbonyl-1-methyl-1,2,3,4- tetrahydro-β-carbolines (4) and their (1R,3S)-diastereomers (5), of which the diastereomer ratios varied from 1 to 5 depending on the reaction conditions. The (1R,3S)-diastereomers (5) are thermodynamically more stable than their (1S,3S)-congeners (4), as shown by equilibration experiments in TFA. The conversion of 4 to 5 (also 5 to 4) should occur under acidic conditions by cleavage of the C(1)-N(2) bond with complete retention of configuration at the C-3 chiral center. The low diastereo-selectivity observed in the Pictet-Spengler reaction of 1 and 2 is concluded to be a stereochemical outcome under conditions of kinetic control (lower temperature, shorter reaction time), while the high diastereo selectivity with preferential formation of the more stable isomer (5) is the result of thermodynamically controlled experiments (higher temperature, longer reaction time).

Full text of DOI:10.1248/cpb.51.1368

1368
Chem. Pharm. Bull. 51(12) 1368—1373 (2003)
Vol. 51, No. 12
b
A Synthesis of Chiral 1,1,3-Trisubstituted 1,2,3,4-Tetrahydro- -carbolines
by the Pictet–Spengler Reaction of Tryptophan and Ketones: Conversion
of (1R,3S)-Diastereomers into Their (1S,3S)-Counterparts by Scission of
the C(1)–N(2) Bond
*
Yoshie HORIGUCHI, Masayoshi NAKAMURA, Toshiaki SAITOH, and Takehiro SANO
Showa Pharmaceutical University; 3–3165, Higashi-tamagawagakuen, Machida, Tokyo 194–8543, Japan.
Received June 18, 2003; accepted September 11, 2003
The Pictet–Spengler cyclization of the imines (3) prepared by the condensation of L-tryptophan methyl ester
(1) and aryl methyl ketones (2), using titanium(IV) isopropoxide as an iminating reagent, quantitatively pro-
ceeded, when treated with trifluoroacetic acid (TFA) or formic acid, to provide two diastereomers, that is (1S,3S)-
1-aryl-3-isopropoxycarbonyl-1-methyl-1,2,3,4-tetrahydro-b-carbolines (4) and their (1R,3S)-diastereomers (5), of
which the diastereomer ratios varied from 1 to 5 depending on the reaction conditions. The (1R,3S)-diastere-
omers (5) are thermodynamically more stable than their (1S,3S)-congeners (4), as shown by equilibration experi-
ments in TFA. The conversion of 4 to 5 (also 5 to 4) should occur under acidic conditions by cleavage of the
C(1)–N(2) bond with complete retention of configuration at the C-3 chiral center. The low diastereo-selectivity
observed in the Pictet–Spengler reaction of 1 and 2 is concluded to be a stereochemical outcome under condi-
tions of kinetic control (lower temperature, shorter reaction time), while the high diastereo selectivity with pref-
erential formation of the more stable isomer (5) is the result of thermodynamically controlled experiments
(higher temperature, longer reaction time).
Key words tetrahydro-b-carboline; Pictet–Spengler reaction; stereoselectivity; tryptophan; aryl methyl ketone
The Pictet–Spengler reaction1) has long been an important
The reaction of 1 and 2a with TFA at 70 °C for 1 h pro-
reaction for the syntheses of biologically important isoquino-
lines and b-carbolines.2,3) Recently, we have developed a
highly efficient method of synthesizing 1,1-disubstituted
tetrahydroisoquinolines4) and tetrahydro-b-carbolines5) by the
Pictet–Spengler reaction of arylethylamines and ketones
using titanium(IV) isopropoxide as an iminating reagent.
This method has an advantage in that the reaction can be car-
ried out without the isolation of the acid-labile imines under
a one-pot procedure. Although the Pictet–Spengler reactions
using tryptophan and aldehydes which produce chiral 1,3-
disubstitued 1,2,3,4-tetrahydro-b-carbolines (THbCs) have
been extensively investigated,6—12) the reaction with ketone
has not been hitherto investigated. Here we describe the
Pictet–Spengler reaction of tryptophan methyl ester with aryl
methyl ketones, which may provide a convenient method of
synthesizing chiral 1,1,3-trisubstituted THbCs.
vided 4a and 5a in yields of 10% and 45%, respectively
(Table 1, Run 1). The same treatment with TFA at room tem-
perature for 1 h improved the reaction to give higher yields of
4a (31%) and 5a (54%) (Table 1, Run 2). When this reaction
mixture reacted at room temperature for a longer period of
time (18 h), the yields of products decreased slightly (4a:
14%, 5a: 50%) (Table 1, Run 3). The facts indicated that
TFA rapidly induced the cyclization and at the same time
slowly decomposed the products 4a and 5a by long contact
with the acid. The reaction with HCOOH also induced the
expected cyclization, although it was slow, to give results
similar to those of TFA-induced cyclization. Thus, the reac-
tion at 70 °C for 18 h gave 4a (13%) and 5a (58%) (Table 1,
Run 4), while at room temperature for 18 h the reaction pro-
duced 4a (39%) and 5a (41%) (Table 1, Run 5).
The reaction of 1 with 1-(4-chlorophenyl)-2-ethanone (2b)
and 1-(4-methoxyphenyl)-2-ethanone (2c) with TFA or
HCOOH gave results similar to those of 2a (2b: Table 1,
Runs 6—10 and 2c: Table 1, Runs 11—15).
