Synthesis and Biological Evaluation of Antifungal Antibiotics, Spirofungin A and B

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Reveromycin A (1) is a novel polyketide-type antibiotic with strong biological activity that makes it potentially useful for treatment of tumor, hyperpotassemia and bone disease. Spirofungins A (2) and B (3) are also polyketide-type antibiotics isolated from Streptomyces violaceusniger Tu 4113 as a mixture of 2:3 in the ratio of 4:1 and show various antifungal activities, particularly against yeasts. The molecular structures of 1,2 and 3 are characterized by a 6,6-spiroketal core bearing two unsaturated side chains ending in carboxylic acid units and two alkyl groups. We have already reported the first asymmetric total synthesis of 1. In connection of our studies concerning the chemical modifications and structure-activity relationships of 1, we examined the synthesis 2 and 3. The relative configuration of the spiroketal core in 2 is quite similar to that of 1. The absolute configuration depicted for 2 was proposed by analogy with 1 and remains unconfirmed. Synthetic studies of 2 were performed to confirm the absolute configuration. The 6,6-spirokeacal segment of 2 was efficiently prepared via the coupling reaction of the Weinreb amide 4 and the alkyne 5 which are readily available from the common intermediate 8. The right side chain of 2 was also constructed using vinyl borane 9 derived from 8. Finally, asymmetric total synthesis of spirofungins A (2) and B (3) has been accomplished with a longest linear sequence of 31 steps, affording (-)-2 and (+)-3 in 7.9% and 5.2% overall yields, respectively. Effects of (-)-2 and (+)-3 on both isoleucyl-tRNA synthetase activity and morphological reversion of src^<te>-NRK cells were examined. Spirofungin A (-)-2 showed weak activities for both assays.