Huperzine alkaloids: forty years of total syntheses.

Covering: up to 2023Huperzine alkaloids are a group of natural products belonging to the Lycopodium alkaloids family. The representative member huperzine A has a unique structure and exhibits potent inhibitory activity against acetylcholine esterase (AChE). This subfamily of alkaloids provides a great opportunity for developing synthetic methodologies and asymmetric synthesis. The efforts towards the synthesis of huperzine A have cultivated dozens of total syntheses and a rich body of new chemistry. Impressive progress has also been made in the synthesis of other huperzine alkaloids. The total syntheses of huperzines B, U, O, Q and R, structure reassignment and total syntheses of huperzines K, M and N have been reported in the past decade. This review focuses on the synthetic organic chemistry and the biosynthesis and medicinal chemistry of huperzines are also covered briefly.

Recent advances in the total synthesis of galantamine, a natural medicine for Alzheimer's disease.

Covering: 2006 to 2023(-)-Galantamine is a natural product with distinctive structural features and potent inhibitory activity against acetylcholine esterase (AChE). It is clinically approved for the treatment of Alzheimer's disease. The clinical significance and scarcity of this natural product have prompted extensive and ongoing efforts towards the chemical synthesis of this challenging tetracyclic structure. The objective of this review is to summarize and discuss recent progress in the total synthesis of galantamine from 2006 to 2023. The contents are organized according to the synthetic strategies for the construction of the quaternary center. Key features of each synthesis have been highlighted, followed by a summary and outlook at the end.

Total Syntheses of ß-Carboline Alkaloids Manzamine C, Orthoscuticelline C, and Quassidine S.

A regioselective olefin hydrofunctionalization reaction of pavettine (4) with various nucleophiles was developed and used as the key step in the total syntheses of ß-carboline natural products manzamine C (3), orthoscuticelline C (5), and quassidine S (6). In the 6-step total synthesis of manzamine C (3), an efficient two-step procedure, comprising a Wittig olefination reaction and a Fukuyama-Mitsunobu reaction, was devised for the synthesis of the N-macrocycle with a Z-olefin.

Syntheses of η1 -Alkyl-η3 -Allyl-η5 -Cyclopentadienyl Cobalt(III) Complexes and Their Use in Low-temperature Atomic Layer Deposition of Cobalt-Containing Thin Films.

Herein, we report the design and scalable synthesis of three new Co(III) complexes, which have an unusual hydrocarbon η1 -alkyl-η3 -allyl-η5 -cyclopentadienyl ligation structure, from the reactions of readily available cobalt(II) compound CoCl2 (PPh3 )2 and biomass material ß-pinene via C-C bond activation. These Co(III) complexes are air-stable, fairly volatile, and thermally stable, so they are excellent candidates as the metal precursors for the vapor deposition of cobalt-containing thin films. As a demonstration, we show that the Co(III) complex of [(3'-5'-η,1-σ)-methylene(2,2,4-trimethyl-4-cyclohexene-1,3-diyl)](η5 -methylcyclopentadienyl)Co (i. e. (seco-pinene)(MeCp)Co) is well suited for the atomic layer deposition (ALD) of Co3 O4 and CoS2 thin films, and the deposited Co3 O4 and CoS2 films are able to conformally cover trench structures with a fairly high aspect ratio of 10 : 1.

Syntheses of Substituted α,ß-Unsaturated δ-Lactams from N-Boc-2,4-dioxopiperidine.

A method for the syntheses of substituted α,ß-unsaturated δ-lactams (2) from the commercially available compound N-Boc-2,4-dioxopiperidine (1) has been developed. The α-substituents were introduced by a reductive Knoevenagel condensation reaction, and the ß-substituents were installed by palladium-catalyzed cross coupling reactions. More than 20 diverse examples were prepared in 2-3 steps. The synthesis was operationally simple, user-friendly, and easy to scale up.

Recent progress on the total syntheses of macrocyclic diamine alkaloids.

Covering: 2006 to 2019Macrocyclic diamine alkaloids derived from 3-alkyldihydropyridine dimers comprise a diverse and highly complex family of natural products. The macrocyclic and caged structural features of these alkaloids have inspired many creative solutions from the synthetic organic community over the past 30 years. This review will cover the successful synthetic campaigns over the past decade, with a focus on (1) key bond disconnections and advances and (2) remaining challenges and opportunities for innovation within this natural product class.

