An efficient synthetic approach to optically active β-carboline derivatives via Pictet-Spengler reaction promoted by trimethylchlorosilane

Article abstract of DOI:10.1016/S0957-4166(02)00793-0

A highly diastereoselective Pictet-Spengler reaction using chiral tryptamine carbamates has been developed. The reaction proceeds using aromatic and aliphatic aldehydes in the presence of trimethylchlorosilane.

Full text of DOI:10.1016/S0957-4166(02)00793-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 177–180
An efficient synthetic approach to optically active b-carboline
derivatives via Pictet–Spengler reaction promoted by
trimethylchlorosilane
Riichiro Tsuji, Masako Nakagawa and Atsushi Nishida*
Graduate School of Pharmaceutical Sciences, Chiba University, 1-33, Yayoi-cho, Chiba 263-8522, Japan
Received 1 November 2002; accepted 21 November 2002
Abstract—A highly diastereoselective Pictet–Spengler reaction using chiral tryptamine carbamates has been developed. The
reaction proceeds using aromatic and aliphatic aldehydes in the presence of trimethylchlorosilane. © 2003 Elsevier Science Ltd.
All rights reserved.
1
. Introduction
has not been successful. Diastereoselective Pictet–Spen-
gler reactions using chiral tryptamine derivatives with a
chiral auxiliary on the nitrogen atom have also been
intensively studied. Koomen and co-workers reported
a diastereoselective Pictet–Spengler reaction using a
b-Carboline alkaloids are an important class of natural
products, and many have various biological activities.
The Pictet–Spengler reaction is a useful method for the
synthesis of tetrahydro-b-carboline derivatives and is
also a key reaction for the synthesis of natural prod-
6
chiral N-sulfinyl group as a removable chiral auxiliary,
6
f
which induced up to 76% diastereoselectivity (ds). We
describe herein an efficient diastereoselective Pictet–
Spengler reaction using chiral tryptamine carbamate
promoted by trimethylchlorosilane.
1
ucts. For example, we achieved the total synthesis of
2
3
Fumitremorgin and Eudistomins using the Pictet–
Spengler reaction to construct the C-1 stereogenic cen-
ter in the tetrahydro-b-carboline moiety. Recently, we
reported the first example of a highly enantioselective
Pictet–Spengler
reaction
using
enantiopure4
2. Results
diisopinocampheylchloroborane as a chiral Lewis acid,
although the substrates were limited to the use of
nitrones. The diastereoselective Pictet–Spengler reaction
using tryptophan or tryptamine derivatives has also
been widely studied. We also found that a combination
First, the Pictet–Spengler reaction of tryptamine
methylcarbamate 1 with benzaldehyde was examined to
determine suitable reaction conditions (Scheme 1).
Based upon our previous observations from Pictet–
5
of Yb(OTf) and TMSCl promoted the Pictet–Spengler
Spengler reactions using imines, the reaction using a
3
reaction of imine itself to give tetrahydro-b-carbolines
combination of Yb(OTf) (0.1 equiv.) and TMSCl (1.0
3
5
in excellent yields under mild conditions. However, the
equiv.) in CH Cl –THF was tested and the desired
2
2
application of this reaction to enantioselective synthesis
product 2a was obtained in 89% yield (Table 1, entry
Scheme 1.
*
Corresponding author. Fax: 81-43-290-2909; e-mail: nishida@p.chiba-u.ac.jp
0
957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00793-0

