H. Miyamoto et al. / Tetrahedron Letters 48 (2007) 1805–1808
1807
b
a
N
N
20
Me
Me
N
H
N
H
Bn
21
d
( )-debromoflustramine B (2)
O
N
c
Me
N
N
H
Me
N
H
H
( )-debromoflustramine E (5)
( )-debromoflustramide B (3)
Scheme 3. Reagents and conditions: (a) AlH3ÆEtNMe2, THF, room temperature, 10 min, 87%; (b) Na, liq NH3/THF, ꢀ78 °C, 15 min; then prenyl
bromide, ꢀ78 °C, 30 min to room temperature, 92%; (c) Na, liq NH3/THF, ꢀ78 °C, 15 min; then Ph2O, i-PrOH, ꢀ78 °C to room temperature, 91%;
(d) prenyl bromide, Na, liq NH3/THF, ꢀ78 °C, 15 min; then Ph2O, ꢀ78 °C to room temperature, 65%.
acid 16. Ketoacid 16 was then converted into exo-meth-
ylene 17 by Wittig olefination with the ylide generated
from methyltriphenylphosphonium bromide and n-BuLi
in 75% yield from 14. Treatment of exo-methylene 17
with concd H2SO4 in the presence of MgSO4 resulted
in the desired isomerization to an internal olefin, afford-
ing 18 as a 20:1 mixture with 17. Carboxylic acid 18 was
transformed to an amide 19, by the mixed anhydride
method using ethyl chloroformate and MeNH2, in
65% yield from 17.7c The lactam carbonyl group of 19
was reduced chemoselectively by an excess of
AlH3ÆEtNMe2 complex at ꢀ15 °C for 5 min, to afford
the cyclized amide 20 in 89% yield.7a
utility of oxindole 14 as a synthetic intermediate of hexa-
hydropyrrolo[2,3-b]indole alkaloids bearing a prenyl
group at C-3a. Further applications of this methodology
including a synthesis of optically active flustramines are
in progress.
Acknowledgments
Support for this research was provided by Chugai Phar-
maceutical Co., Ltd. (A.N.). We thank Professor Masa-
nori Somei (Kanazawa University) for the helpful
discussions.
For the synthesis of 21, which serves as a common pre-
cursor of ( )-debromoflustramine B and E, lactam 20
was further reduced with AlH3ÆEtNMe2 complex, and
the desired tricyclic compound 21 was obtained in 87%
yield (Scheme 3).7a Synthesis of ( )-debromoflustramine
B from 21 was accomplished using a modification of
Bruncko’s protocol7b as follows: N-benzyl derivative
21 was subjected to a Birch reduction with Na in liquid
NH3, followed by the addition of prenyl bromide to the
reaction mixture to obtain ( )-debromoflustramine B
(2) in 92% yield. Synthesis of ( )-debromoflustramine
E (5) was also carried out by Birch reduction and
quenching the reaction mixture with Ph2O and i-PrOH,
giving 5 in 91% yield.11 Transformation of 20 to ( )-
debromoflustramide B (3) was best accomplished by
Birch reduction in the presence of prenyl bromide, fur-
nishing the product in 65% yield. The 1H and 13C
NMR spectra of our synthetic 2, 3 and 5 are consistent
with the reported data.7j
Supplementary data
Supplementary data associated with this article can be
References and notes
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´
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In conclusion, we have completed the total synthesis of
( )-debromoflustramine B and E and ( )-debromoflus-
tramide B based on intramolecular Ullmann coupling
and Claisen rearrangement. We also demonstrated the
´
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