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.     

A New Family of C3‐Symmetrical Carbohydrate Receptors

The formation of the new optically active C₃‐symmetrical receptors (S,S,S)‐ 2 – 4 (Fig. 1), incorporating 1,3,5‐triphenylbenzene and 1,3,5‐tris(phenylethynyl)benzene platforms as ‘floors' and ‘ceilings', is described. The tris(phenylethynyl)benzene derivatives 9 and (S,S,S)‐ 10 (Scheme 1) for the three‐fold peptide coupling to yield the macrocyclic skeletons (Scheme 2) were prepared starting from 1,3,5‐triethynylbenzene by the Sonogashira cross‐coupling reaction. The optical rotations of the three macrocycles (S,S,S)‐ 2 – 4 , two of which ((S,S,S)‐ 2 and (S,S,S)‐ 3 ) are constitutional isomers, differ significantly, which is explained by differential twists induced into the macrocyclic skeletons by the leucine spacer in these bridges. 1 : 1 Host–guest complexes of (S,S,S)‐ 2 – 4 with octyl glucosides (Fig. 3) in CDCl₃ are of modest stability (K_a≤270 M ^?1 at 300 K). In these complexes, the monosaccharides are most probably nesting on one of the H‐bonding faces of the receptor rather than being accommodated in the cavity.     

Synthesis of (±)‐Glaucine and (±)‐Neospirodienone via an One‐Pot Bischler?Napieralski Reaction and Oxidative Coupling by a Hypervalent Iodine Reagent

Condensation of 3,4‐dimethoxybenzeneethanamine ( 3d ) and various benzeneacetic acids, i.e., 4a – e , via a practical and efficient one‐pot Bischler–Napieralski reaction, followed by NaBH₄ reduction, produced a series of 1‐benzyl‐1,2,3,4‐tetrahydroisoquinolines, i.e., 5a – e , in satisfactory yields (Scheme 3). Oxidative coupling of the N‐acyl and N‐methyl derivatives 6a – e of the latter with hypervalent iodine ([IPh(CF₃COO)₂]) yielded products with two different skeletons (Scheme 4). The major products from N‐acyl derivatives 6a – c were (±)‐N‐acylneospirodienones 2a – c , while the minor was the 3,4‐dihydroisoquinoline 7 . (±)‐Glaucine ( 1 ), however, was the major product starting from N‐methyl derivative 6e . Possible reaction mechanisms for the formation of these two types of skeleton are proposed (Scheme 5).     

Eight New Diterpenoids from the Roots of Euphorbia nematocypha

From the dried roots of Euphorbia nematocypha, eight new diterpenoids, with ent‐atisane (i.e., 1 – 5 ) and isopimarane (i.e., 6 – 8 ) type skeletons, together with five known compounds, were isolated. The structures of these new compounds were elucidated by spectroscopic data. Compounds 1 – 8 were evaluated for their cytotoxicity against a small panel of human cancer cell lines.     

New Cytotoxic Meroterpenoids from the Plant Endophytic Fungus Pestalotiopsis fici

Pestalofones I – K ( 1 – 3 ), three new dimeric meroterpenoids with 2‐(7‐benzoyl‐2,3‐dihydrobenzofuran‐2‐yl)‐1‐phenylethan‐1‐one (in 1 ) and 2‐(7‐benzoyl‐2,3‐dihydrobenzofuran‐2‐yl)‐1‐(3,8‐dioxatricyclo[5.1.0.0^2,4]oct‐4‐yl)ethan‐1‐one (in 2 and 3 ) skeletons, were isolated from the solid cultures of the plant endophytic fungus Pestalotiopsis fici. The structures of 1 – 3 were elucidated by NMR experiments. Compound 1 was found to be present as a racemic mixture. The absolute configurations of 2 and 3 were deduced by analogy to the previously isolated metabolites pestalofones G and H ( 4 and 5 ) from the same fungus. Biogenetically, compounds 1 – 3 are derived from the same precursors (co‐isolated compounds 9 and 10 ) as the previously isolated compounds 4 – 8 . Compounds 2 and 3 showed weak cytotoxic activities against four human tumor cell lines T24, HeLa, A549, and MCF‐7.     

Monoterpenoid Indole Alkaloids Bearing an N4‐Iridoid from Gelsemium elegans

Five new alkaloids, gelseganines A–D ( 1 – 4 ) and humantenine N₄‐oxide ( 5 ), were isolated from the stems and leaves of Gelsemium elegans. Compounds 1 – 4 represent a rare class of monoterpenoid indole alkaloids that bear an N₄‐iridoid unit. The structures of 1 – 5 were determined by spectroscopic analysis, single‐crystal X‐ray diffraction, and chemical correlation, and their absolute configurations were elucidated by CD analysis. A plausible biogenetic pathway for alkaloids 1 – 5 was also postulated.     