Results and Discussions
Pictet–Spengler Reaction of Tryptophan Methyl Ester
(1) with Aryl Methyl Ketones (2) The condensation reac-
tion of L-tryptophan methyl ester (1) and aryl methyl ketones
(2a: acetophenone, 2b: 1-(4-chlorophenyl)-2-ethanone, 2c:
1-(4-methoxyphenyl)-2-ethanone) to the imine intermediates
(3a—c) was carried out by heating in titanium(IV) iso-
propoxide at 70 °C for 3 h without using any solvent. To the
mixture of the in situ formed imines (3) was added a large
excess amount of trifluoroacetic acid (TFA) or formic acid
(HCOOH). The reaction mixture was then allowed to react at
70 °C or at room temperature for appropriate times to com-
plete the Pictet–Spengler cyclization. During the imination,
the ester exchange reaction from the methyl ester to the iso-
propyl ester occurred. The reactions, in all cases, produced
two diastereometric 1-aryl-3-isopropoxycarbonyl-1-methyl-
THbCs (4) and (5) in good total yields (Chart 1, Table 1).
The structures of products 4 and 5 were readily deter-
1
mined by elementary and spectral analyses (Mass, IR, H-
1
and 13C-NMR, [a]D). In the H-NMR spectrum of cis-di-
astereomer (4a), the signal of 4-H appeared as a double dou-
blet at d 2.87 (Hax, Jϭ11, 15 Hz) and d 3.19 (Heq, Jϭ4,
15 Hz) and the signal of 3-H appeared as a double doublet at
d 4.00 (Jϭ4, 11 Hz). The coupling constants (Jϭ4, 15 Hz)
between 3-H and 4-H showed that the 3-isopropoxycarbonyl
group is in equatorial orientation when the tetrahydro-b-car-
1
boline ring has a half chair form. In the H-NMR spectrum
of trans-diasteromer (5a), a similar signal pattern appeared.
The similar coupling constant value (Jϭ5, 11 Hz) between 3-
H and 4-H indicated that the 3-isopropoxycarbonyl group of
5a had the same orientation (equatorial) as 4a. The stereo-
chemistries of the substituents at the C-1 and C-3 chiral cen-
To whom correspondence should be addressed. e-mail: horiguti@ac.shoyaku.ac.jp
© 2003 Pharmaceutical Society of Japan

December 2003
1369
Table 1. Pictet–Spengler Reaction of L-Tryptophan Methyl Ester (1) with Aryl Methyl Ketones (2) Using Titanium(IV) Isopropoxide
Ketones (2)
Conditions
Yields (%) of b-carbolines (THbCs)
4 (1S,3S) 5 (1R,3S)
5a
Ratio of
Run
Acids
5/4a)
R
Temp (°C) Time (h)
4ϩ5
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2c
2c
2c
2c
2c
H
H
H
H
H
Cl
Cl
Cl
Cl
TFA
TFA
TFA
HCOOH
HCOOH
TFA
TFA
TFA
HCOOH
HCOOH
TFA
70
rt
1
1
4a
4a
4a
4a
4a
4b
4b
4b
4b
4b
4c
4c
4c
4c
4c
10
31
14
13
39
15
34
14
9
45
54
50
55
41
57
46
68
44
37
59
62
59
47
13
55
85
64
71
80
72
80
82
53
64
73
75
73
62
19
4.5
1.7
3.6
4.2
1.2
3.8
1.4
4.9
4.9
1.4
4.9
4.8
4.2
3.1
2.2
5a
5a
5a
5a
5b
5b
5b
5b
5b
5c
5c
5c
5c
5c
rt
18
18
18
1
70
rt
70
rt
1
rt
18
18
18
1
70
rt
70
rt
Cl
27
14
13
14
15
6
OCH3
OCH3
OCH3
OCH3
OCH3
TFA
TFA
HCOOH
HCOOH
1
rt
18
18
18
70
rt
a) The ratios were calculated by the isolated yields of 4 and 5.
Chart 1
Table 2. 1H- and 13C-NMR Signals (C1 and C3) and [a]D Values of 4 and 5
1H-NMR (d)
13C-NMR (ppm)
THbCs
R
[a]D (c) in MeOH
C1-CH3
C3-H (J, Hz)
C1
C3
4a
4b
4c
5a
5b
5c
H
Cl
OCH3
H
Cl
OCH3
1.92
1.90
1.89
1.86
1.82
1.84
4.00 (4, 11)
3.99 (4, 11)
3.99 (4, 11)
3.50 (5, 11)
3.45 (5, 11)
3.50 (5, 11)
57.0
56.7
56.5
57.0
56.6
56.5
53.3
53.3
53.4
52.2
52.2
52.1
Ϫ53.3° (1.0)
Ϫ45.4° (1.0)
Ϫ50.1° (1.0)
Ϫ10.0° (1.0)
Ϫ14.4° (0.5)
Ϫ14.6° (1.0)
ters were determined on the basis of 2D-nuclear Overhauser hancement of the C-1 phenyl signal (17%), indicating that
and exchange spectroscopy (NOESY) and difference in nu- the relative stereochemistry of the C-1 phenyl group and the
clear Overhauser effect (DIF-NOE). In the NOESY spectrum C-3 proton of 5a is a cis-diaxial orientation. Thus, it was de-
of 4a, the signal of the C-1 methyl proton at d 1.92 showed a termined that the stereochemistry of the C-1 phenyl group
correlation of the C-3 proton at d 4.00. Irradiation of the C-1 and the C-3 isopropyl ester is cis for 4a (cis-diastereomer)
methyl signal caused enhancement of the C-3 proton signal and trans for 5a (trans-diastereomer). The [a]D values of 4a
(14%), indicating that the stereochemistry of the C-1 methyl and 5a obtained by the reaction of runs 1—5 were always
group and the C-3 proton of 4a is a cis-diaxial orientation. In consistent (Table 2). This fact strongly suggested that the
the NOESY spectrum of 5a, the signal of the C-3 proton at d Pictet–Spengler cyclization did not involve any racemiza-
3.50 showed a correlation of the C-1 phenyl proton at d tion process. The structures of products 4b, 4c and 5b, 5c
7.1—7.9. Irradiation of the C-3 proton signal caused en- from 1-(4-chlorophenyl)- (2b) and 1-(4-methoxyphenyl)-2-

1370
Vol. 51, No. 12
Chart 2
Chart 3
ethanone (2c) were readily determined by their analogy in the Table 3. TFA-Induced Isomerization of THbCs (4) and (5)a)
1H- and 13C-NMR signals, and optical rotations with those
for 4a and 5a, respectively (Table 2).
