Practical ex-chiral-pool methodology for the synthesis of dopaminergic tetrahydroindoles

Article abstract of DOI:10.1016/j.tet.2003.11.041

Chemo- and regioselective transformations of asparagine gave access to optically active 5- and 6-amino tetrahydroindolizines when the 3-aminobutyrolactone (S)-2 was employed as a key intermediate. The target compounds were approached by a sequential and r

Full text of DOI:10.1016/j.tet.2003.11.041

Tetrahedron 60 (2004) 1197–1204
Practical ex-chiral-pool methodology for the synthesis of
dopaminergic tetrahydroindoles
*
Markus Bergauer, Harald Hu¨bner and Peter Gmeiner
Department of Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander University, Schuhstraße 19, D-91052 Erlangen, Germany
Received 10 September 2003; revised 13 November 2003; accepted 18 November 2003
Abstract—Chemo- and regioselective transformations of asparagine gave access to optically active 5- and 6-amino tetrahydroindolizines
when the 3-aminobutyrolactone (S)-2 was employed as a key intermediate. The target compounds were approached by a sequential and
regiocontrolled bis-electrophilic attack in the positions 2 and 3 of the pyrrole ring system. Receptor binding experiments showed
stereocontrolled receptor recognition leading to the D3 selective agonist (S)-8 with D3 binding that is comparable to the natural
neurotransmitter dopamine.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
dopamine receptor binding of the test compounds in both
enantiomeric configurations (Scheme 1).
Chemo- and regioselective functionalization of asparagine
and aspartic acid has become an attractive method for the
construction of bioactive compounds including natural
products and non-proteinogenic amino acids.1 We recently
presented efficient methodology for a regioselective prep-
aration of the aspartate derivatives 1a–c disclosing a
straightforward access to a variety of amino alcohols,
b-amino acids and lactam-bridged peptide mimetics.2
Depending on the chemical necessities, the introduction of
nucleophiles can be realized in the positions 1, 2 and 4.
Thus, the building blocks 1 can serve as equivalents for the
chiral synthon A. Exploiting the 1,4-bis-electrophilic
properties, valuable applications in the field of medicinal
chemistry could be disclosed when the attack of pyrrole
derived nucleophiles in the positions 1 and 2 of the
heterocyclic unit led to slaframine derivatives and dopa-
minergic bicyclic ergoline analogs (3a,b).3 As an extension
of our very recent efforts,4 target driven SAR studies
required the access to regioisomeric azabicyclo[4.3.0]-
nonanes of type 4 that should be approached by a sequential
and regiocontrolled bis-electrophilic attack in the positions
2 and 3 of the pyrrole ring system. We envisioned realizing
this plan by C-acylation and aziridinium promoted 6-endo-
tet cyclization5 when the dibenzyl-protected asparagine
derivative (S)-26 should be employed as a synthetic
equivalent for the synthon B. In this paper, we describe an
enantiospecific approach of the 5- and 6-aminotetra-
hydroindoles 4a and 4b, and the regio- and stereoselective
Scheme 1.
Our initial investigations were directed towards the
synthesis of the 5-aminotetrahydroindoles of type 4a. For
the preparation of the dibenzylamino substituted lactone
(S)-2, natural asparagine was converted into the N,N-
dibenzyl protected aparagine benzyl ester. Subsequent
chemoselective reduction of the ester group and lactoniza-
tion afforded the chiral building block (S)-2 in 36% overall
yield, according to our previously described protocol.6 To
attach (S)-2 to the pyrrole moiety, we tried to exploit a
nucleophilic ring-opening reaction with pyrrole lithiated in
2-position (Scheme 2).
Keywords: Ex-chiral pool synthesis; Asparagine; Receptor binding;
Aminobutyrolactone.
*
Corresponding author. Tel.: þ49-9131-8529383; fax: þ49-9131-
To prevent problems with the acidic NH-function, we
8522585; e-mail address: gmeiner@pharmazie.uni-erlangen.de
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.11.041

1198
M. Bergauer et al. / Tetrahedron 60 (2004) 1197–1204
sodium triacetoxyborohydride to give the test compound
(S)-13 in 58% yield.
Starting from dipropylaminotetrahydroindolizines,4 we
recently found that the introduction of a carbaldehyde
function into the 2-position of the pyrrole partial structure
increased the dopaminergic activity, especially the affinity
to the D3 subtype. Therefore, it was interesting for us to see
if we could also improve the receptor binding properties by
a C-formylation of the tetrahydroindole (S)-13. We
subjected (S)-13 to Vilsmeier conditions and obtained the
2-formyl derivative (S)-15 in 85% yield.
To perform systematic structure–activity-relationship
studies, it was also interesting for us to work out a synthesis
for the 5-aminotetrahydroindole (S)-8 with a pyrrole NH
moiety being putatively involved in hydrogen bonding
interaction with the receptor. We first tried the use of
N-protected pyrroles including N-Ts, N-Boc, N-SEM and
NMe2 derivatives when activation for a nucleophilic attack
should be facilitated by o-directed metallation.10–12 How-
ever, lithiation and subsequent treatment with the amino
lactone (S)-2 resulted in hardly separable educt/product
mixtures and the formation of side products. Thus we turned
our attention to a method of Nicolaou et al.13 when a reagent
derived from MeMgCl and pyrrole14 was used to react with
g-butyrolactone. Depending on the reaction temperature
and the stoichiometry, regioselective C–N or C–C bond
formation was detected. We observed that pyrrolemag-
nesium chloride reacted as a N-nucleophile with 1.0 equiv.
of the lactone (S)-2 at 0 8C to afford the hydroxyamide (S)-5
(59%). On the other hand, employing an excess of the
organometallic reagent (2 equiv.) at 100 8C resulted in
formation of the ketopyrrole (S)-6 in 87% yield. Obviously,
(S)-6 is produced by subsequent N-acylation, o-directed
metallation and N,C-acyl migration. Reduction of the
carbonyl group afforded the cyclization precursor (S)-10.
Activation of the alcohol function with trifluoromethane-
sulfonic anhydride led to exclusive C-alkylation resulting in
formation of the tetrahydroindole (S)-9 as well as the N-Tf
substituted compound (S)-11 as a side product. The dipropyl
derivative (S)-8 was obtained from (S)-9 by hydrogenolytic
debenzylation and reductive alkylation in 78% yield.
Employing the identical procedures, we synthesized the
optical antipodes (R)-8, (R)-13 and (R)-15 starting from
unnatural (R)-asparagine.