Three New Diarylheptanoids from Myrica nana

Three new cyclic diarylheptanoids myricananins F–H ( 1 – 3 , resp.), along with five known ones, 4 – 8 , were isolated from the roots of Myrica nana. Compound 3 has been obtained by Nagai et al. by reduction of porson with NaBH₄. In this work, compound 3 was isolated from natural origin for the first time. The structures of 1 – 8 were elucidated using spectroscopic methods.     

New Norcembranoids from the Soft Coral Sinularia Lochmodes

Two new C‐4 norcembranoids sinulochmodins D ( 1 ) and E ( 2 ), along with three known norditerpenoids ( 3–5 ), have been isolated from the organic extract of a Taiwanese soft coral Sinularia lochmodes (Kolonko). The structures of 1 and 2 were determined on the basis of extensive spectroscopic analyses and by comparison of their spectral data with those of related metabolites.     

Neutral Penta‐ and Hexacoordinate Silicon(IV) Complexes Containing Two Bidentate Ligands Derived from the α‐Amino Acids (S)‐Alanine, (S)‐Phenylalanine,and (S)‐tert‐Leucine

The neutral hexacoordinate silicon(IV) complex 6 (SiO₂N₄ skeleton) and the neutral pentacoordinate silicon(IV) complexes 7 – 11 (SiO₂N₂C skeletons) were synthesized from Si(NCO)₄ and RSi(NCO)₃ (R=Me, Ph), respectively. The compounds were structurally characterized by solid‐state NMR spectroscopy ( 6 – 11 ), solution NMR spectroscopy ( 6 and 10 ), and single‐crystal X‐ray diffraction ( 8 and 11 were studied as the solvates 8? CH₃CN and 11? C₅H₁₂ ? 0.5 CH₃CN, respectively). The silicon(IV) complexes 6 (octahedral Si‐coordination polyhedron) and 7 – 11 (trigonal‐bipyramidal Si‐coordination polyhedra) each contain two bidentate ligands derived from an α‐amino acid: (S)‐alanine, (S)‐phenylalanine, or (S)‐tert‐leucine. The deprotonated amino acids act as monoanionic ( 6 ) or as mono‐ and dianionic ligands ( 7 – 11 ). The experimental investigations were complemented by computational studies of the stereoisomers of 6 and 7 .     

Bipolarolides A–G: Ophiobolin‐Derived Sesterterpenes with Three New Carbon Skeletons from Bipolaris sp. TJ403‐B1

Bipolarolides A–G ( 1 – 7 ), seven novel ophiobolin‐derived sesterterpenes with three new types of skeletons, were characterized from fungus Bipolaris sp. TJ403‐B1. Their structures were determined via spectroscopic analyses, X‐ray crystallography, and quantum chemical ¹³C NMR and electronic circular dichroism (ECD) calculations. Compounds 1 and 2 were uniquely defined by a multicyclic caged oxapentacyclo[9.3.0.0^1,6.0^5,9.1^8,12]pentadecane‐bridged system. Compounds 3 and 4 featured an unprecedented 5‐5‐5‐5‐fused core skeleton, while 3 also contained an unexpected C‐3–C‐14 oxygen bridge to construct the caged architecture. Compounds 5 – 7 form a new class of highly modified pentacyclic oxaspiro[4.4]nonane‐containing sesterterpene‐alkaloid hybrids. Their biosynthetic pathways and potential HMG‐CoA reductase inhibitory and antimicrobial activities are also discussed.     

Nortriterpenoids from Schisandra wilsoniana

Three new highly oxygenated nortriterpenoids, wilsonianadilactones A–C ( 1 – 3 ), together with twelve known ones, i.e., 4 – 15 , were isolated from the leaves and stems of Schisandra wilsoniana. Their structures were established by means of extensive analysis of spectroscopic data, and compound 1 was further confirmed by X‐ray crystallographic diffraction. Compounds 1 – 3 showed weak anti‐HIV‐1 activity with EC₅₀ values of 23.5, 55.5, and 66.4 μg/ml, respectively.     

New Triterpenoid Saponins from the Roots of Gypsophila paniculata L.

