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.

seco-Pregnane Glycosides from Australian Caustic Vine (Cynanchum viminale subsp. australe).

Cynanchum viminale subsp. australe, more commonly known as caustic vine, is a leafless succulent that grows in the northern arid zone of Australia. Toxicity toward livestock has been reported for this species, along with use in traditional medicine and its potential anticancer activity. Disclosed herein are novel seco-pregnane aglycones cynavimigenin A (5) and cynaviminoside A (6), together with new pregnane glycosides cynaviminoside B (7) and cynavimigenin B (8). Cynavimigenin B (8) contains an unprecedented 7-oxobicyclo[2.2.1]heptane moiety in the seco-pregnane series, likely arising from a pinacol-type rearrangement. Interestingly, these isolates displayed only limited cytotoxicity in cancer and normal human cell lines, in addition to low activity against acetylcholinesterase and Sarcoptes scabiei bioassays, suggesting that 5-8 are not associated with the reported toxicity of this plant species.

Complexity-Building ESIPT-Assisted Synthesis of Fused Polyheterocyclic Sulfonamides.

Excited State Intramolecular Proton Transfer (ESIPT), originally discovered and explored in depth in a number of extensive photophysical studies, is more recently rediscovered as a powerful synthetic tool, offering rapid access to complex polyheterocycles. In our prior work we have employed ESIPT in aromatic o-keto amines and amides, leading to diverse primary photoproducts-complex quinolinols or azacanes possessing a fused lactam moiety-which could additionally be modified in short, high-yielding postphotochemical reactions to further grow complexity of the heterocyclic core scaffold and/or to decorate it with additional functional groups. Given that sulfonamides are generally known as privileged substructures, in this study we pursued two goals: (i) To explore whether sulfonamides could behave as proton donors in the context of ESIPT-initiated photoinduced reactions; (ii) To assess the scope of subsequent complexity-building photochemical and postphotochemical steps, which give access to polyheterocyclic molecular cores with fused cyclic sulfonamide moieties. In this work we show that this is indeed the case. Simple sulfonamide-containing photoprecursors produced the sought-after heterocyclic products in experimentally simple photochemical reactions accompanied by significant step-normalized complexity increases as corroborated by the Böttcher complexity scores.

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.

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.

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.

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.

EBC-232 and 323: A Structural Conundrum Necessitating Unification of Five In Silico Prediction and Elucidation Methods.

Structurally unique halimanes EBC-232 and EBC-323, isolated from the Australian rainforest plant Croton insularis, proved considerably difficult to elucidate. The two diastereomers, which consist an unusual oxo-6,7-spiro ring system fused to a dihydrofuran, were solved by unification and consultation of five in silico NMR elucidation and prediction methods [i.e., ACDLabs, olefin strain energy (OSE), DP4, DU8+ and TD DFT CD]. Structure elucidation challenges of this nature are prime test case examples for empowering future AI learning in structure elucidation.

The Discreet Structural Diversity of Briarellins: DU8+ Guided Multiple Structure Revisions Yielded Two Unknown Structural Types.

Briarellins, a subset of C2-C11 cyclized cembranoids, were proposed to contain a C3-C14 ether or lactone bridge, similar to asbestinins. However, the total synthesis of the proposed structure of briarellin J revealed a misassignment. We revisited briarellins, computationally, with the help of a recently developed hybrid DFT/parametric method, DU8+, and revised the structures of briarellin C14-C3 ε-lactones to new structural types containing either a C14-C11 or C14-C12 lactone bridge. The original structures of briarellin and asbestinin ethers were confirmed.

Structure Validation of Complex Natural Products: Time to Change the Paradigm. What did Synthesis of Alstofolinine A Prove?

Total synthesis has been an effective and broadly practiced approach for structure validation (or revision) of complex natural products. It appears that computational methods for structure elucidation are gradually becoming a better alternative, being faster and more reliable, as found in the case of alstofolinine A.

Natural Products Containing the Oxetane and Related Moieties Present Additional Challenges for Structure Elucidation: A DU8+ Computational Case Study.

Analysis of published NMR data for natural products containing the oxetane moiety, with the help of a recently developed parametric/DFT hybrid computational method DU8+, has revealed that oxetanes and related compounds constitute yet another significant challenge in structure elucidation and stereochemistry assignment, as more than 30 structures required revision. The most common pitfalls are discussed, and revised structures are suggested for 26 natural products.

Reassignments and Corroborations of Oxo-Bridged Natural Products Directed by OSE and DU8+ NMR Computation.

Structural misassignments of natural products are prevalent in the literature. Developing methods and theoretical concepts to assist those undertaking structural elucidation is therefore of paramount importance, such that biologists and synthetic chemists avoid pursuing phantom chemical entities. Herein described is a strategy for predicting the isolabilities of oxygen-substituted bridgehead natural products based on calculations of olefin strain energies, NMR chemical shifts and coupling constants (DU8+). This approach provides corroborating evidence for the structures of certain bridgehead alkene natural products while leading to the reassignment of several other structures.

Addressing the Challenges of Structure Elucidation in Natural Products Possessing the Oxirane Moiety.