Scheme 2. (i) MeMgCl, toluene, 0 8C; (ii) (S)-2 (1.0 equiv.), 0 8C, 30 min
(59%); (iii) (S)-2 (0.5 equiv.), 100 8C, 75 min (87%); (iv) (1) n-BuLi,
TMEDA, THF, room temperature, 15 min, (2) (S)-2, THF, 278 8C (62%);
(v) AlCl3, t-BuNH2£BH3, CH2Cl2, 0 8C, 1 h ((S)-10: 44%; (S)-12: 73%);
(vi) (F3CSO2)2O, 4-methyl-2,6-di-tert-butylpyridine, CH2Cl2, 0 8C to room
temperature, 1 h ((S)-9: 48% and (S)-11: 18%; (S)-14: 67%); (vii) (1)
Pd(OH)2/C, 1 atm H2, MeOH–EtOAc (1:1), room temperature, 4 h; (2)
NaBH(OAc)3, propionaldehyde, 1,2-DCE, room temperature, 1.75 h ((S)-8:
78%; (S)-13: 58%); (viii) POCl3, DMF, 0 8C, 1 h (85%).
started with N-methylpyrrole which was lithiated with
n-BuLi/TMEDA and subsequently reacted with the lactone
(S)-2.7 In fact, the reaction proceeded smoothly furnishing
the ketone (S)-7 in 62% yield. Employing a mixture of
borane–tert-butylamine complex and AlCl3 as an effective
reducing system,8 the carbonyl function could be degraded
to the methylene unit resulting in formation of the
cyclization precursor (S)-12 (73%). Activation of the
primary alcohol function with trifluoromethanesulfonic
anhydride resulted in a cationic ring closure9 to afford the
N-methyltetrahydroindole (S)-14 in 67% yield. It was
important to conduct the reaction in presence of 4-methyl-
2,6-di-tert-butylpyridine as a sterically demanding and
effective proton scavenger. By contrast, the use of
triethylamine, being previously described for similar
aziridinium promoted reactions, gave only 23% yield in
this case. 4-Methyl-2,6-di-tert-butylpyridine could be easily
separated by flash chromatography and recycled for further
experiments. The exchange of the benzyl protecting groups
with the pharmacophoric propyl substituents was done by
catalytic debenzylation followed by a reductive alkylation
of the resulting primary amine with propionaldehyde and
To prove the optical integrity of the reaction pathway by
diastereomer formation, coupling with the chiral iso-
cyanates (S)-16 and (R)-16 was done and subsequent
HPLC analysis should be performed. Choosing (S)-14 as a
representative final product, hydrogenolysis and coupling of
the resulting primary amine with the enantiomers (S)-16 and
(R)-16 gave the diastereomeric ureas (S;S)-17 and (S;R)-17,
respectively. Subsequent HPLC analysis including doping
experiments indicated a diastereomeric excess .95%
(Scheme 3).
For the synthesis of the 6-amino substituted regioisomers of
type 4b, we had to alter the attachment point for the
acylation of the pyrrole moiety with the chiral C4 equivalent
(S)-2 when metallation in position 3 should be facilitated by
halogen metal exchange of the readily available N-TIPS

M. Bergauer et al. / Tetrahedron 60 (2004) 1197–1204
1199
Scheme 3. (i) Pd(OH)2/C, 1 atm H2, EtOAc–MeOH (1:1), room
temperature, 24 h; (ii) (S)-16, CH2Cl2, room temperature, 6 h (66%); (iii)
(R)-16, CH2Cl2, room temperature, 6 h (73%).
substituted 3-bromopyrrole 18.15 In detail, treatment of 18
with n-BuLi at room temperature followed by addition of
the amino lactone (S)-2 resulted in formation of the amino
alcohol (S)-19 in 47% yield. After reduction of the carbonyl
group with borane–tert-butylamine in presence of AlCl3,
cationic cyclization was induced by activation of the alcohol
function with trifluoromethanesulfonic anhydride. Actually,
electrophilic attack into the positions 2 and 4 of the aromatic
system was observed leading to formation of the tetra-
hydroindole (S)-22 and the tetrahydroisoindole (S)-21,
respectively, as a 4:1 mixture of nearly separable regio-
isomers. Exchange of the benzyl groups with propyl
substituents via hydrogenolysis and reductive alkylation
gave pure (S)-23 (9%) and (S)-24 (62%) after flash
chromatography. Finally, fluoride promoted desilylation
furnished the final products (S)-2516 and (S)-26 in 82 and
69% yield, respectively. Employing the identical pro-
cedures, the preparation of the optical antipodes (R)-25
and (R)-26 was performed starting from unnatural (R)-
asparagine (Scheme 4).
Scheme 4. (i) (1) n-BuLi, pentane, room temperature, 15 min; (2) (S)-2,
THF, 0 8C (47%); (ii) AlCl3, t-BuNH2£BH3, CH2Cl2, 0 8C, 30 min, (51%);
(iii) (F3CSO2)2O, 4-methyl-2,6-di-tert-butylpyridine, CH2Cl2, 0 8C to room
temperature, 60 min (79%; (S)-21–(S)-22¼2:8); (iv) Pd(OH)2/C, 1 atm H2,
MeOH–EtOAc (1:1), room temperature, 2 h; (v) Na(OAc)3BH, propio-
naldehyde, 1,2-DCE, room temperature, 45 min ((S)-23: 9%; (S)-24: 62%);
(vi) Bu4NF, THF, room temperature, 30 min ((S)-25: 82%; (S)-26: 69%).
expressed in CHO cells (Table 1). D1 affinities were
determined by employing porcine striatal membrane
preparations and the D1 selective antagonist
[3H]SCH23390.20 As a reference drug, the neurotransmitter
dopamine was utilized. All the test compounds investigated
The final products (S)-8, (S)-13, (S)-15, (S)-25, (S)-26 and
their enantiomers we evaluated in vitro for their abilities to
displace [3H]spiperone from the cloned human dopamine
17
receptors D2long, D2short
,
D318 and D4.419 being stably
Table 1. Receptor binding data of the tetrahydroindoles 8, 13, 15, 26 and the tetrahydroisoindoles 25 in comparison to the reference compound dopamine at the
human dopamine receptor subtypes D2long, D2short, D3, D4.4 and the porcine D1 receptor (Ki values in nM)
Compound
Ki values (nM)a
[3H]SCH23390, porcine D1
[3H]spiperone
Human D2short
Human D2long
Human D3
Human D4.4
(S)-8
(R)-8
35,000b
28,000
16,000
16,000
45,000
80,000
24,000
43,000
21,000
42,000
7.0þ6500
12,000
28,000
13,000
20,000
72,000
45,000
94þ11,000
28,000
27,000
36,000
20þ1900
9700
17,000
62þ9900
38þ1900c
2000
34þ1800
16,000
12,000
1000
1700
3000
610
3100
17,000
29,000
28þ2500
5400
20,000
14,000
1.2þ62
(S)-13
(R)-13
(S)-15
(R)-15
(S)-25
(R)-25
(S)-26
(R)-26
Dopamine
190þ15,000
56,000
65,000
92þ6900
33þ1100
28,000
27,000
3700
7600
21,000
17þ1100
9400
50þ1600
a
Ki values are the means of 2 to 6 experiments each done in triplicate.
K0.5 values derived from the competition curves calculated in a one-site binding mode.
Ki high and Ki low values for the high and low affinity binding sites, when the analysis of the dose response curve clearly indicated a biphasic competition.
b
c

1200
M. Bergauer et al. / Tetrahedron 60 (2004) 1197–1204
displayed only weak D1 binding. For all the subtypes
investigated, the (R)-enantiomers gave Ki values in the
micromolar range indicating only moderate affinity. On the
other hand, the 5-aminotetrahydroindole (S)-8 showed a
biphasic curve for the D3 receptor with a Ki high of 38 nM
indicating high D3 affinity and selectivity as well as agonist
properties. While alkylation of the indole-N of (S)-8 by a
methyl group leading to (S)-13 resulted in a combination of
2.1.1. (S)-3-Dibenzylamino-4-hydroxypyrrol-1-ylbutane-
1-one ((S)-5). To a solution of methylmagnesium chloride
(0.33 mL, 1.0 mmol, 3.0 M in THF) in toluene (5 mL)
pyrrole (69 mL, 1.0 mmol) was added dropwise at 0 8C and
stirred for 15 min. Then a solution of lactone (S)-2 (281 mg,
1.0 mmol) in toluene (3 mL) was added dropwise and stirred
for further 30 min at 0 8C. Then water and CH2Cl2 were
added. The organic layer was separated, dried (MgSO4) and
evaporated. The residue was purified by flash chromato-
graphy (petroleum ether–EtOAc, 7:3) to give (S)-5
(205 mg, 59%) as a colorless oil: [a]2D0¼þ56.68 (c¼3.0
D3 and D2short activity (Ki high¼62 nM for D2short
,
Ki high¼34 nM for D3), additional formyl substitution in
position 2 decreased receptor binding and showed only
micromolar affinities as indicated for (S)-15. This result is in
contrast to our recent observations for aminoindolizines
when the introduction of a carbaldehyde function gave a
beneficial effect.4 Shifting the propylamino substituent from
position 5 to 6 of the tetrahydroindole scaffold as realized in
(S)-26, the receptor recognition was strongly reduced.
