34 6,6-スピロケタール天然物の合成と活性(口頭発表の部)

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Reveromycin A (1) having 6,6-spiroketal core 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 TO 4113 as a mixture of 2: 3 in the ratio of 4: 1 and show various antifungal activities, particularly against yeasts. The stereocontrolled total synthesis of (-)-2 and (+)-3 has been achieved with the alkyne 7, the Weinreb amide 8, and the alkenylboronatev 6 readily available from the common intermediate alkyne 5 employing Horner-Emmons reaction and Suzuki coupling reaction for the construction of the both side chains. It was determined that the absolute configuration of natural spirofungin A is 4S,5R,11R,12S,15S,18S,19R. The first synthesis proceeded with a longest linear sequence of 31 steps, affording (-)-spirofungin A and (+)-spirofungin B in 7.9% and 5.2% overall yields, respectively. The first asymmetric total synthesis of 1 was accomplished by our group using the succinylation of tertiary alcohols under high pressure as a key step. Now, we have developed a new methodology for the synthesis of the succinates of tertiary alcohols without troublesome high pressure. Namely, 3-butyn-1-ol was converted into the lactone 24 through the Sharpless asymmetric epoxidation of 32 in 14% overall yield in eleven steps. After protection of the hydroxyl groups, the dihydropyrans 29 and 30 was prepared via palladium-catalyzed coupling of the ketene acetal triflate derived from 26 and 27 and zinc derivative. Successive oxidation of 28, 29 and 30 with OsO_4 and Pb(OAc)_4 gave the succinyl derivative 31, 32 and 33. Synthesis of 1 from 33 is in progress. In connection of our studies concerning the chemical modifications and structure-activity relationships of 1, we synthesized 2,3-dihydro- 39 and 40, 4-hydroxy- 41 and 5α-hydroxy derivatives of 1. Effects on isoleusyl-tRNA synthetase activity and morphological reversionactivity on src^<1s>h-NRK cells by the 6,6-spiroketal derivatives were examined.
天然有機化合物討論会の論文
2007-08-24

34 6,6-スピロケタール天然物の合成と活性(口頭発表の部)

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