A Short Synthesis of (R,R)‐(‐)‐Pyrenophorin from (S)‐Propylene Oxide and a 3‐Pentenoic Acid d⁵‐Reagent

Abstract

Analysis of the known syntheses of pyrenophorin (1) (Scheme 1) reveals that they all rest upon the use of reagents with di-, d3-, or a'-reactivity umpolung for the establishment of at least one of the 1,4-distances of functional groups. A different approach, outlined in Scheme 2, has now been realized: the non-conjugated and the conjugated 7-hydroxyoctenoic acids 10 and 11, obtained from dienone dianion derivatives of type 3 and d,l-or (S)-methyloxirane, are converted to the macrodiolides 12 and 13, respectively. These are directly oxidized with introduction of an oxygen function at position 4, see 13 + 1 and 12 + 16 + 17 + 1. The overall transformation of the 7.6-unsaturated ketone 18 to pyrenophorin (1) in 27% yield takes six steps, partly without purification of intermediates. Eine kurze Synthese von (R,R)-( -)-Pyrenophorin aus (S)-Propylenoxid und einem3-Pentensaure-d5-Reagenz 1, 2, Eine Analyse der bisher bekannten Synthesen von Pyrenophorin (l), siehe Schema 1 , zeigt, daR wenigstens einer der 1,4-Abstande funktioneller Gruppen durch Verwendung eines umgepolten Reagenzes (d', d3,az) zustande kommt. Es wird ein neuer, in Schema 2 skizzierter Weg beschrieben: Aus Dienondianion-Derivaten vom Typ 3 und d,i-oder (S)-Methyloxiran entstehen die VorIaufer 10 und 11 der noch nicht vollstandig funktionalisierten Makrodiolide 12 bzw. 13; aus diesen erhalt man durch 1,4-Oxidation Pyrenophorin (l), siehe 13 + 1 und 12-16 + 17 --* 1. Die Reaktionsfolge vom y,S-ungesattigten Keton 18 zu Pyrenophorin (1) besteht aus sechs Schritten, die -Zuni Teil ohne Reinigung der Zwischenprodukte -in 27proz. Gesamtausbeute durchgefiihrt werden.The simple macrodiolides c~l l e t o d i o l~~~) , grahamimycin Al ' ), pyrenophorin lo), vermiculine "), elaiophylin 12), and pyrenophorol 13) have attracted synthetic chemists' attention and rigorous efforts have been made to discover new synthetic routes leading t o this group of compounds. Thus, we are aware of thirteeni4-22,43) and five'5,23-25*43) different syntheses of the symmetrical molecules pyrenophorin (1) and vermiculine (2), respectively.

Bioactivity of the Fungal Metabolite (8R,16R)-(−)-Pyrenophorin on Graminaceous Plants

“…Pyrenophorin was also isolated from cultures of Stemphylium radicinum (Meier, Drechs and ED Eddy), Neergard (17), and Pyrenophora aVenae, Ito and Kuribayashi (1). Although optical stereoisomers of pyrenophorin have been synthesized by various methods (18)(19)(20)(21)(22)(23), the stereochemical structure of the natural product had not been elucidated. The chemical profile (melting point, [R] D 20 , IR, MS, 1 H NMR) of pyrenophorin, obtained from (5S,8R,13S,-16R)-(-)-pyrenophorol oxidation through the Jones reaction, was identical to that of the natural pyrenophorin isolated from D. aVenae cultures.…”

Herbicidal potential of pyrenophorol isolated from aDrechslera avenae pathotype

“…Stereoisomers and stereoisomeric mixtures of pyrenophorol have also been synthesized in the laboratory 6. 13–16 Although the chemistry of natural and synthetic ‘pyrenophorols’ has been studied, little work has been done on their stereochemistry. The structure–activity relationship of the compounds has also not been studied.…”

“…These structural differences seem to play an important role not only on phytotoxicity but possibly on uptake and translocation in the plant as well. According to Mali et al ,14 the COCHCHCOOR moeity is important for antimicrobial activity, suggesting a structure–activity relationship for this class of chemicals. The compound named pyrenophol by Sugawara and Strobel11 appears, according to the reported data, to have the same flat chemical structure but a different stereochemical configuration from the pyrenophorol studied in our work.…”

A Short Enantioselective Formal Synthesis of (+)-(S)-4,4-(Ethylenedioxy)-7-hydroxyoct-2-enoic Acid: The Penultimate Precursor to (-)-(R,R)-Pyranophorin

“…(-)-( R , R )-Pyranophorin (1) , 1 is a naturally occurring antifungal 16-membered macrolide dilactone having C 2 symmetry isolated from the plant pathogenic fungi Pyranophora avenae and Stemphylium radicium .The γoxo-α , β -unsaturated ester moiety, which is also found as structural subunits in several other biological molecules, is crucial to biological activity. 2 Most of the reported synthetic routes to pyranophorin rely on synthesis of the suitably functionalized hydroxy acid in racemic 3 or chiral 4 form followed by dimerization to the dilactone. However, the method of Wadsworth-Emmons olefination 5 to ring closure of macrolide and the method of Hatakeyama and co-workers involving 4-DMAP catalyzed ester exchange reaction of phosphonoacetals with lactols 6 are other approaches employed for dilactone ring closure of pyranophorin.…”