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

Reveromycin A(1)是一种新型聚酮类抗生素，具有较强的生物活性，可用于治疗肿瘤、高钾血症和骨病。Spirofungins A(2)和B(3)也是从violaceusniger Streptomyces Tu 4113中分离出来的聚酮型抗生素，其比例为4:1，比例为2:3，具有多种抗真菌活性，特别是对酵母的抗真菌活性。1,2和3的分子结构以6,6-螺旋酮核为特征，核上有两个以羧酸单位和两个烷基结尾的不饱和侧链。我们已经报道了第一个不对称全合成1。结合我们对1的化学修饰和构效关系的研究，我们考察了2和3的合成。2中螺旋核心的相对构型与1非常相似。描述2的绝对构型是通过类比1提出的，但仍未得到证实。2的综合研究证实了绝对构型。通过Weinreb酰胺4和炔5的偶联反应，有效地制备了2的6,6-螺醛段。2的右侧链也是由乙烯基硼烷9衍生而来。最后，螺旋体菌素A(2)和B(3)的不对称全合成以最长的31步线性序列完成，(-)-2和(+)-3的总产率分别为7.9%和5.2%。研究了(-)-2和(+)-3对src < >- nrk细胞异酰基trna合成酶活性和形态逆转的影响。Spirofungin A(-)-2在两种试验中均表现出弱活性。

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.