Stereoselective synthesis of 1-substituted 1,2,3,4-tetrahydro-β-carbolines by asymmetric electrophilic α-amidoalkylation reactions

Article abstract of DOI:10.3987/COM-04-10213

An efficient procedure for the asymmetric synthesis of 1-substituted1,2,3,4-tetrahydro-9-methyl-β-carbolines based on asymmetric electrophilic α-amidoalkylation reactions is described. Stereoselective addition of various organometallic reagents to a chira

Full text of DOI:10.3987/COM-04-10213

HETEROCYCLES, Vol. 63, No. 12, 2004, pp. 2747 - 2767
Received, 30th August, 2004, Accepted, 21st October, 2004, Published online, 26th October, 2004
STEREOSELECTIVE SYNTHESIS OF 1-SUBSTITUTED 1,2,3,4-TETRA-
HYDRO-β-CARBOLINES BY ASYMMETRIC ELECTROPHILIC α-
AMIDOALKYLATION REACTIONS
Ulrich Weber,a Cornelia Hoesl,b W. Ponikwar,c M. Suter,c Heinrich Nöth,c
and Klaus T. Wannerb*
a) Boehringer Ingelheim Pharma GmbH and Co. KG, Analytical Sciences
Department, 55216 Ingelheim/Rhein, Germany b) Department of Pharmacy –
Center for Drug Research, LMU Munich, Butenandtstr. 5-13, 81377 Munich,
Germany, c) Department of Chemistry, LMU Munich, Butenandtstr. 5-13, 81377
Munich, Germany
Abstract - An efficient procedure for the asymmetric synthesis of 1-substituted
1,2,3,4-tetrahydro-9-methyl-β-carbolines based on asymmetric electrophilic α-
amidoalkylation reactions is described. Stereoselective addition of various
organometallic reagents to a chiral N-acyl-β-carbolinium ion gave the
corresponding 1-substituted 1,2-dihydro-β-carbolines in high yields and very
good to excellent diastereomeric ratios. Catalytic hydrogenation followed by the
removal of the chiral auxiliary via reductive cleavage of the amide bond
proceeded with complete conservation of the absolute configuration at the newly
created stereocenter leading to 1-substituted 1,2,3,4-tetrahydro-9-methyl-β-
carboline derivatives in high yields. Their absolute stereochemistry was proven by
X-Ray analysis. The 1-phenyl-substituted 1,2,3,4-tetrahydro-β-carbolines were
evaluated for their affinity to the PCP binding site of the NMDA receptor.
INTRODUCTION
The β-carboline and tetrahydro-β-carboline nuclei are structural units often found in natural products
exhibiting interesting biological and pharmacological activities.1 Tetrahydro-β-carbolines having a

substituent at the C1 position have proven to be valuable substrates for the synthesis of a wide variety of
complex molecules including indole alkaloids and pharmaceuticals.2 In the context of a study aimed at
the development of new ion channel blockers targeting the PCP binding site of the NMDA receptor,3 we
reasoned that 1-aryl-substituted 1,2,3,4-tetrahydro-β-carbolines (1d) methylated at the nitrogen atom at 9-
position can be regarded as structurally related to the known ion channel blockers MK-801 (2) and FR-
115427 (3) (Scheme 1). The affinity of the (+)-enantiomer of MK-801 to the PCP binding site was
reported to be seven times higher than that of the (-)-enantiomer.4 In an earlier study undertaken by us it
was discovered that the (S)-enantiomer of 1,2,3,4-tetrahydroisoquinoline (4) displays a distinctly higher
potency at the PCP binding site than the (R)-enantiomer.5 Thus, to evaluate C1-substituted 1,2,3,4-
tetrahydro-β-carbolines as potential NMDA antagonists, it was of great interest to us to provide efficient
access to these compounds in enantiopure form.
HN
NH
NH
NH
N
CH3
CH3
H
CH3
1d
(S)-3 (FR-115427)
(S)-4
2 (MK-801)
Scheme 1
Various strategies for the stereoselective synthesis of C1-substituted tetrahydro-β-carbolines have been
reported. Among these synthetic methodologies, variations of the Pictet-Spengler reaction facilitating the
preparation of enantiopure compounds are one of the most extensively studied. They include “ex-chiral-
pool” syntheses employing chiral aldehydes6 or chiral tryptophan esters7 and Pictet-Spengler reactions of
tryptamine derivatives bearing a chiral auxiliary on the aminoethane nitrogen atom.8 An enantioselective
Pictet-Spengler reaction based on diisopinocampheylchloroborane as a chiral Lewis acid catalyst has
been developed by Nakagawa.9 The Bischler-Napieralski reaction of chiral tryptamine derivatives was
shown to proceed diastereoselectively to afford C1-substituted 1,2,3,4-tetrahydro-ß-carboline derivatives,
which were successfully used for the synthesis of various indole alkaloids.10 A vinylogous Mannich
reaction performed on a 3,4-dihydro-β-carboline derivative derived from D-tryptophan was reported to
lead to the corresponding 1,2,3,4-tetrahydro-β-carboline in a highly diastereoselective manner.11 Ohsawa
developed an enantioselective synthesis based on the proline-catalyzed addition of ketones to 9-tosyl-3,4-
dihydro-β-carboline.12 Nakamura reported that allylzinc reagents reacted with 3,4-dihydro-β-carboline in
the presence of a lithiated bisoxazoline ligand to give an allyl adduct in high enantiomeric excess.13 The

transformation of racemic C1-substituted tetrahydro-β-carbolines into enantiopure compounds by
oxidation and subsequent enantioselective hydrogenation using a chiral ruthenium catalyst has been
published by Tietze.14 Meyers developed an asymmetric method based on transforming 1,2,3,4-
tetrahydro-β-carboline into
a
chiral formamidine followed by
a
diastereoselective
deprotonation/alkylation sequence at C1.15 In analogy, Quirion described a general stereospecific route
via electrophilic attack at an α-aminoalkyl carbanion derived from the corresponding chiral 1,2,3,4-
tetrahydro-β-carbolinecarboxylic acid amide derivative.16 Even though the trapping reactions of N-
acyliminium ions with nucleophiles represent a frequently used process in the construction of α-
substituted nitrogen heterocycles,17 to the best of our knowledge, investigations on the versatility of
asymmetric reactions involving addition of nucleophiles to chiral N-acyl-β-carbolinium salts with the
chirality residing in an N1-acyl group are very limited. To date, only Ohsawa described a method18
featuring the generation of a chiral N1,N9-diacyl-β-carbolinium ion wherein the N1-acyl group is achiral
and the N9 is provided with the chiral auxiliary. Trapping reactions of these intermediates with
allyltributyltin or silylenolethers led to C1-substituted 1,2-dihydro-β-carbolines in high
diastereoselectivities. Following reduction, the corresponding 1,2,3,4-tetrahydro-β-carbolines were
obtained. In recent years, a major focus of our research was the stereoselective construction of α-
substituted nitrogen heterocycles. We have developed a synthetic method termed by us as Asymmetric
Electrophilic α-Amidoalkylation (AEαA ). It is based on trapping reactions of chiral N-acyliminium ions
with the chirality residing in the N-acyl group with appropriate nucleophiles. Thus far, the concept has
been proven successful for the asymmetric synthesis of piperidine, pyrrolidine, 1,2-dihydropyridine and
1,2,3,4-tetrahydroisoquinoline derivatives using the carboxylic acid (5) as chiral auxiliary.19 In this paper
we report that this method is also suitable to provide access to 1,2-dihydro-β-carbolines in a
straightforward and stereoselective manner. Upon reduction and removal of the chiral auxiliary,
enantiopure 1,2,3,4-tetrahydro-β-carbolines were readily obtained.
RESULTS AND DISCUSSION
In analogy to a previously published route involving the generation of chiral tetrahydroisoquinolinium
5
ions and subsequent asymmetric electrophilic α-amidoalkylation, we first synthesized the 1,2-dihydro-β-
carboline (7) as a precursor for the requisite N-acyl-β-carbolinium salt. Compound (7) was obtained in
good yield (69%) by the reaction of the chiral carboxylic acid chloride (6) with 9-methyl-β-carboline in a
solvent mixture of CH2Cl2 and toluene at 0°C. This resulted in the formation of a heterogeneous mixture
containing the corresponding N-acyliminium salt as a precipitate which upon treatment with Li[Al(t-
C4H9O)3H] at -78°C provided compound (7). In accordance with related systems previously published by

