Synthesis of simple enantiopure tetrahydro-β-carbolines and tetrahydroisoquinolines

Article abstract of DOI:10.1002/1099-0690(200006)2000:12<2247::AID-EJOC2247>3.0.CO;2-4

Enantioselective hydrogenation of the imines 11-13, 27 and 30 with the Ru complex (R,R)-5 led to the tetrahydro-β-carbolines (1S)-14, (1R)-21 and (1S)-22, and the tetrahydroisoquinoline (1S)-31 with ee > 95%. By employing (S,S)-5 the enantiomers are accessible. The imines 11-12 and 27 were obtained by oxidation of racemic 14, 21 and 22 with KMnO₄ in > 58% yield.

Full text of DOI:10.1002/1099-0690(200006)2000:12<2247::AID-EJOC2247>3.0.CO;2-4

FULL PAPER
Synthesis of Simple Enantiopure Tetrahydro-β-carbolines and
Tetrahydroisoquinolines
[
a]
[a]
[a]
Lutz F. Tietze,* Yifa Zhou, and Enno Töpken
Dedicated to Professor Yishen Zhang (Biology Department of Northeast Normal University, China)
on the occasion of her 60th birthday
Keywords: BischlerϪNapieralski reaction / Asymmetric synthesis / Hydrogenations / Oxidations / Tetrahydro-β-carbolines /
Tetrahydroisoquinolines
Enantioselective hydrogenation of the imines 11−13, 27 and
0 with the Ru complex (R,R)-5 led to the tetrahydro-β-car-
bolines (1S)-14, (1R)-21 and (1S)-22, and the tetrahydroiso-
quinoline (1S)-31 with ee Ͼ 95%. By employing (S,S)-5 the
enantiomers are accessible. The imines 11−12 and 27 were
3
obtained by oxidation of racemic 14, 21 and 22 with KMnO
in Ͼ 58% yield.
4
Introduction
Tetrahydro-β-carbolines and tetrahydroisoquinolines are
found abundantly in the plant kingdom and many of them
exhibit important physiological activities.[ This includes
inhibition of monoamine oxidase, as well as in vivo filarici-
dal activity against Litomosoides carinii and Acanthochei-
lonema viteae in rodents.[ On the other hand, C-1 substi-
tuted tetrahydro-β-carbolines and C-1-substituted tetrahy-
droisoquinolines are valuable substrates for the synthesis of
1]
2]
[3]
indole and isoquinoline alkaloids.
Recently we have
developed an efficient synthesis of the tetracyclic indole
alkaloid hirsutine (4), which is highly effective against
the influenza A virus, using a domino-Knoevenagel
hetero-DielsϪAlder solvolysisϪhydrogenation process
[
4,5]
(Scheme 1).
In this transformation, a mixture of the al-
dehyde 1, Meldrum’s acid (3) and 1-alkoxybutene (2) was
heated to 60 °C and treated with methanol/K CO followed
2
3
by hydrogenation. The enantiopure aldehyde 1 was pre-
pared by chromatographic separation of diastereomeric Scheme 1. Synthesis of hirsutine 4
amides with camphanic acid. Since this method is not
straightforward we were looking for a shorter way to pre- with chiral or achiral hydride reagents, have been de-
pare enantiopure 1 as well as other enantiopure C-1 substi- scribed.[ In addition, catalytic enantioselective procedures
tuted tetrahydro-β-carbolines and C-1 substituted tetrahy- are known.[ Especially useful seems to be the hydrogena-
droisoquinolines which may be used in the described pro- tion of cyclic imines using the chiral N-sulfonated diamine
8]
9]
cess.
Ru complexes 5 as catalysts, as developed by Noyori et
Several methods for the synthesis of the described com- al.[ Here, we describe the synthesis of enantiopure 14,
pounds using a stoichiometric amount of a chiral building which is a precursor of the aldehyde 1, and analogous tetra-
block, auxiliary or reagent, as in the asymmetric hydro-β-carbolines and tetrahydroisoquinolines starting
10]
[6]
PictetϪSpengler reaction, the asymmetric nucleophilic from the corresponding imines using this process.
and electrophilic introduction of a carbon unit at C-1, as
[7]
well as in the asymmetric reduction of dihydroisoquinolines Results and Discussion
[
a]
Institut für Organische Chemie der Georg-August-Universität
Göttingen,
Tammannstraße 2, D-37077 Göttingen, Germany
Fax: (internat.) ϩ 49-5/5139-9476
E-mail: ltietze@gwdg.de
The catalyst 5 (Scheme 2) can be conveniently prepared
6
in situ without isolation. A mixture of [RuCl (η -benzene)]
2
2
and TsDPEN (Ru atom:TsDPEN ϭ 1:1.2) in acetonitrile
was stirred for 5 min and the brown suspension formed was
Eur. J. Org. Chem. 2000, 2247Ϫ2252

WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0612Ϫ2247 $ 17.50ϩ.50/0
2247

L. F. Tietze, Y. Zhou, E. Töpken
FULL PAPER
Scheme 2. Catalysts for the enantioselective hydrogenation
directly employed for the hydrogenation of the imines in a
5
:2 formic acid/triethylamine mixture in acetonitrile.
The necessary imines were prepared by applying the
BischlerϪNapieralski reaction and then the controlled ox-
idation and dehydrogenation of the appropriate 1,2,3,4-
tetrahydro-β-carbolines.[
11]
The reaction of tryptamine 6
and the acid chloride 7 gave the enamine 8 and the imine
1 in a ratio of 9:1 in 50% yield,[12] whereas dehydrogena-
tion of 14 with Pd/C (10%) in refluxing ethanol furnished a
1
1
0:1 mixture of 9 and 12.[13] The reaction of 15 with diethyl
[14]
malonate led to 10 and 13 in a ratio of 10:1 (Scheme 3).
Looking for a more selective method for the synthesis of
the necessary imines we prepared the corresponding ra-
cemic 1,2,3,4-tetrahydro-β-carbolines 14 and 21؊24, using
a PictetϪSpengler reaction of tryptamine hydrochloride
(16) and aldehydes or α-keto acids 17؊20, in good yield.
