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Title: Divergent synthesis of cyclopropane-containing fragments and lead-like compounds for drug discovery
Author: Chawner, Stephen John
ISNI:       0000 0004 6496 9910
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2018
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The cyclopropane ring is key to a large number of medicinally‑relevant compounds that possess a broad spectrum of biological activities. This thesis details the preparation of novel bifunctional cyclopropanes through a divergent functionalisation approach utilising two readily accessible cyclopropyl‑scaffolds. The cyclopropanes generated sampled new areas of chemical space whilst being suitable 3‑dimensional fragments and lead-like compounds for drug discovery. A novel CoII-catalysed cyclopropanation generates two diastereoisomeric bifunctional cyclopropyl-scaffolds from commercially available reagents in an excellent yield and can be conducted on multi-gram scales. Asymmetric cyclopropanation has been explored with max ee = 73%. Divergent functionalisation of the ester was explored, utilising hydrolysis, reduction and amidation reactions to create a variety of functionalised cyclopropyl sulfides. The sulfide synthetic handle was oxidised to give the corresponding sulfoxides or sulfone selectively. Sulfoxide–magnesium exchange was explored and the cyclopropyl-organometallic species generated was trapped with a variety of electrophiles to create a diverse range of cyclopropane-containing products. The cyclopropyl-organometallic species was also utilised in Negishi cross-coupling, proving to be a versatile method to attach an aromatic or heteroaromatic directly onto the cyclopropane ring.
Supervisor: Bull, James Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral