Stereoselective Transformation of Indole Diazabicyclo[3.2.2]nonedione to Azepinoindole

Article abstract of DOI:10.1021/ol0271990

(Matrix Presented) The synthesis of an indole diazabicyclo[3.2.2]nonedione derivative was achieved in a few steps starting from L-tryptophan. Reduction with borane - THF complex leads to fragmentation of the bicycle and the stereoselective formation of an

Full text of DOI:10.1021/ol0271990

ORGANIC
LETTERS
2002
Vol. 4, No. 26
4709-4712
Stereoselective Transformation of Indole
Diazabicyclo[3.2.2]nonedione to
Azepinoindole
,†
,§
David Orain,† Re´gis Denay,‡ Guido Koch,* and Rudolf Giger*
NoVartis Pharma AG, Core Technology, Combinatorial Chemistry Unit, WSJ-507.7.04
Lichtstrasse 35, CH-4056 Basel, Switzerland, NoVartis Pharma AG, Core Technology,
NMR Analytic, WSJ-503.12.01, CH-4056 Basel, Switzerland, and NoVartis Ophthalmics
AG, WKL-127.1.84B, Klybeckstrasse 141, CH-4057 Basel, Switzerland
guido.koch@pharma.noVartis.com
Received October 30, 2002
ABSTRACT
The synthesis of an indole diazabicyclo[3.2.2]nonedione derivative was achieved in a few steps starting from L-tryptophan. Reduction with
borane−THF complex leads to fragmentation of the bicycle and the stereoselective formation of an azepinoindole derivative was observed.
We would like to report in this letter a novel and efficient
route to access 2S,5S disubstituted azepinoindoles from
L-tryptophan. The key transformation of the reaction se-
quence is the stereoselective fragmentation of an indole
diazabicyclo[3.2.2]nonedione with borane-THF complex.
In the eighties, Ottenheijm and co-workers reported the
synthesis of an indole diazabicyclo[3.2.2]nonedione deriva-
tive starting from indole-3-pyruvic acid.1 The key step was
the intramolecular Pictet-Spengler reaction between a R-ke-
toamide and an amide group. In 1996, using the same
strategy, Mortier and co-workers reported the synthesis of a
similar compound starting from an arylidene piperazidione
derivative.2 In both cases, achiral starting materials were used
and led to racemic diastereomeric mixtures of bicyclic
compounds. The same key step was used by Czarnocki in
the diastereoselective synthesis of 1-benzyltetrahydroiso-
quinoline.3
L-Tryptophan 1 was used as starting material for the
synthesis of chiral indole diazabicyclo[3.2.2]nonedione skel-
etons. Amide bond formation was carried out under standard
conditions to give the ethyl amide derivative 2 quantitatively.
After Boc deprotection, the nitrogen was N-benzylated in a
two-step procedure. Acylation of the acyclic precursor 3 with
pyruvyl chloride4 gave the intermediate R-ketoamide deriva-
tive, which was not isolated and was exposed directly to TFA
to afford the bicycle 4 in good yield via a Pictect-Spengler-
type cyclization (Scheme 1).
Compound 4 was submitted for in-house water-solubility
measurements where it was classified in a medium range
(value around 0.05 g/L) but with no measurable pKa. To
improve solubility, it was decided to reduce the amide groups
to tertiary amines. The reduction methodology was chosen
carefully in order to be compatible with solid-phase supports
in view of exploratory work. The selected reaction protocol
used a borane-THF complex reduction followed by a mild
oxidative workup procedure (iodine, triethylamine, and
† Novartis Pharma AG, Core Technology, Combinatorial Chemistry Unit.
‡ Novartis Pharma AG, Core Technology, NMR Analytic.
§ Novartis Ophthalmics AG.
(1) (a) Ottenheijim, H. C. J.; Plate, R.; Noordik, J. H.; Hersheid, J. D.
M. J. Org. Chem. 1982, 47, 2147. (b) Plate, R.; Nivard, R. J. F.; Ottenheijim,
H. C. J. J. Chem. Soc., Perkin Trans. 1 1987, 2473.
(2) Moyroud, J.; Gelin, J.; Cheˆne, A.; Mortier, J. Tetrahedron 1996, 52,
8525.
(3) Zawadzka, A.; Leniewski, A.; Maurin, J. K.; Wojtasiewick, K.;
Czarnocki, Z. Org. Lett. 2001, 3, 997.
(4) Ishibashi, H.; Kobayashi, T.; Machida, N.; Tamura, O. Tetrahedron
2000, 56, 1469.
10.1021/ol0271990 CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/27/2002

