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W.; Gum, A. Green Chem. 2004, 6, 128–141; (b) Swamy,
K. M. K.; Yeh, W.-B.; Lin, M.-J.; Sun, C.-M. Curr. Med.
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15. General procedure for the microwave-accelerated synthe-
sis of tetrahydro-b-carbolinediketopiperazines. In a typi-
cal reaction, (S)-tryptophan methyl ester (40mg,
0.16mmol) was dissolved in [bdmim][PF6]/THF (1:1, v/v;
1mL) containing trifluoroacetic acid (10%, v/v). The
aldehyde (1.89mmol) was added in one portion and
allowed to react at 60ꢀC under microwave irradiation
(60W, Synthewave 402, Prolabo, France) condition in an
open reaction vessel. The reaction was allowed to proceed
until tryptophan methyl ester was completely consumed as
monitored by TLC using the ninhydrin test (typically 25s).
Upon completion of the reaction, the reaction mixture was
concentrated to dryness under reduced pressure to obtain
the Pictet–Spengler adduct as a dissolved residue in ionic
liquid. At the end of the first step, no attempts for product
isolation and purification were made.
4. Yang, J. J.-Y.; Chen, S.-T.; Chu, Y.-H. In Optimization of
Solid-Phase Combinatorial Synthesis; Yan, B., Czarnik,
A., Eds.; Marcel Dekker: New York, USA, 2001; pp 305–
315, Chapter 14.
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carbolinediketopiperazines prepared on solid phase, see:
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13. For recent examples of microwave-accelerated Pictet–
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The Pictet–Spengler reaction product, tetrahydro-b-carbo-
line methyl ester, was then mixed with DIEA (5equiv) in
[bdmim][PF6]/THF (1:1, v/v; 1mL). To the reaction
solution, the Fmoc-protected (S)-proline acid chloride
(5equiv) prepared from Fmoc-proline and excess thionyl
chloride in dichloromethane (1mL) was added to proceed
the acylation reaction for 3min at ambient temperature.
After the acylation reaction, the solution mixture was
washed with 5% citric acid solution (3·) and dried over
anhydrous Na2SO4. The resulting organic layer was
evaporated in vacuo to yield a viscous oil.
The oil was dissolved in [bdmim][PF6]/THF (1:1, v/v;
1mL) containing 20% (v/v) piperidine to carry out the final
cyclization-upon-deprotection reaction at 60ꢀC under
microwave irradiation (60W) condition, again, in an open
reaction vessel. The reaction was allowed to proceed until
the protected dipeptide ester was completely consumed
and cyclized as monitored by TLC (typically 60s). Upon
completion of the total three-step synthesis, the solution
mixture containing the desired tetrahydro-b-carboline-
diketopiperazine was concentrated in vacuo and purified
by silica gel flash column chromatography (ethyl acetate/
hexane = 1:3). The products were afforded as off-white
solid.
16. In this work, the desired products were isolated as a
mixture of cis/trans-isomers of tetrahydro-b-carboline-
diketopiperazines with various diastereomeric ratios.
Because we would like to have the access to both isomers
for further biological activity investigation, our synthesis
of tetrahydro-b-carbolinediketopiperazines was carried
out under nonstereoselective conditions and both diaste-
reomers could be separated and purified chromatograph-
ically (ethyl acetate in hexane, from 40% to 60%).
Although previous studies on the Pictet–Spengler reac-
tions (the first step of this three-step synthesis) have
documented that several factors including reaction tem-
perature and the size of substituents at C-1 and N-2 of the
tetrahydro-b-carboline can influence the outcome of
diastereomeric ratios of the products11 and, in addition,
our preliminary result has showed that no reaction
racemization was observed under rapid microwave-accel-
erated chemical synthesis of tetrahydro-b-carbolines,4 it
appeared that in this work our three-step synthesis of
tetrahydro-b-carbolinediketopiperazines from tryptophan
methyl ester carried out at ambient temperature and under
low-power microwave irradiation gave no apparent sim-
ilar preference for a particular product isomer.