Medicinal Chemistry Based on the Rational Design of the Chemical Reactions

碳氟键的选择性构建是药物化学家的一大兴趣，因为氟原子取代生物活性分子中的氢原子和氧原子可以赋予分子改善的物理化学性质和生物活性。自从首次发现N-氟樟脑磺内酰胺的对映选择性手性拆分以来，我们的合成兴趣一直集中在开发具有对映选择性拆分能力的手性N-氟磺酰胺衍生物上。然而，这些最初的努力揭示了氟化产物的化学产率和对映选择性的几个限制。本论文发展了新型的对映选择性取代反应，并将其应用于具有生物活性的天然产物的氟电子等排体的设计与合成。两种新的方法使用金鸡纳生物碱/Selectfluor[○！R]组合和双（恶唑啉）-Ph分别进行了研究。金鸡纳生物碱/Selectfluor[○！R]组合，即，金鸡纳生物碱的N-氟铵盐被发现是一种有效的对映选择性氟化试剂，用于广泛的底物，如甲硅烷基烯醇醚、β-酮酯、芳基氰基酯和羟吲哚，而不需要任何添加剂。在催化量的金属盐存在下，双（恶唑啉）-Ph被发现是一种有效的和独特的催化剂，用于对映体选择性的手性拆分。在β-酮酸酯的加成反应中观察到一个有趣的现象，即“选择性”对映选择性。在相同的双（恶唑啉）-Ph的存在下，将金属催化剂从铜切换为镍，得到了完全逆转的对映选择性。

The selective construction of carbon-fluorine bonds is of great interest to medicinal chemists because the replacement of hydrogen and oxygen atoms with fluorine atom in biologically active molecules can confer molecules with improved physicochemical properties and biological activities. Since the first discovery of enantioselective fluorination using N-fluorocamphorsultam, our synthetic interests have been focused on the development of chiral N-fluorosulfonamide derivatives capable of enantioselective fluorination. However, these initial efforts revealed several limitations in both chemical yields and enantioselectivities of the fluorinated products. We developed the novel enantioselective fluorination reactions and applied of the methods to the design and synthesis of fluoroisosteres of biologically active natural products. Two novel approaches using the cinchona alkaloids/Selectfluor【○!R】 combination and bis(oxazoline)-Ph have been pursued respectively. Cinchona alkaloid/Selectfluor【○!R】 combination, i.e., N-fluoroammonium salts of cinchona alkaloids, was found to be an effective enantioselective fluorinating reagent for a wide range of substrates such as silyl enol ethers, beta-keto esters, arylcyanoesters, and oxindoles without any additives. The bis(oxazoline)-Ph was found to be an efficient and unique catalyst for enantioselective fluorination in the presence of a catalytic amount of metal salts. An interesting phenomenon, "elective" enantioselectivity, has been observed in the fluorination of beta-keto esters. Switching the metal catalyst from copper to nickel in the presence of the same bis(oxazoline)-Ph gave a complete reversal of enantioselectivity.