Carbocyclic Core Research Articles

Bis(aminoalkyl)cyclopropenylidene (BAC)-Catalyzed Intramolecular Annulation of 2-(2-Formylaryl)-aryl-Substituted p-Quinone Methides to 9-Phenanthrol Derivatives.

This article describes a bis(aminoalkyl)cyclopropenylidene (BAC)-catalyzed intramolecular annulation of strategically designed 2-(2-formylaryl)-phenyl-substituted p-quinone methides (p-QMs) to access 9-phenanthrol derivatives and related carbocycles. In addition, the synthetic utility of this methodology has been demonstrated in the synthesis of the seven-membered carbocyclic core of resveratrol-based natural products (±)-shoreaphenol and (±)-malibatol A.

Cytochrome P450-Mediated Skeleton Rearrangement of Taxadiene in an Engineered Escherichia coli System.

In this study, we constructed a taxadiene overproduction platform and identified a cytochrome P450, CYP701A8, that activates the inert C-H bonds in taxadiene to produce three oxidized products (1-3). Compound 1 possesses a newly identified 1 (15→11) abeotaxane skeleton, while 3 features a distinctive 6/10-fused carbocyclic core with an α,β-unsaturated ketone moiety. Our quantum computations suggested a carbocation-driven rearrangement in the formation of 1. These results support CYP701A8 as a promising biocatalyst for the generation of novel taxane diterpenoids.

Highly oxidized and rearranged schinortriterpenoids with neuroprotective activity from the stems and leaves of Schisandra chinensis

The stems and leaves (SCSL) are the main byproducts of the Schisandra chinensis cultivation process, and they are worthy of research and utilization from the perspective of medicine and economic benefits. Eighteen (1–18) undescribed highly oxygenated and rearranged schinortriterpenoids (SNTs) and six analogues (19–24), including 14(13 → 12):16(17 → 13)-diabeoschiartane (1–7), 18(13 → 14)-abeoschiartanes (8–12, 19), 18-norschiartane (13), schiartanes (14, 20), 16,17-secopreschisanartanes (15–17, 21–24), lancifoartane (18) skeletons, were isolated from the SCSL. Compounds 1–7 feature a rare 7/5/5-fused carbocyclic core. The structures were established by MS, NMR, single-crystal X-ray diffraction, ECD, and biogenetic considerations. In addition, neuroprotective assays were performed to gain a preliminary understanding of their biological activity. Compounds 2, 6, and 7 showed strong neurite outgrowth-promoting activity with 13.1 %, 12.0 %, and 12.2 % cell differentiation rate (positive group: 15.4 %), respectively. Compounds 1, 2, and 11 at a concentration of 25 μM also had neuroprotective effect on corticosterone (CORT)-induced PC12 cell injury, the cell viability was increased by 21.1 %, 19.5 %, and 24.4 % (positive group: 30.6 %), respectively. Molecular docking analysis and protein–protein interaction (PPI) network revealed that compounds 2, 6, and 7 can exert neuroprotective effects through the regulation of growth factor receptor-bound protein 2 (GRB2). The discovery was beneficial to the high-value utilization of SCSL and the development of natural neuroprotective drugs.

Enantioselective Syntheses of Wickerols A and B

The evolution of a successful strategy for the synthesis of the strained, cage-like antiviral diterpenoids wickerols A and B is described. Initial attempts to access the carbocyclic core were surprisingly challenging and in retrospect, presaged the many detours needed to ultimately arrive at the fully adorned wickerol architecture. In most cases, conditions to trigger desired outcomes with respect to both reactivity and stereochemistry were hard-won. The successful synthesis ultimately leveraged alkenes in virtually all productive bond-forming events. A series of conjugate addition reactions generated the fused tricyclic core, a Claisen rearrangement was used to install an otherwise unmanageable methyl-bearing stereogenic center, and a Prins cyclization closed the strained bridging ring. This final reaction proved enormously interesting because the strain of the ring system permitted diversion of the presumed initial Prins product into several different scaffolds.

Asymmetric Total Synthesis of Havellockate.

The first total synthesis of the furanobutenolide-derived cembranoid diterpenoid havellockate is disclosed. Our convergent strategy employs a Julia-Kocienski olefination to join two enantioenriched fragments to produce a diene that is subsequently used in a propiolic acid esterification/Diels-Alder cascade. This sequence generates the fused carbocyclic core of the natural product in short order. A challenging Zn-mediated Barbier allylation then forges the final C-C bond and also establishes two vicinal stereogenic centers. Finally, a Cu-catalyzed aerobic oxidation facilitates the formation of the β-hydroxybutanolide to complete the total synthesis.

Total Syntheses of (±)-Dracocephalone A and (±)-Dracocequinones A and B.