Scheme 1a
Scheme 2a
a Reaction conditions: (i) (a) BH3‚THF (10 equiv), THF, rt, 16
h, (b) MeOH, TEA, I2, THF, rt, 2 h (95%); (ii) (a) BH3‚THF (10
equiv), THF, 80 °C, 24 h, (b) MeOH, TEA, I2, THF, rt, 2 h (60%);
(iii) 4-NO2ArCOCl, TEA, DCM, rt, 2 h (80%).
a Reaction conditions: (i) EtNH2‚HCl, TEA, HOBt, DCC, THF,
rt, 16 h (100%); (ii) 4 N HCl/MeOH, rt, 6 h; (iii) Na2CO3, PhCHO,
TMOF, MeOH, rt, 16 h; (iv) NaBH4, MeOH, rt, 1 h (70%, 3 steps);
(v) MeCOCOCl, TEA, DCM, 0 °C, 1 h then aqueous workup; (vi)
20% TFA/DCM, rt, 2 h (80%, 2 steps).
derivative 7.6 The 3-D structure showed relative trans
configuration between the two substituents (Figure 1).
methanol).5 In the first reduction experiment, 4 was treated
in THF with 10 equiv of BH3‚THF at 50 °C for 6 h. No
more starting material was observed and two new products
were detected by HPLC. The completely reduced material
was not detected by LC/MS. The first product had a mass
+ 14 (corresponding to a monoreduced derivative) and the
second product had a mass + 2 (rupture of a C-C bond).
The two derivatives were isolated by flash chromatography
on silica gel, analyzed, and characterized. They were assigned
to the structures 5 and 6. Conditions for selective formation
of 5 and 6 were optimized. When the reduction was carried
out at rt, 5 was obtained selectively whereas at higher
temperature (80 °C) 6 was the major product. In addition,
we observed that 5 represents an intermediate in the
formation of 6. In fact, when 5 was reacted with borane-
THF complex, 6 was obtained (Scheme 2).
The first amide bond reduction took place from the less
hindered face of the molecule to give 5. The amide group at
the lower face of the molecule is shielded by the N-ethyl,
N-benzyl, and exo-methyl groups whereas only the N-ethyl
and N-benzyl groups surround the amide group of the upper
face. The second amide reduction was more demanding from
an energetic point of view and required higher reaction
temperature; however, no formation of the expected diaz-
abicyclononene was observed. From NMR analysis, it was
not possible to assign the relative configuration of the two
stereocenters (cis or trans) of 6. Different derivatives were
synthesized to obtain suitable crystals for X-ray analysis.
Finally, the structure was solved for the nitrobenzoate
Figure 1. X-ray of 7‚MeOH.
The water-solubility of the azepinoindole was measured
in-house and showed at pH 6.8 low solubility (<0.001 g/L)
for R ) H, and good solubility (>0.1 g/L) was observed for
R ) Ac with measurable pKa at 9.8 and 4.2.
To propose a reaction mechanism, a couple of transforma-
tions were carried out. When 4 was treated with a 1 M
solution of LiAlH4 in THF at 60 °C for 3 h, the tetrahydro
compound 8 was obtained in 60% yield and no fragmentation
was observed. When 8 was treated with borane-THF
complex at 80 °C, the fragmentation product 6 was obtained.
Therefore, the observed fragmentation does not require the
presence of an amide group (Scheme 3).
(5) Hall, D. G.; Laplante, C.; Manku, S.; Nagendran, J. J. Org. Chem.
1999, 64, 698.
(6) CCDC 189473 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge via www.ccdc.ca-
m.ac.uk/conts/retrieving.html (or from the Cambridge Crstallographic Data
Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax (+44) 1223-336-
033; e-mail deposit@ccdc.cam.ac.uk).
To investigate the role of the indole system, compound 4
was reduced with sodium cyanoborohydride in TFA.7 Two
diastereoisomers (only major shown) were obtained in a 6/1
4710
Org. Lett., Vol. 4, No. 26, 2002

