Carbocyclic Skeleton Research Articles

Divergent synthesis of complex withanolides enabled by a scalable route and late-stage functionalization.

Withanolides are a group of naturally occurring C28 steroids based on an ergostane skeleton. They have a high degree of polyoxygenation, and the abundance of O-functional groups has enabled various natural alterations to both the carbocyclic skeleton and the side chain. Consequently, these molecules have intricate structural features that lead to their highly varied display of biological activities including anticancer, anti-inflammatory, and immunomodulating properties. Despite being intriguing leads for further discovery research, synthetic access to the withanolides remains highly challenging-compounds for current biological research are mainly isolated from plants, often inefficiently. Here, we report the divergent synthesis of 11 withanolides in 12 to 20 steps, enabled by a gram-scale route and a series of late-stage functionalizations, most notably a bioinspired photooxygenation-allylic hydroperoxide rearrangement sequence. This approach enables further biological research disconnected from a reliance on minute quantities of the parent natural products or their simple derivatives.

Immunosuppressive steroids quadrilisteroids A−C and derivatives from the terrestrial fungus Aspergillus quadrilineatus

Seven undescribed compounds (1−7) along with six known compounds (8−13) were isolated from Eurotiaceae Aspergillus quadrilineatus. Their structures and absolute configurations were elucidated by NMR, HRESIMS, and ECD calculations. Quadrilisteroids A (1) and B (2) possessed an unprecedented 6/5/6/6/6/5 hexacyclic ring system in conjugation with a highly fused benzene ring, while quadrilisteroid C (3) featured a surprising 6/6/6/5/5-fused carbocyclic skeleton. Quadrilisteroid C (3) exhibited potent inhibitory activity against LPS-induced proliferation of B lymphocyte cells with an IC50 value of 1.03 μM. Compound 4, demonstrated inhibitory activity against Con A-induced proliferation of T lymphocyte cells with IC50 values of 6.42 μM.

Synthesis of the [6-6-7-5-5] Pentacyclic Core of Calyciphylline N.

A new approach for the concise 11-step synthesis of the [6-6-7-5-5] BCDEF pentacyclic core of calyciphylline N is described. A type II [5 + 2] cycloaddition was employed to construct the strained BCD skeleton, which encompasses the challenging bicyclo[2.2.2] and bicyclo[4.3.1] ring systems. With a regio- and diastereoselective Lu's [3 + 2] cycloaddition, followed by intramolecular aldol cyclization and elimination, the desired [5-5]-fused EF ring system has been successfully installed, resulting in the complete carbocyclic skeleton of calyciphylline N.

A relay ring-closing metathesis/Diels-Alder approach to sugar-derived pluramycin-hybrids.

Herein, we present a general approach for synthesizing pluramycin hybrids, which are analogous to the pluramycinone carbocyclic skeleton. This method involves a sequence of relay ring-closing enyne metathesis, Diels-Alder and oxidative aromatization reactions to synthesize pluramycinone-sugar hybrids. As part of our ongoing research, we have successfully synthesized two pluramycin hybrid analogues by carefully monitoring the late-stage oxidative aromatization steps, which depend on the stereo-orientation of the Diels-Alder cycloadduct at the C-4 center. The undesired ring-opening product can also serve as a C-glycoside analog, providing a versatile convergent route to access both types of hybrids and highlighting the significance of this strategy.

Total Syntheses of Scabrolide A and Yonarolide.

The concise total syntheses of oxidized norcembranoid terpenoids (-)-scabrolide A and (-)-yonarolide have been accomplished in 10 and 11 steps, respectively. The carbocyclic skeleton was efficiently constructed from two chiral-pool-derived fragments, including a [5,5]-bicyclic lactone accessed through a powerful Ni-catalyzed pentannulation of functionalized cyclopentenone with methylenecyclopropane and subsequent fragmentation. Additional features included a Liebeskind-Srogl coupling, induction of a cyclization/elimination cascade by a zinc-amido base, and installation of a sensitive enedione motif by late-stage γ-oxidation.

