Chemoselective asymmetric synthesis of C-3a-(3-hydroxypropyl)tetrahydropyrrolo[2,3-b]indole and C-4a-(2-aminoethyl)-tetrahydropyrano[2,3-b]indole derivatives

Article abstract of DOI:10.1016/j.tet.2009.01.004

The asymmetric synthesis of new tetrahydropyrrolo[2,3-b]indole 19 and tetrahydropyrano[2,3-b]indole 20 rings, substituted in position C-3a and C-4a with a hydroxy- and an amino functionalized chain, respectively, was performed starting from the racemic sp

Full text of DOI:10.1016/j.tet.2009.01.004

Tetrahedron 65 (2009) 1995–2004
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Chemoselective asymmetric synthesis of C-3a-(3-hydroxypropyl)-
tetrahydropyrrolo[2,3-b]indole and C-4a-(2-aminoethyl)-
tetrahydropyrano[2,3-b]indole derivatives
Sara Pellegrino a, Francesca Clerici a, Alessandro Contini a, Samantha Leone a,
,
Tullio Pilati b, Maria Luisa Gelmi a
*
a
`
`
Istituto di Chimica Organica, Facolta di Farmacia, Universita di Milano, Via Venezian 21, I-20133 Milano, Italy
CNR Centro Studio delle Relazioni tra Struttura e Reattivita Chimica, via Golgi 19, Milano, Italy
b
`
a r t i c l e i n f o
a b s t r a c t
Article history:
The asymmetric synthesis of new tetrahydropyrrolo[2,3-b]indole 19 and tetrahydropyrano[2,3-b]indole
20 rings, substituted in position C-3a and C-4a with a hydroxy- and an amino functionalized chain, re-
spectively, was performed starting from the racemic spiro[cyclohexane-1,30-indoline]-20,4-diones 7. The
enantiopure spiro oxo-azepinoindolinone (þ)-10, obtained from (ꢀ)-7 by the way of an asymmetric ring
enlargement, and the amino acid (þ)-14, obtained by the hydrolysis of 10, were prepared as key in-
termediates for the synthesis of enantiopure compounds (ꢁ)-19 and (ꢁ)-20. Since the amino acid 14 is
the common intermediate for the chemoselective preparation of derivatives 19 and 20, experimental and
computational studies were performed in order to selectively obtain these compounds and to provide
a mechanistic rationalization for their formation.
Received 21 October 2008
Received in revised form 3 December 2008
Accepted 5 January 2009
Available online 8 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
R
Me
Pyrroloindolines are a subclass of alkaloid structural motifs
that commonly exhibit biological activity. The hexahydropyr-
rolo[2,3-b]indole skeleton is characteristic of alkaloids isolated
from Calabar bean (Physostigma venenosum)1 as well as from other
alkaloids such as those extracted from the skin of Australian
myobatrachid frogs of the genus Pseudophryne2 and from marine
invertebrates of the phylum Bryozoa such as Flustra foliaceae.3
Both pseudophrynamine 1 and flustramine 2 alkaloids have
a methyl group at N-1, a prenyl or ‘reverse’ prenyl chain on C-3a,
and in general differ in the substituent on N-8 and on the aromatic
ring (Fig. 1).
R
R2
R3
N
N
H
Me
Me
R2
N
H
N
R1
R1
1
2
R = Me, CHO, CH2OH, CO2Me
R = A,B
R
1 = H, Me
R
1 = H, A
R2 = H, Me
R2 = H, Br
R3 = H, OMe
B =
A =
Pharmacological investigations on compounds 14 and 23a,b,d,5 or
on analogous compounds6 are scarcely documented, probably be-
cause of the low availability of the naturally occurring compound.
The crucial steps for the formation of the above alkaloids are the
functionalization on C-3a with a different chain, the formation of
the third pyrroline ring and the orthogonal functionalization of the
two nitrogen atoms.
Figure 1. Alkaloids of Pseudophryne and Flustra foliaceae.
literature. Different reagents were used for the preparation of
compounds 1 and/or 2 such as tryptamine derivatives,7 indole-
acetic acid derivatives,8 1-methoxyindole-3-carbaldehyde,9
The structural and stereochemical features of these alkaloids
make their total synthesis appealing as documented by the
L
-tryptophane10 and oxindole.11 Other starting materials are the
2-oxofuro[2,3-b]indolines,12 the 2,3-dihydropyrrolo[2,3-b]indo-
line-2-carboxylate derivatives,13 the 2-allyloxyindolin-3-one,14 the
spirooxindole15 and alkynylcarbodiimides.16
Aside from the hexahydropyrroloindole skeleton, few synthetic
examples on the preparation of alkaloids containing the
* Corresponding author. Tel.: þ39 0250314481; fax: þ39 0250314476.
E-mail address: marialuisa.gelmi@unimi.it (M.L. Gelmi).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.01.004

1996
S. Pellegrino et al. / Tetrahedron 65 (2009) 1995–2004
OH
Me3SiO
R1HN
Cl
4
Cl
H
OSiMe3
O
O
N
O
N
H
R
(-)-20
i
N
N
Me
N
H
H
CO2Et
CO2Et
3
5
(-)-19
HO2C
NH3+ Cl-
ii
O
O
O
O
O
N
H
(+)-14
O
R
iii
63%
O
N
N
NH
O
CO2Et
CO2Et
7
6
O
N
N
R
Scheme 2. Synthesis of spiro ketone 7. Reagents and conditions: (i) toluene,
Et3N$HF, toluene, 25 ꢂC; (iii) H2, Pd/C, toluene.
D; (ii)
(+)-10
( )-7
Scheme 1. Retrosynthetic analysis of compounds 19 and 20.
fluoride (1 equiv) for 2 h at room temperature to give the un-
saturated ketone 6. Its reduction with hydrogen and Pd/C at room
temperature (24 h), afforded pure spiro ketone 7 (63%). The puri-
fication of intermediate 6 by column chromatography (65%) was
also possible.
pyranoindole ring have been reported in the literature,17 even if this
skeleton is included in more complex molecules.18
Considering the biological interest of the above rings, we plan-
ned the asymmetric synthesis of both new hexahydropyrroloindole
and pyranoindole derivatives 19 and 20 (Scheme 1) since the
polyfunctionalized intermediate 14 was available. In fact, as shown
in Scheme 1, the preparation of both hexahydropyrroloindole
derivative 19 and tetrahydropyrano[2,3-b]indole ring 20 takes
advantage of a common intermediate, the new amino acid 14,
which is prepared from the spiro ketone 7, through the spi-
roazepinoindoline derivative 10 containing an interesting scaffold
of biological importance.19 Compound 19 is characterized by an
orthogonal substitution at nitrogen atoms (i.e., methyl group at N-1,
unsubstitution at N-8) and most of all, is substituted on C-3a with
a hydroxy functionalized chain which makes this compound
a valuable synthon for further transformations. Alternatively, the 2-
2,3,4,4a,9,9a-hexahydropyrano[2,3-b]indole 20 is functionalized at
C-4a with a ethanamine chain.
Starting from 7, different synthetic strategies were tested aiming
to transform the cyclohexanone ring into the azepinone, the real
intermediate for the preparation of amino acid 14. The reaction of 7
with hydroxylamine (8 equiv) in EtOH/H2O and sodium acetate at
reflux gave oxime 8 (86%) deprotected at the indole nitrogen atom
(Scheme 3). Beckmann rearrangement of 8 to 10 was studied under
different reaction conditions. The use of strong acids (H2SO4, PPA,
etc.) gave only tarry compounds. Alternatively, oxime 8 was
transformed into the corresponding O-mesylate 9 with mesyl
chloride at 0 ꢂC in CH2Cl2 in the presence of triethylamine (TEA),
NOH
O
The asymmetric transformation of racemic 7 in the enantiopure
compound (þ)-10 was also realized, thus assuring the preparation
of enantiopure compounds (ꢁ)-19 and (ꢁ)-20. Since the trans-
formation of derivative 14 into 19 or 20 requires different reductive
steps, both experimental and computation studies on their che-
moselective formation were performed.
