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