Synthesis of novel indole-based ring systems by acid-catalysed condensation from α-amino aldehydes and L-Trp-OMe

Article abstract of DOI:10.1002/ejoc.200701172

Acid-catalysed condensation of tryptophan with different α-amino aldehyde derivatives has been explored as a useful route to the synthesis of novel amino acid derived heterocycles and peptidomimetic scaffolds. By this approach, compounds containing a tetrahydro-β-carboline and a novel octahydropyrrolo[ 3′,2′:3,4]pyrrolo[2,3-b]indole system have been efficiently synthesized. Here we report the characterization of these new compounds and preliminary studies of the reactivity of the tetrahydro-β- carboline system. Wiley-VCH Verlag GmbH & Co. KGaA.

Full text of DOI:10.1002/ejoc.200701172

FULL PAPER
DOI: 10.1002/ejoc.200701172
Synthesis of Novel Indole-Based Ring Systems by Acid-Catalysed
Condensation from α-Amino Aldehydes and -Trp-OMe
L
Isabel M. Gomez-Monterrey,[a] Pietro Campiglia,[b] Alessia Bertamino,[a] Claudio Aquino,[a]
Orazio Mazzoni,[a] Maria V. Diurno,[a] Rosa Iacovino,[c] Michele Saviano,[d] Marina Sala,[a]
Ettore Novellino,[a] and Paolo Grieco*[a]
Keywords: Indoles / Amino aldehydes / Catalysis / Condensation reactions / Heterocycles
Acid-catalysed condensation of tryptophan with different α-
amino aldehyde derivatives has been explored as a useful
route to the synthesis of novel amino acid derived heterocy-
cles and peptidomimetic scaffolds. By this approach, com-
pounds containing a tetrahydro-β-carboline and a novel oc-
tahydropyrrolo[3Ј,2Ј:3,4]pyrrolo[2,3-b]indole system have
been efficiently synthesized. Here we report the characteri-
zation of these new compounds and preliminary studies of
the reactivity of the tetrahydro-β-carboline system.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
known tetrahydro-β-carboline system[6] and a novel indole-
based tetracyclic ring system, that is, the octahydropyr-
rolo[3Ј,2Ј:3,4]pyrrolo[2,3-b]indole (Scheme 1).
Introduction
Amino acids and their derivatives are well known as ver-
satile building blocks for pharmaceutical applications as
well as essential starting points for the generation of molec-
ular diversity.[1–3] In this context, and as part of a wide pro-
gram to develop methodologies for generating peptidomi-
metics, we have focused our attention on the potential of α-
amino aldehydes as a source of diverse biologically useful
core compounds.
In this context we have recently reported an efficient con-
densation of α-amino aldehydes with cysteine or penicill-
amine to generate thiazolidine derivatives.[4] These struc-
tures offer considerable promise as combinatorial motifs
and as β-turn mimetics. Also, we have reported that the
condensation between an α-amino aldehyde and -DOPA-
OMe under acidic conditions furnishes the corresponding
tetrahydroisoquinoline derivative which can subsequently
be used as an intermediate template to form diazatricyclic
lactam derivatives.[5] Herein we present the adaptation of
this route, starting from α-amino aldehydes and -Trp-
OMe, to the synthesis of compounds containing the well-
[a] Department of Pharmaceutical and Toxicological Chemistry,
University of Naples “Federico II”,
80131 Naples, Italy
Fax: +39-081-678630
Scheme 1. Condensation of -Trp-OMe (1) with α-amino aldehydes
2–7.
E-mail: pagrieco@unina.it
[b] Department of Pharmaceutical Science, University of Salerno,
84084 Fisciano, Italy
[c] Department of Environmental Sciences, Second University of
Naples,
Fmoc-Gyl-H (2) and enantiopure protected α-amino al-
dehydes Fmoc--Ala-H (3), Fmoc--Phe-H (4), Boc--Phe-
H (5), Fmoc--Asp(tBu)-H (6) and Fmoc--Lys(Boc)-H (7)
were prepared from the corresponding Fmoc--amino acids
according to literature methods.[4a,7]
81100 Caserta, Italy
[d] Institute of Biostructures and Bioimaging, CNR,
80134 Naples, Italy
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2008, 1983–1992
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1983

P. Grieco et al.
FULL PAPER
ORTEP diagram (Figure 1). Examination of the structure
of 17a reveals a trans disposition between the 2-meth-
oxycarbonyl and the 4-phenylmethyl moieties (R1). The ori-
entation of the 5-tert-butoxycarbonyl group is directed by
an intermolecular hydrogen bond in the crystal packing be-
tween the N(3) and the O(2) of the carbonyl group. Thus,
the 2-methoxycarbonyl and the 4-tert-butoxycarbonyl
groups were directed towards the less hindered exo face of
the pyrrolo[3Ј,2Ј:3,4]pyrrolo[2,3-b]indole framework.
Results and Discussion
As shown in Scheme 1, treatment for 12 h of a dichloro-
methane solution of -Trp-OMe and α-amino aldehydes 2–
7 at room temperature with 1 equiv. of TFA generated the
cis- and trans-tetrahydro-β-carbolines 8–13a,b (yields 20–
33%). In addition, we obtained the unexpected compounds
14–19 (overall yields 35–63%) containing the novel octahy-
dropyrrolo[3Ј,2Ј:3,4]pyrrolo[2,3-b]indole system.
Under these reaction conditions and as reported in
Table 1, the cis isomers of the tetrahydro-β-carboline sys-
tem (8–11a, entries 1–4) were predominant with respect to
the trans isomers 8–11b (ratio cis/trans, 3:1–2:1). The corre-
sponding β-carbolines derived from Fmoc--Asp(tBu)-H
and Fmoc--Lys(Boc)-H (12a,b and 13a,b, entries 5 and 6)
were obtained with lower yields and diastereoselectivities
(ratio cis/trans, 3:2). In the formation of the tetracyclic de-
rivatives, unhindered amino aldehydes 2 and 3 exclusively
gave isomers 14a and 15a, respectively, whereas α-amino
aldehydes 4–7 bearing hindered groups in the side-chain
also provided 16–19b as minor isomers. These data indicate
that the formation of the octahydropyrrolo[3Ј,2Ј:3,4]pyr-
rolo[2,3-b]indole system is particularly influenced by the
character and size of the starting aldehydes. Moreover,
Fmoc- or Boc-protecting groups used for the N-protection
of the α-amino aldehydes had no effect on the condensation
reaction (entries 3 and 4).
Figure 1. ORTEP representation of the structure of isomer 17a at
the 50% probability level. Hydrogen atoms have been omitted for
clarity.
Unfortunately, we could not obtain good crystals for the
analysis of 17b. Therefore the assignments of the stereo-
chemistry at the fusion positions in the minor diastereoiso-
mer 17b were attempted on the basis of the NOE corre-
lations observed in the 2D ROESY spectra (Figure 2).
Thus, NOE effects between 5a-H and 2-H and 1b-H and
between 3a-H and 4-H and 4Јa-H indicate a cis disposition
between these protons. In contrast, exchange of magnetiza-
Assignments of each H and C atom were made by analy-
sis of 2D NMR data, including COSY, HSQC, HMBC and
ROESY. The configuration at C-1 for all the cis- and trans-
1
tetrahydro-β-carbolines 8–13a,b was determined by H and
13C NMR analysis and is supported by analogies in the
literature.[6a,8] With respect to these derivatives, compounds
14–19 showed diagnostic spectroscopic signals for a quater-
nary C-10b and two methine groups C-3a and C-5a, the
1
latter shifted remarkably downfield in the H NMR spec-
trum.[9] Accordingly, the 13C NMR spectra showed the dis-
appearance of the indole C-2 and C-3 signals and the ap-
pearance of the corresponding fusion carbons C-5a and C-
10b at δ = 82.7 and 63.2 ppm, respectively. The stereochem-
istry at these fusion positions in the major diastereoisomers
was established on the basis of X-ray diffraction studies of
compound 17a[10] which indicated 3aR,5aS,10bR configura-
Figure 2. NOE effects observed in the ROESY 2D spectra for iso-
tions at three new stereogenic centres, as depicted in the mer 17b.
Table 1. Yield and isomeric ratio of products 8–19a,b.
Entry
1
Aldehyde
R
R1
β-Carboline
% Yield
Tetracycle
% Yield
2
2
3
3
4
4
5
5
6
6
7
7
Fmoc
Fmoc
Fmoc
Fmoc
Fmoc
Fmoc
Boc
H
H
CH3
CH3
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2COOtBu
CH2COOtBu
(CH2)4NHBoc
(CH2)4NHBoc
8a
8b
9a
9b
10a
10b
11a
11b
12a
12b
13a
13b
20
7
14a
14b
15a
15b
16a
16b
17a
17b
18a
18b
19a
19b
35
–
38
–
35
7
36
7
50
12
48
15
2
3
4
5
6
22
11
20
10
21
10
14
9
Boc
Fmoc
Fmoc
Fmoc
Fmoc
12
8
1984
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Eur. J. Org. Chem. 2008, 1983–1992

Synthesis of Novel Indole-Based Ring Systems
Scheme 2. Condensation the -Trp-OMe with Fmoc--Phe-H.
tion between 4-H and/or 2-H and 5-H was not observed, in
accord with a trans relationship between these protons.
On the basis that the stereochemistry at C-2 and C-4 is
fixed, we have assigned the configurations at C-3a, C-5a
and C-10b in 17b as 3aS,5aR and 10bS, respectively. Fi-
nally, the stereochemical assignments for compounds 14a,
15a, 16a,b, 18a,b and 19a,b were made by correlation of
1
their H and 13C NMR spectra with those of 17a and 17b.
At this point, to determine the influence of the chirality of
the amino aldehyde on the stereochemical outcome of the
cyclization reaction, Fmoc--Phe-H was condensed with -
Trp-OMe under the above conditions (Scheme 2).
In this case we observed the formation of a mixture of
cis- and trans-β-carbolines (20a and 20b, 1:1 ratio) whereas
the tetracyclic derivative 21 was obtained as a single isomer.
The stereochemical assignments for the fusion positions C-
3a, C-5a and C-10b of this compound are 3aS, 5aR and
10bS, respectively, and were established on the basis of
NOE correlations observed in the 2D ROESY spectra.
Scheme 3. Proposed mechanism for the synthesis of octahydropyr-
rolo[3Ј,2Ј:3,4]pyrrolo[2,3-b]indole derivatives.
Thus, 5a-H showed NOE effects with 2-H and 1b-H, and recently, the synthesis and characterization of tetra- and
the methyl ester demonstrated NOE effects with the 3a-H pentacyclic derivatives obtained by the reaction of tryptam-
proton, which did not show a NOE with 2-H or 5-H. From ine with different aldehydes and amino aldehydes by the
these data it seems that the stereoselectivity of the conden- Pictet–Spengler reaction have been reported.[14]
sation reactions is particularly influenced by the chirality of
Results of this preliminary study show the potential
the starting aldehyde. Thus, the interactions between the value of our synthetic approach to the generation of struc-
phenyl moieties of the aldehyde group and the indole, which tural diversity which, in this case, was accomplished in one
might contribute to the stabilization of both the intermedi- pot.
ate and the final 3aS,5aR,10bS tetracyclic isomer, could ex-
Scheme 4 illustrates the synthesis of a series of additional
plain the inversion in selectivity observed with the use of β-carbolines as building blocks with three points of diver-
Fmoc--Phe-H when compared with the corresponding  sity and different protecting groups. Protection of the free
derivative. The formation of the tetracyclic derivatives could secondary amino group of compounds 8–10a,b, 12a,b,
be explained by a domino mechanism[11] involving an initial 13a,b and 20a,b with (Boc)2O in TEA and THF, and suc-
attack on the imine by the C-3 of indole with formation of cessive alkali hydrolysis (2 equiv. of LiOH in MeOH) af-
a spiroindolenine,[12] followed by trapping of the iminium forded the derivatives 22–27a,b in high yields (60% overall
ion by the amide nitrogen (Scheme 3).
yields). As expected, the use in this step of LiOH produced
Regarding the synthesis of this class of ring system, Pa- a partial removal of the Fmoc-protecting group (about
tek and co-workers have reported the formation of a penta- 20%, as detected by analytical HPLC), which can be re-
cyclic analogue derived from 1-acyl-3-oxopiperazines by in- introduced by treatment with Fmoc chloride in DMF using
tramolecular N-acyliminium cyclization reactions.[13] More DIEA as base.