Conditions
Ratio of
Run
THbCs
R
5/4b)
In order to determine whether the L-tryptophan chiral cen-
ter had been partially racemized before inducing the
Pictet–Spengler cyclization, we carried out following experi-
ment. D-Tryptophan methyl ester (ent-1) on the Pictet–Spen-
gler reaction with 2a using TFA at room temperature for 1 h
yielded two products, ent-4a (24%) ([a]D ϩ52.7°) and ent-
5a (38%) ([a]D ϩ9.9°). Their 1H- and 13C-NMR signals were
identical with those of 4a and 5a, but the specific optical ro-
tations were opposite in sign (4a: [a]D Ϫ53.3°) and (5a: [a]D
Ϫ10.0°).
Temp (°C)
Time
1
2
3
4
5
6
7
8
9
4a
4a
4b
4b
4c
4c
5a
5b
5b
5c
H
H
Cl
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
1 h
3 h
1 h
3 h
20 min
1 h
3 h
3 h
18 h
20 min
1.4
3.0
0.8
3.0
3.0
3.0
4.0
10.0
4.5
4.0
Cl
OCH3
OCH3
H
Cl
Cl
10
OCH3
The optical purities of 5a and ent-5a were shown to be
1
a) The products 4 and 5 were quantitatively recovered and no other products were
detected by the TLC inspections. b) The ratios were measured by the intensity of the
C3-H signal.
100% by the H-NMR spectral inspection of the Mosher
esters 7 and 8, which did not show any contamination of
their corresponding diastereomers. This fact also supported
that the epimerization at the C-3 chiral had not occurred
before the Pictet–Spengler cyclization. Thus, the structures
of 4a and 5a, including the stererocheimstry C-1 and C-3
chiral centers, were assigned to be (1S,3S)- and (1R,3S)-3-
isopropoxycarbonyl-3-methyl-1-phenyl-THbC, respectively
(Chart 3).
Epimerization at C-1 Chiral Center The diastereomer
ratio of 5/4 in the Pictet–Spengler reactions varied from 1 to Fig. 1. Most Stable Comformer of 4a and 5a Optimized by AM1
5 depending on such reaction conditions as the nature of
acid, temperature, and time, as shown in Table 1. The reac-
The pure cis-diastereomer (4), when treated with TFA at
tion under more forced conditions showed high diastereo-se- room temperature for the appropriate times, caused the iso-
lectivity, while the reaction under milder conditions gave low merization to form a 1 : 3 mixture of 4 and 5 in a quantitative
diastereo-selectivity. For example, the ratio of 5a/4a in the yield. The trans-diastereomer (5) on similar reactions with
reaction of 2a with HCOOH at 70 °C for 18 h is 4.2 (Table 1, TFA also quantitatively produced the mixture of 4 and 5 in
Run 4), while the ratio of 5a/4a in the reaction at room tem- about a 1 : 4 ratio, as shown in Table 3. These experiments re-
perature for 18 h is 1.2 (Table 1, Run 5). The Pictet–Spengler vealed that the trans-diastereomer (5) is thermodynamically
reactions of 2b and 2c gave stereochemical outcomes similar more stable than the cis-diastereomer (4). The 1H-NMR
to those of 2a. The facts clearly demonstrated that the acid- spectra as described above showed that the cis- (4a) and
induced cyclization of the imine intermediate (3) occurred in trans-diastereomer (5a) adopts half-chair conformations with
a non-diastereoselective manner to yield the cis-diastereomer 3-equatorial isopropoxycarbonyl groups, as shown in Fig. 1.
(4) and trans-diastereomer (5) in about a 1 : 1 ratio, then the Using their conformation, we calculated the heat of forma-
cis-diastereomer (4) was converted into the trans isomer (5) tion of 4a and 5a by AM1 theory, which showed that 5a
by acid-induced isomerization.
is more stable (DHfϭϪ9.71 kcal/mol) than 4a (DHfϭ

December 2003
1371
Chart 4
Yanaco CHN-corder MT-3. Optical rotations were determined using a
JASCO DIP-1000 digital polarimeter in MeOH. TLC was performed on
Merck precoated Silica gel 60 F254 plates. Column chromatography was car-
ried out with silica gel (Wakogel C-200). The organic extract from each re-
Ϫ6.17 kcal/mol), supporting the conclusion obtained from
the isomerization experiments.
Furthermore, either the cis-isomer (4) or the trans-isomer
(5) recovered after this isomerization reaction showed [a]D action mixture was washed with brine, dried over anhydrous Na2SO4, and
concentrated in vacuo to dryness.
The Pictet–Spengler Reaction of L-Tryptophan methyl ester with Ace-
tophenone (2a): Typical procedure L-Tryptophan methyl ester hy-
drochloride (1) (1.2 g, 4.59 mmol) in H2O (50 ml) was basified with 10%
values and signs identical with those of the starting materials,
indicating that the racemization of either 4 or 5 did not occur.