The seven new triterpenoid saponins 1 – 7 were isolated from the roots of Gypsophila paniculata L. Their structures were established by 1D ‐ and 2D‐NMR techniques, HR‐MS, and acid hydrolysis. The isolated compounds include 3,28‐O‐bidesmosides with or without a 4‐methoxycinnamoyl group (see 1 vs. 2 and 3 ), and 3‐O‐monoglucosides 4 – 7 . All isolated saponins 1 – 7 and their aglycones were evaluated for their α‐glucosidase inhibition activity. Compound 1 showed inhibitory activity against yeast α‐glucosidase with an IC₅₀ value of 100.9±3.3 μM , whereas compounds 2 – 7 were inactive.     

Tigliane Diterpene Esters from the Leaves of Croton tiglium

Three new tigliane‐type diterpene esters, 1 – 3 with unusual 7‐oxo‐5‐ene or 7‐hydroxy‐5‐ene moieties in their skeletons, were isolated from the leaves of Croton tiglium. Their structures were unambiguously elucidated on the basis of spectroscopic data.     

Chemical and Toxicological Investigations of a Previously Unknown Poisonous European Mushroom Tricholoma terreum

The established tradition of consuming and marketing wild mushrooms has focused attention on mycotoxicity, which has become a global issue. In the present study, we describe the toxins found in a previously unknown poisonous European mushroom Tricholoma terreum. Fifteen new triterpenoids terreolides A–F ( 1 – 6 ) and saponaceolides H–P ( 8 – 16 ) were isolated from the fruiting bodies of the toxic mushroom T. terreum. Terreolides A–C ( 1 – 3 ) possessed a unique 5/6/7 trioxaspiroketal system, whereas terreolides D–F ( 4 – 6 ) possessed an unprecedented carbon skeleton. Two abundant compounds in the mushroom, saponaceolide B ( 7 ) and saponaceolide M ( 13 ), displayed acute toxicity, with LD₅₀ values of 88.3 and 63.7 mg kg^?1 when administered orally in mice. Both compounds were found to increase serum creatine kinase levels in mice, indicating that T. terreum may be the cause of mushroom poisoning ultimately leading to rhabdomyolysis.     

Complex Polypropionates from a South China Sea Photosynthetic Mollusk: Isolation and Biomimetic Synthesis Highlighting Novel Rearrangements

Placobranchus ocellatus is well known to produce diverse and complex γ‐pyrone polypropionates. In this study, the chemical investigation of P. ocellatus from the South China Sea led to the discovery and identification of ocellatusones A–D, a series of racemic non‐γ‐pyrone polyketides with novel skeletons, characterized by a bicyclo[3.2.1]octane ( 1 , 2 ), a bicyclo[3.3.1]nonane ( 3 ) or a mesitylene‐substituted dimethylfuran‐3(2H)‐one core ( 4 ). Extensive spectroscopic analysis, quantum chemical computation, chemical synthesis, and/or X‐ray diffraction analysis were used to determine the structure and absolute configuration of the new compounds, including each enantiomer of racemic compounds 1 – 4 after chiral HPLC resolution. An array of new and diversity‐generating rearrangements is proposed to explain the biosynthesis of these unusual compounds based on careful structural analysis and comparison with six known co‐occurring γ‐pyrones ( 5 – 10 ). Furthermore, the successful biomimetic semisynthesis of ocellatusone A ( 1 ) confirmed the proposed rearrangement through an unprecedented acid induced cascade reaction.     

Hydrosilylation Induced by N→Si Intramolecular Coordination: Spontaneous Transformation of Organosilanes into 1‐Aza‐Silole‐Type Molecules in the Absence of a Catalyst

Our attempts to synthesize the N→Si intramolecularly coordinated organosilanes Ph₂L¹SiH ( 1 a ), PhL¹SiH₂ ( 2 a ), Ph₂L²SiH ( 3 a ), and PhL²SiH₂ ( 4 a ) containing a CH?N imine group (in which L¹ is the C,N‐chelating ligand {2‐[CH?N(C₆H₃‐2,6‐iPr₂)]C₆H₄}^? and L² is {2‐[CH?N(tBu)]C₆H₄}^?) yielded 1‐[2,6‐bis(diisopropyl)phenyl]‐2,2‐diphenyl‐1‐aza‐silole ( 1 ), 1‐[2,6‐bis(diisopropyl)phenyl]‐2‐phenyl‐2‐hydrido‐1‐aza‐silole ( 2 ), 1‐tert‐butyl‐2,2‐diphenyl‐1‐aza‐silole ( 3 ), and 1‐tert‐butyl‐2‐phenyl‐2‐hydrido‐1‐aza‐silole ( 4 ), respectively. Isolated organosilicon amides 1 – 4 are an outcome of the spontaneous hydrosilylation of the CH?N imine moiety induced by N→Si intramolecular coordination. Compounds 1–4 were characterized by NMR spectroscopy and X‐ray diffraction analysis. The geometries of organosilanes 1 a – 4 a and their corresponding hydrosilylated products 1 – 4 were optimized and fully characterized at the B3LYP/6‐31++G(d,p) level of theory. The molecular structure determination of 1 – 3 suggested the presence of a Si?N double bond. Natural bond orbital (NBO) analysis, however, shows a very strong donor–acceptor interaction between the lone pair of the nitrogen atom and the formal empty p orbital on the silicon and therefore, the calculations show that the Si?N bond is highly polarized pointing to a predominantly zwitterionic Si⁺N^? bond in 1 – 4 . Since compounds 1 – 4 are hydrosilylated products of 1 a – 4 a , the free energies (ΔG₂₉₈), enthalpies (ΔH₂₉₈), and entropies (ΔH₂₉₈) were computed for the hydrosilylation reaction of 1 a – 4 a with both B3LYP and B3LYP‐D methods. On the basis of the very negative ΔG₂₉₈ values, the hydrosilylation reaction is highly exergonic and compounds 1 a – 4 a are spontaneously transformed into 1 – 4 in the absence of a catalyst.     

