Pseudomonic acids

Structure-activity relationships 9.4 Mupirocin (pseudomonic acid A)... 

Fig. 5.14 Miscellaneous antibiotics A, chloramphenicol B, fusidic acid C, lincomycin D, clindamycin E, mupirocin (pseudomonic acid A).

Other pseudomonic acids (B, C, D) are also produced. Mupirocin is active predominantly against staphylococci and most streptococci, but Enterococcus faecalis and Gramnegative bacilli are resistant There is also evidence of plasmid-mediated mupirocin resistance in some chnical isolates of Staph, aureus. 

Scheme 1.13. Cationic domino process in the synthesis of pseudomonic acid C analogue.

Some older examples of this type of process include the studies of Marko on the synthesis of pseudomonic acid C analogues [118], the preparation ofindanones by Snider [119], and synthesis of the skeleton of the sesquiterpenes khusiman and zi-zaen by Wenkert and Giguere and their coworkers [120, 121]. 

Hughes, J., and Mellows, G. (1980). Interaction of pseudomonic acid A with Escherichia coli B isoleucyl-tRNA synthetase. Biochem. J. 191, 209—219. 

A microwave assisted Comforth rearrangement of oxazole-4-carboxamides 106 efficiently afforded 5-aminooxazole-4-carboxylates 107. This procedure was applied to the formal synthesis of a natural antibiotic derived from pseudomonic acid <06TL4698>. 

The rearrangement provides a stereocontrolled synthesis of the C-pyranoside 2, present in pseudomonic acids.2... 

Pseudomonic Acid A Pseudomonic Acid B Pseudomonic Acid C Pseudomonic Acid D... 

Mupirocin, pseudomonic acid, is a product of Pseudomonas fluorescens discovered by Fuller etal. It is an inhibitor of isoleucyl-transfer ribonucleic acid (isoleucyl-tRNA) synthetase. 

Stierle, D.B. Stierle, A.A. (1992) Pseudomonic acid derivatives from a marine bacterium. Experientia, 48, 1165-9. 

Mupirocin (pseudomonic acid) is a natural product produced by Pseudomonas fluorescens. It is rapidly inactivated after absorption, and systemic levels are undetectable. It is available as an ointment for topical application. 

Mupirocin (pseudomonic acid A) is structurally unrelated to other currently available topical antibacterial agents. Most gram-positive aerobic bacteria, including methicillin-resistant S aureus (MRSA), are sensitive to mupirocin (see Chapter 50). It is effective in the treatment of impetigo caused by S aureus and group A -hemolytic streptococci. 

Analogous addition of a sugar radical to an unsaturated sulfone has been described by the same authors in the course of pseudomonic acid synthesis. For this, UV irradiation of the iodosugar was used to generate a secondary radical [120],... 

G. E. Keck and A. M. Tafesh, Free-radical addition fragmentation reactions in synthesis A second generation synthesis of (+)-pseudomonic acid C, J. Org. Chem. 54 5845 (1989). 

D. P. Curran, An approach to the enantiocontrolled synthesis of pseudomonic acids via a novel mon-Claisen rearrangement, Tetrahedron Lett. 23 4309 (1982). 

D. P. Curran and Y. Suh, Synthetic applications of a substituent controlled Claisen rearrangement. Preparation of advanced intermediates for the synthesis of pseudomonic acid, Tetrahedron Lett. 25 4179 (1984). 

Many antibiotics, which inhibit protein synthesis, do not bind to ribosomes but block any of a variety of vital chemical processes needed for growth. Among them are pseudomonic acid, which inhibits isoleucyl-tRNA synthetase from many gram-positive bacteria.1111/VV Rapamycin, best known as an immunosuppressant (Box 9-F), inhibits phosphoinositide-3-kinase and also phosphorylation of the cap-binding protein 4G, a component of the eukaryotic initiation factor complex (Fig. 29-11 ).ww The bacterial enzyme peptide deformylase, which is absent from the human body, has been suggested as a target for design of synthetic antibiotics. 01... 

Dihydropyrane synthesis." A novel synthesis of a dihydropyrane intermediate (2) for a synthesis of pseudomonic acid (3) involves an ene reaction of formaldehyde with a 1,4-diene, followed by a quasi intramolecular Diels-Alder reaction with formaldehyde as dienophile, both reactions being catalyzed by ethylaluininum dichloride. Thus, reaction of 1 with CH20 (3 equiv.) and C2H5A1C12 (4.5 equiv.) gives 2 in 35-40% yield via a number of intermediates. 

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