The methyl ester 22 was obtained from the ethyl ester 14 by
solvolysis with methanol/K CO . Oxidation of the tetrahy-
2
3
dro-β-carbolines 14, 21 and 22 with solid potassium per-
manganate in tetrahydrofuran at Ϫ10 to 0 °C gave the cor-
responding imines in 58Ϫ97% yield,[
11d]
with the lowest
Scheme 4. Enantioselective synthesis of tetrahydro-β-carbolines
yield found for the methyl ester 22 due to its reduced
stability relative to 14. The oxidation of 23 and 24 did not
lead to the desired imines but furnished the corresponding
β-carbolines 25 and 26 instead.
For the hydrogenation, in some cases we used the mixture
of the imines and enamines and in others the pure imines.
Reaction of the mixtures 8/11, 9/12 and 10/13 in formic
acid/triethylamine 5:2 using the catalyst (R,R)-5 gave (1S)-
1
4, (1R)-21 and (1S)-22, respectively, with 96Ϫ97% ee in
5
9Ϫ72% yield based on the amount of the imine in the
mixture (Scheme 4). The enamines did not react under these
conditions and were recovered unchanged. The hydrogena-
tion of the imines 11؊13 and 27 under the same conditions
led to the C-1 substituted tetrahydro-β-carbolines (1S)-14,
(
1R)-21 and (1S)-22 in 50Ϫ93% yield based on racemic 14
and 21؊22, with 95Ϫ97% ee. The obtained products are
Scheme 3. Synthesis of β-carbolines
248
almost pure, so in most cases chromatography is not
2
Eur. J. Org. Chem. 2000, 2247Ϫ2252

Enantiopure Tetrahydro--carbolines and Tetrahydroisoquinolines
FULL PAPER
Conclusion
In summary, simple racemic C-1 substituted tetrahydro-
β-carbolines were transformed into the enantiopure com-
pounds using a sequence of oxidation with potassium per-
manganate and hydrogenation in formic acid/triethylamine
with the Ru catalyst 5. The products were obtained in
5
0Ϫ93% yield and 95Ϫ99% ee. Similarly, enantiopure C-1
substituted tetrahydroisoquinolines were prepared from the
corresponding imine. Since both (R,R)-5 and (S,S)-5 are
available, (1S)-tetrahydro-β-carbolines and (1S)-tetrahy-
droisoquinolines, as well as their enantiomers, can be pre-
pared in excellent enantiopurity.
Scheme 5. Enantioselective synthesis of tetrahydroisoquinoline 31
Experimental Section
2
General: All reactions were carried out under N and monitored
by TLC (POLYGRAM SIL G/UV254, MachereyϪNagel GmbH &
Co. KG). Ϫ All reagents from commercial suppliers were used
without further purification. Ϫ Products were isolated by flash col-
umn chromatography on silica gel (Silica gel, particle size
0
.040Ϫ0.063 mm, MachereyϪNagel GmbH & Co. KG). Ϫ HPLC:
Kroma-system 2000; Detector DAD 440; Column: OR-D,
Chiralcel; Solvents: MeOH/H O ϭ 80/20; flow rate: 0.5 mL/min.
Ϫ H NMR and C NMR: Varian XL-200 and VXR-200. Ϫ IR:
Scheme 6. Synthesis of Mosher derivatives
2
1
13
necessary. Since the catalyst (S,S)-5 is also available, the en- Bruker VECTOR 22. Ϫ MS: Varian MAT 311A and Varian MAT
antiomeric tetrahydro-β-carbolines can also be prepared. 731 for high resolution.
Hydrogenation of 12 with (S,S)-5 as catalyst led to (1R)-14
in 93% yield and 97% ee.
For the synthesis of the enantiopure tetrahydroisoquino-
6
[17]
Dichloro(η -benzene)ruthenium(II):
300 mg, 41% Ru), ethanol (4 mL) and cyclohexadiene (3 mL) was
refluxed for 4 h, filtered, and dried under reduced pressure to give
3 2
A mixture of RuCl ⋅H O
(
line 31 the imine 30 was prepared by condensation of 28 [RuCl (C H )] (300 mg, 1.20 mmol, 98%) as a brown powder. Ϫ
2
6
6 2
ϩ
2 6 6
with 29 in the presence of SnCl to give 30 in 92% yield MS (DCI): m/z (%) ϭ 285 [M ϩ 17 ϩ 18] . Ϫ [RuCl (C H )]
4
[
15]
(Scheme 5).
Surprisingly, in this reaction only the imine (250.1).
is formed; the corresponding enamine was not found. En-
antioselective hydrogenation of 30 with (R,R)-5 gave (1S)-
(
1R,2R)-1,2-Diphenyl-N-(p-tolylsulfonyl)ethylenediamine: A solu-
tion of p-TosCl (0.45 g, 2.40 mmol) in 5 mL THF was added to a
mixture of (1R,2R)-(Ϫ)-1,2-diphenylethylenediamine (0.50 g,
3
1 in 85% yield and 99% ee.
The absolute configuration of the tetrahydro-β-carbol- 2.40 mmol) in THF (20 mL) and triethylamine (1 mL) over a
ines (1R)-14 and (1S)-14 as well as tetrahydroisoquinoline period of 0.5 h at 0 °C. After stirring for 12 h the solvent was re-
3
1 was determined according to an X-ray analysis of the moved under reduced pressure. The remaining solid was treated
with aqueous sat. NaHCO
3
solution (40 mL) and CH
Cl
2 2
(40 mL).
SO , and
corresponding Mosher acid derivative 32 (Scheme 6, Fig-
ure 1).
