David Cladingboel

Synthesis and evaluation of dual domain macrocyclic FKBP12 ligands.

Abstract A number of dual domain, macrocyclic FKBP12 ligands were synthesised in which the FK506 effector domain was fused to simplified FKBP12 bindings domains. The resulting macrocyclic compounds possessed moderate binding affinities for FKBP12 but showed no activity in an assay for FKBP12 dependent calcineurin inhibition.

Synthetic FKBP12 ligands. Design and synthesis of pyranose replacements.

Abstract A number of FKBP12 ligands were designed and synthesised and their affinity for FKBP12 assessed. In these ligands the pyranose ring of FK506 was replaced by other more synthetically accessible groups. The preparation of suitable intermediates for the synthesis of “dual domain” inhibitors (compounds 6a–c, 15 and 22) is also described.

Tandem radical cyclisations : Synthesis of lysergic acid derivatives

Abstract A novel free radical cyclisation approach for the synthesis of lysergic acid analogues has been investigated. The homolytic cleavage of carbon-bromine bond, mediated by tri-n-butyltin hydride, led to the development of a method for the construction of 3,4-disubstituted dihydroindoles via single cyclisation; hexahydrobenz[cd]indoles via double tandem cyclisations and both octahydroindolo[6,5,4-cd]indoles and decahydroindolo[4,3-fg]quinolines via triple radical cyclisations. A successful tandem double 5-exo-trig,6-endo-trig cyclisation of aryl radical generated from N-3-[3-(N-acetyl-N-allylamino)-2-bromophenyl]-5-(carbomethoxy)-1,4,5,6-tetrahydro-N-methylpyridine afforded methyl 1-acetyl-2,3,9,10-tetrahydrolysergate.

Synthesis of lysergic acid derivatives by triple radical cyclisation

The lysergic acid ring system, characteristic of the ergot alkaloids, is constructed from 2-bromoaniline derivatives by triple radical cyclisation, initiated with tri-n-butyltin hydride; formation of a 6- rather than a 5-membered D ring is controlled by a terminal phenylthio group.