Oritani's Synthesis of (-)-Antimycin A3b

Oritani et al. prepared unnatural enantiomer (-)-antimycin A3b (ent-94-3b) and its deformylamidodehydroxy analog using chelation-controlled alkyla-tion as the key step (Scheme 13) [106-108]. Aldehyde 113 [103] derived from ethyl (S)-lactate was treated with allylic stannyl compound under chelation control (MgBr2) to give all-syn product 120 [104,109]. The ratio of 120 to other diastereomers was 95 : 5. The hydroxyl group was protected as benzyl ether and the MOM ether was cleaved to afford 121. The formed hydroxyl group was inverted by Mitsunobu reaction to give 122. Then, the D-threonine residue 123 [110] was coupled with 122 to afford 124 in 87% yield. Direct introduction of 123 to 121 failed. The double bond of 124 was cleaved to give the enantiomer of Kinoshita's intermediate ent-104 [98]. This compound was deprotected and condensed with acid 126 by using DEPC. In this step the 7-position was partially epimerized but the 7-epimer was not acylated in the next step, probably due to the steric hindrance. Finally, the unnatural enantiomer, (-)-AA3b [(-)-ent-94-3b] and, in the same manner, deformyl-amidodehydroxyantimycin A3b [(-)-ent-127] were synthesized. In addition, natural enantiomer (+)-105 was prepared for the formal synthesis. These unnatural enantiomers (-)-ent-94-3b and (-)-ent-127, compared with natural antimycin mixture, scarcely inhibited the growth of Saccharomyces cereviciae nor the electron transport of rat liver mitochondria. Miyoshi et al. reported the importance of formylamido and hydroxyl substituents on the phenyl ring for the latter activity [87].

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