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Title: A novel photocatalytic strategy for complex aliphatic amine synthesis and the total synthesis of alkaloids (−) FR901483 and (+)-TAN1251C
Author: Reich, Dominik
ISNI:       0000 0004 8507 6978
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2020
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Owing to their unique properties, the synthesis and functionalization of aliphatic amines plays a central role in the field of visible light photoredox chemistry. In this thesis, the development of a novel, visible light mediated process for the synthesis of complex aliphatic amines is described. The novel multicomponent reaction between secondary amines, aldehydes and electron-deficient olefins efficiently furnishes complex aliphatic tertiary amine products. Selective generation of an α-amino radical species is achieved via photocatalytic single electron reduction of in situ generated all-alkyl iminium ions. Under optimized reaction conditions, the photocatalytic olefin-hydroaminoalkylation procedure was shown to be compatible with a broad range of benzyl amine, aldehyde, and olefin substrates. A detailed study of the mechanism of the transformation is described, revealing an unusual 1,5-hydrogen atom transfer step and an unprecedented redox-relay of iminium ions. In further studies, the reaction scope was expanded to include non-benzylic amines and enamines, enabling the generation of synthetically valuable α-tertiary amines. α-Tertiary amines are a common feature in a number of bioactive natural products. Immunosuppressant (-)-FR901483 (1) and muscarinic antagonist (+)-TAN1251C (2) are biosynthetically related di-tyrosine-derived alkaloids, which have attracted significant attention from the synthetic community by virtue of their biological activity and the challenges posed by their architecturally complex structures. The development of a variant of the multicomponent photocatalytic olefin-hydroaminoalkylation approach to couple primary amines, ketones and olefins, and its use in total synthesis, is described. The novel transformation enabled the rapid, divergent total synthesis of both (-)-FR901483 and (+)-TAN1251C via a common spirolactam precursor. Finally, the reaction proved amenable to a number of primary amines and ketones, giving direct, modular access to a series of useful chiral spirolactam scaffolds.
Supervisor: Gaunt, Matthew J. Sponsor: AstraZeneca
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: total synthesis ; amine synthesis ; photoredox catalysis