[
16]
The organic phase was washed with brine, dried over Na
2
4
then concentrated in vacuo. The crude product was purified by
chromatography with ethyl acetate to give (1R,2R)-1,2-diphenyl-N-
(
p-tolylsulfonyl)ethylenediamine (0.79 g, 2.20 mmol, 90%) as a
2
0
). Ϫ 1H NMR
white solid. Ϫ [α]
D
ϭ Ϫ25.0 (c ϭ 0.2 in CHCl
, D O exchange): δ ϭ 7.25 (d, J ϭ 8.0 Hz, 2 H,
arom.), 7.55Ϫ7.00 (m, 10 H, Ph-H), 6.88 (d, J ϭ 8.0 Hz, 2 H,
arom.), 4.30 (d, J ϭ 5.5 Hz, 1 H, CHϪNHSO ), 4.05 (d, J ϭ
.5 Hz, 1 H, CHϪNH ), 2.25 (s, 3 H, CH ). Ϫ C NMR
50.3 MHz, CDCl ): δ ϭ 142.4, 141.4, 139.3, 137.1, 129.1, 128.3,
28.2, 127.34, 127.26, 126.9, 126.8, 126.5 (arom.-C), 63.3, 60.4
3
(
200 MHz, CDCl
3
2
2
1
3
5
(
1
2
3
3
ϩ
(
CH
2
), 21.4 (CH
3
). Ϫ MS (DCI): m/z (%) ϭ 367 [M ϩ 1] , 384 [M
ϩ
ϩ 18] . Ϫ C21H O N S (366.5).
22 2 2
In a similar manner (1S,2S)-1,2-diphenyl-N-(p-tolylsulfonyl)ethy-
lenediamine was obtained.
General Procedure for Enantioselective Hydrogenation: Prior to use,
the catalyst (R,R)-5 or (S,S)-5 was prepared by stirring 0.02 equiv.
6
Figure 1. X-ray structure of (1R)-32
Eur. J. Org. Chem. 2000, 2247Ϫ2252
of dichloro(η -benzene)ruthenium(II) and 0.024 equiv. of (1R,2R)-
2249

L. F. Tietze, Y. Zhou, E. Töpken
FULL PAPER
2
0
1
,2-diphenyl-N-(p-tolylsulfonyl)ethylenediamine or (1S,2S)-1,2-di-
0.71 mmol, 96%) as a yellow oil. Ϫ [α]
CHCl ); [α]
3 D
D
ϭ ϩ61.4 (c ϭ 0.5 in
ϭ Ϫ44.0 (c ϭ 0.5 in MeOH). Ϫ IR (KBr): ν˜ ϭ 3314
(NϪH Indol), 2982, 2848 (CϪH), 1728 (CϭO), 1180 (CϪOϪEt),
2
0
phenyl-N-(p-tolylsulfonyl)ethylenediamine in acetonitrile for 5 min.
Formic acid/triethylamine (5:2, 2 mL/equiv.) and the obtained cata-
lyst was added to a solution of 1 equiv. of the imine in acetonitrile
Ϫ1
1
3
744 (Ph-H) cm . Ϫ H NMR (200 MHz, CDCl ): δ ϭ 8.62 (br s,
(
5 mL/equiv.). After stirring at room temp. for 8 h, the mixture was
1 H, NϪH Indol), 7.52Ϫ7.02 (m, 4 H, arom.-H), 4.47 (t, J ϭ 8.0,
Hz, 1 H, 1-H), 4.42 (q, J ϭ 8.0 Hz, 2 H, 3Ј-H), 3.01Ϫ3.03 (m, 2
made basic by addition of aqueous Na CO solution and extracted
2
3
with ethyl acetate. The organic phase was washed with brine, dried H, 3-H), 2.81 (d, J ϭ 8.0 Hz, 2 H, 1Ј-H), 2.73 (m, 2 H, 4-H), 1.85
1
3
with Na
the product.
2
SO
4
, and concentrated under reduced pressure to afford
(br s, 1 H, NH), 1.29 (t, J ϭ 8.0 Hz, 3 H, 4Ј-H). Ϫ C NMR
(50.3 MHz, CDCl ): δ ϭ 173.1 (CϭO), 135.4, 134.9, 127.0, 121.6,
19.2, 118.0, 110.9, 108.9 (8 C, arom.), 61.0 (OCH ), 48.7, 41.9 (C-
), 40.8 (C-3), 22.5 (C-4), 14.1 (CH ). Ϫ MS (70 eV): m/z (%) ϭ
3
1
1
2
2
1,2,3,4-Tetrahydro-β-carboline (1R)-21: Tryptamine hydrochloride
3
(1.0 g, 5.1 mmol) was dissolved in ethanol (20 mL), cooled to 0° C,
ϩ
ϩ
11 2 18 2 2
58 (56) [M] , 171.0 (100) [C11H N ] . Ϫ HRMS (C15H N O ):
and then a solution of glyoxylic acid ethyl ester (1.3 mL, 6.1 mmol)
in toluene was added. The reaction mixture was stirred over night
at room temp., the solvents were removed under reduced pressure,
and the obtained mixture was treated with sat. aqueous NaHCO
solution (30 mL) and ethyl acetate (30 mL). The aqueous phase
was extracted with ethyl acetate (30 mL). The combined organic
calcd. 258.1368; found 258.1368.
14 (0.26 g, 1.0 mmol) was treated with catalyst (S,S)-5 in the same
manner to give (1R)-14 (0.23 g, 0.90 mmol, 93%) as a yellow oil. Ϫ
[α] ϭ Ϫ61.9 (c ϭ 0.5 in CHCl ); [α]D ϭ ϩ44.6 (c ϭ 0.5 in
3
2
0
20
D
3
MeOH).
2 4
phases were dried with Na SO and the solvent was removed under
reduced pressure. Purification by flash chromatography with ethyl
acetate and triethylamine (100:1) afforded the compound 21
1
(
,2,3,4-Tetrahydro-β-carboline (1S)-22: A solution of ethyl ester 14
0.50 g, 1.90 mmol) in MeOH (10 mL) was stirred with a catalytic
amount of K CO for 4 h to give the methyl ester (0.43 g,
1.80 mmol, 93%) as a yellow oil. As described for 14, the product
2 (0.20 g, 82.0 µmol) was treated with KMnO and (R,R)-5 to
give (1S)-22 (0.11 g, 0.43 mmol, total yield 55%) as a yellow oil. Ϫ
(
0.62 g, 2.50 mmol, 50%) as a yellow oil which is not stable at room
2
3
Ϫ1
1
temp. ϪIR (film): ν˜ ϭ 3395, 2978, 2932, 1732, 743 cm . Ϫ
NMR (200 MHz, CDCl ): δ ϭ 8.30 (s, 1 H, indole-H), 7.60Ϫ7.05
m, 4 H, arom.), 4.76 (br s, 1 H, 1-H), 4.30 (qd, J ϭ 7.0, 1.2 Hz, 2
H
2
4
3
(
2
0
20
α]
D 3 D
[ ϭ ϩ50.0 (c ϭ 0.5 in CHCl ); [α] ϭ Ϫ28.0 (c ϭ 0.5 in
H, CH
2
), 3.20Ϫ3.05 (m, 2 H, 3-H), 2.85Ϫ2.70 (m, 2 H, 4-H), 2.60
). Ϫ HRMS
MeOH). Ϫ IR (KBr): ν˜ ϭ 3394, 3110 (NϪH), 1727 (CϭO), 745
(s, 1 H, NH), 1.35 (t, J ϭ 7.0 Hz, 3 H, CH
): calcd. 244.1221; found 244.1221.