NMR data for natural products containing the epoxy moiety have been revisited and reanalyzed with the help of a recently developed parametric/DFT hybrid computational method, DU8+. More than 20 structures needed revision, which points to challenges in NMR solution structure assignment for molecules possessing this structural feature. Among the revised structures are achicretin 2, acremine P, aromaticane I, artanomalide B, botryosphaerihydrofuran, chloroklotzchin, crithmifolide, crotodichogamoin A, emervaridone C, 9α,15-epoxyafricanane, fischambiguine B, grandilobalide B, guaianolide A, guatterfriesols A and B, juncenolide G, roscotane D, secoafricane 7, taccalonolides AJ and AF, and related compounds.

Step-Economical Photoassisted Diversity-Oriented Synthesis: Sustaining Cascade Photoreactions in Oxalyl Anilides to Access Complex Polyheterocyclic Molecular Architectures.

Atom- and step-economy in photoassisted diversity-oriented synthesis (DOS) is achieved with a versatile oxalyl linker offering rapid access to complex alkaloid mimics in very few experimentally simple steps: (i) it allows for fast tethering of the photoactive core to the unsaturated pendants, especially important in the case of (hetero)aromatic amines-essentially a one-pot reaction with no isolation of intermediates; (ii) the α-dicarbonyl tether acts as a chromophore enhancer, extending the conjugation chain and facilitating the "harvest" of the lower energy photons for the primary and secondary photoreactions; (iii) it enhances the quantum yield of intersystem crossing (ISC), i.e., it is capable of sensitizing secondary photochemical processes in the cascade; and (iv) the tether forms an additional heterocyclic moiety, imidazolidine-4,5-dione, a known pharmacophore. The overall photoassisted cascade is an efficient complexity-building process as quantified by computed step-normalized complexity indices, leading to extended polyheterocyclic molecular architectures comparable in complexity to natural products such as paclitaxel while requiring only 2-4 simple synthetic steps from readily available chemical feedstock.

Triquinanes and Related Sesquiterpenes Revisited Computationally: Structure Corrections of Hirsutanols B and D, Hirsutenol E, Cucumin B, Antrodins C-E, Chondroterpenes A and H, Chondrosterins C and E, Dichrocephone A, and Pethybrene.

NMR data for 90+ natural sesquiterpenes possessing triquinane cores were examined with the help of a relatively fast parametric/DFT hybrid computational method, DU8+. Thirteen of these compounds, i.e., approximately 14% of the sample, required structure correction. This rate of misassignment is similar to the percentage of misassigned halogenated sesquiterpenes reported previously.

High-Throughput in Silico Structure Validation and Revision of Halogenated Natural Products Is Enabled by Parametric Corrections to DFT-Computed 13C NMR Chemical Shifts and Spin-Spin Coupling Constants.

Halogenated natural products constitute diverse and promising feedstock for molecular pharmaceuticals. However, their solution-structure elucidation by NMR presents several challenges, including the lack of fast methods to compute 13C chemical shifts for carbons bearing heavy atoms. We show that parametric corrections to DFT-computed chemical shifts in conjunction with rff-computed spin-spin coupling constants allow for fast and reliable screening of a large number of reported halogenated natural products, resulting in expedient structure validation or revision. In this paper, we examine more than 100 structures of halogenated terpenoids and other natural products with the new parametric approach and demonstrate that the accuracy of the combined method is sufficient to identify misassignments and suggest revisions in most cases (16 structures are revised). As the 1D 1H and 13C NMR data are ubiquitous and most routinely used in solution structure elucidation, this fast and efficient two-criterion method (nuclear spin-spin coupling and 13C chemical shifts) which we term DU8+ is recommended as the first essential step in structure assignment and validation.

A novel withanolide with an unprecedented carbon skeleton from Physalis angulata.

A novel withanolide, aromaphysalin A (1), possessing an exceptional C(11)-C(15) bond and an unprecedented 4,9-cyclized aromatic ring (ring A), is isolated from stems and leaves of Physalis angulata L. Its structure was determined by a combination of HRESIMS, 2D NMR spectra, and theoretical calculations. Compound 1 exhibited inhibitory activity on NO production with an IC50 value of 51.64 µM. A plausible biosynthetic pathway for 1 is also discussed.

Structure Determination and Mechanism of Formation of a seco-Moreliane Derivative Supported by Computational Analysis.

Basic hydrolysis of a dichloromethane extract of Stevia lucida yielded (4R,5S,7R,9R,10R,11R)-7,9-dihydroxylongipin-2-en-1-one (1), which was oxidized and subjected to acidic conditions to generate the new seco-moreliane derivative 3. The structure of 3 was established based on NMR data interpretation and confirmed computationally. A plausible mechanism for the carbocationic rearrangement of the trione 2 to the seco-moreliane 3 was supported by DFT computations.

Oxazolines as Dual-Function Traceless Chromophores and Chiral Auxiliaries: Enantioselective Photoassisted Synthesis of Polyheterocyclic Ketones.

2-(o-Amidophenyl)oxa- and -thiazolines undergo excited-state intramolecular proton transfer (ESIPT), generating aza-o-xylylenes capable of intramolecular [4+2] and [4+4] cycloadditions with tethered unsaturated pendants. Facile hydrolysis of the primary photoproducts, spiro-oxazolidines and thiazolidines, under mild conditions unmasks a phenone functionality. Variations in linkers allow for access to diverse core scaffolds in the primary photoproducts, rendering the approach compatible with the philosophy of diversity-oriented synthesis. Chiral oxazolines, readily available from the corresponding amino alcohols, yield enantioenriched keto-polyheterocycles of complex topologies with enantiomeric excess values up to 90%.