Antibiotics Mitsunobu reaction

A further reaction mechanistically similar to the Mitsunobu reaction as shown in Scheme 26, with the use of AT,iV-dimethylformamide dineopentylacetal (80), can also be employed for macrolactonization [47]. Takei and coworkers [48] applied it to the synthesis of the macrocyclic antibiotic A26771B (55). As shown in Scheme 27, treatment of the linear precursor 82 with 80 in refluxing dichloromethane for 7 h afforded the lactone 83 (39% yield). 

In total syntheses of 3-lactam antibiotics, the formation of 2-azetidinones is crucial. In a biomimetic synthesis, the N—C4 bond is best closed by the open chain hydroxamate (equation 48), because, depending on the different pATa values of the three potentially ionizable positions, only the ring-forming amide is ionized. 3-halohydroxamates are cyclized by base treatment, whereas 3-hydroxyhydroxamates cyclize via the Mitsunobu reaction (diethyl azodicarboxylate, PhsP). More highly substituted precursors yield isomeric 3-lactams after rearrangement. ... 

The naturaiiy occurring potent antitumor antibiotic (+)-duocarmycin A, its epimer, and unnatural enantiomers were prepared by D.L. Boger et al." The last step of the synthesis was the elaboration of the reactive cyclopropane moiety, which was carried out via a transannular spirocyclization using Mitsunobu conditions. This is a special case when the Mitsunobu reaction is utilized to create new carbon-carbon bonds. 

Diethyl azodicarboxylate (Et02C-N=N-C02Et, DEAD) is a key reagent in the Mitsunobu reaction (sec. 2.7.A.ii) and has also been used for macrolactonization. Reaction of 230 with DEAD gave 15% of 231 in White s synthesis of the antibiotic vermiculine. ... 

Lactone substrate 77 was obtained from 57 in one step in 90% yield and its C-4 epimeric analog was prepared by standard inversion procedure. Epoxidation was achieved by action of sodium hypochlorite in pyridine, while conversion to 3-azide required reduction of the epoxide with phenylse-leno(triisopropyloxy)borate, followed by treatment with diphenylphosphory-lazide under Mitsunobu reaction conditions [69]. The acetylated mixture of thioglycosides, obtained from 80, afforded good yield of the desired a-linked antibiotic upon reaction with daimomycinone. All four 2,6-dideoxy-3-azido-L-hexopyranoses were obtained from rhamnal via 4-epimeric lactones. 

Roush WR, Lin X-F. Studies on the synthesis of aureolic acid antibiotics highly stereoselective synthesis of aryl 2-deoxy-p-glycosides via the Mitsunobu reaction and synthesis of the olivomycin A-B disaccharide. J. Am. Chem. Soc. 1995 117 2236 2250. 

Alcohols can be converted into halides if lithium halides (F, Cl, Br, I) or Mel are used in the presence of TPP/DEAD. Kim and Kim were interested in the preparation of (5)-(-)-7,8-difluoro-3,4-dihydro-3-methyl-2//-1,4-benzoaxine (223), a key intermediate for the synthesis of the commercially available quinolone antibiotic levofloxacin. Initial attempts to cyclize 222 under the standard Mitsunobu conditions employing the TTP/DEAD conditions failed to give acceptable yields even when the reaction was refluxed for 1 h in benzene or acetonitrile. Addition of several equivalents of zinc chloride gave the desired cyclized product, some chlorinated intermediate, and none of the DEAD adduct 224. The DEAD adduct was the major product under the standard Mitsunobu conditions. The stereochemistry of the obtained products, which indicates retention of stereochemistry, suggests that the reaction proceeded via a chloride intermediate. 

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