Total synthesis of bleomycin

Condensation of 27 with the tripeptide derivative 28 afforded the respective peptide 29 in 61% yield, which underwent removal of the Boc groups using DMS-TFA to give 30 in 59% yield, which upon coupling with Boc-pyrimidoblamic acid (31) afforded 32. Deblocking with 0.1M NaOH followed by treatment with DMS-TFA produced bleomycin 

Bonadonna, G. Tancini, G. Bajetta, E. Prog. Biochem. Pharmacol. 11 (1976) 172. 

Crooke, S.T. In Bleomycin Current Status and New Developments Carter, S.K., Crooke, S.T., Umezawa, 

Takita, T. Umezawa, Y Saito, S. Morishima, H. Naganawa, H. Umezawa, H. Tsuchiya, T. Miyake, T. Kageyama, S. Umezawa, S. Muraoka, Y Suzuki, M. Otsuka, M. Narita, M. Kobayashi, S. Ohno, M. 

Calyculins A-H are bioactive metabolites isolated from the sponge Discodermia calyx Calyculins are potent serine-threonine protein phosphatase (PPl and PP2A) inhibitors and endowed with remarkable cell membrane permeability. The absolute stereochemistry of calyculins and its C33—C37 portion has been investigated. The relative configuration of the stereocenters was determined by X-ray analysis.  

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Cooperative work with Prof. Nobuo Tanaka (Professor Emeritus of the University of Tokyo) in 1969 showed the mechanism of action of bleomycin to involve DNA strand-scission. The difficult total synthesis of bleomycin was accomplished (1981) in cooperation with Takita and others, including Hamao s son, Yoji Umezawa. H. Umezawa was very satisfied with the success of this total synthesis, and his sustained enthusiasm for improved bleomycins led to peplomycin (1978 used clinically since 1981) and libro-mycin(1985). 

In 1980, in collaboration with Professor Ohno, Faculty of Phanmaceutical Sciences, the University of Tol o, we were successful in the chemical synthesis of pyrimidoblamic acid (84). This was one of the most important parts of the total synthesis of bleomycin. Soon therecifter. Dr. Takita et (55) in my institute were successful in the synthesis of the entire peptide peu t of bleomycin A2 1981 and then in the total synthesis of bleomycin A2 in the same year (56,54). Before this, we chemically converted bleomycin A2 to bleomycin demethyl A2 and estcibllshed synthetic processes for preparing bleonycinic acid from bleomycin demethyl A2 and for preparing various bleomycins from bleonycinic acid (62). Thus, the structures of bleomycins shown in Fig. 4 were conclusively estcibllshed. After our synthesis, Hecht al.also reported on the synthesis of the deglycobleomycin demethyl A2 (3) and the synthesis of bleomycin demethyl A2 (1). 

Boger, D L, Honda, T, Total synthesis of bleomycin A2 and related agents. 4. Synthesis of the disaccharide subunit 2-0-(3-0-carbamoyl-a-D-mannopyranosyl)-L-gulopyranose and completion of the total synthesis of bleomycin A2, J. Am. Chem. Soc., 116, 5647-5656, 1994. 

D.L Boger et al. reported the total synthesis of bleomycin A2. They devised an efficient synthesis for the construction of the tripeptide S, tetrapeptide S, and pentapeptide S subunits of the natural product." " " In their strategy, they utilized an Evans aidoi reaction between the (Z)-enolate derived from (S)-4-isopropyl-3-propionyl-oxazolidin-2-one and A/-Boc-D-alaninal. In order to synthesize one of the diastereomers of the pentapeptide S subunit, they carried out an Evans aidoi reaction between the same aldehyde and the (Z)-enolate of (R)-4-isopropyl-3-propionyl-oxazolidin-2-one. The formation of the diastereomeric syn aldol product in this reaction clearly shows that the stereochemical outcome of the transformation is determined by the chiral auxiliary. 

