Organocatalytic Asymmetric Synthesis of SynVesT-1, a Synaptic Density Positron Emission Tomography Imaging Agent.

Heterocyclic nonacetamide ligands are used as positron emission tomography (PET) imaging agents of the synaptic vesicle glycoprotein 2A (SV2A), with potential applications in the diagnosis of various neuropsychiatric diseases. To date, the main synthetic strategy to access these optically active compounds has involved the racemic synthesis of a late-stage intermediate followed by the separation of the enantiomers. Here, we describe the use of iminium organocatalysis for the asymmetric synthesis of SynVesT-1, an important PET imaging agent of SV2A. The key step involved the conjugate addition of nitromethane with a cinnamaldehyde in the presence of the Jørgensen-Hayashi catalyst using the Merck dual acid cocatalyst system. Pinnick-type oxidation and esterification of the adduct was then followed by chemoselective nitro group reduction and cyclization using nickel borate. N-Alkylation of the resulting lactam then completed the seven-step synthesis of SynVesT-1. This approach was amenable for the synthesis of an organotin analogue, which following copper(II)-mediated fluoro-destannylation allowed rapid access to [18F]SynVesT-1.

Aryl Boronic Acid Catalysed Dehydrative Substitution of Benzylic Alcohols for C-O Bond Formation.

A combination of pentafluorophenylboronic acid and oxalic acid catalyses the dehydrative substitution of benzylic alcohols with a second alcohol to form new C-O bonds. This method has been applied to the intermolecular substitution of benzylic alcohols to form symmetrical ethers, intramolecular cyclisations of diols to form aryl-substituted tetrahydrofuran and tetrahydropyran derivatives, and intermolecular crossed-etherification reactions between two different alcohols. Mechanistic control experiments have identified a potential catalytic intermediate formed between the aryl boronic acid and oxalic acid.

Direct Hydrodecarboxylation of Aliphatic Carboxylic Acids: Metal- and Light-Free.

A mild and inexpensive method for direct hydrodecarboxylation of aliphatic carboxylic acids has been developed. The reaction does not require metals, light, or catalysts, rendering the protocol operationally simple, easy to scale, and more sustainable. Crucially, no additional H atom source is required in most cases, while a broad substrate scope and functional group tolerance are observed.

Selectivity Control in Gold-Catalyzed Hydroarylation of Alkynes with Indoles: Application to Unsymmetrical Bis(indolyl)methanes.

Gold-catalyzed hydroarylation of unactivated alkynes with indoles have previously been reported to proceed with double indole addition to produce symmetrical bis(indolyl)methanes (BIMs). We demonstrate for the first time that the selectivity of the gold-catalyzed reaction can be fully switched to allow for isolation of the vinylindole products instead. Furthermore, this selective reaction can be utilized to synthesize the more difficult to access unsymmetrical BIMs from readily available starting materials.

Arylboronic Acid Catalyzed C-Alkylation and Allylation Reactions Using Benzylic Alcohols.

The arylboronic acid catalyzed dehydrative C-alkylation of 1,3-diketones and 1,3-ketoesters using secondary benzylic alcohols as the electrophile is reported, forming new C-C bonds (19 examples, up to 98% yield) with the release of water as the only byproduct. The process is also applicable to the allylation of benzylic alcohols using allyltrimethylsilane as the nucleophile (12 examples, up to 96% yield).

Dual copper- and photoredox-catalysed C(sp2)-C(sp3) coupling.

The use of copper catalysis with visible light photoredox catalysis in a cooperative fashion has recently emerged as a versatile means of developing new C-C bond forming reactions. In this work, dual copper and photoredox catalysis is exploited to effect C(sp2)-C(sp3) cross-couplings between aryl boronic acids and benzyl bromides.