Divergent Total Synthesis of Fornicin A,Fornicin D,and Ganodercin D,Meroterpenoids from Ganoderma Mushrooms

The meroterpenoids fornicin A, fornicin D, and ganodercin D, found in mushrooms of the Ganoderma genus, have been prepared in a concise and divergent synthesis route. The characteristic unsaturated γ-ketoacid moiety was obtained via an optimized step-wise aldol condensation between two readily accessible building blocks. THP-protection of a phenolic hydroxyl group under basic conditions was developed, a protocol that adds to the versatility of this protecting group.     

Enantioselective Syntheses of Rigidiusculamides A and B: Revision of the Relative Stereochemistry of Rigidiusculamide A

The first enantioselective synthesis of cytotoxic natural products rigidiusculamides A (ent‐ 21 ) and B ( 8 ) has been achieved by two synthetic routes. The first one is convergent based on the common intermediate 11 , obtained through a high yielding SmI₂‐mediated Reformatsky‐type reaction. A highly diastereoselective one‐pot Dess–Martin periodinane‐mediated bis‐oxidation allowed the direct conversion of the diastereomeric mixture of 11 into rigidiusculamide B ( 8 ). Isolation of minor diastereomer 21 , in combination with computational work, allowed us to suggest the structure of the natural rigidiusculamide A to be 21 , as synthesized by the second route. Four diastereomers ( 7 , 7 , 22a , and 22b ) and an enantiomer ( 21 ) of rigidiusculamide A ( 21 ) have been synthesized. On the basis of literature precedents and computational work, a biosynthetic pathway for rigidiusculamides A and B was proposed to account for the opposite configuration at C‐5 of those two congeners.     

Cattleianal and Cattleianone: Two New Meroterpenoids from Psidium cattleianum Leaves and Their Selective Antiproliferative Action against Human Carcinoma Cells

The Myrteacae family is known as a rich source of phloroglucinols, a group of secondary metabolites with notable biological activities. Leaves of Psidium cattleianum were extracted with chloroform: methanol 8:2 to target the isolation of phloroglucinol derivatives. Isolated compounds were characterized using different spectroscopic methods: nuclear magnetic resonance (NMR), ultra-violet (UV) and mass spectrometry (MS). Two new phloroglucinols were evaluated for cytotoxicity against a panel of six human cancer cell lines, namely colorectal adenocarcinoma cells (HT-29 and HCT-116); hepatocellular carcinoma cells (HepG-2); laryngeal carcinoma (Hep-2); breast adenocarcinoma cells (MCF7 and MDA-MB231), in addition to normal human melanocytes HFB-4. Additionally, cell cycle analysis and annexin-V/FITC-staining were used to gain insights into the mechanism of action of the isolated compounds. The new phloroglucinol meroterpenoids, designated cattleianal and cattleianone, showed selective antiproliferative action against HT-29 cells with IC₅₀’s of 35.2 and 32.1 μM, respectively. Results obtained using cell cycle analysis and annexin-V/FITC-staining implicated both necrosis and apoptosis pathways in the selective cytotoxicity of cattleianal and cattleianone. Our findings suggest that both compounds are selective antiproliferative agents and support further mechanistic studies for phloroglucinol meroterpenoids as scaffolds for developing new selective chemotherapeutic agents.     

1H NMR‐Guided Isolation of Formyl‐Phloroglucinol Meroterpenoids from the Leaves of Eucalyptus robusta

