Recent advances in the total synthesis of alkaloids using chiral secondary amine organocatalysts.

Since the early 21st century, organocatalytic reactions have undergone significant advancements. Notably, numerous asymmetric reactions utilizing chiral secondary amine catalysts have been developed and applied in the total synthesis of natural products. In this review, we provide an overview of alkaloid syntheses reported since 2017, categorized by scaffold, with a focus on key steps involving asymmetric reactions catalyzed by secondary amine organocatalysts.

New Entries in Organocatalysts from an Alkaloid Library; Development of Aminal Catalysis for a Michael Reaction Based on Calycanthine.

Natural products have historically been actively evaluated for their biological activity in the development of pharmaceuticals, while their evaluation as asymmetric catalysts has rarely been explored. In this study, we evaluated the catalytic activity of the natural product library. Three naturally occurring alkaloids, gardnerine, spiradine A, and calycanthine, were found to catalyze an asymmetric Michael reaction using oxindole and nitrostyrene.

Indole C5-Selective Bromination of Indolo[2,3-a]quinolizidine Alkaloids via In Situ-Generated Indoline Intermediate.

There are many indole alkaloids that contain diverse functional groups attached to the benzene ring on the indole core. Promising biological activities of these alkaloids have been reported. Herein, we report the indole C5-selective bromination of indolo[2,3-a]quinolizidine alkaloids by adding nearly equimolar amounts of Br ⋅ PyH and HCl in MeOH.

Bioinspired Total Synthesis of (+)-Kopsiyunnanine B.

The first enantioselective total synthesis of kopsiyunnanine B, which has a unique folded and complex pentacyclic structure containing six contiguous chiral centers, has been achieved along our originally proposed biosynthetic pathway. The key reaction of this synthesis includes a bioinspired cascade that builds three ring structures and three chiral centers in one step and features the stereoselective reduction of a β-acrylate and oxidation to an oxindole.

Constituents of and their anti-amyloidogenic activity.

The aggregation of amyloid-β (Aβ) remains the most acceptable pathological hallmark of Alzheimer's disease (AD). In search for natural products exhibiting anti-amyloidogenic effects, phytochemical analyses were conducted on leading to the purification of oxindole alkaloid uncarine E (isopteropodine) (), the phenylethanoid tyrosol (), the megastigmane vomifoliol (), and the previously reported alkaloids mitraphylline and isomitraphylline. This is the first report of compounds - in the title plant, and tyrosol () from the genus .

Sticklac-Derived Natural Compounds Inhibiting RNase H Activity of HIV-1 Reverse Transcriptase.

The emergence of drug-resistant viruses is a serious concern in current chemotherapy for human immunodeficiency virus type-1 (HIV-1) infectious diseases. Hence, antiviral drugs aiming at targets that are different from those of approved drugs are still required, and the RNase H activity of HIV-1 reverse transcriptase is a suitable target. In this study, a search of a series of natural compounds was performed to identify the RNase H inhibitors.

Enantioselective Total Syntheses of (-)-Silicine and (-)-20-Episilicine.

The enantioselective total syntheses of (-)-silicine and (-)-20-episilicine, which contain a chiral piperidine with three contiguous chiral centers (-ring) and a strained seven-membered ring (-ring) attached to an indole, were achieved. The key steps of these syntheses included a chiral secondary amine-catalyzed formal aza-[3 + 3] cycloaddition reaction and Lewis acid-mediated irreversible ring-closing reaction. In addition, the stereochemistry at C20 was controlled at a later stage in the syntheses.

Rhamnogalacturonan-I as a nematode chemoattractant from L. super-growing root culture.

Introduction: The soil houses a tremendous amount of micro-organisms, many of which are plant parasites and pathogens by feeding off plant roots for sustenance. Such root pathogens and parasites often rely on plant-secreted signaling molecules in the rhizosphere as host guidance cues. Here we describe the isolation and characterization of a chemoattractant of plant-parasitic root-knot nematodes (, RKN).

Asymmetric Total Synthesis of Senepodine F.

The first asymmetric total synthesis of the alkaloid senepodine F, which contains a decahydroquinoline ring (-ring) and a quinolizidine ring (-ring) connected by a methylene tether, has been achieved. The key steps of this synthesis include an organocatalytic asymmetric Diels-Alder reaction, a diastereoselective intramolecular -Michael reaction, and an intramolecular S2 cyclization to construct multisubstituted nitrogen-containing heterocycles. In addition, our total synthesis led to the stereochemical reassignment on the decahydroquinoline ring of senepodine F.