1
78
R. Tsuji et al. / Tetrahedron: Asymmetry 14 (2003) 177–180
1
). In the reaction with acetaldehyde, which is more
The absolute configuration of the newly formed stereo-
genic center in 4a was determined to be S by HPLC
reactive than benzaldehyde, 2b was obtained under
similar conditions but in 46% yield (entry 2). Surpris-
ingly, this reaction proceeded faster in the presence of
TMSCl alone and was complete within 30 min in 86%
yield (entry 3). Other acidic promoters such as
BF ·OEt , ZnCl , Yb(OTf) , TFA, CSA and TMSOTf
10
analysis in comparison with enantiomerically pure 4a
prepared from -tryptophan methyl ester in seven steps
by diastereoselective Pictet–Spengler reaction (33% d.e.)
L
11
(
Scheme 2).
3
2
2
3
7
gave unsuccessful results.
We then studied the effects of aldehyde substitution
entries 5–9): The substrate 3b was found to be quite
(
Comins and co-workers reported the diastereoselective
Pictet–Spengler reaction using a chiral carbamate
obtained from 3,4-dimethoxyphenethylamine and (−)-8-
reactive with various aldehydes. For example, steri-
cally hindered aldehyde (R=c-Hex, entry 8) and lin-
ear primary aldehydes (R=Et, n-Bu, entries 6 and 7)
were smoothly converted to the corresponding prod-
ucts 4f–g with good d.e. On the other hand, the less
encumbered acetaldehyde gave 4d in 22% d.e. We
assume that the diastereoselectivity of this reaction
might depend on the bulkiness of the R group, which
would affect the stereochemistry of the CꢀN bond in
the iminium cation intermediate (see below). With the
less reactive benzaldehyde, the reaction proceeded at
8
phenylmenthyl chloroformate. Therefore, (−)-menthyl
carbamate was used in our reaction to obtain optically
active tetrahydro-b-carbolines. Although the diastereo-
selective Pictet–Spengler reaction of menthyl carbamate
3
a, prepared from tryptamine and (−)-menthyl chloro-
formate proceeded smoothly even at −30°C to give the
desired 4a in 86% yield, its d.e. was only 7% (Table 2,
entry 1). However, we were pleased to find that the
diastereoselectivity increased dramatically (89% yield,
higher temperature in the presence of Yb(OTf) and
8
0% d.e.) when a (−)-8-phenylmenthyl group (3b) was
3
occurred with lower selectivity (53% yield, 53% d.e.,
entry 9).
used as the chiral auxiliary instead of the (−)-menthyl
group (entry 2). N-Protected derivatives such as 3c and
3
d exhibited higher reactivity and enabled the reaction
to proceed at lower temperature to give 4b (81% d.e. at
We found that the Pictet–Spengler reaction using (−)-8-
9
12
−
40°C) and 4c (90% d.e. at −60°C) (entries 3 and 4),
phenoxyphenylmenthyl carbamate
6
with isobu-
although these reactions required longer reaction times.
tyraldehyde gave the opposite absolute configuration of
Table 1. Pictet–Spengler reaction of tryptamine carbamate
Entry
Aldehyde R
Yb(OTf)3 (equiv.)
TMSCl (equiv.)
Time (h)
Product (%)
1
2
3
Ph
Me
Me
0.1
0.1
None
1.0
1.0
1.0
5
3
0.5
2a (89)
2b (46)
2b (86)
Table 2. Diastereoselective Pictet–Spengler reactions of chiral tryptamine carbamates with aldehydes
Entry
Substrate
R1
X
Aldehyde R2
Temp. (°C)
Time (h)
Product
Yield (%)
d.e.%a (config.)
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3b
3b
3b
3b
3b
H
H
TBS
Bn
H
H
H
H
H
H
i-Pr
i-Pr
i-Pr
i-Pr
Me
−30
−30
−40
−60
−30
−30
−30
−30
0
21
24
26
115
9
21
17
21
10
4a
4b
4b
4c
4d
4e
4f
86
89
97
83
86
72
72
73
53
7b
80 (S)
81 (S)
90 (S)
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
b
22
71
70
69
b
Et
b
n-Bu
c-Hex
Ph
b
4g
4h
c
b
9
53
a
Diastereomeric excesses were determined by HPLC.10
The absolute configuration was not determined.
Reaction was carried out in the presence of Yb(OTf)3 (0.1 equiv.) as a co-promoter in CH Cl –THF (4:1).
b
c
2
2
Scheme 2.

R. Tsuji et al. / Tetrahedron: Asymmetry 14 (2003) 177–180
179
Scheme 3.
Scheme 4.
4
a with 77% d.e., as shown in Scheme 3. Its absolute
Acknowledgements
configuration was again determined by HPLC analysis
in comparison with enantiomerically pure 7 derived
from
L
-tryptophan. These results show that readily
This research was supported by a Grant-in-Aid for
Scientific Research on Priority Areas (A) ‘Exploitation
of Multi-Element Cyclic Molecules’ from the Ministry
of Education, Culture, Sports, Science, and
Technology.
available chiral menthyl auxiliaries with the same stereo-
chemistry can induce opposite stereoselectivity at C-1
of the b-carbolines by controlling the transition state.
The stereoselectivities using 3b and 6 can be explained
by the transition state models shown in Scheme 4. In
the reaction of 3b, transition state A should be most
favorable when considering steric interactions between
R and the indole ring leading to (1S)-b-carbolines. On
the other hand, when the phenyl group in the chiral
auxiliary has a phenoxy substituent at the 4-position,
transition state B should be the most stable and gives
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2
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Pictet–Spengler reaction using TMSCl as a promoter.
The results described here may lead to further progress
in the synthesis of homochiral b-carbolines.

1
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4
1
0. Representative procedure (synthesis of 4b, Table 2, entry
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2
(
−
−
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3
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1
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2
2
7
. Trimethylchlorosilane may activate aldehydes by behav-
ing as a mild Lewis acid and can also remove water from
1
the reaction mixture to form (TMS) O. Stronger Lewis
2