Medicinal Chemistry Based on the Rational Design of the Chemical Reactions

碳氟键的选择性构建引起了药物化学家的极大兴趣，因为用生物活性分子中的氟原子取代氢和氧原子可以使分子具有更好的物理化学性质和生物活性。自从首次发现使用n -氟莰磺坦的对映选择性氟化以来，我们的合成兴趣一直集中在开发能够对映选择性氟化的手性n -氟磺酰胺衍生物上。然而，这些初步努力表明，在化学产量和氟化产物的对映选择性方面存在一些局限性。我们开发了新的对映选择性氟化反应，并将其应用于设计和合成具有生物活性的天然产物氟异构体。金鸡纳生物碱的两种新方法R】组合和双（恶唑啉）-Ph分别进行了研究。金鸡纳生物碱/精选氟【〇！R】组合，即金鸡纳生物碱的n -氟铵盐，是一种有效的对映选择性氟化试剂，可在不添加任何添加剂的情况下，对硅烯醇醚、-酮酯、芳基氰酸酯和吲哚等多种底物进行氟化。发现双（恶唑啉）-Ph在金属盐的催化量存在下是一种有效而独特的对映选择性氟化催化剂。在-酮酯的氟化反应中观察到一个有趣的现象，即“选择性”对映体选择性。在相同的双（恶唑啉）ph下，将金属催化剂从铜换成镍，完全逆转了对映体选择性。

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.