-
+
5
us, hydride abstraction accomplished using Ph3C BF4 led to the N-acyl-β-carbolinium ion (8). According
to TLC the oxidation was complete within 14 hours at room temperature. Following precipitation induced
by the addition of THF, N-acyl-α-carbolinium salt (8) was obtained as yellow crystals and could be fully
characterized. Since the N-acyl-β-carbolinium ion is formed irreversibly and its generation does not
suffer from any unfavorable equilibria, the presented reduction/oxidation reaction sequence is an
improvement over direct procedures for the generation of N-acyliminium ions. 19d, 20
CH3
N
O
O
1)
CH3
N
CH3
O
-
BF4
N+
N
N
Ph3C+BF4
CH2Cl2, rt, 14 h
-
R*
CH2Cl2, toluene, rt
X
R*
N
2) Li[Al(t-C4H9O)3H], -78°C
O
O
7
8
5 X= OH
(COCl)2,
DMF cat.
6 X= Cl
Scheme 2
Next, the asymmetric addition reaction to the N-acyl-β-carbolinium tetrafluoroborate (8) was investigated
extensively. Grignard, lithium, aluminium and zinc reagents were employed as nucleophiles to study the
influence of the nature of the organometallic species. The reactions were performed by adding four
equivalents of the organometallic compounds (solution in ether or THF) to a solution of the chiral N-acyl-
ß-carbolinium ion (8) in CH2Cl2 at -78 °C. The addition reaction of Grignard reagents proceeded in good
yields (65-90%) as depicted in Table 1. However, diastereoselectivities were found to be only average
(Entries 1, 2, and 5), with only the phenylation reaction being an exception (Entry 9). When
phenylmagnesium bromide was employed, an excellent diastereoselectivity of ds ≥ 99.9/0.1 (Entry 9) has
to be assumed, since, despite of an intensive search, no minor isomer (10e) could be detected. The
ethylation reaction was chosen as model system to perform optimization studies regarding the addition of
alkyl substituents. Using (C2H5)3Al a significant increase of the diastereoselectivity (ds = 93.2/6.8, Entry
3) was observed with a yield only slightly lower compared to the corresponding Grignard reagent.
Employing (C2H5)2Zn the diastereoselectivity even rose to ds = 96.2/3.8 (Entry 4). A similar trend was
observed for the butylation reaction with n-C4H9MgBr providing a low (ds = 78.1/21.9, Entry 5) and (n-
C4H9)2Zn a high diasteroselectivity (ds = 95.4/4.6, Entry 6). It is noteworthy that even the addition of the
bulky tert-butyl substituent resulted in high yield (79%) and diastereoselectivity (ds = 93.9/6.1) using (t-
C4H9)2Zn as nucleophile. Also of note is the successful addition of highly reactive t-C4H9Li. However, in

this case both the yield and the diastereoselectivity were low (Entry 7). The attempted addition reaction
with (CH3)2Zn and (CH3)3Al to the desired 1-methyl products (9a) and (10a) failed even when the
reaction was carried out using high excess of the reagents at elevated temperatures (refluxing THF). This
indicates that these organometallic reagents are not sufficiently reactive. The observed influence of the
organometallic reagent on the asymmetric electrophilic α-amidoalkylation reaction of the β-carbolinium
5
ion (8) parallels the results previously reported for addition reactions to tetrahydroisoquinolinium ions
with organozinc and organoaluminum compounds being more favorable than organomagnesium reagents
with respect to high diastereoselectivities.
R
R
O
O
CH3
CH3
RM
N
N
+
R*
R*
8
N
N
9a-e
10a-d
Scheme 3
Entry Product
d.s.
Yield [%]
RM
9+10
9/10
9+10
87
65
62
60
89
82
44
79
-
9
10
23
19
4
1
2
3
4
5
6
7
8
9
CH3MgCla
C2H5MgI(Et2O)a
(C2H5) 3Ala
74.1/25.9
70.4/29.6
93.2/6.8
96.2/3.8
78.1/21.9
95.4/4.6
65.1/34.9
93.9/6.1
99.9/<0.1
64
46
58
58
70
79
29
74
90
a
b
(C2H5)2Znb
2
n-C4H9MgBra
(n-C4H9)2Zna
(t-C4H9)Lia
(t-C4H9)2Zna
PhMgBr (THF)a
19
4
c
d
e
15
5
-
a 4 equiv., 1.5 h, -78 °C b2 equiv. (the second equiv. was added after 1 h)
Table 1
The stereochemistry of the newly created stereocenter of the major diastereomers (9a) and (9e) obtained
by methylation or phenylation, respectively, was established by X-Ray crystallography (Figure 1). In both
cases, the configuration was found to be (S). The stereochemical assignment of the amidoalkylation

1
products (9b-d) and (10b-d), was delineated from a comparison of their H NMR spectral data with the
1H spectrum obtained for 9a and 10a. The spectra of the compounds (9b-d) formed predominantly were
of high similarity to the spectrum of 9a, as were the spectra of the minor isomer (10b-d) with the
spectrum of the minor compound (10a). Therefore, it is reasonable to assume that the major
diastereomers (9b-d) are (S)- and the minor isomers (10b-d) are (R)-configurated as well.
CH3
CH3
CH3
O
O
O
O
N
N
N
N
O
O
9a
9e
C4
C3
C5
C6
C7
C10
C19
O2 C20
O1
C18
C11
N2
C2
C1
N1
C21
C8
C17
C15
C12
H12A
C24
C9
C13
C16
C14
C22
C23
O3
Figure 1
The addition of organometallic nucleophiles to the prochiral iminium subunit of 8 has occurred
preferentially from the si face. In recent studies on the addition reaction to N-acylisoquinolinium ion (11)
5
and related compounds, we observed the same sense of asymmetric induction. The auxiliary (5) is
thought to cause asymmetric induction by a precomplexation mechanism. It involves the coordination of
the lactone functionality to the metal ion of the organometallic reagent and the subsequent intramolecular
transfer of a residue from the preorientated organic metal center to the iminium subunit.4, 19 We previously
proposed - based on NOE experiments - that the s-cis conformer of the N-acylisoquinolinium ion (11)
predominates over the s-trans conformer. Furthermore, we suggested that the OC-NC subunit adopts a
synperiplanar orientation with the dimethyl substituted 8'-carbon of the bicyclic ring system (for details
see reference 19). Similarly, we performed NOE measurements on the N-acyl-β-carbolinium ion (8). The
intensity of the interaction between 3H-7´Hendo was three times higher than the NO effect observed for
1H-7´Hendo. Apart from these NO effects, no other significant NOE’s between the H1 and H3 of the
isocarbolinium moiety and the protons of the bicyclic lactone subunit were seen. This indicates that for

both, compound (8) and compound (11), a conformation predominates where the OC-NC is of s-cis
orientation and is aligned synperiplanar with the dimethyl-substituted 8'-carbon of the bicyclic ring
5
system. Accordingly, in analogy to the stereomodel for 11, we suggest a mechanistic rationale based on
structure (12) in Figure 2 for the asymmetric induction obtained by addition reactions to the N-acyl-β-
carbolinium ion (8). This is, of course, in line with the configuration of the major diastereomers (9a-e),
which according to the proposed model must be formed by si face addition.
-
O
O
BF4
- 1
3
BF4
N+
N+
1
O
7
3
O
O
O
7
H
H
2.9%
5.4%
6.5%
12.5%
11 s-cis
11 s-trans
O
O
-
-
CH3
3
BF4
N+
BF4
1
N+
N
1
O
7
3
O
O
O
H
H
7
1.8%
4.3%
N
7.3%
13.3%
8 s-cis
CH3
8 s-trans
Scheme 4
O
-
CH3
BF4
N+
R
N
M
X
O
X
O
12
Figure 2 Model for asymmetric induction
Since we planned to determine the binding affinities of the enantiopure 1,2,3,4-tetrahydro-β-carbolines
(1) to the PCP binding site of the NMDA receptor, the N-acyl-1,2-dihydro-β-carbolines (9) and (10) had
to be converted to their tetrahydro counterparts. First, the major diastereomers (9a-e) and the minor

diastereomer (10a), which was also accessible in a reasonable amount, were separated from the respective
diastereomeric mixture by preparative HPLC and purified at least to > 99%. Hydrogenation of the ∆3,4
double bond using Pd/C as catalyst led to the required N-acyl-1,2,3,4-tetrahydro-β-carbolines (13a-e) and
(14a) in excellent yields.5, 21 The hydrogenation proceeded quantitatively at normal pressure and room
temperature, except for the reduction of the tert-butyl derivative (9d) requiring a pressure of 3 bar.
R
O
O
R
R
CH3
CH3
CH3
N
N
N
R*
H2, Pd/C
N
Li[Al(OCH3)2H2]
THF, -25°C
R*
N
HN
9a-e:
10a:
13a-e:
14a:
(S)-1a-d:
(R)-1a:
Scheme 5
The chiral auxiliary can be easily removed by cleavage of the amide bond using Li[(CH3O)2AlH2] or
Na[(CH3O)2AlH2] as reducing agents. In the present case, Li[(CH3O)2AlH2] was used which was
employed at a reaction temperature of -25 °C to prevent the formation of tertiary amines as a result of
overreduction. The products (1) were obtained in about 80% yield. Attempts to cleave the amide bond of
compound (13d) bearing the bulky tert-butyl substituent in α-position failed under reducing as well as
basic or acidic conditions.
R
CH3
O
O
O
N
N
(C2H5)3N, CH2Cl2
Cl
NH
R
+
O
O
O
N
CH3
(S)-1a
(S)-1e
6
13a
13e
Scheme 6

