Montecrinanes A–C: Triterpenes with an Unprecedented Rearranged Tetracyclic Skeleton from Celastrus vulcanicola. Insights into Triterpenoid Biosynthesis Based on DFT Calculations

Three new triterpenoids with an unprecedented 6/6/6/6‐fused tetracyclic carbon skeleton, montecrinanes A–C ( 1 – 3 ), were isolated from the root bark of Celastrus vulcanicola, along with known D:B‐friedobaccharanes ( 4 – 6 ), and lupane‐type triterpenes ( 7 – 12 ). The stereostructures of the new metabolites were elucidated based on spectroscopic (1D and 2D NMR) and spectrometric (HR‐EIMS and HR‐ESIMS) techniques. Their absolute configurations were determined by both NMR spectroscopy, with (R)‐(?)‐α‐methoxyphenylacetic acid as a chiral derivatizing agent, and biogenetic considerations. Biogenetic pathways for montecrinane and D:B‐friedobaccharane skeletons were proposed and studied by DFT methods. The theoretical results support the energetic feasibility of the putative biogenetic pathways, in which the 1,2‐methyl shift from the secondary baccharenyl cation represents a novel and key reaction step for a new montecrinane skeleton.     

Trangmolins A–F with an Unprecedented Structural Plasticity of the Rings A and B: New Insight into Limonoid Biosynthesis

The absolute stereostructures of trangmolins A–F ( 1 – 6 ), limonoids with three new and one known topologies of the rings A and B, were unambiguously determined by NMR spectroscopic investigations, single‐crystal XRD analysis, and quantum‐chemical electronic circular dichroism calculations. Compounds 1 – 3 contain a hexahydro‐1H‐inden‐4‐one motif, compound 4 comprises a hexahydro‐2,6‐methanobenzofuran‐7‐one cage, and compound 5 consists of a hexahydro‐2H‐2,8‐epoxychromene scaffold. The C1?C30 linkage in 1 – 3 and the C3?C30 connection in 4 form two unprecedented types of ring A/B‐fused carbobicyclic cores: viii and ix . The oxidative cleavage of the C2?C3 bond in 5 and heterocyclization in 4 and 5 constitute the unprecedented tricyclic 6/6/5 ring A/B¹/B²‐ and 6/5/6 ring A¹A²/B‐fused topologies, respectively, which are uncovered, for the first time, in the construction of limonoid architectures. The diverse cyclization patterns of 1 – 6 reveal an unparalleled structural plasticity of rings A and B in limonoid biosynthesis.     

Isolation and Structural Elucidation of Armeniaspirols A–C: Potent Antibiotics against Gram‐Positive Pathogens

In an antibiotic lead discovery program, the known strain Streptomyces armeniacus DSM19369 has been found to produce three new natural products when cultivated on a malt‐containing medium. The challenging structural elucidation of the isolated compounds was achieved by using three independent methods, that is, chemical degradation followed by NMR spectroscopy, a computer‐assisted structure prediction algorithm, and X‐ray crystallography. The compounds, named armeniaspirol A–C ( 2 – 4 ), exhibit a compact, hitherto unprecedented chlorinated spiro[4.4]non‐8‐ene scaffold. Labeling experiments with [1‐¹³C] acetate, [1,2‐¹³C2] acetate, and [U‐¹³C] proline suggest a biosynthesis through a rare two‐chain mechanism. Armeniaspirols displayed moderate to high in vitro activities against Gram‐positive pathogens such as methicillin‐resistant S. aureus (MRSA) or vancomycin resistant E. faecium (VRE). As analogue 2 was active in vivo in an MRSA sepsis model, and showed no development of resistance in a serial passaging experiment, it represents a new antibiotic lead structure.     