Total Syntheses of Cystobactamids and Structural Confirmation of Cystobactamid 919-2.

The cystobactamids are a family of antibacterial natural products with unprecedented chemical scaffolds that are active against both Gram-positive and Gram-negative pathogens. Herein, we describe the first total synthesis of cystobactamid 919-2 from three fragments. Our convergent synthesis enabled both the confirmation of the correct structure and the determination of the absolute configuration of cystobactamid 919-2.

A Highly Convergent and Biomimetic Total Synthesis of Portentol.

An efficient total synthesis of the unusual polyketide portentol is reported. Three boron aldol reactions were used to assemble the linear carbon chain of the natural product, which contains two challenging anti-anti stereotriads. A biomimetic double cyclization cascade, triggered by an oxidation, then afforded portentol and its known dehydration product, anhydroportentol. The biosynthesis of portentol and the biosynthetic relevance of our key step are discussed.

Total synthesis of (-)-nakadomarin A.

The convergent synthesis of the polycyclic alkaloid (-)-nakadomarin A (1) is reported. The synthesis plan identified macrocyclic lactam 4 as one of the important synthons (eight steps). The other synthon (five steps) was bicyclo[6.3.0] lactam 5 containing a single stereocenter that controlled all of the subsequent stereochemistry during the assembly process. A silyl triflate-promoted cascade of 4 and 5 was used to assemble the bulk of the alkaloid skeleton with the exception of the C5-C6 bond. The nakadomarin synthesis was then completed in one additional step.

A Photoswitchable Inhibitor of the Human Serotonin Transporter.

The human serotonin transporter (hSERT) terminates serotonergic signaling through reuptake of neurotransmitter into presynaptic neurons and is a target for many antidepressant drugs. We describe here the development of a photoswitchable hSERT inhibitor, termed azo-escitalopram, that can be reversibly switched between trans and cis configurations using light of different wavelengths. The dark-adapted trans isomer was found to be significantly less active than the cis isomer, formed upon irradiation.

Total Synthesis of (±)-Exotine B.

The heterodimeric indole/coumarin natural product exotine B was synthesized for the first time. The carbon skeleton of the natural product was formed rapidly by a palladium-catalyzed Suzuki cross-coupling reaction and a gallium-catalyzed three-component [4 + 3] cycloaddition reaction. An alternative biosynthesis of exotine B is proposed based on the total synthesis. Improved syntheses of coumarin natural products gleinadiene and coumurrayin are also reported.

Photoswitchable Inhibitor of a Glutamate Transporter.

Excitatory amino acid transporters clear glutamate from the synaptic cleft and play a critical role in glutamatergic neurotransmission. Their differential roles in astrocytes, microglia, and neurons are poorly understood due in part to a lack of pharmacological tools that can be targeted to specific cells and tissues. We now describe a photoswitchable inhibitor, termed ATT, that interacts with the major mammalian forebrain transporters EAAT1-3 in a manner that can be reversibly switched between trans (high-affinity) and cis (low-affinity) configurations using light of different colors. In the dark, ATT competitively inhibited the predominant glial transporter EAAT2 with ∼200-fold selectivity over the neuronal transporter EAAT3. Brief exposure to 350 nm light reduced the steady-state blocker affinity by more than an order of magnitude. Illumination of EAAT2 complexed with ATT induced a corresponding increase in the blocker off-rate monitored in the presence of glutamate. ATT can be used to reversibly manipulate glutamate transporter activity with light and may be useful to gain insights into the dynamic physiological roles of glutamate transporters in the brain, as well as to study the molecular interactions of transporters with ligands.

Fullerenes as a tert-butylperoxy radical trap, metal catalyzed reaction of tert-butyl hydroperoxide with fullerenes, and formation of the first fullerene mixed peroxides C(60)(O)(OO(t)Bu)(4) and C(70)(OO(Bu)(10).

tert-Butylperoxy radicals generated by TBHP and Ru(PPh3)3Cl2 or other catalysts adds to C60 and C70 to form stable multiadducts, C60(O)(OOtBu)4 and C70(OOtBu)10. The four tert-butylperoxy groups in the C60 mixed peroxide are located around a pentagon, and the epoxy O occupies the remaining 6,6-bond connected to the same pentagon. The C70 decaadduct shows an unprecedented C2 symmetry with the 10 tert-butylperoxy groups added around the central part of C70 by consecutive 1,4-addition. The compounds are fully characterized by spectroscopic data.