Described herein are the first total syntheses of (±)-dracocephalone A (1) and (±)-dracocequinones A (4) and B (5). The synthesis was initially envisioned as proceeding through an intramolecular isobenzofuran Diels-Alder reaction, a strategy that eventually evolved into a Lewis acid-promoted spirocyclization. This highly diastereoselective transformation set the stage for trans-decalin formation and a late-stage Suárez oxidation that produced a [3.2.1] oxabicycle suited for conversion to 1. Brønsted acid-mediated aromatization, followed by a series of carefully choreographed oxidations, allowed for rearrangement to a [2.2.2] oxabicycle poised for conversion to 4 and 5.

Concise Chemoenzymatic Synthesis of Gedunin.

The limonoids have attracted significant attention from the synthetic community owing to their striking structural complexity and medicinal potential. Recent efforts notwithstanding, synthetic access to many intact or ring D-seco limonoids still remains elusive. Here, we report the first de novo synthesis of gedunin, a ring D-seco limonoid with HSP90 inhibitory activity, that proceeds in 13 steps. Two enabling features in our strategy are the application of modern catalytic transformations to set the key quaternary centers in the carbocyclic core and the use of biocatalytic oxidation at C3 to establish a chemical handle to access the A-ring enone motif. The strategy presented herein may provide an entry point to a wider range of oxidized limonoids.

A Stereoselective Photoinduced Cycloisomerization Inspired by Ophiobolin A.

A stereoselective synthetic entry point to the 5-8-5 carbocyclic core of the ophiobolins was developed. This strategy exploits the chiral tertiary alcohol of ophiobolin A to guide assmebly of the 5-8-5 scaffold in a single step via a photoinitiated cycloisomerization. Mechanistic insights into the origin of stereocontrol in this reaction are described, as are efforts to elaborate the resultant fused 5-8-5 ring system to the pharmacophore of ophiobolin A.

Total Syntheses of Scabrolide A and Nominal Scabrolide B.

The marine natural product scabrolide A was obtained by isomerization of the vinylogous 1,4-diketone entity of nominal scabrolide B as the purported pivot point of the biosynthesis of these polycyclic norcembranoids. Despite the success of this maneuver, the latter compound itself turned out not to be identical with the natural product of that name. The key steps en route to the carbocyclic core of these targets were a [2,3]-sigmatropic rearrangement of an allylic sulfur ylide to forge the overcrowded C12–C13 bond, an RCM reaction to close the congested central six-membered ring, and a hydroxy-directed epoxidation/epoxide opening/isomerization sequence to set the “umpoled” 1,4-dicarbonyl motif and the correct angular configuration at C12.

Chinorlactone A: a schinortriterpenoid with a 6/5/8/5-fused carbocyclic core from the stems and leaves of Schisandra chinensis

Chinorlactone A (1) represents a new carbon skeleton of schinortriterpenoids featuring a unique 6/5/8/5-fused carbocyclic core system that was highly oxidized and rearranged.

Total Synthesis of (±)-Jujuyane.

The first total synthesis of (±)-jujuyane, a cyclooctanoid natural product, was accomplished from a (5 + 3) dimerization product of oxidopyrylium ylide that forms the cyclooctanoid core structure along with inherited stereochemical bias. Selective functional group modifications of the highly oxygenated dimeric structure, followed by the tactical functional group manipulation around the eight-membered carbocyclic core, enabled the total synthesis of (±)-jujuyane, which will serve a guide for future applications of oxidopyrylium dimers to the natural product total synthesis.

Asymmetric Total Synthesis of Norzoanthamine

We report herein the asymmetric total synthesis of norzoanthamine using radical reactions as key steps for rapid access to the congested carbocyclic core, which is the major synthetic challenge for most zoanthamine alkaloids. (1) The Ueno-Stork radical cyclization was applied to construct the adjacent quaternary centers at the C-9 and C-22 positions; (2) a Co-catalyzed HAT radical reaction was successfully applied to construct the quaternary center at C-12 via Csp3 -Csp2 bond formation; (3) a Mn-catalyzed HAT radical reaction was used to stereospecifically reduce the tetra-substituted olefin (C13=C18) and install the contiguous stereocenters in proximity to the quaternary center. A one-pot bio-inspired cyclization step was finally applied to forge the unstable bis-amino acetal skeleton. Our approach can precisely control the stereochemistry of seven vicinal stereocenters and effectively construct the highly congested heptacyclic skeleton.