In a representative experiment, the methyl derivative ((S)-1a) and the phenyl derivative ((S)-1e) were
attached to the chiral auxiliary (Scheme 6) to investigate whether epimerization might have occurred
during cleavage. The diastereomeric purity of the resulting amides was determined by analytical HPLC.
As expected, only one peak was detected in both cases at the retention time of compounds (13a) and
(13e) indicating that reductive removal of the chiral auxiliary had proceeded without epimerization.
Ki [µM]a - [3H]MK-801
NH
NH
NH
NH
N
N
N
H
CH3
CH3
H
(S)-1d
(rac)-1d
(rac)-15
4
18.9±0.4
27.1±1.7
58.4±3.1
1.38±0.07
a Means±standard error of the mean from three independent experiments each carried out in triplicate.
Table 2
The enantiopure 1-aryl-1,2,3,4-tetrahydro-β-carboline ((S)-1e) was evaluated for its in vitro activity on the
PCP binding site of the NMDA receptor. The binding affinity was determined by a radioligand binding
assay on pig cortical brain membranes with [3H]MK-801 as the specific ligand.22 Due to excellent
stereoselectivity the minor stereoisomer (R)-1-aryl-1,2,3,4-tetrahydro-β-carboline ((R)-1e) was not
accessible by employing the herein presented synthetic route. Therefore, we decided to prepare the
racemic mixture ((rac)-1e) to get an estimate of the receptor binding affinity of the (R)-configurated
enantiomer ((R)-1e). We chose the (rac)-1-phenyl-1,2,3,4-tetrahydro-β-carboline ((rac)-15), which was
easily prepared according to literature, as a precursor for the synthesis of (rac)-1e. To study the influence
of the substituents on the indole nitrogen atom (methyl versus hydrogen), (rac)-15 was also included in
the biological study. As depicted in Table 2, the 1-aryl-1,2,3,4-tetrahydro-β-carbolines ((S)-1e, (rac)-1e
and (rac)-15) were found to be less potent as compared to the structurally related 1-aryl-1,2,3,4-
tetrahydroisoquinoline ((S)-4). The N-methyl derivatives ((S)-1e) and ((rac)-1e) showed greater affinity to
the PCP binding site than compound ((rac)-15) lacking a methyl substituent on the indole nitrogen atom.
In addition, it was observed that the enantiopure 1,2,3,4-tetrahydro-β-carboline ((S)-1e) displays enhanced
binding affinity as compared to the racemic mixture ((rac)-1e). We therefore conclude that the (R)-
enantiomer ((R)-1e) is less potent than the (S)-enantiomer ((S)-1e). This result corroborates our previous

report on the enantioselectivity of binding of 1-aryl-1,2,3,4-tetrahydroisoquinolines to the PCP binding
site of the NMDA receptor.19g
In summary, we have realized the asymmetric synthesis of 1-substituted 1,2,3,4-tetrahydro-β-carbolines
based on the employment of a chiral N-acyl-iminium ion (8) derived from 9-methyl-β-carboline. NOE
experiments performed on the chiral N-acyl-β-carbolinium salt (8) support the recently published model
for asymmetric induction by the chiral auxiliary (5). The addition reactions leading to the 1-substituted N-
acyl-1,2-dihydro-β-carbolines (9) and (10) were found to occur from the si face of the N-acyl-β-
carbolinium salt (8). The addition products (9a-c), (9e) and (10a) were transformed into the
corresponding 1-substituted 1,2,3,4-tetrahydro-β-carbolines. The 1-phenyl derivative ((S)-1e) was
biologically evaluated for its binding affinity to the PCP binding site of the NMDA receptor.
EXPERIMENTAL
All reactions were carried out in vacuum dried glassware under nitrogen atmosphere. All reagents were
used as commercially available. Solvents were dried and distilled prior to use. THF and toluene were
freshly distilled from sodium metal/benzophenone ketyl, CH2Cl2 and DMF from CaH2, and CH3OH from
Mg. Melting points were determined on a Büchi melting point apparatus (no. 510 Dr. Tottoli or Linström)
and are uncorrected. IR spectra were recorded with a Perkin Elmer FT-IR spectrophotometer IR 430,
Paragon 1000 or Paragon 1600, and NMR spectra were obtained with a BRUKER AC 300 spectrometer
(300 MHz for 1H) or JEOL JNM-GX 400 spectrometer (400 MHz for 1H) with TMS as internal standard.
MS spectra were recorded on a Kratos MJ25RS, a Finnigan Match 7 or a Hewlett Packard 5989 A with
59980 B particle beam LC/MS interface. CHN-analyses were determined with an elemental analysator
340B or 340C (Perkin Elmer) or an elemental analysator Rapid (Heraeus). TLC: Merck 60 F-254.
Column chromatography (CC) was performed as flash chromatography with silica gel Merck 60 F-254
(0.032−0.063 mm). Analytical HPLC: L-6200 pump, L-4250 UV/Vis detector, D-2500 Chromato
Integrator (Merck-Hitachi), column: LiChroCart® with Lichrosorb® Si 60 cartridge (5 µm, 250x4 mm
with precolumn 4x4 mm), (Merck). Preparative HPLC: L-6000 pump, L-4000 UV/Vis, D-2000 Chromato
Integrator (Merck-Hitachi), column: Hibar RT LiChrosorb® Si 60 (7 µm, 250x25 mm) (Merck).
(1S,5R)-1-[1,2-Dihydro-9-methylpyrido[3,4-b]indol-2-ylcarbonyl]-5,8,8-trimethyl-3-
oxabicyclo[3.2.1]octan-2-one (7).
One drop of DMF was added to a slurry of 519c (72 mg, 0.34 mmol) in 1.5 mL of CH2Cl2. The slurry was
cooled to 0 °C and oxalyl chloride (33 µL, 0.38 mmol) was added dropwise. The resulting mixture was