Eur. J. Org. Chem. 2008, 1983–1992
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1985

P. Grieco et al.
FULL PAPER
ing points were measured with a Köfler apparatus and are uncor-
rected. Optical rotations were determined with a Perkin-Elmer 241
1
MC polarimeter. H and 13C NMR spectra were recorded with a
Bruker 500 spectrometer operating at 500 and 100 MHz, respec-
tively. Chemical shifts are reported in δ values (ppm) relative to
internal Me4Si and J values are reported in Hz. Mass spectra were
obtained using a FAB mass spectrometer.
General Procedure for the Synthesis of the Tetrahydro-β-carbolines
8–13 and 20 and Octahydropyrrolo[3Ј,2Ј:3,4]pyrrolo[2,3-b]indoles
Derivatives 14–19: -Trp-OMe·HCl (2 g, 2 mmol) and TFA
(2 mmol) were added to a solution of -amino aldehydes 2–7 or
Fmoc--Phe-H (2 mmol) in dichloromethane (40 mL) and the mix-
ture was stirred at room temperature for 12 h. Then, the mixture
was concentrated in vacuo and dichloromethane was added. The
organic layer was washed with H2O (2ϫ25 mL), dried with
Na2SO4, and the solvents evaporated. The title compounds were
purified by flash chromatography (FC) using different eluents.
Scheme 4. Reaction of β-carboline derivatives.
Methyl (1S,3S)-1-[(Fluorenylmethoxycarbonyl)aminomethyl]-1,2,3,4-
tetrahydro-β-carboline-3-carboxylate (8a): FC: EtOAc/n-hexane
(3:2). White solid (193 mg, 20%), m.p. 157–158 °C. [α]2D0 = +8.1 (c
Finally, the new 7-substituted cis-6,10-iminoazocino[4,5-
b]indole derivatives 28–33a[5,15,16] were easily obtained in
quantitative yields by intramolecular lactamization of the
corresponding cis-tetrahydro-β-carbolines 8–10a, 12a, 13a
and 20a under conditions suitable for the cleavage of the
Fmoc-protecting group using a 33% DIEA/THF solution
at room temperature. Under these conditions, the trans dia-
stereoisomers gave the corresponding Fmoc-deprotected
1
= 1.0, MeOH). H NMR (400 MHz, CDCl3): δ = 2.97–3.01 (m, 1
H, 4Ј-H), 3.15–3.18 (m, 1 H, 4ЈЈ-H), 3.37–3.39 (m, 1 H, 1Ј-H), 3.68
(d, J = 1.0 Hz, 1 H, 1-H), 3.76 (s, 3 H, OCH3), 4.20 (t, 1 H, CH
Fmoc), 4.35–4.37 (m, 1 H, 1Ј-H), 4.41–4.44 (m, 2 H, CH2 Fmoc),
5.63 (s, 1 H, NH), 7.12–7.16 (m, 2 H, 6-H, 7-H), 7.26 (t, J = 7.6 Hz,
2 H, CH Fmoc), 7.38 (t, 3 H, 8-H, aryl), 7.47 (d, J = 7.6 Hz, 1 H,
5-H), 7.52 (t, J = 7.6 Hz, 2 H, aryl), 7.74 (m, J = 7.6 Hz, 2 H,
aryl), 8.71 (s, 1 H, NH indole) ppm. 13C NMR (100 MHz, CDCl3):
tetrahydro-β-carbolines 34–39b. The structures of these δ = 25.7 (C-4), 44.6 (C-3), 52.6 (C-1), 54.0 (C-1Ј), 118.3, 119.7,
122.3, 132.1, 136.4, 141.5, 144.1 (aryl), 157.2, 174.3 (C=O) ppm.
FAB-MS: calcd. for C29H27N3O4 481.2002; found 481.2021.
compounds were confirmed by analytical and spectroscopic
data.
Methyl (1R,3S)-1-[(Fluorenylmethoxycarbonyl)aminomethyl]-1,2,3,4-
tetrahydro-β-carboline-3-carboxylate (8b): FC: EtOAc/n-hexane
(3:2). White solid (70 mg, 7%), m.p. 159–160 °C. [α]2D0 = +21.4 (c
Conclusions
1
= 1.3, MeOH). H NMR (400 MHz, CDCl3): δ = 2.85 (dd, J = 8,
In summary, the preliminary results described herein
show the real advantage of the acid-promoted condensation
of -Trp-OMe with amino aldehyde derivatives in the syn-
thesis of both tetrahydro-β-carbolines and octahydropyr-
rolo[3Ј,2Ј:3,4]pyrrolo[2,3-b]indole derivatives. From a struc-
tural point of view, this latter class of compound represents
14.8 Hz, 1 H, 4Ј-H), 3.14 (dd, J = 4.4, 14.8 Hz, 1 H, 4ЈЈ-H), 3.65
(d, J = 1.2 Hz, 1 H, 1-H), 3.74–3.76 (m, 1 H, 3-H), 3.81 (s, 3 H,
OCH3), 4.07–4.11 (m, 1 H, 1Ј-H), 4.28–4.31 (m, 2 H, CH Fmoc,
1Ј-H), 4.37–4.40 (m, 2 H, CH2 Fmoc), 5.89 (s, 1 H, NH), 7.06–7.13
(m, 2 H, 6-H, 7-H), 7.14–7.22 (m, 2 H, aryl), 7.24–7.36 (m, 2 H,
aryl), 7.39 (t, J = 7.6 Hz, 1 H, 8-H), 7.46 (m, 3 H, 5-H, aryl), 7.68
an interesting example of conformationally rigid peptidomi- (d, J = 7.6 Hz, 2 H, aryl), 8.71 (s, NH indole) ppm. 13C NMR
(100 MHz, CDCl3): δ = 25.4 (C-4), 44.7 (C-1), 51.1 (C-3), 52.5 (C-
1), 118.1, 119.9, 122.3, 132.5, 136.6, 141.4, 144.0 (aryl), 157.1, 173.7
(C=O) ppm. FAB-MS: calcd. for C29H27N3O4 481.2002; found
481.2081.
metics with a cyclic structure.
In turn, structural manipulation of the tetrahydro-β-car-
boline derivatives allows access to new 7-substituted 6,10-
iminoazocino[4,5-b]indole derivatives, as well as to orthogo-
nally substituted tetrahydro-β-carbolines. Therefore, studies
to explore the reactivity of the new octahydropyr-
Methyl (1S,3S,1ЈS)-1-[1Ј-(Fluorenylmethoxycarbonyl)aminoethyl]-
1,2,3,4-tetrahydro-β-carboline-3-carboxylate (9a): FC: EtOAc/n-
rolo[3Ј,2Ј:3,4]pyrrolo[2,3-b]indoles and the introduction of hexane (3:2). White solid (218 mg, 22%), m.p. 178–179 °C. [α]2D0
=
–10.3 (c = 1.0, MeOH). 1H NMR (400 MHz, CD3OD): δ = 1.01
(d, J = 6.8 Hz, 3 H, 2Ј-H), 2.75–2.80 (m, 1 H, 4Ј-H), 3.07 (dd, J =
3.6, 15.2 Hz, 1 H, 4ЈЈ-H), 3.70 (dd, J = 3.6, 11.2 Hz, 1 H, 3-H),
3.85 (s, 3 H, OCH3), 4.18 (t, 1 H, CH Fmoc), 4.30–4.33 (m, 2 H,
1-H, 1Ј-H), 4.31–4.34 (m, 2 H, CH2 Fmoc), 7.14–7.21 (m, 2 H, 6-
H, 7-H), 7.31 (m, 3 H, 8-H, aryl), 7.40–7.44 (m, 2 H, aryl), 7.49
(d, J = 7.6 Hz, 1 H, 5-H), 7.61 (d, J = 7.6 Hz, 2 H, aryl), 7.77 (d,
J = 7.6 Hz, 2 H, aryl) ppm. 13C NMR (100 MHz, CD3OD): δ =
13.3 (C-2Ј), 25.4 (C-4), 49.3 (C-3), 56.4 (C-1), 56.5 (C-1Ј), 118.8,
119.8, 121.2, 132.7, 137.0, 141.5, 144.3 (aryl), 157.2, 173.9
(C=O) ppm. FAB-MS: calcd. for C30H29N3O4 495.2158; found
495.2124.
additional substituents into this ring system are in progress
in our laboratory.
Experimental Section
General: Reagents, starting material and solvents were purchased
from commercial suppliers and used as received. Analytical TLC
was performed on plates coated with a 0.25 mm layer of silica gel
60 F254 Merck and preparative TLC on 20ϫ20 cm glass plates
coated with a 2 mm layer of silica gel PF254 Merck. Silica gel 60
(300–400 mesh, Merck) was used for flash chromatography. Melt-
1986
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Eur. J. Org. Chem. 2008, 1983–1992

Synthesis of Novel Indole-Based Ring Systems
Methyl (1R,3S,1ЈS)-1-[1Ј-(Fluorenylmethoxycarbonyl)aminoethyl]- 163 °C. [α]2D0 = +41.0 (c = 1.1, MeOH). 1H NMR (400 MHz,
1,2,3,4-tetrahydro-β-carboline-3-carboxylate (9b): FC: EtOAc/n-
CDCl3): δ = 1.32 (s, 9 H, CH3), 2.81–2.94 (m, 2 H, 2Ј-H), 3.15–
3.27 (m, 2 H, 4-H), 3.62 (s, 3 H, OCH3), 4.07–4.11 (m, 1 H, 3-H),
hexane (3:2). White solid (110 mg, 11%), m.p. 180–181 °C. [α]2D0
=
+7.2 (c = 1.1, MeOH). 1H NMR (400 MHz, CD3OD): δ = 1.35 (d, 4.31–4.34 (m, 1 H, 1Ј-H), 4.44 (d, J = 1.4 Hz, 1 H, 1-H), 5.27 (s, 1
J = 6.6 Hz, 3 H, 2Ј-H), 2.73 (t, J = 12.8 Hz, 1 H, 4Ј-H), 3.05 (dd,
H, NH-Boc), 7.01–7.48 (m, 9 H, 5-H, 6-H, 7-H, 8-H, aryl), 8.68 (s,
J = 3.6, 15.2 Hz, 1 H, 4ЈЈ-H), 3.61 (s, 3 H, OCH3), 4.10–4.13 (m, 1 H, NH indole) ppm. 13C NMR (100 MHz, CDCl3): δ = 24.3 (C-
1 H, CH Fmoc), 4.16–4.22 (m, 2 H, 3-H, 1Ј-H), 4.25 (d, J = 1.2 Hz,
1 H, 1-H), 4.37–4.40 (m, 2 H, CH2 Fmoc), 6.98 (t, J = 7.6 Hz, 1
H, 6-H), 7.06 (t, J = 7.6 Hz, 1 H, 7-H), 7.29–7.34 (m, 3 H, 8-H,
4), 39.0 (C-2Ј), 51.9 (C-1), 55.0 (C-3), 55.5 (C-1Ј), 108.5, 111.3,
118.0, 118.1, 119.3, 121.8, 126.4, 127.3, 128.7, 129.2, 129.4, 132.1,
138.2, 138.6 (aryl), 156.3, 174.6 (C=O) ppm. FAB-MS: calcd. for
aryl), 7.38–7.44 (m, 3 H, 5-H, aryl), 7.66–7.70 (m, 2 H, aryl), 7.78 C26H31N3O4 449.2315; found 449.2343.
