Synthesis of Cyclopamine Using a Biomimetic and Diastereoselective Approach
Synthesis of Cyclopamine Using a Biomimetic and Diastereoselective Approach
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DOI：
10.1002/anie.200902520
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发表时间：
2009-01-01
影响因子：
16.6
通讯作者：
Stossel, Anne
中科院分区：
文献类型：
--
作者：
Giannis, Athanassios;Heretsch, Philipp;Stossel, Anne
刺猬信号（Hh）通路是胚胎发生和成体细胞维持和生成的关键调节因子。[1]由于Hh通路的异常激活导致恶性肿瘤，包括基底细胞癌、成神经管细胞瘤、横纹肌肉瘤以及前列腺癌、胰腺癌和乳腺癌，因此Hh信号传导的抑制提供了新的抗癌疗法的途径。[2，3]藜芦生物碱环巴胺是第一个已知的Hh信号抑制剂;它影响蛋白Smoothened的活性和非活性形式之间的平衡。尽管对环巴胺以及代谢上更稳定和有效的类似物存在很高的需求，但仍然缺少这种甾体生物碱的有效化学合成。本文报道了一种从市售的脱氢表雄酮出发，利用仿生和非对映选择性转化快速合成环巴胺的方法。虽然可以基于先前的出版物设想一种全合成策略[4-6]，但这种方法是繁琐的、非立体选择性的和低产率的。我们的合成，这需要一个铜介导的区域选择性C-H活化/羟基化，阳离子环收缩/膨胀，最后一个Alder-ene反应，使这种不寻常的分子的快速建设。该策略还提供了获得自然界中不存在的各种环巴胺类似物的途径，这可能有助于研究这种独特的天然产物的生物活性。环巴胺（1;方案1）最早是在1957年报道的，当时美国爱达荷州的牧羊人对新生羊羔的前额中央有一只独眼巨人般的眼睛感到不安。[7]深入的调查发现，怀孕的绵羊摄入玉米百合（Veratrum californicum）会导致产下患有独眼症的羔羊。藜芦生物碱环巴胺被鉴定为致病剂。畸形独眼症自古以来就被人类所知。在严重的前脑无裂畸形（HPE）病例中观察到，这是一种大脑畸形，其中前脑未能分裂，导致大脑半球、端脑和间脑以及嗅神经和视神经不分裂或不完全分裂。[8]与大脑异常相关的是一系列中线颅面异常，包括眼距缩短和眶间长鼻（筛头）。[9]HPE的病因是异质性的，可能包括遗传和/或致畸因素。直到最近才阐明环巴胺的细胞靶点。该分子与质膜蛋白smoothened结合，诱导构象变化，并抑制hedgehog信号通路。[3]环巴胺（1）显示出许多不寻常的结构特征，因此其合成面临重大挑战。其中包括C-去甲-D-高甾体亚结构和高度取代的呋喃环，其通过螺键连接至D环，并且还稠合至具有碱性仲氮原子的哌啶单元。此外，环巴胺对酸非常敏感：在pH< 3或用刘易斯酸处理1时，呋喃环断裂，D环芳构化形成有毒的环巴胺。
The hedgehog signaling (Hh) pathway is a key regulator in embryogenesis and in the maintenance and generation of cells in adults.[1] Since aberrant activation of the Hh pathway leads to malignancies including basal cell carcinoma, medulloblastoma, rhabdomyosarcoma, and prostate, pancreatic and breast cancers, inhibition of Hh signaling provides a route to novel anticancer therapies.[2, 3] The Veratrum alkaloid cyclopamine was the first known inhibitor of Hh signaling; it influences the balance between active and inactive forms of the protein Smoothened. Though high demand exists for cyclopamine as well as for metabolically more stable and potent analogues, an efficient chemical synthesis of this steroidal alkaloid is still missing. We report herein an expeditious synthesis of cyclopamine starting from commercially available dehydroepiandrosterone and making use of biomimetic and diastereoselective transformations. While one total synthesis strategy can be envisioned based on previous publications,[4–6] this approach is tedious, non-stereoselective, and low yielding. Our synthesis, which entails a copper-mediated regioselective C–H activation/hydroxylation, cationic ring contraction/expansion, and finally an Alder-ene reaction, enables the rapid construction of this unusual molecule. This strategy also provides access to various cyclopamine analogues that do not exist in nature which might be useful in investigations of the biological activity of this unique natural product. Cyclopamine (1; Scheme 1) was first reported in 1957, when sheepherders in Idaho, USA, were alarmed by the unsettling observation of newborn lambs with a single eye located, cyclops-like, in the middle of their foreheads.[7] Intense investigation led to the finding that the ingestion of the corn lily (Veratrum californicum) by pregnant sheep caused the birth of lambs with cyclopia. The Veratrum alkaloid cyclopamine was identified as the causative agent. The malformation cyclopia has been known in humans since ancient times. It has been observed in severe cases of holoprosencephaly (HPE), a malformation of the brain in which the prosencephalon fails to cleave, resulting in undivided or incompletely divided cerebral hemispheres, telencephalon and diencephalon, and olfactory and optic nerves.[8] Associated with the brain abnormalities is a spectrum of midline craniofacial anomalies, including ocular hypotelorism and interorbital proboscis (ethmocephaly).[9] The etiology of HPE is heterogeneous and can include genetic and/or teratogenic factors.Only recently was the cellular target of cyclopamine elucidated. This molecule binds to the plasma membrane protein smoothened, induces a conformational change, and inhibits the hedgehog signaling pathway.[3] Cyclopamine (1) displays a plethora of unusual structural features, and therefore its synthesis poses significant challenges. Among them are the C-nor-D-homo steroid substructure and a highly substituted furan ring, which is attached through a spiro linkage to the D ring and also fused to a piperidine unit having a basic secondary nitrogen atom. Additionally, cyclopamine is quite acid sensitive: at pH< 3 or upon treatment of 1 with Lewis acids the furan ring is cleaved and the D ring aromatizes to form the toxic veratramine.