N
H
8
i
ii
86%
NOMs
O
O
O
2. Results
N
H
9
N
Recently,20 we reported on a three step synthesis of reagent 7
(55% overall yield) using a Diels–Alder reaction starting from 3-
chloromethylene-2-indolone 3 and the Danishefsky’s diene. Some
disadvantages, related to the formation of by-products deriving
from the transformation of the primary cycloadduct into diphenyl
compounds, had been encountered using this diene. Furthermore,
the difficulty to reproduce the reaction time and the use of the
expensive Danishefsky’s diene prompted us to revisit this reaction
and a different synthetic protocol was planned starting from
dienophile 3 and the cheaper 2-trimethylsilyloxybutadiene 4
(Scheme 2). The reaction was performed on a multi-gram scale
(24 g), without isolation of the intermediates, by reacting an excess
of diene 4 (3/4, 1:3) in toluene at reflux. After 3 h the spi-
rocyclohexenoneindolone 5 was formed (1H NMR analysis). The
crude reaction mixture was treated with triethylamine hydrogen
CO2Et
7
O
iv
iii
NH
O
N
R
10a: R = H, 66%
10b: R = CO2Et, 90%
Scheme 3. Synthesis of spiro azepinoindole 10. Reagents and conditions: (i) AcONa,
EtOH/H2O, NH2OH$HCl, reflux; (ii) MsCl, TEA, CH2Cl2, 0 ꢂC; (iii) 10a: chromatography
on neutral Al2O3; (iv) 10b: H2SO4, NaN3, CHCl3 (from ꢁ10 to 25 ꢂC).

S. Pellegrino et al. / Tetrahedron 65 (2009) 1995–2004
1997
O
O
O
Ph
N
N
Ph
HO
H
S
ii
O
O
96%
N
N
O
CO2Et
CO2Et
N3
Ph
HO
(-)-12a
(+)-13
H
11
iii
O
+
- PhCOCHCH2
70%
i
N
98%
CO2Et
O
O
( )-7
Ph
N
NH
O
HO
H
R
O
N
CO2Et
N
COEt
12b
(+)-10a
Scheme 4. Synthesis of enantiopure compound (þ)-10. Reagents and conditions: (i) CH2Cl2, ꢁ80 ꢂC, BF3$Et2O, then 25 ꢂC, then 5% NaHCO3; (ii) PCC, SiO2, CH2Cl2, 25 ꢂC; (iii) NaH,
THF, 65 ꢂC.
which allowed the regioselective functionalization of the hydroxy
group. The azepinone derivative 10a (66%) was directly obtained
during the chromatographic work-up of compound 9 using neutral
alumina (Scheme 3).
An alternative and more efficient protocol to build the azepino
ring was found using the modified Schmidt reaction21 consisting in
the reaction of a cooled solution (ꢁ10 ꢂC) of ketone 7 in CHCl3
under stirring with H2SO4 (11 mmol) followed by addition of so-
dium azide (4 equiv). Aiming to increase the yield, it is essential to
operate in a closed round-bottle flask, to interrupt the stirring after
30 min and to warm the reaction at room temperature (12 h). Pure
lactame 10b, protected at the indole nitrogen atom, was isolated in
90% yield (Scheme 3).
The asymmetric synthesis of enantiopure derivative (þ)-10b
was also planned using the procedure reported by Sahasrabudhe
et al.22 consisting of the reaction of a cyclic ketone with an
enantiopure organic azide containing a stereocentre. In our case,
R-3-azido-1-phenylpropanol (11) was made to react with racemic
7 in dichloromethane at ꢁ80 ꢂC in the presence of a catalytic
amount of BF3$Et2O. The reaction occurred in good diastereo-
selectivity and compounds (ꢁ)-12a and 12b were obtained in 98%
yield and 87:13 ratio (HPLC analysis) after hydrolysis (5% NaHCO3)
(Scheme 4).
atom, as confirmed by X-ray analysis (Fig. 2). Any attempt to isolate
pure stereoisomer 12b failed.
The deprotection of the nitrogen atom of the azepino ring was
first performed by oxidizing the hydroxy group of the chain with
PCC in dichloromethane (25 ꢂC, 3.5 h) in presence of SiO2 to gave
the keto derivative (þ)-13 (96%), which was then treated with NaH
in THF at 65 ꢂC (3 h). Compound (þ)-10a was isolated in 70% yield
after purification (Scheme 4).
The selective hydrolysis of the lactam function of the azepine
ring was performed in aqueous HCl (20%, 100 ꢂC) starting from both
(ꢀ)-10b and (þ)-10a giving amino acids (ꢀ)-14 and (ꢁ)-14, re-
spectively, in quantitative yield. Their treatment with EtOH in the
presence of SOCl2 gave the corresponding esters (ꢀ)-15 and (ꢁ)-15
(95%) (Scheme 5).
The formation of the hexahydropyrroleindole nucleus was
achieved according to the method reported by Somei et al.9 con-
sisting of the protection of the amino group as carbonate followed
by its transformation into the tetrahydropyrroloindole ring by re-
duction. The amino group was protected using ethyl chlorocar-
bonate (2 equiv) operating in dichloromethane and in the presence
O
Pure compound (ꢁ)-12a, obtained by simple crystallization, is
HO2C
NH
NH3+Cl-
characterized by an S absolute configuration at the spiro carbon
i
ii
O
O
100%
95%
N
R
N
H
(+)-10a: R = H
( )-10b: R = CO2Et
( )-14, (-)-14
EtO2C
EtO2C
NHCO2Et
O
NH3+Cl-
iii
85%
O
N
N
R
H
( )-16a, (-)-16a: R = H
( )-16b, (-)-16b: R = CO2Et
( )-15, (-)-15
Scheme 5. Synthesis of amino acids 14 and derivatives. Reagents and conditions:
(i) 20% HCl, 100 ꢂC; (ii) EtOH, SOCl2, reflux; (iii) 16a: ClCO2Et, (2 equiv), K2CO3, CH2Cl2,
25 ꢂC; 16b: ClCO2Et (4 equiv), TEA, CH2Cl2, 25 ꢂC.
Figure 2. ORTEP plot of compound (ꢁ)-12a with numbering scheme. ADPs at 20%
probability level. For clarity, only H atom bonded to the stereo centre C-18 and of
hydroxy group is shown.

1998
S. Pellegrino et al. / Tetrahedron 65 (2009) 1995–2004
OH
N
OH
3
OH
R1HN
5
NHCO2Et
OH
NHCO2Et
4
7
3
1
4
4
7
2
N
2
O
5
6
5
6
1
6
7
3
2
3a
4a
9
8a
O
1
8
Me
N
H
N
H
N
8a
8
H
CO2Et
H
R
20a: R = H, R1 = Me
17
18
19
20b: R = R1 = CO2Et
Chart 1. Products of the reduction of compounds 16.
of an aqueous solution of potassium carbonate. The corresponding
protected amino acids (ꢀ)-16a (75%) and (ꢁ)-16a (75%) were iso-
lated from (ꢀ)-15 and (ꢁ)-15, respectively (Scheme 5). It has to be
pointed out that the use of TEA as the base gave a mixture of
compounds 16a and 16b, the last one protected at both amino
groups. To achieve the protected compound (ꢁ)-16b (85%), an ex-
cess of ethyl chlorocarbonate (4 equiv) is needed in the presence of
TEA starting from (ꢁ)-15 (Scheme 5).
main compound at room temperature by using conditions reported
in entries 5 and 6. Pyran derivative 20b was also obtained when
using a strong excess of LiAlH4 (entry 6). Performing the reduction
with an excess of LiAlH4 and heating (entry 7), gave compound 19
as the main product. Tetrahydropyrano[2,3-b]indole derivative 20a,
functionalized at C-4a with the 2-aminoethyl chain and un-
protected at N-9a, was isolated as by-product. To prevent reduction
of the ester function before the carbonyl group of the oxindole ring,
16b was treated both with selectrides and with NaBH4. The use of
both K- and L-Selectride is not effective in the formation of com-
pounds like 18 and/or 20 (1H NMR analyses). A mixture of com-
pounds was first obtained by using NaBH4 in a mixture of THF and
EtOH, but by controlling the reaction temperature as well as the
amount of EtOH, which is necessary to make the reduction opera-
tive, our synthetic target was achieved. As reported in entry 8, the
use of THF/EtOH (1:1, from 25 ꢂC to reflux) gave 17 as the main
compound (50%) together with the N-protected compound 18
(mixture of two diastereoisomers) in which both the ester function
and the carbonyl group of the oxindole ring were reduced. By de-
creasing the temperature (from 0 to 25 ꢂC) and the amount of EtOH
(entry 9), the hemiaminal 18 was the sole reaction product. Instead,
by performing the reaction as reported in entry 10, both in-
termediate 18 and product 20b (2:1) were isolated. Interestingly,
when the same crude reaction mixture was heated in toluene in
presence of p-TSA, the complete transformation of 18 into 20b was
observed. The competitive formation of tetrahydropyrroloindole
and tetrahydropyranoindole ring, as a mixture of compounds, was
reported in the literature.23
The chemoselective reduction of the functional groups in
compounds 16 was studied aiming to obtain both tetrahydro-
pyrrolo[2,3-b]indole and tetrahydropyrano[2,3-b]indole scaffolds
by using selective reactive conditions. Compounds deriving from
the partial or total reduction of the different functional groups are
shown in Chart 1 and the reaction conditions adopted to reduce
reagents 16 are reported in Table 1.