Organocatalytic Desymmetric Conjugate Addition to Cyclobutanone: An Enantio- and Diastereoselective Synthesis of [6,5,4]-Fused Carbocycles.

The first organocatalytic, non-destructive desymmetrisation of 3-substituted cyclobutanone followed by intramolecular cyclisation is described. Owing to the slow activation of the pronucleophile by the weak Brønsted base, the α-functionalization of ketones with tertiary-amine-derived Brønsted base catalysis has been chemically challenging in asymmetric transformations. Herein, we demonstrate that the cinchona-derived squaramide catalyst works effectively for the intramolecular Michael addition of cyclobutanone to enones and affords the architecturally fascinating [6,5,4]-fused carbocyclic skeleton in good yields and excellent diastereo- and enantioselectivities (up to >20 : 1 dr and 96 % ee). Furthermore, as a synthetic application, this method provides an alternative pathway to enantioenriched high-value products like γ-lactones and indan-2-ol derivatives.

Sinulariaone A: a novel diterpenoid with a 13-membered carbocyclic skeleton from an octocoral Sinularia species.

Chemical composition screening of an octocoral identified as Sinularia species led to the isolation of a novel diterpenoid, sinulariaone A (1), featuring a 13-membered carbocyclic skeleton. The structure of 1 was established by spectroscopic elucidation, computed calculation, and X-ray diffraction analysis. Moreover, a single-crystal X-ray diffraction analysis of chlorofurancembranoid B (2), obtained in our previous study from the same octocoral species, was reported for the first time to demonstrate the absolute configuration. Diterpenoid 1 showed cytotoxicity towards human promyelocytic leukemia HL-60 cells, with an IC50 value of 38.01 μM.

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The cover picture shows that the enantioselective construction of 6‐4 carbocyclic scaffolds with ring‐junction all‐carbon stereocenters has been achieved through Pd(II)/chiral N,N’‐disulfonyl bisimidazoline (Bim) ligand‐catalyzed asymmetric reaction of yne‐allenones and arylboronic acids. In this reaction, realization of 6‐6‐4 carbocyclic skeletons with high chemo‐, regio‐ and enantio‐selectivities is a one‐step process from benzene‐linked yne‐allenones while synthesizing 6‐4 skeleton is a two‐step process, which begins with intramolecular [2 + 2] reaction of alkyl‐tethered yne‐allenones, followed by Pd catalyzed asymmetric addition of arylboronic acids to cyclic enones generated in the first step. DFT calculations have been applied to understand these reaction processes. More details are discussed in the article by Jiang et al. on page 1767—1776.image

Nickel-catalyzed skeletal transformation of tropone derivatives via C-C bond activation: catalyst-controlled access to diverse ring systems.

We report herein on nickel-catalyzed carbon–carbon bond cleavage reactions of 2,4,6-cycloheptatrien-1-one (tropone) derivatives. When a Ni/N-heterocyclic carbene catalyst is used, decarbonylation proceeds with the formation of a benzene ring, while the use of bidentate ligands in conjunction with an alcohol additive results in a two-carbon ring contraction with the generation of cyclopentadiene derivatives. The latter reaction involves a nickel–ketene complex as an intermediate, which was characterized by X-ray crystallography. The choice of an appropriate ligand allows for selective synthesis of four different products via the cleavage of a seven-membered carbocyclic skeleton. Reaction mechanisms and ligand-controlled selectivity for both types of ring contraction reactions were also investigated computationally.