stirred for 30 min at rt. The solution was cooled to 0 °C and a solution of 9-methyl-β-carboline (60 mg,
0.33 mmol) in 2.00 mL of CH2Cl2 was added. Following addition of toluene (3.00 mL), the mixture was
stirred for 1 h at rt and cooled to –78 °C. A solution of Li[Al(t-C4H9O)3H] (346 mg, 1.36 mmol) in 3.00
mL of THF was added. After 30 min at –78 °C the reaction mixture was allowed to warm to rt. After 16 h
the reaction was quenched by addition of water (2.00 mL). The resulting mixture was chromatographed
on a small bed of silica (length ~ 3.50 cm, Ø ~ 5.00 cm) using CH2Cl2/C2H5OAc = 4:1. Product (7) was
obtained following evaporation of the solvents in vacuo. Yield: 77 mg (60%), colorless crystals, mp
25
1
155 °C (C2H5OAc). [α]D = +112.5° (c = 0.8, CH2Cl2). H NMR (CDCl3): δ = 0.85 (s, 3 H, CH3), 0.95
(s, 3 H, CH3), 1.15 (s, 3 H, CH3), 1.70-1.80 (m, 2 H, CH2CH2), 2.05-2.15 (m, 1 H, CH2CH2), 2.50-2.55
(m, 1 H, CH2CH2), 3.66 (s, 3 H, NCH3), 3.91 (d, J = 11.0 Hz, 1 H, CH2O), 4.07 (d, J = 11.0 Hz, 1 H,
CH2O), 4.59 (d, J = 16.7 Hz, 1 H, NCH2), 5.42 (d, J = 16.7 Hz, 1 H, NCH2), 6.01 (d, J = 7.3 Hz, 1 H,
NCH=CH), 6.43 (d, J = 7.3 Hz, 1 H, NCH=CH), 7.08 (t, J = 7.2 Hz, 1 H, Har), 7.20 (t, J = 7.2 Hz, 1 H,
Har), 7.25 (d, J = 7.2 Hz, 1 H, Har), 7.47 (d, J = 7.2 Hz, 1 H, Har). IR (KBr): ν= 2961 cm-1, 1727, 1654,
1625, 1472. MS (70 eV); m/z: 378 (M+), 183, 57. Anal. Calcd for C23H26N2O3: C, 72.99; H, 6.93; N, 7.40.
Found: C, 73.45; H, 7.03; N, 6.84.
9-Methyl-2-[(1S,5R)-5,8,8-trimethyl-2-oxo-3-oxabicyclo[3.2.1]octylcarbonyl]pyrido[3,4-
b]indolinium tetrafluoroborate (8).
-
A solution of 7 (30 mg, 0.08 mmol) was added dropwise to a solution of Ph3C+ BF4 (31 mg, 0.09 mmol)
in 1.5 mL of CH2Cl2 at 0 °C. The mixture was stirred for 14 h at rt followed by evaporation of ~ 25% of
the solvent in vacuo. THF (1.00 mL) was added and the mixture was stirred until a yellow solid
precipitated (after ~ 20 min). Following the removal of the solution via cannula, the product was washed
two times with 1.00 mL of THF and dried in vacuo. Yield: 28 mg (75%), yellow crystals, mp 133-134°C
25
(THF/CH2Cl2). [α]D = +39.6° (c = 2.0, CH2Cl2). UV/VIS (CH2Cl2): λmax (lg ε) = 431 nm (3.73), 335
(4.38), 285 (4.54). 1H NMR (CDCl3): δ = 0.92 (s, 3 H, CH3), 1.20 (s, 3 H, CH3), 1.40 (s, 3 H, CH3), 1.80-
1.89 (m, 1 H, CH2CH2), 2.00-2.10 (m, 1 H, CH2CH2), 2.42 (t, J = 7.3 Hz, 2 H, CH2CH2), 4.12 (d, J = 11.1
Hz, 1 H, CH2O), 4.16 (s, 3 H, NCH3), 4.22 (d, J = 11.1 Hz, 1 H, CH2O), 7.62 (d, J = 8.1 Hz, 1 H,
NCCHCH), 7.84 (t, J = 8.1 Hz, 1 H, NCCHCH), 7.43 (t, J = 8.1 Hz, 1 H, NCCHCHCH), 8.22 (d, J = 8.1
Hz, 1 H, NCCHCHCHCH), 8.30 (d, J = 6.8 Hz, 1 H, NCHCH), 8.74 (d, J = 6.8 Hz, 1 H, NCHCH), 9.45
(s, 1 H, NCHC). IR: ν = 1792 cm-1, 1712, 1636, 1517, 1074. MS (70 eV); m/z: 377 (N-acyl-β-carbolinium
ion), 362, 192, 182. Anal. Calcd for C23H25N2O3BF4: C, 59.50; H, 5.43; N, 6.03; Found: C, 59.73; H,
5.50; N, 6.08.

General procedure for electrophilic α-amidoalkylation reactions leading to compounds (9) and (10)
(GP1). A solution of 8 (28 mg, 0.06 mmol) in 2.00 mL of CH2Cl2 was cooled to -78 °C. A solution of the
respective organometallic reagent (4 equiv.) was added dropwise. The mixture was stirred at -78 °C for
1.5 h. Following addition of 1.5 mL of water, the mixture was allowed to warm to rt, 5.00 mL of water
were added and the aqueous layer was extracted four times with CH2Cl2 (5.00 mL for each extraction).
The organic layers were dried over Na2SO4. Following evaporation of the solvent in vacuo, the crude
product was purified by CC (petrol ether/C2H5OAc = 4:1).
(1S,5R)-1-[(1S)-1,2-Dihydro-1,9-dimethylpyrido[3,4-b]indolylcarbonyl]-5,8,8-trimethyl-3-oxa-
bicyclo[3.2.1]octan-2-one
(9a)
and
(1S,5R)-1-[(1R)-1,2-Dihydro-1,9-dimethylpyrido[3,4-
b]indolylcarbonyl]-5,8,8-trimethyl-3-oxa-bicyclo[3.2.1]octan-2-one (10a).
According to GP1. Yields and diastereoselectivities see Table 1. Analytical HLPC (n-heptane/C2H5OAc
= 8:2; 1 mL/min).
1
9a: Colorless crystals, mp 75 °C (n-heptane). tR = 20.2 min. [α]D = +242° (c = 0.2, CH2Cl2). H NMR
(400 MHz, CDCl3): δ = 1.01 ppm (s, 3 H, CH3), 1.25 (s, 3 H, CH3), 1.35 (d, J = 6.4 Hz, 3 H, NCHCH3),
1.42 (s, 3 H, CH3), 1.81-1.85 (m, 2 H, CH2CH2), 2.10-2.18 (m, 1 H, CH2CH2), 2.57-2.64 (m, 1 H,
CH2CH2), 3.73 (s, 3 H, NCH3), 3.97 (d, J = 11.1 Hz, 1 H, CH2O), 4.16 (d, J = 11.1 Hz, 1 H, CH2O), 5.85
(q, J = 6.4 Hz, 1 H, NCHCH3), 6.19 (d, J = 7.7 Hz, 1 H, NCH=CH), 6.40 (d, J = 7.70 Hz, 1 H,
NCH=CH), 7.15 (t, J = 7.8 Hz, 1 H, Har), 7.22 (t, J = 7.8 Hz, 1 H, Har), 7.30 (d, J = 7.8 Hz, 1 H, Har), 7.55
(d, J = 7.8 Hz, 1 H, Har). IR (KBr): ν = 2968 cm-1, 2925, 1728, 1654, 1616, 1459, 1336, 1320, 1218, 1124,
816, 735. MS (70 eV); m/z: 392 (M+), 377, 195, 167. Anal. Calcd for C24H28N2O3: C, 73.44; H, 7.19; N,
7.14. Found: C, 73.45; H, 7.18; N, 7.14.
1
10a: Colorless crystals, mp 112 °C (n-heptane). tR = 37.4 min. [α]D = -52° (c = 0.2, CH2Cl2). H NMR
(400 MHz, CDCl3): δ = 0.71 ppm (s, 3 H, CH3), 0.81 (s, 3 H, CH3), 1.04 (s, 3 H, CH3), 1.29 (d, J = 6.4
Hz, 3 H, NCHCH3), 1.75-1.81 (m, 2 H, CH2CH2), 2.05-2.10 (m, 1 H, CH2CH2), 3.17 (dt, J = 8.1, 12.8 Hz,
1 H, CH2CH2), 3.67 (s, 3 H, CH3), 3.90 (d, J = 11.1 Hz, 1 H, CH2O), 4.15 (d, J = 11.1 Hz, 1 H, CH2O),
6.04-6.06 (m, 2 H, NCHCH3, NCH=CH), 6.31 (d, J = 7.6 Hz, 1 H, NCH=CH), 7.09 (t, J = 7.3 Hz, 1 H,
Har), 7.15 (t, J = 7.3 Hz, 1 H, Har), 7.25 (d, J = 7.3 Hz, 1 H, Har), 7.51 (d, J = 7.3 Hz, 1 H, Har). IR (KBr):
ν = 1726 cm-1, 1647, 1468, 1321, 1121, 743. MS (70 eV); m/z: 392 (M+), 377, 195, 167.
(1S,5R)-1-[(1S)-1-Ethyl-1,2-dihydro-9-methylpyrido[3,4-b]indolylcarbonyl]-5,8,8-trimethyl-3-
oxabicyclo[3.2.1]octan-2-one (9b) and (1S,5R)-1-[(1R)-1-Ethyl-1,2-dihydro-9-methylpyrido[3,4-
b]indolylcarbonyl]-5,8,8-trimethyl-3-oxabicyclo[3.2.1]octan-2-one (10b).

