Semisynthesis of A23187 (calcimycin) analogs. II. Introduction of a methyl group on the benzoxazole ring.

The Biosynthesis of the Benzoxazole in Nataxazole Proceeds via an Unstable Ester and has Synthetic Utility

“…Benzoxazoles are frequently found in pharmaceutically active compounds and natural products for example in plants (neosalvianen, salvianen, and salvianan); marine sponges (nakijinol, pseudopteroxazole, and ileabethoxazole) as well as bacteria (UK‐1, caboxamycin, A33853, calcimycin, nataxazole, and AJI956) . Benzoxazole compounds are prescribed as anticancers, anti‐inflammatories (flunoxaprofen, benoxaprofen), antibacterial (calcimycin, boxazomycin), and muscle relaxant (chlorzoxazone). Tafamidis (Figure a) is the only approved medicine to delay progression of transthyretin familial amyloid polyneuropathy …”

“…[1] Heterocycles are rigid molecules that can form hydrogen bonds as well as hydrophobic interactions,m oreover they can be modified to adjust lipophilicity,p olarity,a queous solubility,a nd selectivity.O xazoles (and oxazolines) are very common heterocycles and are found isolated or conjugated to aromatic rings,f or example, with benzene,k nown as benzoxazoles.B enzoxazoles are frequently found in pharmaceutically active compounds [2] and natural products for example in plants (neosalvianen, salvianen, and salvianan); [3] marine sponges (nakijinol, [4] pseudopteroxazole, [5] and ileabethoxazole) [6] as well as bacteria (UK-1, [7] caboxamycin, [8] A33853, [9] calcimycin, [10] nataxazole, [11] and AJI956). [12] Benzoxazole compounds are prescribed as anticancers,a nti-inflammatories (flunoxaprofen, [13] benoxaprofen [14] ), antibacterial (calcimycin, [15] boxazomycin [16] ), and muscle relaxant (chlorzoxazone [17] ). Tafamidis (Figure 1a)i s the only approved medicine to delay progression of transthyretin familial amyloid polyneuropathy.…”

Characterization of the Biosynthesis Gene Cluster for the Pyrrole Polyether Antibiotic Calcimycin (A23187) in Streptomyces chartreusis NRRL 3882

“…Calcimycin and a number of similar molecules have been chemically synthesized (26)(27)(28). Calcimycin derivatives have also been generated by microbial transformation (1).…”

Semi-synthesis of A23187 (calcimycin) analogs. III. Modification of benzoxazole ring substituents, ionophorous properties in an organic phase.

“…This compound was unstable and treated without further study. 5-(Ethylmethylamino)-2-((3,9,11-trimethyl-8-(1-methyl-2-oxo -2-(1 H-pyrrol-2-yl)ethyl) -1,7-dioxaspiro-(5.5)-undec-2-yl)methyl)-4-benzoxazolecarboxylic Acid (9) To a solution of A23187 (200 mg) in MeOH (50 ml) was added KOH (33 mg). Ethyliodide (1 ml) was added dropwise to the stirred solution at 10°C and the mixture left overnight at room temp.…”