Total Synthesis and Antimicrobial Evaluation of Pagoamide A

Abstract

Natural products are often the starting point for drug development and also the testing ground for synthetic methods. Herein we describe the total synthesis and antimicrobial evaluation of a marine natural product, pagoamide A, which is a macrocyclic depsipeptide with two backbone thiazole units and a dimethylated N-terminus. The two thiazole building blocks were synthesized from commercially available materials in four or fewer steps and employed directly in solid-phase peptide synthesis (SPPS) to afford pagoamide A. The use of SPPS ensured that the synthetic sequence is operationally straightforward and, if needed, permits modular substitution of building blocks to easily access diverse structural analogs. Our antimicrobial assays showed that pagoamide A has moderate activity against Bacillus subtilis.

Macrocyclization strategies for the total synthesis of cyclic depsipeptides

“…Macrolactamization was accomplished with (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP) and DIEA, affording the depsipeptide 25 . Of note is that the macrolactamization occurred in the presence of two free Ser hydroxyl groups without competing macrolactonization 34 (Fig. 4B).…”

“…Similarly, pagoamide A, 25 , was synthesized on 2-Cl-Trt resin by incorporating Thr with a free alcohol that could be esterified with Boc-Phe-OH under Steiglich-like conditions. 34 The peptide was further elongated, incorporating the N-terminal thiazole residues, and was cleaved and deprotected to generate the branched peptide 24 . Macrolactamization was accomplished with (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP) and DIEA, affording the depsipeptide 25 .…”

“…The amide bond site of macrolactamization is often selected to limit branched peptide synthesis, as seen in the syntheses of polydiscamides B–D, 28 szentiamide, 32 theonellapeptolide Id 33 and pagoamide A. 34 It is however not uncommon to perform several orthogonally protected couplings to generate a macrocyclization point further from the ester bond. This design choice is seen in challenging depsipeptide syntheses such as with kahalalide F, 27 which contains a dehydro residue neighbouring the ester forming residue, or in the diversity-generating synthesis seen in the ohmyungsamycin A, deoxyecumicin and ecumicin synthesis, 30 where they share a similar macrocycle with differing N-terminal residues.…”

Marine natural products

“…has been reported simultaneously by two groups, conrming the structure assigned. 366,367 A review of the use of invasive algal species, especially chlorophytes, as sources of valuable marine bioactives has been published. 368 The bioactivity of two related norterpenoids has been reported in different publications.…”