Spirofungin A: Stereoselective synthesis and inhibition of isoleucyl-tRNA synthetase
Spirofungin A: Stereoselective synthesis and inhibition of isoleucyl-tRNA synthetase
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DOI：
10.1002/anie.200702440
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发表时间：
2007-01-01
影响因子：
16.6
通讯作者：
Kozmin, Sergey A.
中科院分区：
文献类型：
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作者：
Marjanovic, Jasmina;Kozmin, Sergey A.
螺旋菌素A和螺旋菌素B是紫色链霉菌Tü4113的一个次生代谢物家族。[1]这两种天然产物源于螺旋酮亚基的异构化[2]，最初是以混合物的形式分离出来的，据报道可以抑制白色念珠菌的生长。[1]虽然每个同系物的抗真菌活性还没有被评估，但密切相关的反转菌素[3，4]的构效关系强烈表明，螺旋菌素A(1)不仅在酵母中显示出抗增殖活性，而且在哺乳动物细胞中也显示出抗增殖活性，可能是通过特异性地抑制异亮氨酰-tRNA合成酶。6]清水等人最近首次报道了螺菌素A和B的合成。[7]然而，组装过程需要在到达最终目标的过程中对这两个非对映异构体螺酮进行层析分离。我们的合成策略是专为解决具有挑战性的螺酮化问题而设计的，并为螺菌素A(1)提供了完全立体选择性的途径。在这里，我们报告了一种高度立体控制和高效合成这种天然产物的开发。我们进一步证明，螺旋藻A(1)在一组癌细胞中显示出显著的抗增殖活性，并选择性地抑制哺乳动物细胞中异亮氨酰-tRNA合成酶的活性。螺菌素A(1)的逆合成分析涉及两个不饱和侧臂在C(20)±C(21)烯基上从螺酮亚基上最初的分离，以及在C(7)和C(8)上的二烯碎片(方案1)。螺酮事件的控制是合成中最具挑战性的方面。[8]虽然所需的螺酮2在立体电子学上是有利的，但C(19)取代基的轴向布置会导致显著的空间堵塞。因此，两个螺酮2和3的混合物有望在自发的螺酮化过程中形成。[9]为了使螺酮2能够独占形成，我们利用了两个螺酮单元中侧臂(R1和R2)的不同空间取向。事实上，如果两个臂被临时连接(即，使用环状硅烷4)，[10]这将迫使15元硅环酮5的螺酮化以专门生成螺酮4。[11]环酮5将从二烯酮6衍生，二烯酮6将通过采用我们的基于环丙烯缩醛歧化的聚酮组装方法来组装，该方法最初是在合成双环胺A的过程中开发的。[12]合成是通过在GRUBS催化剂13的存在下使烯烃11[13]与环丙烯酮缩醛12反应开始的[14]这促进了开环歧化反应，在随后的脱硅反应中生成二烯14(方案2)。将醇14和15的混合物[13]依次暴露在二氯二异丙基硅烷和咪唑中，引入了所需的二烷氧基硅烷连接器。用草酸加成酮16，有效地实现了1，3-二恶烷的化学选择性脱除。
SpirofunginsA and B constitute a family of secondary metabolites from Streptomyces violaceusniger Tü 4113.[1] The two natural products arise from epimerization of the spiroketal subunit [2] and were initially isolated as a mixture, which was reported to inhibit growth of Candida albicans.[1] While the antifungal activity of each congener has not been assessed, the structure–activity relationship of the closely related reveromycins [3, 4] strongly suggested that spirofungin A (1) should display antiproliferative activity not only in yeast, but also in mammalian cells, possibly by specific inhibition of isoleucyl-tRNA synthetase.[5, 6] The first syntheses of spirofunginsA and B were recently reported by Shimizu et al.[7] The assembly process, however, required chromatographic separation of the two diastereomeric spiroketals en route to the final targets. Our synthetic strategy was uniquely designed to solve a challenging spiroketalization problem and to provide a fully stereoselective access to spirofungin A (1). Herein we report the development of a highly stereocontrolled and efficient synthesis of this natural product. We further demonstrate that spirofunginA (1) displays notable antiproliferative activity in a panel of cancer cell lines, and selectively inhibits the activity of isoleucyl-tRNA synthetase in mammalian cells. The retrosynthetic analysis of spirofungin A (1) involves the initial detachment of the two unsaturated side arms from the spiroketal subunit at the C (20) ÀC (21) alkene and the diene fragments at C (7) and C (8)(Scheme 1). Control of the spiroketalization event entailed the most challenging aspect of the synthesis.[8] While the desired spiroketal 2 is favored stereoelectronically, the axial disposition of the C (19) substituent leads to significant steric congestion. As a result, a mixture of two spiroketals 2 and 3 is expected to form upon spontaneous spiroketalization.[9] To enable the exclusive formation of spiroketal 2, we exploited different spatial orientation of the side arms (R1 and R2) in the two spiroketal units. Indeed, if the two arms were held by a temporary connection (that is, using a cyclic silane 4),[10] this would force the spiroketalization of the 15-membered silacyclic ketone 5 to produce spiroketal 4 exclusively.[11] Cyclic ketone 5, in turn, would derive from dienone 6, which would be assembled from four simple building blocks (7–10) by employing our cyclopropenone acetal metathesis-based approach for polyketide assembly, which was initially developed during the synthesis of bistramide A.[12]The synthesis began by subjecting alkene 11 [13] to cyclopropenone acetal 12 in the presence of the Grubbs catalyst 13,[14] which promoted the ring-opening metathesis to give diene 14 upon subsequent desilylation (Scheme 2). Sequential exposure of a mixture of alcohols 14 and 15 [13] to dichlorodiisopropylsilane and imidazole introduced the requisite dialkoxysilane connector. Chemoselective removal of the 1, 3-dioxane was efficiently achieved using oxalic acid to give ketone 16. Exposure of 16 to the Grubbs catalyst 13 resulted