Interestingly, the tetrahydroisoindole regioisomer (S)-25
revealed substantial receptor affinities to all subtypes of the
D2 family with Ki high values of 94, 92, 33 and 28 nM for
D2long, D2short, D3 and D4, respectively. Considering the
absolute configuration of the active enantiomer, this result
corroborates previous observations that the pyrroleethyl-
amine moiety, which is part of the BCD tricyclic partial
structure of the ergolines, is the active portion of this class
of dopamine agonists.16 To confirm the binding property of
the most promising, D3 selective compound (S)-8, we
determined its agonist activity in a mitogenesis assay
utilizing D3 expressing CHO dhfr2 cells measuring the
increase of [3H]thymidine uptake stimulated by the test
compound. The data (EC50¼28 nM, agonist effect¼55%
compared to the effect of the full agonist quinpirol (100%))
clearly indicate agonist properties and, thus, are in
agreement with the binding experiments.
1
CHCl3); IR 3445, 1713 cm21; H NMR (360 MHz) d 2.65
(s, 1H), 2.79 (dd, J¼15.0, 8.0 Hz, 1H), 3.14 (dd, J¼15.0,
5.0 Hz, 1H,), 3.5–3.7 (m, 3H), 3.55 (d, J¼13.0 Hz, 2H),
3.85 (d, J¼13.0 Hz, 2H), 6.30 (d, J¼2.4 Hz, 2H), 7.2–7.3
(m, 2H), 7.2–7.4 (m, 10H); 13C NMR (90 MHz) d 31.9,
53.5, 56.4, 61.5, 113.3, 118.9, 127.2, 128.1, 128.3, 138.4,
170.9; APCI-MS: 349 (Mþ). Anal. Calcd for C22H24N2O2
(348.45): C, 75.83; H, 6.94; N, 8.04. Found: C, 75.89; H,
6.90; N, 8.07.
2.1.2. (S)-3-Dibenzylamino-4-hydroxy-1-(1H-pyrrol-2-
yl)-butane-1-one ((S)-6). To a solution of methylmag-
nesium chloride (3.33 mL, 10.0 mmol, 3.0 M in THF) in
toluene (10 mL) pyrrole (0.83 mL, 12.0 mmol) was added
dropwise at 0 8C. The mixture was stirred at 50 8C for 1 h.
Then a solution of lactone (S)-2 (1.41 g, 5 mmol) in toluene
(10 mL) was added. After stirring for a further 75 min at
100 8C the mixture was allowed to cool to room tempera-
ture. Then saturated NH4Cl and Et2O were added. The
organic layer was separated, dried (MgSO4) and evaporated.
The residue was purified by flash chromatography
(petroleum ether–EtOAc, 7:3) to give (S)-6 (1.51 g, 87%)
as a colorless oil: [a]D20¼þ46.38 (c¼2.0, CHCl3); IR 3403,
3027, 1634 cm21; 1H NMR (360 MHz) d 2.70 (dd, J¼14.0,
4.0 Hz, 1H), 2.96 (s, 1H), 3.16 (dd, J¼14.0, 8.0 Hz, 1H),
3.4–3.6 (m, 3H), 3.50 (d, J¼13.0 Hz, 2H), 3.87 (d,
J¼13.0 Hz, 2H), 6.28 (ddd, J¼4.0, 2.5, 2.5 Hz, 1H), 6.90
(ddd, J¼4.0, 2.5, 1.5 Hz, 1H), 7.04 (ddd, J¼2.5, 2.5, 1.5 Hz,
1H), 7.3–7.5 (m, 10H), 9.56 (s, 1H); 13C NMR (90 MHz) d
34.8, 53.6, 57.1, 61.8, 110.9, 116.5, 125.00, 127.3, 128.5,
129.0, 131.9, 138.9, 188.8. CIMS 349 (Mþ). Anal. Calcd for
C22H24N2O2 (348.45): C, 75.83; H, 6.94; N, 8.04. Found: C,
75.47; H, 7.04; N, 7.69. The enantiomer (R)-6 was prepared
as described for (S)-6 using (R)-2: [a]2D0¼247.78 (c¼1.0,
CHCl3).
In conclusion, chemo- and regioselective transformations of
asparagine gave access to optically active 5- and 6-amino
tetrahydroindolizines. Additionally, tetrahydroisoindoles
were obtained as side products. Receptor binding experi-
ments showed stereocontrolled receptor recognition leading
to the D3 selective agonist (S)-8 with D3 binding that is
comparable to dopamine. Compounds of this type might be
of interest for the treatment of Parkinson’s disease.
2. Experimental
2.1. General
2.1.3. (S)-3-Dibenzylamino-4-hydroxy-1-(1-methyl-pyr-
rol-2-yl)-butan-1-one ((S)-7). TMEDA (4.86 mL,
32.3 mmol) and N-methylpyrrole (3.75 mL, 42.1 mmol)
were added to n-BuLi (20.2 mL, 32.3 mmol, 1.6 M in
hexane) and allowed to stir 15 min at room temperature.
This mixture was then added dropwise to a solution of (S)-2
(3.04 g, 10.8 mmol) in THF (80 mL) at 278 8C until no
more (S)-2 could be detected via TLC (petroleum ether–
EtOAc 7:3). Saturated NaHCO3 (20 mL) was added and the
reaction mixture was warmed to room temperature. Et2O
and water were added. The organic layer was separated,
dried (MgSO4) and evaporated. The residue was purified by
flash chromatography (petroleum ether–EtOAc, 7:3) to give
(S)-7 (2.43 g, 62%) as a colorless oil: [a]2D0¼þ39.68 (c¼0.5,
Solvents and reagents were purified and dried by standard
procedures. Unless otherwise noted reactions were con-
ducted under dry N2. Evaporations of final product solutions
were done under vacuo with a rotatory evaporator. Flash
chromatography was carried out with 230–400 mesh silica
gel. If not otherwise stated MS were run by EI ionization
(70 eV) with solid inlet, HRMS were obtained employing
peak matching M/DM¼10,000. 1H NMR spectra were
recorded at 360 MHz spectrometers, if not otherwise stated
in CDCl3 relative to TMS; 13C NMR spectra were recorded
at 90 MHz in CDCl3. Elemental analyses were performed
by Beetz Microanalysis Laboratory and by the Institute of
Organic Chemistry (Analytical Departments) of the
Friedrich-Alexander University Erlangen-Nu¨rnberg.