Nine formyl‐phloroglucinolmeroterpenoids (FPMs), namely, eucalrobusones A–I ( 1 – 9 ), were isolated from the leaves of Eucalyptus robusta by tracking the phenolic hydroxyl ¹H NMR peaks. The Snatzke helicity rules for the Cotton effects of twisted benzene rings were applied to elucidate the absolute configurations of the FPMs. These findings, along with NMR spectroscopy, the circular dichroism (CD) exciton chirality method, and CD calculations, allowed complete structures for the FPMs to be assigned. Eucalrobusones A–F ( 1 – 6 ) are novel adducts formed between a formyl‐derived carbon atom on the phloroglucinol ring and monoterpene and sesquiterpene components. Eucalrobusones G–I ( 7 – 9 ) are the first examples of FPMs with cubebane part structures connected by an unusual 1‐oxaspiro[5.5]undecane subunit. Among these isolates, eucalrobusone C ( 3 ) showed significant cytotoxicity against HepG2, MCF‐7, and U2OS cancer cell lines, with IC₅₀ values less than 10 μm . Compound 3 significantly blocks cell proliferation in MCF‐7 cells and induces MCF‐7 cell death through apoptosis.     

Cimicifoetones A and B,Dimeric Prenylindole Alkaloids as Black Pigments of Cimicifuga foetida

Two dimeric prenylindole alkaloids with a unique indole‐benzoindolequinone skeleton, cimicifoetones A ( 1 ) and B ( 2 ), were isolated as black pigments from the rhizomes of Cimicifuga foetida . The structures were elucidated by spectroscopic methods including HRMS and 2D NMR, as well as single‐crystal X‐ray diffraction and computational chemical modeling techniques. Cimicifoetones A and B represented the first examples of dimeric indole alkaloids generated through [4+2] Diels–Alder cycloaddition between the prenyl side chain in one 3‐prenylindole and the aromatic ring in another. The two compounds showed promising anti‐proliferative activity on seven tumor cell lines with IC₅₀ values in the range of 1.36–21.09 μm . Flow cytometric and western blot analysis revealed that compound 2 induced cell apoptosis via death receptor‐mediated extrinsic and mitochondrial‐mediated intrinsic pathways.     

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.     

Enantioselective Total Synthesis of Terreumols A and C from the Mushroom Tricholoma terreum

The cytotoxic meroterpenoids terreumol A and C from the grey knight mushroom Tricholoma terreum were synthesized for the first time. The key step of the enantioselective total synthesis of terreumol C is a ring‐closing metathesis to form a trisubstituted Z double bond embedded in the 10‐membered ring of the [8.4.0] bicycle. Interestingly, the presence of a free hydroxy group in the metathesis precursor prevents cyclization and favors cross metathesis. (?)‐Terreumol C was converted into (?)‐terreumol A by diastereoselective epoxidation. Starting from 2‐bromo‐3,5‐dimethoxybenzaldehyde, 14 steps with an overall yield of 23 % are needed for the synthesis of (?)‐terreumol A. X‐ray analysis of the benzoquinone analogue of terreumol A provides independent proof of the absolute configuration.     

Suffrutines A and B: A Pair of Z/E Isomeric Indolizidine Alkaloids from the Roots of Flueggea suffruticosa

Suffrutines A ( 1 ) and B ( 2 ), a pair of novel photochemical Z/E isomeric indolizidine alkaloids, with a unique and highly conjugated C₂₀ skeleton, were isolated from the roots of Flueggea suffruticosa. The structures were elucidated by extensive analysis of NMR spectra and single‐crystal X‐ray diffraction. The light‐induced isomerization and hypothetical biogenetic pathway to 1 and 2 , as well as their activity for regulating the morphology of Neuro‐2a cells are also discussed.     

Synthesis and Structure Revision of Dichrocephones A and B

Herein, we report the first enantioselective synthesis of dichrocephones A and B, which are cytotoxic triquinane sesquiterpenes with a dense array of stereogenic centers within a strained polycyclic environment. Key features include the application of a catalytic asymmetric Wittig reaction, followed by stereoselective functionalization of the propellane core into a pentacyclic intermediate. Double reductive ring cleavage yielded the proposed structure of dichrocephone A. Mismatched spectroscopic data for our synthetic material compared to the natural isolate led us to revise the previously proposed configuration based on biosynthetic considerations and NMR calculations. Implementation of these findings culminated in the synthesis of dichrocephones A and B.     

