Proline-Catalyzed Asymmetric Addition Reaction of 9-Tosyl-3,4-dihydro- β-carboline with Ketones

Article abstract of DOI:10.1021/ol030103x

(Equation presented) 9-Tosyl-3,4-dihydro-β-carboline (1) reacted with a ketone in the presence of (S)-proline as a catalyst to give the corresponding addition product in good yield and high enantioselectivity. In the process, a small amount of water was f

Full text of DOI:10.1021/ol030103x

ORGANIC
LETTERS
2003
Vol. 5, No. 23
4301-4304
Proline-Catalyzed Asymmetric Addition
Reaction of
9-Tosyl-3,4-dihydro-â-carboline with
Ketones
Takashi Itoh, Masashi Yokoya, Keiko Miyauchi, Kazuhiro Nagata, and
Akio Ohsawa*
School of Pharmaceutical Sciences, Showa UniVersity, 1-5-8 Hatanodai,
Shinagawa-ku, Tokyo 142-8555, Japan
ohsawa@pharm.showa-u.ac.jp
Received August 19, 2003
ABSTRACT
9-Tosyl-3,4-dihydro-â-carboline (1) reacted with a ketone in the presence of (S)-proline as a catalyst to give the corresponding addition product
in good yield and high enantioselectivity. In the process, a small amount of water was found to affect the stereoselectivity of the products.
The system was applied to reaction of compound 1 and 3-buten-2-one to give 3,4,6,7,12,12b-hexahydro-1H-indolo[2,3-a]quinolizin-2-one, which
is a versatile precursor for the synthesis of some indole alkaloids.
Asymmetric reactions catalyzed by metal-free chiral organic
compounds1 have become a rapidly expanded research area
in organic synthesis because they are more benign to the
environment than conventional metal-catalyzed reactions, and
intensive studies have revealed that several organic com-
pounds, which include chiral Lewis bases and phase-transfer
catalysts, are good enantioselective catalysts. In these reac-
tions, the proline-catalyzed asymmetric reaction2 is among
the most useful processes due to its simple procedure and
low cost. Thus, there have been numerous papers reporting
proline-catalyzed asymmetric reactions, that is, aldol reac-
tions,3 Mannich reactions,4 Michael reactions,5 R-aminations,6
Baylis-Hillman reactions,7 and so on. In the Mannich
reactions, imines formed in situ by reaction of aldehydes
and amines react with enamines, which are derived from
ketones and (S)-proline to give â-aminoketones in good
stereoselectivities.4 The amines used as the reactants,
however, were limited to aromatic ones, and there are no
(3) (a) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615-1621.
(b) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. 1971, 10,
496-497. (c) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc.
2000, 122, 2395-2396. (d) Notz, W.; List, B. J. Am. Chem. Soc. 2000,
122, 7386-7387. (e) List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3,
573-575. (f) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am.
Chem. Soc. 2001, 123, 5260-5267. (g) Northrup, A. B.; MacMillan, D.
W. C. J. Am. Chem. Soc. 2002, 124, 6798-6799. (h) Alcaide, B.;
Almendros, P. Angew. Chem., Int. Ed. 2003, 42, 858-860.
(4) (a) List, B. J. Am. Chem. Soc. 2000, 122, 9336-9337. (b) Notz, W.;
Sakthivel, K.; Bui, T.; Zhong, G.; Barbas, C. F., III. Tetrahedron Lett. 2001,
42, 199-201. (b) List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am.
Chem. Soc. 2002, 124, 827-833.
(1) (a) Gro¨ger, H.; Wilken, J. Angew. Chem., Int. Ed. 2001, 40, 529-
532. (b) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3726-
3748. (c) Jarvo, E. R.; Miller, S. J. Tetrahedron 2002, 58, 2481-2495, and
references therein.
(2) (a) List, B. Synlett 2001, 1675-1686. (b) List, B. Tetrahedron 2002,
58, 5573-5590.
(5) (a) Yamaguchi, M.; Yokota, N.; Minami, T. J. Chem. Soc., Chem.
Commun. 1991, 1088-1089. (b) List, B.; Pojarliev, P.; Martin, H. J. Org.
Lett. 2001, 3, 2423-2425. (c) Hanessian, S.; Pham, V. Org. Lett. 2000, 2,
2975-2978. (d) Enders, D.; Seki, A. Synlett 2002, 26-28.
10.1021/ol030103x CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/22/2003