The TFA-induced epimerization at the C-1 chiral center
is able to occur via two processes; a) the recombination of
the imines (3) generated by a retro-Pictet–Spengler reaction,
and b) the C(1)–N(2) bond fission-recombination. The mech-
anism of the retro-Pictet–Spengler reaction can be discarded
since in the product of the isomerization experiments de-
scribed above, there is no indication of the formation of the
acid-labile imines (3) that readily produce tryptophan iso-
propyl ester and aryl methyl ketone.
The facts described above, in turn, supported the
C(1)–N(2) bond fission-recombination mechanism proposed
by Zhang13,14) and Cook12) for the epimerization at the C-1
chiral center of 1,3-disubstituted THbC. That is, the epimer-
ization is able to occur via the carbocation 9 and its rotatory
isomer 10 formed by the acid-induced cleavage of the
C(1)–N(2) bond (Chart 4). This epimerization mechanism is
K2CO3 solution and extracted with AcOEt. After removal of the solvent in
vacuo, the residue was mixed with 2a (0.46 g, 3.83 mmol) and Ti(O-iPr)4
(1.63 g, 5.75 mmol), and the mixture was heated at 70 °C for 3 h under an
argon atmosphere. To the reaction mixture was added the mixture of TFA
(43.6 g, 0.383 mol) and trifluoroacetic anhydride (0.8 g, 3.83 mmol) at 0 °C,
then the mixture was heated at 70 °C for 1 h. The reaction mixture was di-
luted with MeOH (100 ml) and passed through a short SiO2 column (MeOH)
to remove TiO2. The eluent was concentrated in vacuo (ca. 30 ml) and the
residue was neutralized with 10% NaOH solution and extracted with CHCl3.
After removal of the solvent of the extract in vacuo, the residue was purified
by column chromatography over SiO2 (benzene–acetoneϭ30 : 1) to give 4a
(111 mg, 10%) and 5a (600 mg, 45%).
(1S,3S)-3-Isopropoxycarbonyl-1-methyl-1-phenyl-1,2,3,4-tetrahydro-b-
carboline (4a): Colorless prisms recrystallized from Et2O–hexane, mp 184—
185 °C. IR: 3374, 3343, 2977, 1735, 1710. UV: 279.0 (8800). 1H-NMR:
1.30 (3H, d, Jϭ7 Hz, CH(CH3)2), 1.32 (3H, d, Jϭ7 Hz, CH(CH3)2), 1.92
(3H, s, CH3), 2.87 (1H, dd, Jϭ11, 15 Hz, 4-H), 3.19 (1H, dd, Jϭ4, 15 Hz, 4-
H), 4.00 (1H, dd, Jϭ 4, 11 Hz, 3-H), 5.11 (1H, m, CH(CH3)2), 7.1—7.6
consistent with the fact that the 4-methoxyphenyl derivatives (10H, m, Ph-H, Ar-H). 13C-NMR: 21.8 (2ϫCH(CH3)2), 25.7 (CH3), 26.4
(4c, 5c) isomerized more rapidly than phenyl (4a, 5a) or
4-chlorophenyl derivatives (4b, 5b). The methoxy moiety
would help to stabilize the carbocation 9cA via the resonance
form 9cB, and therefore to facilitate not only the cleavage of
the C(1)–N(2) bond but also the epimerization of the C-1
chiral center.
(C4), 53.3 (C3), 57.0 (C1), 68.6 (CH(CH3)2), 108.1 (C4a), 110.9 (C8), 118.3
(C6), 119.5 (C5), 121.9 (C7), 126.9 (C4b), 127.0 (2ϫPhCH), 127.8 (PhCH),
128.6 (2ϫPhCH), 136.0 (PhC), 139.1 (C9a), 145.3 (C8a), 172.9 (COO).
LR-EI-MS: m/z 348 (Mϩ), 245 (base peak). HR-EI-MS: Calcd for
C22H24N2O2: 348.1835. Found: 348.1817. Anal. Calcd for C22H24N2O2: C,
75.83; H, 6.94; N, 8.04. Found: C, 75.94; H, 7.07; N, 8.08. [a]D Ϫ53.3°
(cϭ1.0 in MeOH).
(1R,3S)-3-Isopropoxycarbonyl-1-methyl-1-phenyl-1,2,3,4-tetrahydro-b-
carboline (5a): Colorless needles recrystallized from Et2O–hexane, mp
175—176 °C. IR: 3369, 2979, 1724, 1654. UV: 278.5 (8500). 1H-NMR:
1.24 (3H, d, Jϭ6 Hz, CH(CH3)2), 1.27 (3H, d, Jϭ6 Hz, CH(CH3)2), 1.86
(3H, s, CH3), 2.82 (1H, dd, Jϭ11, 15 Hz, 4-H), 3.01 (1H, dd, Jϭ5, 15 Hz, 4-
H), 3.50 (1H, dd, Jϭ5, 11 Hz, 3-H), 5.06 (1H, sep, Jϭ6 Hz, CH(CH3)2),
7.1—7.9 (10H, m, Ph-H, Ar-H). 13C-NMR: 21.7 (CH(CH3)2), 21.8
(CH(CH3)2), 25.9 (C4), 29.3 (CH3), 52.2 (C3), 57.0 (C1), 68.5 (CH(CH3)2),
108.8 (C4a), 110.9 (C8), 118.4 (C6), 119.7 (C5), 122.0 (C7), 126.5
(2ϫPhCH), 127.1(C4b), 127.2 (PhCH), 128.2 (2ϫPhCH), 135.9 (PhC),
137.4 (C9a), 145.9 (C8a), 173.1 (COO). LR-EI-MS: m/z 348 (Mϩ), 218
(base peak). HR-EI-MS: Calcd for C22H24N2O2: 348.1838. Found: 348.1863.