Sesquiterpenoids with various carbocyclic skeletons from Nardostachys chinensis with nitric oxide inhibitory activity

• The twenty-one sesquiterpenoids were isolated from N. chinensis. • Two new ( 1 and 3 ) and one new natural ( 2 ) sesquiterpenoids were identified. • 13 - 15 showed stronger NO inhibitory activity than positive control. • NO inhibitory structure-relationships of these sesquiterpenoids were discussed. • 13 dose-dependently inhibited IL-6, IL-10, and IL-23 mRNA expression. Chemical investigation on the roots and rhizomes of Nardostachys chinensis Batal led to the isolation of twenty-one sesquiterpenoids with various carbocyclic skeletons including three eudesmane-type ( 1 - 2, 4 ), nine nardosinane-type ( 3 , 5 - 12 ), and nine aristolane-type sesquiterprenoids ( 13 - 21 ). The structures of the new compounds 1 and 3 , and the new natural product 2 were established by extensive spectroscopic analysis, and their absolute configurations were established by computational electronic circular dichroism (ECD) method. Nitric oxide (NO) is one of the most important inflammatory modulators in many inflammatory diseases. Thus, inhibitory effects of compounds 1 - 21 on NO production were investigated in lipopolysaccaride (LPS)-mediated RAW 264.7 cells, and compounds 13 - 15 displayed NO inhibitory activity with IC 50 values of 2.67, 2.79, 9.87 μ M, respectively. Moreover, a further study revealed that compound 13 exhibited anti-inflammatory activity via suppression of IL-6, IL-10, and IL-23.

A model study for the total synthesis of lophotoxin

A concise synthetic approach to construct [6,6,6]-tricyclic core, bearing 14-membered carbocyclic skeleton and oxygen at C13 of lophotoxin, has been described. This approach features a diastereoselective intermolecular Diels–Alder furan reaction and intramolecular Michael reaction. N-methylmaleimide was found to be critical for achieving the stable intermolecular Diels–Alder furan outcome.

Applications of transition state calculations in the key cyclization of small molecule natural product synthesis

The diversification of the conformation and configuration of the carbocyclic skeleton of natural products is an important reason for the diversity and complexity of the structure of natural products. The corresponding cyclization synthesis has attracted much attention. Computational chemistry approaches have the advantages of non-toxic, harmless and relatively low cost, and they are increasingly used to model and understand molecular phenomena. The reaction mechanism and thermodynamic parameters determine the feasibility of the cyclization and the enantioselectivity of the cyclization products. The transition state calculations can provide these thermodynamic parameters, which helps to elucidate the cyclization mechanism, calculate the reaction rationality, predict the performance of the new synthesis method and provide a basis for the comprehensive synthesis design.

Enantioselective construction of substituted pyridine and a seven-membered carbocyclic skeleton: biomimetic synthesis of (-)-rupestine D, (-)-guaipyridine, (-)-epiguaipyridine, and (-)-cananodine and their stereoisomers.

Guaipyridine alkaloids (-)-rupestine D, (-)-guaipyridine, (-)-epiguaipyridine, and (-)-cananodine together with two stereoisomers 8-epi-rupestine D and 5-epi-cananodine were synthesized enantioselectively from readily available citronellol. The key steps in this synthesis are (i) intermolecular opening of a trisubstituted epoxide for the formation of a chiral center at C-8; (ii) ring-closing metathesis for the construction of a seven-membered carbocyclic ring; and (iii) biomimetic cyclization of a 1,5-dicarbonyl compound for the construction of a pyridine-fused bicyclic skeleton.

Total Synthesis of Kopsinitarine E.

Kopsinitarines A-E are complex octacyclic caged Kopsia alkaloids with strained cage skeletons and a unique cyclic hemiaminal bridge that makes total synthesis challenging. Herein, we disclose the first total synthesis of kopsinitarine E. The key synthetic features include a SmI2 -mediated radical cascade cyclization and a subsequent semi-pinacol rearrangement to install the key carbocyclic skeleton, a chemoselective hydrosilyl amide reduction to construct the hemiaminal ether bridge, and an intramolecular Mannich reaction to establish the highly strained cage system.