(t, J = 7.6 Hz, 2 H, aryl) ppm. 13C NMR (100 MHz, CD3OD): δ
Methyl (1S,3S,1ЈS)-1-[2Ј-(tert-Butoxycarbonyl)-1Ј-(fluorenylmeth-
= 17.3 (C-2Ј), 24.2 (C-4), 49.5 (C-1), 52.8 (C-3), 55.2 (C-1Ј), 118.6,
119.6, 121.2, 132.1, 136.9, 141.3, 144.2 (aryl), 156.9, 174.3
(C=O) ppm. FAB-MS: calcd. for C30H29N3O4 495.2158; found
495.2133.
oxycarbonyl)aminoethyl]-1,2,3,4-tetrahydro-β-carboline-3-carboxyl-
ate (12a): FC: EtOAc/n-hexane (1:2). Oil (160 mg, 14%). [α]2D0
=
1
–16.1 (c = 1.6, MeOH). H NMR (400 MHz, CDCl3): δ = 1.36 (s,
9 H, CH3), 2.15–2.19 (m, 1 H, 2Ј-H), 2.39–2.43 (m, 1 H, 2ЈЈ-H),
2.79 (t, J = 13.2 Hz, 1 H, 4Ј-H), 3.13 (dd, J = 2.5, 14.0 Hz, 1 H,
4ЈЈ-H), 3.72 (dd, J = 2.5, 11.4 Hz, 1 H, 3-H), 3.82 (s, 3 H, OCH3),
4.08 (br. s, 1 H, 1-H), 4.13 (t, 1 H, CH Fmoc), 4.40–4.45 (m, 2 H,
CH2 Fmoc), 4.50–4.52 (m, 1 H, 1Ј-H), 5.95 (d, 1 H, NH), 7.14–
7.26 (m, 2 H, 6-H, 7-H), 7.31–7.50 (m, 6 H, 5-H, 8-H, aryl), 7.63
(d, J = 7.6 Hz, 2 H, aryl), 7.75 (d, J = 7.6 Hz, 2 H, aryl), 9.08 (s,
1 H, NH indole) ppm. 13C NMR (100 MHz, CDCl3): δ = 25.4 (C-
4), 38.0 (C-2Ј), 50.7 (C-3), 55.7 (C-1), 56.4 (C-1Ј), 111.5, 118.3,
Methyl
(1S,3S,1ЈS)-1-[1Ј-(Fluorenylmethoxycarbonyl)amino-2Ј-
phenylethyl]-1,2,3,4-tetrahydro-β-carboline-3-carboxylate (10a): FC:
EtOAc/n-hexane (2:3). White solid (229 mg, 20%), m.p. 191–
192 °C. [α]2D0 = –21.3 (c = 1.0, MeOH). 1H NMR (400 MHz,
CDCl3): δ = 2.75–2.89 (m, 2 H, 4Ј-H, 2Ј-H), 3.03 (dd, J = 3.8,
13.6 Hz, 1 H, 2ЈЈ-H), 3.09–3.13 (m, 1 H, 4ЈЈ-H), 3.85 (dd, J = 3.2,
12.4 Hz, 1 H, 3-H), 3.82 (s, 3 H, OCH3), 4.12 (t, 1 H, CH Fmoc),
4.27–4.30 (m, 2 H, CH2 Fmoc), 4.51–4.56 (m, 2 H, 1-H, 1Ј-H), 5.65
(d, 1 H, NH), 7.12–7.20 (m, 3 H, 6-H, 7-H, 8-H), 7.25–7.29 (m, 3 120.1, 122.2, 125.3, 127.2, 128.0, 132.2, 136.8, 143.8, 144.1 (aryl),
H, 5-H, aryl), 7.32–7.58 (m, 7 H, aryl), 7.61 (d, J = 7.6 Hz, 2 H, 156.5, 171.5, 173.5 (C=O) ppm. FAB-MS: calcd. for C35H37N3O6
aryl), 7.77 (d, J = 7.6 Hz, 2 H, aryl), 8.61 (s, 1 H, NH indole) ppm. 595.2682; found 595.2713.
13C NMR (100 MHz, CDCl3): δ = 24.5 (C-4), 38.5 (C-2Ј), 53.7 (C-
3), 55.4 (C-1), 58.3 (C-1Ј), 118.6, 120.1, 121.4, 126.3, 128.5, 132.1,
137.2, 138.2, 141.8, 144.6 (aryl), 158.1, 174.3 (C=O) ppm. FAB-
MS: calcd. for C36H33N3O4 571.2471; found 571.2429.
Methyl (1R,3S,1ЈS)-1-[2Ј-(tert-Butoxycarbonyl)-1Ј-(fluorenylmeth-
oxycarbonyl)aminoethyl]-1,2,3,4-tetrahydro-β-carboline-3-carboxyl-
ate (12b): FC: EtOAc/n-hexane (1:2). Oil (107 mg, 9%). [α]2D0 = +5.9
1
(c = 1.5, MeOH). H NMR (400 MHz, CDCl3): δ = 1.40 (s, 9 H,
Methyl
(1R,3S,1ЈS)-1-[1Ј-(Fluorenylmethoxycarbonyl)amino-2Ј- CH3), 2.56–2.62 (m, 2 H, 2Ј-H), 3.06–3.11 (m, 2 H, 4-H), 3.64 (s,
phenylethyl]-1,2,3,4-tetrahydro-β-carboline-3-carboxylate (10b): FC:
EtOAc/n-hexane (2:3). White solid (115 mg, 10%), m.p. 195–
196 °C. [α]2D0 = +7.4 (c = 1.0, MeOH). 1H NMR (400 MHz,
3 H, OCH3), 4.02–4.11 (m, 1 H, 3-H), 4.22 (t, 1 H, CH Fmoc),
4.40–4.43 (m, 2 H, CH2 Fmoc), 4.46 (br. s, 1 H, 1-H), 4.60–4.63
(m, 1 H, 1Ј-H), 5.69 (s, 1 H, NH), 7.09–7.19 (m, 2 H, 8-H, 6-H),
CDCl3): δ = 2.59 (dd, J = 3.6, 14.6 Hz, 1 H, 2Ј-H), 2.77–2.83 (m, 7.25–7.29 (m, 3 H, aryl, 5-H), 7.32–7.58 (m, 7 H, aryl, 7-H), 7.60
2 H, 2ЈЈ-H, 4ЈЈ-H), 3.03 (dd, J = 4.2, 13.6 Hz, 1 H, 4ЈЈ-H), 3.84 (s,
3 H, OCH3), 4.01 (dd, J = 4.2, 12.8 Hz, 1 H, 3-H), 4.18 (t, 1 H,
(d, J = 7.6 Hz, 2 H, aryl), 7.78 (d, J = 7.6 Hz, 2 H, aryl), 8.68 (s,
1 H, NH indole) ppm. 13C NMR (100 MHz, CDCl3): δ = 24.5 (C-
CH Fmoc), 4.27–4.31 (m, 1 H, 1Ј-H), 4.33–4.36 (m, 2 H, CH2 4), 38.3 (C-2Ј), 52.3 (C-1), 52.5 (C-3), 53.6 (C-1Ј), 111.3, 118.4,
Fmoc), 4.50 (d, J = 1.4 Hz, 1 H, 1-H), 7.09 (t, J = 8.0 Hz, 1 H, 6-
H), 7.14–7.20 (m, 2 H, 7-H, 8-H), 7.23–7.29 (m, 4 H, aryl), 7.36–
7.55 (m, 8 H, 5-H, aryl), 7.81 (d, J = 7.6 Hz, 2 H, aryl), 8.81 (s, 1
H, NH indole) ppm. 13C NMR (100 MHz, CDCl3): δ = 23.1 (C-
4), 39.0 (C-2Ј), 52.5 (C-1), 54.7 (C-3), 56.8 (C-1Ј), 118.5, 120.1,
121.1, 126.4, 128.5, 132.2, 137.4, 138.7, 141.7, 144.1 (aryl), 158.7,
174.3 (C=O) ppm. FAB-MS: calcd. for C36H33N3O4 571.2471;
found 571.2498.
120.1, 122.2, 125.2, 127.3, 127.9, 131.4, 136.5, 141.5, 144.2 (aryl),
156.3, 171.1, 174.5 (C=O) ppm. FAB-MS: calcd. for C35H37N3O6
595.2682; found 595.2768.
Methyl (1S,3S,1ЈS)-1-[5Ј-(tert-Butoxycarbonylamino)-1Ј-(fluorenyl-
methoxycarbonylamino)pentyl]-1,2,3,4-tetrahydro-β-carboline-3-car-
boxylate (13a): FC: EtOAc/n-hexane (3:2). Oil (161 mg, 12%).
[α]2D0 = –4.9 (c = 1.8, MeOH). 1H NMR (400 MHz, CDCl3): δ =
1.26–1.29 (m, 2 H, γ-H), 1.34–1.41 (m, 4 H, β-H, δ-H), 1.45 (s, 9
Methyl
(1S,3S,1ЈS)-1-[1Ј-(tert-Butoxycarbonyl)amino-2Ј-phenyl- H, CH3), 2.16–2.18 (m, 2 H, ε-H), 2.82 (d, J = 6.0, 13.2 Hz, 1 H,
ethyl]-1,2,3,4-tetrahydro-β-carboline-3-carboxylate
(11a):
FC:
4Ј-H), 3.79–3.83 (m, 1 H, 4ЈЈ-H), 3.72–3.77 (m, 1 H, 3-H), 3.80 (s,
3 H, OCH3), 4.22 (t, 1 H, CH Fmoc), 4.42 (br. s, 1 H, 1-H), 4.45–
4.47 (m, 2 H, CH2 Fmoc), 4.60–4.62 (m, 1 H, 1Ј-H), 5.34 (d, 1 H,
EtOAc/n-hexane (2:3). White solid (235 mg, 21%), m.p. 158–
159 °C. [α]2D0 = +34.1 (c = 1.0, MeOH). 1H NMR (400 MHz,
CDCl3): δ = 1.35 (s, 9 H, CH3), 2.81–2.96 (m, 3 H, 2Ј-H, 2ЈЈ-H, NH-Boc), 7.08–7.17 (m, 2 H, 8-H, 6-H), 7.28–7.58 (m, 6 H, aryl,
4ЈЈ-H), 3.15 (dd, J = 3.2, 14 Hz, 1 H, 4ЈЈ-H), 3.73 (dd, J = 3.2, 5-H, 7-H), 7.61 (d, J = 8.0 Hz, 2 H, aryl), 7.75 (d, J = 7.8 Hz, 2
11.2 Hz, 1 H, 3-H), 3.84 (s, 3 H, OCH3), 4.26 (d, J = 1.0 Hz, 1 H,
H, aryl), 9.01 (s, 1 H, NH indole) ppm. 13C NMR (100 MHz,
1-H), 4.47–4.50 (m, 1 H, 1Ј-H), 7.05–7.46 (m, 9 H, 5-H, 6-H, 7-H, CDCl3): δ = 21.3, 27.6, 29.2 (C-δ,γ,ε), 26.3 (C-4), 39.6 (C-β), 53.4
8-H, aryl), 8.73 (s, 1 H, NH indole) ppm. 13C NMR (100 MHz,
CDCl3): δ = 25.2 (C-4), 37.3 (C-2Ј), 52.1 (C-3), 54.2 (C-1), 56.1 (C-
1Ј), 108.1, 110.7, 117.3, 117.6, 118.8, 121.2, 126.3, 127.9, 128.3,
(C-3), 56.6 (C-1), 56.7 (C-1Ј), 111.6, 119.6, 120.2, 125.3, 127.3,
127.9, 132.8, 136.8, 141.6, 144.1 (aryl), 156.1, 156.8, 174.0
(C=O) ppm. FAB-MS: calcd. for C38H44N4O6 652.3261; found
129.1, 129.4, 131.5, 137.0, 138.6 (aryl), 157.0, 173.2 (C=O) ppm. 652.3273.
FAB-MS: calcd. for C26H31N3O4 449.2315; found 449.2323.