Anal. Calcd for C22H24N2O2: C, 75.83; H, 6.94; N, 8.04. Found: C, 75.74; H,
6.98; N, 8.05. [a]D Ϫ10.0° (cϭ1.0 in MeOH).
The Pictet–Spengler Reaction of 1 with 2b The reaction of 1
(4.59 mmol) and 2b (590 mg, 3.83 mmol) under the condition described in
Table 1 (Run 6) gave 4b (490 mg, 34%) and 5b (670 mg, 46%).
(1S,3S)-1-(4-Chlorophenyl)-3-isopropoxycarbonyl-1-methyl-1,2,3,4-
tetrahydro-b-carboline (4b): Colorless needles recrystallized from Et2O–
hexane, mp 195—197 °C. IR: 3384, 3342, 2979, 2935, 1718. 1H-NMR: 1.30
(3H, d, Jϭ6 Hz, CH(CH3)2), 1.32 (3H, d, Jϭ6 Hz, CH(CH3)2), 1.90 (3H, s,
CH3), 2.86 (1H, dd, Jϭ11, 15 Hz, 4-H), 3.19 (1H, dd, Jϭ4, 15 Hz, 4-H),
3.99 (1H, dd, Jϭ4, 11 Hz, 3-H), 5.12 (1H, sep, Jϭ6 Hz, CH(CH3)2), 7.1—
It is concluded that the low diastereo-selectivity observed
in the Pictet–Spengler reaction of 1 and 2 is the stereochemi-
cal outcome based on conditions of kinetic control, and that
the higher stereoselectivity with the preferential formation of
the trans-diastereomer (5) is the result of the thermodynamic
control experiment.
Experimental
Unless otherwise noted, the following procedures were adopted. Melting
points were taken on a Yanagimoto SP-M1 hot-stage melting point apparatus
and are uncorrected. IR spectra were measured as films for oils and gums,
and on KBr disks for solids with a HORIBA FT-710 spectrophotometer, and
the values are given in cmϪ1. NMR spectra were measured on a JEOL JNM-
AL300 (1H-NMR: 300 MHz, 13C-NMR: 75 MHz) or a JEOL JNM a500
(1H-NMR: 500 MHz, 13C-NMR: 125 MHz) NMR spectrometer in CDCl3
with tetramethylsilane as an internal standard, and the chemical shifts are
given in d values. Low-resolution electron impact ionization mass spectra
(LR-EI-MS) were taken on a JEOL JMS-AM20 mass spectrometer at 70 eV
using a direct inlet probe. High-resolution electron impact ionization mass
spectra (HR-EI-MS) were taken on a JEOL JMS-D300 mass spectrometer at
70 eV using a direct inlet probe. Elemental analyses were recorded on a

1372
Vol. 51, No. 12
7.6 (9H, m, Ar-H, Ph-H). 13C-NMR: 21.8 (2ϫCH(CH3)2), 25.6 (CH3), 26.2
(C4), 53.3 (CH(CH3)2), 56.7 (C1), 68.7 (CH(CH3)2), 108.3 (C4a), 110.9
(C5), 118.4 (C8), 119.7 (C6), 122.1 (C7), 126.8 (C4b), 128.6 (2ϫPhCH),
128.7 (2ϫPhCH), 133.7 (PhC), 136.1 (PhC), 138.4 (C9a), 144.0 (C8a),
172.8 (COO). LR-EI-MS: m/z 382, 384 (Mϩ), 367 (base peak). HR-EI-MS:
Calcd for C22H23N2O2Cl: 382.1448, 384.1416. Found: 382.1469, 384.1411.
Anal. Calcd for C22H23N2O2Cl: C, 69.01; H, 6.05; N, 7.32. Found: C, 68.84;
H, 6.19; N, 7.30. [a]D Ϫ45.4° (cϭ1.0 in MeOH).
348.1838. Found: 348.1859. Anal. Calcd for C22H24N2O2: C, 75.83; H, 6.94;
N, 8.04. Found: C, 75.77; H, 7.06; N, 8.06. [a]D ϩ52.7° (cϭ1.0 in MeOH).
(1S,3R)-3-Isopropoxycarbonyl-1-methyl-1-phenyl-1,2,3,4-tetrahydro-b-
carboline (ent-5a): Colorless needles recrystallized from Et2O–hexane, mp
170—172 °C. IR, 1H- and 13C-NMR were identical with those of 5a. LR-EI-
MS: m/z 348 (Mϩ), 333 (base peak). HR-EI-MS: Calcd for C22H24N2O2:
348.1835. Found: 348.1829. Anal. Calcd for C22H24N2O2: C, 75.83; H, 6.94;
N, 8.04. Found: C, 75.75; H, 7.13; N, 7.90. [a]D ϩ9.9° (cϭ1.0 in MeOH).