reports concerning the reaction using cyclic imines as
substrates.
Scheme 1. Reaction of 9-Tosyl-3,4-dihydro-â-carboline (1)
with Acetone in the Presence of (S)-Proline
In the course of our study of asymmetric addition of
â-carboline derivatives,8 we have now applied the proline-
catalyzed reaction, and, as a result, it was found that 9-tosyl-
3,4-dihydro-â-carboline (1) is a good substrate for the
proline-catalyzed asymmetric addition of ketones. Moreover,
it was revealed that a certain amount of water played a crucial
role in obtaining the high stereoselectivity. Then, the reaction
was applied to the synthesis of 12-tosyl-3,4,6,7,12,12b-
hexahydro-1H-indolo[2,3-a]quinolizin-2-one, which is a
versatile precursor for the synthesis of some indole alkaloids.
This paper describes these results.
1,2,3,4-Tetrahydro-â-carboline derivatives having a sub-
stituent at the C-1 position widely exist in nature as a
constituent of indole alkaloids, and there have been many
reports concerning their syntheses.9 The Pictet-Spengler
reaction10 and the vinylogous Mannich reaction11 are among
the most representative methods and have been applied to
asymmetric syntheses using (S)-tryptophan as the starting
material. On the other hand, Meyers et al. has developed an
(S)-valine-derived chiral auxiliary to introduce an alkyl or
aryl substituent to the C-1 position of the â-carboline nucleus
in a highly diastereoselective manner.12 In addition, Naka-
mura et al. reported that a chiral allylzinc reagent reacted
with 3,4-dihydro-â-carboline (2) to give an allyl adduct in
high ee.13 To the best of our knowledge, however, there is
no study on application of the asymmetric catalytic process
to the ring system.
Table 1. Reaction of Compound 1 with Acetone in the
Presence of a Catalytic Amount of (S)-Proline
proline
H2O
yield of 3 ee
entry solvent (mol %) (equiv) temp time
(%)
76
79
(%)a
1
2
CH2Cl2
CH2Cl2
CH2Cl2
acetone
acetone
acetone
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
30
30
30
30
30
30
30
30
30
30
30
30
30
3
b
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
1.5 h
3.5 h
1 day tracec
34
80
10
50
b
3
4
2 h
2 h
2 h
2 h
2 h
2 h
2 h
2 h
69
24
80
82
5
5
10
50d
b
92
6
quant
quant
96
7
8
10
50
100
150
50
100
2
67
80
86
87
93
92
4
9
quant
98
10
11
12
13
14
15
16
quant
91
At first, 3,4-dihydro-â-carboline (2) was allowed to react
with acetone in the presence of (S)-proline, and it was found
that the substrate decomposed to a complicated mixture.
Thus, 9-tosyl-3,4-dihydro-â-carboline (1)14 was selected as
the next substrate.
-2 °Ce 2.5 h
-2 °Ce 3 h
99
rt
rt
2 h
2 h
91
3
10
50
92
60
94
3
-2 °Ce 23 h
99
a All the dominant enantiomers formed have the same chirality except
that of entry 7. b Although contaminated water was not detected in CH2Cl2,
a small amount of water was detected by the coulometer in two other
solvents (0.70 equiv in acetone, 1.04 equiv in DMSO). The detection limit
of water by this system was 0.35 equiv with respect to the substrate.
c Solvent became a bilayer in this case. d In the case of 100 equiv of H2O,
the yield and the ee both decreased. e Reaction medium was cooled to -2
°C because it was the lowest temperature at which the solvent did not
solidify.
(6) (a) List, B. J. Am. Chem. Soc. 2002, 124, 5656-5657. (b) Bøgevig,
A.; Juhl, K.; Kumaragurubaran, N.; Zhuang, W.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2002, 41, 1790-1793. (c) Kumaragurubaran, N.; Juhl, K.;
Zhuang, W.; Bøgevig, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2002, 124,
6254-6255. (c) Duthaler, R. O. Angew. Chem., Int. Ed. 2003, 42, 975-
978.
(7) Shi, M.; Jiang, J.-K.; Li, C.-Q. Tetrahedron Lett. 2001, 43, 127-
130.
(8) (a) Itoh, T.; Matsuya, Y.; Enomoto, Y.; Nagata, K.; Miyazaki, M.;
Ohsawa, A. Tetrahedron 2001, 57, 7277-7289. (b) Itoh, T.; Miyazaki, M.;
Ikeda, S.; Nagata, K.; Yokoya, M.; Matsuya, Y.; Enomoto, Y.; Ohsawa,
A. Tetrahedron 2003, 59, 3527-3536 and references therein.
(9) The Chemistry of Heterocyclic Compounds; Saxton, J. E., Ed.;
Wiley: Chichester, 1994; Part 4, supplement of Vol. 25.
(10) (a) Cox, E. D.; Cook, J. M. Chem. ReV. 1995, 95, 1797-1842 and
references therein. (b) Li, J.; Wang, T.; Yu, P.; Peterson, A.; Weber, R.;
Soerens, D.; Grubisha, D.; Bennett, D.; Cook, J. M. J. Am. Chem. Soc.
1999, 121, 6998-7010. (c) Yu, S.; Berner, O. M.; Cook, J. M. J. Am. Chem.
Soc. 2000, 122, 7827-7828.
(11) (a) Martin, S. F.; Benage, B.; Geraci, L. S.; Hunter, J. E.; Mortimore,
M. J. Am. Chem. Soc. 1991, 113, 6161-6171. (b) Martin, S. F.; Clark, C.
C.; Corbett, J. W. J. Org. Chem. 1995, 60, 3236-3242. (c) Martin, S. F.;
Chen, K. X.; Eary, C. T. Org. Lett. 1999, 1, 79-81. (d) Martin, S. F. Acc.
Chem. Res. 2002, 35, 895-904.
(12) (a) Meyers, A. I.; Sohda, T.; Loewe, M. F. J. Org. Chem. 1986, 51,
3108-3112. (b) Meyers, A. I.; Miller, D. B.; White, F. H. J. Am. Chem.
Soc. 1988, 110, 4778-4787. (c) Beard, R. L.; Meyers, A. I. J. Org. Chem.
1991, 56, 2091-2096. (d) Meyers, A. I.; Highsmith, T. K.; Buonora, P. T.
J. Org. Chem. 1991, 56, 2960-2964.
(13) Nakamura, M.; Hirai, A.; Nakamura, E. J. Am. Chem. Soc. 1996,
118, 8489-8490.
(14) Rey, A. W.; Szarek, W. A. Can. J. Chem. 1992, 70, 2922-
2928.
The reaction of 1 with acetone in the presence of 30 mol
% (S)-proline completed smoothly in dichloromethane,
acetone, or DMSO to give the 1-acetonyl-9-tosyl-1,2,3,4-
tetrahydro-â-carboline (3) in good yields, but the stereose-
lectivities were quite low (Table 1, entries 1, 4, and 7).15
Thus, we scrutinized the reaction conditions and found
that addition of a small amount of water improved the
selectivity. When water was added, however, the reaction
rate became slower, probably due to hydrolysis of an
intermediary enamine obtained from acetone and (S)-proline.
Thus, the optimal amount of water, which was analyzed
with a coulometer, is about 50-100 equiv with respect to
(15) Among these reactions, contaminated water was not detected in CH2-
Cl2, but a small amount of water was detected by a coulometer in other
solvents (0.70 equiv in acetone, 1.04 equiv in DMSO).
4302
Org. Lett., Vol. 5, No. 23, 2003

