Tietze Lutz F, Kinzel Tom, Brazel C Christian
Institut für Organische und Biomolekulare Chemie der Georg-August-Universität Göttingen, Germany.
Acc Chem Res. 2009 Feb 17;42(2):367-78. doi: 10.1021/ar800170y.
Stereoselective allylations of carbonyl compounds such as aldehydes and ketones are useful but challenging reactions in organic chemistry. The resulting chiral secondary and tertiary homoallylic alcohols or ethers are valuable building blocks in the synthesis of biologically active natural compounds and pharmaceuticals. Although researchers have developed several methods for the facially selective allylation of aldehydes, the stereoselective allylation of ketones still poses a severe problem. We have developed a highly diastereoselective domino multicomponent allylation reaction of a ketone and allyltrimethyl silane using the trimethylsilyl ether of a norpseudoephedrine or mandelic acid derivative as an auxiliary with a diastereoselectivity of up to 98:2. The reaction is performed at -78 degrees C in the presence of a catalytic amount of trifluoromethanesulfonic acid and leads to the corresponding tertiary ethers. The procedure can also be used for the allylation of aliphatic aldehydes with a diastereomeric ratio >99:1. Ketones give the 4,1'-syn product while the aldehydes give the reversed selectivity to yield a 4,1'-anti product. In addition, the reaction of gamma-substituted allyl silanes with ketones yields a product with two stereogenic centers and an anti diastereoselectivity of >99:1. The homoallylic ethers formed in the domino multicomponent process can be used in further synthetic transformations: the auxiliary can serve as a protecting group or can be cleaved reductively to give the corresponding homoallylic alcohols. Based on a number of both experimental and theoretical studies of the reaction mechanism, we conclude that an intermediate oxocarbenium ion is formed in the reaction of ketones. The oxocarbenium ion is attacked by the allyl silane during the stereogenic step. Using density functional theory methods, we could trace the observed stereoselectivity phenomena back to open transition states (TSs) where there is no interaction between the silane's trimethylsilyl group and the former carbonyl oxygen. On the contrary, the reaction with aldehydes forms an intermediate oxazolidinium salt, which explains the opposite selectivity. We have used the new allylation procedure in several total syntheses of natural products such as vitamin E, (+)-hydroxymyoporone, 5,6-dihydrocineromycin B, and polyoxygenated cembrenes.
醛和酮等羰基化合物的立体选择性烯丙基化反应在有机化学中是有用但具有挑战性的反应。所得的手性仲和叔高烯丙醇或醚是合成生物活性天然化合物和药物的重要结构单元。尽管研究人员已经开发出几种醛的面选择性烯丙基化方法，但酮的立体选择性烯丙基化仍然是一个严峻的问题。我们开发了一种使用去甲伪麻黄碱或扁桃酸衍生物的三甲基硅醚作为助剂，使酮与烯丙基三甲基硅烷发生高度非对映选择性多米诺多组分烯丙基化反应，非对映选择性高达98:2。该反应在-78℃下，在催化量的三氟甲磺酸存在下进行，生成相应的叔醚。该方法也可用于脂肪醛的烯丙基化反应，非对映体比例>99:1。酮生成4,1'-顺式产物，而醛则产生相反的选择性，生成4,1'-反式产物。此外，γ-取代的烯丙基硅烷与酮的反应生成具有两个立体中心的产物，非对映选择性>99:1。在多米诺多组分过程中形成的高烯丙基醚可用于进一步的合成转化：助剂可作为保护基团，或可通过还原裂解得到相应的高烯丙醇。基于对反应机理的大量实验和理论研究，我们得出结论，酮的反应中形成了中间体氧鎓离子。在立体化学步骤中，烯丙基硅烷进攻氧鎓离子。使用密度泛函理论方法，我们可以将观察到的立体选择性现象追溯到开放过渡态（TSs），在该状态下硅烷的三甲基硅基与前羰基氧之间没有相互作用。相反，与醛的反应形成中间体恶唑烷鎓盐，这解释了相反的选择性。我们已经在天然产物如维生素E、(+)-羟基肌醇酮、5,6-二氢西内霉素B和多氧化松节烯的几个全合成中使用了新的烯丙基化方法。