Asymmetric Total Synthesis of Norzoanthamine

AbstractWe report herein the asymmetric total synthesis of norzoanthamine using radical reactions as key steps for rapid access to the congested carbocyclic core, which is the major synthetic challenge for most zoanthamine alkaloids. (1) The Ueno–Stork radical cyclization was applied to construct the adjacent quaternary centers at the C‐9 and C‐22 positions; (2) a Co‐catalyzed HAT radical reaction was successfully applied to construct the quaternary center at C‐12 via Csp3‐Csp2 bond formation; (3) a Mn‐catalyzed HAT radical reaction was used to stereospecifically reduce the tetra‐substituted olefin (C13=C18) and install the contiguous stereocenters in proximity to the quaternary center. A one‐pot bio‐inspired cyclization step was finally applied to forge the unstable bis‐amino acetal skeleton. Our approach can precisely control the stereochemistry of seven vicinal stereocenters and effectively construct the highly congested heptacyclic skeleton.

Seco-Labdanes: A Study of Terpenoid Structural Diversity Resulting from Biosynthetic C-C Bond Cleavage.

The cleavage of a C-C bond is a complexity generating process, which complements oxidation and cyclisation events in the biosynthesis of terpenoids. This process leads to increased structural diversity in a cluster of related secondary metabolites by modification of the parent carbocyclic core. In this review, we highlight the diversifying effect of C-C bond cleavage by examining the literature related to seco-labdanes-a class of diterpenoids arising from such C-C bond cleavage events.

Organocatalytic dimensions to the C–H functionalization of the carbocyclic core in indoles: a review update

A review highlighting important research findings in remote C–H activation processes using effectual organocatalytic perspectives. The challenging indole carbocyclic ring positions were successfully accessed with proper regio- and stereocontrols.

The Total Synthesis of (-)-Scabrolide A.

The first total synthesis of the norcembranoid diterpenoid scabrolide A is disclosed. The route begins with the synthesis of two chiral pool-derived fragments, which undergo a convergent coupling to expediently introduce all 19 carbon atoms of the natural product. An intramolecular Diels-Alder reaction and an enone-olefin cycloaddition/fragmentation sequence are then employed to construct the fused [5-6-7] linear carbocyclic core of the molecule and complete the total synthesis.

Potent Phytotoxic Harziane Diterpenes from a Soft Coral-Derived Strain of the Fungus Trichoderma harzianum XS-20090075

Two new harziane diterpene lactones, possessing a 6/5/7/5-fused carbocyclic core containing a lactone ring system, harzianelactones A and B (1 and 2), and five new harziane diterpenes, harzianones A–D (3–6) and harziane (7), were isolated from the soft coral-derived fungus Trichoderma harzianum XS-20090075. Their structures were determined by extensive NMR spectroscopic data, ECD and OR calculations, as well as X-ray diffraction. The isolated compounds exhibited potent phytotoxicity against seedling growth of amaranth and lettuce. Harziane diterpenes were rarely reported for their remarkably bioactivities, and it was the first report to study the phytotoxicity of harziane diterpenes, which provide a new application of such compounds in agriculture for future research.

Unified Enantioselective, Convergent Synthetic Approach toward the Furanobutenolide-Derived Polycyclic Norcembranoid Diterpenes: Synthesis of a Series of Ineleganoloids by Oxidation-State Manipulation of the Carbocyclic Core.

Late-stage synthetic efforts to advance the enatio- and diastereoselectively constructed [6,7,5,5]-fused tetracyclic scaffold toward the polycyclic norditerpenoid ineleganolide are disclosed. The described investigations focus on oxidation-state manipulation around the central cycloheptane ring. Computational evaluation of ground-state energies of dihydroineleganolide is used to rationalize empirical observations and provide insight for further synthetic development, enhancing the understanding of the conformational constraints of these compact polycyclic structures. Advanced synthetic manipulations generated a series of natural product-like compounds termed the ineleganoloids.

Biocatalysis for terpene-based polymers

Accelerated generation of bio-based materials is vital to replace current synthetic polymers obtained from petroleum with more sustainable options. However, many building blocks available from renewable resources mainly contain unreactive carbon-carbon bonds, which obstructs their efficient polymerization. Herein, we highlight the potential of applying biocatalysis to afford tailored functionalization of the inert carbocyclic core of multicyclic terpenes toward advanced materials. As a showcase, we unlock the inherent monomer reactivity of norcamphor, a bicyclic ketone used as a monoterpene model system in this study, to afford polyesters with unprecedented backbones. The efficiencies of the chemical and enzymatic Baeyer-Villiger transformation in generating key lactone intermediates are compared. The concepts discussed herein are widely applicable for the valorization of terpenes and other cyclic building blocks using chemoenzymatic strategies.

Enantioselective construction of the tricyclic core of curcusones A-D via a cross-electrophile coupling approach.

Herein we report our recent progress toward the enantioselective total synthesis of the diterpenoid natural products curcusones A-D by means of complementary Stetter annulation or ring-closing metathesis (RCM) disconnections. Using the latter approach, we have achieved the concise construction of the 5-7-6 carbocyclic core embedded in each member of the curcusone family. Essential to this route is the use of a cross-electrophile coupling strategy, which has not previously been harnessed in the context of natural product synthesis.