Scheme 2. Reaction of Compound 1 with Methyl Ketone in
the Presence of (S)-Proline
Scheme 3. Alternative Synthesis of 3 and 4 (R ) Et) from
Chiral 5
Table 2. Reaction of Compound 1 with a Ketone in the
Presence of a Catalytic Amount of (S)-Proline
proline H2O
yield of 4 ee
entry
R
(mol %) (equiv) temp time
(%)
(%)
1
2
3
4
5
6
7
8
9
Et
Et
Et
Et
Et
Et
Pr
Pr
Pr
50
50
50
50
5
rt
rt
rt
6.5 h
8 h
78
81
81
85
98
81
61
77
76
86
66
57
65
72
51
28
80
87
89
85
91
7
10
50
50
50
50
and 4; thus, the absolute configuration of 3 and 4 was
assigned as (R).
Then, 3-buten-2-one was used as a ketone to construct
the D-ring of indole alkaloids, and the results are shown in
Scheme 4. The reaction using compound 1 was carried out
8.5 h
-2 °C 30 h
rt
3 days
5
-2 °C 5 days
rt
50
50
50
5
4 h
50
50
50
50
rt
7 h
88
92
85
92
20
51
73
75
-2 °C 2 days
rt 36 h
-2 °C 5 days
rt
rt
rt
rt
10 Pr
11 Pr
Scheme 4. Reaction of Compound 1 with 3-Buten-2-one in
the Presence of (S)-Proline
5
12 i-BuOC2H4
13 i-BuOC2H4
14 i-BuOC2H4
15 i-BuOC2H4
50
50
50
50
26 h
20 h
20 h
20 h
10
30
50
the substrate. A decrease in the amount of the catalyst
resulted in no loss of the ee, and even in the presence of
3 mol % (S)-proline, good selectivity was observed (entry
16). The effect of water was also shown in these cases
(entries 14-16). Therefore, the yield and selectivity were
improved by using DMSO solvent and 3 mol % (S)-proline
in the presence of 50 equiv of water at -2 °C16 to give
compound 3 in 99% yield and 94% ee (Table 1, entry
16).
Next, the same procedure was applied to other ketones,
and the results are summarized in Table 2 (Scheme 2). In
these cases, the effect of H2O was observed again, and the
products were obtained in a highly enantioselective manner
in the presence of water (Table 2, entries 4, 9, and 15) using
50 mol % proline. Although a decrease in the amount of the
catalyst lengthened the reaction time, high enantioselectivity
was obtained (Table 2, entries 6 and 11).
The stereochemistry of compounds 3 and 4 (R ) Et) thus
obtained was determined by an alternative synthesis from a
chiral (S)-1-allyl-1,2,3,4-tetrahydro-â-carboline (5), whose
absolute configuration was confirmed by our group8a (Scheme
3).
in DMSO, and 12-tosyl-3,4,6,7,12,12b-hexahydro-1H-indolo-
[2,3-a]quinolizin-2-one (6) was formed in 76% yield with
92% ee even in the absence of H2O. The addition of H2O in
this system resulted in only retardation of the reaction
progress without variation of the stereoselectivity. The
absolute configuration of 6 was determined by derivatization
of 6 to detosylated compound 7,17 which has been reported
as a versatile precursor for the syntheses of some indole
alkaloids such as yohimbine18 and deserpidine.19
(16) Reaction medium was cooled to -2 °C because it was the lowest
temperature at which the solvent remains liquid.
(17) Waldmann, H.; Braun, M.; Weymann, M.; Gewehr, M. Tetrahedron
1993, 49, 397-416.
(18) Kametani, T.; Hirai, Y.; Kajiwara, M.; Takahashi, T.; Fukumoto,
K. Chem. Pharm. Bull. 1975, 23, 2634-2642.
The obtained compounds shown in Scheme 3 had the same
NMR spectra and opposite specific rotations to those of 3
Org. Lett., Vol. 5, No. 23, 2003
4303