According to GP1. Yields and diastereoselectivities see Table 1. Analytical HLPC (n-heptane/C2H5OAc
= 8:2; 2 mL/min).
9b: Colorless crystals, mp 70 °C (n-heptane). tR = 8.5 min. [α]D = +72° (c = 1.0, CH2Cl2). 1H NMR (400
MHz, CDCl3): δ = 0.81 ppm (s, 3 H, CH3), 0.90 (t, J = 7.5 Hz, 3 H, CH2CH3), 0.94 (s, 3 H, CH3), 1.33 (s,
3 H, CH3), 1.70-1.78 (m, 4 H, CH2CH3, CH2CH2), 2.03-2.07 (m, 1 H, CH2CH2), 2.50-2.57 (m, 1 H,
CH2CH2), 3.67 (s, 3 H, NCH3), 3.89 (d, J = 10.7 Hz, 1 H, CH2O), 4.08 (d, J = 10.7 Hz, 1 H, CH2O), 5.74
(t, J = 6.6 Hz, 1 H, NCHCH2), 6.13 (d, J = 7.3 Hz, 1 H, NCH=CH), 6.36 (d, J = 7.3 Hz, 1 H, NCH=CH),
7.10 (t, J = 7.9 Hz, 1 H, Har), 7.15 (t, J = 7.9 Hz, 1 H, Har), 7.24 (d, J = 7.9 Hz, 1 H, Har), 7.50 (d, J = 7.9
Hz, 1 H, Har). IR (KBr): ν = 2295 cm-1, 1724, 1654, 1468, 1336, 1232, 1126, 1070, 737. MS (50 eV); m/z:
406 (M+), 377, 195, 167. Anal. Calcd for C25H30N2O3: C, 73.86; H, 7.44; N, 6.89. Found: C, 73.62; H,
8.43; N, 6.11.
1
10b: Colorless crystals, mp 45 °C (n-heptane). tR = 14.3 min. [α]D = -195° (c = 1.0, CH2Cl2). H NMR
(400 MHz, CDCl3): δ = 0.85 ppm (s, 3 H, CH3), 0.93 (t, J = 7.3 Hz, 3 H, CH2CH3), 0.99 (s, 3 H, CH3),
1.30 (s, 3 H, CH3), 1.60-1.80 (m, 3 H, CH2CH3, CH2CH2), 2.00-2.10 (m, 2 H, CH2CH2), 3.05 (dd, J = 5.1,
10.2 Hz, 1 H, CH2CH2), 3.67 (s, 3 H, NCH3), 3.89 (d, J = 10.7 Hz, 1 H, CH2O), 4.14 (d, J = 10.7 Hz, 1 H,
CH2O), 6.10-6.12 (m, 2 H, NCHCH2, NCH=CH), 6.45 (d, J = 7.3 Hz, 1 H, NCH=CH), 7.10 (t, J = 7.9
Hz, 1 H, Har), 7.15 (t, J = 7.9 Hz, 1 H, Har), 7.30 (d, J = 7.9 Hz, 1 H, Har), 7.55 (d, J = 7.9 Hz, 1 H, Har).
IR (KBr): ν = 2294 cm-1, 1725, 1650, 1465, 1339, 1240, 1124, 1074, 740. MS (70eV); m/z = 406 (M+),
377, 195, 167, 139, 57.
(1S,5R)-1-[(1S)-1-Butyl-1,2-dihydro-9-methylpyrido[3,4-b]indolylcarbonyl]-5,8,8-trimethyl-3-
oxabicyclo[3.2.1]octan-2-one (9c) and (1S,5R)-1-[(1R)-1-Butyl-1,2-dihydro-9-methylpyrido[3,4-
b]indolylcarbonyl]-5,8,8-trimethyl-3-oxabicyclo[3.2.1]octan-2-one (10c).
According to GP1. Yields and diastereoselectivities see Table 1. Analytical HLPC (n-heptane/C2H5OAc
= 8:2; 1 mL/min).
9c: Colorless crystals, mp 65 °C (n-heptane). tR = 7.2 min. [α]D = -211° (c = 0.3, CH2Cl2). 1H NMR (400
MHz, CDCl3): δ = 0.76 ppm (t, J = 7.0 Hz, 3 H, CH3), 0.81 (s, 3 H, CH3), 0.92 (s, 3 H, CH3), 1.16-1.27
(m, 7 H, CH3, 2 x CH2), 1.65-1.87 (m, 4 H, 2 x CH2), 1.98-2.05 (m, 1 H, CH2), 2.45-2.56 (m, 1 H, CH2),
3.66 (s, 3 H, NCH3), 3.88 (d, J = 11.1 Hz, 1 H, CH2O), 4.07 (d, J = 11.1 Hz, 1 H, CH2O), 5.76 (t, J = 6.5
Hz, 1 H, NCHCH2), 6.14 (d, J = 7.3 Hz, 1 H, NCH=CH), 6.36 (d, J = 7.3 Hz, 1 H, NCH=CH), 7.09 (t, J =
8.1 Hz, 1 H, Har), 7.15 (t, J = 8.1 Hz, 1 H, Har), 7.30 (d, J = 8.1 Hz, 1 H, Har), 7.54 (d, J = 8.1 Hz, 1 H,
Har). IR (KBr): ν = 2957 cm-1, 2927, 1732, 1654, 1468, 1334, 1218, 1124, 738. MS (70 eV); m/z: 434

(M+), 377, 195, 167, 139. Anal. Calcd for C27H34N2O3: C, 74.62; H, 7.89; N, 6.45. Found: C, 74.69; H,
7.93; N, 6.53.
1
10c: Colorless oil. tR = 10.4 min. [α]D = -11° (c = 1.0, CH2Cl2). H NMR (400 MHz, CDCl3): δ = 0.75
ppm (s, 3 H, CH3), 0.81-0.99 (m, 12 H, 2 x CH3, 3 x CH2), 1.26 (s, 3 H, CH3), 1.65-1.80 (m, 2 H, CH2),
2.05-2.10 (m, 1 H, CH2), 3.23 (dt, J = 5.2, 11.3 Hz, 1 H, CH2), 3.74 (s, 3 H, NCH3), 3.95 (d, J = 11.1 Hz,
1 H, CH2O), 4.20 (d, J = 11.1 Hz, 1 H, CH2O), 6.13-6.16 (m, 2 H, NCHCH2, NCH=CH), 6.41 (d, J = 7.3
Hz, 1 H, NCH=CH), 7.16 (t, J = 7.4 Hz, 1 H, Har), 7.22 (t, J = 7.4 Hz, 1 H, Har), 7.33 (d, J = 7.4 Hz, 1 H,
Har), 7.54 (d, J = 7.4 Hz, 1 H, Har). IR (KBr): ν = 2955 cm-1, 1738, 1652, 1468, 1340, 1217, 1110, 740.
MS (CI); m/z: 435 (M+1), 391, 239, 149.
(1S,5R)-1-[(1S)-1-tert-Butyl-1,2-dihydro-9-methylpyrido[3,4-b]indolylcarbonyl]-5,8,8-trimethyl-3-
oxabicyclo[3.2.1]octan-2-one (9d) and (1S,5R)-1-[(1R)-1-tert-Butyl-1,2-dihydro-9-methylpyrido[3,4-
b]indolylcarbonyl]-5,8,8-trimethyl-3-oxabicyclo[3.2.1]octan-2-one (10d).
According GP1. Yields and diastereoselectivities see Table 1. Analytical HLPC (n-heptane/C2H5OAc =
8:2; 2 mL/min).
9d: Colorless crystals, mp 95 °C (n-heptane). tR = 9.8 min. [α]D = +329° (c = 0.2, CH2Cl2). 1H NMR (400
MHz, CDCl3): δ = 0.86 ppm (s, 3 H, CH3), 0.98 (s, 3 H, CH3), 1.03 (s, 9 H, t-C4H9), 1.37 (s, 3 H, CH3),
1.77 (t, J = 8.5 Hz, 2 H, CH2CH2), 1.97 (dt, J = 10.2, 8.5 Hz, 1 H, CH2CH2), 2.58 (dt, J = 10.2, 8.5 Hz, 1
H, CH2CH2), 3.75 (s, 3 H, NCH3), 3.94 (d, J = 11.1 Hz, 1 H, CH2O), 4.13 (d, J = 11. 1 Hz, 1 H, CH2O),
5.81 (s, 1 H, NCHCH2), 6.23 (d, J = 7.3 Hz, 1 H, NCH=CH), 6.51 (d, J = 7.3 Hz, 1 H, NCH=CH), 7.14 (t,
J = 7.1 Hz, 1 H, Har), 7.20 (t, J = 7.1 Hz, 1 H, Har), 7.33 (d, J = 7.1 Hz, 1 H, Har), 7.59 (d, J = 7.1 Hz, 1 H,
-1
~
Har). IR (KBr): ν = 2958 cm , 1734, 1654, 1617, 1468, 1317, 738. MS (CI); m/z: 435 (M+1), 377.
Anal. Calcd for C27H34N2O3: C, 74.62; H, 7.89; N, 6.45. Found: C, 74.44; H, 7.58; N, 6.16.
1
10d: Colorless crystals, mp 107 °C (n-heptane). tR = 13.1 min. [α]D = -282° (c = 0.1, CH2Cl2). H NMR
(400 MHz, CDCl3): δ = 0.61 ppm (s, 3 H, CH3), 0.78 (s, 3 H, CH3), 0.87 (s, 3 H, CH3), 0.94 (s, 9 H, t-
C4H9), 1.65-1.78 (m, 2 H, CH2CH2), 2.00-2.09 (m, 1 H, CH2CH2), 3.20 (dt, J = 5.1, 11.4 Hz, 1 H,
CH2CH2), 3.70 (s, 3 H, CH3), 3.89 (d, J = 11.1 Hz, 1 H, CH2O), 4.10 ( d, J = 11.1. Hz, 1 H, CH2O), 6.08-
6.10 (m, 2 H, NCHCH2, NCH=CH), 6.42 (d, J = 7.7 Hz, 1 H, NCH=CH), 7.10-7.30 (m, 3 H, Har), 7.53 (d,
J = 7.2 Hz, 1 H, Har). IR (KBr): ν = 2953 cm-1, 1738, 1650, 1615, 1450, 1320, 740. MS (CI); m/z: 435
(M+1).
(1S,5R)-1-[(1S)-1,2-Dihydro-9-methyl-1-phenylpyrido[3,4-b]indolylcarbonyl]-5,8,8-trimethyl-3-
oxabicyclo[3.2.1]octan-2-one (9e).