Total Syntheses of (+)-Villocarine A, (-)-Apogeissoschizine, and (+)-Geissoschizine.

Total syntheses of geissoschizine-type monoterpenoid indole alkaloids (MTIAs) are reported. An intramolecular Pictet-Spengler cyclization was developed for the selective construction of the 3R stereocenter. The first total synthesis of (+)-villocarine A was then achieved.

Divergent Total Syntheses of Hetero-Oligomeric Iridoid Glycosides.

Divergent total syntheses of the hetero-oligomeric iridoid glycosides mainly found in were achieved. Thus, loganin (), which is important as a monomer unit, was efficiently synthesized by stereoselective reductive cyclization using secologanin () as a substrate. Sequential condensation reactions of derivatives of and as monomer units led to the first enantioselective total syntheses of the heterooligomers cantleyoside, ()-aldosecologanin, dipsaperine, (3, 5)-5-carboxyvincosidic acid 22-loganin ester, and dipsanoside A.

Exhibits In Vitro Anti-Amyloidogenic Activity and Promotes Neuroprotective Effects in Amyloid-β-Induced SH-SY5Y Cells.

Accumulation of amyloid- (Aβ) plaques leading to oxidative stress, mitochondrial damage, and cell death is one of the most accepted pathological hallmarks of Alzheimer's disease (AD). , commonly recognized as fragrant screw pine due to its characteristic smell, is widely distributed in Southeast Asia and is consumed as a food flavor. In search for potential anti-AD agents from terrestrial sources, was explored for its in vitro anti-amyloidogenic and neuroprotective effects.

Asymmetric Total Syntheses of Mitragynine, Speciogynine, and 7-Hydroxymitragynine.

A number of alkaloids found in Mitragyna species belonging to the Rubiaceae family have been shown to have potent biological activity such as analgesic properties. Here, we report the asymmetric total syntheses of mitragynine, speciogynine, and 7-hydroxymitragynine, which are classified as corynantheine-type monoterpenoid indole alkaloids, isolated from Mitragyna speciosa. These syntheses were accomplished within 12 steps and in >11% total yield from commercial 3-(trimethylsilyl)propanal using an organocatalytic anti-selective Michael reaction and bioinspired transformations.

Secorubenine, a Monoterpenoid Indole Alkaloid Glycoside from Adina rubescens: Isolation, Structure Elucidation, and Enantioselective Total Synthesis.

A new pentacyclic monoterpenoid indole alkaloid glycoside named secorubenine (1) was isolated from the heartwood of Adina rubescens, collected in Indonesia. The structure was elucidated by spectroscopic analysis and chemical modification of isolated secorubenine (1). The bioinspired enantioselective total synthesis of 1 was accomplished in 12 steps, whereafter its structure was determined and the absolute stereochemistry was confirmed.

Borocyclic Radicals Prepared from Orthoquinone-Containing Polycyclic Aromatics by Photoirradiation.

Borocyclic radicals with highly conjugated aromatics were generated from orthoquinone-containing polycyclic aromatic compounds by trapping the photoinduced triplet state with simple boron halide under irradiation with light of appropriate wavelength. The picene-based borocyclic radical was remarkably stable when stored at 23 °C in a desiccator for over 1 year. The crystal structure of this stable radical had a stacking structure of a planar π-conjugated system, and the electrical conductivity was higher than those of ordinary organic radical systems.

Asymmetric Total Synthesis and Structure Elucidation of Huperzine H.

A first asymmetric total synthesis of huperzine H has been achieved in a 12% overall yield from commercially available (+)-pulegone. The key steps of this synthesis include a highly diastereoselective Mukaiyama-Michael addition reaction of a pyrrole bearing a silyl enol ether and an intramolecular S2 cyclization reaction with iodinated pyrrole acting as an effective nucleophile for the formation of the nine-membered ring. As a result, the relative and absolute stereochemistry of huperzine H is established.

Bioinspired Transformations Using Strictosidine Aglycones: Divergent Total Syntheses of Monoterpenoid Indole Alkaloids in the Early Stage of Biosynthesis.

