Validating predictive sequence analysis in polyketide stereochemical determination though the synthesis of stambomycin D

Thesis

In recent years, predictive gene sequence analysis of biosynthetic enzymes has emerged as a powerful tool for the stereochemical determination of natural products. The stambomycins, a family of 51-membered bioactive macrolides isolated from Streptomyces ambofaciens, are examples of this, having their stereochemistry predicted entirely through gene sequence analysis of the polyketide synthase, apart from two stereocentres (C28 and C50) which were installed through cytochrome P450-catalysed oxidations. This thesis investigates the synthesis of stambomycin D, a member of the family, to validate the genomics-based stereochemical assignment of the natural product. Through the synthesis of various intermediate and model fragments of the macrolide, the synthetic route to the target natural product was established and conditions for a global deprotection were developed. Moreover, a comparative analysis of the NMR data of two of those fragments (C1–C27 and C13–C48) with that of stambomycin D provided preliminary proof of the accuracy of the genomics-based stereochemical assignment of the natural product and revealed the identity of the unassigned C28 stereocentre. This culminated in the completion of the full-length acyclic C1–C51 fragment, setting the stage for completion of the target natural product.

Authors: Lim, J

• DOI: 10.5287/ora-jxeynwjzx
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: natural product synthesis; polyketide; stereochemical determination
• Subjects: Organic chemistry