Absolute stereochemistry of proclavaminic acid, the monocyclic biosynthetic precursor of clavulanic acid

Abstract

Proclavaminic acid (1) has been synthesized b y a route which indicated the absolute stereochemistry of the t w o chiral centres to be (2S,3R).

Spectroscopic Studies of Substrate Interactions with Clavaminate Synthase 2, a Multifunctional α-KG-Dependent Non-Heme Iron Enzyme: Correlation with Mechanisms and Reactivities

“…18 For the PC substrate, the 4′-(pro-S) hydrogen was specifically lost in the process of cyclization to the 3-OH group, which also proceeds with retention of stereochemistry. 25,26 The PC substrate has been suggested to be able to bind through the 3-OH group to the reactive iron species. 27 Earlier studies on the primary and R-secondary tritium kinetic isotope effects 21 and more recent studies of the β-secondary deuterium kinetic isotope effect 28 in the ring-closure and desaturation reactions favor a homolytic C-H abstraction by the reactive oxo-ferryl intermediate to form a carbon-centered radical (or possibly an organoiron species), resulting in the cyclization of substrate to produce dihydroclavaminate and the release of water.…”

“…This is followed by nucleophilic attack of the iron-bound dioxygen onto the α-keto carbon, which results in the oxidative decarboxylation of α-KG to yield succinate, CO 2 , and a reactive iron−oxygen species, , proposed to be an oxo-ferryl (Fe IV O II- ) intermediate for other α-KG-dependent enzymes. − In the hydroxylation reaction, this reactive iron species inserts oxygen to hydroxylate DGPC substrate with retention of configuration and removal of the 3-( pro-R ) hydrogen . For the PC substrate, the 4‘-( pro-S ) hydrogen was specifically lost in the process of cyclization to the 3-OH group, which also proceeds with retention of stereochemistry. , The PC substrate has been suggested to be able to bind through the 3-OH group to the reactive iron species . Earlier studies on the primary and α-secondary tritium kinetic isotope effects 21 and more recent studies of the β-secondary deuterium kinetic isotope effect in the ring-closure and desaturation reactions favor a homolytic C−H abstraction by the reactive oxo-ferryl intermediate to form a carbon-centered radical (or possibly an organoiron species), resulting in the cyclization of substrate to produce dihydroclavaminate and the release of water.…”

The biosynthesis of plant alkaloids and nitrogenous microbial metabolites

“…As previously found (see also above) the (R)and ( 9 -Nmethylcoclaurines were not interconverted during biosynthesis and the 1,2-didehydro-derivative corresponding to (88) is not involved. Cycleanine (93) was confirmed as having the same biosynthesis from (R)-N-methyl-coclaurine (88) Glaucine [as (97)] derives in Dicentra eximia by way of Nnorprotosinomenine (94).6 In Litsea glutinosa on the other hand the key benzylisoquinoline intermediate is reticuline [as (72)]. 40 The glaucine in this plant has the S configuration (97) and appropriately it derives via (9-reticuline (72) and not (R)reticuline.…”