β-氟烷基化α，β-不饱和2-吡啶砜与硝酮的不对称1,3-偶极环加成反应合成手性氟烷基化异恶唑烷和γ-氨基醇外文翻译资料

 2022-08-11 01:08

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文献一

Catalytic Asymmetric 1,3-Dipolar Cycloaddition of beta;-Fluoroalkylated alpha;,beta;-Unsaturated 2-Pyridylsulfones with Nitrones for Chiral Fluoroalkylated Isoxazolidines and gamma;-Amino Alcohols

beta;-氟烷基化alpha;，beta;-不饱和2-吡啶砜与硝酮的不对称1,3-偶极环加成反应合成手性氟烷基化异恶唑烷和gamma;-氨基醇

【作者】

2-Pyridylsulfone- and fluoroalkylated group-activated olefins underwent highly efficient diastereo- and enantioselective 1,3-dipolar cycloadditions across various aromatic and aliphatic nitrones in the presence of a chiral Ni II /bis(oxazoline) catalyst. The process was tuned by 4 c molec-ular sieves, chiral bis(oxazoline) ligands, reaction solvents, and temperature. A wide array of optically pure fluoroalkylated isoxazolidines were obtained, thus facilitating the asymmetric synthesis of an enantioenriched alpha;-trifluoromethylated gamma;-amino alcohol in gram-scale and a trifluoromethylated derivative of 1,3-oxazinan-2-one with potential pharmaceutical interest. A stereochemical model, based on the absolute configuration of one adduct and some control experiments, was postulated to account for the observed endo- and enantioselectivity.

摘要：在手性Ni （II）/双（恶唑啉）催化剂存在下，2-吡啶基砜和氟烷基化的活性烯烃在各种芳香族和脂肪族硝酮上进行了高效的非对映体选择性的1,3-偶极环加成反应。用4Aring;分子筛、手性双（恶唑啉）配体、反应溶剂和温度对反应过程进行了优化。获得了一系列光谱纯氟烷基化异恶唑烷类化合物，从而促进了一种以克计的对映体富集的alpha;-三氟甲基gamma;-氨基醇和一种具有潜在药用价值的1,3-恶嗪-2-酮的三氟甲基衍生物的不对称合成。基于一个加合物的绝对构型和一些对照实验，建立了一个立体化学模型来解释所观察到的内选择性和对映选择性。

Chiral alpha;-fluoroalkylated gamma;-amino alcohol motifs are widely presented in pharmaceutically active compounds. For example, as shown in Figure 1, trifluoromethylated (CF3) oxazine (I) is a beta;-secretase (BACE1) inhibitor, fluorinated azetidinones (II) are newly developed trinem antibiotics, and efavirenz (III) serves as an inhibitor of HIV. Additionally, compound IV with the same key motif was used as a 19 F NMR label to analyze the structure of membrane-active peptides. Therefore, the discovery of efficient synthetic methodologies to access chiral a-fluoroalkylated g-amino alcohols has attracted great attention to organic chemists. However, to our knowledge, all of the procedures reported so far are uniformly based on diastereoselective reactions.Developing a catalytic asymmetric route to optically pure alpha;- fluoroalkylated gamma;-amino alcohols remains challenging and highly desirable.

手性alpha;-氟烷基化gamma;-氨基醇结构广泛存在于药物活性化合物中。例如，如图1所示，三氟甲基（CF3）恶嗪（I）是一种beta;-分泌酶（BACE1）抑制剂，含氟氮杂环丁酮（II）是新开发的三元抗生素，依非韦仑（III）是一种HIV抑制剂。此外，以具有相同关键结构的化合物IV作为19f NMR标记，分析了膜活性肽的结构。因此，寻找获得手性alpha;-氟烷基化gamma;-氨基醇的有效合成方法引起了有机化学家的极大关注。然而，据我们所知，到目前为止所报道的所有步骤都是基于非对映选择性反应的，开发一种催化不对称合成光学纯alpha;-氟烷基化gamma;-氨基醇的方法仍然具有挑战性，并且是非常值得做的。

From the synthetic point of view, chiral alpha;-fluoroalkylated gamma;-amino alcohols can be transformed from chiral fluoroalkylated isoxazolidines through reduction. The catalytic asymmetric 1,3-dipolar cycloaddition of nitrones and prochiral fluoroalkylated olefins affords ready access to chiral isoxazo- lidines (Scheme 1), which is the key study in this report. Over the past two decades, catalytic asymmetric 1,3-dipolar cyclo- additions with nitrones have witnessed tremendous prog- ress, albeit no application for chiral isoxazolidines and gamma;- amino alcohols bearing a CF 3 -stereogenic center. As a continuous program on the construction of fluorinated hetero- cycles, we herein report unprecedented prochiral fluoroalkylated building blocks and the corresponding asymmetric 1,3-dipolar cycloadditions assisted by a chiral Ni II /(S,S)-Ph-dbfox catalyst (Ph-dbfox=4,6-dibenzofurandiyl-2,2-bis(4- phenyloxazoline)), as well as the synthetic utilities of chiral a-fluoroalkylated g-amino alcohol derivatives.

