Synthesize the potent antibiotic lactonamycin
File(s)
Author(s)
Heidrich, Joseph
Type
Thesis
Abstract
The lactonamycins are a unique class of natural products, exhibiting biological activity against
cancer cell lines and multi-drug-resistant bacterial infections. The synthesis of the ABCDE
fragment (ii) of lactonamycin (iii) was carried out as part of ongoing efforts toward its total
synthesis, building on previous work conducted within the Parsons group (Scheme I). This work
included the synthesis of the key hexa-substituted aromatic intermediate (i) over seven steps,
which required the redevelopment of the hydroxymethylation step to improve reliability.
To support the final stages of the total synthesis of lactonamycin, the synthesis of a novel CDEF
model (iv) of lactonamycinone was also investigated. Both the proposed CDEF model (iv) and
lactonamycinone share common retrosynthetic steps for construction of the F-ring, facilitating
further studies toward the total synthesis. The cis-diol intermediate (v) was constructed from
the sulfone (vi) via a novel Hauser-Kraus annulation to provide the CDE rings. Subsequent
oxidation to the quinone, followed by cis-dihydroxylation, provided the cis-diol (v).
cancer cell lines and multi-drug-resistant bacterial infections. The synthesis of the ABCDE
fragment (ii) of lactonamycin (iii) was carried out as part of ongoing efforts toward its total
synthesis, building on previous work conducted within the Parsons group (Scheme I). This work
included the synthesis of the key hexa-substituted aromatic intermediate (i) over seven steps,
which required the redevelopment of the hydroxymethylation step to improve reliability.
To support the final stages of the total synthesis of lactonamycin, the synthesis of a novel CDEF
model (iv) of lactonamycinone was also investigated. Both the proposed CDEF model (iv) and
lactonamycinone share common retrosynthetic steps for construction of the F-ring, facilitating
further studies toward the total synthesis. The cis-diol intermediate (v) was constructed from
the sulfone (vi) via a novel Hauser-Kraus annulation to provide the CDE rings. Subsequent
oxidation to the quinone, followed by cis-dihydroxylation, provided the cis-diol (v).
Version
Open Access
Date Issued
2025-05-28
Date Awarded
01/11/2025
License URL
Advisor
Parsons, Philip
Publisher Department
Department of Chemistry
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)