Total synthesis of (+)-zampanolide
Total synthesis of (+)-zampanolide
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DOI：
10.1021/ja012220y
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发表时间：
2001-12-12
影响因子：
15
通讯作者：
Corbett, RM
中科院分区：
文献类型：
--
作者：
Smith, AB;Safonov, IG;Corbett, RM
1996年，Tanaka和Higa报道了（-）-zampanalide的分离、部分结构解析和生物活性，（-）-zampanalide是一种来自冲绳海绵Fasciospongia rimosa的结构新颖的大环内酯（方案1）。关键结构元素包括高度不饱和的骨架和不常见的N-酰基半缩醛胺侧链。2增加了结构的复杂性，仅指定了C（11），C（15）和C（19）之间的相对立体化学。尽管（-）-赞潘生丁的极度缺乏阻碍了对生物学特性的全面评价，但对P388、HT 29、A549和MEL 28细胞系的令人印象深刻的细胞毒性（IC 50 1-5 ng/mL），以及有趣的结构，促使我们启动了针对该代谢物的合成计划。在此，我们公开了非天然存在的对映体（+）-赞潘生丁（1）的首次全合成和初步立体化学归属。在逆合成中，1在酰胺、大环内酯和C（2-3）、C（8-9）和C（17-18）键上的断开产生片段C（3-8）A、C（9-17）B、C（18-20）C和C（1′-6′）D。在正向方向，我们设想通过醛A与砜B的Kocienski-Julia烯化3，然后依次用来自AB的高阶铜酸盐4亲核打开环氧化物C，掺入C（1-2）酰基膦酸酯，以及分子内Horner-Emmons大环化来构建大环内酯。5合成的最后阶段的重点是通过R-烷氧基酸2的立体特异性Curtius重排6然后用酰氯D酰化来安装N-酰基半缩醛胺部分。为了组装片段B，我们选择Petasis-Ferrier重排，7最近在我们的实验室中建立为顺式-2，6-二取代四氢吡喃的强有力的立体控制进入。8为此，醛310的布朗不对称烯丙基化9（方案2），然后依次通过羟基的TES保护和臭氧分解得到（+）-4，其在氧化11和脱甲硅烷基化后得到β-羟基酸（-）-5（57%产率，五步）。双甲硅烷基化12，然后在TMSOTf 14的促进下与（2 E）-3-溴丁-2-烯醛13结合，得到二氧杂环己酮（+）-6，总产率为82%[C（15）下为10：1]。然后用Petasis-Tebbe试剂15进行亚甲基化，得到相应的烯醇醚[72%产率，在C（15）下为6：1]，其在用Me 2AlCl 8处理后进行所需的Petasis-Ferrier重排7，得到59%产率的顺式吡喃酮（+）-7。16酮亚甲基化、脱甲硅烷基化、通过Mitsunobu反应掺入硫四唑17和氧化18顺利进行，得到砜（-）-B（62%产率，4步）。亚基A和C的构建如方案3所述。值得注意的是在子目标A中立体选择性地安装C（4-5）烯烃。有了必要的子目标，大环内酯的组装开始于醛的Kocienski修饰的3 Julia烯化21
In 1996 Tanaka and Higa reported the isolation, partial structure elucidation, and biological activity of (-)-zampanolide, an architecturally novel macrolide from the Okinawan sponge Fasciospongia rimosa (Scheme 1). 1 Key structural elements include the highly unsaturated framework and the uncommon N-acyl hemiaminal side chain. 2 Adding to the structural complexity, only the relative stereochemistry between C (11), C (15), and C (19) had been assigned. Although the extreme scarcity of (-)-zampanolide precluded a comprehensive evaluation of the biological profile, the impressive cytotoxicity against P388, HT29, A549, and MEL28 cell lines (IC50 1-5 ng/mL), in conjunction with the interesting architecture, prompted us to launch a synthetic program targeting this metabolite. Herein, we disclose the first total synthesis and tentative stereochemical assignment of the nonnaturally occurring antipode,(+)-zampanolide (1). Retrosynthetically, disconnections of 1 at the amide, the macrolide, and the C (2-3), C (8-9), and C (17-18) linkages gave rise to fragments C (3-8) A, C (9-17) B, C (18-20) C, and C (1′-6′) D. In the forward direction, we envisioned construction of the macrolide via Kocienski-Julia olefination3 of aldehyde A with sulfone B, followed in turn by nucleophilic opening of epoxide C with a higher-order cuprate4 derived from AB, incorporation of a C (1-2) acyl phosphonate, and intramolecular Horner-Emmons macrocyclization. 5 Highlights of the closing stage of the synthesis would then entail installation of the N-acyl hemiaminal moiety via a stereospecific Curtius rearrangement6 of R-alkoxy acid 2 followed by acylation with acid chloride D. To assemble fragment B we elected the Petasis-Ferrier rearrangement, 7 recently established in our laboratory as a powerful, stereocontrolled entry to cis-2, 6-disubstituted tetrahydropyrans. 8 Toward this end, Brown asymmetric allylation9 of aldehyde 310 (Scheme 2) followed in turn by TES protection of the hydroxyl and ozonolysis afforded (+)-4, which upon oxidation11 and desilylation led to β-hydroxy acid (-)-5 (57% yield, five steps). Bis-silylation12 followed by union with (2E)-3-bromobut-2-enal13 promoted by TMSOTf 14 furnished dioxanone (+)-6 in 82% overall yield [10: 1 at C (15)]. Methylenation with the Petasis-Tebbe reagent15 then furnished the corresponding enol ethers [72% yield, 6: 1 at C (15)], which upon treatment with Me2AlCl8 underwent the desired Petasis-Ferrier rearrangement7 to deliver cis-pyranone (+)-7 in 59% yield. 16 Ketone methylenation, desilylation, incorporation of the thiotetrazole via Mitsunobu reaction, 17 and oxidation18 proceeded smoothly to afford sulfone (-)-B (62% yield, 4 steps).Construction of subunits A and C was achieved as outlined in Scheme 3. 19 Noteworthy is the stereoselective20 installation of the C (4-5) olefin in subtarget A. With the requisite subtargets in hand, assembly of the macrolide began with the Kocienski-modified3 Julia olefination21 of aldehyde