Reduction of 5a with LiAlH4: Typical Procedure LiAlH4 (22 mg,
0.575 mmol) was added to a solution of 5a (200 mg, 0.575 mmol) in THF
(10 ml) at 0 °C, then the mixture was stirred for 2.5 h at the same tempera-
ture. Water was added to the reaction mixture and the mixture was extracted
with CHCl3. After removal of the solvent, the residue was purified by col-
umn chromatography over SiO2 (AcOEt–hexaneϭ4 : 1) to give (1R,3S)-3-
hydoxymethyl-1-methyl-1-phenyl-1,2,3,4-tetrahydro-b-carboline (6) (154
(1R,3S)-1-(4-Chlorophenyl)-3-isopropoxycarbonyl-1-methyl-1,2,3,4-
tetrahydro-b-carboline (5b): Colorless needles recrystallized from Et2O–
1
AcOEt, mp 245—247 °C. IR: 3417, 3349, 2975, 1720. H-NMR: 1.25 (3H,
d, Jϭ6 Hz, CH(CH3)2), 1.28 (3H, d, Jϭ6 Hz, CH(CH3)2), 1.82 (3H, s, CH3),
2.80 (1H, dd, Jϭ11, 15 Hz, 4-H), 3.08 (1H, dd, Jϭ5, 15 Hz, 4-H), 3.45 (1H,
dd, Jϭ5, 11 Hz, 3-H), 5.06 (1H, sep, Jϭ6 Hz, CH(CH3)2), 7.1—7.6 (8H, m,
Ph-H, Ar-H), 7.94 (1H, br s, Ar-NH). 13C-NMR: 21.7 (CH(CH3)2), 21.8
(CH(CH3)2), 25.9 (C4), 29.2 (CH3), 52.2 (C3), 56.6 (C1), 68.6 (CH(CH3)2),
108.9 (C4a), 111.0 (C8), 118.5 (C6), 119.8 (C5), 122.3 (C7), 127.0 (C4b),
128.0 (2ϫPhCH), 128.3 (2ϫPhCH), 133.1 (PhC), 135.9 (PhC), 136.9 (C9a),
144.5 (C8a), 173.1 (COO). LR-EI-MS: m/z 382, 384 (Mϩ), 367 (base peak).
HR-EI-MS: Calcd for C22H23N2O2Cl: 382.1446, 384.1418. Found:
382.1430, 384.1420. Anal. Calcd for C22H23N2O2Cl: C, 69.01; H, 6.05; N,
7.32. Found: C, 68.75; H, 6.10; N, 7.35. [a]D Ϫ14.4° (cϭ0.5 in MeOH).
The Pictet–Spengler Reaction of 1 with 2c The reaction of 1
(4.59 mmol) and 2c (570 mg, 3.83 mmol) under the condition described in
Table 1 (Run 11) gave 4c (183 mg, 13%) and 5c (892 mg, 62%).
1
mg, 92%) as a colorless gum. IR: 3397, 3291, 2969, 2925. H-NMR: 1.80
(3H, s, CH3), 2.47 (1H, dd, Jϭ11, 15 Hz, 4-H), 2.70 (1H, dd, Jϭ4, 15 Hz, 4-
H), 2.9—3.0 (1H, m, 3-H), 3.48 (1H, dd, Jϭ9, 11 Hz, CH2OH), 3.69 (1H,
dd, Jϭ4, 11 Hz, CH2OH), 7.1—7.5 (9H, m, Ar-H, Ph-H), 7.99 (1H, br s, Ar-
NH). 13C-NMR: 24.7 (C4), 29.8 (CH3), 51.2 (C3), 57.3 (C1), 66.0 (CH2OH),
109.3 (C4a), 110.9 (C8), 118.4 (C6), 119.6 (C5), 122.0 (C7), 126.6
(2ϫPhCH), 127.1 (C4a), 128.2 (2ϫPhCH), 135.9 (PhC), 138.1 (C9a), 146.1
(C8a). LR-EI-MS: m/z 292 (Mϩ), 277 (base peak). HR-EI-MS: Calcd for
C19H20N2O: 292.1573. Found: 292.1572. [a]D ϩ38.0° (cϭ0.5 in MeOH).
Reduction of ent-5a with LiAlH4 Reduction of ent-5a (200 mg,
0.575 mmol) with LiAlH4 (22 mg, 0.575 mmol) and purification by column
chromatography over SiO2 (benzene–acetoneϭ3 : 1) gave (1R,3R)-3-hy-
doxymethyl-1-methyl-1-phenyl-1,2,3,4-tetrahydro-b-carboline (ent-6) (140
mg, 83%) as a colorless gum. IR, 1H- and 13C-NMR were identical with
those of 6. LR-EI-MS: m/z 292 (Mϩ), 277 (base peak). HR-EI-MS: Calcd
for C19H20N2O: 292.1573. Found: 292.1558. [a]D Ϫ39.7° (cϭ0.5 in MeOH).
Synthesis of (1R,3S)-(1-Methyl-1-phenyl-1,2,3,4-tetrahydro-b-carbo-
line-3-yl)methyl (R)-a-Methoxy-a-trifluoromethylphenyl Acetate (7):
(1S,3S)-3-Isopropoxycarbonyl-1-(4-methoxyphenyl)-1-methyl-1,2,3,4-
tetrahydro-b-carboline (4c): Colorless needles recrystallized from Et2O–
1
hexane, mp 125—127 °C. IR: 3378, 2977, 1724, 1608. H-NMR: 1.30 (3H,
d, Jϭ6 Hz, CH(CH3)2), 1.31 (3H, d, Jϭ6 Hz, CH(CH3)2), 1.89 (3H, s, CH3),
2.85 (1H, dd, Jϭ11, 15 Hz, 4-H), 3.18 (1H, dd, Jϭ4, 15 Hz, 4-H), 3.79 (3H,
s, OCH3), 3.99 (1H, dd, Jϭ4, 11 Hz, 3-H), 5.11 (1H, sep, Jϭ
6 Hz, CH(CH3)2), 6.8—6.9 (2H, m, Ph-H), 7.1—7.2, 7.5—7.6 (total 4H, m,
Ar-H), 7.3—7.4 (2H, m, Ph), 7.44 (1H, br s, Ar-NH). 13C-NMR: 21.8
(2ϫCH(CH3)2), 25.8 (CH3), 26.4 (C4), 53.4 (C3), 55.3 (OCH3), 56.5 (C1),
68.5 (CH(CH3)2), 108.0 (C4a), 110.9 (C8), 113.8 (2ϫPhCH), 118.2 (C6),
119.5 (C5), 121.9 (C7), 127.0 (C4b), 128.3 (2ϫPhCH), 136.0 (PhC), 137.5
(C9a), 139.3 (C8a), 159.0 (PhC), 172.9 (COO). LR-EI-MS: m/z 378 (Mϩ),
363 (base peak). HR-EI-MS: Calcd for C23H26N2O3: 378.1944. Found:
378.1979. Anal. Calcd for C23H26N2O3: C, 72.99; H, 6.92; N, 7.40. Found:
C, 72.74; H, 7.02; N, 7.31. [a]D Ϫ50.1° (cϭ1.0 in MeOH).
