Kallopterolides A-I, a New Subclass of seco-Diterpenes Isolated from the Southwestern Caribbean Sea Plume Antillogorgia kallos.

Kallopterolides A-I (1-9), a family of nine diterpenoids possessing either a cleaved pseudopterane or a severed cembrane skeleton, along with several known compounds were isolated from the Caribbean Sea plume Antillogorgia kallos. The structures and relative configurations of 1-9 were characterized by analysis of HR-MS, IR, UV, and NMR spectroscopic data in addition to computational methods and side-by-side comparisons with published NMR data of related congeners. An investigation was conducted as to the potential of the kallopterolides as plausible in vitro anti-inflammatory, antiprotozoal, and antituberculosis agents.

Identification of a poly-cyclopropylglycine-containing peptide via bioinformatic mapping of radical S-adenosylmethionine enzymes.

Peptide-derived natural products are a large class of bioactive molecules that often contain chemically challenging modifications. In the biosynthesis of ribosomally synthesized and posttranslationally modified peptides (RiPPs), radical-SAM (rSAM) enzymes have been shown to catalyze the formation of ether, thioether, and carbon-carbon bonds on the precursor peptide. The installation of these bonds typically establishes the skeleton of the mature RiPP. To facilitate the search for unexplored rSAM-dependent RiPPs for the community, we employed a bioinformatic strategy to screen a subfamily of peptide-modifying rSAM enzymes which are known to bind up to three [4Fe-4S] clusters. A sequence similarity network was used to partition related families of rSAM enzymes into >250 clusters. Using representative sequences, genome neighborhood diagrams were generated using the Genome Neighborhood Tool. Manual inspection of bacterial genomes yielded numerous putative rSAM-dependent RiPP pathways with unique features. From this analysis, we identified and experimentally characterized the rSAM enzyme, TvgB, from the tvg gene cluster from Halomonas anticariensis. In the tvg gene cluster, the precursor peptide, TvgA, is comprised of a repeating TVGG motif. Structural characterization of the TvgB product revealed the repeated formation of cyclopropylglycine, where a new bond is formed between the γ-carbons on the precursor valine. This novel RiPP modification broadens the functional potential of rSAM enzymes and validates the proposed bioinformatic approach as a practical broad search tool for the discovery of new RiPP topologies.

Brief overview of recently reported misassigned natural products and their in silico revisions enabled by DU8ML, a machine learning-augmented DFT computational NMR method.

Mostly covering 2018 to 2022This Highlight article describes a personal selection of recent misassigned structures of natural products and their revision with the aid of DU8ML, a machine learning-augmented DFT computational method for fast and accurate calculations of solution NMR chemical shifts and spin-spin coupling constants.

DU8ML: Machine Learning-Augmented Density Functional Theory Nuclear Magnetic Resonance Computations for High-Throughput In Silico Solution Structure Validation and Revision of Complex Alkaloids.

Machine learning (ML) profoundly improves the accuracy of the fast DU8+ hybrid density functional theory/parametric computations of nuclear magnetic resonance spectra, allowing for high throughput in silico validation and revision of complex alkaloids and other natural products. Of nearly 170 alkaloids surveyed, 35 structures are revised with the next-generation ML-augmented DU8 method, termed DU8ML.

Peculiar Reaction Products and Mechanisms Revisited with Machine Learning-Augmented Computational NMR.

DU8ML, a fast and accurate machine learning-augmented density functional theory (DFT) method for computing nuclear magnetic resonance (NMR) spectra, proved effective for high-throughput revision of misassigned natural products. In this paper, we disclose another important aspect of its application: correction of unusual reaction mechanisms originally proposed because of incorrect product structures.

Maximizing Step-Normalized Increases in Molecular Complexity: Formal [4+2+2+2] Photoinduced Cyclization Cascade to Access Polyheterocycles Possessing Privileged Substructures.

A new complexity building photoinduced cascade which amounts to an unprecedented formal [4+2+2+2] cycloaddition topology is developed to access complex nitrogen polyheterocycles. This photocascade is initiated by the excited state intramolecular proton transfer (ESIPT) in aromatic amino ketones with tethered dual unsaturated pendants, i.e. pyrrole and alkenic moieties, resulting in the formation of four σ-bonds and setting six new stereogenic centers in a single experimentally simple photochemical step with up to 220 mcbit complexity increases.

DU8+ Computations Reveal a Common Challenge in the Structure Assignment of Natural Products Containing a Carboxylic Anhydride Moiety.

DU8+ computations of NMR spectra revealed a relatively common error in the structure assignment of carboxylic anhydride-containing natural products. Computationally driven revisions of ten of these structures are reported in this Note. The majority of the misassigned structures featured a hydroxy group that is proximal to the proposed anhydride moiety and capable of lactone formation.

Systematic Photoassisted Access to Designer Polyheterocycles via Modular Blocks and Scaffolding.

Diverse polyheterocycles are accessed via scaffolded photoassisted synthesis involving decarboxylative aromatization of the primary photoproducts from intramolecular cycloadditions of azaxylylenes and tethered heteroaromatic unsaturated pendants.

Oxidative Control of Photoinduced Cascade Electrocyclizations in Aromatic Azido Imines to Access Complex Fused Imidazoles or Pyrazoles.

Photoinduced cascade of two 6π-electron six- and five-center electrocyclizations in aromatic azido imines is oxidatively controlled to yield complex fused benzimidazoles or indazoles. Formation of benzimidazoles occurs via an unprecedented carbon-to-nitrogen o-iminoaryl 1,2-shift.

Complexity-Building Photoinduced Cascade Involving Csp2-Csp3 Coupling of Aromatic Amides via [2 + 2] Reactivity of ESIPT-Generated o-Azaxylylenes.

A new mode for complexity-building photochemical cascades which offers experimentally simple transition metal-free intramolecular Csp2-Csp3 cross coupling of aromatic amides is attained via an unprecedented [2 + 2] reactivity of ESIPT-generated azaxylylenes. Coupled with short and straightforward postphotochemical modifications of the primary photoproducts, these cascades allow for a significant step-normalized growth of molecular complexity while accessing diverse and complex polyheterocyclic molecular architectures.

Penicitone: Structural Reassignment of a Proposed Natural Product Acid Chloride.

The proposed structure for the natural product penicitone, which contained a chemically improbable acid chloride functional group, was reassigned to a more probable structure using a combination of chemical knowledge, computer-assisted structure elucidation, and DFT methods.