Methyl (1R,3S,1ЈS)-1-[5Ј-(tert-Butoxycarbonylamino)-1Ј-(fluorenyl-
Methyl
ethyl]-1,2,3,4-tetrahydro-β-carboline-3-carboxylate
EtOAc/n-hexane (2:3). White solid (118 mg, 10%), m.p. 162–
(1R,3S,1ЈS)-1-[1Ј-(tert-Butoxycarbonyl)amino-2Ј-phenyl-
methoxycarbonylamino)pentyl]-1,2,3,4-tetrahydro-β-carboline-3-car-
(11b): FC:
boxylate (13b): FC: EtOAc/n-hexane (3:2). Oil (102 mg, 8%). [α]2D0
1
= +15.8 (c = 1.3, MeOH). H NMR (400 MHz, CDCl3): δ = 1.41
Eur. J. Org. Chem. 2008, 1983–1992
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1987

P. Grieco et al.
FULL PAPER
(s, 9 H, CH3), 1.43–1.64 (m, 6 H, γ-H, β-H, δ-H), 2.61–2.64 (m, 2 OCH3), 3.79 (m, 1 H, 3a-H), 3.96 (dd, J = 4.2, 11.8 Hz, 1 H, 2-H),
H, ε-H), 3.10–3.14 (m, 1 H, 4Ј-H), 3.27 (dd, J = 4.0, 14.0 Hz, 1 H, 4.36–4.39 (m, 1 H, CH Fmoc), 4.52–4.56 (m, 2 H, CH2 Fmoc),
4ЈЈ-H), 3.61 (s, 3 H, OCH3), 3.90–3.93 (m, 1 H, 3-H), 4.00–4.09 5.26 (s, 1 H, 5a-H), 6.47 (d, J = 8.4 Hz, 1 H, 7-H), 6.56 (d, J =
(m, 1 H, CH Fmoc), 4.16–4.22 (m, 2 H, CH2 Fmoc), 4.35–4.39 (m,
8.4 Hz, 1 H, 10-H), 6.69–6.72 (m, 2 H, 8-H, 9-H), 7.03–7.09 (m, 2
1 H, 1Ј-H), 4.56 (br. s, 1 H, 1-H), 5.48 (d, 1 H, NH-Boc), 6.98 (t, H, aryl), 7.30–7.44 (m, 3 H, aryl), 7.61–7.66 (m, 2 H, aryl), 7.77–
J = 7.8 Hz, 1 H, 6-H), 7.06 (t, J = 7.8 Hz, 1 H, 7-H) 7.29–7.34 (m, 7.79 (m, 1 H, aryl) ppm. 13C NMR (100 MHz, CDCl3): δ = 43.0
3 H, aryl, 8-H), 7.38–7.44 (m, 3 H, aryl, 5-H), 7.66–7.70 (m, 2 H, (C-1), 52.9 (C-4), 64.1 (C-10b), 67.4 (C-3a), 82.0 (C-5a), 113.1,
aryl), 7.78 (d, J = 7.6 Hz, 2 H, aryl) ppm. 13C NMR (100 MHz,
CDCl3): δ = 21.2, 29.6, 29.9 (C-δ,γ,ε), 23.3 (C-4), 40.4 (C-β), 49.5
(C-1), 53.3 (C-3), 54.2 (C-1Ј), 111.4, 119.6, 120.2, 125.0, 127.2.
127.6, 132.3, 136.6, 141.4, 144.2 (aryl), 157.0, 158.4, 174.9
(C=O) ppm. FAB-MS: calcd. for C38H44N4O6 652.3261; found
652.3273.
117.0, 125.9, 126.8, 133.1, 147.0 (aryl), 153.6, 173.2 (C=O) ppm.
FAB-MS: calcd. for C30H29N3O4 495.2158; found 495.2223.
5-Fluorenylmethyl 2-Methyl (2S,3aR,4S,5aS,10bR)-4-Benzyl-
1,2,3,3a,4,5,5a,6-octahydropyrrolo[3Ј,2Ј:3,4]pyrrolo[2,3-b]indole-2,5-
dicarboxylate (16a): FC: EtOAc/n-hexane (2:3). White solid
(399 mg, 35%), m.p. 247–248 °C. [α]2D0 = –27.9 (c = 1.0, MeOH).
Methyl
(1S,3S,1ЈR)-1-[1Ј-(Fluorenylmethoxycarbonyl)amino-2Ј- 1H NMR (400 MHz, CD3OD): δ = 2.03–2.07 (m, 1 H, 4Ј-H), 2.39–
phenylethyl]-1,2,3,4-tetrahydro-β-carboline-3-carboxylate (20a): FC:
EtOAc/n-hexane (2:3). White solid (183 mg, 16%), m.p. 187–
189 °C. [α]2D0 = +29.7 (c = 1.0, MeOH). 1H NMR (400 MHz,
CDCl3): δ = 2.79–2.89 (m, 3 H, 4Ј-H, 2Ј-H), 3.13 (dd, J = 3.8,
14.0 Hz, 1 H, 4ЈЈ-H), 3.80–3.83 (m, 1 H, 3-H), 3.86 (s, 3 H, OCH3),
4.07 (t, 1 H, CH Fmoc), 4.13–4.21 (m, 2 H, CH2 Fmoc), 4.35 (br.
2.43 (m, 1 H, 1Ј-H), 2.51–2.55 (m, 1 H, 1ЈЈ-H), 2.87–2.90 (m, 1 H,
4ЈЈ-H), 3.66 (d, J = 3.8 Hz, 1 H, 3a-H), 3.74 (s, 3 H, OCH3), 3.88
(dd, J = 4.2, 12.4 Hz, 1 H, 2-H), 4.19 (t, J = 4.0 Hz, 1 H, 4-H),
4.24–4.26 (m, 1 H, CH Fmoc), 4.43–4.49 (m, 2 H, CH2 Fmoc),
5.00 (s, 1 H, 5a-H), 6.67–6.81 (m, 2 H, aryl), 6.94–7.02 (m, 2 H,
aryl), 7.13–7.22 (m, 5 H, aryl), 7.38–7.55 (m, 8 H, aryl) ppm. 13C
s, 1 H, 1-H), 4.52–4.58 (m, 1 H, 1Ј-H), 5.68 (d, 1 H, NH), 7.12– NMR (100 MHz, CDCl3): δ = 38.8 (C-4Ј), 39.9 (C-1), 57.4 (C-2),
7.26 (m, 3 H, 6-H, 7-H, 8-H), 7.29–7.58 (m, 12 H, 5-H, aryl), 7.60–
63.8 (C-10b), 65.4 (C-4), 71.9 (C-3a), 82.6 (C-5a), 109.4, 118.7,
122.6, 126.2, 128.4, 128.9, 129.1, 130.0, 138.4, 149.6 (aryl), 155.7,
7.64 (d, 4 H, aryl), 8.56 (s, 1 H, NH indole) ppm. 13C NMR
(100 MHz, CDCl3): δ = 23.6 (C-4), 38.6 (C-2Ј), 53.4 (C-3), 54.9 (C- 174.6 (C=O) ppm. FAB-MS: calcd. for C36H33N3O4 571.2471;
1), 57.8 (C-1Ј), 109.2, 111.4, 118.4, 120.0, 121.4, 125.9, 127.4, 128.4,
132.5, 137.3, 138.1, 141.6, 144.6 (aryl), 158.1, 174.3 (C=O) ppm.
FAB-MS: calcd. for C36H33N3O4 571.2471; found 571.2571.
found 571.2547.
5-Fluorenylmethyl 2-Methyl (2S,3aS,4S,5aR,10bS)-4-Benzyl-
1,2,3,3a,4,5,5a,6-octahydropyrrolo[3Ј,2Ј:3,4]pyrrolo[2,3-b]indole-2,5-
Methyl
(1R,3S,1ЈR)-1-[1Ј-(Fluorenylmethoxycarbonyl)amino-2Ј- dicarboxylate (16b): FC: EtOAc/n-hexane (2:3). White solid (80 mg,
phenylethyl]-1,2,3,4-tetrahydro-β-carboline-3-carboxylate (20b): FC:
EtOAc/n-hexane (2:3). White solid (175 mg, 15%), m.p. 195–
196 °C. [α]2D0 = +51.1 (c = 1.0, MeOH). 1H NMR (400 MHz,
CDCl3): δ = 2.79–2.83 (m, 2 H, 2Ј-H), 3.17–3.23 (m, 2 H, 4-H),
7%), m.p. 260–261 °C. [α]2D0 = +5.1 (c = 0.8, MeOH). 1H NMR
(400 MHz, CD3OD): δ = 1.98–2.05 (m, 1 H, 4Ј-H), 2.31–2.36 (m,
1 H, 1Ј-H), 2.58–2.62 (m, 1 H, 1ЈЈ-H), 2.79–2.83 (m, 1 H, 4ЈЈ-H),
3.73 (s, 3 H, OCH3), 3.78 (dd, J = 4.2, 12.4 Hz, 1 H, 3a-H), 3.95–
3.66 (s, 3 H, OCH3), 3.90–3.94 (m, 1 H, 3-H), 4.09 (t, 1 H, CH 4.00 (m, 1 H, 2-H), 4.12 (dd, J = 4.2, 12.0 Hz, 1 H, 4-H), 4.26–
Fmoc), 4.32–4.37 (m, 1 H, 1Ј-H), 4.42–4.46 (m, 2 H, CH2 Fmoc), 4.29 (m, 1 H, CH Fmoc), 4.41–4.48 (m, 2 H, CH2 Fmoc), 5.40 (s,
4.59 (br. s, 1 H, 1-H), 5.24 (d, 1 H, NH), 7.12–7.45 (m, 15 H, 5-H, 1 H, 5a-H), 6.71–6.83 (m, 2 H, aryl), 7.02 (d, J = 7.8 Hz, 2 H,
6-H, 7-H, 8-H, aryl), 7.50–7.58 (m, 2 H, aryl), 7.79 (d, J = 7.6 Hz,
aryl), 7.18–7.26 (m, 5 H, aryl), 7.40–7.58 (m, 8 H, aryl) ppm. 13C
2 H, aryl) ppm. 13C NMR (100 MHz, CDCl3): δ = 23.7 (C-4), 39.1 NMR (100 MHz, CDCl3): δ = 38.7 (C-4Ј), 41.0 (C-1), 57. (C-2),
(C-2Ј), 53.1 (C-1), 55.2 (C-3), 56.4 (C-1Ј), 108.6, 111.0, 118.3, 120.1, 64.1 (C-10b), 65.9 (C-4), 70.8 (C-3a), 82.7 (C-5a), 109.3, 118.7,
121.4, 125.9, 127.3, 128.2, 132.4, 137.2, 138.1, 141.3, 144.5 (aryl),
158.1, 174.1 (C=O) ppm. FAB-MS: calcd. for C36H33N3O4
571.2471; found 571.2565.
123.1, 126.2, 128.4, 128.9, 129.2, 130.0, 138.6, 149.8 (aryl), 156.0,
174.5 (C=O) ppm. FAB-MS: calcd. for C36H33N3O4 571.2471;
found 571.2522.
5-Fluorenylmethyl 2-Methyl (2S,3aR,4S,5aS,10bR)-1,2,3,3a,4,5,5a,6- 5-tert-Butyl 2-Methyl (2S,3aR,4S,5aS,10bR)-4-Benzyl-
octahydropyrrolo[3Ј,2Ј:3,4]pyrrolo[2,3-b]indole-2,5-dicarboxylate
(14a): FC: EtOAc/n-hexane (3:2). White solid (337 mg, 35%), m.p.
1,2,3,3a,4,5,5a,6-octahydropyrrolo[3Ј,2Ј:3,4]pyrrolo[2,3-b]indole-2,5-
dicarboxylate (17a): FC: EtOAc/n-hexane (2:3). White solid
(324 mg, 36%), m.p. 250–251 °C. [α]2D0 = +6.3 (c = 1.0, MeOH). 1H
1
202–203 °C. [α]2D0 = –25.1 (c = 1.1, MeOH). H NMR (400 MHz,
CDCl3): δ = 2.22–2.31 (m, 2 H, 1-H), 3.31–3.34 (m, 1 H, 3a-H), NMR (400 MHz, CD3OD): δ = 1.39 (s, 9 H, Boc), 1.96–2.00 (m,
3.60 (s, 3 H, CH3 ester), 3.86 (d, J = 6.6 Hz, 1 H, 2-H), 4.38–4.42 1 H, 4Ј-H), 2.44–2.47 (m, 2 H, 1-H), 2.82–2.85 (m, 1 H, 4ЈЈ-H),
(m, 1 H, CH Fmoc), 4.81–4.86 (m, 2 H, CH2 Fmoc), 5.43 (s, 1 H,
5a-H), 6.30 (d, J = 8.4 Hz, 1 H, 7-H), 6.58 (d, J = 8.4 Hz, 1 H, 10-
3.60 (s, 1 H, 3a-H), 3.71 (s, 3 H, OCH3), 3.97 (dd, J = 2.8, 11.4 Hz,
1 H, 2-H), 4.14 (m, 1 H, 4-H), 5.34 (s, 1 H, 5a-H), 6.67–6.81 (m, 2
H), 6.69–6.72 (m, 2 H, 8-H, 9-H), 6.99–7.12 (m, 2 H, aryl), 7.36– H, aryl), 6.94–7.00 (m, 2 H, aryl), 7.13–7.22 (m, 5 H, aryl) ppm.
