Recent Advances in Naturally Occurring [4+2] Type Terpenoid Dimers Assembled through Unmatched-electron-demand Cycloaddition.

Terpenoid dimers of the [4+2] type, which are naturally occurring compounds biosynthetically derived from the [4+2] cycloaddition of two synthons, have garnered considerable attention due to their complex molecular structures, diverse biological activities, and intriguing biosynthetic pathways. We have previously summarized the advancements in three types of [4+2] terpenoid dimers. In this review, we will focus on the lesser-explored class of [4+2] terpenoid dimers which assembled from two electron-deficient synthons via the unmatched-electron-demand Diels-Alder reaction  (UMEDDA). We will summarize their sources, biological activities, proposed biosynthesis, and chemical syntheses. Finally, a summary and outlook for this fascinating class of compounds will be presented.

Asymmetric synthesis of the fully functionalized six-membered A-ring of siphonol A.

A synthetic study toward the construction of the fully functionalized six-membered A-ring of siphonol A is described. The salient features include the introduction of a six-membered ring system through a HWE reaction, the construction of a stereocenter at C5 via a hetero-Diels-Alder reaction, and the installation of the fully functionalized six-membered A-ring of siphonol A through photolytic decarboxylation.

Asymmetric Total Synthesis of Euphordraculoate A and Pedrolide.

Here we report the asymmetric total syntheses of two rearranged tigliane diterpenoids, euphordraculoate A and pedrolide. A reductive dihydroxylation cascade and Nazarov cyclization were performed to generate euphordraculoate A, which was subjected to a cascade of Eu-promoted dienyl enolization, intramolecular Diels-Alder reaction and enol-ketone tautomerization to afford pedrolide, a pathway consistent with our proposal for the biogenesis of pedrolide.

Stereodivergent Construction of [5,5]-Oxaspirolactones of Phainanoids.

A stereodivergent synthesis of [5,5]-oxaspirolactones of phainanoids is presented herein. Through precisely tuning the inherent substitution differences on cyclopropanol, a palladium-catalyzed cascade carbonylative lactonization enables the stereodivergent synthesis of [5,5]-oxaspirolactones of phainanoids.

Asymmetric syntheses of ent-pimarane diterpenoids.

Aromatic ent-pimaranes are a group of aromatized tricyclic diterpenoids that exhibit diverse bioactivities. In this work, the first total syntheses of two aromatic ent-pimaranes were achieved via a C-ABC construction sequence enabled by chiral auxiliary controlled asymmetric radical polyene cyclization, and the subsequent substrate-controlled stereo-/regio-specific hydroboration of alkene allowed for access to both natural products with C19 oxidation modifications.

Total Synthesis of Sculponin†U through a Photoinduced Radical Cascade Cyclization.

We have accomplished the total synthesis of sculponin U, a polycyclic C-20-oxygenated kaurane diterpenoid featuring a 7,20-lactone-hemiketal bridge, through a radical cascade cyclization triggered by photoinduced electron transfer (PET) of a silyl enolate to form the cyclohexanone-fused bicyclo[3.2.1]octane skeleton. Other key points in our synthetic strategy encompass a Diels-Alder reaction to construct the middle six-membered ring of sculponin U, and an intramolecular radical cyclization induced by iron-catalyzed hydrogen atom transfer to close the western cyclohexane ring. Successful preparation of the enantiopure silyl enolate as the PET precursor enables the asymmetric total synthesis of sculponin U, opening a new avenue for divergent syntheses of structurally related C-20-oxygenated kaurane congeners and pharmaceutical derivatives thereof.

Asymmetric Total Synthesis of Natural Lindenane Sesquiterpenoid Oligomers via a Triene as a Potential Biosynthetic Intermediate.

A previously proposed triene of the lindenane skeleton was synthesized, characterized, and identified as the common intermediate for the non-enzymatic synthesis of natural lindenane oligomers through linear, [4+2]-type and [6+6]-type homo- and hetero- dimerization under simulated physiological conditions. As a result, the following six natural products were successfully synthesized through thermal head-to-head, head-to-tail, and head-to-back binding modes: shizukaols A and J, cycloshizukaol A, chlorahupetone F, chlotrichene B, and trishizukaol A.

Asymmetric Total Synthesis of Shizukaol J, Trichloranoid C and Trishizukaol A.

