Total Synthesis and Initial Structure–Activity Relationships of Longicatenamycin A

Abstract

Natural products have provided the majority of lead structures for marketed antibacterials. In addition, they are biological guide principles to new therapies. Nevertheless, numerous “old” classes of antibiotics such as the longicatenamycins have never been explored by chemical postevolution. Longicatenamycin A is the first defined longicatenamycin congener that has been totally synthesized and tested in pure form. This venture required the de novo syntheses of the non‐proteinogenic amino acids (2S,3R)‐β‐hydroxyglutamic acid (HyGlu), 5‐chloro‐D‐tryptophan (D‐ClTrp), and (S)‐2‐amino‐6‐methylheptanoic acid (hhLeu). In the key step, the sensitive HyGlu building block was coupled as a pentafluorophenyl active ester to the unprotected H‐D‐ClTrp‐Glu‐hhLeu‐D‐Val‐D‐(Cbz)Orn‐OH fragment. This first total synthesis of longicatenamycin A provided new congeners of the natural product (deacetyllongicatenamycin, dechlorolongicatenamycin, and longicatenamycin‐A‐amide).

Gausemycins A,B: Cyclic Lipoglycopeptides fromStreptomycessp.**

“…10,11 β-Hydroxyglutamic acid (hGlu4, Figure 2) rarely occurs in natural peptides as several diastereomers. [29][30][31][32][33] 3-Amino-4-hydroxy-4-phenylbutyric acid (Ahpb3) and N ε -(β-alaninoyl)ornithine (Orn2) (Figure 2) have never been encountered in natural peptides before. Gausemycin biosynthetic gene cluster.…”

Synthesis of nonracemic hydroxyglutamic acids

“…For identification purposes (2 S* ,3 R* )- 2 and (2 S* ,3 S* )- 2 were resolved by chiral reversed-phase TLC [26]. Kinetic resolution of dibenzyl (2 S* ,3 R* )- N -Boc-3-hydroxyglutamate was achieved in the presence of Subtilisin Carlsberg to give dibenzyl (2 R ,3 S )- N -Boc-3-hydroxyglutamate and (2 S ,3 R )-5-(benzyloxy)-2-[( tert -butoxycarbonyl)amino]-3-hydroxy-5-oxopentanoic acid [25].…”

“…Thus, (2 S ,3 R )-5-(benzyloxy)-2-[( tert -butoxycarbonyl)amino]-3-hydroxy-5-oxopentanoic acid served as a precursor in the total synthesis of longicatenamycin A [25]. Syntheses of several modified cephems started from dimethyl (2 S ,4 R )- N -Boc-4-hydroxyglutamate ( 81 ) [114].…”

“…Indeed, the interest in 3-hydroxyglutamic acid started many years ago by the discovery of this amino acid in hydrolysates of an antibiotic peptide S-520 [24]. It has been proved recently that it was actually the isomer (2 S ,3 R )- 2 and it is a fragment of a cyclohexapeptide [25]. (2 R ,3 S )- 2 and (2 R ,3 R )- 2 were found as components of antifungal and antimicrobial hexadepsipeptides called kutznerides isolated from the actinomycete Kutzneria sp.…”

Regioselective Synthesis of Symmetrical and Unsymmetrical Bis(heteroaryl)methane (BHM)‐Containing Amino Acids

“…These modified peptides have good control over conformational flexibility and improve pharmacodynamics compared to native peptides. [8] Among all the amino acids tryptophan stands out unique because it is the only amino acids which contain indole ring and also it is the metabolic precursor of serotonin (a neurotransmitter), melatonin (a neurohormone), and niacin (vitamin B3) in human body. plasma concentration of homoarginine (hArg) is used as a clinical marker in various cardiovascular diseases [6,7] and also hArg is the integral part of antiplatelate drug eptifibatide whereas D-Homoleucine is present in antibacterial natural product longicatenamycin A.…”