7.62 (m, 4 H, aryl), 7.64–7.83 (m, 2 H, aryl) ppm. 13C NMR 13C NMR (100 MHz, CDCl3): δ = 39.8 (C-4Ј), 42.6 (C-1), 60.1 (C-
(100 MHz, CDCl3): δ = 41.8 (C-1), 46.7 (C-4), 51.9 (OCH3), 59.7 2), 63.2 (C-10b), 66.8 (C-4), 72.3 (C-3a), 82.7 (C-5a), 109.3, 118.7,
(C-2), 62.5 (C-10b), 75.9 (C-3a), 81.5 (C-5a), 108.6, 119.0, 123.2,
124.8, 125.2, 127.4, 127.6, 127.9, 128.6, 128.9, 130.4, 141.7, 144.4,
123.0, 126.2, 128.3, 128.8, 129.3, 130.8, 138.8, 149.9 (aryl), 156.3,
174.5 (C=O) ppm. FAB-MS: calcd. for C26H31N3O4 449.2315;
149.0 (aryl), 154.9, 174.2 (C=O) ppm. FAB-MS: calcd. for found 449.3311.
C29H27N3O4 481.2002; found 481.2009.
5-tert-Butyl 2-Methyl (2S,3aS,4S,5aR,10bS)-4-Benzyl-
5-Fluorenylmethyl 2-Methyl (2S,3aR,4S,5aS,10bR)-4-Methyl-
1,2,3,3a,4,5,5a,6-octahydropyrrolo[3Ј,2Ј:3,4]pyrrolo[2,3-b]indole-2,5-
dicarboxylate (15a): FC: EtOAc/n-hexane (3:2). White solid
(376 mg, 38%), m.p. 214–215 °C. [α]2D0 = –37.4 (c = 1.0, MeOH).
1H NMR (400 MHz, CDCl3): δ = 0.72 (d, J = 6.8 Hz, 3 H, CH3),
2.40–2.43 (m, 2 H, 1-H), 3.49–3.54 (m, 1 H, 4-H), 3.61 (s, 3 H,
1,2,3,3a,4,5,5a,6-octahydropyrrolo[3Ј,2Ј:3,4]pyrrolo[2,3-b]indole-2,5-
dicarboxylate (17b): FC: EtOAc/n-hexane (2:3). White solid (63 mg,
7%), m.p. 245–246 °C. [α]2D0 = +31.1 (c = 1.1, MeOH). 1H NMR
(400 MHz, CD3OD): δ = 1.42 (s, 9 H, Boc), 1.95–2.04 (m, 1 H, 4Ј-
H), 2.20–2.23 (m, 1 H, 1Ј-H), 2.61–2.66 (m, 1 H, 1ЈЈ-H), 2.83–2.86
(m, 1 H, 4ЈЈ-H), 3.71 (s, 3 H, OCH3), 3.80 (br. s, 1 H, 3a-H), 3.97–
1988
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Eur. J. Org. Chem. 2008, 1983–1992

Synthesis of Novel Indole-Based Ring Systems
4.01 (m, 1 H, 2-H), 4.06 (dd, J = 4.2, 11.8 Hz, 1 H, 4-H), 5.45 (s, [3Ј,2Ј:3,4]pyrrolo[2,3-b]indole-2,5-dicarboxylate (19b): FC: EtOAc/
1 H, 5a-H), 6.68–6.80 (m, 2 H, aryl), 6.94 (d, J = 7.8 Hz, 2 H, aryl), n-hexane (2:3). White solid (195 mg, 15%), m.p. 277–278 °C. [α]2D0
7.13–7.23 (m, 5 H, aryl) ppm. 13C NMR (100 MHz, CD3OD): δ = +18.5 (c = 1.1, MeOH). 1H NMR (400 MHz, CD3OD): δ = 0.80–
= 39.5 (C-4Ј), 43.3 (C-1), 59.7 (C-2), 63.9 (C-10b), 67.0 (C-4), 71.2
0.83 (m, 2 H, γ-H), 1.08–1.11 (m, 2 H, δ-H), 1.22–1.27 (m, 2 H, β-
(C-3a), 82.9 (C-5a), 109.3, 118.7, 123.0, 126.2, 128.3, 128.8, 129.3, H), 1.41 (s, 9 H, tBu), 2.30–2.33 (m, 1 H, 1Ј-H), 2.40–2.44 (dd, J
130.0, 138.5, 149.7 (aryl), 156.1, 174.5 (C=O) ppm. FAB-MS:
calcd. for C26H31N3O4 449.2315; found 449.2343.
= 9.4, 15.0 Hz, 1 H, 1ЈЈ-H), 2.78–2.81 (m, 2 H, ε-H), 3.42–3.44 (m,
1 H, 4-H), 3.55 (br. s, 1 H, 3a-H), 3.59 (s, 3 H, OCH3), 4.31 (t, 1
H, CH Fmoc), 4.47–4.51 (dd, J = 5.6, 10.1 Hz, 1 H, 2-H), 4.69–
4.73 (m, 2 H, CH2 Fmoc), 5.02 (s, 1 H, 5a-H), 6.47 (d, J = 7.6 Hz,
1 H, 7-H), 6.53 (d, J = 7.6 Hz, 1 H, 10-H), 6.68 (t, J = 7.2 Hz, 1
H, 8-H), 6.97–7.03 (m, 2 H, 9-H, aryl), 7.30–7.39 (m, 3 H, aryl),
7.58–7.76 (m, 2 H, aryl), 7.84 (d, J = 7.6 Hz, 2 H, aryl) ppm. 13C
NMR (100 MHz, CD3OD): δ = 32.7 (C-β), 42.6 (C-1), 60.1 (C-2),
63.3 (C-10b), 66.7 (C-4), 73.1 (C-3a), 82.9 (C-5a), 109.1, 118.8,
124.6, 127.2, 127.6, 128.2, 130.3, 134.6, 141.3, 144.3, 149.2 (aryl),
155.6, 159.5, 171.9 (C=O) ppm. FAB-MS: calcd. for C38H44N4O6
652.3261; found 652.3432.
5-Fluorenylmethyl 2-Methyl (2S,3aR,4S,5aS,10bR)-4-(tert-Butoxy-
carbonylmethyl)-1,2,3,3a,4,5,5a,6-octahydropyrrolo[3Ј,2Ј:3,4]pyr-
rolo[2,3-b]indole-2,5-dicarboxylate (18a): FC: EtOAc/n-hexane
(2:3). White solid (598 mg, 50%), m.p. 257–258 °C. [α]2D0 = –41.1 (c
= 1.0, MeOH). 1H NMR (400 MHz, CD3OD): δ = 1.40 (s, 9 H,
tBu), 1.46 (dd, J = 9.6, 15.6 Hz, 1 H, 4Ј-H), 2.00 (dd, J = 4.0,
15.8 Hz, 1 H, 4ЈЈ-H), 2.35–2.41 (m, 1 H, 1-H), 2.45–2.49 (dd, J =
4.4, 13. 6 Hz, 1 H, 1-H), 3.63 (br. s, 1 H, 3a-H), 3.68 (s, 3 H,
OCH3), 4.02–4.08 (m, 2 H, 2-H, 4-H), 4.31 (t, 1 H, CH Fmoc),
4.49–4.51 (m, 2 H, CH2 Fmoc), 5.28 (s, 1 H, 5a-H), 6.48 (d, J =
7.6 Hz, 1 H, 7-H), 6.56 (d, J = 7.6 Hz, 1 H, 10-H), 6.70 (t, J =
7.2 Hz, 1 H, 8-H), 7.05–7.08 (m, 2 H, 9-H, aryl), 7.30–7.39 (m, 3
5-Fluorenylmethyl 2-Methyl (2S,3aS,4R,5aR,10bS)-4-Benzyl-
1,2,3,3a,4,5,5a,6-octahydropyrrolo[3Ј,2Ј:3,4]pyrrolo[2,3-b]indole-2,5-
H, aryl), 7.65–7.72 (m, 2 H, aryl), 7.83 (d, J = 7.6 Hz, 2 H, dicarboxylate (21): FC: EtOAc/n-hexane (2:3). White solid (457 mg,
aryl) ppm. 13C NMR (100 MHz, CD3OD): δ = 38.2 (C-4Ј), 41.5
40%), m.p. 250–251 °C. [α]2D0 = +12.6 (c = 1.0, MeOH). H NMR
1
(C-1), 59.8 (C-2), 61.5 (C-10b), 63.3 (C-4), 73.9 (C-3a), 82.1 (C-5a), (400 MHz, CD3OD): δ = 1.65 (t, J = 13.2 Hz, 1 H, 4Ј-H), 2.10–
109.3, 119.7, 122.8, 127.3, 128.8, 128.9, 129.7, 141.3, 144.1, 148.8
(aryl), 154.8, 170.6, 174.5 (C=O) ppm. FAB-MS: calcd. for
C35H37N3O6 595.2682; found 595.2735.
2.13 (m, 2 H, 1-H, 4ЈЈ-H), 2.51 (dd, J = 7.6, 13.8 Hz, 1 H, 1-H),
3.57 (s, 1 H, 3a-H), 3.68 (s, 3 H, OCH3), 3.81 (t, J = 7.4 Hz, 1 H,
2-H), 3.96 (dd, J = 4.0, 11.2 Hz, 1 H, 4-H), 4.15 (t, 1 H, CH Fmoc),
4.64–4.69 (m, 2 H, CH2 Fmoc), 5.33 (s, 1 H, 5a-H), 6.50 (d, J =
7.2 Hz, 1 H, 7-H), 6.61 (d, J = 8.0 Hz, 1 H, 10-H), 6.76–6.83 (m,
2 H, 8-H, 9-H), 7.06–7.17 (m, 5 H, aryl), 7.30–7.42 (m, 4 H, aryl),
7.63–7.64 (m, 4 H, aryl) ppm. 13C NMR (100 MHz, CDCl3): δ =
38.7 (C-4Ј), 42.8 (C-1), 63.5 (C-10b), 65.9 (C-2), 66.7 (C-4), 70.5
(C-3a), 82.9 (C-5a), 109.3, 118.7, 119.9, 123.0, 124.6, 126.1, 127.1,
127.6, 128.2, 128.8, 129.1, 138.1, 141.5, 144.2, 149.9 (aryl), 155.6,
174.5 (C=O) ppm. FAB-MS: calcd. for C36H33N3O4 571.2471;
found 571.2535.
