A Pyridine Dearomatization Approach for the Gram Scale Synthesis of (±)-Sparteine.

Both enantiomers of sparteine have suffered from pricing and supply chain variability, which has inspired efforts toward efficient chemical synthesis. Here, we build upon our reported synthesis of the matrine-type lupin alkaloids in order to synthesize (±)-sparteine. Specifically, selective quenching of the cyclization between glutaryl chloride and pyridine with methanol provides a functionalized quinolizidine core that was elaborated to (±)-sparteine in six additional steps on gram scale. This synthesis provides a scalable route to sparteine from inexpensive commodity chemicals utilizing a dearomative cyclization. In addition, this route provides concise access to (±)-lupinine.

A convergent fragment coupling strategy to access quaternary stereogenic centers.

The formation of quaternary stereogenic centers via convergent fragment coupling is a longstanding challenge in organic synthesis. Here, we report a strategy for the formation of quaternary stereogenic centers in polycyclic systems based upon the semi-pinacol reaction. In the key transformation, two fragments of a similar size and complexity are joined by a 1,2-addition of an alkenyl lithium to an epoxy ketone, and the resulting epoxy silyl ether undergoes a semi-pinacol rearrangement catalyzed by N-(trimethylsilyl)bis(trifluoromethanesulfonyl)imide (TMSNTf2) or trimethylsilyl trifluoromethanesulfonate (TMSOTf). Polycyclic scaffolds were generated in high yields and the reaction conditions tolerated a variety of functional groups including esters, silyl ethers, enol ethers, and aryl triflates. This method provides a useful strategy for the synthesis of complex polycyclic natural product-like scaffolds with quaternary stereogenic centers from simplified fragments.

A Pyridine Dearomatization Approach to the Matrine-Type Lupin Alkaloids.

(+)-Matrine and (+)-isomatrine are tetracyclic alkaloids isolated from the plant Sophora flavescens, the roots of which are used in traditional Chinese medicine. Biosynthetically, these alkaloids are proposed to derive from three molecules of (-)-lysine via the intermediacy of the unstable cyclic imine Δ1-piperidine. Inspired by the biosynthesis, a new dearomative annulation reaction has been developed that leverages pyridine as a stable surrogate for Δ1-piperidine. In this key transformation, two molecules of pyridine are joined with a molecule of glutaryl chloride to give the complete tetracyclic framework of the matrine alkaloids in a single step. Using this dearomative annulation, isomatrine is synthesized in four steps from inexpensive commercially available chemicals. Isomatrine then serves as the precursor to additional lupin alkaloids, including matrine, allomatrine, isosophoridine, and sophoridine.

Design of an Imaging Probe to Monitor Real-Time Redistribution of L-type Voltage-Gated Calcium Channels in Astrocytic Glutamate Signaling.

PURPOSE: In the brain, astrocytes are non-excitable cells that undergo rapid morphological changes when stimulated by the excitatory neurotransmitter glutamate. We developed a chemical probe to monitor how glutamate affects the density and distribution of astrocytic L-type voltage-gated calcium channels (LTCC). PROCEDURES: The imaging probe FluoBar1 was created from a barbiturate ligand modified with a fluorescent coumarin moiety. The probe selectivity was examined with colocalization analyses of confocal fluorescence imaging in U118-MG and transfected COS-7 cells. Living cells treated with 50 nM FluoBar1 were imaged in real time to reveal changes in density and distribution of astrocytic LTCCs upon exposure to glutamate. RESULTS: FluoBar1 was synthesized in ten steps. The selectivity of the probe was demonstrated with immunoblotting and confocal imaging of immunostained cells expressing the CaV1.2 isoform of LTCCs proteins. Applying FluoBar1 to astrocyte model cells U118-MG allowed us to measure a fivefold increase in fluorescence density of LTCCs upon glutamate exposure. CONCLUSIONS: Imaging probe FluoBar1 allows the real-time monitoring of LTCCs in living cells, revealing for first time that glutamate causes a rapid increase of LTCC membranar density in astrocyte model cells. FluoBar1 may help tackle previously intractable questions about LTCC dynamics in cellular events.

Total Synthesis of Isodihydrokoumine, (19 Z)-Taberpsychine, and (4 R)-Isodihydroukoumine N4-Oxide.

We report the total synthesis of the natural products isodihydrokoumine and (19 Z)-taberpsychine in 11 steps each and (4 R)-isodihydrokoumine N4-oxide in 12 steps from commercially available starting materials. The key reactions include an intramolecular [3 + 2] nitrone cycloaddition and Lewis acid mediated cyclizations of a common intermediate to provide the core structures of either taberpsychine or isodihydrokoumine.

N-ß-Methylamino-L-Alanine and Its Naturally Occurring Isomers in Cyanobacterial Blooms in Lake Winnipeg.

Cyanobacterial blooms have affected Lake Winnipeg since the mid-1990s due to an increased phosphorus loading into the lake, which has been exacerbated by stressors such as climate change and eutrophication. Aquatic ecosystems involving cyanobacteria have been found to contain N-ß-methylamino-L-alanine (BMAA) and 2,4-diaminobutyric acid (DAB), non-protein amino acids that are associated with neurodegenerative disease, as well as two of the naturally occurring isomers, N-2(amino)ethylglycine (AEG) and ß-amino-N-methylalanine (BAMA). We hypothesized that the cyanobacterial bloom in Lake Winnipeg produces BMAA and/or its naturally occurring isomers. Samples of cyanobacteria were collected by the Lake Winnipeg Research Consortium from standard sampling stations and blooms in July and September of 2016 and were analyzed for BMAA, DAB, AEG, and BAMA using previously published validated analytical methods. BMAA and BAMA were found in the highest concentration in the center of the north basin, the deepest and lowest-nitrogen zone of the lake, at an average concentration of 4 µg/g (collected in July and September 2016) and 1.5 mg/g (collected in July 2016), respectively. AEG and DAB were found in the highest concentration in cyanobacterial blooms from the nearshore region of the north basin, the slightly shallower and more nitrogen-rich zone of the lake, at 2.1 mg/g (collected in July 2016) and 0.2 mg/g (collected in July and September 2016), respectively. These findings indicate that the production of non-protein amino acids varies with the depth and nutrient contents of the bloom. It is important to note that we did not measure food or water samples directly and further study of the Lake Winnipeg food web is required to determine whether BMAA bioaccumulation represents an increased risk factor for neurodegenerative disease in the region.