The reduction of (ꢀ)-16a was performed with LiAlH4 in THF at
different temperatures and equivalents of hydride ion. As shown in
Table 1, by using the reducing agent (from 4 to 32 equiv, entries 1
and 3) at 25 ꢂC or by heating (4 equiv, entry 2), the selective re-
duction of the ester function was operative giving the alcohol
(ꢀ)-17 in good yield. The goal in the formation of the pyrrole[2,3-
b]indole ring from (ꢀ)-16a was achieved by using an excess of
LiAlH4 and heating (entry 4). 2,3,8,8a-Tetrahydro-1H-pyrrole[2,3-
b]indole derivative 19, unprotected at N-8, functionalized at C-3a
with the 3-hydroxypropyl chain and at N-1 with a methyl group
was isolated in good yield.
Considering that the N-alkoxycarbonylamide group is reduced
to a hemiaminal function faster then the amide and carbamate
functions, we planned the reduction of 16b with the aim of
obtaining the tetrahydropyrano[2,3-b]indole ring, via an in-
termediate such as 18. In this case too, different reaction conditions
were tested (Table 1, entries 5–7) using LiAlH4, which gave mixture
of compounds as shown by 1H NMR spectra. Alcohol 17 was the
In order to understand if a transformation between 19 and 20
was possible, compound 20a was treated both with a catalytic
amount of a base (TEA in CH2Cl2, both at 25 ꢂC and reflux) or an
acid. In the first case, the transformation of 20a into 19 was not
observed. Instead, operating at room temperature in the presence
of p-TSA in CH2Cl2 after 16 h a quantitative transformation of 20a
into 19 was operative. It has to be concluded that the tetrahy-
dropyrroloindole derivative 19 is probably the thermodynamic
compound and is not in equilibrium with the kinetic compound
20a. In fact, 19 did not equilibrate to 20a when standing in CH2Cl2 at
room temperature in presence of p-TSA (Scheme 6).
Table 1
Reaction conditions for the reduction of compounds 16
Entry Reagent Reducing Equiv Solvent
T (ꢂC)
Reaction Products
time (h)
agent
(ratio)
To confirm our hypothesis, energies of the optimized structures
for compounds 19 and 20a (Fig. 3) were computed at the MP2/
6-311þG(3df,2p)//HF-6-31þG(d,p) level in order to verify their
thermodynamic stability. As expected, compound 19 was the most
1
2
3
4
5
6
7
8
16a
16a
16a
16a
16b
16b
16b
16b
LiAlH4
LiAlH4
LiAlH4
LiAlH4
LiAlH4
LiAlH4
LiAlH4
NaBH4
4
4
32
32
4
32
32
8
THF
THF
THF
THF
THF
THF
THF
THF/EtOH
(1:1)
THF/EtOH From 0
(4:1) to 25
THF/EtOH From 0
(4:1) to reflux
25
Reflux
25
Reflux
25
25
4
6
17 (80%)a
17b
12
12
8
12
15
2
17b
19 (79%)a
17b
17/20b (2:1)b
19/20a (7:1)a
17/18 (3:1)b
Reflux
OH
c
Me HN
9
16b
16b
NaBH4
NaBH4
8
8
8
18 (85%)a
i, 83%
N
O
H
10
4d
18/20ba (2:1)
Me
N
N
H
H
H
a
Isolated compound.
1H NMR analysis.
From 25 ꢂC to reflux.
20a
19
b
c
Scheme 6. Isomerization of pyrano- to pyrroloindole. Reagents and conditions:
(i) p-TSA, CH2Cl2, 25 ꢂC.
d
See Experimental (Supplementary data).

S. Pellegrino et al. / Tetrahedron 65 (2009) 1995–2004
1999
H
H
(a)
O-Li+
OH
- LiOH
N
H
N
N
Li+
O-Li+
N
OH
(b)
N
H
N
- LiOH
Li+
O
N
(c)
+ LiOCH3
N
N
N
N
Li+
Figure 3. Optimized geometries for compounds 19 and 20a.
(d)
+ LiN(CH3)2
Li+
OH
Scheme 8. Theoretically modelled reaction steps.
N
Me
EtO2C
N
H
As confirmed by an independent experiment, 18 was trans-
formed into pyran derivative 20b by heating in toluene in the
presence of p-TSA as the catalyst. Instead, the heating of 18 in the
absence of a catalyst resulted in the failure of this transformation
suggesting that the cyclization occurs via an imine intermediate
whose formation is favoured by the presence of the acid.
NHCO2Et
H
(-)-19
i, 79%
ii, 80%
O
N
R
NH CO2Et
(-)-16a: R = H
The basis for the regiochemical cyclization outcome in the re-
ductive process was also clarified by computational studies. A
simple but explicative computational model for comparing the two
possible cyclizations of compound 16 leading to products 19 and
20a was adopted. Indeed, a comprehensive reaction model would
have been too computationally expensive due to system’s di-
mensions and flexibility, so we thought to study the most repre-
sentative reaction steps as simplified models. Intermediate 16a
bears three groups that can be reduced by hydrides, namely the
side chain ester, the carbamate and the amidic carbonyl of the
oxindole moiety. It is known that esters are easily reduced to al-
cohols, while amides need harder conditions due to the hydroxy
group elimination from the hemiaminal intermediate to give an
imine, which is then reduced to the amine. Carbamates follow an
analogous path, since formamides are reduction intermediates,
with the hydroxy group elimination being the rate limiting step.
The pyranoindole derivative could reasonably arise from the nu-
cleophilic attack of the alcohol on the imine intermediate, occur-
ring before complete reduction of the side chain carbamate, as
competition between N-nucleophiles and O-nucleophiles should
favour the first with the obtainment of the only pyrroloindole de-
rivative. On the other hand, the pyranoindole could lead to the
pyrroloindole, thus being an effective reaction intermediate, as
soon as the reduction of the carbamate complete and through pyran
ring opening and subsequent cyclization. In order to confirm or
rebut the above assumptions, theoretical models for the hydroxyl
eliminations and alcohol or amine nucleophilic attacks were
(-)-16b: R = CO2Et
O
H
N
CO2Et
(-)-20b
Scheme 7. Preparation of tetrahydropyrroloindole and pyranoindole scaffolds. Re-
agents and conditions: (i) LiAlH4 (32 mmol), THF, reflux; (ii) NaBH4 (8 mmol), THF/
EtOH (4:1), from 0 ꢂC (0.30 h), then 25 ꢂC (1.30 h), then reflux (2 h); then p-TSA, tol-
uene, reflux.
stable
findings.
(
D
G19–20a¼ꢁ4.1 kcal/mol), confirming the experimental
With the synthetic protocols, which selectively gave the tetra-
hydropyrroloindole or pyranoindole scaffold, the preparation of
enantiopure compounds (ꢁ)-19 and (ꢁ)-20b was also accom-
plished. Starting from (ꢁ)-16a, operating with a large excess of
LiAlH4 in THF and by heating, (ꢁ)-19 was isolated in 79% yield
(Scheme 7).
Enantiopure derivative (ꢁ)-20b was obtained from (ꢁ)-16b, by
reduction with NaBH4 in THF/EtOH (4:1) operating at 0 ꢂC (0.30 h)
then heating at 25 ꢂC (1.30 h) and then at reflux (2 h). After work-
up, the reaction mixture was heated (2 h) in CH2Cl2 in presence of
p-TSA as the catalyst, and compound (ꢁ)-20b was isolated in 80%
yield (Scheme 7).
The data concerning the reduction of compounds 16 suggest
that the competitive reduction of the ester function and of the
carbonyl of the oxindole balances the formation of the pyran or
indoline ring. If the ester was first reduced, sodium ethoxide was
formed, which induced the deprotection of nitrogen atom of the
oxindole ring of 16b preventing the reduction of its carbonyl
group. Alcohol 17 was generated and then transformed into
pyrrole[2,3-b]indole derivative 19 by using an excess of LiAlH4
and heating.
The formation of compound 20 must be ascribed to the forma-
tion of the corresponding intermediates 18. If the reduction of the
carbonyl function of oxindole to hemiaminal occurred first and
then that of the ester function, intermediates 18 are formed, which
can cyclize to 20.