According to GP1. Yields and diastereoselectivities see Table 1. Analytical HLPC (n-heptane/C2H5OAc
= 9:1; 2 mL/min).
1
9e: Colorless crystals, mp 238 °C (n-heptane). tR = 31.2 min. [α]D = +605° (c = 0.2, CH2Cl2). H NMR
(400 MHz, CDCl3): δ = 0.82 ppm (s, 3 H, CH3), 0.98 (s, 3 H, CH3), 1.35 (s, 3 H, CH3), 1.76-1.78 (m, 2 H,
CH2CH2), 2.05-2.13 (m, 1 H, CH2CH2), 2.53-2.61 (m, 1 H, CH2CH2), 3.61 (s, 3 H, NCH3), 3.88 (d, J =
11.1 Hz, 1 H, OCH2), 4.07 (d, J = 11.1 Hz, 1 H, OCH2), 6.20 (d, J = 7.3 Hz, 1 H, NCH=CH), 6.37 (d, J =
7.3, 1 H, NCH=CH), 6.89 (s, 1 H, NCHC), 7.09-7.18 (m, 8 H, Har), 7.56 (d, J = 8.1 Hz, 1 H, Har). IR
(KBr): ν = 3447 cm-1, 2925, 1727, 1654, 1472, 1329, 1228, 734. MS (70 eV); m/z: 454 (M+), 377, 259,
244, 195. Anal. Calcd for C29H30N2O3: C, 76.63; H, 6.62; N, 6.16. Found: C, 76.43; H, 6.63; N, 6.07.
General procedure for the hydrogenation of 9 and 10 leading to 13 and 14 (GP2).
Compound (9) or (10) (1.00 mmol), respectively, was dissolved in anhydrous CH3OH (35.0 mL).
Whenever the compound was poorly soluble in CH3OH, a small amount of anhydrous C2H5OAc was
added. Pd/C (400 mg, 10% Pd, oxidized form, Merck) was added for each mmol of 9 or 10. The vessel
was flushed with H2 and a balloon filled with H2 was put on the vessel. The reaction mixture was stirred
under H2 atmosphere at normal pressure and at rt for 14 h (for 9/10d: 3 bar, 5 days). The mixture was
filtered followed by thorough washes with CH2Cl2 and evaporation of the solvent in vacuo. Purification
by CC (petrol ether/C2H5OAc = 7:3). The reaction proceeded quantitatively in each case.
(1S,5R)-1-[(1S)-1,2,3,4-Tetrahydro-1,9-dimethylpyrido[3,4-b]indolylcarbonyl]-5,8,8-trimethyl-3-
oxabicyclo[3.2.1]octan-2-one (13a).
According to GP2. Analytical HLPC (n-heptane/C2H5OAc = 85:15; 1 mL/min).
1
Colorless crystals, mp 82 °C (n-heptane). tR = 31.1 min. [α]D = +18° (c = 1.0, CH2Cl2). H NMR (400
MHz, d5-nitrobenzene, 120 °C): δ = 0.92 ppm (s, 3 H, CH3), 1.13 (s, 3 H, CH3), 1.42 (s, 3 H, CH3), 1.59
(d, J = 6.3 Hz, 3 H, NCHCH3), 1.94-2.07 (m, 3 H, CH2), 2.38-2.64 (m, 1 H, CH2), 2.70 (d, J = 14.6 Hz, 1
H, CH2), 2.84-3.13 (m, 1 H, CH2), 3.48 (dt, J = 12.4, 3.8 Hz, 1 H, CH2), 3.58 (s, 3 H, NCH3), 4.02 (d, J =
11.2 Hz, 1 H, CH2O), 4.15-4.28 (m, 2 H, CH2, CH2O), 5.60-5.76 (br, 1 H, NCHCH3), 7.09-7.15 (t, 1 H,
Har), 7.17-7.28 (m, 2 H, Har), 7.43-7.47 (m, 1 H, Har). IR (KBr): ν = 2924 cm-1, 1729, 1636, 1472, 1414,
1121, 1072, 1023, 741. MS (70 eV); m/z: 394 (M+), 397, 199. Anal. Calcd for C24H30N2O3: C, 73.07; H,
7.66; N, 7.10. Found: C, 72.77; H, 7.81; N, 7.25.
(1S,5R)-1-[(1R)-1,2,3,4-Tetrahydro-1,9-dimethylpyrido[3,4-b]indolylcarbonyl]-5,8,8-trimethyl-3-
oxabicyclo[3.2.1]octan-2-one (14a).

According to GP2. Analytical HLPC (n-heptane/C2H5OAc = 85:15; 1 mL/min).
1
Colorless crystals, tR = 39.4 min. [α]D = –11° (c = 1.0, CH2Cl2). H NMR (400 MHz, nitrobenzene-d5,
120 °C): δ = 0.93 ppm (s, 3 H, CH3), 1.13 (s, 3 H, CH3), 1.43 (s, 3 H, CH3), 1.52 (d, J = 6.3 Hz, 3 H,
NCHCH3), 1.80-1.95 (m, 4 H, CH2), 2.40-2.58 (m, 1 H, CH2), 2.75 (dt, J = 14.6, 3.3 Hz, 1 H, CH2), 3.04-
3.16 (m, 1 H, CH2), 3.51 (dt, J = 12.8, 3.6 Hz, 1 H, CH2), 3.59 (s, 3 H, NCH3), 4.02 (d, J = 11.2 Hz, 1 H,
CH2O), 4.14-4.26 (m, 2 H, CH2, CH2O), 5.98 (q, J = 6.3 Hz, 1 H, NCHCH3), 7.08 (t, J = 6.4 Hz, 1 H,
Har), 7.16-7.19 (m, 2 H, Har), 7.44 (d, J = 6.4 Hz, 1 H, Har ). IR (KBr): ν = 2928 cm-1, 1725, 1637, 1472,
1414, 1121, 1070, 1032, 740. MS (70 eV); m/z: 394 (M+), 379, 199. Anal. Calcd for C24H30N2O3: C,
73.07; H, 7.66; N, 7.10. Found: C, 73.10; H, 8.08; N, 6.95.
(1S,5R)-1-[(1S)-1-Ethyl-1,2,3,4-tetrahydro-9-methylpyrido[3,4-b]indolylcarbonyl]-5,8,8-trimethyl-
3-oxabicyclo[3.2.1]octan-2-one (13b).
According to GP2. Colorless crystals, mp 75 °C (n-heptane). tR = 28.5 min (n-heptane/C2H5OAc = 85:15;
1 mL/min). [α]D = + 41° (c = 0.4, CH2Cl2). 1H NMR (400 MHz, nitrobenzene-d5, 130 °C): δ = 0.92 ppm
(s, 3 H, CH3), 1.13 (s, 3 H, CH3), 1.21 (t, J = 7.2 Hz, 3 H, CH2CH3), 1.43 (s, 3 H, CH3), 2.01-2.10 (m, 5
H, CH2), 2.45-2.55 (m, 1 H, CH2), 2.71 (dt, J = 2.8, 11.2 Hz, 1 H, CH2), 3.00-3.09 (m, 1 H, CH2), 3.55-
3.66 (m, 4 H, NCH3, CH2), 4.01 (d, J = 11.1 Hz, 1 H, CH2O), 4.16 (dt, J = 3.2, 11.2 Hz, 1 H, CH2), 4.21
(d, J = 11.1 Hz, 1 H, CH2O), 5.86-5.91 (m, 1 H, NCHCH2), 7.09 (t, J = 6.6 Hz, 1 H, Har), 7.20-7.28 (m, 2
H, Har), 7.46 (d, J = 7.2 Hz, 1 H, Har). IR (KBr): ν = 2926 cm-1, 1733, 1636, 1471, 1412, 1377, 1227,
1070, 1022, 740. MS (70 eV); m/z: 408 (M+), 379, 195, 167. Anal. Calcd for C25H32N2O3: C, 73.50; H,
7.89; N, 6.86. Found: C, 73.81; H, 8.05; N, 6.41.
(1S,5R)-1-[(1S)-1-Butyl-1,2,3,4-tetrahydro-9-methylpyrido[3,4-b]indolylcarbonyl]-5,8,8-trimethyl-
3-oxabicyclo[3.2.1]octan-2-one (13c).
According to GP2. Colorless crystals, mp 88 °C (n-heptane). tR = 25.3 min (n-heptane/C2H5OAc = 85:15;
1 mL/min). [α]D = +30° (c = 0.3, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 0.70-0.82 ppm (m, 9 H, 3 x
CH3), 1.21-1.32 (m, 6 H, CH2), 1.35 (s, 3 H, CH3), 1.72-1.82 (m, 4 H, CH2), 2.18 (dt, J = 3.2, 11.2 Hz,
0.2 x 1 H, CH2), 2.48-2.57 (m, 0.8 x 1 H, CH2), 2.63 (dd, J = 10.8, 2.5 Hz, 0.2 x 1 H, CH2), 2.65-2.71 (m,
0.8 x 1 H, CH2), 3.25 (dt, J = 11.2, 3.7 Hz, 0.2 x 1 H, CH2), 3.45-3.53 (m, 0.8 x 2 H and 0.2 x 1 H, CH2),
3.59 (s, 0.2 x 3 H, NCH3), 3.61 (s, 0.8 x 3 H, NCH3), 3.85 (d, J = 11.1 Hz, 0.2 x 1 H, CH2O), 3.89 (d, J =
11.1 Hz, 0.8 x 1 H , CH2O), 3.95 (d, J = 11.1 Hz, 0.2 x 1 H, CH2O), 4.07 (d, J = 11.1. Hz, 0.8 x 1 H,
CH2O), 5.68-5.70 (m, 0.8 x 1 H, NCHCH2), 6.06-6.08 (m, 0.2 x 1 H, NCHCH2), 6.99-7.04 (m, 1 H, Har),
7.10 (t, J = 8.2 Hz, 1 H, Har), 7.18-7.21 (m, 1 H, Har), 7.36 (d, J = 7.8 Hz, 1 H, Har); ratio of rotamers: 8:2.