Scheme 3a
Scheme 5a
a Reaction conditions: (i) 1 M LiAlH4/THF, 60 °C, 3 h (60%),
(ii) (a) BH3‚THF (20 equiv), THF, 75 °C, 24 h, (b) MeOH, TEA,
I2, THF, rt, 2 h (80%).
ratio in favor of diastereoisomer 9 bearing the two hydrogens
in the same side of the N-ethyl amide (less hindered face).
The amide bond reduction was carried out under identical
reaction conditions as for conversion of 4 to 6. No frag-
mentation was observed and the reduced material 10 was
quantitatively obtained as a borohydride complex (Scheme
4).
a Reaction conditions: (i) EtNH2‚HCl, TEA, HOBt, DCC, THF,
rt, 16 h (82%); (ii) 4 N HCl/MeOH, rt, 6 h; (iii) Na2CO3, PhCHO,
TMOF, MeOH, rt, 16 h; (iv) NaBH4, MeOH, rt, 1 h (70%, 3 steps);
(v) MeCOCOCl, TEA, DCM, 0 °C, 1 h; (vi) 10% TFA/DCM, 50
°C, 16 h (84%, 2 steps); (vii) BH3‚THF (10 equiv), THF, 70 °C,
16 h; (viii) MeOH, TEA, I2, THF, rt, 2h (60%, 2 steps).
served (Scheme 6). Modeling of 14 gave a torsion angle of
10° for the CdC-C(Me)-N, which allowed no possible
overlap of the orbitals.
Scheme 4a
Scheme 6a
a Reaction conditions: (i) TFA, NaBH3CN (6 equiv), rt, 30 min
(70%), (ii) (a) BH3‚THF (10 equiv), THF, 80 °C, 24 h, (b) MeOH,
TEA, I2, THF, rt, 2 h (90%).
To explore the scope and limitation of this novel frag-
mentation, tryptophan was replaced by 3,4-dimethoxy L-
DOPA. The same reaction sequence was carried out to obtain
the [3.2.2] bicycle. When 12 was subjected to the borane
reduction step, bireduced compound 13 was obtained with
one boron complexed to the adduct. No fragmentation was
observed (Scheme 5).
The series of experiments demonstrates that the indole ring
and the presence of boron are essential for the fragmentation,
therefore a possible mechanism for the stereoselective
formation of 6 was postulated (Scheme 7). The final product
of the reduction (tetrahydro derivative 5a) was obtained as
a borane complex. This intermediate could probably undergo,
under heating, a boron-assisted retro-Michael addition or an
aza-type fragmentation.8 Computer modeling shows a torsion
angle of 58.6° for CdC-C(Me)-N allowing a possible
overlap of the π orbital of CdC and the C-N bonds which
helps to facilitate the fragmentation. In addition, when similar
conditions of amide bond reduction were used for an indole
diazabicyclo[3.3.1]nonenone,9 no fragmentation was ob-
a Reaction conditions: (i) (a) BH3‚THF (20 equiv), THF, 75 °C,
24 h, (b) MeOH, TEA, I2, THF, rt, 2 h (65%).
In the second step, one hydride from a molecule of BH3
(in excess in the reaction mixture) complexed to the
secondary nitrogen 5b is transferred to the Michael acceptor
from the top face to afford 6 (Scheme 7).
Scheme 7. Proposed Mechanism for the Transformation of 5
to 6
(7) Royer, D.; Doe´ de Maindreville, M.; Laronze, J.-Y.; Le´vy, J.; Wen,
R. Tetrahedron 1996, 52, 9069.
(8) Wang, J.-J.; Hu, W.-P.; Chung, H.-W.; Wang, L.-F.; Hsu, M.-H.
Tetrahedron 1998, 54, 13149.
(9) Orain, D.; Canova, R.; Dattilo, M.; Klo¨ppner, E.; Denay, R.; Koch,
G.; Giger, R. Synlett 2002, 1443.
In conclusion, we have shown an efficient synthesis of
chiral indole [3.2.2] bicycles that can be used as starting
material to obtain azepinoindole derivatives stereoselectively.
Org. Lett., Vol. 4, No. 26, 2002
4711

Acknowledgment. The authors thank Prof. S. Ley and
Prof. D. Seebach for their helpful suggestions, Dr. B. Faller
for the water-solubility measurements, Mr. H. Walter for the
X-ray analyses, Dr. F. Stoll for modeling, Novartis Chemistry
Council for funding (D.O.), and the CCU staff for their
support.
Supporting Information Available: Detailed descrip-
tions of experimental procedures for the synthesis of 4, 5,
6, 8, 9, 12, and 13. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL0271990
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Org. Lett., Vol. 4, No. 26, 2002