Table 2
MP2/6-311þG(3df,2p)//HF/6-31þG(d,p) activation and reaction free energies
Step
DG
z (kcal/mol)
D
G (kcal/mol)
a
b
c
6.7
15.4
1.2
0.0
7.1
ꢁ0.2
c reverse
d
d reverse
1.4
0.2
ꢁ8.1
ꢁ23.3
23.3
15.2

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S. Pellegrino et al. / Tetrahedron 65 (2009) 1995–2004
substituent on N-1 position, confirms the reduction of the carba-
mate group as well as the signal at
d
¼3.55 (t, J 6.4 Hz, CH2OH) of the
ester function. The NOESY experiment established the cis re-
lationship between H-8a and the C-3a chain. In fact a positive
Overhauser effect was observed between H-8a and the signals at
d
¼3.55 corresponding to the CH2OH protons.
Pyranoindoline derivatives 20 are characterized by the typical
signal of H-9a17a that ranges from
d
¼5.63 (20a, C-9a:
d¼87.4) to
d
¼6.06 (20b: dC¼80.8). A singlet at
d
¼2.76 (dC¼34.3) revealed the
presence of the N-Me group in compound 20a, whose NH resonates
at low field (
¼11.65) indicating the formation of a hydrogen bond
d
probably with the oxygen of the pyran ring. Our hypothesis is
confirmed by the NOESY experiment, which revealed spatial
proximity between this proton and both the methyl group and
H-9a, thus confirming the cis junction between the two rings.
Instead, no information is given regarding the stereochemistry of
the ring-junction in 20b, which is tentatively assigned as cis con-
formation in agreement with the stereochemistry assigned to 20a.
In conclusion, the preparation in enantiopure form of the new
oxindole amino acid (ꢁ)-14 was performed taking advantage of the
asymmetric synthesis of oxo-azepinoindolinone (þ)-10. Amino acid
derivatives 16, deriving from 14, are the key intermediates for the
chemoselective preparation of the new tetrahydropyrroloindole
and pyranoindoline alkaloid scaffolds, functionalized at C-3a with
the 3-hydroxypropyl- and at C-4a with the 2-aminoethyl chain,
respectively. Our synthetic strategy is very versatile with the
possibility of starting from chloromethyleneoxindole differently
functionalized on the aromatic ring, to transform the hydroxy
chain at C-3a in case of 19 or the amino chain at C-4a in case of
compound 20.
Figure 4. Transition states for the modelled reaction steps. Vectors corresponding to
the unique imaginary frequency are represented as blue arrows.
realized as depicted in Scheme 8. Strong basic conditions were
simulated and Liþ was chosen as an approximation of the cationic
counterion. Activation and reaction free energies, computed at
the MP2/6-311þG(3df,2p)//HF/6-31þG(d,p) level, are reported in
Table 2, while optimized geometries for the located transition
states TSa–d are represented in Figure 4.
The hydroxyl elimination from indolin-2-ol (step a) presents an
activation barrier of 6.7 kcal/mol and is almost isoergonic, while the
corresponding elimination from the aliphatic aminoalcohol (step b,
i.e., the intermediate of the reduction of carbamate) has a more
than doubled activation barrier (15.4 kcal/mol) and is quite endo-
thermic (7.1 kcal/mol). Those data confirm that the reduction of the
oxindole carbonyl is decidedly favoured over the side chain car-
bamate. It is thus certain that, at an early reaction stage, the only
nucleophile able to react with the 3-H-indole C-2 is the side chain
alcoholic group. The reaction model (step c) for the O-attack
presents an activation barrier of only 1.2 kcal/mol and is slightly
exothermic, suggesting that the O-cyclization could occur as soon
as the cyclic imine is formed, but also that a ring-chain equilibrium
is possible due to the low activation barrier of the reverse reaction
(1.4 kcal/mol). On the other hand the N-attack (step d) occurs
barrierless (ꢁ8.1 kcal/mol) and is highly exothermic (ꢁ23.3 kcal/
mol), confirming that the N-cyclization is only limited by the side
chain carbamate reduction rate.
Those computational results are in perfect concordance with the
experimental outcome of entry 6 (Table 1), where the pyranoindole
derivative 20b, bearing the unreduced carbamate on the side chain,
is obtained by operating at room temperature. In conclusion, con-
sidering the computational results reported above, it appears rea-
sonable that product 20a can only be obtained as a by-product in
low yields (see entry 7, Table 1) thus justifying the adopted differ-
ent approaches, which led to derivative 20b. Finally, it could be
argued that both the O- and N-cyclization proceed directly through
an intramolecular SN2 substitution, thus avoiding the cyclic imine
intermediate, with the indoline nitrogen or the pyran oxygen be-
having as the leaving groups. However, despite many trials, any
attempt to localize a SN2 like transition state for the oxygen or ni-
trogen attack failed.
Computational studies on the competitive formation of pyrro-
lineindole and pyranindole rings were performed from which was
evidenced the thermodynamic stability of the first ring and
a rationalization of the observed chemoselectivity.
3. Experimental section
3.1. Theoretical calculations
Structures of compounds 19 and 20a were obtained from a sto-
chastic conformational search conduced at the molecular mechanic
level using the MMFF94x forcefield implemented in the MOE
software with the default parameters.25,26 The most stable geom-
etries, as well as reactants, transition states and products of the
modelled reaction steps a–d were fully optimized ab initio at the
HF/6-31þG(d,p) level, and vibrational frequencies were computed
at the same level of theory in order to define optimized geometries
as minima (no imaginary frequencies) or transition states (a unique
imaginary frequency corresponding to the vibrational stretching of
the forming/breaking bonds) and to calculate ZPVE and thermo-
chemical corrections to electronic energies (1 atm, 298.15 K). In
order to recover the electron–electron correlation energies, single
point calculations were conducted in the gas phase at the MP2/6-
311þG(3df,2p) level. All quantum-chemical calculations were per-
formed with the Gaussian03 package.27
3.2. General remarks
The structure of compounds 18b, 19 and 20a,b was confirmed by
analytical and spectroscopic data (see Supplementary data). The 1H
and 13C NMR spectra of compound 19 are in agreement with the
structure assigned.24 The condensation of the two nitrogen con-
taining pentaatomic rings was confirmed by the typical signals at
Reactions were monitored by thin-layer chromatography on
0.25 mm silica gel plates (60 F254) using UV light as a visualizing
agent. 1H and 13C NMR spectra were recorded in CDCl3 with CHCl3
as internal standard, 1H NMR at 200 or 500 MHz, 13C NMR at 50 or
125 MHz. Infrared spectra were recorded on a Fourier transform IR
spectrometer, and values are reported in cmꢁ1 units. MAT LCQ ion
trap mass spectrometer equipped with a Microsoft Window NT
d¼4.48 (C-8a:
d
¼87.0) associated to H-8a as well as of C-3a at
d¼63.1. The singlet at
d
¼2.44, corresponding to the methyl

S. Pellegrino et al. / Tetrahedron 65 (2009) 1995–2004
2001
data system (ESI). Coupling constants (J) are given in hertz. C,H,N
analysis on Perkin–Elmer CHN Analyzer Series II 2400.
3.22 (s, 3H), 3.23–3.06 (m, 2H), 2.68–2.56 (m, 1H), 2.19–1.88 (m,
5H). The crude reaction mixture, containing mesylate (ꢀ)-9 was
directly transformed into lactam (ꢀ)-10a (151.8 mg, 66%) by chro-
matography on neutral Al2O3 (CH2Cl2/MeOH, 1:0 to 20:1). Mp
125 ꢂC (CH2Cl2/Et2O), colourless solid; IR (KBr) nmax 3182,
3.3. Ethyl 20,4-dioxaspiro[cyclohex-2-en-1,30-indoline]-10-
carboxylate ( )-6
1638 cmꢁ1; 1H NMR (CDCl3)
d
¼8.71 (br s, 1H, exch., NH), 7.29–6.93
Operating under a nitrogen atmosphere, oxindole 3 (24 g,
95.7 mmol) was dissolved in anhydrous toluene (500 mL) and the
solutionwas heated at reflux. Diene 4 (50 mL, 287 mmol) was added
in portions over a period of 1.5 h. The reaction was monitored by 1H
NMR spectroscopy until the disappearance of the signals of the
starting oxindole. The crude reaction mixture was cooled and
transferred into a polyethylene vessel. TEA$HF (15.6 mL, 99.7 mmol)
was added. The mixture was kept stirring at room temperature for
3 h. Unsaturated ketone 6 (17.7 g, 65%) was isolated after column
chromatography (cyclohexane/Et2O, from 10:1 to 10:6). Mp 128 ꢂC
(Et2O), colourless solid; IR (KBr) nmax 1730, 1710, 1680 cmꢁ1; 1H NMR
(m, 4H, Ph), 6.66 (t, J¼5.1, 1H, exch., NH), 4.35–4.19 (m, 1H, H-2),
3.69–3.55 (m, 1H, H-6), 3.28–3.13 (m, 1H, H-2), 2.51–2.40 (m, 1H, H-
6), 2.07–1.95 (m, 4H, H-3, H-5); 13C NMR (CDCl3)
d¼30.4, 30.5, 36.6
(2C), 47.9, 110.2, 122.6, 122.9, 128.3, 134.9, 139.7, 179.3, 182.5. MS
(ESI) m/z 253.2 (MþNa)þ. Anal. Calcd for C13H14N2O2: C, 67.81; H,
6.13; N, 12.17. Found: C, 67.84; H, 6.11; N, 12.21.
