A new entry to asymmetric synthesis of 1-substituted 1,2,3,4-tetrahydro-β-carbolines employing a pyroglutamic acid derivative as a chiral auxiliary

Article abstract of DOI:10.1055/s-2002-31931

β-Carboline which was protected at N-9 by an acyl group derived from L-pyroglutamic acid reacted with allyltributyltin or silyl enol ethers in the presence of an alkyl chloroformate in a highly diastereoselective manner to give 1-substituted 1,2-dihydro-β

Full text of DOI:10.1055/s-2002-31931

LETTER
1005
A New Entry to Asymmetric Synthesis of 1-Substituted 1,2,3,4-Tetrahydro- -
carbolines Employing a Pyroglutamic Acid Derivative as a Chiral Auxiliary
A
symmetric Sy
a
1
k
,2,3,4-Tetrah
a
ydro- -car
s
boline
s
hi Itoh, Kazuhiro Nagata, Masashi Yokoya, Michiko Miyazaki, Sachiko Ikeda, Yuji Matsuya,
Yasuko Enomoto, Akio Ohsawa*
School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
Fax +81(3)37845982; E-mail: ohsawa@pharm.showa-u.ac.jp
Received 4 April 2002
Abstract: -Carboline which was protected at N-9 by an acyl group
NCO2CH2CCl3
N
ClCO2CH2CCl3 (2 eq.)
derived from L-pyroglutamic acid reacted with allyltributyltin or si-
lyl enol ethers in the presence of an alkyl chloroformate in a highly
diastereoselective manner to give 1-substituted 1,2-dihydro- -car-
bolines. The compounds were readily transformed to the corre-
sponding asymmetric 1-substituted tetrahydro- -carbolines that are
common partial structures in a variety of indole alkaloids.
N
N
H
N
O
O
(3 eq.), CH2Cl2
–40 °C, 24 h
Bu3Sn
N
R
R
2
1
O
O
NaOH, THF-H2O
rt., 30 min
NCO2CH2CCl3
N
H
H
Key words: -carboline, allyltributyltin, silyl enol ether, pyro-
glutamic acid, asymmetric addition, indole alkaloid
3
Scheme 1
-Carboline nucleus which has a chiral center at C-1 posi-
tion exists widely in nature as a part of various indole al-
kaloids.1 In the course of our study of the asymmetric
synthesis of 1-substituted 1,2,3,4-tetrahydro- -carbo-
lines, we found that allyltin reagents reacted with -carbo-
line having a chiral auxiliary derived from L-proline at N-
9 position to give 1-allyl-1,2-dihydro derivatives in good
yields with high diastereoselectivity.2 Moreover, it was
also found that the synthesis of the both enantiomers was
readily performed in the presence of the same chiral aux-
iliary by simply selecting allyltributyltin or tetraallyltin.3
Thus the previous reaction was proved to be useful for the
synthesis of chiral 1-allyl derivatives of -carboline.
give a 1,2-dihydro adduct 2, which was successively hy-
drolyzed to 3 in a quantitative yield.8 The chiral auxiliary
was completely recovered under the mild hydrolytic con-
ditions. When the amide hydrogen of L-pyroglutamyl
group was displaced with phenylsulfonyl group, the R iso-
mer was obtained through the mechanism in which was
supposed to involve coordination of the sulfonyl group of
the chiral auxiliary to allyltributyltin (entry 1). When me-
thyl group was introduced instead of sulfonyl group, the
stereoselectivity was changed from R to S despite the low
ee (entry 2). The ee was increased by the use of bulkier
benzyl and naphthylmethyl groups (entries 3–5), and the
employment of N-anthracenylmethyl group afforded a
To our disappointment, however, nucleophiles other than
allyltins gave poor results.4 To overcome the disadvan-
tage, we have investigated other chiral auxiliaries at N-9
position of -carboline, and found that a pyroglutamic
acid derivative gave a good stereoselectivity for the reac-
tion with both allyltributyltin and silyl enol ethers. This
paper describes these results.
Table 1 Asymmetric Addition Reaction of Allyltributyltin with -
Carboline, which have a Chiral Auxiliary Derived from Pyroglutamic
Acid at N-9
Entry
Com-
pound
R
Yield of 2 ee of 3a
(%)
(%)
In the previous study,2,3 the asymmetric induction was
supposed to be originated from the coordination of an al-
lyltin reagent to a sulfonyl group in the chiral auxiliary.5
Thus, it was thought that removal of the sulfonyl group
would simplify the reaction mechanism and that the use of
a simple steric factor would improve the reaction system
toward a more general procedure. Our study revealed that
N-(9-anthracenylmethyl)pyroglutamyl group was a good
chiral auxiliary (Scheme 1 and Table 1).6
1
2
3
4
a
b
c
-SO2Ph
-Me
51
79 (R)
7 (S)
22
-CH2Ph
95
21 (S)
58 (S)
d
87
5
6
e
f
Quant.
98
66 (S)
91 (S)
In the event, the compound 17 was allowed to react with
allyltributyltin and 2,2,2-trichloroethyl chloroformate to
Synlett 2002, No. 6, 04 06 2002. Article Identifier:
1437-2096,E;2002,0,06,1005,1007,ftx,en;Y04502ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
a The ee was estimated by HPLC after removal of the chiral auxiliary.