The asymmetric total synthesis of three lindenane sesquiterpenoid oligomers, shizukaol J, trichloranoid C and trishizukaol A, has been accomplished concisely in 15, 16 and 18 longest linear steps, respectively. The expeditious construction of molecular architectures was facilitated by Nelson's catalytic asymmetric ketene-aldehyde cycloaddition, a sequence of allylic alkylation/reduction/acidic cyclization to forge a lactone, and a double aldol condensation cascade to construct the 5/6 bicyclic system. Diastereoselective nucleophilic substitution promoted by a phase transfer catalyst constructed the C11 quaternary stereogenic center, thus prompting synthetic efficacy toward shizukaol J. The synthesis of trichloranoid C and trishizukaol A was achieved after a cascade involving furanyl diene formation and a Diels-Alder reaction, as well as a one-pot sequence involving furan oxidation and global deprotection. Furthermore, our biological evaluation revealed that two compounds exhibited unexpected toxicity against tumor cell lines.

Naturally occurring [4 + 2] type terpenoid dimers: sources, bioactivities and total syntheses.

Covering: up to January 2020[4 + 2] type terpenoid dimers are natural products biosynthetically derived from [4 + 2] cycloaddition between two terpenoid monomers. They have attracted the attention of scientists due to their complex architectures, biological activities, natural production pathways and synthetic challenges. In this review article, we highlight recent research progress on naturally occurring [4 + 2] type terpenoid dimers, including their sources, bioactivities, biosynthetic hypotheses and total chemical syntheses.

Recent advances in alkaline earth metal-enabled syntheses of heterocyclic compounds.

Heterocyclic compounds are widely distributed in natural products, pharmaceuticals and materials, thus drawing considerable attention from the synthetic communities. Generally, alkaline earth metals are earth-abundant and environmentally friendly compared to precious metals. To date, researchers have achieved great progress in utilization of alkaline earth metals in the syntheses of various heterocyclic compounds. Herein, this review will summarize recent advances in the syntheses of heterocyclic compounds enabled by alkaline earth metals, including magnesium, calcium and strontium. In addition, the summary is also presented.

Total synthesis of (±)-epi-stemodan-13α,17-diol.

Stemodan-13α,17-diol is a natural stemodane-type diterpenoid isolated from Stemodia chilensis. Herein we report the total synthesis of its epimer, stemodan-13ß,17-diol, by applying titanium-mediated polyene cyclization and iron-catalyzed [5 + 2] cycloaddition as the key transformations to expeditiously install the molecular scaffold.

Total synthesis and structural revision of an isopanepoxydone analog isolated from Lentinus strigellus.

Asymmetric total synthesis of compound 1, as a proposed molecular structure of a natural product, in 11 steps is described. The inconsistency of the characterization data between our synthesized sample and the natural product prompted us to propose a different molecular structure as compound 2 and accordingly accomplish total synthesis in 9 steps and confirm the structural revision of this natural product. Both total syntheses feature highly regio- and diastereoselective epoxidation, Stille cross-coupling and cross-metathesis.

Manganese-Catalyzed Upgrading of Ethanol into 1-Butanol.

Biomass-derived ethanol is an important renewable feedstock. Its conversion into high-quality biofuels is a promising route to replace fossil resources. Herein, an efficient manganese-catalyzed Guerbet-type condensation reaction of ethanol to form 1-butanol was explored. This is the first example of upgrading ethanol into higher alcohols using a homogeneous non-noble-metal catalyst. This process proceeded selectively in the presence of a well-defined manganese pincer complex at the parts per million (ppm) level. The developed reaction represents a sustainable synthesis of 1-butanol with excellent turnover number (>110 000) and turnover frequency (>3000 h-1). Moreover, mechanistic studies including control experiments, NMR spectroscopy, and X-ray crystallography identified the essential role of the "N-H moiety" of the manganese catalysts and the major reaction intermediates related to the catalytic cycle.

Ligand-Controlled Cobalt-Catalyzed Transfer Hydrogenation of Alkynes: Stereodivergent Synthesis of Z- and E-Alkenes.

Herein, we report a novel cobalt-catalyzed stereodivergent transfer hydrogenation of alkynes to Z- and E-alkenes. Effective selectivity control is achieved based on a rational catalyst design. Moreover, this mild system allows for the transfer hydrogenation of alkynes bearing a wide range of functional groups in good yields using catalyst loadings as low as 0.2 mol %. The general applicability of this procedure is highlighted by the synthesis of more than 50 alkenes with good chemo- and stereoselectivity. A preliminary mechanistic study revealed that E-alkene product was generated via sequential alkyne hydrogenation to give Z-alkene intermediate, followed by a Z to E alkene isomerization process.