3
Ϫ1
1
cm (Ph-H). Ϫ H NMR (200 MHz, CDCl
indole-NH), 7.60Ϫ7.00 (m, 4 H, arom.-H), 4.50 (t, J ϭ 6.5 Hz, 1
H, 1-H), 3.80 (s, 3 H, OCH ), 3.20Ϫ3.05 (m, 2 H, 3-H), 2.86 (d,
J ϭ 6.5 Hz, 2 H, 1Ј-H), 2.74 (t, J ϭ 6.0 Hz, 2 H, 4-H), 1.85 (br s,
3
): δ ϭ 8.60 (br s, 1 H,
14 16 2 2
(C H N O
To a vigorously stirred solution of 21 (0.20 g, 0.82 mmol) in dry
tetrahydrofuran (20 mL) at Ϫ10 °C was added powdered potassium
permanganate (1.0 g) in small portions over a period of 1 h while
the temperature was raised to 0 °C. After stirring for 0.5 h TLC
indicated that all of the starting material had been oxidized. The
precipitate was filtered off and washed with THF (2 ϫ 10 mL). The
combined filtrates were concentrated to leave crude imine as a pale
yellow foam (0.12 g, 0.50 mmol, 60%). According to the general
procedure, the product (0.12 g, 0.50 mmol) was dissolved in aceton-
itrile (5 mL) and to the solution were added formic acid/triethylam-
3
13
1
1
H, NH). Ϫ C NMR (50.3 MHz, CDCl
35.5, 134.8, 127.1, 121.8, 119.3, 118.1, 111.0, 109.0 (8 C, arom.-
, C-1), 41.9, 40.6, 22.6 (3 CH ). Ϫ HRMS
): calcd. 244.1211; found 244.1211.
3
): δ ϭ 173.6 (CϭO),
C), 52.1, 48.7 (OCH
3
2
(
C
14
H
16
N
O
2 2
1,2,3,4-Tetrahydro-β-carboline 23: A solution of 4-oxobutyric acid
methyl ester (0.7 g, 6.0 mmol) and tryptamine hydrochloride (0.8 g,
4.0 mmol) in ethanol (50 mL) was stirred at room temp. for 20 h.
After evaporating the solvent under reduced pressure, the residue
ine (2 mL) and the preformed catalyst (R,R)-5 {[RuCl
2 6 6 2
(C H )] ,
(
6.0 mg, 24 µmol) and (1R,2R)-1,2-diphenyl-N-(p-tolylsulfonyl)e-
was treated with CH
2
Cl
2
(100 mL) and sat. aqueous NaHCO
3
solu-
Cl
SO
The solvent was evaporated under reduced pressure to give 23
thylenediamine (7.3 mg, 20 µmol) in 2.0 mL CH
3
CN}, and the mix- tion (100 mL). The aqueous phase was extracted with CH
2
2
ture was stirred whilst warming from 0 °C to room temp. for 6 h.
Purification of the crude product by flash chromatography with
(20 mL) and the combined organic phases were dried with Na
2
4
.
ethyl acetate/triethylamine (100:1) gave (1R)-21 (80.0 mg, (0.95 g, 3.70 mmol, 70%) as a yellow oil after chromatography with
1
0
.33 mmol, 67%) as a brown oil. The spectra are identical with
ethyl acetate/triethylamine (100:1). Ϫ H NMR (200 MHz, CDCl
δ ϭ 8.24 (br s, 1 H, indole-NH), 7.54Ϫ7.01 (m, 4 H, arom. H),
4.10Ϫ4.00 (m, 1 H, 1-H), 3.67 (s, 3 H, OCH ), 3.35Ϫ3.19 (m, 1 H,
3-H), 3.13Ϫ2.93 (m, 1 H, 3-H), 2.71 (t, J ϭ 5 Hz, 2 H, 4-H),
3
):
20
those of racemic 21. Ϫ [α]
optical rotation is not highly accurate due to the instability of 21
at room temp.
D 3
ϭ ϩ15.2 (c ϭ 0.2 in CHCl ). The
3
2
7
.65Ϫ2.40 (m, 2 H, CH
2 2
), 2.30Ϫ2.11 (m, 1 H, CH ), 1.96 (dd, J ϭ
1
,2,3,4-Tetrahydro-β-carboline (1S)-14: To a vigorously stirred solu-
.0, 3.0 Hz, 1 H, CH ), 0.78 (br s, 1 H, NH).