IR (KBr): ν = 2957 cm-1, 1739, 1636, 1469, 1412, 1214, 1120, 1074, 1023, 740. MS (70 eV); m/z: 436
(M+), 379, 167. Anal. Calcd for C27H36N2O3: C, 74.28; H, 8.31; N, 6.42. Found: C, 74.22; H, 8.69; N,
5.00.
(1S,5R)-1-[(1S)-1-tert-Butyl-1,2,3,4-tetrahydro-9-methylpyrido[3,4-b]indolylcarbonyl]-5,8,8-
trimethyl-3-oxabicyclo[3.2.1]octan-2-one (13d).
According to GP2 (3 bar, 5 days). Colorless crystals, mp 27 °C (n-heptane). tR = 20.1 min (n-
heptane/C2H5OAc = 85:15; 1 mL/min). [α]D = +23° (c = 0.3, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ =
0.86 ppm (s, 0.75 x 3 H, CH3), 0.94 ppm (s, 0.25 x 3 H, CH3), 0.98 (s, 0.25 x 3 H, CH3), 1.01 (s, 0.75 x 3
H, CH3), 1.10 (s, 0.25 x 9 H, CH3), 1.15 (s, 0.75 x 9H, CH3), 1.31 (s, 0.25 x 3 H, CH3), 1.34 (s, 0.75 x 3
H, CH3), 1.80-1.95 (m, 2 H, CH2), 2.12-2.17 (m, 1 H, CH2), 2.50-2.61 (m, 1 H, CH2), 2.73-2.99 (m, 1 H,
CH2), 3.21-3.37 (m, 1 H, CH2), 3.62 (s, 0.25 x 3 H, NCH3), 3.65 (s, 0.75 x 3 H, NCH3), 3.75-3.81 (m, 1
H, CH2), 3.95 (d, J = 11.1 Hz, 0.75 x 1 H, CH2O), 4.05 (d, J = 11.1 Hz, 0.25 x 1 H, CH2O), 4.12 (d, J =
11.1 Hz, 0.75 x 1 H, CH2O), 4.21 (d, J = 11.1 Hz, 0.25 H, CH2O), 5.60 (s, 0.75 H, NCHC), 5.98 (s, 0.25
H, NCHC), 7.05-7.20 (m, 2 H, Har), 7.31 (d, J = 8.1 Hz, 1 H, Har), 7.47 (d, J = 8.1 Hz, 1 H, Har); ratio of
rotamers:75:25. IR (KBr): ν = 2924 cm-1, 1739, 1636, 1472, 1217, 1121, 1062, 1014, 834, 741. MS (CI);
m/z: 437 (M++1), 379, 202, 149. Anal. Calcd for C27H36N2O3: C, 74.28; H, 8.31; N, 6.42. Found: C,
74.51; H, 8.42; N, 6.96.
(1S,5R)-1-[(1S)-1,2,3,4-Tetrahydro-9-methyl-1-phenylpyrido[3,4-b]indolylcarbonyl]-5,8,8-
trimethyl-3-oxabicyclo[3.2.1]octan-2-one (13e).
According to GP2. Colorless crystals, mp 250 °C (n-heptane). tR = 26.1 min (n-heptane/C2H5OAc =
1
85:15; 1 mL/min). [α]D = +153° (c = 1.0, CH2Cl2). H NMR (400 MHz, nitrobenzene-d5, 130 °C): δ =
0.95 ppm (s, 3 H, CH3), 1.10-1.15 (m, 1 H, CH2), 1.20-1.35 (m, 7 H, 2 x CH3 and 1 x CH2), 1.95-2.01 (m,
1 H, CH2), 2.40-2.45 (m, 2 H, CH2), 2.76 (dd, J = 10.5, 1.5 Hz, 1 H, CH2), 3.15-3.20 (m, 1 H, CH2), 3.35
(s, 3 H, NCH3), 3.45 (dt, J = 10.5, 3.2 Hz, 1 H, CH2), 3.96 (d, J = 11.1 Hz, 1 H, CH2O), 4.21 (d, J = 11.1
Hz, 1 H, CH2O), 7.10-7.25 (m, 8 H, NCHC, Har), 7.47 (d, J = 7.2 Hz, 1 H, Har), 7.55 (d, J = 7.2 Hz, 1 H,
Har). IR (KBr): ν = 2936 cm-1, 1727, 1626, 1469, 1409, 1116, 1021, 754. MS (70 eV); m/z: 456, 430, 262,
232, 149. Anal. Calcd for C29H32N2O3: C, 76.29; H, 7.06; N, 6.14. Found: C, 76.20; H, 7.17; N, 6.38.
General procedure for the reductive removal of the chiral auxiliary (GP3).
LiAlH4 (2.5 equiv., 1.00 M in (C2H5)2O) was added to CH3OH (5 equiv., 1.00 M in THF). The resulting
mixture was added dropwise to a solution of the respective N-acyl-1,2,3,4-tetrahydro-β-carboline (1