从综合的角度来看，手性alpha;-氟烷基化gamma;-氨基醇可由手性氟烷基化异恶唑烷经反应转化而来。硝酮和前手性氟烷基化烯烃的催化不对称1，3-偶极环加成反应为手性异恶唑烷类化合物（方案1）的制备提供了方便，这是本报告的关键研究内容。近二十年来，尽管对于以CF3为立体生成中心的手性异恶唑烷gamma;-氨基醇没有得到应用，但硝酮催化不对称1，3-偶极环加成反应却取得了巨大的进展。作为含氟杂环结构的进一步研究，我们在这里报道了前所未有的前手性氟烷基化构建块和相应的在手性Ni II/(S，S)-Ph-dbfox催化剂(Ph-dbfox=4，6-二苯并呋喃二基-2，2-双(4-苯基恶唑啉))辅助下的不对称1，3-偶极环加成反应，以及手性a-氟烷基化g-氨基醇衍生物的合成用途。

Lewis-acid-catalyzed asymmetric nitrone–alkene cycloaddition reactions mainly relied on the bidentate coordination of electron-deficient olefins with various metal ions to control stereoselectivity. Until now, many types of bidentate templates have been reported, such as N-alkenoyl amides, 2- alkenoyl imidazoles, alpha;rsquo;-hydroxy enones, alpha;rsquo;-phosphoric enones, alkenoyl pyridine N-oxides, and alkylidenemalonates. Considering the importance and synthetic versatility of sulfones in organic and medicinal chemistry, we designed and used beta;-fluoroalkylated alpha;,beta;-unsaturated 2-pyridylsulfones 1 as dipolarophiles. The model reaction of substrate 1a andnitrone 2a was undertakenin the presence of 4 c MS in CH 2 Cl 2 at 30℃, and various metal Lewis acids (5 mol%) combined with the chiral ligand L1 ((S,S)-Phdbfox) (5.5 mol%) were screened (Table 1, entries 1–3, and Supporting Information). Ni(ClO 4 ) 2 ·6H 2 O proved to be the best choice in terms of yield and enantioselectivity, producing the desired chiral CF 3 -isoxazolidine 3aa in 97% yield with 98:2 d.r. and 88% ee (Table 1, entry 3). When the temperature was decreased to 0℃, comparable results were obtained (entry 4). Other solvents, such as CHCl 3 and THF, could not improve the enantioselectivity (Supporting Information). Further decreasing the temperature to -20℃ gave rise to higher enantioselectivity, albeit a longer reaction time was required (entry 5). Inferior results were obtained at a lower reaction temperature (-30℃) (entry 6) or by using other chiral bis(oxazoline) ligands (L2, L3, L4; entries 7–9). To our delight, when we prepared the catalyst (L1 and Ni(ClO 4 ) 2 ·6H 2 O) in the presence of 4 Aring; MS for 12 h to remove the crystal water as much as possible, a satisfactory result (96% yield and 95% ee) was achieved in CH 2 Cl 2 at-20℃ (Table 1, entry 10).

Lewis酸催化的不对称硝基-烯烃环加成反应主要依靠缺电子烯烃与各种金属离子的双齿配位来控制立体选择性。到目前为止，已经报道了许多类型的双齿模板，如N-烯基酰胺、2烯基席咪唑、alpha;rsquo;-羟基烯酮、alpha;rsquo;-磷烯酮、烯基吡啶N-氧化物和烷基烯丙酸酯。考虑到砜类化合物在有机化学和药物化学中的重要性和合成的多功能性，我们设计并使用了beta;-氟烷基化alpha;，beta;-不饱和2-吡啶基砜1作为亲偶极子。底物1a和硝基2a在30℃的ch2cl2中在4Aring;分子筛存在下进行模型反应，筛选出与手性配体L1（（S，S）-Phdbfox）（5.5mol%）结合

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