LETTER
Synthesis of Isoindolobenzazepine Alkaloid, Lennoxamine
3409
OHC
Br
O
O
O
Cl
O
6
MeO
MeO
O
O
MeO
MeO
MeO
MeO
O
O
N
PMB
N PMB
MeO
MeO
SPh
c
N
PMB
b
a
N
PMB
SPh
O
O
O
8
7
9
10
O
O
MeO
MeO
MeO
O
N
O
N
O
MeO
MeO
MeO
H
N H
d
e
f
O
O
OH
12
O
11
O
O
O
5: lennoxamine
Scheme 1 Reagents and conditions: (a) 1, DIBAL-H, THF, –78 °C, 2, PhSH, BF3·OEt2, CH2Cl2, 61% (two steps); (b) LDA, HMPA, THF,
53%; (c) LiAlH4, CuI, THF, –40 °C, 86%; (d) TFA, 80 °C, 70%; (e) 1, OsO4, NMO, THF–H2O (1:1), 2, NaIO4, THF–H2O (1:1), 3, NaBH4,
THF–H2O (4:1), 42% (three steps); (f) 1, MsCl, Et3N, CH2Cl2, 2, NaH, THF, 58%.
mL) was added N-(p-methoxybenzyl)-3-benzyl-3-phenyl-
thiophthalimidine (0.100 g, 0.221 mmol) in THF (1 mL) at
–20 °C. After the mixture was stirred for 30 min at the same
temperature, it was quenched with the addition of aq Et2O (1
mL) and filtered with celite pad, followed by extraction with
EtOAc (3 × 20 mL). The combined organic layers were dried
(Na2SO4) and concentrated in vacuo. The crude was
chromatographed and eluted with hexane–EtOAc (5:1) to
give N-(p-methoxybenzyl)-3-benzylphthalimidine (0.071 g,
0.208 mmol) in 94% isolated yield. 1H NMR (CDCl3): d =
2.81 (dd, J = 8.1, 13.4 Hz, 1 H), 3.37 (dd, J = 5.0, 13.6 Hz, 1
H), 3.79 (s, 3 H), 4.15 (d, J = 15 Hz, 1 H), 4.55 (dd, J = 4.8,
8.1 Hz, 1 H), 5.40 (d, J = 15 Hz, 1 H), 6.83–7.44 (m, 12 H),
7.81–7.84 (m, 1 H). IR (thin film): 747, 1032, 1250, 1514,
1690 cm–1.
In summary, we have disclosed herein the instructive ex-
ample of the reductive desulfurization reaction of a wide
range of g-phenylthio-substituted aromatic lactams medi-
ated by lithium aluminum hydride in the presence of cu-
prous iodide, whose process found application in the
novel synthetic strategy of a structurally sophisticated and
biologically important isoindolobenzazepine alkaloid,
lennoxamine.
Acknowledgment
This work was supported in part by a Grant-in-Aid for Scientific
Research from Japan Society for the Promotion of Science.
(5) For isolation and characterization, see: (a) Valencia, E.;
Freyer, A. J.; Shamma, M.; Fajardo, V. Tetrahedron Lett.
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Under N2 atmosphere, to a black solution of LiAlH4 (0.025
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Synlett 2006, No. 20, 3407–3410 © Thieme Stuttgart · New York