Forazoline A: Marine‐Derived Polyketide with Antifungal In Vivo Efficacy

Forazoline A, a novel antifungal polyketide with in vivo efficacy against Candida albicans, was discovered using LCMS‐based metabolomics to investigate marine‐invertebrate‐associated bacteria. Forazoline A had a highly unusual and unprecedented skeleton. Acquisition of ¹³C–¹³C gCOSY and ¹³C–¹⁵N HMQC NMR data provided the direct carbon–carbon and carbon–nitrogen connectivity, respectively. This approach represents the first example of determining direct ¹³C–¹⁵N connectivity for a natural product. Using yeast chemical genomics, we propose that forazoline A operated through a new mechanism of action with a phenotypic outcome of disrupting membrane integrity.     

Total Synthesis of Plakortone B

Plakortone B is a naturally occurring bicyclic[3.3.0]furanolactone compound with attractive bioactivities. Although the relative configuration of plakortone B’s central core had been established by NMR spectroscopic methods, the absolute configuration of its four stereocenters remained unknown. In the present paper, all four possible isomers of plakortone B were synthesized and one of these molecules was found to be identical with the natural plakortone B on the basis of ¹H, ¹³C NMR spectra and specific rotation comparisons. Thus, the absolute configuration of the natural plakortone B was determined to be (3S,4S,6R,10R).     

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 Synthesis and Structure Revision of Didemnaketal B

Didemnaketal B, a structurally complex spiroacetal that exhibits potent HIV‐1 protease inhibitory activity, was originally discovered by Faulkner and his colleagues from the ascidian Didemnum sp. collected at Palau. Its absolute configuration was proposed on the basis of degradation/derivatization experiments of the authentic sample. However, our total synthesis of the proposed structure of didemnaketal B questioned the stereochemical assignment made by Faulkner et al. Here we describe in detail our first total synthesis of the proposed structure 2 of didemnaketal B, which features 1) a convergent synthesis of the C7–C21 spiroacetal domain by means of a strategy exploiting Suzuki–Miyaura coupling, 2) an Evans syn‐aldol reaction and a vinylogous Mukaiyama aldol reaction for the assembly of the C1–C7 acyclic domain, and 3) a Nozaki–Hiyama–Kishi reaction for the construction of the C21–C28 side chain domain. The NMR spectroscopic discrepancies observed between synthetic 2 and the authentic sample as well as careful inspection of the Faulkner’s stereochemical assignment led us to postulate that the absolute configuration of the C10–C20 domain of 2 has been erroneously assigned. Accordingly, the total synthesis of the revised structure 65 was achieved to show that the NMR spectroscopic properties of synthetic 65 were in good agreement with those of the authentic sample. Furthermore, application of the phenylglycine methyl ester (PGME) method to the C7–C21 spiroacetal domain enabled us to establish the absolute configuration of didemnaketal B.     

Total Synthesis of the Putative Structure of Xylarinol B

The total synthesis of the putative structure of xylarinol B is described and the need to revise its structure is demonstrated. The central benzoxepine skeleton was constructed by employing a cobalt‐mediated bimolecular [2+2+2] Reppe–Vollhardt alkyne cycloaddition reaction.     

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.     

Synthesis and Stereochemical Revision of the C31–C67 Fragment of Amphidinol 3

Amphidinol 3 (AM3) is a marine natural product produced by the dinoflagellate Amphidinium klebsii. Although the absolute configuration of AM3 was determined in 1999 by extensive NMR analysis and degradation of the natural product, it was a daunting task because of the presence of numerous stereogenic centers on the acyclic carbon chain and the limited availability from natural sources. Thereafter, revisions of the absolute configurations at C2 and C51 were reported in 2008 and 2013, respectively. Reported herein is the revised absolute configuration of AM3: 32S, 33R, 34S, 35S, 36S, and 38S based on the chemical synthesis of partial structures corresponding to the C31–C67 fragment of AM3 in combination with degradation of the natural product. The revised structure is unique in that both antipodal tetrahydropyran counterparts exist on a single carbon chain. The structural revision of AM3 may affect proposed structures of congeners related to the amphidinols.