Medicinal Chemistry Based on the Rational Design of the Chemical Reactions

碳-氟键的选择性构筑引起了药物化学家的极大兴趣，因为在生物活性分子中用氟原子取代氢原子和氧原子可以赋予分子更好的物理化学性质和生物活性。自从N-氟苯磺酰胺对映体选择性氟化首次被发现以来，我们的合成兴趣一直集中在开发能够进行对映体选择性氟化的手性N-氟磺酰胺衍生物上。然而，这些初步的努力揭示了氟化产品在化学产率和对映体选择性方面的一些局限性。我们开发了新的对映体选择性氟化反应，并将其应用于生物活性天然产物的氟同位素的设计和合成。分别采用金鸡纳生物碱/选择氟[0！R]组合和双恶唑啉-Ph进行了两种新方法的研究。金鸡纳生物碱/选择氟[0！R]的组合，即金鸡纳生物碱的N-氟铵盐，被发现是一种有效的对硅烯醇醚、β-酮酯、芳基氰酸酯和氧吲哚等底物的不对称氟化试剂，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是一种高效、独特的对映体选择性氟化催化剂。在β-酮酯的氟化反应中观察到了一个有趣的现象，即“选择性”对映体选择性。在相同的双恶唑啉-Ph存在下，将金属催化剂从铜切换到镍，完全逆转了对映体的选择性。

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.