In this paper, we have disclosed the first catalytic
asymmetric addition reaction of 3,4-dihydro-â-carboline
using (S)-proline as the chiral catalyst. Although the stereo-
selectivity shown in this work20 is in accord with the
mechanism proposed by List et al.,4b the effect of H2O on
the stereoselectivity in our reaction system remained unclear.
As shown in Table 1 (entries 7-9 vs 14-16), the ratio of
water to (S)-proline seldom affected the enantioselectivity.
Thus, this suggests that the effect of water derives from the
interaction of H2O with the substrate rather than with proline.
In the case of 3-buten-2-one, the addition of H2O only
resulted in decrease of the reaction rate, and the high
selectivity was observed in the absence of water. Thus, there
might be alternative reaction pathways in the addition to
cyclic imine systems. Study of the detailed reaction mech-
anism, a search for other substrates, and application of the
reaction products to the synthesis of indole alkaloids are now
in progress.
Supporting Information Available: Detailed experi-
mental procedures and spectral data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL030103X
(20) Substrate of the present reaction has the (Z)-imine structure; thus,
the transition state was supposed to be similar to that of the aldol reaction
(ref 3, Re face attack) rather than the one for the (E)-imine Mannich reaction
(ref 4, Si face attack).
(19) Sza´ntay, C.; Blasko´, G.; Honty, K.; Szabo´, L.; To¨ke, L. Heterocycles
1977, 7, 155-160.
4304
Org. Lett., Vol. 5, No. 23, 2003