Goh Sennari

Tropolones are non-benzenoid aromatics with broad bioactivity, yet their inherent planarity and metal-chelating properties pose challenges to a medicinal chemistry campaign. We developed a liquid-phase peptide synthesis strategy that leveraged a hydrophobic TAG carrier to streamline condensation, deprotection, and purification steps, overcoming challenges that hinder traditional solution-phase derivatization of tropolones. Among the synthesized tropolone-peptide hybrid derivatives, the lead analogue exceeded antimalarial potency of puberulic acid and artemisinin, highlighting the advantage of three-dimensional peptide hybridization.

Methicillin-resistant Staphylococcus aureus (MRSA) poses a major clinical threat due to resistance to β-lactam antibiotics, such as cefazolin. Although several conventional antibiotics can be used for the treatment of MRSA, the rapid emergence of resistant strains limits their utility. To address this challenge, we envisioned that a combination therapy using β-lactam potentiators would be a promising approach to expand the application of cefazolin to MRSA. In this study, with our aim to explore natural products that potentiate the β-lactams against clinical MRSA strains, we identified a new atromentin A congener, named atromentin B (1), from the culture broth of Aspergillus sp. FKI-9941. Although our structural analysis revealed the presence of a 2,5-dihydroxycyclohexa-2,5-diene-1,4-dione motif in 1, the inherent ¹³C NMR propensity of this class of compounds made definitive structural confirmation difficult. In addition, its low productivity through fermentation limited detailed biological evaluation. The total synthesis of 1 enabled unambiguous structural determination and provided sufficient information for biological studies. The synthetic sample of 1 exhibited cefazolin potentiation activity comparable to the naturally occurring product. Combination assays demonstrated that 1 enhanced cefazolin activity, even against clinical MRSA isolates. These findings show that atromentin B (1) is a promising β-lactam potentiator.

Herein, the total synthesis of the antimalarial natural products, koshidacins A and B, is disclosed. We developed an inverse peptide elongation sequence to elaborate the linear tetrapeptide by leveraging a soluble hydrophobic tag (TCbz group) for liquid-phase peptide synthesis. The key advances involve head-to-tail macrocyclization to provide the carrier-supported cyclic tetrapeptide and photoinduced deaminative alkylation to edit the native peptide residue that enabled us to construct the requisite alkyl chain in this unique natural product family.

Herein, total synthesis of the antimalarial natural product, koshidacin B, is disclosed. We developed an inverse peptide elongation sequence to elaborate the linear tetrapeptide by leveraging a soluble hydrophobic tag (TCbz group) for liquid-phase peptide synthesis (LPPS). The key advances involve head-to-tail macrocyclization to provide the carrier-supported cyclic tetrapeptide and photo-induced deaminative alkylation to edit the native peptide functional group that enabled to construct the requisite alkyl chain in this unique natural product family.

A skeletal modification approach to the designed 16-membered macrocycle en route to actinoallolides is disclosed. Key to this approach was Mitsunobu macro-etherification, followed by Birch reduction and Ozonolysis to edit the macrocycle.

Here, we disclose the first total synthesis of tetraselide and determination of its absolute structure. We implemented bioinformatic analyses, chemical degradation, chiral pool fragment synthesis and convergent synthesis of this natural product.

The avermectins make up a biologically relevant class of complex natural products that continue to inspire the development of new strategies in chemical synthesis. Herein, we disclose a concise synthesis of the southern core of avermectin aglycon. The key hydrobenzofuran was forged by either reductive cyclization or cycloisomerization, both using a cationic palladium precatalyst. This hydropalladation strategy generated the hydrofuran ring under mild conditions, enabling the rapid construction of the tetra-substituted carbon stereocenter.

Camphor and related monoterpenoid natural products have served as versatile “chiral pool” materials in organic chemistry for over half a century. Historically, many researchers have used a variety of transformations involving orchestrated rearrangements of the bornane skeleton to functionalize the camphor framework, expanding the utility of this chiral building block. Recent developments in C–H functionalization methodologies provide myriad opportunities to derivatize the camphor framework in a selective and predictable fashion. In this review, a short summary of the methods for functionalization of the camphor scaffold using rearrangement chemistry is provided followed by a discussion of emerging methods for directed C–H functionalizations that provide diverse new ways to derivatize the camphor framework.

Macrocyclic peptides and depsipeptides are the emerging class of a new modality in drug discovery research. Tetraselide, an antifungal cyclic peptide isolated from a marine-derived filamentous fungus, possesses the unique amphiphilic structural feature that represents the five consecutive β-hydroxy-amino acid and fatty acid moieties. Because the structure elucidation of the naturally occurring product left six stereocenters ambiguous, we implemented bioinformatic analyses, chemical degradation study and chiral pool fragment synthesis to identify two of the undetermined stereochemistry. Convergent total synthesis of four remaining plausible isomers of tetraselide was accomplished via liquid-phase peptide synthesis using the soluble hydrophobic tag auxiliaries. The key advance involves fragment coupling by the serine/threonine ligation reaction and head-to-tail macrolactamization of the carrier-supported precursors that enabled systematic elaboration of the amphiphilic cyclic peptides. Ultimately, we determined the absolute structure of this natural product.