Direct Amination and Synthesis of Fused N‐Substituted Isothiochromene Derivatives

Isothiochromene[3,4‐d] pyrimidine derivatives 2 , 3 , and 4a , b were synthesized from the reaction of 3‐amino‐1‐(pyridin‐4‐yl)‐5‐(pyridin‐4‐ylmethylene)‐5,6,7,8‐tetrahydro‐1H‐isothiochromene‐4‐carbonitrile 1 with acetic anhydride, formamide, urea, or thiourea in appropriate experimental conditions. Combination of 1 with carbon acid derivatives afforded isothiochromene [3,4‐b]pyridine 6 – 8 in good yield. A simple approach for N‐substituted fused isothiochromene derivatives has been explored. A POCl₃‐mediated direct amination of isothiochromene amide 2 with NH₂‐heterocycles, secondary amines, and carbohydrazides is described and compared with classical method, yielding 10 – 14 . The structures of the newly synthesized compounds were elucidated on the basis of elemental analysis, and spectral data.     

Four New Cuparene‐Type Sesquiterpenes from Flammulina velutipes

Flamvelutpenoids A–D ( 1 – 4 ), four new cuparene‐type sesquiterpenes, were isolated from the solid culture of Flammulina velutipes. Their structures were elucidated by NMR experiments. The absolute configurations of 1 and 2 were assigned via the circular dichroism data of the [Rh₂(OCOCF₃)₄] complex, whereas that of C(3) of 3 was determined by applying the octant rule for the α,β‐unsaturated ketone moiety. Compounds 1 – 4 showed weak antibacterial activity against Escherichia coli, Bacillus subtilis, and methicillin‐resistant Staphylococcus aureus with MIC values larger than 100 μM .     

Four New Nortriterpenoids from Schisandra lancifolia

Four new highly oxygenated nortriterpenoids, lancifodilactones O–R ( 1 – 4 ), together with six known ones, i.e., 5 – 10 , were isolated from the leaves and stems of Schisandra lancifolia. Their structures were elucidated by spectroscopic analyses, including 1D‐ and 2D‐NMR experiments and mass spectrometry. Compounds 1 – 3 were evaluated for their cytotoxicity against NB4, A549, SHSY5Y, PC‐3, and MCF‐7 cell lines. No compounds exhibited significant cytotoxicity, the IC₅₀ values being above 50 μM .     

Synthesis of Some New 2‐Oxo‐N‐[(10H‐phenothiazin‐10‐yl)alkyl] Derivatives of Azetidine‐1‐carboxamides

The synthesis of a new series of 4‐aryl‐3‐chloro‐2‐oxo‐N‐[3‐(10H‐phenothiazin‐10‐yl)propyl]azetidine‐1‐carboxamides, 4a – 4m , is described. Phenothiazine on reaction with Cl(CH₂)₃Br at room temperature gave 10‐(3‐chloropropyl)‐10H‐phenothiazine ( 1 ), and the latter reacted with urea to yield 1‐[3‐(10H‐phenothiazin‐10‐yl)propyl]urea ( 2 ). Further reaction of 2 with several substituted aromatic aldehydes led to N‐(arylmethylidene)‐N′‐[3‐(phenothiazin‐10‐yl)propyl]ureas 3a – 3m , which, on treatment with ClCH₂COCl in the presence of Et₃N, furnished the desired racemic trans‐2‐oxoazetidin‐1‐carboxamide derivatives 4a – 4m . The structures of all new compounds were confirmed by IR, and ¹H‐ and ¹³C‐NMR spectroscopy, FAB mass spectrometry, and chemical methods.