Catalytic one-carbon homologation of alkenes

The subtle changes to chemical properties brought about by one-carbon homologation can have profound impacts on the physiochemical properties of functional molecules, including pharmaceutical agents, natural products, agrochemicals and fragrances. Consequently, the development of efficient and direct methods for one-carbon homologation represents an important goal in organic synthesis. While homologation strategies are available for several functional groups, direct and broadly applicable methods for homologating alkenes remains an unmet synthetic need. This thesis describes the development of a catalytic, one-pot method for the one-carbon homologation of alkenes. The methodology leverages the intrinsic reactivity of an allyl sulfone reagent, which undergoes coupling with the target alkene via an olefin metathesis reaction. This process installs the requisite methylene unit, generating a latent homolog intermediate. In situ deprotection of the latent homolog yields an unstable allyl sulfinic acid intermediate, which is predisposed to undergo a spontaneous retro-ene reaction, yielding the one-carbon homologated alkene. The homologation methodology demonstrates compatibility with monosubstituted, disubstituted, and macrocyclic alkenes. The mild conditions employed by the homologation process renders the methodology compatible with a broad range of complex functionalities. Amongst several distinct applications to natural products, agrochemicals and drugs. This methodology demonstrates the capacity to generate unexplored homologs of Cyclosporine A, which exhibit altered pharmacological and biological properties.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2024

Author dc:creator

• Grocott, Marcus

Advisor dc:contributor.advisor

• Gaunt, Matthew

• alkene
• chemical biology
• homologation
• organic chemistry
• total synthesis

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/685e4924-adb6-48f0-b62c-3ea5f2a7e631/download
• http://purl.org/NET/rdflicense/allrightsreserved

Author Identifier

0000-0002-4661-6957

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/385632