Polycyclic molecules from linear precursors: Stereoselective synthesis of clavolonine and related complex structures
Polycyclic molecules from linear precursors: Stereoselective synthesis of clavolonine and related complex structures
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DOI：
10.1002/anie.200502296
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发表时间：
2005-01-01
影响因子：
16.6
通讯作者：
Scheerer, JR
中科院分区：
文献类型：
--
作者：
Evans, DA;Scheerer, JR
首先，让我们考虑路径A。大环化合物通常具有明确的构象，对反应的立体化学过程有明显的影响。[5]该路线的研究需要合成16元大环11 a（方案1）。通过硼介导的（R）-3-丙酰基-4-苄基恶唑烷酮与肉桂醛的羟醛加成开始合成，得到作为单一非对映异构体的结晶4。[6]该羟醛加合物被连续还原成二醇并作为衍生的亚苄基缩醛被捕获。随后的还原裂解揭示了伯醇（DibalH，CH 2Cl 2，CH 358 C），其通过中间体甲苯磺酸酯转化为腈5。[7]苯乙烯经臭氧分解后，与β-酮基膦酸酯7缩合得到α，β-不饱和酮8，收率90%。[8]在对8中的烯酮进行保护后，腈和被保护的羟基末端被修饰成大环化所需的前体9。[9]通过活化伯醇作为其碘化物衍生物来完成大环化，将其立即进行酮酯烷基化条件（Cs2 CO 3，THF，378 ℃，0.007 m）。[10]以这种方式，以良好的产率可再现地获得大环10。氧化烯丙醇得到所需的烯酮11 a，将其结晶为单一的非对映异构体（mp：1278 ℃）并通过X-射线衍射分析。脱保护的大环胺11 B可以与C13或C5羰基反应。我们预测胺的脱保护将导致在C13酮处缩合以提供乙烯基氨基甲酸酯12（方案2）。[11]在这种情况下，胺Ila的氨基甲酸酯裂解没有得到所需的烯胺酮12;相反，观察到13的排他性形成（在C5处攻击）（97%产率）。将13暴露于质子酸或刘易斯酸促进了酮酯与α，β-不饱和亚胺离子14的立体选择性跨环迈克尔加成。衍生的三环烯胺15是不稳定的，并且在尝试通过硅胶或氧化铝上的色谱法纯化时经历自发的分子内曼尼希环化成四环酮酯17。在实践中，烯胺13在与乙酸哌啶鎓一起在乙醇中加热时直接转化为17（81%产率）。该化合物的结构归属通过衍生物18（mp：1948 C）的X射线衍射分析来验证。为了完整表征的目的，将烯胺15选择性地还原为胺19，并通过X射线衍射分析其盐酸盐（mp：2258 C）。对大环11 a的固态构象的检查没有为所观察到的胺11 B的N-C5缩合提供明确的理由。被保护的胺位于距C5和C13处的酮相同的距离处（分别为5.38和5.41）。由于跨环胺缩合反应具有不希望的化学选择性，[12]我们将注意力转向了另一种事件顺序。
First, let us consider path A. Macrocycles often adopt well-defined conformations that exhibit a pronounced influence on the stereochemical course of reactions.[5] The investigation of this route required the synthesis of the 16-membered macrocycle 11 a (Scheme 1). The synthesis began by the boron-mediated aldol addition of (R)-3-propionyl-4-benzyloxazolidinone to cinnamaldehyde to provide crystalline 4 as a single diastereomer.[6] This aldol adduct was successively reduced to the diol and trapped as the derived benzylidine acetal. Subsequent reductive cleavage revealed the primary alcohol (DibalH, CH2Cl2, À358C) which was transformed into nitrile 5 via the intermediate tosylate.[7] Following ozonolysis of the styrene moiety, the aldehyde derived from 5 was condensed with β-ketophosphonate 7 to afford α, β-unsaturated ketone 8 in 90% yield.[8] After protection of the enone in 8, the nitrile and protected hydroxyl termini were modified to the macrocyclization requisite precursor 9.[9] Macrocyclization was accomplished by activation of the primary alcohol as its iodide derivative, which was immediately subjected to ketoester alkylation conditions (Cs2CO3, THF, 378C, 0.007 m).[10] In this manner, macrocycle 10 was reproducibly obtained in good yield. Oxidation of the allylic alcohol afforded the desired enone 11 a, which was crystallized as a single diastereomer (mp: 1278C) and analyzed by X-ray diffraction. The deprotected macrocyclic amine 11 b may react with either the C13 or the C5 carbonyl groups. We predicted that deprotection of the amine would result in condensation at the C13 ketone to provide the vinylogous urethane 12 (Scheme 2).[11] In the event, carbamate cleavage of amine 11 a afforded none of the desired enaminone 12; rather, exclusive formation of 13 (attack at C5) was observed (97% yield). Exposure of 13 to protic or Lewis acids promoted a stereoselective transannular Michael addition of the ketoester to the α, β-unsaturated iminium ion 14. The derived tricyclic enamine 15 was unstable and underwent a spontaneous intramolecular Mannich cyclization to the tetracyclic ketoester 17 upon attempted purification by chromatography on silica gel or alumina. In practice, enamine 13 was transformed directly into 17 (81% yield) upon heating in ethanol with piperidinium acetate. The structural assignment of this compound was verified by X-ray diffraction analysis of derivative 18 (mp: 1948C). For the purpose of complete characterization, enamine 15 was selectively reduced to amine 19 and analyzed by X-ray diffraction as its hydrochloride salt (mp: 2258C). An examination of the solid-state conformation of macrocycle 11 a provides no clear rationale for the observed N–C5 condensation of amine 11 b. The protected amine is positioned at the same distance from both the ketones at C5 and C13 (5.38 and 5.41, respectively). As a result of the undesired chemoselectivity of the transannular amine condensation,[12] we turned our attention to an alternative sequence of events.