Organocatalytic asymmetric synthesis of SynVesT-1, A synaptic density positron emission tomography imaging agent

McErlain, H., McLean, E. B., Morgan, T. E. F., Burianova, V. K., Tavares, A. A. S. and Sutherland, A. (2022) Organocatalytic asymmetric synthesis of SynVesT-1, A synaptic density positron emission tomography imaging agent. Journal of Organic Chemistry, 87(21), pp. 14443-14451. (doi: 10.1021/acs.joc.2c01895) (PMID:36222243)

Abstract

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.

• Item Type: Articles
• Additional Information: Financial support from the Wellcome Trust (221295/Z/20/ Z), Dr. Ian Sword (Ph.D. studentship to H.M.), and the University of Glasgow is gratefully acknowledged. AAST is funded by the British Heart Foundation (FS/19/34/34354).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Sutherland, Professor Andrew and Morgan, Mr Timaeus and Mcerlain, Miss Holly and Burianova, Ms Valeriia and McLean, Mr Euan
• Authors: McErlain, H., McLean, E. B., Morgan, T. E. F., Burianova, V. K., Tavares, A. A. S., and Sutherland, A.
• College/School: College of Science and Engineering > School of Chemistry
• Journal Name: Journal of Organic Chemistry
• Publisher: American Chemical Society
• ISSN: 0022-3263
• ISSN (Online): 1520-6904
• Published Online: 12 October 2022
• Copyright Holders: Copyright © 2022 The Authors
• First Published: First published in Journal of Organic Chemistry 87(21): 14443-14451
• Publisher Policy: Reproduced under a Creative Commons License