Synthetic Efforts toward the Synthesis of a Fluorinated Analog of 5-Aminolevulinic Acid: Practical Synthesis of Racemic and Enantiomerically Defined 3-Fluoro-5-aminolevulinic Acid.

In 2017, the FDA authorized 5-aminolevulinic acid (5-ALA) for intraoperative optical imaging of suspected high-grade gliomas. This was the first authorized optical imaging agent for brain tumor surgery to enhance the visualization of malignant tissue. Herein we report the synthesis of a racemic and enantiopure fluorinated analog of 5-ALA, i.e., 3-fluoro-5-aminolevulinic acid (3F-5-ALA). We anticipate that these studies will provide the foundation for the future construction of a fluorine-18-labeled 5-ALA PET tracer to be used for functional and metabolic imaging of gliomas.

Concise and Scalable Radiosynthesis of (+)-[18F]MDL100907 as a Serotonin 5-HT2A Receptor Antagonist for PET.

5-Hydroxytryptamine (5-HT2A) receptors play an important role in several psychiatric disorders. In order to investigate the serotonin (5-HT) receptor in vivo, reliable syntheses are required for positron emission tomography (PET) 5-HT radioligands. Owing to the excellent in vivo properties of [18F]MDL100907 for PET, there has been great interest to develop a novel synthetic route for [18F]MDL100907. Here, we report a highly efficient, scalable, and expedient synthesis for [18F]MDL100907. The radiofluorination was performed on a 18F-labeling boron pinacol ester precursor, which is synthesized using the Liebeskind-Srogl cross-coupling reaction as a key step. Our method is practically more suitable to employ late-stage Cu-mediated radiofluorination and facilitate the production of the [18F]MDL100907 radioligand in excellent decay-corrected RCY of 32 ± 10% (n = 7) within 60 min. We prepared [18F]MDL100907 in high molar activity (2.1 Ci/µmol) and compared it to [11C]MDL100907 in the brain of a nonhuman primate.

Syntheses of 2-Aroyl Benzofurans through Cascade Annulation on Arynes.

The highly efficient and expedient route for the syntheses of 2-aroyl benzofurans has been developed via the cascade [2+2] followed by a [4+1] annulation on arynes. The overall transformation proceeded through the formation of ortho-quinone methide by the insertion of transient aryne into N, N-dimethylformamide and subsequent trapping with sulfur ylide. Moreover, this transformation has a broad range of substrate scope with a high functional-group tolerance. This new reaction was successfully utilized in the synthesis of the potent CYP19 aromatase inhibitor and late-stage functionalization on the bioactive complex estrone.

Cp*Co(III)-Catalyzed C-H Functionalization Cascade of N-Methoxyamides with Alkynedione for the Synthesis of Indolizidines.

Cp*Co(III)-catalyzed C-H functionalization cascade of N-methoxyamides with alkynedione has been reported for the synthesis of indolizidine scaffolds under redox-neutral conditions. The reaction displays broad functional group tolerance along with excellent yield. The reaction proceeds with kinetically relevant C-H bond activation through carboxylate assistance with excellent diastereoselectivity and complete opposite selectivity with respect to alkyne insertion.