Biosynthetic Studies on the Fungal Secondary Metabolites CP-225,917 and CP-263,114

Studies on the Biosynthesis of Phomoidride B (CP-263,114): Evidence for a Decarboxylative Homodimerization Pathway

“…In this case, the biosynthetic pathway requires the decarboxylative condensation of two 16-carbon unsaturated anhydrides (Scheme ). One possible scenario involves a cascade of bond-forming steps starting with a decarboxylative condensation between a Michael donor anhydride and an enzyme-bound Michael acceptor anhydride (bond a formation) ( 4 , C 16 + C 16 ). , In earlier work, using suspended cells and 13 C-labeled precursors, we demonstrated that seven carbons of phomoidride B are derived from succinic acid and the remaining carbons derived from acetic acid but left unproven the decarboxylative homodimerization step . To establish support for this condensation ( 4 , C 16 + C 16 ) and side-chain oxidation ( 5 → 6 ) steps shown in Scheme , anhydrides 22 - d 2 and 23 - d 2 were synthesized and individually fed to cultures of ATCC 74256.…”

“…6,7 In earlier work, using suspended cells and 13 C-labeled precursors, we demonstrated that seven carbons of phomoidride B are derived from succinic acid and the remaining carbons derived from acetic acid but left unproven the decarboxylative homodimerization step. 8 To establish support for this condensation ( Anhydride 22-d 2 was synthesized following a procedure developed by our group for a biomimetic synthesis of the phomoidrides (Scheme 3). 9 Thus, alkylation of di-tert-butyl malonate with hexenyl iodide 8 gave malonate 9 in >95% crude yield.…”

Biomimetic Synthesis of Non‐Aromatic Polycyclic Polyketides

“…Biogenetically, 10 would be formed by the controlled dimerization and functionalization of anhydride 9. With regard to polyketide biosyntheses, Sulikowski and coworkers speculated that both monomers (9) were covalently attached to an enzyme active site (thioester linkages) during the dimerization process [14]. This would serve to govern the topology of the reaction toward the cyclononene ring through a stepwise mechanism involving two Michael additions between the anhydride units 9 (C13 → C14, C17 → C9).…”

In silico analyses of maleidride biosynthetic gene clusters

“…9 In recent years, studies [10][11][12][13][14][15] have begun to reveal the genetic basis and complexity of the biosynthetic pathways to these fascinating molecules. Isotopic labelling, [16][17][18] heterologous expression experiments, 10,13,15 gene knock-outs 11,12,14 and in vitro work 19 and have led to the proposal that the biosynthetic pathway begins with precursors (e.g. 11) assembled by an iterative highly reducing polyketide synthase (hrPKS), where the chain length and level of saturation varies according to the structure of the mature natural product.…”