3.7. Ethyl 7,20-dioxa-1,2,3,5,6,7-hexahydrospiro[4H-azepine-
4,30-3H-indole]-10-carboxylate ( )-10b
To a cooled solution (ꢁ10 ꢂC) of 7 (9 g, 31.35 mmol) in CHCl3
(130 mL), concentrated H2SO4 (18.8 mL, 344.9 mmol) was added
with stirring. Sodium azide (8.6 g, 132.4 mmol) was added over
a 15–20 min period. After stirring for 15 min, the reaction mixture
was allowed to stand overnight at room temperature. Crushed ice
was added to the mixture, which was then treated with 2 M NaOH
until pH 6. The crude reaction mixture was extracted with CHCl3
(3ꢃ50 mL). The organic layers were dried over Na2SO4 and, after
evaporation of the solvent, the azepino compound (ꢀ)-10b (8.54 g,
90%) was obtained. Mp 118 ꢂC (CH2Cl2/Et2O), colourless solid; IR
(CDCl3)
d
¼7.97 (d, 1H, J¼8.4, H-70), 7.45–7.36 (m, 1H, Ph), 7.28–7.19
(m, 2H, Ph), 6.50 (d,1H, J¼10.3, H-2), 6.30 (d,1H, J¼10.3, H-3), 4.47 (q,
2H, J¼7.0, OCH2), 3.19–3.02 (m,1H, H-5), 2.67–2.17 (m, 3H, H-6, H-5),
1.46 (t, 3H, J¼7.0, Me); 13C NMR (CDCl3)
¼14.4, 33.0, 33.5, 50.2, 64.0,
d
115.8,123.8,125.5,129.7,130.5,132.2,138.9,145.3,150.9,174.4,197.5.
MS (ESI) m/z 286.4 (MþH)þ. Anal. Calcd for C16H15NO4: C, 67.36; H,
5.30; N, 4.91. Found: C, 67.34; H, 5.36; N, 4.89.
3.4. Ethyl 20,4-dioxaspiro[cyclohexane-1,30-indoline]-10-
carboxylate ( )-7
(KBR) nmax 3435,1780,1668 cmꢁ1; 1H NMR (CDCl3)
d
¼7.89 (d, J¼8.0,
1H, H-70), 7.34–7.19 (m, 3H, Ph), 6.23 (br s, 1H, exch., NH), 4.49 (q,
J¼7.3, 2H, OCH2), 4.21–4.38 (m, 1H, H-2), 3.66–3.53 (m, 1H, H-6),
3.16–3.09 (m, 1H, H-2), 2.44–2.33 (m, 1H, H-6), 2.13–1.96 (m, 4H, H-
The crude mixture containing 6 in toluene, prepared as de-
scribed before, was directly hydrogenated at room temperature for
24 h using Pd/C as the catalyst (10.17 g, 9.566 mmol). The catalyst
was filtered over a Celite pad and after column chromatography
(cyclohexane/Et2O, from 10:1 to 10:6) pure keto compound 7 was
obtained (17.3 g, 63%). Mp 110 ꢂC (Et2O); lit.:20 110 ꢂC (Et2O).
3, H-5), 1.47 (t, J¼7.3, 3H, Me); 13C NMR (CDCl3)
¼14.47, 30.51,
d
31.58, 36.66, 37.59, 47.63, 63.82, 115.42, 122.69, 125.33, 128.81,
133.47, 137.80, 151.07, 177.83, 178.81. (ESI) m/z 325.2 (MþNa)þ. Anal.
Calcd for C16H18N2O4: C, 63.56; H, 6.00; N, 9.27. Found: C, 63.58; H,
6.01; N, 9.10.
3.5. Oxime of spiro[cyclohexane-1,30-indoline]-20,4-
dione ( )-8
3.8. Ethyl 7,20-dioxa-1,2,3,5,6,7-hexahydrospiro[1-(3-hydroxy-
3-phenyl-propyl)-4H-azepine-4,30-3H-indole]-10-
carboxylates (12)
Compound 7 (287.3 mg, 1 mmol) was dissolved in hot EtOH
(10 mL). An aqueous solution (2 mL) of NH2OH$HCl (556 mg,
8 mmol) and AcONa (1.15 g, 14 mmol) was added and the mixture
was heated at reflux for 2 h. EtOH was evaporated and the mixture
taken up with H2O (20 mL) and extracted with AcOEt (3ꢃ10 mL).
The organic layers were dried over Na2SO4 and the solvent was
A
solution of (R)-3-azido-1-phenylpropanol 11 (924 mg,
5.22 mmol) and spirocyclohexanone (ꢀ)-7 (1 g, 3.48 mmol) in
CH2Cl2 (60 mL) was cooled to ꢁ80 ꢂC. BF3$OEt2 (1.32 mL,
10.4 mmol) was added dropwise. The reaction was gradually
warmed to room temperature over a period of 48 h. CH2Cl2 (20 mL)
and an aqueous solution of NaHCO3 (5%, 60 mL) were added and the
mixture was stirred at room temperature. After 18 h the layers were
separated and the aqueous one was extracted with CH2Cl2
(2ꢃ20 mL). The combined organic layers were washed with NH4Cl
(10 mL), dried over MgSO4 and the solvent was removed under
vacuum. A mixture of diastereoisomers 12a/12b (1.65 g, 98%) was
obtained. HPLC analysis of the crude reaction mixture showed an
removed under vacuum. After crystallization pure oxime
(200 mg, 86%) was obtained. Mp 194 ꢂC (Et2O), colourless solid; IR
(KBr) nmax 3360, 1670 cmꢁ1; 1H NMR (CDCl3)
8
d
¼8.37 (br s, 1H, exch.,
NH), 8.04 (br s, 1H, exch., OH), 7.30–6.91 (m, 4H, Ph), 3.11–2.88 (m,
3H, H-3, H-5), 2.58–2.45 (m, 1H, H-3), 2.18–1.83 (m, 4H, H-2, H-6);
13C NMR (CDCl3)
d
¼19.7, 26.9, 32.1, 33.3, 46.9, 109.9, 122.5, 123.3,
128.1, 134.3, 139.8, 159.1, 182.0. MS (ESI) m/z 231.2 (MþH)þ. Anal.
Calcd for C13H14N2O2: C, 67.81; H, 6.13; N, 12.17. Found: C, 67.78; H,
6.15; N, 12.13.
83:13 ratio of diastereomeric lactams (Hypersil column, 5 m,
250ꢃ4.6 mm, CH2Cl2/iPrOH 95:5, 1.2 mL/min). Pure di-
3.6. 1,2,3,5,6,7-Hexahydrospiro[4H-azepine-4,30-3H-indol]-
astereoisomer (ꢁ)-12a (1.2 g, 71%) was obtained by crystallization
7,20-dione ( )-10a
from Et2O. Compound (ꢁ)-12a: mp 128 ꢂC, colourless solid; [
a]
D
ꢁ12 (c 0.01, CHCl3); IR (KBr) nmax 2924, 1783 cmꢁ1; 1H NMR (CDCl3)
A solution of oxime 8 (230.3 mg, 1 mmol) in anhydrous CH2Cl2
(5 mL) was cooled to 0 ꢂC under nitrogen. TEA (0.2 mL, 1.5 mmol in
0.5 mL of CH2Cl2) and then MsCl (0.1 mL, 1.4 mmol in 0.5 mL of
CH2Cl2) were added with stirring at 0 ꢂC. After 1.5 h the organic
layer was washed with 5% HCl (5 mL), with a saturated solution of
NaHCO3 (5 mL) and then with H2O (5 mL). The combined organic
layers were dried over Na2SO4 and the solvent removed under
vacuum to give 9. Crude compound: IR (KBr) nmax 3200, 1704,
d
¼7.91 (d, J¼8.1, 1H, H-70), 7.43–7.17 (m, 8H, Ph), 4.76 (dd, J¼9.4, 3.4,
1H, CHPh), 4.56 (dd, J¼14.7, 5.4, 1H, H-2), 4.51 (q, J¼7.1, 2H, OCH2),
4.06–4.00 (m, 1Hþ1H exch., CHN, OH), 3.59–3.57 (m, 1H, H-6), 3.34
(dt, J¼9.1, 4.8, 1H, CHN), 3.20 (dd, J¼14.7, 4.1, 1H, H-2), 2.50–2.43 (m,
1H, H-6), 2.10–1.87 (m, 6H, H-3, H-5, CH2CHOH), 1.49 (t, J¼7.1, 3H,
Me); 13C NMR (CDCl3)
d¼14.6, 31.3, 32.2, 37.1, 38.2, 44.5, 46.1, 47.2,
64.1, 70.8, 115.7, 122.7, 125.6, 125.9 (2C), 127.7, 128.9 (2C), 129.2,
133.3, 138.1, 144.4, 151.2, 176.8, 178.0. (ESI) m/z 459.5 (MþNa)þ.
