7 Total Synthesis of Blasticidin S
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Blasticidin S (1) is a representative peptidyl-nucleoside antibiotic first isolated from Streptomyces griseochromogenes in 1958 by Yonehara and co-workers. This antibiotic was once commercialized as a fungicide against the virulent fungus, Piricularia oryzae, a serious cause of rice blast disease in Asia. Its biological activity results from specific inhibition of protein biosynthesis by interfering with the peptide bond formation in the ribosomal machinery. Yamaguchi found two blasticidin S-resistance genes, bsr from Bacillus cereus and BSD from Aspergillus terreus which code blasticidin S deaminase. Both genes are now widely used for genetic engineering experiments to select both prokaryotic and eukaryotic cells expressing the blasticidin S-resistance gene. The Renaissance of blasticidin S, originally used as a microbial fungicide, is now flourishing in the research area of molecular biology. The structure and absolute configuration of blasticidin S have been elucidated via chemical degradation and spectroscopic studies by Otake and co-workers, who isolated two components, blastidic acid and cytosinine by acid-catalyzed hydrolysis of blasticidin S. Blastidic acidis an unusual b-amino acid counterpart of arginine with a modified N-methyl guanidine group. Such a -amino acid motif is also manifested in cytosinine, and the highly functionalized feature in cytosinine is characterized with a unique hexopyranosyl-nucleoside containing 2,3-unsaturated-4-amino pyranose attached with cytosine. The richness with functional complexity found in blasticidin S poses synthetic challenges. Although a pioneering work of Kondo and Goto reported the first synthesis of cytosinine in 1972 and two reports for the syntheses of blastidic acid appeared in 2001, there has been no report on the total synthesis of blasticidin S. A key step in the synthetic scheme with cytosinine is a sigmatropic rearrangement of an ally cyanate to give rise to an efficient and stereoselective access to 2,3-dideoxy-4-amino-D-hex-2-enopyranose. Further elaboration into methyl hex-2-enopyranouronate, and cytosine N-glycosylation by the Vorbruggen method furnished the differentially protected cytosinine in 11 steps starting from 2-acetoxy-D-glucal (4.7% overall yield). In the synthesis of Boc-protected blastidic acid, the Weinreb protocol for the preparation of benzyl amide and Fukuyama's method for the synthesis of secondary amine effectively worked to result in the 9-step synthesis starting from chiral carboxylic acid (23% overall yield). Assembly of the protected cytosinine and blastidic acid by the Bop method in the presence of HOBT, and final deprotection of the fully protected blasticidin S established the total synthesis route of blasticidin S.
