Hennoxazoles, oxazole natural products

New methods for the synthesis of 2,4-disubstitued oxazoles are summarized in a recent review. 2-Alkyl-1,3-oxazoles bearing alkyl, aryl, or acyl substitution at C4 are common substructures in natural products. Examples include macrolides such as rhizoxin (4), hennoxazole A (5), and phorboxazole A (6), ° as well as many cyclic peptides that incorporate an oxazole subunit presumably derived from serine. ... 

The total synthesis of the antiviral marine natural product (-)-hennoxazole A was accomplished by F. Yokokawa and co-workers." The mild reduction of a secondary alkyl azide at C9 was carried out using triphenylphosphine in a THF/water mixture at slightly elevated temperature. The corresponding primary amine was obtained in good yield and was subsequently acylated and converted to one of the oxazole rings of the natural product. 

The antiviral marine natural product, (-)-hennoxazole A, was synthesized in the laboratory of F. Yokokawa." The highly functionalized tetrahydropyranyl ring moiety was prepared by the sequence of a Mukaiyama aldol reaction, cheiation-controiied 1,3-syn reduction, Wacker oxidation, and an acid catalyzed intramolecular ketalization. The terminal olefin functionality was oxidized by the modified Wacker oxidation, which utilized Cu(OAc)2 as a co-oxidant. Interestingly, a similar terminal alkene substrate, which had an oxazole moiety, failed to undergo oxidation to the corresponding methyl ketone under a variety of conditions. 

The antiviral marine natural product 93, [( )-hennoxazo e A] is synthesized by a convergent approach and the final step includes the coupling of oxazole carboxylic acid (95) and pyran derivative (94) using DEPC.36,37 Hennoxazole A is active against herpes with peripheral analgesic activity comparable to that of indomethacin. 

Oxazoles are known in natural products and also find wide incorporation into synthetic medicinal compounds. Oxazoles can be found in the natural products (-)-hennoxazole A (antiviral) and leucascandrolide A (cytotoxic and antifungal). Benzoxazoles and isoxazoles are less common in natural products. Pseudo-pteroxazole (benzoxazole-containing anti-tubercular agent) and ibotenic acid (isoxazole-containing neurotoxin) are two examples. 

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