Aplysiasecosterol A: A 9,11‐Secosteroid with an Unprecedented Tricyclic γ‐Diketone Structure from the Sea Hare Aplysia kurodai

A new 9,11‐secosteroid having an unprecedented tricyclic γ‐diketone structure, aplysiasecosterol A ( 1 ), was isolated from the sea hare Aplysia kurodai. The structure was determined by one‐ and two‐dimensional NMR spectroscopic analysis, molecular modeling studies, a comparison of experimental and calculated ECD spectra, and a modified Mosher′s method. Aplysiasecosterol A ( 1 ) exhibited cytotoxicity against human myelocytic leukemia HL‐60 cells. A biosynthetic pathway for 1 from a known cholesterol was proposed and includes twice α‐ketol rearrangements and an intramolecular acetalization.     

Involucratustones A–C: Unprecedented Sesquiterpene Dimers Containing Multiple Contiguous Quaternary Carbons from Stahlianthus involucratus

Involucratustones A–C ( 1 – 3 ), three cadinane dimers containing multiple contiguous quaternary carbons, were isolated from the rhizomes of Stahlianthus involucratus. Their structures were determined by a combination of NMR spectroscopy, chemical conversion, and X‐ray diffraction analysis. Compounds 1 and 2 are rearranged homodimers of cadinane sesquiterpene fused with a unique fully substituted 1‐oxaspiro[4.4]nonane core observed for the first time in natural products, and 3 is a novel 3′,4′‐seco‐cadinane‐dimer. Compounds 1 and 2 exhibited potent cytotoxic activities, and 3 showed notable anti‐inflammatory effect.     

Shuangancistrotectorines A–E,Dimeric Naphthylisoquinoline Alkaloids with Three Chiral Biaryl Axes from the Chinese Plant Ancistrocladus tectorius

Five novel dimeric naphthylisoquinoline alkaloids, shuangancistrotectorines A ( 3 a ), B ( 3 b ), C ( 4 ), D ( 5 a ), and E ( 5 b ), have been isolated from the twigs of the Chinese plant Ancistrocladus tectorius. Their absolute stereostructures were determined by spectroscopic and chiroptical methods in combination with quantum chemical CD calculations. In contrast to all other known dimeric naphthylisoquinoline alkaloids, in which the central binaphthalene axis is 6′,6′′‐coupled and thus not rotationally hindered, the dimers described here are linked via the sterically more hindered 3′,3′′‐ or 1′,1′′‐positions of the naphthalene units. They are thus the first such dimers—and even the very first natural products at all—that have three consecutive stereogenic axes. Hence, including the stereogenic centers, they have up to seven stereogenic units in total. Some of the compounds, in particular shuangancistrotectorines A, B, and D ( 3 a , 3 b , and 5 a ) exhibit very good, and specific, antiplasmodial activities.     

Perquinolines A–C: Unprecedented Bacterial Tetrahydroisoquinolines Involving an Intriguing Biosynthesis

Metabolic profiling of Streptomyces sp. IB2014/016‐6 led to the identification of three new tetrahydroisoquinoline natural products, perquinolines A–C ( 1 – 3 ). Labelled precursor feeding studies and the cloning of the pqr biosynthetic gene cluster revealed that 1 – 3 are assembled by the action of several unusual enzymes. The biosynthesis starts with the condensation of succinyl‐CoA and l ‐phenylalanine catalyzed by the amino‐7‐oxononanoate synthase‐like enzyme PqrA, representing rare chemistry in natural product assembly. The second condensation and cyclization events are conducted by PqrG, an enzyme resembling an acyl‐CoA ligase. Last, ATP‐grasp RimK‐type ligase PqrI completes the biosynthesis by transferring a γ‐aminobutyric acid or β‐alanine moiety. The discovered pathway represents a new route for assembling the tetrahydroisoquinoline cores of natural products.     