Typical Procedure
A solution of 6 (42 mg, 0.144 mmol), pyridine
(1.7 ml), DMAP (7 mg) and (Ϫ)-MTPA-Cl (90 mg, 0.360 mmol) in CCl4
(3.5 ml) was stirred at room temperature for 24 h under an argon atmo-
sphere. The reaction mixture was diluted with water and the mixture was ex-
tracted with CHCl3. After removal of the solvent in vacuo, the residue was
purified by column chromatography over SiO2 (AcOEt–hexaneϭ4 : 1) to
give 7 (48 mg, 66%) as a pale yellow gum. IR: 3058, 2965, 2921, 1745. 1H-
NMR: 1.69 (3H, s, CH3), 2.57 (1H, dd, Jϭ11, 15 Hz, 4-H), 2.73 (1H, dd,
Jϭ5, 15 Hz, 4-H), 3.1—3.2 (1H, m, 3-H), 3.46 (3H, d, Jϭ1 Hz, OCH3), 4.32
(1H, dd, Jϭ7, 11 Hz, CH2O), 4.45 (1H, dd, Jϭ4, 11 Hz, CH2O), 7.1—7.6
(14H, m, 2ϫPh-H, Ar-H), 7.91 (1H, br s, Ar-NH). 13C-NMR: 24.8 (C4),
29.5 (CH3), 48.2 (C3), 55.4 (C1), 57.2 (OCH3), 69.5 (CH2O), 84.7 (C–CF3),
108.7 (C4b), 110.9 (C8), 118.3 (C6), 119.6 (C5), 122.0 (C7), 126.4
(2ϫPhCH), 127.0 (C4a), 127.1 (PhCH), 127.4 (2ϫPhCH), 128.1
(2ϫPhCH), 128.4 (2ϫPhCH), 129.7 (PhCH), 132.1 (PhC), 135.9 (C9a),
137.6 (C8a), 146.0 (PhC), 166.5 (s, O–CO). LR-EI-MS: m/z 508 (Mϩ), 58
(base peak). HR-EI-MS: Calcd for C29H27N2O3F3: 508.1972. Found:
508.1952.
(1R,3S)-3-Isopropoxycarbonyl-1-(4-methoxyphenyl)-1-methyl-1,2,3,4-
tetrahydro-b-carboline (5c): Colorless needles recrystallized from Et2O–
1
hexane, mp 178—180 °C. IR: 3369, 2979, 1724, 1608. H-NMR: 1.24 (3H,
d, Jϭ6 Hz, CH(CH3)2), 1.28 (3H, d, Jϭ6 Hz, CH(CH3)2), 1.84 (3H, s, CH3),
2.81 (1H, dd, Jϭ11, 15 Hz, 4-H), 3.09 (1H, dd, Jϭ5, 15 Hz, 4-H), 3.50 (1H,
dd, Jϭ5, 11 Hz, 3-H), 3.76 (3H, s, OCH3), 5.06 (1H, sep, Jϭ6 Hz,
CH(CH3)2), 6.8—6.9 (2H, m, Ph-H), 7.1—7.2 (4H, m, Ar-H), 7.3—7.6 (2H,
m, Ph-H), 7.88 (1H, br s, Ar-NH). 13C-NMR: 21.7 (CH(CH3)2), 21.8
(CH(CH3)2), 25.9 (C4), 29.3 (CH3), 52.1 (C3), 55.2 (OCH3), 56.5 (C1), 68.4
(CH(CH3)2), 108.6 (C4a), 110.9 (C8), 113.4 (2ϫPhCH), 118.4 (C6), 119.6
(C5), 122.0 (C7), 127.1 (C4b), 127.7 (2ϫPhCH), 135.9 (PhC), 137.6 (C9a),
138.0 (C8a), 158.6 (PhC), 173.2 (COO). LR-EI-MS: m/z 378 (Mϩ), 149
(base peak). HR-EI-MS: Calcd for C23H26N2O3: 378.1944. Found: 378.1964.
Anal. Calcd for C23H26N2O3: C, 72.99; H, 6.92; N, 7.40. Found: C, 72.94; H,
7.00; N, 7.36. [a]D Ϫ14.6° (cϭ1.0 in MeOH).
The Pictet–Spengler Reaction of D-Tryptophan Methyl Ester with 2a
D-Tryptophan methyl ester hydrochloride (ent-1) (1.2 g, 4.59 mmol) in H2O
(50 ml) was basified with 10% K2CO3 solution and extracted with AcOEt.
After removal of the solvent in vacuo, the residue was mixed with 2a
(0.46 g, 3.83 mmol) and Ti(O-iPr)4 (1.63 g, 5.75 mmol), then the mixture
was heated at 70 °C for 3 h under an argon atmosphere. To the reaction mix-
ture was added a mixture of TFA (43.6 g, 0.383 mol) and trifluoroacetic an-
hydride (0.8 g, 3.83 mmol) at 0 °C, then the mixture was stirred at room tem-
perature for 1 h. The reaction mixture was diluted with MeOH (100 ml) and
passed through a short SiO2 column (MeOH) to remove TiO2. The eluent
was concentrated in vacuo (ca. 30 ml) and the residue was neutralized with
10% NaOH solution and extracted with CHCl3. After removal of the sol-
vent in vacuo, the residue was purified by column chromatography over
SiO2 (benzene–acetoneϭ30 : 1) to give ent-4a (315 mg, 24%) and ent-5a
(505 mg, 38%), respectively.
