Total Synthesis and Structure Elucidation of JBIR‐39: A Linear Hexapeptide Possessing Piperazic Acid and γ‐Hydroxypiperazic Acid Residues

Abstract

The total synthesis and stereochemical structural elucidation of JBIR-39, containing four nonproteinogenic piperazic acid (Piz) residues, is reported. The synthesis includes Sc(OTf)3 -catalyzed acylation of a Piz(γ-OTBS) derivative with piperazic acid chloride, providing the desired Piz-Piz(γ-OTBS) dipeptide in high yield without epimerization. After assembling two additional Piz moieties and (S)-isoleucic acid at the N-terminus, amidation with the (R)-α-methylserine ester at the C-terminus, and deprotection afforded the desired (2R,8S)-hexapeptide, which is the assumed structure of JBIR-39. Although the spectral data of the (2R,8S)-hexapeptide was not identical to JBIR-39, further synthesis of three stereoisomers confirmed the stereochemical structure of JBIR-39 to be (2S,6S,8S,11R,16S,21R,26S,27S).

Synthetic and biosynthetic routes to nitrogen–nitrogen bonds

“…42,43 Compound 33 was also used as the building block for total synthesis of 26. 29 Strecker amino acid synthesis can also be used to produce (3R,5R)-5-hydroxypiperazic acid. Hydrazone precursor 43 was prepared from aldehyde 42 treated with hydrazine and then protected with benzoyl chloride.…”

“…25 Compounds ( S )- 20–24 could be obtained using the chiral auxiliary with the opposite configuration. Precursors 21 and 22 were widely used for total synthesis of piperazic acid-containing compounds, such as chloptosin 25 , 26–28 JBIR-39 26 , 29 azinothricin 27 30 and its analogs kettapeptin 28 and A38586C 29 . 31,32 The absolute structure of cyclic hexapeptide antibiotic NW-G01 30 , which contains one ( R )-piperazic acid and two ( S )-piperazic acid residues, was determined by total synthesis employing R / S - 23 as building blocks.…”

Concise Total Synthesis and Biological Evaluation of Pargamicin A and its Diastereomer, Piperazic Acid‐containing Cyclopeptides

“…Therefore, the direct coupling of piperazic acid derivatives is preferable as it would facilitate a simple and concise analog synthesis, which would allow the elucidation of structure-activity relationships. Based on a direct coupling approach, we have already successfully achieved the total synthesis of the piperazic acid-containing natural products JBIR-39 [11] and hytramycin V. [12] Herein, we report a concise total synthesis of pargamicin A (1) and one of its diastereomers via the direct coupling of piperazic acid derivatives under ambient conditions. Additionally, we report on the antibacterial activity of 1 and the diastereomer against several gram-negative bacterial strains including MRSA and VRE.…”

Total Synthesis of Pargamicin A

“…Candidate sites for macrolactamization in PrgA are limited due to the presence of a single secondary amide linkage between the d -Phe and Sar residues. Moreover, difficulties associated with incorporating preformed Nε-protected Piz residues into such sequences are well-documented and are attributed to steric bulk and strong electronic deactivation from the N α -(acyloxy)­amino group. , We expected that a more efficient assembly of the peptide chain could be achieved using protected linear precursors to the d -Piz and γ-OH- d -Piz residues and formation of the diazinane rings at a late stage of the synthesis (Figure ). At the outset of our campaign, we also hypothesized the configuration of the unassigned ( N -OH)-Ile residue to be 2 S ,3 S based on the alternating l / d pattern found in related macrocyclic nonribosomal hexapeptide natural products…”