Boger, D. L., Colletti, S. L., Honda, T., Menezes, R. F. Total Synthesis of Bleomycin A2 and Related Agents. 1. Synthesis and DMA Binding Properties of the Extended C-Terminus Tripeptide S, Tetrapeptide S, Pentapeptide S, and Related Agents. J. Am. Chem. Soc. 1994,116, 5607-5618. 

Moreover, Sumio Umezawa had broad interests in the chemistry of other sugar-containing antibiotics. Bleomycins are useful antitumor agents discovered by Hamao Umezawa and co-workers in 1966 and are glycopeptides composed of a novel hexapeptide, a terminal amine, and a disaccharide. Collaboration with Hamao s group led to elucidation of the stmctnre of the disaccharide portion common to the bleomycins. For this work Shoji Omoto (Meiji Seika Kaisha) received his Ph.D., and Umezawa, with Tsuchiya and Miyake, synthesized the disaccharide. Later, he and co-workers successfully achieved the first total synthesis of bleomycin A2 in collaboration with the groups of Hamao Umezawa and Masaji Ohno (Professor of the University of Tokyo). 

For the total synthesis of bleomycin A2 (1), the glycosyl donor 21 was prepared (Schemes 3 and A) Disaccharide 19 " was treated with a 3 1 mixture of acetic anhydride and acetic... 

Another total synthesis of bleomycin Az (1) has been achieved starting with the bromide 35 (Scheme 5). ° The latter was prepared from 2-0-(a-D-mannopyranosyl)-a-L-gulopyranose (33) by treatment with TBSCl followed by A,A -carbonyldiimidazole and subsequent removal of the silyl groups and acetylation to afford 34. Dissolving 34 in liquid ammonia followed by acetylation and treatment with HBr afforded 35. Coupling of the pentapeptide 36 with 35 in anhydrous sulfolane produced a mixture including 37, which... 

A superb example of this approach is the total synthesis of bleomycin A2 (252) reported by Hecht. Bleomycin was isolated by Umezawa and co-workers Q nd shown to be a potent anticancer agent.l69 While determining the structure, it was shown that hydrolyses and other chemical manipulations of 252 gave nine identifiable fragments (a) aminopropyldimethyl sulfonium (253) (b) 2-aminoethyl-2, 4-bithiazole-4 -carboxylic acid (254) (c) L-threonine (255) (d) (2f ,3S,4R)-4-amino-3-hydroxy-2-methylpentanoic acid (256) (e) L-eryr/zro-(3-hydroxyhistidine (258) (f) (3-amino-P-(4-amino-6-carboxy-5-methylpyrimidin-2-yl)propionic acid (259) (g) a rearrangement product, L- 3-aminoalanine (257) (h) gulose (260) and, (j) carbamoyl mannose (261). 

A review describes the pharmacological properties of l,2-benzisothiazoles. In connection with thiazoles, we find several reviews or papers thiazoles in food aromas patellamides, which are antineoplastic cyclic peptides, from the marine tunicate Lissoclinum patella, which contain an unusual fused oxazoline-thiazole unit and polythiazole-containing peptide antibiotics. An interesting total synthesis of the aglycon of bleomycin A2 should also be mentioned. ... 

Hecht s synthetic approach was to first synthesize each of the individual pieces. The total synthesis required connection of the nine molecules to give bleomycin. The disconnected pieces are shown in Scheme 10.2li O and the plan to synthesize bleomycin from these pieces constitutes an outline of the synthetic tree. Hecht s synthesis of bleomycin A2 is also an excellent example of a convergent synthesis (sec. 10.3.C). Boger synthesized bleomycin using a different strategy. 

Kojima Y, Sunazuka T, Nagai K, Julfakyan K, Fukuda T, Tomoda H, Omura S (2008) Total Synthesis of Malformin C, an Inhibitor of Bleomycin-Induced G2 Arrest. J Antibiot 61 297... 

The stmcture of bleomycin shown in Figure 13 was reported in 1978 (250) total synthesis was reported in 1982 (251—253). The commercial fermentation and purification of bleomycin has been described (244) as has its nonribosomal synthesis using a large multien2yme complex (254). 

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