5-Fluorenylmethyl 2-Methyl (2S,3aS,4S,5aR,10bS)-4-(tert-Butoxy-
carbonylmethyl)-1,2,3,3a,4,5,5a,6-octahydropyrrolo[3Ј,2Ј:3,4]pyr-
rolo[2,3-b]indole-2,5-dicarboxylate (18b): FC: EtOAc/n-hexane
(2:3). White solid (143 mg, 12%), m.p. 265–266 °C. [α]2D0 = +12.3
1
(c = 0.9, MeOH). H NMR (400 MHz, CD3OD): δ = 1.40 (s, 9 H,
tBu), 1.55 (dd, J = 9.4, 16.0 Hz, 1 H, 4Ј-H), 2.29–2.31 (m, 1 H, 4ЈЈ-
H), 2.39–2.45 (m, 2 H, 1-H), 3.60 (s, 3 H, OCH3), 3.74 (br. s, 1 H,
3a-H), 4.04–4.07 (m, 1 H, 4-H), 4.17 (dd, J = 4.4, 9.3 Hz, 1 H, 2-
H), 4.26 (t, 1 H, CH Fmoc), 4.67–4.69 (m, 2 H, CH2 Fmoc), 5.01
(s, 1 H, 5a-H), 6.47 (d, J = 7.5 Hz, 1 H, 7-H), 6.57 (d, J = 7.5 Hz, Synthesis of the Tetrahydro-β-carboline-3-carboxylic Acid Deriva-
1 H, 10-H), 6.72 (t, J = 7.0 Hz, 1 H, 8-H), 7.06–7.08 (m, 2 H, 9- tives 22–27a,b: (Boc2)O (1 mmol) and KOH (pH = 8) were added
H, aryl), 7.35–7.41 (m, 3 H, aryl), 7.61–7.78 (m, 2 H, aryl), 7.82
(d, J = 7.6 Hz, 2 H, aryl) ppm. 13C NMR (100 MHz, CD3OD): δ
= 38.3 (C-4Ј), 41.7 (C-1), 59.5 (C-2), 61.7 (C-10b), 63.5 (C-4), 73.1
to a solution of the tetrahydro-β-carbolines, the cis (8–10a, 12a,
13a and 20a) or trans (8–10b, 12b, 13b and 20b) isomer, (0.2 mmol)
in H2O/dioxane (20:20 mL) and the mixture was stirred at room
(C-3a), 82.9 (C-5a), 109.0, 119.9, 122.8, 127.0, 127.8, 130.1, 141.4, temperature for 16 h. Then the reaction mixture was concentrated
144.32, 149.3 (aryl), 155.3, 170.4, 174.5 (C=O) ppm. FAB-MS:
calcd. for C35H37N3O6 595.2682; found 595.2723.
and purified by flash chromatography using EtOAc/n-hexane (1:2)
as eluent. LiOH 1  (2 equiv.) was then added to a solution of the
corresponding 2-N-Boc-protected derivatives (0.3 mmol) in MeOH
(20 mL) and the mixture was stirred at room temperature for 2 h.
Afterwards, the reaction mixture was neutralized sequentially with
1  HCl, concentrated and diluted with EtOAc. The organic
phase was successively washed with H2O (2ϫ25 mL) and brine
(2ϫ25 mL), dried with Na2SO4 and the solvents evaporated to dry-
ness. The resulting orthogonally protected tetrahydro-β-carboline-
carboxylic acids 22–27a,b were collected as solids.
5-Fluorenylmethyl 2-Methyl (2S,3aR,4S,5aS,10bR)-4-[4Ј-(tert-
Butoxycarbonylamino)butyl]-1,2,3,3a,4,5,5a,6-octahydropyrrolo-
[3Ј,2Ј:3,4]pyrrolo[2,3-b]indole-2,5-dicarboxylate (19a): FC: EtOAc/
n-hexane (2:3). White solid (627 mg, 48%), m.p. 272–274 °C. [α]2D0
= –23.9 (c = 1.1, MeOH). 1H NMR (400 MHz, CD3OD): δ = 0.78–
0.82 (m, 2 H, γ-H), 1.07–1.10 (m, 2 H, δ-H), 1.20–1.24 (m, 2 H, β-
H), 1.40 (s, 9 H, tBu), 2.37–2.41 (m, 2 H, 1-H), 2.80–2.82 (m, 2 H,
ε-H), 3.49 (br. s, 1 H, 3a-H), 3.68 (s, 3 H, OCH3), 3.85 (dd, J =
4.8, 8.8 Hz, 1 H, 4-H), 3.99–4.03 (m, 1 H, 2-H), 4.23 (t, 1 H, CH (1S,3S)-2-(tert-Butoxycarbonyl)-1-[(fluorenylmethoxycarbonyl)-
Fmoc), 4.62–4.64 (m, 2 H, CH2 Fmoc), 5.23 (s, 1 H, 5a-H), 6.46 aminomethyl]-1,2,3,4-tetrahydro-β-carboline-3-carboxylic Acid
(d, J = 7.6 Hz, 1 H, 7-H), 6.56 (d, J = 7.6 Hz, 1 H, 10-H), 6.70 (t,
(22a): White solid (74 mg, 65 %), m.p. 239–240 °C. 1H NMR
J = 7.2 Hz, 1 H, 8-H), 6.99–7.07 (m, 2 H, 9-H, aryl), 7.31–7.39 (m, (400 MHz, CD3OD): δ = 1.31 (s, 9 H, Boc), 2.49 (dd, J = 3.4,
3 H, aryl), 7.64–7.68 (m, 2 H, aryl), 7.84 (d, J = 7.6 Hz, 2 H, 15.6 Hz, 1 H, 4Ј-H), 2.77–2.81 (m, 1 H, 4ЈЈ-H), 2.89 (dd, J = 1.6,
aryl) ppm. 13C NMR (100 MHz, CD3OD): δ = 33.1 (C-β), 42.4 (C-
15.6 Hz, 1 H, 1Ј-H), 3.32 (dd, J = 5.2, 15.6 Hz, 1 H, 1ЈЈ-H), 3.82
1), 60.2 (C-2), 62.7 (C-10b), 66.4 (C-4), 73.5 (C-3a), 82.4 (C-5a), (dd, J = 3.2, 11.2 Hz, 1 H, 3-H), 4.18–4.22 (m, 1 H, 1-H) ppm.
108.8, 119.9, 124.9, 127.2, 128.7, 128.6, 130.6, 134.8, 141.6, 144.1,
148.8 (aryl), 155.1, 159.3, 171.3 (C=O) ppm. FAB-MS: calcd. for
C38H44N4O6 652.3261; found 652.3316.
FAB-MS: calcd. for C33H33N3O6 567.2369; found 567.2486.
(1R,3S)-2-(tert-Butoxycarbonyl)-1-[(fluorenylmethoxycarbonyl)-
aminomethyl]-1,2,3,4-tetrahydro-β-carboline-3-carboxylic Acid
(22b): White solid (78 mg, 69 %), m.p. 251–253 °C. 1H NMR
(400 MHz, CD3OD): δ = 1.28 (s, 9 H, Boc), 2.59–2.65 (m, 1 H, 4Ј-
5-Fluorenylmethyl 2-Methyl (2S,3aS,4S,5aR,10bS)-4-[4Ј-(tert-
Butoxycarbonylamino)butyl]-1,2,3,3a,4,5,5a,6-octahydropyrrolo-
Eur. J. Org. Chem. 2008, 1983–1992
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1989

P. Grieco et al.
FULL PAPER
H), 2.73 (dd, J = 4.0, 15.1 Hz, 1 H, 4ЈЈ-H), 2.83 (dd, J = 4.0,
14.6 Hz, 1 H, 1Ј-H), 3.49 (dd, J = 4.2, 8.8 Hz, 1 H, 1ЈЈ-H), 4.01
(dd, J = 4.0, 11.6 Hz, 1 H, 3-H), 4.22–4.25 (m, 1 H, 1-H) ppm.
FAB-MS: calcd. for C33H33N3O6 567.2369; found 567.2425.
(1R,3S,1ЈS)-2-(tert-Butoxycarbonyl)-1-[5Ј-(tert-butyoxycarbonyl)-
amino-1Ј-(fluorenylmethoxycarbonyl)aminopentyl]-1,2,3,4-tetra-
hydro-β-carboline-3-carboxylic Acid (26b): White solid (91 mg,
1
62%), m.p. 287–289 °C. H NMR (400 MHz, CD3OD): δ = 1.32–
1.38 (m, 2 H, δ-H), 1.43–1.64 (m, 4 H, β-H, γ-H), 2.53–2.60 (m, 2
H, ε-H), 3.14–3.25 (m, 2 H, 4Ј-H), 4.16–4.18 (m, 1 H, 3-H), 4.31–
4.36 (m, 1 H, 1Ј-H), 4.52 (br. s, 1 H, 1-H) ppm. FAB-MS: calcd.
for C42H50N4O8 738.3629; found 738.3694.
(1S,3S,1ЈS)-2-(tert-Butoxycarbonyl)-1-[1Ј-(fluorenylmethoxycar-
bonyl)aminoethyl]-1,2,3,4-tetrahydro-β-carboline-3-carboxylic Acid
(23a): White solid (78 mg, 67 %), m.p. 268–269 °C. 1H NMR
(400 MHz, CD3OD): δ = 1.18 (d, J = 6.2 Hz, 3 H, 2Ј-H), 1.28 (s,
9 H, Boc), 2.75–2.80 (m, 1 H, 4Ј-H), 3.07 (dd, J = 3.6, 15.2 Hz, 1
H, 4ЈЈ-H), 3.85 (dd, J = 3.5, 11.2 Hz, 1 H, 3-H), 4.30–4.33 (m, 2 H,
1-H, 1Ј-H) ppm. FAB-MS: calcd. for C34H35N3O6 581.2526; found
581.2572.
(1S,3S,1ЈR)-2-(tert-Butoxycarbonyl)-1-[1Ј-(fluorenylmethoxycar-
bonyl)amino-2Ј-phenylethyl]-1,2,3,4-tetrahydro-β-carboline-3-car-
boxylic Acid (27a): White solid (87 mg, 65%), m.p. 271–273 °C. 1H
NMR (400 MHz, CD3OD): δ = 2.77–2.89 (m, 3 H, 4Ј-H, 2Ј-H),
3.13 (dd, J = 3.8, 14.0 Hz, 1 H, 4ЈЈ-H), 4.00–4.03 (m, 1 H, 3-H),
4.24 (br. s, 1 H, 1-H), 4.42–4.48 (m, 1 H, 1Ј-H) ppm. FAB-MS:
calcd. for C40H39N3O6 657.2839; found 657.2924.
(1R,3S,1ЈS)-2-(tert-Butoxycarbonyl)-1-[1Ј-(fluorenylmethoxycar-
bonyl)aminoethyl]-1,2,3,4-tetrahydro-β-carboline-3-carboxylic Acid
(23b): White solid (70 mg, 60 %), m.p. 280–281 °C. 1H NMR
(400 MHz, CD3OD): δ = 1.29 (d, J = 6.6 Hz, 3 H, 2Ј-H), 2.73 (t,
J = 12.8 Hz, 1 H, 4Ј-H), 3.05 (dd, J = 3.6, 15.2 Hz, 1 H, 4ЈЈ-H),
4.06–4.08 (m, 1 H, 3-H), 4.22–26 (m, 1 H, 1Ј-H), 4.28 (d, J =
1.2 Hz, 1 H, 1-H) ppm. FAB-MS: calcd. for C34H35N3O6 581.2526;
found 581.2570.
(1R,3S,1ЈR)-2-(tert-Butoxycarbonyl)-1-[1Ј-(fluorenylmethoxycar-
bonyl)amino-2Ј-phenylethyl]-1,2,3,4-tetrahydro-β-carboline-3-car-
boxylic Acid (27b): White solid (90 mg, 68%), m.p. 272–274 °C. 1H
NMR (400 MHz, CD3OD): δ = 2.79–2.83 (m, 2 H, 2Ј-H), 3.17–
3.23 (m, 2 H, 4-H), 4.13–4.16 (m, 1 H, 3-H), 4.29–4.32 (m, 1 H,
1Ј-H), 4.49 (br. s, 1 H, 1-H) ppm. FAB-MS: calcd. for C40H39N3O6
657.2839; found 657.2924.
(1S,3S,1ЈS)-2-(tert-Butoxycarbonyl)-1-[1Ј-(fluorenylmethoxycar-
bonyl)amino-2Ј-phenylethyl]-1,2,3,4-tetrahydro-β-carboline-3-car-
boxylic Acid (24a): White solid (213 mg, 65%), m.p. 278–279 °C.
1H NMR (400 MHz, CD3OD): δ = 1.30 (s, 9 H, Boc), 2.53 (dd, J
= 3.6, 14.8 Hz, 1 H, 4Ј-H), 2.75–2.81 (m, 2 H, 4ЈЈ-H, 2Ј-H), 2.97
(dd, J = 3.2, 15.6 Hz, 1 H, 2ЈЈ-H), 3.93 (dd, J = 3.6, 13.6 Hz, 1 H,
3-H), 4.12 (d, J = 1.2 Hz, 1 H, 1-H), 4.40–4.43 (m, 1 H, 1Ј-H) ppm.