Mild and Selective Cobalt-Catalyzed Chemodivergent Transfer Hydrogenation of Nitriles.

Herein, we describe a selective cobalt-catalyzed chemodivergent transfer hydrogenation of nitriles to synthesize primary, secondary, and tertiary amines. The solvent effect plays a key role for the selectivity control. The general applicability of this procedure was highlighted by the synthesis of more than 70 amine products bearing various functional groups in high chemoselectivity. Moreover, this mild system achieved >2000 TONs (turnover numbers) for the transfer hydrogenation of nitriles.

Ruthenium(II)-catalyzed direct addition of indole/pyrrole C2-H bonds to alkynes.

A ruthenium-catalyzed C2-hydroindolation of alkynes has been achieved. This protocol provides a rapid and concise access to kinds of 2-alkenyl-substituted N-(2-pyridyl)indoles in which the pyridyl moiety can be easily removed to afford free (N-H) indoles under mild conditions. Various arenes and alkynes, including electron-deficient and electron-rich internal alkynes and terminal alkynes, allow for this transformation.

A Photoinduced Radical Cascade Cyclization for the Synthesis of Angularly Fused Tricyclic Compounds.

A photoinduced electron transfer (PET)-triggered cascade reaction has been devised for the conversion of second-generation enol silyl ethers into angularly fused tricyclic scaffolds. Utilizing readily available and cost-effective DCA and phenanthrene as the catalytic systems, this cascade transformation is achieved with high efficiency. The reaction demonstrates a good substrate scope and excellent stereoselectivity, thereby enriching the realm of PET-induced cascade reactions. Additionally, the radical adducts generated through this process can serve as valuable subunits for the synthesis of complex molecules.

Climatic Warming-Induced Drought Stress Has Resulted in the Transition of Tree Growth Sensitivity from Temperature to Precipitation in the Loess Plateau of China.

Ongoing climate warming poses significant threats to forest ecosystems, particularly in drylands. Here, we assess the intricate responses of tree growth to climate change across two warming phases (1910-1940 and 1970-2000) of the 20th century in the Loess Plateau of China. To achieve this, we analyzed a dataset encompassing 53 ring-width chronologies extracted from 13 diverse tree species, enabling us to discern and characterize the prevailing trends in tree growth over these warming phases. The difference in the primary contributors over two warming phases was compared to investigate the association of tree growth with climatic drivers. We found that the first warming phase exerted a stimulating effect on tree growth, with climate warming correlating to heightened growth rates. However, a contrasting pattern emerged in the second phase as accelerated drought conditions emerged as a predominant limiting factor, dampening tree growth rates. The response of tree growth to climate changed markedly during the two warming phases. Initially, temperature assumed a dominant role in driving the tree growth of growth season during the first warming phase. Instead, precipitation and drought stress became the main factors affecting tree growth in the second phase. This drought stress manifested predominantly during the early and late growing seasons. Our findings confirm the discernible transition of warming-induced tree growth in water-limited regions and highlight the vulnerability of dryland forests to the escalating dual challenges of heightened warming and drying. If the warming trend continues unabated in the Loess Plateau, further deterioration in tree growth and heightened mortality rates are foreseeable outcomes. Some adaptive forest managements should be encouraged to sustain the integrity and resilience of these vital ecosystems in the Loess Plateau and similar regions.

Asymmetric Construction of the Core of C6, C7-Epoxy Daphnane Diterpenoid Orthoesters.

Asymmetric construction of the core of C6, C7-epoxy daphnane diterpenoid orthoesters is developed through a convergent synthetic strategy. The salient features include a diastereoselective nucleophilic assembly of two bulky cyclic fragments, an oxidative cleavage/transesterification/aldol cascade to fashion the seven-membered ring, and a base-mediated transesterification/retro-aldol/aldol/epoxidation cascade to install the epoxy moiety with proper stereochemistry.

Oxime ester-enabled anti-Markovnikov hydrosilylation of alkenes.

An oxime ester-enabled anti-Markovnikov hydrosilylation of alkenes is developed. This protocol is operationally simple and atom economical. The reaction shows broad functional group tolerance, such as ketones, amides, esters, epoxides, alcohols and carboxylic acids. Mono-substituted and geminally substituted alkenes could be chemoselectively hydrosilylated.