Anal. Calcd for C25H28N2O5: C, 68.79; H, 6.47; N, 6.42. Found: C,
1620 cmꢁ1; 1H NMR (CDCl3)
d
¼8.11 (s, 1H, exch.), 7.31–6.93 (m, 4H),

2002
S. Pellegrino et al. / Tetrahedron 65 (2009) 1995–2004
68.75; H, 6.50; N, 6.39. Compound 12b (mixture with 12a): 13C
NMR (CDCl3)
115.7, 122.9, 125.6 (2C), 126.0, 127.6, 128.8 (2C), 128.9, 133.3, 138.1,
144.3, 151.2, 177.1, 178.1.
2.52 (m, 2H, CH2NH3þ), 2.24–1.84 (m, 6H, CH2CH2CO2Et,
d
¼14.6, 31.2, 32.0, 36.0, 37.9, 43.5, 45.4, 47.2, 64.1, 70.3,
CH2CH2NHþ3 ), 1.12 (t, J¼7.0, 3H, Me); 13C NMR (CD3OD)
d 13.3, 28.9,
32.1, 34.2, 35.6, 50.9, 60.6, 110.4, 122.9, 123.5, 128.9, 130.1, 141.9,
172.9, 180.8. Anal. Calcd for C15H21ClN2O3: C, 57.60; H, 6.77; N, 8.96.
Found: C, 57.56; H, 6.80; N, 8.94.
3.9. Ethyl 7,20-dioxa-1,2,3,5,6,7-hexahydrospiro[1-(3-
oxa-3-phenyl-propyl)-4H-azepine-4,30-3H-indole]-10-
carboxylates (D)-13
3.13. Synthesis of compounds 16
Method A. Compound (ꢁ)-15 or (ꢀ)-15 (312.8 mg, 1 mmol) was
suspended in CH2Cl2 (10 mL). Operating at 25 ꢂC a solution of
K2CO3 (414 mg, 3 mmol) in H2O (2 mL) was added with vigorous
Compound (ꢁ)-12a (570 mg, 1.3 mmol) was dissolved in CH2Cl2
(10 mL). PCC (565 mg, 2.6 mmol) and silica gel (1 g) were added
under stirring. After 3.5 h (TLC: cyclohexane/EtOAc, 1:1) the crude
reaction mixture was concentrated under vacuum. Column chro-
matography on silica gel was performed (cyclohexane/EtOAc, 1:1)
giving pure (þ)-13 (540 mg, 96% yield). Mp 115 ꢂC (Et2O), colourless
stirring. A solution of ClCO2Et (187 mL, 2 mmol) in CH2Cl2 (1 mL)
was dropped. The stirring was continued for 2 h. The layers were
separated and the water one was extracted with CH2Cl2 (10 mL).
The combined organic layers were washed with H2O (10 mL) and
then with brine (10 mL). After drying over Na2SO4, the crude re-
action mixture was chromatographed on silica gel (cyclohexane/
AcOEt¼1:1). Pure compound (ꢁ)-16a or (ꢀ)-16a (261 mg, 75%)
was obtained as an oil. Method B. Compound (ꢁ)-15 (312.8 mg,
1 mmol) was suspended in dry CH2Cl2 (10 mL). The solution was
solid; [
a]
þ16 (c 0.01, CHCl3); IR (KBr) nmax 2924, 1783 cmꢁ1
;
1H
D
NMR (CDCl3)
d
¼8.01 (d, J¼7.1, 2H, Ph), 7.89 (d, J¼8.1, 1H, Ph), 7.64–
7.59 (m, 1H, Ph), 7.53–7.48 (m, 2H, Ph), 7.36–7.30 (m, 1H, Ph), 7.18
(dt, J¼7.5, 0.7, 1H, Ph), 7.07 (dd, J¼6.7, 0.8, 1H, Ph), 4.59–4.55 (m, 1H,
H-2), 4.53 (q, J¼7.1, 2H, OCH2), 3.96 (ddd, J¼13.3, 6.8, 6.5, 1H, CHN),
3.79 (ddd, J¼13.3, 6.8, 6.5, 1H, CHN), 3.66–3.56 (m, 1H, H-6), 3.51–
3.20 (m, 3H, CH2COPh, H-2), 2.50–2.40 (m, 1H, H-6), 2.05–1.88 (m,
cooled at 0 ꢂC and ClCO2Et (561
(739 L, 5 mmol) was dropped under stirring. The stirring was
mL, 4 mmol) was added. TEA
m
4H, H-3, H-5), 1.48 (t, J¼7.1, 3H, Me); 13C NMR (CDCl3)
d¼14.6, 31.5,
continued for 6 h at room temperature. A solution of HCl (10%,
10 mL) was added and the layers were separated and the aqueous
was extracted with CH2Cl2 (10 mL). The combined organic layers
were washed with HCl (10%, 2ꢃ10 mL) and then with H2O
(10 mL). After drying over Na2SO4, the crude reaction mixture was
purified by column chromatography on silica gel (n-pentane/Et2O,
1:0 to 0:1) obtaining pure compound (ꢁ)-16b or (ꢀ)-16b (300 mg,
85%).
32.0, 36.8, 38.0, 45.3, 45.7, 47.2, 64.0, 115.5, 122.8, 125.5, 128.6 (2C),
129.0 (2C), 129.1, 133.5, 133.8, 137.2, 138.0, 151.2, 175.8, 178.1, 199.5.
(ESI) m/z 457.4 (MþNa)þ. Anal. Calcd for C25H26N2O5: C, 69.11; H,
6.03; N, 6.45. Found: C, 69.07; H, 6.06; N, 6.43.
3.10. 1,2,3,5,6,7-Hexahydrospiro[4H-azepine-4,30-(3H)-indol]-
7,20-diones (D)-10a
NaH (60%, 1 g, 25 mmol,) was suspended in anhydrous THF
(30 mL) under nitrogen. Compound (þ)-13 (520 mg, 1.19 mmol)
dissolved in anhydrous THF (15 mL) was added to the mixture,
which was heated at 65 ꢂC under stirring for 3 h (TLC: cyclohexane/
EtOAc, 1:1). The solid was filtered, the solvent was removed under
vacuum and the crude reaction mixture was purified by column
chromatography on silica gel (CH2Cl2/MeOH, 50:1) giving pure
(þ)-10a (250 mg, 70%). Mp 128 ꢂC (CH2Cl2/Et2O) colourless solid;
3.13.1. Ethyl 3-[3-(2-ethoxycarbonylaminoethyl)-2-oxo-2,3-
dihydro-1H-indol-3-yl]-propionate (ꢁ)-16a
Oil; [
a
]
ꢁ12 (c 0.60, CHCl3); IR (KBr) nmax 2929, 1730,
D
1612 cmꢁ1; 1H NMR (CDCl3)
d
¼8.46 (br s, 1H, exch., NH), 7.28–6.90
(m, 4H, Ph), 4.78 (br s, 1H, exch., NH), 4.09–3.95 (m, 4H, OCH2),
3.06–2.91 (m, 2H, CH2NH), 2.28–1.71 (m, 6H, CH2CH2CO2Et,
CH2CH2NH), 1.16 (t, J¼7.0, 6H, Me); 13C NMR (CDCl3)
¼14.5, 14.9,
d
29.4, 33.1, 37.4, 37.6, 51.5, 60.1, 61.1, 110.4, 123.4, 123.9, 128.8, 131.1,
141.2, 156.7, 173.0, 181.6. (ESI) m/z 349.1 (MþH)þ. Anal. Calcd for
C18H24N2O5: C, 62.05; H, 6.94; N, 8.04. Found: C, 62.01; H, 6.97; N,
8.02. A second tautomer is present as evidenced in 1H NMR spec-
[
a]
D þ27 (c 0.01, MeOH).