1
CHCl3); IR 3447, 1639 cm21; H NMR (360 MHz) d 2.70
(dd, J¼14.0, 8.5 Hz, 1H), 2.98 (s, 1H), 3.16 (dd, J¼14.0,

M. Bergauer et al. / Tetrahedron 60 (2004) 1197–1204
1201
4.0 Hz, 1H), 3.40–3.60 (m, 1H), 3.40–3.60 (m, 2H), 3.50
(d, J¼13.5 Hz, 2H), 3.86 (d, J¼13.5 Hz, 2H), 3.93 (s, 3H),
6.13 (dd, J¼4.0, 2.5 Hz, 1H), 6.83 (dd, J¼2.5, 1.5 Hz,
1H), 6.93 (dd, J¼4.0, 1.5 Hz, 1H), 7.20–7.35 (m, 10H);
13C NMR (90 MHz) d 36.0, 37.7, 53.6, 57.2, 61.8,
108.1, 119.6, 127.3, 128.5, 129.0, 130.6, 131.6, 139.0,
189.4; CIMS 362 (Mþ). Anal. Calcd for C23H26N2O2
(362.48): C, 76.21; H, 7.23; N, 7.73. Found: C, 76.34; H,
7.34; N, 7.74. The enantiomer (R)-7 was prepared as
described for (S)-7 using (R)-2: [a]2D0¼241.58 (c¼0.5,
CHCl3).
Found: C, 61.55; H, 5.18; N, 6.20. The enantiomers (R)-9
and (R)-11 were prepared as described for (S)-9 and (S)-11
using (R)-10: (R)-9: [a]D20¼þ57.28 (c¼3.0, CHCl3); (R)-11:
[a]2D0¼þ13.48 (c¼3.0, CHCl3).
2.1.6. (S)-2-Dibenzylamino-4-(1H-pyrrol-2-yl)-butan-1-
ol ((S)-10). AlCl3 (2.62 g, 19.70 mmol) was suspended in
CH2Cl2 (90 mL) and cooled to 0 8C. Borane–tertbutyl-
amine complex (3.43 g, 39.40 mmol) was slowly added.
The mixture was allowed to stir for 10 min giving a clear
colorless solution. A solution of (S)-6 (2.29 g; 6.57 mmol)
in as little CH2Cl2 as can be was added dropwise to the ice-
cooled solution and stirred for a further 60 min. Then water
was carefully added at 0 8C. The solution was warmed up to
room temperature and 0.1 M HCl was added until the gas
evolution stopped. Then CH2Cl2 was added. The organic
layer was separated, dried (MgSO4) and evaporated. The
residue was purified by flash chromatography (petroleum
ether–EtOAc, 7:3) to give (S)-10 (959 mg, 44%) as a
colorless oil: [a]2D0¼þ70.08 (c¼1.0, CHCl3); IR 3427,
3376 cm21; 1H NMR (360 MHz) d 1.54 (dddd, J¼13.5, 9.0,
8.0, 6.0 Hz, 1H), 2.04 (dddd, J¼13.5, 9.0, 7.0, 4.0 Hz, 1H),
2.52 (ddd, J¼15.0, 8.0, 7.0 Hz, 1H), 2.63 (ddd, J¼15.0, 9.0,
6.0 Hz, 1H), 2.83 (dddd, J¼9.0, 9.0, 5.5, 4.0 Hz, 1H), 2.92
(s, 1H), 3.4–3.6 (m, 2H), 3.43 (d, J¼14.0 Hz, 2H), 3.79 (d,
J¼14.0 Hz, 2H), 5.93 (ddd, J¼3.5, 2.5, 1.5 Hz, 1H), 6.14
(ddd, J¼3.5, 3.0, 1.5 Hz, 1H), 6.63 (ddd, J¼3.0, 2.5, 1.5 Hz,
1H), 7.3–7.5 (m, 10H), 7.80 (s, 1H); 13C NMR (90 MHz) d
25.1, 25.9, 53.3, 58.4, 60.9, 105.2, 108.5, 116.3, 127.2,
128.5, 129.1, 131.6, 139.3; EIMS 334 (Mþ). Anal. Calcd for
C22H26N2O (334.37): C, 79.01; H, 7.84; N, 8.38. Found: C,
78.98; H, 7.82; N, 8.07. The enantiomer (R)-10 was
prepared as described for (S)-10 using (R)-6: [a]2D0-69.08
(c¼1.0, CHCl3).
2.1.4. (S)-5-Dipropylamino-4,5,6,7-tetrahydroindole
((S)-8). Compound (S)-8 was prepared as described for
(S)-13 using (S)-9 (45 mg, 0.142 mmol). The residue was
purified by flash chromatography (CH2Cl2–MeOH 9:1) to
give (S)-8 (24 mg, 78%) as a colorless oil: [a]2D0¼249.58
1
(c¼1.0, CHCl3); H NMR (360 MHz) d 0.89 (t, J¼7.4 Hz,
6H, CH2CH2CH3), 1.5–1.6 (m, 4H, CH2CH2CH3), 1.7 (m,
1H, H-6ax), 2.1 (m, 1H, H-6eq), 2.5–2.6 (m, 4H, CH2CH2-
CH3), 2.6–2.7 (m, 4H, H-4eq,ax, H-7eq,ax), 3.0–3.1 (m, 1H,
H-5ax), 5.97 (dd, J¼2.7, 2.7 Hz, 1H, H-3), 6.63 (dd, J¼2.7,
2.7 Hz, 1H, H-2), 7.80 (s, 1H, NH); 13C NMR (90 MHz) d
11.85 (NCH2CH2CH3), 21.68 (NCH2CH2CH3), 22.82,
24.53 (C-4, C-7), 26.09 (C-6), 52.83 (NCH2CH2CH3),
58.26 (C-5), 107.66 (C-3), 116.00 (C-3a), 116.52 (C-2),
126.13 (C-7a); EIMS 220 (Mþ). Anal. Calcd for C14H24N2
(220.36): C, 76.31; H, 10.98; N, 12.71. Found: C, 76.25; H,
10.99; N, 12.66. The enantiomer (R)-8 was prepared as
described for (S)-13 using (R)-9: [a]2D0¼þ50.08 (c¼0.5,
CHCl3).
2.1.5. (S)-5-Dibenzylamino-4,5,6,7-tetrahydro-1H-indole
((S)-9) and (S)-1-trifluoromethylsulfonyl-5-dibenzyl-
amino-4,5,6,7-tetrahydro-1H-indole ((S)-11). Trifluoro-
methanesulfonic anhydride (0.59 mL, 3.60 mmol) was
added dropwise to an ice cooled solution of (S)-10
(926 mg, 2.77 mmol) and 2,6-di-tert-butyl-4-methylpyri-
dine (1.48 g, 7.20 mmol). The mixture was stirred for 1 h at
room temperature. Then saturated NaHCO3 and CH2Cl2
were added. The organic layer was separated, dried
(MgSO4) and evaporated. The residue was purified by
flash chromatography (petroleum ether–EtOAc, 9:1) to give
(S)-9 (423 mg, 48%) and (S)-11 (220 mg, 18%) as colorless
oils: (S)-9: [a]D20¼258.98 (c¼2.0, CHCl3); 1H NMR
(360 MHz) d 1.81 (dddd, J¼12.5, 12.0, 12.0, 6.0 Hz, 1H),
2.14 (ddd, J¼12.5, 2.5, 2.2 Hz, 1H), 2.5–2.7 (m, 4H), 3.01
(dddd, J¼12.0, 10.0, 6.0, 2.2 Hz, 1H), 3.66 (d, J¼14.0 Hz,
2H), 3.75 (d, J¼14.0 Hz, 2H), 5.96 (dd, J¼2.6, 2.6 Hz, 1H),
6.59 (dd, J¼2.6, 2.6 Hz, 1H), 7.3–7.5 (m, 10H), 7.64 (s,
1H); 13C NMR (90 MHz) d 22.9, 24.4, 25.4, 54.0, 54.3,
115.0, 122.4, 125.2, 126.8, 128.3, 128.4, 130.4, 140.4.
