A novel photocatalytic strategy for complex aliphatic amine synthesis and the total synthesis of alkaloids (−) FR901483 and (+)-TAN1251C

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.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2020

Author dc:creator

• Reich, Dominik

Advisor dc:contributor.advisor

• Gaunt, Matthew J.

• total synthesis
• amine synthesis
• photoredox catalysis

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/f69b625d-c640-4dea-a269-d1e09d4dd20c/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

en

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.48852

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/301779