Chemoenzymatic Synthesis of Pleiogenone A: An Antiproliferative Trihydroxyalkylcyclohexenone Isolated from Pleiogynium timorense

Abstract

The first total synthesis of polyhydroxylated cyclohexenone 1, isolated from Pleiogynium timorense and named pleiogenone A, is reported that also serves as a proof of structure and absolute configuration. Enzymatic dihydroxylation of benzoic acid with R. eutrophus B9 provided enantiomerically pure diene diol 6. Elaboration of the carboxylate moiety to the alkyl side chain was followed by singlet oxygen cycloaddition to furnish an endoperoxide whose reduction with thiourea led to cyclitol 19. Several protective operations were required before oxidation and the final extension of the side chain by a Wittig reaction. After final deprotection of the acetonide functionality the desired pleiogenone A (1) was obtained in 14 operations from benzoic acid.

Biocatalytic Oxidation Reactions: A Chemist's Perspective

“…Dioxygenase (DO)-catalysed cis dihydroxylation of aromatic compounds and arepresentative selection of DO-derived products. TDO:toluene dioxygenase; [44] BDO:benzoate dioxygenase; [45] NDO: naphthalene dioxygenase. [46] Thus far, FMO-catalysed hydroxylations of phenols have been reported to occur only in combination with rearomatisation, hence giving aromatic products.V ery recently,N arayan and co-workers,h owever, reported various FMOs catalysing the oxidative dearomatisation of substituted phenols,g iving access to aw hole world of new synthons for organic synthesis (Scheme 11).…”

Chemoenzymatic Synthesis of Advanced Intermediates for Formal Total Syntheses of Tetrodotoxin

“…The resulting iodine‐substituted diol 5 was converted into the key enone 7 in a five‐step sequence: Acetonide protection, palladium‐catalyzed methoxycarbonylation, and DIBAL reduction produced allylic alcohol 10 . The tetrasubstituted carbon atom at C6 (TTX numbering) was constructed through a [4+2] hetero‐Diels–Alder cycloaddition with singlet oxygen followed by Kornblum–DeLaMare rearrangement, utilized recently in our synthesis of pleiogenone . The singlet oxygen cycloaddition took place exclusively from the less sterically hindered face of the diene moiety.…”

Quantitative 1H-NMR analysis reveals steric and electronic effects on the substrate specificity of benzoate dioxygenase in Ralstonia eutropha B9

“…Since then, R. eutropha B9 has been employed in several notable synthetic applications. Some examples include preparation of tetracycline antibiotics (Charest et al, 2005 ), novel heterocyclic scaffolds using cycloadditions (Adams et al, 2014 ; Fischer et al, 2010 ; Jenkins et al, 1995 ; Pazos et al, 2015 ), epoxiquinol natural products (Collins et al, 2019 ), pleiogenone A (Froese et al, 2016 ), and grandifloracin derivatives (Alexander et al, 2020 ). Despite the recent surge in interest in these ipso,ortho cis -dihydrodiols, applications of non-native substrates of BZDO are still rare (Nash et al, 2017 ).…”