equiv., 0.04 M in THF) at -25 °C. Following 24 h stirring, the reaction was quenched by the addition of
CH3OH (10 equiv.). The mixture was allowed to warm to rt. The mixture was diluted with H2O, acidified
with 1.00 M HClaqu to pH 1 and the aqueous layer was extracted 3 times with CH2Cl2. The pH of the
aqueous layer was brought to pH 8 with Na2CO3(s) and 1.00 M NaOHaqu. The aqueous layer was extracted
3 times with CH2Cl2. The resulting organic layers were dried over MgSO4 and concentrated in vacuo.
Purification by CC (C2H5OAc/CH3OH/C2H5(CH3)2N = 100:10:1).
(S)-1,9-Dimethyl-1,2,3,4-tetrahydropyrido[3,4-b]indole ((S)-1a). According to GP3. Yield: 80%.
Colorless crystals, mp 105 °C. [α]D = +10.2° (C2H5OAc) (c = 1.0, CHCl3). 1H NMR (400 MHz, CDCl3):
δ = 1.43 ppm (d, J = 6.8 Hz, 3 H, CHCH3), 1.75 (s, 1 H, NH), 2.66 (t, J = 5.6 Hz, 2 H, NHCH2CH2), 3.06
(td, J = 5.6, 13.3 Hz, 1 H, NHCH2CH2), 3.16 (td, J = 5.6, 13.3 Hz, 1 H, CH2, NHCH2CH2), 3.57 (s, 3 H,
NCH3), 4.16 (q, J = 6.8 Hz, 1 H, NCHCH3), 7.04 (t, J = 6.8 Hz, 1 H, NCCCHCH), 7.12 (t, J = 6.8 Hz, 1
H, NCCHCH), 7.24 (d, J = 6.8 Hz, NCCH), 7.42 (d, J = 6.8 Hz, 1 H, NCCCH). IR (KBr): ν = 2971 cm-1,
1470, 1377, 1260, 1184, 800, 739. MS (70 eV); m/z: 200 (M+), 185. Anal. Calcd for C13H16N2: C, 77.97;
H, 8.05; N, 13.98. Found: C, 77.88; H, 8.19; N, 13.94. The analytical data (1H NMR, IR and MS) are in
1
6
accordance with literature.
(R)-1,9-Dimethyl-1,2,3,4-tetrahydropyrido[3,4-b]indole ((R)-1a). According to GP3. Yield: 76%.
Colorless crystals. [α]D = -10.8° (c = 1.0, CHCl3). Anal. Calcd for C13H16N2: C, 77.97; H, 8.05; N, 13.98.
Found: C, 77.83; H, 8.18; N, 13.99. The spectral (1H NMR, IR, and MS) data were identical with those of
(S)-1a.
(S)-1-Ethyl-9-methyl-1,2,3,4-tetrahydropyrido[3,4-b]indole ((S)-1b). According to GP3. Yield: 62%.
Colorless crystals, mp 102 °C (C2H5OAc). [α]D = -13.2° (c = 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ
= 0.95 ppm (t, J = 6.1 Hz, 2 H, NCHCH2CH3), 1.36-1.40 (m, 2 H, NCHCH2CH3), 1.80 (s, 1 H, NH), 2.69
(m, 2 H, NCH2CH2), 3.10 (td, J = 4.6, 13.4 Hz, 1 H, NHCH2CH2), 3.15 (td, J = 7.1, 13.4 Hz, 1 H,
NHCH2CH2), 3.35 (s, 3 H, NCH3), 4.11 (t, J = 7.1 Hz, 1 H, NHCHCH2), 7.08 (t, J = 7.2 Hz, 1 H, Har),
7.13 (t, J = 7.2 Hz, 1 H, Har), 7.26 (d, J = 7.2 Hz, 1 H, Har), 7.42 (d, J = 7.2 Hz, 1 H, Har). IR (KBr): ν =
2972 cm-1, 1455, 1305, 1163, 1100, 738. MS (70 eV): m/z = 214 (M+), 199. Anal. Calcd for C14H18N2: C,
78.46; H, 8.47; N, 13.07. Found: C, 78.50; H, 8.69; N, 12.82.
(S)-1-Butyl-9-methyl-1,2,3,4-tetrahydropyrido[3,4-b]indole ((S)-1c). According to GP3. Yield: 81%.
Colorless crystals, mp 82 °C (C2H5OAc). [α]D = -4.6° (c = 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ =

0.94 ppm (t, J = 7.1 Hz, 3 H, CH3), 1.36-1.57 (m, 4 H, CH2, NH), 1.63-1.70 (m, 2 H, CH2), 2.65-2.78 (m,
3 H, CH2, NHCH2CH2), 3.05 (td, J = 6.9, 13.2 Hz 1 H, NHCH2CH2), 3.31 (td, J = 5.2, 13.2 Hz, 1 H,
NHCH2CH2), 3.45 (s, 3 H, NCH3), 4.05-4.07 (m, 1 H, NHCHCH2), 7.09 (t, J = 7.9 Hz, 1 H, Har), 7.15 (t,
J = 7.9 Hz, 1 H, Har), 7.31 (d, J = 7.9 Hz, 1 H, Har), 7.48 (d, J = 7.9 Hz, 1 H, Har). IR (KBr): ν = 2960 cm-
1, 2931, 1472, 1456, 1368, 1323, 1170, 1098, 739. MS (70 eV); m/z: 242 (M+), 227. Anal. Calcd for
C16H22N2: C, 79.29; H, 9.15; N, 11.56. Found: C, 79.09; H, 9.46; N, 11.46.
(S)-9-Methyl-1-phenyl-1,2,3,4-tetrahydropyrido[3,4-b]indole ((S)-1e). According to GP3. Yield: 80%.
Colorless crystals, mp 77 °C (C2H5OAc). [α]D = -86° (c = 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ =
1.75 ppm (s, 1 H, NH), 2.68-2.89 (m, 2 H, NCH2CH2), 3.03-3.15 (m, 2 H, NCH2CH2), 3.26 (s, 3 H, CH3),
5.24 (s, 1 H, NHCH), 7.13-7.35 (m, 8 H, Har), 7.58 (d, J = 7.2 Hz, 1 H, Har). IR (KBr): ν = 2920 cm-1,
1457, 1350, 1310, 1171, 740. MS (70 eV); m/z: 262 (M+), 232, 217, 185. Anal. Calcd for C18H18N2: C,
82.41; H, 6.92; N, 10.67. Found: C, 82.78; H, 7.12; N, 10.45.
X-Ray analyses
Crystal data for 9a. C24H28N2O3, M=392.48, orthorhombic, space group P212121, a=6.9559(4) Å,
b=11.5318(7) Å, c=25.1755(16) Å, volume 2019.4(2) Å3, Z=4, Dc=1.291 mg m-3, µ=0.118 mm-1, crystal
dimensions 0.40x0.30x0.20 mm, F(000) 840, T=193(2) K, 2Θ=3.24° to 58.08°. 11659 reflections
measured, independent reflections 4074 [Rint=0.0376], min. and max. transmission coefficient 0.8879 and
0.6889, R1=0.0429, wR2=0.0831 for all 4074 reflections with I>2σ(I ) and R1=0.0692, wR2=0.0913 for
all reflections and 374 refined parameters. Final electron density 0.169 and -0.201 eÅ-3, S=1.034, absolute
structure parameter 0.3(13).
Crystal data for 9e. C29H30N2O3, M=454.55, monoclinic, space group P21, a=7.4796(2) Å, b=10.1096(1)
Å, c=15.8532(2) Å, volume 1185.23(4) Å3, Z=2, Dc=1.274 mg m-3, µ=0.083 mm-1, crystal dimensions
0.45x0.11x0.05 mm, F(000) 484, T=193 K, 2Θ=4.80° to 57.04°. 6205 reflections measured, independent
reflections 3504 [Rint=0.0379], R1=0.0834, wR2=0.1524 for all 3504 reflections with I>2σ(I ) and
R1=0.0912, wR2=0.1552 for all reflections and 311 refined parameters. Final electron density 0.265
and -0.263 eǺ-3, S=1.377, absolute structure parameter -1(3).
All data sets were collected on a Siemens P4 diffractometer equipped with a LT2device and a CCD area
detector; Mo Kα radiation, graphite monochromator. Single crystals were covered with perfluoroether oil

and mounted on the tip of a glass fibre. Data were collected in the hemisphere mode implemented in the
23
24
2
3
program SMART. Data reduction was performed with the program SAINT. The SHELX97 program
was used for structure solution and refinement. All non-hydrogen atoms were refined anisotropically, and
the hydrogen atoms were included in the final refinement as a riding model on placing them on calculated
positions. Crystal and data collection parameters, relevant structure refinement parameters, atomic
coordinates for the non-hydrogen atoms, positional and isotropic displacement coefficients for hydrogen
atoms, a list of anisotropic displacement coefficients for the non-hydrogen atoms and a full list of bond
distances and bond angles have been deposited with the Cambridge Crystallographic Data Center. The
data will be sent on quoting the CCDCnumbers 251682 (e-mail: deposit@ccdc.cam.ac.uk)
Radioreceptor Assay
2
2
The binding assay was performed as described previously. Ki values for test compounds were calculated
from competition experiments with at least six concentrations of test compounds, by the use of InPlot 4.0
(GraphPad Software, San Diego, CA). Data are expressed as means ± standard error of the means (SEM)
of three experiments, each carried out in triplicate.
ACKNOWLEDGEMENT
Financial support of this work by the Deutsche Forschungsgemeinschaft, the Fonds der Chemischen
Industrie and the BMBF is gratefully acknowledged.
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