3.11. 3-[3-(2-Aminoethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-
propionic acid hydrochloride (14)
trum (
d¼9.5, br, exch.; 5.50, br s, exch.).
Operating in a sealed tube, lactam (þ)-10a (230 mg, 1 mmol) or
(ꢀ)-10b (302 mg, 1 mmol) was suspended in HCl (3 mL, 20%). The
mixture was heated at 100 ꢂC for 12 h. The water was removed
obtaining compound (ꢁ)-14 or (ꢀ)-14 in quantitative yield
3.13.2. Ethyl 3-[3-(2-ethoxycarbonylaminoethyl)-1-ethoxy-
carbonyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-propionate (ꢁ)-16b
Mp 93 ꢂC (Et2O), colourless; [
a
]
ꢁ27 (c 0.60, CHCl3); IR (KBr)
D
nmax 2934,1733,1608 cmꢁ1; 1H NMR
d
¼(CDCl3) 7.87 (d, J¼8.1,1H, H-
(284 mg). Mp 221–225 ꢂC (acetone), colourless; [
a]
ꢁ25 (c 0.80,
7), 7.37–7.19 (m, 3H, Ph), 4.58 (t, J¼5.5, 1H, exch., NH), 4.45 (q, J¼7.0,
2H, OCH2), 3.95 (q, J¼7.0, 4H, OCH2), 2.90–2.83 (m, 2H, CH2NH),
2.30–1.80 (m, 6H, CH2CH2CO2Et, CH2CH2NH), 1.46 (t, J¼7.0, 3H), 1.12
D
H2O); IR (KBr) nmax 3500–3000, 1690, 1610 cmꢁ1 1H NMR (D2O)
;
d
¼7.29–6.94 (m, 4H, Ph), 2.70–2.34 (m, 2H, CH2NHþ3 ), 2.24–1.70 (m,
6H, CH2CH2CO2H, CH2CH2NHþ3 ); 13C NMR (D2O)
d
¼28.8, 31.8, 33.9,
(t, J¼7.0, 6H); 13C NMR (CDCl3)
¼14.1, 14.2, 14.6, 29.0, 33.8, 37.0,
d
35.3, 51.5, 111.1, 123.7, 124.0, 129.4, 129.6, 141.0, 177.1, 182.3. Anal.
Calcd for C13H17ClN2O3: C, 54.84; H, 6.02; N, 9.84. Found: C, 54.86;
H, 6.04; N, 9.82.
38.2, 51.1, 60.6, 60.9, 63.6, 115.4, 123.0, 125.3, 129.0, 129.2, 139.5,
150.7, 156.3, 172.3, 177.7. Anal. Calcd for C21H28N2O7: C, 59.99; H,
6.71; N, 6.66. Found: C, 59.95; H, 6.76; N, 6.60.
3.12. Ethyl 3-[3-(2-aminoethyl)-2-oxo-2,3-dihydro-1H-indol-
3.14. General procedures for the reduction of 16b
3-yl]-propionate hydrochloride (15)
Method A. Operating under nitrogen and stirring, LiAlH4
(238 mg, 6.4 mmol) was suspended in dry THF (15 mL). Com-
pound (ꢀ)-16b (351 mg, 0.8 mmol) dissolved in anhydrous THF
(15 mL) was added and the solution was heated at reflux for 15 h.
A saturated solution of NH4Cl was added until no more gas was
formed. The mixture was extracted with AcOEt (3ꢃ10 mL). After
drying over Na2SO4, the solvent was removed under vacuum.
After column chromatography (CH2Cl2/MeOH, 10:1), compounds
Amino acid (ꢁ)-14 or (ꢀ)-14 (284.7 mg, 1 mmol) was suspended
in EtOH (10 mL) and SOCl2 (1 mL) was added. The mixture was
heated at reflux for 5 h under stirring. After solvent evaporation the
product was crystallized giving pure (ꢁ)-15 or (ꢀ)-15 (296 mg,
95%). Mp 195 ꢂC (acetone), colourless solid; [
a]
ꢁ15 (c 0.70,
D
MeOH); IR (KBr) nmax 3600–2700, 1692, 1610 cmꢁ1
;
1H NMR
(CD3OD)
d
7.33–6.98 (m, 4H, Ph), 3.93 (q, J¼7.0, 2H, OCH2), 2.70–

S. Pellegrino et al. / Tetrahedron 65 (2009) 1995–2004
2003
19 (126 mg, 68%) and 20a (20 mg, 10%) were isolated. Method B.
Compound (ꢀ)-16b (150 mg, 0.34 mmol) was dissolved in THF
(8 mL) and the solution was cooled to 0 ꢂC. A suspension of NaBH4
(26 mg, 0.68 mmol) in EtOH (1.5 mL) was dropped. The mixture
was left under stirring for 30 min at 0 ꢂC. The temperature was
raised to 25 ꢂC and then the mixture was heated at reflux for 2 h.
The solvent was removed under vacuum, EtOAc (10 mL) and
water (8 mL) were added to the residue. The layers were sepa-
rated, the organic one was dried over Na2SO4 and the solvent was
removed under vacuum. After column chromatography (CH2Cl2/
MeOH, from 10:0 to 10:1) compounds (ꢀ)-18 (100 mg, 40%),
(ꢀ)-20b (55 mg, 20%) were obtained. Method C. Operating under
nitrogen and stirring, LiAlH4 (30 mg, 0.8 mmol) was suspended in
dry THF (15 mL). Compound (ꢀ)-16a (278.4 mg, 0.8 mmol) or
(ꢀ)-16b (351 mg, 0.8 mmol) dissolved in anhydrous THF (15 mL)
was added and the solution was stirred at room temperature for
4 h. A saturated solution of NH4Cl was dropped until no more gas
was formed. The mixture was extracted with AcOEt (3ꢃ10 mL).
After drying over Na2SO4, the solvent was removed under vacuum
obtaining pure compound (ꢀ)-17 (16a: 196 mg, 80%; 16b: 182 mg,
75%). Method D. Operating as described for the preparation of 17,
starting from (ꢁ)-16a and using an excess of LiAlH4 (238 mg,
6.4 mmol) at reflux for 4 h, compound (ꢁ)-19 (146 mg, 79%) was
obtained as an oil. Method E. Compound 16b (150 mg, 0.34 mmol)
was dissolved in THF (8 mL) and the solution was cooled to 0 ꢂC. A
suspension of NaBH4 (26 mg, 0.68 mmol) in EtOH (1.5 mL) was
added. The mixture was left under stirring for 30 min at 0 ꢂC and
then was warmed to room temperature. After 7.3 h the solvent
was removed under vacuum, EtOAc (10 mL) and water (8 mL)
were added to the residue. The layers were separated, the organic
one was dried over Na2SO4 and the solvent was removed under
vacuum. After column chromatography (CH2Cl2/MeOH, from 10:0
to 10:1) compound (ꢀ)-18 (210 mg, 85%) was isolated from
(ꢀ)-16b. Crude compound, mixture of two diastereoisomers.
Method F. Starting from (ꢁ)-16b (150 mg, 0.34 mmol) operating as
described before, compound (ꢁ)-18 was obtained. The crude re-
action mixture was dissolved in toluene (15 mL) and a catalytic
amount of p-TSA was added. The mixture was stirred at reflux for
2 h. A solution of NaOH (2 M, 15 mL) was added and the organic
layer was separated. After drying over Na2SO4, the solvent
was removed affording pure compound (ꢁ)-20b (230 mg, 80%)
as an oil.
48.3, 60.1, 61.6, 62.3, 89.4, 114.1, 122.4, 122.9, 127.6, 134.4, 138.8,
155.9. Minor isomer, significative signals: 1H NMR
5.59 (s, 1H),
5.00 (br s, 1H, exch.), 3.62–3.50 (m, 2H; 13C NMR
¼62.1), 3.45–3.22
d
d
(m, 2H). Trace amount of other conformers is present in the NMR
spectra. (ESI) m/z 403.3 (MþNa)þ. Anal. Calcd for C19H28N2O6: C,
59.98; H, 7.42; N, 7.36. Found: C, 59.93; H, 7.48; N, 7.31.