EIMS 316 (Mþ). Anal. Calcd for C22H24N2 (316.45): C,
83.50; H, 7.64; N, 8.85. Found: C, 83.49; H, 7.65; N, 8.87.
(S)-11: [a]2D0¼211.58 (c¼2.0, CHCl3); 1H NMR (360 MHz)
d 1.76 (dddd, J¼12.5, 12.0, 12.0, 5.3 Hz, 1H), 2.20 (ddd,
J¼12.5, 5.3, 2.4 Hz, 1H), 2.5–2.7 (m, 4H), 2.9–3.0 (m,
1H), 3.65 (d, J¼14.0 Hz, 2H), 3.74 (d, J¼14.0 Hz, 2H), 6.16
(d, J¼3.5 Hz, 1H), 6.94 (d, J¼3.5 Hz, 1H), 7.2–7.5 (m,
10H); 13C NMR (90 MHz) d 22.9, 24.4, 25.4, 53.9, 54.3,
115.0, 119.3 (q, J¼323 Hz), 122.4, 125.2, 126.8, 128.2,
128.4, 130.4, 140.3;. EIMS 448 (Mþ). Anal. Calcd for
C23H23F3N2O2S (448.51): C, 61.59; H, 5.17; N, 6.25.
2.1.7. (S)-2-Dibenzylamino-4-(1-methyl-1H-pyrrol-2-yl)-
butan-1-ol ((S)-12). AlCl3 (1.16 g, 8.70 mmol) was sus-
pended in CH2Cl2 (30 mL) and cooled to 0 8C. Borane–
tertbutylamine complex (1.51 g, 17.4 mmol) was added
slowly. The mixture was allowed to stir for 10 min giving a
clear colorless solution. A solution of (S)-7 (1.05 g;
2.90 mmol) in as little CH2Cl2 as can be was added
dropwise to the ice-cooled solution and stirred for a further
60 min. Then water was carefully added at 0 8C. The
solution was warmed up to room temperature and 0.1 M
HCl was added until the gas evolution stopped. Then
CH2Cl2 was added. The organic layer was separated, dried
(MgSO4) and evaporated. The residue was purified by
flash chromatography (CHCl3–EtOAc, 95:5) to give (S)-
12 (734 mg, 73%) as a colorless oil: [a]2D0¼þ92.08 (c¼1.0,
CHCl3); IR 3439 cm21 1H NMR (360 MHz) d 1.55
;
(dddd, J¼13.5, 9.5, 9.0, 5.5 Hz, 1H), 2.07 (dddd, J¼13.5,
10.0, 6.5, 4.0 Hz, 1H), 2.45 (ddd, J¼15.5, 9.0, 6.5 Hz,
1H) 2.52 (ddd, J¼15.5, 10.0, 5.5 Hz, 1H), 2.87 (dddd,
J¼9.5, 9.5, 5.5, 4.0 Hz, 1H), 3.04 (s, 1H), 3.43 (d,
J¼13.0 Hz, 2H), 3.50 (s, 3H), 3.5–3.6 (m, 2H), 3.83 (d,
J¼13.0 Hz, 2H), 5.91 (dd, J¼3.0, 2.0 Hz, 1H), 6.07
(dd, J¼3.0, 2.5 Hz, 1H), 6.56 (dd, J¼2.5, 2.0 Hz, 1H),
7.2–7.4 (m, 10H); 13C NMR (90 MHz) d 23.9, 24.6, 33.5,
53.2, 58.8, 60.8, 105.6, 106.8, 121.3, 127.2, 128.5, 129.1,
132.5, 139.2; EIMS 348 (Mþ). Anal. Calcd for C23H28N2O
(348.49): C, 79.27; H, 8.10; N, 8.04. Found: C, 79.01; H,
7.95; N, 7.89. The enantiomer (R)-12 was prepared as

1202
M. Bergauer et al. / Tetrahedron 60 (2004) 1197–1204
described for (S)-12 using (R)-7: [a]2D0¼291.58 (c¼1.0,
(46 mg, 0.196 mmol) in DMF (5 mL). The reaction mixture
was stirred for a further 60 min. After that the reaction
solution was added to ice cooled 1 N NaOH and the product
was extracted with Et2O. The organic layer was separated,
dried (MgSO4) and evaporated. The residue was purified by
flash chromatography (CH2Cl2–MeOH 9:1) to give (S)-15
(44 mg, 85%) as a colorless oil: [a]2D0¼265.58 (c¼0.4,
CHCl3).
2.1.8. (S)-5-Dipropylamino-1-methyl-4,5,6,7-tetra-
hydroindole ((S)-13). A solution of (S)-14 (386 mg,
1.17 mmol) and Pd(OH)2/C (333 mg) in EtOAc and
MeOH (1:1) (20 mL) was stirred under hydrogen atmos-
phere (1 atm) at room temperature for 24 h. The solution
was filtered and evaporated to give the crude amine
(176 mg). The crude product was dissolved in 1,2-
dichloroethane (20 mL), propionaldehyde (0.17 mL,
2.34 mmol) and sodium triacetoxyborohydride (595 mg,
2.81 mmol) were added. After stirring for 1 h at room
temperature, NaHCO3 and CH2Cl2 were added. The organic
layer was separated, dried (MgSO4) and evaporated. The
residue was purified by flash chromatography (CH2Cl2–
MeOH 9:1) to give (S)-13 (160 mg, 58%) as a colorless oil:
[a]2D0¼248.48 (c¼0.25, CHCl3); 1H NMR (360 MHz) d
0.87 (t, J¼7.5 Hz, 6H, NCH2CH2CH3), 1.45 (tq, J¼7.5,
7.5 Hz, 4H, NCH2CH2CH3), 1.69 (dddd, J¼12.0, 12.0, 12.0,
6.0 Hz, 1H, H-6ax), 2.02 (dddd, J¼12.0, 6.0, 4.0, 2.0 Hz,
1H, H-6eq), 2.4–2.5 (m, 4H, NCH2CH2CH3), 2.4–2.7 (m,
4H, H-4, H-7), 2.95 (dddd, J¼12.0, 11.5, 5.0, 2.0 Hz,
H-5ax), 3.46 (s, 3H, NCH3), 5.89 (d, J¼2.5 Hz, 1H, pyrrole-
H-3), 6.48 (d, J¼2.5 Hz, 1H, pyrrole-H-2); 13C NMR
(90 MHz) d 11.84 (NCH2CH2CH3), 21.82, 24.71 (NCH2-
CH2CH3, C-4, C-7), 26.02 (C-6), 33.03 (NCH3), 52.81
(NCH2CH2CH3), 57.93 (C-5), 106.11 (C-3), 116.34 (C-3a),
120.39 (C-2), 127.43 (C-7a); EIMS 234 (Mþ);
combustion analysis from the dibenzoyl-L-tartaric acid
salt (mp 107 8C). Anal. Calcd for C33H40N2O2 (592.69):
C, 72.47; H, 11.77; N, 7.35. Found: C, 72.53; H, 11.69; N,
7.29; HRMS calcd for C15H26N2 (Mþ): 234.20997. Found:
234.20959. The enantiomer (R)-13 was prepared as
described for (S)-13 using (R)-14: [a]2D0¼þ49.48 (c¼1.0,
CHCl3).
