The chemistry of pseudomonic acid. Part 2. The conversion of pseudomonic acid A into monic acid A and its esters

Abstract

By suitable protection and deprotection, the 9-hydroxynonanoic acid side-chain of pseudomonic acid A (1 a), a naturally occurring antibiotic, was cleaved in a highly efficient one-pot reaction to the allylic acid (3a). 4-[5S-(2S.3S-epoxy-5shydroxy-4s-methylhexyl) -3R.4R-di hydroxytetrahydropyran -2S-ylI -3-methylbut-2 ( E ) -enoic acid. We have ascribed the trivial name, monic acid A, to this allylic acid. Esters of monic acid A were readily prepared from the free acid (3a) and also from the ketone (2) which could be condensed with phosphonoacetates.PSEUDOMONIC ACID A, a naturally occurring antibiotic produced by fermentation of a strain of Pseudomonas fluorescens, was assigned the gross structure (la) by general protein binding appears to correlate with lipoyhilicity one approach to reducing the extent of binding was to attempt the replacement of this C-9 acidic alcohol with shorter chain alcohols. In other words, we sought to effect a transesterification of pseudomonic acid A (la).In our first approach to simple esters of the allylic acid (3a), to which we have given the trivial name monic acid A, we utilised the readily available ketone triol (2). Reaction of (2) with the Wadsworth-Emmons reagent, triethyl phosphonoacetate (4a), in a stirred suspension of sodium hydride in tetrahydrofuran, provided a complex mixture in which both ethyl monate A (3c) and ethyl 1 2 isomonate A (5a) were present as shown by h p.1.c.

[3-(Diethylphosphono)propionato]triphenyltin

“…A commercial sample of ethyl 3-(diethylphosphono)propionate was hydrolyzed to 3-(diethylphosphono)propionic acid, duplicating the literature procedure of Clayton, Luk & Rogers (1979) for the hydrolysis of 3-(diethylphosphono)acetic acid. A slight molar excess of the acid was briefly heated with triphenyltin hydroxide in ethanol; slow cooling of the filtered solution afforded crystals of the organotin ester.…”

Interaction of pseudomonic acid A with Escherichia coli B isoleucyl-tRNA synthetase

“…), Beecham Pharmaceuticals Research Division for financial support and Dr. P. J. Clayton, Dr. N. Rogers, Dr. R. Sutherland and Dr. B. Slocombe for helpful discussions. We also thank Dr. N. Rogers for a sample of monic acid and for providing details of the synthesis of pseudomonic acid before publication (Clayton et al, 1979).…”

Nasal Decolonisation of MRSA

“…Decolonisation of MRSA within nares is a precautionary part of surgical premedication, for which mupirocin (Bactroban; pseudomonic acid A) is widely prescribed [1]. The rapid intra-gastric cleavage to monic acid A, discovered during its development in the 1970s, limited its clinical use to topical application [2]. Notably, mupirocin is not absorbed through skin [1]; thus its intra-nasal function as an antibiotic for MRSA is superficial on nasal membranes.…”

“…Usually there is no means of monitoring compliance in real time or in retrospect. From clinical experience, a challenge for the first time to devise a method to monitor efficient intra-nasal application of mupirocin was addressed, because its degradation in humans to monic acid A is known and a unique reference sample was available from its original synthesis and subsequent scientific use [2,3]. There was absolutely no precedent for choosing to work with mupirocin on account of any suspicion of its efficacy as an antibiotic, particularly for its relevance in MRSA control.…”