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