1
CHCl3); IR 1654 cm21; H NMR (360 MHz) d 0.89 (t,
J¼7.5 Hz, 6H, NCH2CH2CH3), 1.3–1.5 (m, 4H, NCH2-
CH2CH3), 1.6–1.7 (m, 1H, H-6ax), 2.0–2.1 (m, 1H, H-6eq),
2.4–2.5 (m, 4H, NCH2CH2CH3), 2.4–2.8 (m, 4H, H-4,
H-7), 2.8–3.0 (m, 1H, H-5ax), 3.80 (s, 3H, NCH3), 6.64 (m,
1H, pyrrole-H-3), 9.38 (s, 1H, CHO); 13C NMR (90 MHz) d
11.84 (NCH2CH2CH3), 22.01, 22.19, 24.88 (NCH2CH2-
CH3, C-4,C-7), 25.41 (C-6), 32.18 (NCH3), 52.78 (NCH2-
CH2CH3), 57.33 (C-5), 119.76 (C-3a), 122.84 (C-3), 131.42
(C-7a), 139.60 (C-2), 178.54 (CHO); EIMS 262 (Mþ). Anal.
Calcd for C16H26N2O (262.40): C, 73.24; H, 9.99; N, 10.68.
Found: C, 72.91; H, 10.00; N, 10.65. The enantiomer (R)-15
was prepared as described for (S)-15 using (R)-13:
[a]2D0¼þ63.58 (c¼0.5, CHCl3).
2.1.11. 1-[(S)-1-Methyl-4,5,6,7-tetrahydro-1H-indol-5-
yl]-3-[(S)-phenylethyl]-urea ((S,S)-17) and 1-[(S)-1-
methyl-4,5,6,7-tetrahydro-1H-indol-5-yl]-3-[(R)-phenyl-
ethyl]-urea ((S,R)-17). Compound (S)-14 (83 mg,
0.251 mmol) and Pd(OH)2/C (83 mg), dissolved in
EtOAc–MeOH (9:1, 5 mL), were stirred for 24 h at room
temperature under hydrogen atmosphere (1 atm). After
removing the catalyst by filtration, the solution was divided
in two equal parts and evaporated separately. (R)-Phenyl-
ethyl isocyanate (R)-16 (17 mL, 0.123 mmol) was added to a
solution of one part of the residue (14 mg, 0.092 mmol) in
CH2Cl2 (3 mL). After stirring for 6 h at room temperature,
the solvent was removed and the residue was purified by
flash chromatography (CH2Cl2–MeOH 9:1) to give (S;R)-
17 (20 mg, 73%) as a colorless oil. (S)-Phenylethyl
isocyanate (17 mL, 0.123 mmol) was added to a solution
of the second part of the residue (17 mg, 0.112 mmol) in
CH2Cl2 (3 mL). After stirring for 6 h at room temperature,
the solvent was removed and the residue was purified by
flash chromatography (CH2Cl2–MeOH 9:1) to give (S,S)-17
(22 mg, 66%) as a colorless oil. An analytical sample was
prepared: (S,S)-17: [a]D20¼213.18 (c¼0.7, CHCl3); IR 3332,
1623 cm21; 1H NMR (360 MHz) d 1.45 (d, J¼6.8 Hz, 3H),
1.82 (m, 1H), 1.97 (m, 1H), 2.25 (m, 1H), 2.45–2.80 (m,
3H), 3.45 (s, 3H), 4.05 (m, 1H), 4.25 (d, J¼7.5 Hz, 1H),
4.42 (d, J¼7.5 Hz, 1H), 4.79 (m, 1H), 5.84 (d, J¼2.7 Hz,
1H), 6.47 (d, J¼2.7 Hz, 1H), 7.2–7.4 (m, 5H); EIMS 297
(Mþ). Anal. Calcd for C18H23N3O (297.40): C, 72.70; H,
7.80; N, 14.13. Found: C, 72.44; H, 7.68; N, 14.25. (S,R)-17:
2.1.9. (S)-5-Dibenzylamino-1-methyl-4,5,6,7-tetra-
hydroindole ((S)-14). Trifluoromethanesulfonic anhydride
(0.48 mL, 2.94 mmol) was added dropwise to an ice cooled
solution of (S)-12 (682 mg, 1.96 mmol) and 2,6-di-tert-
butyl-4-methyl-pyridine (1.21 g, 5.88 mmol). The mixture
was stirred for 1 h at room temperature. Then saturated
NaHCO3 and CH2Cl2 were added. The organic layer was
separated, dried (MgSO4) and evaporated. The residue was
purified by flash chromatography (petroleum ether–EtOAc,
9:1) to give (S)-14 (433 mg, 67%) as a colorless oil:
[a]2D0¼247.08 (c¼1.0, CHCl3); 1H NMR (360 MHz) d 1.79
(dddd, J¼12.0, 12.0, 12.0, 5.5 Hz, 1H), 2.17 (m, 1H), 2.44
(m, 1H), 2.60–2.76 (m, 3H), 2.98 (dddd, J¼12.0, 10.0, 6.0,
2.5 Hz, 1H), 3.40 (s, 3H), 3.66 (d, J¼14.0 Hz, 2H), 3.73 (d,
J¼14.0 Hz, 2H), 5.88 (d, J¼2.5 Hz, 1H), 6.44 (d, J¼2.5 Hz,
1H), 7.10–7.40 (m, 10H, ArH); 13C NMR (90 MHz) d 21.6,
24.7, 24.9, 32.8, 53.8, 55.1, 105.9, 116.5, 120.1, 126.4,
127.3, 128.0, 128.3, 140.7; EIMS 330 (Mþ). Anal. Calcd for
C23H26N2 (330.48): C, 83.59; H, 7.93; N, 8.48. Found: C,
83.56; H, 7.76; N, 8.37. The enantiomer (R)-14 was
prepared as described for (S)-14 using (R)-12:
[a]2D0¼þ47.58 (c¼1.0, CHCl3).
IR 3330, 1627 cm21 1H NMR (360 MHz) d 1.42 (d,
;
J¼6.8 Hz, 3H), 1.81 (dddd, J¼15.0, 13.1, 13.0, 6.7 Hz, 1H),
2.17 (m, 1H), 2.34 (dd, J¼15.5, 6.0 Hz, 1H), 2.44 (dd,
J¼15.5, 12.4 Hz, 1H), 2.3–2.5, 2.7–2.9 (m, 2H), 3.39 (s,
3H), 4.05 (m, 1H), 4.33 (d, J¼8.6 Hz, 1H), 4.53 (d,
J¼5.8 Hz, 1H), 4.67 (ddd, J¼13.0, 12.4, 6.0 Hz, 1H), 5.85
(d, J¼2.7 Hz, 1H), 6.46 (d, J¼2.7 Hz, 1H), 7.2–7.4 (m, 5H,
ArH);. EIMS 297 (Mþ); HRMS calcd for C18H23N3O (Mþ):
297.18411. Found: 297.18418. HPLC (Lichrosorb Si 60 7m,
CH2Cl2–MeOH 99:1, 1.5 mL min21, detection UV:
256 nm) tR 13.0 min (97.5%, (S,R)-17), 10.2 min (2.5%,
(S,S)-17).
