Investigation into 9(S)-HPODE-derived allene oxide to cyclopentenone cyclization mechanism via diradical oxyallyl intermediates

Abstract

The cyclopentane core is ubiquitous among a large number of biologically relevant natural products. Cyclopentenones have been shown to be versatile intermediates for the stereoselective preparation of highly substituted cyclopentane derivatives. Allene oxides are oxygenated fatty acids which are involved in the pathways of cyclopentenone biosynthesis in plants and marine invertebrates; however, their cyclization behavior is not well understood. Recent work by Brash and co-workers (J. Biol. Chem. 2013, 288, 20797) revealed an unusual cyclization property of the 9(S)-HPODE-derived allene oxides: the previously unreported 10Z-isomer cyclizes to a cis-dialkylcyclopentenone in hexane/isopropyl alcohol (100:3,v/v), but the known 10E-isomer does not yield cis-cyclopentenone under the same conditions. The mechanism for cyclization has been investigated for unsubstituted and methyl substituted vinyl allene oxide using a variety of methods including CASSCF, ωB97xD, and CCSD(T) and basis sets up to cc-pVTZ. The lowest energy pathway proceeds via homolytic cleavage of the epoxide ring, formation of an oxyallyl diradical, which closes readily to a cyclopropanone intermediate. The cyclopropanone opens to the requisite oxyallyl which closes to the experimentally observed product, cis-cyclopentenone. The calculations show that the open shell, diradical pathway is lower in energy than the closed shell reactions of allene oxide to cyclopropanone, and cyclopropanone to cyclopentenone.

Biosynthesis of Jasmonates from Linoleic Acid by the Fungus Fusarium oxysporum. Evidence for a Novel Allene Oxide Cyclase

“…As reported here, fungal AOC transform 12,13 S ‐EOD, but may nevertheless use the same reaction mechanism. Fungal AOC may, therefore, catalyze homolytic cleavage of the epoxide of 12,13 S ‐EOD with formation of an oxyallyl radical, which rearranges to 9 S ,13 S ‐12‐OPEA (González‐Pérez et al, ; Hebert et al, ). An outline of the transformation of 12,13 S ‐EOD into 9 S ,13 S ‐12‐OPEA by AOC and then into 9,10‐dihydro‐(+)‐7‐ iso ‐JA‐Ile is shown in Fig.…”

“…Allene oxides can differ in the geometry of the double bond (Z or E), which can affect cyclization. For example, the 10Z isomer of the 9S-HPODE-derived allene oxides cyclizes to two cis isomers of a cyclopentenone derivative in aprotic solvents, but the 10E-isomer is not reactive (Brash et al, 2013;Hebert et al, 2016). This difference may apply to 11Z and 11E isomers of 13S-LOX-derived allene oxides (González-Pérez et al, 2017), but flaxseed AOS (CYP74A) forms allene oxides with 11E configuration (Medvedeva et al, 2005).…”

“…The enzymatic mechanism of formation of cyclopentenone derivatives from allene oxides has been studied intensively (Hofmann et al, 2006;Ziegler et al, 1999Ziegler et al, , 2000, and in recent years also by quantum physics (González-Pérez et al, 2017;Hebert et al, 2016). It was originally proposed that the cyclopentenone was formed via an ionic mechanism (Grechkin et al, 2002).…”

Charge migration fragmentation in the negative ion mode of cyclopentenone and cyclopentanone intermediates in the biosynthesis of jasmonates

“…A cytochrome P450, designated allene oxide synthase, then dehydrates this hydroperoxide to the allene oxide, 12,13( S )‐epoxy‐9( Z ),11,15( Z )‐octadecatrienoic acid (12,13 S ‐EOT) . Allene oxide cyclase (AOC), in turn, converts the allene oxide via di‐radical intermediates into a cyclopentenone, 12‐oxo‐10,15( Z )‐phytodienoic acid (12‐OPDA) . JA is then formed by the reduction of the ring double bond followed by three steps of β‐oxidation .…”

A new class of fatty acid allene oxide formed by the DOX-P450 fusion proteins of human and plant pathogenic fungi, C. immitis and Z. tritici

“…The allene oxides can be transformed enzymatically or nonenzymatically to cyclopentenone fatty acids, e.g., analogs of jasmonic acid and prostaglandin A 2 , respectively (37)(38)(39). The process leading to a cyclopentenone from the 10Z-isomer of the 9S-HPODE-derived allene oxide was recently studied in detail (40,41). This allene oxide undergoes homolytic cleavage with formation of a ketone at C-10, a radical at C-9, and an allyl-like radical at C-11 to C-13.…”