2
[
18]
tion of 14 (0.26 g, 1.00 mmol) in dry tetrahydrofuran (20 mL) at
°C was added powdered potassium permanganate (1.0 g) in small
portions over 0.5 h, the reaction mixture was kept at 0° C and (1.8 g, 10 mmol) was added to a solution of tryptamine hydro-
stirred for 1 h (TLC control). The precipitate was filtered off, chloride (1.9 g, 9.6 mmol) in ethanol (30 mL). After refluxing over-
washed with THF (2 ϫ 10 mL), and the combined filtrates were night ethanol was removed under reduced pressure. The products
0
1,2,3,4-Tetrahydro-β-carboline 24: 4-Benzyloxybutyraldehyde[19]
evaporated to leave the crude imine as a pale yellow solid (0.25 g,
.96 mmol, 97%). According to the general procedure, the crude
were treated with 2  NaOH (30 mL) and ethyl acetate (30 mL),
and the aqueous phase was washed with ethyl acetate (30 mL). The
0
product (0.19 g, 0.74 mmol) was dissolved in acetonitrile (5 mL)
and to the solution were added formic acid/triethylamine (2 mL)
combined organic phases were washed with sat. aqueous NaHCO
solution, and dried over Na SO . The solvent was removed and the
remaining oil was purified by chromatography with EtOAc/EtOH/
NEt (100:10:1) to give the compound 24 as a yellow oil (2.1 g,
CN}. The mixture was stirred 6.6 mmol, 70%). Ϫ H NMR (200 MHz, CDCl
at room temp. for 8 h and afforded, after flash chromatography indole-H), 7.50Ϫ7.05 (m, 9 H, arom., Ph-H), 4.55 (s, 2 H, PhCH
with ethyl acetate/EtOH/triethylamine (100:10:1), (1S)-14 (0.18 g, 4.13 (s, 1 H, 1-H), 3.58 (t, J ϭ 5.0 Hz, 2 H, CH ), 3.40Ϫ3.20 (m,
3
2
4
and the preformed catalyst (R,R)-5 {[RuCl
µmol) and (1R,2R)-1,2-diphenyl-N-(p-tolylsulfonyl)ethylenediam-
ine (7.3 mg, 20 µmol) in 2.0 mL CH
2 6 6 2
(C H )] (6.0 mg, 24
3
1
3
3
): δ ϭ 8.13 (s, 1 H,
),
2
2
2250
Eur. J. Org. Chem. 2000, 2247Ϫ2252

Enantiopure Tetrahydro--carbolines and Tetrahydroisoquinolines
FULL PAPER
1
H, 3-Heq), 3.10Ϫ2.95 (m, 1 H, 3-Hax), 2.66 (t, J ϭ 5.0 Hz, 2 H, (18 mg, 70 µmol, 7%) as a yellow oil after flash chromatography
CH ), 1.93Ϫ1.65 (m, 5 H, 2 CH
, NH). Ϫ 13C NMR (50.3 MHz, with ethyl acetate/EtOH/triethylamine (100:10:1) (during chroma-
CDCl ): δ ϭ 138.1, 135.8, 135.6, 128.5, 127.85, 127.82, 127.4,
21.4, 119.2, 118.0, 110.8, 108.7 (arom.-C), 73.2 (OCH Ph), 70.4
OCH ), 52.2 (C-1), 42.2, 31.9, 26.0, 22.5 (4 CH ). Ϫ HRMS
O): calcd. 320.1888; found 320.1888.
2
2
tography saponification and decarboxylation to 14 occurred).
3
1
2
1
Enamine 10: Ϫ H NMR (200 MHz, CDCl ): δ ϭ 10.30, 9.85 (2 s,
3
(
(
2
2
2
4
H, NH, indole-H), 7.65Ϫ7.05 (m, 4 H, arom.-H), 4.30Ϫ4.05 (m,
H, OCH CH ), 3.63Ϫ3.51 (m, 2 H, 3-H), 2.99 (t, J ϭ 7.0 Hz, 2
21 24 2
C H N
2
3
1
3
1
,2,3,4-Tetrahydroisoquinoline (1S)-31: A solution of ethyl cy-
anoacetate (11.3 g, 100 mmol), β-phenethyl chloride (16.0 g, 110
mmol) and anhydrous stannic chloride (26.1 g, 100 mmol) was 120.2, 119.6, 118.5, 112.4 (arom. C), 88.5 [C(CO
heated for 3 h at 110 °C and then poured into 250 mL of 20%
(OCH CH ), 40.3 (C-3), 20.4 (C-4), 14.4, 14.1 (CH
): calcd. 328.1423; found 328.1423.
H, 4-H), 1.33 (m, 6 H, CH
δ ϭ 171.7, 169.9 (CϭO), 151.9, (C-1), 136.9, 125.8, 125.1, 124.9,
Et) ], 61.4, 59.8
). Ϫ HRMS
3 3
). Ϫ C NMR (50.3 MHz, CDCl ):
2
2
2
3
3
NaOH solution. The aqueous solution was kept below 5 °C by (C18
20 2 4
H N O
external cooling and addition of ice and then extracted with ether
Amine (1S)-14: The spectra are identical with those shown above.
(3 ϫ 200 mL). The combined organic phases were extracted with
2
0
20
D 3 D
Ϫ [α] ϭ ϩ62.5 (c ϭ 0.2 in CHCl ); [α] ϭ Ϫ44.5 (c ϭ 0.2 in
10% HCl solution. The aqueous phase was cautiously neutralized
MeOH).
with 35% NaOH solution and the resulting oil was taken up in
ether. After drying and concentrating the ethereal solution, crude
dihydroisoquinoline 30 (20.0 g, 92.0 mmol, 92%) remained as a
1,2,3,4-Tetrahydro-β-carboline (1S)-22 and Enamine 8: To a stirred
and cooled (0 °C) solution of tryptamine (2.00 g, 12.5 mmol) in
CH Cl (80 mL) and NEt (20 mL) was added a solution of methyl
ϩ
pale yellow oil. Ϫ MS (DCI): m/z (%) ϭ 218.1 [M ϩ 1]. Ϫ
2
2
3
C
13
H15NO
2
(217.3).
2 2
malonyl chloride (1.90 g, 13.7 mmol) in CH Cl (50 mL). The re-
sulting mixture was stirred at room temp. for 2 h, washed with sat-
urated NaHCO solution, and dried with Na SO . The solvent was
removed and the crude product was purified by chromatography
According to the general procedure, compound 30 (200.0 mg,
3
2
4
0
.920 mmol) was dissolved in acetonitrile (5 mL) and to the solu-
tion were added formic acid/triethylamine (2 mL) and the pre-
formed catalyst (R,R)-5 {[RuCl (C )] , (6.0 mg, 24 µmol) and
1R,2R)-1,2-diphenyl-N-(p-tolylsulfonyl)ethylenediamine (7.3 mg,
0 µmol) in 2.0 mL CH CN} at 0 °C and the mixture was stirred
with ethyl acetate/pentane (2:1) to give the amide ester (2.7 g,
2
6
H
6
2
1
1
0 mmol, 83%) as a yellow solid. Ϫ H NMR (200 MHz, CDCl
3
):
(
2
δ ϭ 8.12 (s, 1 H, indole-NH), 7.70Ϫ6.95 (m, 6 H, arom. H,
CONH), 3.75Ϫ3.55 (m, 5 H, OCH , CH ), 3.28 (s, 2 H, CH ), 2.98
t, J ϭ 7.0 Hz, 2 H, 4-H).