FAB-MS: calcd. for C40H39N3O6 657.2839; found 657.2926.
Synthesis of Hexahydroazocino[4,5-b]indole Derivatives 28–33 and
Tetrahydro-β-carboline Derivatives 34–39: Diisopropylethylamine
(3 mL) was added to a solution of corresponding cis-tetrahydro-
β-carboline derivatives 8–10a, 12a, 13a or 20a (0.5 mmol) in dry
tetrahydrofuran (7 mL) and the mixture was stirred at room tem-
perature for 2 h. Then the solution was evaporated under reduced
pressure and the corresponding hexahydroazocino[4,5-b]indole de-
rivatives 28–33 were precipitated by treatment of the crude residue
with EtOAc/n-hexane. Under these conditions the trans isomers 8–
10b, 12b, 13b or 20b gave the corresponding Fmoc-deprotected
tetrahydro-β-carbolines 34–39 which were purified by flash
chromatography using CHCl3/CH3OH (9:1) as eluent.
(1R,3S,1ЈS)-2-(tert-Butoxycarbonyl)-1-[1Ј-(fluorenylmethoxycarbon-
ylamino)-2Ј-phenylethyl]-1,2,3,4-tetrahydro-β-carboline-3-carboxylic
1
Acid (24b): White solid (85 mg, 67%), m.p. 281–282 °C. H NMR
(400 MHz, CD3OD): δ = 1.27 (s, 9 H, Boc), 2.49–2.60 (m, 3 H, 4Ј-
H, 4ЈЈ-H, 2Ј-H), 2.79 (dd, J = 3.8, 15.6 Hz, 1 H, 2ЈЈ-H), 4.12–4.15
(m, 2 H, 3-H, 1-H), 4.31 (dd, J = 3.8, 14.2 Hz, 1 H, 1Ј-H) ppm.
FAB-MS: calcd. for C40H39N3O6 657.2839; found 657.2921.
(6S,10S)-6,10-Imino-6,7,8,9,10,11-hexahydro-5H-azocino[4,5-
b]indol-9-one (28): White solid (96 mg, 85%), m.p. 146–147 °C.
[α]2D0 = +7.3 (c = 0.8, MeOH). H NMR (400 MHz, CD3OD): δ =
1
(1S,3S,1ЈS)-2-(tert-Butoxycarbonyl)-1-[2Ј-(tert-butoxycarbonyl)-1Ј-
(fluorenylmethoxycarbonylamino)ethyl]-1,2,3,4-tetrahydro-β-carbo-
line-3-carboxylic Acid (25a): White solid (80 mg, 60%), m.p. 285–
287 °C. 1H NMR (400 MHz, CD3OD): δ = 1.36 (s, 9 H, CH3),
2.15–2.19 (m, 1 H, 2Ј-H), 2.39–2.43 (m, 1 H, 2ЈЈ-H), 2.75–2.80 (m,
1 H, 4Ј-H), 3.13 (dd, J = 3.5, 14.0 Hz, 1 H, 4ЈЈ-H), 3.90 (dd, J =
3.5, 11.4 Hz, 1 H, 3-H), 4.12 (br. s, 1 H, 1-H), 4.40–4.42 (m, 1
H, 1Ј-H) ppm. FAB-MS: calcd. for C39H43N3O8 681.3050; found
681.3132.
3.07–3.11 (m, 1 H, 11Ј-H), 3.40 (dd, J = 6.0, 15.6 Hz, 1 H, 11ЈЈ-
H), 3.62 (d, J = 13.6 Hz, 1 H, 7Ј-H), 4.02 (dd, J = 4.0, 13.6 Hz, 1
H, 7ЈЈ-H), 4.51 (d, J = 5.2 Hz, 1 H, 10-H), 5.19 (d, J = 3.6 Hz, 1
H, 6-H), 7.08 (t, J = 7.6 Hz, 1 H, 3-H), 7.19 (t, J = 7.6 Hz, 1 H,
2-H), 7.38 (d, J = 7.6 Hz, 1 H, 1-H), 7.48 (d, J = 7.6 Hz, 1 H, 4-
H) ppm. 13C NMR (100 MHz, CD3OD): δ = 23.8 (C-11), 45.6 (C-
7), 46.0 (C-6), 53.7 (C-10), 106.1 (C-11a), 111.8 (C-1), 117.9 (C-4),
119.9 (C-3), 123.7 (C-2), 125.9 (C-11b), 126.1 (C-5a), 137.0 (C-
4a), 167.7 (C=O) ppm. FAB-MS: calcd. for C13H13N3O 227.1059;
found 227.1121.
(1R,3S,1ЈS)-2-(tert-Butoxycarbonyl)-1-[2Ј-(tert-butoxycarbonyl)-1Ј-
(fluorenylmethoxycarbonyl)aminoethyl]-1,2,3,4-tetrahydro-β-carbo-
line-3-carboxylic Acid (25b): White solid (88 mg, 65%), m.p. 279–
(6S,7S,10S)-6,10-Imino-7-methyl-6,7,8,9,10,11-hexahydro-5H-azo-
cino[4,5-b]indol-9-one (29): White solid (102 mg, 87%), m.p. 163–
165 °C. [α]2D0 = +19.3 (c = 1.1, MeOH). 1H NMR (400 MHz,
CD3OD): δ = 1.33 (d, J = 6.4 Hz, 3 H, CH3), 2.94 (dd, J = 1.2,
16 Hz, 1 H, 11Ј-H), 3.12 (dd, J = 10.0, 16.4 Hz, 1 H, 11ЈЈ-H), 3.64
(dd, J = 1.0, 6.4 Hz, 1 H, 7-H), 3.86–3.90 (m, 1 H, 10-H), 4.04 (d,
J = 1.0 Hz, 1 H, 6-H), 6.98 (t, J = 7.6 Hz, 1 H, 3-H), 7.07 (t, J =
7.6 Hz, 1 H, 2-H), 7.28 (d, J = 7.6 Hz, 1 H, 1-H), 7.39 (d, J =
7.6 Hz, 1 H, 4-H) ppm. 13C NMR (100 MHz, CD3OD): δ = 16.9
(CH3), 22.5 (C-11), 45.0 (C-6), 48.2 (C-10), 49.8 (C-7), 106.8 (C-
11a), 112.4 (C-1), 118.0 (C-4), 119.6 (C-3), 124.1 (C-2), 125.4 (C-
11b), 126.1 (C-5a), 136.9 (C-4a), 166.9 (C=O) ppm. FAB-MS:
calcd. for C14H15N3O 241.1215; found 241.1263.
1
280 °C. H NMR (400 MHz, CD3OD): δ = 2.56–2.62 (m, 2 H, 2Ј-
H), 3.06–3.11 (m, 2 H, 4-H), 4.02–4.11 (m, 1 H, 3-H), 4.31 (br.
s, 1 H, 1-H), 4.39–4.42 (m, 1 H, 1Ј-H) ppm. FAB-MS: calcd. for
C39H43N3O8 681.3050; found 681.3132.
(1S,3S,1ЈS)-2-(tert-Butoxycarbonyl)-1-[5Ј-(tert-butyoxycarbonyl)-
amino-1Ј-(fluorenylmethoxycarbonyl)aminopentyl]-1,2,3,4-tetra-
hydro-β-carboline-3-carboxylic Acid (26a): White solid (95 mg,
1
63%), m.p. 290–292 °C. H NMR (400 MHz, CD3OD): δ = 1.20–
1.24 (m, 2 H, γ-H), 1.29–1.38 (m, 4 H, β-H, δ-H), 2.15–2.17 (m, 2
H, ε-H), 2.82 (d, J = 5.6, 14.1 Hz, 1 H, 4Ј-H), 3.62–3.65 (m, 1 H,
4ЈЈ-H), 3.91–3.93 (m, 1 H, 3-H), 4.32 (br. s, 1 H, 1-H), 4.43–4.45
(m, 1 H, 1Ј-H) ppm. FAB-MS: calcd. for C42H50N4O8 738.3629;
found 738.3734.
(6S,7S,10S)-7-Benzyl-6,10-imino-6,7,8,9,10,11-hexahydro-5H-azo-
cino[4,5-b]indol-9-one (30): White solid (126 mg, 80%), m.p. 181–
1990
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1983–1992

Synthesis of Novel Indole-Based Ring Systems
183 °C. [α]2D0 = –23.5 (c = 1.1, MeOH). 1H NMR (400 MHz,
CD3OD): δ = 3.28–3.34 (m, 3 H, 11Ј-H, 7Ј-H, 7ЈЈ-H), 3.44 (dd, J
= 5.6, 16.4 Hz, 1 H, 11ЈЈ-H), 3.99 (t, J = 7.2 Hz, 1 H, 7-H), 4.47
(d, J = 5.6 Hz, 1 H, 10-H), 4.88 (d, J = 1.2 Hz, 1 H, 6-H), 7.05 (t,
J = 7.2 Hz, 1 H, 3-H), 7.14 (t, J = 7.2 Hz, 1 H, 2-H), 7.31–7.47
(m, 7 H, 1-H, 4-H, aryl) ppm. 13C NMR (100 MHz, CD3OD): δ =
Methyl (1R,3S,1ЈS)-1-(1Ј-Aminoethyl)-1,2,3,4-tetrahydro-β-carbo-
line-3-carboxylate (35): White solid (130 mg, 95 %), m.p. 115–
116 °C. H NMR (400 MHz, CD3OD): δ = 1.19 (d, J = 6.6 Hz, 3
H, 2Ј-H), 2.55 (t, J = 12.8 Hz, 1 H, 4Ј-H), 2.98 (dd, J = 3.6,
15.2 Hz, 1 H, 4ЈЈ-H), 3.42–3.45 (m, 1 H, 1Ј-H), 3.59 (s, 3 H, OCH3),
4.02–4.05 (m, 1 H, 3-H), 4.18 (d, J = 1.2 Hz, 1 H, 1-H), 6.93 (t, J
1
24.3 (C-11), 40.5 (C-7Ј), 47.3 (C-6), 52.1 (C-10), 58.2 (C-7), 105.8 = 7.6 Hz, 1 H, 6-H), 7.11 (t, J = 7.6 Hz, 1 H, 7-H), 7.31 (d, J =
(C-11a), 111.5 (C-1), 118.0 (C-4), 119.7 (C-3), 123.0 (C-2), 125.8 8.0 Hz, 1 H, 8-H), 7.38 (d, J = 8.0 Hz, 1 H, 5-H) ppm. FAB-MS:
(C-11b), 127.3 (C-5a), 129.0, 129.4, 136.4 (aryl), 137.0 (C-4a), 168.0 calcd. for C15H19N3O2 273.1477; found 273.1512.
(C=O) ppm. FAB-MS: calcd. for C20H19N3O 317.1528; found
Methyl (1R,3S,1ЈS)-1-(1Ј-Amino-2Ј-phenylethyl)-1,2,3,4-tetrahydro-
317.1608.
β-carboline-3-carboxylate (36): White solid (158 mg, 91%), m.p.
