Background and Originality Content
Piperazic
acid (Piz), a non-proteinogenic
amino acid bearing a unique cyclic hydrazine side chain, has been found
in more than 30 families of natural products (over 140 compounds), many
of which possess potent biological activities.[1]Like conformationally rigid proline, the Piz residue may also act as a
turn-inducing motif in the structure of these peptides, furthermore
another nucleophilic nitrogen of Piz potentially confers some
significant structural and biological effects.[2]Chemically, N1 nitrogen is more nucleophilic than
N2 nitrogen in the Piz structure, but
biological outcomes are often surprising as N2 nitrogen is usually
selected to form the amide bond in the backbone of most Piz-containing
natural products only except for
sanglifehrin[3]. As free Piz has been proved to be
directly adenylated and incorporated into the nonribosomal
peptides,[4] enzymes may overcome this barrier via
active site orientation, acid-base reactions, and/or coupled enzymatic
reactions. However, chemists tend to solve this synthetic problem by
adopting two various protective groups of nitrogens, leading to a
prolonged synthetic route and lowered synthetic efficiency.[5,6] Free and N -protected Piz can be
obtained from diverse asymmetric
synthetic strategies: chiral
substrate[7], chiral auxiliary[8-10], or chiral
catalyst[11], as such. Among them, Chen et
al developed one of the most concise synthetic method of
N1,N2-diCbz-Piz via proline-catalyzed asymmetric α-hydrazination,
oxidation, and cyclization (3 steps from commercially available
reagents).[11] Thus N1,N2-diCbz-Piz is preferred
as the building block to construct Piz-containing natural products and
analogs. However, the tedious
handlings of protecting groups were also needed to realize selective
amide condensation of N2 nitrogen (Figure 1A). Since selective removal
of N2-Cbz at N1,N2-diCbz Piz was mentioned available with the aid of
adjacent carboxy group,[11] we speculated that
selective deprotection of N2-protecting group (Cbz) at late-stage,
posterior to the direct coupling of
the carboxylic acid within the N1,N2-diCbz Piz residue would be superior
for the syntheses of Piz-containing natural products (Figure 1B), to the
usually adopted orthogonal protecting strategy with deprotecting
N1,N2-diCbz into free Piz at initial stage (Figure 1A)
Figure 1 Synthetic
strategies to assemble piperazic acid-containing peptides.
Therefore, we commenced to try
late-stage selective deprotection
strategy to synthesize the Piz-containing cyclodepsipeptide core of
Verucopeptin (VE), an antibiotic isolated from Philippino soil
microorganism Actinomadura verrucospora in 1993. Structurally, VE
is composed of a
cyclodepsipeptide core, a
hemiketal formed tetrahydropyran ring, and a tetramethyl-substituted
carbon chain with 3 chiral centers. [12-15] A
pyranylated dipeptide composed of Piz and
(2S ,3S )-3-hydroxyleucine, and an N-hydroxylated amide in
C-terminal of Piz (red segments in Figure 2) are common features in the
class of cyclic hexadepsipeptides including azinothricin, diperamycin,
aurantimycin A and VE (Figure 2).
Among them, VE exhibits potent antiproliferative activities against a
wide range of cancer cell lines and was recently identified as a potent
chemotherapeutic agent against multidrug-resistant (MDR) cancers, by
targeting vacuolar
H+-ATPase.[16]
Figure 2 Representative structures of Verucopeptin family with
the Piz-containing cyclodepsipeptide core.
Hale’s group reported a [2 + 2
+ 2]-fragment condensation strategy to construct the cyclodepsipeptide
core of VE in total 18 steps from known
compound.[17] Until 2019, Kakeya et al
accomplished the first total synthesis of VE, in which the
cyclodepsipeptide core 2 was synthesized via the combination of
solid phase peptide synthesis (SPPS), and
macrolactamization as well as
dispositions of protecting groups in solution phase (Scheme
2).[18]However, more efficient synthesis
is still in demand for the further mechanism study and drug-like
derivatization of VE members.
Herein,
we report an efficient chemical synthesis toward cyclodepsipeptide core2 of VE (Scheme 2). We envision that the amide bond between N9
and C10 can serve as the final lactamization site for the cyclic peptide
core, and the resulting cyclization precursor 3 can be
constructed via challenging amide condensation between acid chloride4 and dipeptide 5 , which allows reduced synthetic
steps of substrates bearing the expensive non-proteinogenic amino acids.
Although AgCN has been proved to promote the coupling of N2 nitrogen in
Piz with 3-hydroxyleucine,[19] the applicability
of this strategy to more complex acid derivatives 4 also needs
verifying. Piz-containing dipeptide 5 would be prepared via
selective deprotection of N2-Cbz in 8 , posterior to the
coupling of 9 and 10 . Esterification between readily
available tripeptide 6 and alcohol 7 , followed by
deprotection and chlorination of carboxylic acid, would furnish4 in 3 steps.
Scheme 1 Synthetic strategies to cyclodepsipeptide fragment of
VE