3
3
2
2
whilst warming from 0 °C to room temp. for 8 h. After flash chro-
matography with ethyl acetate/EtOH/triethylamine (100:10:1) (1S)-
(
3
1 (170.0 mg, 0.776 mmol, 85%) was obtained as a dark yellow oil. The amide ester (200.0 mg, 0.769 mmol) was stirred in POCl
3
20
20
Ϫ [α]
D
ϭ Ϫ12.5 (c ϭ 0.2 in CHCl
3
); [α]
D
ϭ Ϫ10.0 (c ϭ 0.2 in
(5 mL) at room temp. for 12 h. Excess POCl
vacuo and the residue was basified with saturated NaHCO
3
was evaporated in
Ϫ1
EtOH). Ϫ IR (KBr): ν˜ ϭ 3347 (NH), 1729 (CϭO), 747 cm (Ph-
H). Ϫ 1H NMR (200 MHz, CDCl
): δ ϭ 7.40Ϫ7.05 (m, 4 H,
arom.-H), 4.46 (dd, J ϭ 10.0, 4.0 Hz, 1 H, 1-H), 4.17 (q, J ϭ which was, according to the general procedure, treated with formic
.2 Hz, 2 H, CH CH ), 3.13Ϫ2.70 (m, 6 H, 3 CH ), 2.50 (br s, 1 acid/triethylamine (2 mL) and the preformed catalyst (R,R)-5
H, NH), 1.29 (t, J ϭ 7.2 Hz, 3 H, CH (C )] (6.0 mg, 24 µmol) and (1R,2R)-1,2-diphenyl-N-(p-
). Ϫ 13C NMR (50.3 MHz, {[RuCl
CDCl ): δ ϭ 172.3 (CϭO), 137.4, 135.4, 129.4, 128.3, 126.3, 125.9 tolylsulfonyl)ethylenediamine (7.3 mg, 20 µmol) in 2.0 mL
arom.-C) 60.6 (OCH ), 52.7 (C-1), 41.3, 40.6, 29.7 (3 CH ), 14.2 CH CN}. The mixture was stirred at room temp. for 8 h and af-
CH ). Ϫ HRMS (C13 ): calcd. 219.1259; found 219.1259. forded enamine 8 (110 mg, 0.45 mmol, 55%) and amine (1S)-22
12 mg, 49 µmol, 5.9%) as yellow oils after flash chromatography
,2,3,4-Tetrahydro-β-carboline 14 and Enamine 10: α-Oxo-β-carboli-
and
3
3
extracted with CH Cl . Usual workup gave the crude product
2
2
7
2
3
2
3
2
6 6 2
H
3
(
(
2
2
3
3
H17NO
2
(
1
ne
with ethyl acetate/EtOH/triethylamine (100:10:1).
[
14a]
3
(5.0 g, 27 mmol) was stirred with POCl (20 mL) for 10 h at
1
room temp. and then diethyl ether (50 mL) was added. The formed
Enamine 8: H NMR (200 MHz, CDCl
3
): δ ϭ 8.13 (s, 2 H, NH,
precipitate was isolated, dissolved in MeOH (100 mL), the solution
indole-H), 7.62Ϫ7.05 (m, 4 H, arom.-H), 4.85 (s, 1 H, CHϭC),
), 3.55 (t, J ϭ 6.0 Hz, 2 H, CH ), 2.97 (t, J ϭ
stirred for 2 h at 60 °C and then cooled to room temp. Diethyl 3.74 (s, 3 H, OCH
ether (150 mL) was then added and the newly formed precipitate
6.0 Hz, 2 H, CH ).
was treated with sat. aqueous NaHCO solution. The mixture was
3
2
2
3
Amine (1S)-22: the spectra are identical with those shown above.
extracted with diethyl ether and the organic phase dried with
2
0
20
Ϫ [α]
D 3 D
ϭ ϩ51.2 (c ϭ 0.5 in CHCl ); [α] ϭ Ϫ29.0 (c ϭ 0.5 in
Na SO , concentrated under reduced pressure, and purified by
flash chromatography with ethyl acetate/pentane (1:2) to give com-
2
4
MeOH).
[
14b]
(2.5 g, 13 mmol, total yield 48%). Ϫ 1H NMR
): δ ϭ 8.20 (s, 1 H, indole), 7.71Ϫ7.70 (m, 4 H,
pound 15
200 MHz, CDCl
1,2,3,4-Tetrahydro-β-carboline (1S)-14 and Enamine 9: Tetrahydro-
β-carboline 14 (258 mg, 1.00 mmol) was refluxed in EtOH (10 mL)
, 3-H), 2.90 (t, J ϭ 8.0 Hz, 2 with Pd/C (10%, 100 mg) for 4 h. The catalyst was removed by
filtration and the solvent was evaporated. According to the general
(
3
arom.-H), 3.95Ϫ3.80 (m, 5 H, OCH
3
H, 4-H).
procedure, the obtained crude product was treated with formic
Compound 15 (200 mg, 1.00 mmol) was heated at 130 °C in ma-
lonic acid diethyl ester (5 mL) for 5 h and then the solvents were
removed under reduced pressure. The crude products were not isol-
ated, but, according to the general procedure, dissolved in aceton-
itrile (5 mL) and to the solution formic acid/triethylamine (2 mL)
acid/triethylamine (2 mL) and the preformed catalyst (R,R)-5
[RuCl (C )] (6.0 mg, 24 µmol) and (1R,2R)-1,2-diphenyl-N-(p-
tolylsulfonyl)ethylenediamine (7.3 mg, 20 µmol) in 2.0 mL
CH CN} and stirred at room temp. for 8 h. Purification by flash
{
2
6 6 2
H
3
chromatography with ethyl acetate/EtOH/triethylamine (100:10:1)
gave enamine 9 (174.0 mg, 0.680 mmol, 68%) and amine (1S)-14
and the preformed catalyst (R,R)-5 {[RuCl
µmol) and (1R,2R)-1,2-diphenyl-N-(p-tolylsulfonyl)ethylenediam-
ine (7.3 mg, 20 µmol) in 2.0 mL CH CN} were added. The mixture
was stirred at room temp. for 12 h and afforded enamine 10
216.0 mg, 0.659 mmol, 66%) as a yellow solid and amine (3S)-14
2 6 6 2
(C H )] (6.0 mg, 24
(
17 mg, 66 µmol, 6.5%) as yellow oils.