Total Synthesis of Kopsinitarine E

AbstractKopsinitarines A–E are complex octacyclic caged Kopsia alkaloids with strained cage skeletons and a unique cyclic hemiaminal bridge that makes total synthesis challenging. Herein, we disclose the first total synthesis of kopsinitarine E. The key synthetic features include a SmI2‐mediated radical cascade cyclization and a subsequent semi‐pinacol rearrangement to install the key carbocyclic skeleton, a chemoselective hydrosilyl amide reduction to construct the hemiaminal ether bridge, and an intramolecular Mannich reaction to establish the highly strained cage system.

An Improved Biomimetic Formal Synthesis of Abyssomicin C and atrop‐Abyssomicin C

Biomimetic approaches towards the synthesis of abysssomicin C and atrop‐abyssomicin C are based on a powerful intramolecular Diels–Alder reaction (IMDA) of a butenolide derivative attached to a keto‐triene side chain, where the stereogenic centers and the carbon framework are established in one step. The synthesis of the IMDA precursor is based on an ionic coupling of methyl γ‐methylene‐β‐tetronate with various aldehydes. However, the low yields of the coupling and the high sensitivity of the precursor hampered the efficiency of the developed routes and should be met. In the present work, a modified aldehyde is coupled with methyl γ‐methylene‐β‐tetronate, in a substantially higher yield. Asymmetric synthesis of this aldehyde is based on the use of the widely available and cheap Amano lipase AK. In addition, the development of a highly convenient one‐pot oxidation‐IMDA reaction protocol obviates the isolation of the sensitive IMDA‐precursor and augments the yield towards the carbocyclic skeleton of abysssomicin C and atrop‐abyssomicin C.

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.

Complex Carbocyclic Skeletons from Aryl Ketones through a Three-Photon Cascade Reaction.

Starting from readily available 7‐substituted 1‐indanones, products with a tetracyclo[5.3.1.01,704,11]undec‐2‐ene skeleton were obtained upon irradiation at λ=350 nm (eight examples, 49–67 % yield). The assembly of the structurally complex carbon framework proceeds in a three‐photon process comprising an ortho photocycloaddition, a disrotatory [4π] photocyclization, and a di‐π‐methane rearrangement. The flat aromatic core of the starting material is converted into a functionalized polycyclic hydrocarbon with exit vectors in three dimensions. Ring opening reactions at the central cyclopropane ring were explored, which enable the preparation of tricyclo[5.3.1.04,11]undec‐2‐enes and of tricyclo[6.2.1.01,5]undecanes.

Complex Carbocyclic Skeletons from Aryl Ketones through a Three‐Photon Cascade Reaction

AbstractStarting from readily available 7‐substituted 1‐indanones, products with a tetracyclo[5.3.1.01,704,11]undec‐2‐ene skeleton were obtained upon irradiation at λ=350 nm (eight examples, 49–67 % yield). The assembly of the structurally complex carbon framework proceeds in a three‐photon process comprising an ortho photocycloaddition, a disrotatory [4π] photocyclization, and a di‐π‐methane rearrangement. The flat aromatic core of the starting material is converted into a functionalized polycyclic hydrocarbon with exit vectors in three dimensions. Ring opening reactions at the central cyclopropane ring were explored, which enable the preparation of tricyclo[5.3.1.04,11]undec‐2‐enes and of tricyclo[6.2.1.01,5]undecanes.

Scholarinine A, a N3 type caged-monoterpene indole alkaloid as Cav3.1 T-type calcium channel inhibitor from Alstonia scholaris

Scholarinine A (1), a new N3-type caged monoterpene indole alkaloid was isolated from the branches and leaves of Alstonia scholaris. Structurally, 1 is featured by unique 6/5/6/5/5/6 carbocyclic skeleton bearing a novel imidazolidine ring E. The structure of 1 was determined by extensive spectroscopic analyses and X-ray crystallography. Biological studies exhibited that compound 1 is a potent Cav3.1 T-type calcium channel inhibitor with an IC50 value of 4.28 μM. In addition, 1 enhanced the neurite outgrowth of nerve growth factor (NGF) mediated PC12 cells at 10 μM.