1006
T. Itoh et al.
LETTER
higher yield and the best stereoselectivity (entry 6).9 Thus, The dihydro adduct was reduced with triethylsilane to
we found that the naturally more required S isomer was give the corresponding tetrahydro derivative, which was
obtained from the naturally dominant S isomer of pyro- further reduced with zinc-acetic acid, and succeeding es-
glutamyl group.
terification (the yield not optimized) of a free carboxylic
acid afforded methyl ester of tetrahydro- -carboline 1-
acetic acid. The absolute configuration was determined as
S by the comparison of the specific rotation with the re-
ported one.11 Thus, it was proved that the reaction pro-
ceeded in an S selective manner regardless the
nucleophilic species.
Next, silyl enol ethers were adopted as nucleophiles in-
stead of allyltributyltin, and the results are summarized in
Table 2 (Scheme 2).
R2
R2
OTMS
R1
N
NaOH
THF-H2O
N
O
In order to investigate the origin of stereoselectivity,
PM3 calculations12 were carried out for the intermediary
N-2 acylated quaternary salts of -carboline 7 whose op-
timized structures are shown in Figure.
rt. 1 h
ClCO2CH2CCl3 (2 eq.)
CH2Cl2
N
1
O
NCO2CH2CCl3
N
H
H
O
R2
R2 R1
4
Scheme 2
Table 2 Asymmetric Addition Reaction of Silyl Enol Ethers with
9-(N-Anthracenylmethylpyroglutamyl)- -carboline
Entry R1
R2
Temp. Time
Prod- Yield eea
(°C)
(h)
uct
4a
4b
4c
4d
4e
(%)
(%)
1
2
3
4
5
Me
H
0
24
40
79
Ph
H
0
2.5
0.5
12
19
79
86
OMe
OBn
SBn
Me
H
0
quant. 82
–40
–40
81
83
88
87
H
a The ee was estimated by HPLC after removal of the chiral
auxiliary.
Figure Calculated PM3 structures of 2-(trichloroethoxycarbonyl)-
9-(N-anthracenylmethylpyroglutamyl)- -carbolinium cation (7)
In our previous system, silyl enol ethers afforded poor re-
sults because the reagents do not have coordinative inter-
action with the substrate. In the present reaction, however,
the reaction proceeded in a highly diastereoselective man-
ner to give the dihydro adducts 4 in good yields after a hy-
drolytic process.10 Thus, a general method for the
synthesis of naturally occurring S isomer of 1-substituted
1,2,3,4-tetrahydro- -carboline was accomplished using L-
pyroglutamic acid as a chiral auxiliary.
In the optimized conformation (A), anthracenyl group is
located at the syn position to the -carboline group proba-
bly due to - interaction of these two groups. The re face
of the C-1 reaction site of -carboline ring is effectively
shielded. A conformation in which the si face is shielded
was obtained as a local minimum structure (B), but it was
3.22 kcal/mol less stable than (A). Thus, the stereoselec-
tivity could be accounted for by the shielding of the re
face by the anthracenyl group.
For the determination of stereoselectivity using silyl enol
ethers, the adduct 4d was transformed to a tetrahydro de-
rivative as mentioned in Scheme 3.
In this paper, we described a new method for the asym-
metric addition of allyltributyltin or silyl enol ethers to -
carboline at C-1 position using a novel chiral auxiliary de-
rived from (S)-pyroglutamic acid. The auxiliary was
readily recovered quantitatively by hydrolysis. Although
pyroglutamic acid has been used for a versatile building
block for asymmetric synthesis,13 there are few examples
using its derivatives as chiral auxiliaries.14 Application of
the adducts obtained by this method to the total synthesis
of indole alkaloids is now under investigation.
Et3SiH
4d
NCO2CH2CCl3
CH2Cl2, rt., 15 min
N
87%
H
H
CO2Bn
5
1) Zn, AcOH
THF/H2O, rt. 0.5 h
[α]D=+42.47 (c=0.23, CHCl3)
{lit [α]D=+50.0 [(S)-isomer]}
NH
N
2) NaOMe-MeOH
rt., 10 min
H
H
CO2Me
6 47%
Scheme 3
Synlett 2002, No. 6, 1005–1007 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Asymmetric Synthesis of 1,2,3,4-Tetrahydro- -carbolines