3
1
Enamine 9: H NMR (200 MHz, CDCl
3
): δ ϭ 8.45Ϫ8.25 (br s, 2
(
H, NH, indole-H), 7.57Ϫ7.14 (m, 4 H, arom. H), 4.90 (s, 1 H,
Eur. J. Org. Chem. 2000, 2247Ϫ2252
2251

L. F. Tietze, Y. Zhou, E. Töpken
FULL PAPER
[
[
2]
A. Agarwal, S. K. Agarwal, S. N. Singh, N. Fatma, R. K. Chat-
CHϭC), 4.17 (q, J ϭ 7.2 Hz, 2 H, OCH
2
), 3.60 (dt, J ϭ 6.9, 2.5 Hz,
terjee, Bioorg. Med. Chem. Lett. 1996, 6, 225Ϫ228.
2
3
H, NCH
H, CH ).
2 2
), 2.99 (t, J ϭ 7.0 Hz, 2 H, CH ), 1.30 (t, J ϭ 7.2 Hz,
3] [3a]
Z. Czarnocki, D. B. MacLean, W. A. Szarek, Can. J. Chem.
3
[3b]
1
986, 64, 2205Ϫ2210. Ϫ
Z. Czarnocki, D. B. MacLean, W.
A. Szarek, Bull. Soc. Chim. Belg. 1986, 95, 749Ϫ770.
Amine (1S)-14: the spectra are identical with those shown above.
[4] [4a]
[4b]
Review: L. F. Tietze, Chem. Rev. 1996, 96, 115Ϫ136. Ϫ
L. F. Tietze, U. Beifuss, Angew. Chem. 1993, 105, 137Ϫ170;
Ϫ [α]2
0
20
D
3 D
ϭ ϩ61.2 (c ϭ 0.5 in CHCl ); [α] ϭ Ϫ44.3 (c ϭ 0.5 in
[
4c]
MeOH).
Angew. Chem. Int. Ed. Engl. 1993, 32, 131Ϫ163. Ϫ
L. F.
Tietze, J. Bachmann, J. Wichmann, O. Burkhard, Synthesis
[4d]
Determination of Configuration and ee Value From Mosher Acid
Derivatives: To a solution of (1R)-14 (20 mg, 78 µmol) in CH Cl
5 mL) and triethylamine (0.5 mL) at 0 °C, was added a solution
of (S)-(ϩ)-α-methoxy-α-trifluoromethylphenylacetic acid chloride
20.0 mg, 0.96 mmol) in THF (2 mL). After stirring at room temp.
for 8 h, the reaction mixture was washed with saturated NaHCO
solution, dried with Na SO , and concentrated under reduced pres-
sure to give compound 32 as a white solid (32 mg, 68 µmol, 85%).
1994, 1185Ϫ1194. Ϫ
L. F. Tietze, J. Bachmann, J. Wich-
mann, Y. Zhou, T. Raschke, Liebigs Ann./Recueil 1997,
2
2
8
81Ϫ886.
(
[5]
L. F. Tietze, Y. Zhou, Angew. Chem. 1999, 111, 2076Ϫ2077;
Angew. Chem. Int. Ed. 1999, 38, 2045Ϫ2047.
6] [6a]
[
(
D. L. Comins, M. Badawi, Tetrahedron Lett. 1991, 32,
[6b]
2995Ϫ2996. Ϫ
T. Kawate, H. Yamada, M. Matsumizu, A.
3
[6c]
Nishida, M. Nakagawa, Synlett. 1997, 761Ϫ762. Ϫ
E. D.
2
4
[
6d]
Cox, J. M. Cook, Chem. Rev. 1995, 95, 1797Ϫ1842. Ϫ
Waldmann, G. Schmidt, M. Jansen, J. Geb, Tetrahedron 1994,
H.
1
Ϫ
3
H NMR (200 MHz, CDCl ): δ ϭ 8.95 (s, 1 H, indole-NH),
50, 11865Ϫ11884.
[
[
7]
7
5
4
3
CH
4
.72Ϫ6.90 (m, 9 H, Ar-H), 6.00 (dd, J ϭ 11.0, 2.0 Hz, 1 H, 1-H),
.19, 4.88 (dd, d, J ϭ 11.0, 2.0 Hz, J ϭ 8.0 Hz, 0.2 H, 3-Heq),
A. I. Meyers, Tetrahedron 1992, 48, 2589Ϫ2612.
8] [8a]
K. Yamada, M. Takeda, T. Iwakuma, J. Chem. Soc. Perkin
[
8b]
Trans. 1 1983, 265Ϫ270. Ϫ
R. P. Polniaszek, C. R. Kauf-
.22Ϫ4.03 (m, 2.8 H, 3-Heq, OCH
.25Ϫ2.50 (m, 5 H, 3-Hax, 4-H, 1Ј-H), 1.30 (t, J ϭ 8.0 Hz, 3 H,
). HRMS (C25 ): calcd. 474.1766; found
74.1766.
2 3
), 3.78, 3.70 (2 s, 3 H, OCH ),
man, J. Am. Chem. Soc. 1989, 111, 4859Ϫ4863.