A series of bioinspired transformations that are applied to convert strictosidine aglycones into monoterpenoid indole alkaloids is reported. The highly reactive key intermediates, strictosidine aglycones, were prepared in situ by simple removal of a silyl protecting group from the silyl ether derivatives, and converted selectively via bioinspired transformations under substrate control into heteroyohimbine- and corynantheine-type, and akagerine and naucleaoral related alkaloids. Thus, concise, divergent total syntheses of 13 monoterpenoid indole alkaloids, (-)-cathenamine, (-)-tetrahydroalstonine, (+)-dihydrocorynantheine, (-)-corynantheidine, (-)-akagerine, (-)-dihydrocycloakagerine, (-)-naucleaoral B, (+)-naucleidinal, (-)-naucleofficines D and III, (-)-nauclefiline, and (-)-naucleamides A and E, were accomplished in fewer than 13 steps.

Amakusamine from a sp. Sponge: Isolation, Synthesis, and SAR Study on the Inhibition of RANKL-Induced Formation of Multinuclear Osteoclasts.

A simple methylenedioxy dibromoindole alkaloid, amakusamine (), was isolated from a marine sponge of the genus , and its structure was determined from spectroscopic data, time-dependent density-functional theory calculations, and synthesis. Compound inhibited the receptor activator of nuclear factor-κB ligand (RANKL)-induced formation of multinuclear osteoclasts with an IC value of 10.5 μM in RAW264 cells.

Root-knot nematode chemotaxis is positively regulated by l-galactose sidechains of mucilage carbohydrate rhamnogalacturonan-I.

Root-knot nematodes (RKNs) are plant parasites and major agricultural pests. RKNs are thought to locate hosts through chemotaxis by sensing host-secreted chemoattractants; however, the structures and properties of these attractants are not well understood. Here, we describe a previously unknown RKN attractant from flaxseed mucilage that enhances infection of and tomato, which resembles the pectic polysaccharide rhamnogalacturonan-I (RG-I).

Calcium sulfate and calcium carbonate as root-knot-nematode attractants and possible trap materials to protect crop plants.

Root-knot nematodes (RKNs, genus ) are a class of plant parasites that seek out and infect the roots of many plant species. The identification of RKN attractants can be used in agriculture in conjunction with nematode-trapping technology to redirect RKN movements and eventually reduce their prevalence in the field. Here, we discovered that some commercial silica gels can attract nematodes.

Discovery, characterization and functional improvement of kumamonamide as a novel plant growth inhibitor that disturbs plant microtubules.

The discovery and useful application of natural products can help improve human life. Chemicals that inhibit plant growth are broadly utilized as herbicides to control weeds. As various types of herbicides are required, the identification of compounds with novel modes of action is desirable.

Epoxyquinophomopsins A and B from endophytic fungus Phomopsis sp. and their activity against tyrosine kinase.

Two new quinone derivatives, epoxyquinophomopsins A (1) and B (2), were purified from the EtOAc extract of endophytic fungus Phomopsis sp isolated from Morus cathayana. The structures of both compounds were determined based on 1D and 2D NMR and mass spectral data, as well as by x-ray diffraction analysis for 1. Compounds 1 and 2 were screened against eight receptor- (RTKs) and eight non-receptor tyrosine kinases (nRTKs).

Total Syntheses of (-)-Strictosidine and Related Indole Alkaloid Glycosides.

A collective synthesis of glycosylated monoterpenoid indole alkaloids is reported. A highly diastereoselective Pictet-Spengler reaction with α-cyanotryptamine and secologanin tetraacetate as substrates, followed by a reductive decyanation reaction, was developed for the synthesis of (-)-strictosidine, which is an important intermediate in biosynthesis. This two-step chemical method was established as an alternative to the biosynthetically employed strictosidine synthase.

5,6-Dihydro-α-pyrones from the leaves of Cryptocarya pulchinervia (Lauraceae).

Three new 5,6-dihydro-α-pyrones derivatives, named (S)-rugulactone (1) pulchrinervialactone A (2), and pulchrinervialactone B (4), along with one known pyrone, cryptobrachytone C (3), and three known amide derivatives (5-7) have been isolated from the leaves of Cryptocarya pulchrinervia. The structures of 1-7 were elucidated based on extensive spectroscopic data and comparison with literatures. The configurations of compounds 3 and 4 were established by single crystal X-ray diffraction analysis.

Correction: Enantioselective total synthesis of the unnatural enantiomer of quinine.

[This corrects the article DOI: 10.1039/C9SC03879E.].