1007
mmol), 2,2,2-trichloroethyl chloroformate (0.2 mmol) was
added at -40 °C under Ar atmosphere, and the reaction was
continued for 24 h at the same temperature. Then 3 M
aqueous KF solution was added to the solution, and the
mixture was allowed to stir vigorously for 1 h. The organic
layer was separated, dried over MgSO4, and evaporated off
to leave the residue, which was chromatographed on silica
gel to afford the adduct 2. The compound 2 was dissolved in
THF (1 mL), and treated with 1 M aqueous KOH solution (2
mL) for 30 min. Then H2O was added to the mixture, which
was extracted with CH2Cl2 to give pure 3. The aqueous layer
was acidified with HCl and extracted with CH2Cl2 to afford
the recovered chiral auxiliary.
References
(1) The Chemistry of Heterocyclic Compounds, Vol. 25, Part 4;
Saxton, J. E., Ed.; John Wiley & Sons: Chichester, 1994.
(2) Itoh, T.; Matsuya, Y.; Enomoto, Y.; Nagata, K.; Miyazaki,
M.; Ohsawa, A. Synlett 1999, 1799.
(3) (a) Matsuya, Y.; Itoh, T.; Enomoto, Y.; Ohsawa, A.
Heterocycles 2000, 53, 2357. (b) Itoh, T.; Matsuya, Y.;
Enomoto, Y.; Ohsawa, A. Tetrahedron 2001, 57, 7277.
(4) In the previous reaction which adopted N-
phenylsulfonylprolinyl group as a chiral auxiliary, the
addition using silyl enol ethers afforded the products in good
yields but poor diastereoselectivity (<20%).
(5) The coordination mechanism was supposed to participate
only in the reaction of -carbolines. In the cases of
isoquinoline derivatives, only the steric factor might control
the stereochemistry; see: (a) Itoh, T.; Nagata, K.; Miyazaki,
M.; Ohsawa, A. Synlett 1999, 1154. (b) Itoh, T.; Nagata, K.;
Miyazaki, M.; Kameoka, K.; Ohsawa, A. Tetrahedron 2001,
57, 8827. (c) Nagata, K.; Itoh, T.; Kameoka, K.; Miyazaki,
M.; Ohsawa, A. Heterocycles 2001, 55, 2269.
(6) N-Protected L-pyroglutamic acids were readily prepared
from the reaction of t-butyl L-pyroglutamate and an alkyl
halide in the presence of NaH, followed by hydrolysis.
(7) The compound 1 was obtained as follows: To the mixture of
N-alkyl L-pyroglutamic acid (0.5 mmol) and -carboline
(0.5 mmol) in CH2Cl2 (1 mL) was added ethyl-(N,N -
dimethylaminopropyl)carbodiimide hydrochloride (0.6
mmol), and the mixture was reacted for 3 h at room
temperature. Then the solvent was evaporated off, and the
residue thus formed was chromatographed on silica gel
(EtOAc) to give 9-acyl- -carbolines 1.
(9) The absolute configuration of the allyl adduct 3 was
determined by the previous mentioned method; see ref.3b
(10) In these cases, the dihydro adduct initially obtained was
hydrolyzed without the isolation to give the compound 4,
because of the instability of the intermediate.
(11) Tietze, L. F.; Zhou, Y.; Töpken, E. Eur. J. Org. Chem. 2000,
2247.
(12) The molecular orbital calculations were carried out using the
PM3 procedure with the standard parameters, as
implemented in the MOPAC2000 program.
(13) Najera, C.; Yus, M. Tetrahedron: Asymmetry 1999, 10,
2245; and references cited therein.
(14) (a) Menezes, R. F.; Zazza, C. A.; Sheu, J.; Smith, M. B.
Tetrahedron Lett. 1989, 30, 3295. (b) O’Meara, J. A.; Jung,
M.; Durst, T. Tetrahedron Lett. 1995, 36, 2559. (c) Roth,
E.; Altman, J.; Kapon, M.; Ben-Ishai, D. Tetrahedron 1995,
51, 801. (d) Behr, J. B.; Defoin, A.; Pires, J.; Streith, J.;
Kacko, J. L.; Zehnder, M. Tetrahedron 1996, 52, 3283.
(e) Ezquerra, J.; Prieto, L.; Avendano, C.; Martos, J. L.; de
la Cuesta, E. Tetrahedron Lett. 1999, 40, 1575.
(8) Experimental procedure: To the CH2Cl2 solution (1 mL) of
9-acyl- -carboline 1 (0.1 mmol) and allyltributyltin (0.3
Synlett 2002, No. 6, 1005–1007 ISSN 0936-5214 © Thieme Stuttgart · New York