3.14.3. 3-(1-Methyl-2,3,8,8a-tetrahydro-1H-pyrrolo[2,3-b]indol-
3a-yl)-propan-1-ol (ꢁ)-(19)
[
a
]
D ꢁ59 (c 0.80, CHCl3); IR (KBr) nmax 2852, 1698 cmꢁ1; 1H NMR
(CDCl3)
d
¼7.05–7.01 (m, 2H, Ph), 6.76–6.71 (m, 1H, Ph), 6.59 (d,
J¼7.8, 1H, Ph), 4.48 (s, 1H, H-8a), 3.87 (br s, 1H, exch., OH), 3.55 (t,
J¼6.4, 2H, CH2OH), 2.70–2.67 (m, 1H, H-2), 2.67–2.58 (m, 1H, H-2),
2.44 (s, 3H, Me), 2.08–1.99 (m, 2H, H-3), 1.99–1.78 (m, 2H,
CH2CH2OH), 1.65–1.35 (m, 3H, CH2CH2, CH2OH, NH); 13C NMR
(CDCl3)
d
¼29.2, 36.4, 37.0, 39.9, 52.5, 57.9, 63.1, 87.0, 109.5, 119.4,
123.6, 128.1, 134.9, 150.5. (ESI) m/z 233.2 (MþH)þ. Anal. Calcd for
C14H20N2O: C, 72.38; H, 8.68; N, 12.06. Found: C, 72.35; H, 8.71; N,
12.05.
3.14.4. 2-(2,3,4,4a,9,9a-Hexahydropyrano[2,3-b]indol-4a-yl)-N-
methylethanamine (20a)
Oil; IR (KBr) nmax 3500–3300, 1611 cmꢁ1 1H NMR (CDCl3)
;
d
¼11.65 (br s, 1H, exch., NHMe), 7.15 (t, J¼7.3, 1H, Ph), 7.07 (d, J¼7.2,
1H, Ph), 6.89 (t, J¼7.3, 1H, Ph), 6.78 (d, J¼7.8, 1H, Ph), 5.68 (s, 1H,
exch., NH), 5.63 (s,1H, H-9a), 3.58–3.39 (m, 3H, H-2, CHNH), 2.81 (d,
J¼4.4, 3H, Me), 2.66–2.52 (m, 2H, CHCHNH), 2.30–2.14 (m, 2H, H-4,
CHCHNH), 2.06–1.92 (m, 1H, H-4), 1.56–1.27 (m, 2H, H-3); 13C NMR
(CDCl3)
d
¼28.7, 34.6, 35.3, 38.3, 52.5, 58.3, 62.1, 87.0, 110.5, 120.8,
123.3, 129.2, 132.1, 149.3. (ESI) m/z 233.1 (MþH)þ. Anal. Calcd for
C14H20N2O: C, 72.38; H, 8.68; N, 12.06. Found: C, 72.00; H, 8.80; N,
11.95.
3.14.5. Ethyl 4a-(2-N-ethoxycarbonylethanamine)-2-(2,3,4,4a,9,9a-
hexahydropyrano[2,3-b]indole)-9-carboxylate (ꢁ)-(20b)
[
a
]
ꢁ40 (c 0.80, CHCl3); IR (KBr) nmax 3500–3300, 2925,
D
1711 cmꢁ1
;
1H NMR (CDCl3)
d
¼7.70 (d, J¼6.8, 1H, H-7), 7.29–7.05
(m, 4H, Ph), 6.06 (s, 1H, H-9a), 4.41–4.27 (m, 2H, OCH2), 4.18 (q,
J¼7.2, 2H, OCH2), 3.99 (dd, J¼6.5, 6.4, 1H, CHN), 3.84 (dd, J¼11.0, 7.6,
1H, H-2), 3.58 (dd, J¼6.4, 6.3,1H, H-2), 2.92 (ddd, J¼11.3, 6.2, 5.4,1H,
CHN), 2.17 (dd, J¼12.2, 5.4, 1H, CHCH2N), 2.03 (dd, J¼12.2, 7.6, 1H,
CHCH2N), 1.97–1.77 (m, 2H, H-4), 1.70–1.50 (m, 1H, H-3), 1.38 (t,
J¼7.1, 3H, Me), 1.34–1.12 (m, 4H, H-3, Me); 13C NMR (CDCl3)
¼14.9,
d
3.14.1. 3-[3-(2-Ethoxycarbonylaminoethyl)-2-oxo-2,3-dihydro-1H-
indol-3-yl]-propan-1-ol (ꢀ)-(17)
15.0, 28.6, 35.3, 37.2, 46.2, 54.2, 61.7, 62.3, 63.2, 80.8, 116.9, 123.3,
124.0, 126.3, 128.8, 129.1, 153.9, 155.1. (ESI) m/z 385.3 (MþNa)þ.
Anal. Calcd for C19H26N2O5: C, 62.97; H, 7.23; N, 7.73. Found: C,
62.93; H, 7.27; N, 7.70.
Mp 135 ꢂC (Et2O), colourless; IR (KBr) nmax 2933, 1713,
1620 cmꢁ1; 1H NMR (CDCl3)
d
¼8.71 (br s, 1H, exch., NH), 7.27–6.90
(m, 4H, Ph), 4.78 (br s, 1H, exch., NH), 4.02 (q, J¼7.0, 2H, OCH2), 3.48
(t, J¼7.0, 2H, CH2OH), 3.05–2.80 (m, 2H, CH2NH), 2.40–1.30 (m,
6Hþ1H exch., CH2CH2NH, CH2CH2CH2OH), 1.18 (t, J¼7.0, 3H, Me);
3.15. Isomerization of 20a to 19
13C NMR (CDCl3)
d
¼15.0, 25.9, 30.2, 34.6, 37.8, 52.0, 61.1, 62.8, 110.3,
123.3, 123.6, 129.2, 132.1, 141.1, 156.8, 182.1. (ESI) m/z 329.6
(MþNa)þ. Anal. Calcd for C16H22N2O4: C, 62.73; H, 7.24; N, 9.14.
Found: C, 62.70; H, 7.27; N, 9.11. A second isomer is present as
Compound 20a (10 mg, 0.04 mmol) was dissolved in dry CH2Cl2
(1 mL) and a catalytic amount of p-TSA was added. The mixture was
stirred at room temperature. After 16 h a solution of NaOH (0.5 mL,
25%) was added. The layers were separated and the aqueous one
was extracted with CH2Cl2 (2ꢃ2 mL). The organic layer was dried
over Na2SO4 and the solvent was evaporated giving compound 19
as an oil (8 mg, 83%).
evicted both in 1H NMR (
NMR (
d
¼9.15, br, exch.; 5.05, br s, exch.) and 13
C
d¼30.1, 37.4, 63.2) spectra.
3.14.2. 3-[3-(2-Ethoxycarbonylaminoethyl)-1-ethoxycarbonyl-2-
hydroxy-2,3-dihydro-1H-indol-3-yl]-propan-1-ol (18)
IR (KBr) nmax 3500–3300, 1687, 1647 cmꢁ1. Main isomer: 1H
NMR (CDCl3)
d
¼7.26–7.06 (m, 4H, Ph), 5.62 (s, 1H, H-2), 4.57 (br s,
3.16. Transformation of 18 into 20b
1H, exch., NH), 4.39 (q, J¼6.9, 2H, OCH2), 4.13–4.07 (m, 2H, OCH2),
3.75–3.62 (m, 2H CH2OH), 3.22–3.12 (br s, 1H, CHNH), 3.12–3.00 (br
s, 1H, CHNH), 1.98–1.67 (m, 4H, CH2CH2NH, CH2CH2OH), 1.60 (br s,
2H, exch., OH), 1.45–1.42 (m, 5H, CH2CH2CH2OH, Me), 1.26 (t, J¼7.1,
Compound 18 (20 mg, 0.05 mmol) was dissolved in toluene
(0.5 mL) and a catalytic amount of p-TSA was added. The mixture
was stirred at reflux for 2 h. A solution of NaOH (2 M, 0.5 mL) was
added and the organic layer was separated. After anhydrification
3H, Me); 13C NMR (CDCl3)
d
¼13.9 (ꢃ2), 27.4, 29.0, 35.8, 37.0, 44.9,

2004
S. Pellegrino et al. / Tetrahedron 65 (2009) 1995–2004
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We thank MIUR (PRIN 2006) for financial support. The ‘Centro
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Supplementary data
Spectroscopic discussion for compounds 17–20; HPLC data for
compounds 12; X-ray data for compound (ꢁ)-12a; Cartesian co-
ordinates, absolute energies, thermochemical corrections number
and value of imaginary frequencies for all the stationary points
herein mentioned. Supplementary data associated with this article
can be found in the online version, at doi:10.1016/j.tet.2009.01.004.
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