1
142–143 °C. H NMR (400 MHz, CD3OD): δ = 2.65 (dd, J = 3.6,
(6S,7S,10S)-7-(tert-Butoxycarbonylmethyl)-6,10-imino-
6,7,8,9,10,11-hexahydro-5H-azocino[4,5-b]indol-9-one (31): White
solid (151 mg, 89%), m.p. 187–189 °C. [α]2D0 = –9.2 (c = 0.7,
MeOH). 1H NMR (400 MHz, CD3OD): δ = 1.48 (s, 9 H, tBu),
2.18 (dd, J = 9.2, 16.0 Hz, 1 H, 7Ј-H), 2.73 (dd, J = 4.8, 16.1 Hz,
1 H, 7ЈЈ-H), 2.97 (d, J = 14.8 Hz, 1 H, 11Ј-H), 3.15 (dd, J = 6.8,
14.6 Hz, 1 H, 11ЈЈ-H), 3.93 (d, J = 6.8 Hz, 1 H, 10-H), 4.25 (d, J
= 4.6 Hz, 1 H, 6-H), 4.31 (dd, J = 4.4, 9.2 Hz, 1 H, 7-H), 7.00 (t,
J = 8.0 Hz, 1 H, 3-H), 7.10 (t, J = 6.8 Hz, 1 H, 2-H), 7.33 (d, J =
8.0 Hz, 1 H, 4-H), 7.41 (d, J = 7.0 Hz, 1 H, 1-H) ppm. 13C NMR
(100 MHz, CD3OD): δ = 27.2 (C-11), 39.7 (CЈ), 48.7 (C-7), 53.7
(C-6), 55.6 (C-10), 109.4 (C-11a), 111.3 (C-1), 118.5 (C-4), 119.8
(C-3), 122.5 (C-2), 127.0 (C-11b), 129.7 (C-5a), 135.9 (C-4a), 170.8,
172.7 (C=O) ppm. FAB-MS: calcd. for C19H23N3O3 341.1739;
found 341.1829
14.6 Hz, 1 H, 2Ј-H), 2.81–2.88 (m, 2 H, 2ЈЈ-H, 4Ј-H), 3.09 (dd, J =
4.2, 13.6 Hz, 1 H, 4ЈЈ-H), 3.62 (s, 3 H, OCH3), 3.82–3.85 (m, 1 H,
1Ј-H), 4.09 (dd, J = 4.2, 12.8 Hz, 1 H, 3-H), 4.21 (d, J = 1.4 Hz, 1
H, 1-H), 7.04 (t, J = 8.0 Hz, 1 H, 6-H), 7.18–7.23 (m, 2 H, 7-H,
8-H), 7.39 (d, J = 7.8 Hz, 1 H, 5-H) ppm. FAB-MS: calcd. for
C21H23N3O2 349.1790; found 349.1837.
Methyl (1R,1ЈS,3S)-1-[1Ј-Amino-2Ј-(tert-butoxycarbonyl)ethyl]-
1,2,3,4-tetrahydro-β-carboline-3-carboxylate (37): Colourless oil
1
(178 mg, 96%). H NMR (400 MHz, CD3OD): δ = 2.20 (dd, J =
3.6, 14.4 Hz, 1 H, 2Ј-H), 2.54–2.57 (m, 2 H, 2ЈЈ-H, 4Ј-H), 3.15 (dd,
J = 4.0, 15.6 Hz, 1 H, 4ЈЈ-H), 3.72 (s, 3 H, OCH3), 3.91–3.93 (m,
1 H, 1Ј-H), 4.06 (dd, J = 4.2, 12.8 Hz, 1 H, 3-H), 4.24 (d, J =
1.4 Hz, 1 H, 1-H), 7.04 (t, J = 8.0 Hz, 1 H, 6-H), 7.15 (t, J =
8.0 Hz, 1 H, 7-H), 7.39 (d, J = 8.0 Hz, 1 H, 8-H), 7.39 (d, J =
7.8 Hz, 1 H, 5-H) ppm. FAB-MS: calcd. for C20H27N3O4 373.2002;
found 373.2051.
(6S,7S,10S)-7-[4Ј-(tert-Butoxycarbonylamino)butyl]-6,10-imino-
6,7,8,9,10,11-hexahydro-5H-azocino[4,5-b]indol-9-one (32): White
solid (179 mg, 90%), m.p. 221–223 °C. [α]2D0 = +15.3 (c = 1.1,
Methyl (1R,3S,1ЈS)-1-[5Ј-(tert-Butoxycarbonylamino)-1Ј-aminopen-
tyl]-1,2,3,4-tetrahydro-β-carboline-3-carboxylate (38): White solid
1
MeOH). H NMR (400 MHz, CD3OD): δ = 1.27–1.31 (m, 4 H, δ-
1
(203 mg, 95%), m.p. 162–164 °C. H NMR (400 MHz, CDCl3): δ
H, γ-H), 1.41 (s, 9 H, tBu), 1.52–1.57 (m, 2 H, β-H), 2.98–3.08 (m,
5 H, ε-H, 7Ј-H, 7ЈЈ-H, 11Ј-H), 3.15 (dd, J = 6.4, 16.0 Hz, 1 H, 11ЈЈ-
H), 3.93 (m, 1 H, 7-H), 3.98 (d, J = 5.2 Hz, 1 H, 10-H), 4.34 (d, J
= 4.0 Hz, 1 H, 6-H), 6.99 (t, J = 6.8 Hz, 1 H, 3-H), 7.09 (t, J =
7.6 Hz, 1 H, 2-H), 7.35 (d, J = 8.0 Hz, 1 H, 4-H), 7.40 (d, J =
7.6 Hz, 1 H, 1-H) ppm. 13C NMR (100 MHz, CD3OD): δ = 22.7
(C-γ), 26.8 (C-11), 29.8 (C-δ), 31.8 (C-β), 39.7 (C-ε), 49.0 (C-7),
52.7 (C-6), 58.0 (C-10), 107.5 (C-11a), 111.1 (C-1), 117.5 (C-4),
118.9 (C-3), 121.7 (C-2), 126.7 (C-11b), 129.3 (C-5a), 136.8 (C-4a),
166.3, 173.7 (C=O) ppm. FAB-MS: calcd. for C22H30N4O3
398.2318; found 398.2413.
= 1.23–1.33 (m, 2 H, γ-H, δ-H), 1.41 (s, 9 H, CH3), 1.62–1.67 (m,
2 H, β-H), 2.53–2.57 (m, 2 H, ε-H), 3.10–3.14 (m, 2 H, 4Ј-H), 3.46–
3.49 (m, 1 H, 1Ј-H), 3.62 (s, 3 H, OCH3), 3.71–3.73 (m, 1 H, 3-H),
4.00 (br. s, 1 H, 1-H), 7.00 (t, J = 7.6 Hz, 1 H, 6-H), 7.10 (t, J =
8.0 Hz, 1 H, 7-H), 7.36–7.40 (m, 2 H, 8-H, 5-H) ppm. FAB-MS:
calcd. for C23H34N4O4 430.2580; found 430.2623.
Methyl (1R,1ЈR,3S)-1-(1Ј-Amino-2Ј-phenylethyl)-1,2,3,4-tetrahydro-
β-carboline-3-carboxylate (39): White solid (166 mg, 95%), m.p.
1
142–143 °C. H NMR (400 MHz, CD3OD): δ = 2.63 (dd, J = 8.8,
14.6 Hz, 1 H, 2-H), 2.91 (dd, J = 4.2, 13.6 Hz, 1 H, 4ЈЈ-H), 3.07–
3.10 (m, 2 H, 2ЈЈ-H, 4ЈЈ-H), 3.53 (s, 3 H, OCH3), 3.92–3.95 (m, 1
H, 1-H, 3-H), 4.39 (br. s, 1 H, 1-H), 6.99 (t, J = 8.0 Hz, 1 H, 6-H),
7.13–7.18 (m, 2 H, 7-H, 8-H), 7.37 (d, J = 8.0 Hz, 1 H, 5-H) ppm.
FAB-MS: calcd. for C21H23N3O2 349.1790; found 349.1837.
(6S,7R,10S)-7-Benzyl-6,10-imino-6,7,8,9,10,11-hexahydro-5H-azo-
cino[4,5-b]indol-9-one (33): White solid (138 mg, 87%), m.p. 195–
196 °C. [α]2D0 = +18.9 (c = 1.3, MeOH). 1H NMR (400 MHz,
CD3OD): δ = 2.46 (dd, J = 10.0, 14.0 Hz, 1 H, 7Ј-H), 3.30–3.36
(m, 2 H, 11Ј-H, 7ЈЈ-H), 3.42 (dd, J = 6.0, 15.9 Hz, 1 H, 11ЈЈ-H),
4.48–4.53 (m, 2 H, 7-H, 10-H), 5.20 (d, J = 3.2 Hz, 1 H, 6-H), 7.11
(t, J = 7.6 Hz, 1 H, 3-H), 7.23 (t, J = 8.0 Hz, 1 H, 2-H), 7.30–7.37
(m, 5 H, aryl), 7.40 (d, J = 8.0 Hz, 1 H, 4-H), 7.53 (d, J = 8.0 Hz,
1 H, 1-H) ppm. 13C NMR (100 MHz, CD3OD): δ = 24.3 (C-11),
37.3 (C-7Ј), 49.8 (C-6), 52.0 (C-10), 56.2 (C-7), 107.1 (C-11a), 112.0
(C-1), 118.0 (C-4), 120.0 (C-3), 124.2 (C-2), 125.9 (C-11b), 127.3
(C-5a), 129.0, 129.5, 136.0 (aryl), 137.5 (C-4a), 168.2 (C=O) ppm.
FAB-MS: calcd. for C20H19N3O 317.1528; found 317.1608.
Supporting Information (see also the footnote on the first page of
this article): As example, the experimental 1D and 2D NMR spec-
troscopic data for compounds 17a, 17b and 21 are reported.
Acknowledgments
The LC-MS and NMR spectroscopic data were provided by the
Centro di Ricerca Interdipartimentale di Analisi Strumentale, Uni-
versità degli Studi di Napoli “Federico II”; the assistance of the
staff is gratefully appreciated. This work was supported by a grant
from the Ministero dell’Università e della Ricerca Scientifica e Tec-
nologica (MURST) (PRIN 2005) and from the Centro Autonomo
di Ricerca Scientifica (CARS).
Methyl (1R,3S)-1-Aminomethyl-1,2,3,4-tetrahydro-β-carboline-3-
1
carboxylate (34): White solid (120 mg, 93%), m.p. 101–102 °C. H
NMR (400 MHz, CD3OD): δ = 2.64 (dd, J = 8.0, 14.8 Hz, 1 H,
4Ј-H), 3.10 (dd, J = 4.4, 14.8 Hz, 1 H, 4ЈЈ-H), 3.21–3.30 (m, 2 H,
1Ј-H), 3.65–3.69 (m, 1 H, 3-H), 3.77 (s, 3 H, OCH3), 4.02 (br. s, 1
H, 1-H), 7.15–7.19 (m, 2 H, 6-H, 8-H), 7.28 (d, J = 7.6 Hz, 1 H, 7-
H), 7.46–7.49 (m, 1 H, 5-H) ppm. FAB-MS: calcd. for C14H17N3O2
259.1321; found 259.1475.
[1] E. M Gordon, Combinatorial Chemistry and Molecular Diver-
sity in Drug Discovery (Eds.: E. M. Gordon, J. F. Kerwin Jr),
Wiley-Liss, New York, 1998.
Eur. J. Org. Chem. 2008, 1983–1992
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1991

P. Grieco et al.
FULL PAPER
[2] M. R. Pavia, T. K. Sawyer, W. H. Moose, Bioorg. Med. Chem.
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structure of 17a was solved by direct methods using SIR-97
(A. Altomare, M. C. Burla, M. Camalli, G. Cascarano, C. Gia-
covazzo, A. Guagliardi, A. G. G. Moliterni, G. Polidori, R.
Spagna, SIR-97, University of Bari, Italy, 1997) and expanded
using difference Fourier techniques, refined using SHELX-97
(G. M. Sheldrick, SHELX-97, Program for Crystal Structure
Refinement, University of Göttingen, Göttingen, Germany,
1997). CCDC-623949 (for 17a) contains the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
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[16] Lee and Park recently reported the formation of this type of
tetracyclic indole system via sequential cyclic iminium forma-
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Received: December 11, 2007
[9] Derivatives 10–13 exist as mixtures of two rotamers about the
urethane linkage.
[10] Crystallographic data for 17a: C26H31N3O4·CH2Cl2, M =
533.47, orthorhombic, space group P212121, a = 11.23(2), b =
14.720(10), c = 17.260(10) Å, V = 2853(6) Å3, Z = 4, d =
1.244 g/cm3, crystal dimensions 0.30ϫ0.30ϫ0.25 mm were
used for measurements on a Nonius-Mach3 instrument with a
graphite monochromator (ω–2θ scans, θmax = 25.0°), Mo-Kα
radiation. The total number of reflections measured was 2829,
of which 2829 were unique and 1621 observed, IϾ2σ(I). Final
indices: Rf = 0.0699, Rw = 0.1644 for observed reflections, and
R1 = 0.1407, wR2 = 0.2111 for all reflections (2829). The crystal
Published Online: February 27, 2008
1992
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1983–1992