[9] [9a]
H. B. Kagan, N. Langlois, T. P. Dang, J. Organomet. Chem.
3
Ϫ
H
25
F
3
N
2
O
4
1
975, 90, 353Ϫ365. Ϫ
[9b]
K. Achiwa, Heterocycles 1977, 8,
[9c]
247Ϫ248. Ϫ
C. A. Willoughby, S. L. Buchwald, J. Am.
[9d]
Chem. Soc. 1994, 116, 8952Ϫ8965. Ϫ
C. A. Willoughby, S.
To a solution of (1S)-14 (20 mg, 78 µmol) in CH
triethylamine (0.5 mL) at 0 °C, was added a solution of (S)-(ϩ)-α-
methoxy-α-trifluoromethylphenylacetic acid chloride (20.0 mg,
Cl
2 2
(5 mL) and
L. Buchwald, J. Am. Chem. Soc. 1994, 116, 11703Ϫ11714. Ϫ
[9e]
M. Kitamura, Y. Hsiao, M. Ohta, M. Tsukamoto, T. Ohta,
H. Takaya, R. Noyori, J. Org. Chem. 1994, 59, 297Ϫ310. Ϫ
[9f]
T. Morimoto, K. Achiwa, Tetrahedron: Asymmetry 1995, 6,
0
.96 mmol) in THF (2 mL). After stirring at room temp. for 8 h,
the reaction mixture was washed with saturated NaHCO solution,
dried with Na SO , and concentrated under reduced pressure to
give compound 33 as a white solid (34 mg, 72 µmol, 90%). Ϫ H
NMR (200 MHz, CDCl ): δ ϭ 8.91, 8.65 (2 s, 1 H, indole-NH),
.75Ϫ6.95 (m, 9 H, Ar-H), 6.15Ϫ5.81 (m, 1 H, 1-H), 4.95Ϫ5.10
m, 0.2 H, 3-Heq), 4.5Ϫ3.9 (m, 2.8 H, 3-Heq, OCH ), 3.80, 3.45 (2
s, 3 H, OCH ), 3.13Ϫ2.05 (m, 5 H, 3-Hax, 4-H, 1Ј-H), 1.30 (t, J ϭ
.0 Hz, 3 H, CH ). Ϫ HRMS (C25 ): calcd. 474.1766;
found 474.1766.
2661Ϫ2664. Ϫ [9g] T. Morimoto, N. Suzuki, K. Achiwa,
[9h]
Heterocycles 1996, 43, 2557Ϫ2560. Ϫ
T. Morimoto, N. Su-
3
zuki, K. Achiwa, Tetrahedron: Asymmetry 1998, 9, 183Ϫ187.
Ϫ [ J. Kang, J. B. Kim, K. H. Cho, B. T. Cho, Tetrahedron:
Asymmetry 1997, 8, 657Ϫ660.
[10] [10a]
2
4
9i]
1
3
N. Uematsu, A. Fujii, S. Hashiguchi, T. Ikariya, R. Noyori,
[10b]
7
(
J. Am. Chem. Soc. 1996, 118, 4916Ϫ4917. Ϫ
Hashiguchi, Acc. Chem. Res. 1997, 30, 97Ϫ102.
11] [11a]
R. Noyori, S.
2
[
W. H. Perkin, R. Robinson, J. Chem. Soc., 1919, 115,
3
[11b]
9
33Ϫ967. Ϫ
R. H. F. Manske, W. H. Perkin, R. Robinson,
[11c]
8
3
H
25
F
3
N
O
2 4
J. Chem. Soc. 1927, 1Ϫ14. Ϫ
J. D. Spenser, Can. J. Chem.
[
11d]
1959, 37, 1851Ϫ1858. Ϫ
985, 1134Ϫ1135.
S. Misztal, M. Cegla, Synthesis
1
To a solution of (1S)-31 (20 mg, 92 µmol) in CH
triethylamine (0.5 mL) at 0 °C, was added (S)-(ϩ)-α-methoxy-α-
trifluoromethylphenylacetyl chloride. After stirring at room temp.
Cl
2 2
(5 mL) and
[12]
Y. Torisawa, A. Hashimoto, M. Nakagawa, H. Seki, R. Hara,
T. Hino, Tetrahedron 1991, 47, 8067Ϫ8078.
13]
[
[
S. Murahashi, N. Yoshimura, T. Tsumiyama, T. Kojima, J. Am.
Chem. Soc. 1983, 105, 5002Ϫ5011.
for 8 h, the reaction mixture was washed with saturated NaHCO
solution, dried with Na SO , and concentrated under reduced pres-
sure to give compound 34 as a yellow oil. Ϫ H NMR (200 MHz,
CDCl ): δ ϭ 7.70 Ϫ7.05 (m, 9 H, arom. H), 6.12, 6.00 (2 t, J ϭ
.5 Hz, 1 H, 1-H), 4.25Ϫ3.25 (m, 6 H, CO CH , OCH , 3-Heq),
.95Ϫ2.05 (m, 5 H, CH , 3-Hax), 1.30Ϫ1.20 (m, 2 H, CH ). Ϫ
NO ): calcd. 449.1814; found 449.1814.
3
14] [14a]
F. Bracher, D. Hildebrand, Liebigs Ann. Chem. 1992,
2
4
[14b]
1
315Ϫ1319. Ϫ
H. Henecka, H. Timmler, R. Lorenz, Med.
1
Chem. (Leverkusen Ger.) 1963, 7, 277Ϫ286.
[
[
15]
16]
3
W. Sobotka, W. N. Beverung, G. G. Munoz, J. C. Sircar, A. I.
Meyers, J. Org. Chem. 1965, 30, 3667Ϫ3671.
5
2
2
2
3
Crystallographic data (excluding structure factors) for the
structures reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC-140352. Copies of the data can be ob-
tained free of charge on application to CCDC, 12 Union Road,
2
3
HRMS (C24
H
26
F
3
4
Cambridge
44(1223)336Ϫ033; E-mail: deposit@ccdc.cam.ac.uk].
17] [17a]
CB2
1EZ,
UK
[Fax:
(internat.)
ϩ
Acknowledgments
We thank the Fonds der Chemischen Industrie for financial sup-
port and the Degussa AG for chemicals. Y. Z. thanks the DAAD
for a scholarship.
[
M. A. Bennett., A. K. Smith, J. Chem. Soc. Dalton Trans.
[17b]
1974, 233Ϫ241. Ϫ
G. Winkhaus, H. Singer, J. Organomet.
Chem. 1967, 7, 487Ϫ491.
[
[
18]
19]
G. B. Kline, J. Am. Chem. Soc. 1959, 81, 2251Ϫ2255.
M. I. Dawson, M. Vasser, J. Org. Chem. 1977, 42, 2783Ϫ2785.
Received December 7, 1999
[
1]
B. T. Ho, W. M. McIsaac, K. E. Walker, V. Estevez, Journal of
Pharmaceutical Sciences 1968, 57, 269Ϫ273.
[O99666]
2252
Eur. J. Org. Chem. 2000, 2247Ϫ2252