2.1.10. (S)-5-Dipropylamino-1-methyl-4,5,6,7-tetra-
hydroindol-2-carbaldehyde ((S)-15). POCl3 (36 mL,
0.392 mmol) was added at 0 8C to a solution of (S)-13

M. Bergauer et al. / Tetrahedron 60 (2004) 1197–1204
1203
1
2.1.12. (S)-3-Dibenzylamino-4-hydroxy-(1-triisopropyl-
silyl-1H-pyrrol-3-yl)-butan-1-one ((S)-19). To a solution
of 3-bromo-1-triisopropylsilyl pyrrole (605 mg, 2.0 mmol)
in pentane (5 mL), n-BuLi (1.25 mL, 2.0 mmol, 1.6 M in
hexane) was added dropwise. The mixture was stirred for
15 min at room temperature. The solution was then slowly
added to (S)-2 (281 mg, 1.0 mmol) dissolved in THF (5 mL)
at 0 8C. The addition was stopped, when no more lactone
(S)-2 could be detected via TLC (petroleum ether–Et2O
1:1). Then water and Et2O were added. The organic layer
was separated, dried (MgSO4) and evaporated. The residue
was purified by flash chromatography (petroleum ether
-Et2O 1:1) to give (S)-19 (234 mg, 47%) as a colorless oil:
7.5 (m, 10H); (S)-21: H NMR (360 MHz) d 6.36 (s, 1H),
6.40 (s, 1H). EIMS 472 (Mþ); The enantiomers (R)-22 and
(R)-21 were prepared as described for (S)-14 using (R)-20.
2.1.15. (S)-6-Dipropylamino-1-triisopropylsilyl-4,5,6,7-
tetrahydro-1H-indole ((S)-24), (S)-5-dipropylamino-2-
triisopropylsilyl-4,5,6,7-tetrahydro-2H-isoindole ((S)-
23). A solution of (S)-21 and (S)-22 (563 mg, 1.19 mmol)
and Pd(OH)2/C (563 mg) in EtOAc and MeOH (1:1) was
stirred under hydrogen atmosphere (1 atm) at room
temperature for 2 h. The solution was filtered and
evaporated to give the crude amines (307 mg). The crude
product was dissolved in 1,2-dichloroethane, propionalde-
hyde (0.17 mL, 2.38 mmol) and sodium triacetoxyboro-
hydride (605 mg, 2.86 mmol) were added. After stirring for
45 min at room temperature, NaHCO3 and CH2Cl2 were
added. The organic layer was separated, dried (MgSO4) and
evaporated. The residue was purified by flash chromato-
graphy (CH2Cl2–MeOH 9:1) to give (S)-24 (278 mg, 62%)
and (S)-23 (40 mg, 9%) as colorless oils: (S)-24:
[a]2D0¼229.88 (c¼0.5, CHCl3); 1H NMR (360 MHz) d
0.89 (t, J¼7.2 Hz, 6H), 1.11 (d, J¼7.5 Hz, 18H),1.3–1.7
(m, 8H), 1.9–2.1 (m, 1H), 2.4–2.8 (m, 8H), 3.0 (m, 1H),
6.02 (d, J¼2.7 Hz, 1H), 6.69 (d, J¼2.7 Hz, 1H); 13C NMR
(90 MHz) d 11.8, 12.5, 18.2, 22.0, 23.0, 26.2, 27.7, 52.9,
58.2, 108.8, 119.9, 124.6, 131.5; EIMS 376 (Mþ). Anal.
Calcd for C23H44N2Si (376.71)£1/4H2O: C, 72.47; H,
11.77; N, 7.35. Found: C, 72.53; H, 11.69; N, 7.29. (S)-23:
[a]2D0¼235.88 (c¼0.5, CHCl3); 1H NMR (360 MHz) d 0.88
(t, J¼7.2 Hz, 6H), 1.08 (d, J¼7.5 Hz, 18H),1.39 (q,
J¼7.5 Hz, 3H), 1.4–1.5 (m, 4H), 1.5–1.7 (m, 1H), 1.9–
2.0 (m, 1H), 2.5–2.6 (m, 4H), 2.5–2.9 (m, 4H), 3.0–3.1 (m,
1H), 6.40 (s, 1H), 6.42 (s, 1H); EIMS 376 (Mþ). Anal. Calcd
for C23H44N2Si (376.71)£1/2H2O: C, 71.62; H, 11.76; N,
7.26. Found: C, 71.43; H, 11.76; N, 7.29. The enantiomers
(R)-23 and (R)-24 were prepared as described for (S)-24 and
(S)-23 using (R)-21/(R)-22: (R)-24: [a]2D0¼þ31.38 (c¼1.5,
CHCl3); (R)-23: [a]2D0¼þ35.58 (c¼0.5, CHCl3).
[a]D20þ50.08 (c¼0.5, CHCl3); IR 3445, 1652 cm21
;
1H
NMR (360 MHz) d 1.11 (d, J¼7.5 Hz, 18H), 1.47 (qq,
J¼7.5, 7.5 Hz, 3H), 2.70 (dd, J¼14.5, 7.7 Hz, 1H), 3.05 (s,
1H), 3.14 (dd, J¼14.5, 4.3 Hz, 1H), 3.53 (d, J¼13.4 Hz,
2H), 3.5–3.6 (m, 3H), 3.85 (d, J¼13.4 Hz, 2H), 6.70 (dd,
J¼3.0, 1.5 Hz, 1H), 6.75 (dd, J¼3.0, 2.0 Hz, 1H), 7.2–7.4
(m, 10H), 7.39 (dd, J¼2.0, 1.5 Hz, 1H); 13C NMR (90 MHz)
d 11.3, 17.4, 36.6, 53.4, 56.6, 61.7, 110.7, 125.5, 127.0,
127.8, 128.2, 128.8, 129.3, 139.0, 194.6. Anal. Calcd for
C31H44N2O2Si (504.79): C, 73.76; H, 8.79; N, 5.55. Found:
C, 73.83; H, 8.70; N, 5.59. The enantiomer (R)-19 was
prepared as described for (S)-19 using (R)-2: [a]2D0¼248.58
(c¼0.5, CHCl3).
2.1.13. (S)-2-Dibenzylamino-4-(1-triisopropylsilyl-1H-
pyrrol-3-yl)-butan-1-ol ((S)-20). Compound (S)-20 was
prepared as described for (S)-12 using (S)-19 (1.44 g,
2.86 mmol). The residue was purified by flash chromato-
graphy (petroleum ether–Et2O, 8:2) to give (S)-20 (721 mg,
51%) as a colorless oil: [a]2D0¼þ80.98 (c¼2.0, CHCl3); IR
3449 cm21
;
1H NMR (360 MHz) d 1.09 (d, J¼7.5 Hz,
18H), 1.44 (qq, J¼7.5, 7.5 Hz, 3H), 1.4–1.5 (m, 1H), 2.04
(dddd, J¼13.5, 9.5, 6.5, 4.0 Hz, 1H), 2.45 (ddd, J¼14.5, 9.0,
6.5 Hz, 1H), 2.52 (ddd, J¼14.5, 9.5, 5.5 Hz, 1H), 2.86
(dddd, J¼9.5, 9.5, 4.5, 4.0 Hz, 1H), 3.14 (s, 1H), 3.4–3.6
(m, 2H), 3.44 (d, J¼13.5 Hz, 2H), 3.81 (d, J¼13.5 Hz, 2H),
6.17 (dd, J¼2.5, 1.5 Hz, 1H), 6.52 (dd, J¼2.0, 1.5 Hz, 1H),
6.72 (dd, J¼2.5, 2.0 Hz, 1H), 7.2–7.4 (m, 10H); 13C NMR
(90 MHz) d 11.6, 17.7, 24.7, 26.7, 53.2, 59.0, 60.9, 110.4,
121.0, 124.3, 125.3, 127.1, 128.4, 129.1, 139.5; EIMS 490
(Mþ). Anal. Calcd for C31H46N2OSi (490.81): C, 75.86; H,
9.45; N, 5.71. Found: C, 75.60; H, 9.51; N, 5.71. The
enantiomer (R)-20 was prepared as described for (S)-12
using (R)-19: [a]D20¼279.68 (c¼2.0, CHCl3).