New Energetic Materials: Functionalized 1‐Ethyl‐5‐aminotetrazoles and 1‐Ethyl‐5‐nitriminotetrazoles

A new way to make a bang : Several functionalized 1‐ethyl‐5‐aminotetrazoles, 1‐ethyl‐5‐nitrimino‐tetrazoles, and copper complexes have been synthesized and their chemical and energetic properties have been comprehensively characterized. The compounds belong to all classes of “energetic materials”: explosives, propellants, and pyrotechnics.

     

Annulation Approach to Doubly Linked (A‐type) Oligocatechins: Syntheses of (+)‐Procyanidin A2 and (+)‐Cinnamtannin B1

The first stereoselective syntheses of doubly linked (A‐type) oligocatechins, (+)‐procyanidin A₂ and (+)‐cinnamtannin B₁, have been achieved. Ethylenedioxy‐bridged flavans served as excellent platforms, thus allowing annulation with nucleophilic catechin units in a stereoselective manner. An additional key was the new synthetic approach to selectively protected nucleophilic catechin, thus enabling regioselective construction of the key dioxabicyclo skeleton of the A‐type oligocatechins.     

Total Syntheses of (+)‐Grandilodine C and (+)‐Lapidilectine B and Determination of their Absolute Stereochemistry

Enantioselective total syntheses of the Kopsia alkaloids (+)‐grandilodine C and (+)‐lapidilectine B were accomplished. A key intermediate, spirodiketone, was synthesized in 3 steps and converted into the chiral enone by enantioselective deprotonation followed by oxidation with up to 76 % ee. Lactone formation was achieved through stereoselective vinylation followed by allylation and ozonolysis. The total synthesis of (+)‐grandilodine C was achieved by palladium‐catalyzed intramolecular allylic amination and ring‐closing metathesis to give 8‐ and 5‐membered heterocycles, respectively. Selective reduction of a lactam carbonyl gave (+)‐lapidilectine B. The absolute stereochemistry of both natural products was thereby confirmed. These syntheses enable the scalable preparation of the above alkaloids for biological studies.     

Enantioselective Synthesis of Lepadins A–D from a Phenylglycinol‐Derived Hydroquinolone Lactam

The marine alkaloids (?)‐lepadins A–C and (+)‐lepadin D, belonging to two diastereoisomeric series, were synthesized from an (R)‐phenylglycinol‐derived tricyclic lactam via a common cis‐decahydroquinoline intermediate. Crucial aspects of the synthesis are the stereochemical control in the assembly of the cis‐decahydroquinoline platform, in the introduction of the C2 methyl and C3 hydroxy substituents, and in the generation of the C5 stereocenter.     

Synthetic and Structural Studies on Copper 1 H‐[1,10]‐Phenanthrolin‐2‐one Coordination Complexes: Isolation of a Novel Intermediate During 1,10‐Phenanthroline Hydroxylation

The synthesis and crystal structure elucidation of a novel dinuclear heteroleptic copper(II) complex has led to an alternative mechanism in the formation of covalent hydrates. During further studies on the synthesis and properties of [Cu₂(ophen)₂] ( 1 ), a dinuclear complex of copper(I) with 1 H‐[1,10]‐phenanthrolin‐2‐one (Hophen), two intermediates/alternative products 2 and 3 were isolated. The dinuclear, antiferromagnetic complex [Cu₂(ophen)₂(phen)₂] ? (NO₃)₂ ? 9H₂O ( 3 , phen=1,10‐phenanthroline) contains two five‐coordinate copper(II) ions, both with trigonal‐bipyramidal coordination, which are bridged together through deprotonated hydroxyl groups with a Cu? Cu non‐bonding distance of 3.100 Å. Complex [Cu(phen)₂(H₂O)] ? (NO₃)₂ ( 2 ) is a polymorph of a previously reported material. The occurrence of 2 and 3 has led us to propose a variation to the Gillard mechanism for the formation of covalent hydrates in bidentate N‐heterocycles in which the attacking nucleophile may be the deprotonated form of 2 , [Cu(phen)₂(OH)]^?, rather than free OH^?.