Synthesis and Biological Evaluation of Spiroketal Derivatives

逆转霉素A是从链霉菌属中分离得到的一种6，6-螺酮类抗生素，具有很强的生物活性，可作为一种基于抑制异亮氨酰-tRNA合成酶的抗肿瘤药物。反转霉素A也有望成为治疗高钙血症和骨病的药物。螺旋菌素A和螺菌素B也是从紫色链霉菌Tu 4113中以4：1的比例分离出来的聚酮类抗生素，具有多种抗真菌活性，特别是对酵母菌。合成了以5S羟基和C18半琥珀酰基为侧重点的反转霉素A和螺旋霉素A的各种衍生物，考察了它们对破骨细胞异亮氨酰-tRNA合成酶活性和细胞存活的抑制作用，以及对src^&lt；ts&gt；-NRK细胞形态逆转的作用。从活性和稳定性来看，2，3-二氢逆转霉素A、4-羟基-3-逆转霉素A和3，5-二羟基衍生物是很有前途的逆转霉素A的衍生物。提出了一种新的合成反转霉素A的叔醇丁二酸酯的合成方法。3-丁基-1-醇经11步反应生成内酯。在钯的催化下，三氟缩酮缩醛和高烯醇锌与OSO4-Pb(OAc)4反应生成的二氢吡喃被氧化裂解，得到叔醇丁二酸酯。然后，丁二酸酯通过与炔的偶联反应转化为6，6-螺酮。

Reveromycin A is a 6, 6-spiroketal antibiotic isolated from the genus Streptomyces and shows strong biological activities that makes it potentially useful as an antitumor drug based on inhibition of isoleucyl-tRNA synthetase. Reveromycin A is also expected as a therapeutic agent for hypercalcemia and bone disease. Spirofungins A and B are also polyketide-type antibiotics isolated from Streptomyces violaceusniger Tu 4113 as a mixture in the ratio of 4: 1 and show various antifungal activities, particularly against yeasts. Various derivatives of reveromycin A and spirofungin A, focusing on the 5S hydroxyl group and C18 hemisuccinyl group, were synthesized and their inhibitory effects on both the isoleucyl-tRNA synthetase activity and the survival of osteoclasts, and activities on the morphological reversion of src^<ts>-NRK cells were examined. It was found that 2, 3-dihydroreveromycin A, 4-hydrox3rreveromycin A and the 3, 5-dihydroxyl derivative are the promising derivative of reveromycin A based on the activity and stability. We have developed a novel method for the preparation of the succinates of tertiary alcohols for the synthesis of reveromycin A. 3-Butyn-1-ol was converted into a lactone in eleven steps. Oxidative cleavage of the dihydropyrans prepared via the palladium-catalyzed coupling of the ketene acetal triflates and zinc homoenolate with 0_s0_4-Pb (OAc) _4 gave the succinates of tertiary alcohols. Then, the succinates were converted into the 6, 6-spiketal via the coupling with an alkyne.