Total synthesis of (+)-blasticidin s.
The first total synthesis of the peptidyl nucleoside antibiotic, blasticidin S (1), has been achieved by the coupling reaction of cytosinine (3) and blastidic acid (2). A key step in the synthesis of cytosinine (3) is the sigmatropic rearrangement of allyl cyanate 24; this reaction provided efficient and stereoselective access to 2,3-dideoxy-4-amino-D-hex-2-enopyranose (26 a). Further elaboration of 26 a gave methyl hex-2-enopyranouronate 29, and cytosine N-glycosylation of 31 using the Vorbrüggen conditions for the silyl Hilbert-Johnson reaction furnished the differentially protected cytosinine (32) in 11 steps from 2-acetoxy-D-glucal (14) (4.0 % overall yield). Synthesis of the Boc-protected blastidic acid 47 in nine steps starting from chiral carboxylic acid 35 (23 % overall yield) utilized Weinreb's protocol for the preparation of benzyl amide 38 and Fukuyama's protocol for the synthesis of the secondary amine 40. Assembly of the protected cytosinine (32) and blastidic acid (47) by the BOP method in the presence of HOBt, and finally elaboration to 1 by deprotection of the fully protected 54 established the total synthesis of blasticidin S (1).
Ichikawa
Yoshiyasu
Y
Laboratory of Organic Chemistry, School of Bioagricultural Sciences, Nagoya University, Chikusa, Nagoya 464-8601, Japan. ichikawa@agr.nagoya-u.ac.jp
Hirata
Keiko
K
Ohbayashi
Masayoshi
M
Isobe
Minoru
M
D000596:Amino Acids / Q000737:chemistry; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry; D003596:Cytosine / Q000031:analogs & derivatives* / Q000737:chemistry; D019906:Nuclear Magnetic Resonance, Biomolecular; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013055:Spectrophotometry, Infrared
D000596:Amino Acids; D000935:Antifungal Agents; D009705:Nucleosides; C095343:cytosinine; C004500:blasticidin S; D003596:Cytosine