Synthesis of (1S,3R)-(1-Methyl-1-phenyl-1,2,3,4-tetrahydro-b-carbo-
line-3-yl)methyl (R)-a-Methoxy-a-trifluoromethylphenyl Acetate (8)
8
(54 mg, 89%) was obtained from the reaction of ent-6 (35 mg, 0.120 mmol)
and (Ϫ)-MTPA-Cl (90 mg, 0.360 mmol) after purification by column chro-
matography over SiO2 (AcOEt–hexaneϭ1 : 1) as a pale yellow gum. IR:
1
3407, 2962, 2919, 1751. H-NMR: 1.73 (3H, s, CH3), 2.56 (1H, dd, Jϭ11,
15 Hz, 4-H), 2.71 (1H, dd, Jϭ4, 15 Hz, 4-H), 3.08 (1H, m, 3-H), 3.46 (3H, d,
Jϭ1 Hz, OCH3), 4.33 (1H, dd, Jϭ7, 11 Hz, CH2O), 4.39 (1H, dd, Jϭ4,
11 Hz, CH2O), 7.1—7.5 (14H, m, 2ϫPh-H, Ar-H), 7.92 (1H, br s, Ar-NH).
13C-NMR: 24.6 (C4), 29.4 (–CH3), 48.3 (C3), 55.4 (C1), 57.2 (OCH3), 69.4
(CH2O), 84.6 (C–CF3), 108.7 (C4b), 110.9 (C8), 118.3 (C6), 119.6 (C5),
122.0 (C7), 126.3 (2ϫPhCH), 127.0 (C4a), 127.1 (PhCH), 127.4
(2ϫPhCH), 128.1 (2ϫPhCH), 128.4 (2ϫPhCH), 129.7 (PhCH), 132.2
(PhC), 135.9 (PhC), 137.4 (C9a), 146.1 (C8a), 166.4 (O–CO). LR-EI-MS:
m/z 508 (Mϩ), 58 (base peak). HR-EI-MS: Calcd for C29H27N2O3F3:
508.1974. Found: 508.2011.
Epimerization Reaction of 4 and 5 under Acidic Condition: General
Procedure 4 or 5 (50 mg, 0.14 mmol) in TFA (5 ml) was stirred at room
temperature at the appropriate time (see Table 3). The 1H-NMR spectrum of
the mixture was measured. The ratios of 5/4 were calculated from the inten-
sities of the C-3 H signals of the products. Optical rotations of 4 and 5 were
measured after column chromatographic purification. 4a: [a]D Ϫ55.8°
(cϭ1.0 in MeOH). 4b: [a]D Ϫ44.5° (cϭ0.5 in MeOH). 4c: [a]D Ϫ51.0°
(1R,3R)-3-Isopropoxycarbonyl-1-methyl-1-phenyl-1,2,3,4-tetrahydro-b-
carboline (ent-4a): Colorless prisms recrystallized from Et2O–hexane, mp
186—187 °C. IR, 1H- and 13C-NMR were identical with those of 4a. LR-EI-
MS: m/z 348 (Mϩ), 333 (base peak). HR-EI-MS: Calcd for C22H24N2O2:

December 2003
1373
(cϭ0.5 in MeOH). 5a: [a]D Ϫ12.5° (cϭ0.9 in MeOH). 5b: [a]D Ϫ14.0°
(cϭ1.0 in MeOH). 5c: [a]D Ϫ14.9° (cϭ1.0 in MeOH).
(1979).
7) Massiot G., Mulamba T., J. Chem. Soc., Chem. Commun., 37, 1147—
1149 (1983).
8) Nakagawa M., Fukushima H., Kawate T., Hongu M., Une T., Kodama
S.-I., Taniguchi M., Hino T., Chem. Pharm. Bull., 37, 23—32 (1989).
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Prince S. N., Reynold C. D., Wood S. D., J. Chem. Soc., Perkin Trans.
1, 1993, 431—439 (1993).
References and Notes
1) Pictet A., Spengler T., Chem. Ber., 44, 2030 (1911).
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thesis,” Vol. 6, ed. by Trost B. M., Fleming I., Pergamon Press, Ox-
ford, 1991, pp. 736—740.
10) Wang H., Usui T., Osada H., Ganesan A., J. Med. Chem., 43, 1577—
1585 (2000).
3) Recent Review: Cox E. D., Cook J. M., Chem. Rev., 95, 1797—1842
(1995).
11) Singh K., Deb P. K., Venugopalan P., Tetrahedron, 57, 7939—7949
(2001).
4) Horiguchi Y., Kodama H., Nakamura M., Yoshimura T., Hanezi K.,
Hamada H., Saitoh T., Sano T., Chem. Pharm. Bull., 50, 253—257
(2002).
5) Horiguchi Y., Nakamura M., Kida A., Kodama H., Saitoh T., Sano T.,
Heterocycles, 59, 691—705 (2003).
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Bannett D. W., Cook J. M., J. Org. Chem., 62, 44—61 (1997).
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14) Zhang L. H. Gupta A. K., Cook J. M., J. Org. Chem., 54, 4708—4712
(1989).
6) Sorens D., Sandrin J., Ungemach F., Mokry P., Wu G. S., Yamanaka E.,
Huchinins L., DiPierro M., Cook J. M., J. Org. Chem., 44, 535—545