Though the pharmaceutical potential of these natural com-
pounds is high, isolation and purification of larger quantities
of this class of products is difficult. The development of
synthetic strategies for natural compounds and their ana-
logues is essential for the discovery of lead compounds of
this type for use in drug discovery.4
enzymes hydrolyzing the ester bond and the thioester
bond.9 Our recent studies have shown that a cyclic peptide
can be formed through direct aminolysis of a peptide
benzylthioester catalyzed by imidazole.10 The generally
accepted mechanism of the imidazole catalysis involves
the reaction intermediates of acyl imidazole and the acyl
imidazolium cation, which are formed by the direct attack
of imidazole on the carbonyl group. This mechanism can
also be envisioned for the formation of a cyclic depsipep-
tide by macrolactonization. The mild imidazole-catalytic
condition may also eliminate the risk of racemization
during acyl activation. Herein, we report a imidazole-
catalytic approach for the synthesis of cyclic depsipeptides
by macrolactonization of peptide thioesters and the use
of this application in the synthesis of kahalalide B and
its analogues.
The most commonly used methodology for the synthesis
of cyclic depsipeptide involes cyclization of a linear
depsipeptide containing an internal ester bond. The
intramolecular macrolactamization can be carried out
either in solution or on resin.5 Problematically, the
endoester bond may break during the acidic cleavage when
a typical solid-phase synthetic strategy is applied to make
the linear precursor and/or cyclic product. The choice of
resins is thus limited, and some of the widely used resins,
which require strong acidic cleavage conditions, cannot
be successfully used. To overcome this limitation, mac-
rolactonization is a favorable alternative. Since the lac-
tonization is much less efficient than the lactamization
under conventional coupling conditions, synthesis of cyclic
depsipeptides by this strategy is rarely reported and
remains a challenge.6
Biosynthesis of cyclic depsipeptides through peptide
synthetase has been reported by using peptide thioester
as substrate.7 Studies of different peptide synthetase
systems suggest the possibility that a histidine residue
functions as a catalyst of condensation/elongation/cycliza-
tion reaction in the peptide synthesis.8 Imidazole has been
reported as a catalyst mimicking the histidine residues of
The stepwise synthesis of the linear peptides starts with
functionalized mercaptomethylphenyl silica gel 1 as the
“volatilizable” support (Scheme 1).11 PyBOP/DIEA was
used as the protected amino acid activation reagent to
generate resin bound 2. Boc-glycine was coupled on the
resin as the C-terminal residue based on the structure of
kahalalide B. After removal of the Boc group with 55%
TFA, threonine, proline, D-leucine, phenylalanine, D-
serine, tyrosine, and 5-methylhexanoic acid were coupled
stepwise to form the on-resin synthetic precursor of
kahalalide B 3a. The resin-bound 3a was then treated with
anhydrous HF for 2 h at 0 °C. Following evaporation of
the anhydrous HF with a gaseous nitrogen stream, the
unprotected peptide thioester 4a was obtained following
lyophlization.
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Xxx was Ser or Thr. It was found the concentration of
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