2.1.16. (S)-5-Dipropylamino-4,5,6,7-tetrahydro-2H-iso-
indole ((S)-25). Compound (S)-25 was prepared as
described for (S)-26 using (S)-23 (27 mg, 0.072 mmol).
The residue was purified by flash chromatography
(CH2Cl2–MeOH 8:2) to give (S)-25 (13 mg, 82%) as a
colorless oil: [a]D20¼252.18 (c¼0.5, CHCl3); 1H NMR
(360 MHz) d 0.88 (t, J¼7.5 Hz, 6H, NCH2CH2CH3), 1.50
(tq, J¼7.5, 7.5 Hz, 4H, NCH2CH2CH3), 1.61 (dddd,
J¼12.0, 12.0, 12.0, 5.0 Hz, 1H, H-6ax), 2.0 (m, 1H,
H-6eq), 2.4–2.5 (m, 4H, NCH2CH2CH3), 2.5–2.7 (m, 2H,
H-7eq,ax), 2.7–2.9 (m, 2H, H-4eq,ax), 2.99 (dddd, J¼12.0,
12.0, 5.0, 2.0 Hz, 1H, H-5ax), 6.47, 6.49 (s, 2H, H-1, H-3),
8.03 (s, 1H, NH).; 13C NMR (90 MHz) d 11.91 (NCH2-
CH2CH3), 22.03, 22.19 (NCH2CH2CH3, C-7), 24.38 (C-4),
27.01 (C-6), 52.83 (NCH2CH2CH3), 58.59 (C-5), 112.85,
113.53 (C-3a, C-7a), 119.09, 119.46 (C-1, C-3); EIMS 220
(Mþ); HRMS calcd for C14H24N2 (Mþ): 220.19395. Found:
220.19379. The enantiomer (R)-25 was prepared as
described for (S)-26 using (R)-23: [a]2D0¼þ53.68 (c¼0.8,
CHCl3).
2.1.14. (S)-6-Dibenzylamino-1-triisopropylsilyl-4,5,6,7-
tetrahydro-1H-indole ((S)-22), (S)-5-dibenzylamino-2-
triisopropylsilyl-4,5,6,7-tetrahydro-2H-isoindole ((S)-
21). Compounds (S)-22 and (S)-21 were prepared as
described for (S)-14 using (S)-20 (730 mg, 1.49 mmol).
The residue was purified by flash chromatography
(petroleum ether–Et2O, 100:0, 98:2, 95:5) to give a 8:2
mixture (estimated by 1H NMR) of (S)-22 and (S)-21
(556 mg, 79%) as a colorless oil: (S)-22: 1H NMR
(360 MHz) d 1.09 (d, J¼7.5 Hz, 18H), 1.46 (qq, J¼7.5,
7.5 Hz, 3H), 1.73 (dddd, J¼12.0, 12.0, 12.0, 5.5 Hz, 1H),
2.0–2.1 (m, 1H), 2.4–2.5 (m, 1H), 2.4–2.5 (m, 1H), 2.6–
2.7 (m, 1H), 2.8–2.9 (m, 1H), 3.02 (dddd, J¼12.0, 11.0, 4.5,
2.0 Hz, 1H), 3.66 (d, J¼14.0 Hz, 2H), 3.76 (d, J¼14.0 Hz,
2H), 5.97 (d, J¼2.5 Hz, 1H), 6.64 (d, J¼2.5 Hz, 1H), 7.2–
2.1.17. (S)-6-Dipropylamino-4,5,6,7-tetrahydro-1H-
indole ((S)-26). A solution of (S)-24 (45 mg, 0.119 mmol)
and TBAF (119 mL, 0.119 mmol, 1.0 M in THF) in THF

1204
M. Bergauer et al. / Tetrahedron 60 (2004) 1197–1204
(5 mL) was stirred at room temperature for 20 min.
Then, satd NaHCO3 solution and Et2O were added. The
organic layer was separated, dried (MgSO4) and evaporated.
The residue was purified by flash chromatography
(CH2Cl2–MeOH 8:2) to give (S)-26 (18 mg, 69%) as a
colorless oil: [a]D20¼252.08 (c¼1.0, CHCl3); 1H NMR
(360 MHz) d 0.88 (t, J¼7.5 Hz, 6H, NCH2CH2CH3), 1.49
(tq, J¼7.5, 7.5 Hz, 4H, NCH2CH2CH3), 1.63 (dddd,
J¼12.0, 12.0, 12.0, 5.5 Hz, 1H, H-5ax), 2.0 (m, 1H,
H-5eq), 2.4–2.5 (m, 4H, NCH2CH2CH3), 2.5–2.8 (m, 4H,
H-4eq,ax, H7eq,ax), 3.09 (dddd, J¼12.0, 11.0, 5.0, 2.0 Hz, 1H,
H-6ax), 5.96 (dd, J¼2.5, 2.5 Hz, 1H, H-2), 6.63 (dd, J¼2.5,
2.5 Hz, 1H, H-3), 7.77 (s, 1H, NH); 13C NMR (90 MHz) d
11.86 (NCH2CH2CH3), 22.04 (NCH2CH2CH3), 22.62
(C-4), 25.24 (C-7), 26.46 (C-5), 52.82 (NCH2CH2CH3),
107.02 (C-3), 116.41 (C-2), 116.55 (C-3a), 126.26 (C-7a);
EIMS 220 (Mþ). Anal. Calcd for C14H24N2 (220.36): C,
76.31; H, 10.98; N, 12.71. Found: C, 76.25; H, 10.84; N,
12.61. The enantiomer (R)-26 was prepared as described for
(S)-26 using (R)-24: [a]2D0¼þ53.98 (c¼0.1, CHCl3).
References and notes
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2.2. Receptor binding studies and mitogenesis
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Acknowledgements
19. Asghari, V.; Sanyal, S.; Buchwaldt, S.; Paterson, A.;
Jovanovic, V.; Van Tol, H. H. M. J. Neurochem. 1995, 65,
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The authors thank Dr. J. -C. Schwartz and Dr. P. Sokoloff
(INSERM, Paris), Dr. H. H. M. Van Tol (Clarke Institute of
Psychiatry, Toronto) as well as Dr. J. Shine (The Garvan
Institute of Medical Research, Sydney) for providing
dopamine D3, D4 and D2 receptor expressing cell lines,
respectively. Thanks are also due to Dr. R. Waibel for
helpful discussions. This work was supported by the BMBF,
and the Fonds der Chemischen Industrie.
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