The Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OXI 3TA, UK.
Future Med Chem. 2009 Aug;1(5):847-63. doi: 10.4155/fmc.09.47.
Fluorinated organic compounds constitute a significant proportion of medicines marketed today. Since heterocycles are submotifs frequently encountered in lead compounds, the corresponding fluorinated molecules that possess coupling functional groups to increase structural complexity are sought-after building blocks, especially those with stereogenic elements. To access fluoro-heterocycles, fluorocyclizations constitute an important category of reactions that permit multiple bond construction in one pot. Reactions featuring both nucleophilic and electrophilic sources of fluorine have proved valuable for the delivery of fluorinated carbo- and heterocycles. Mechanistically, two scenarios have been validated with the fluorination occurring either prior to or after the cyclization event. Fluorinated biologically active molecules prepared by employing a fluorocyclization protocol are rare, with two notable exceptions being the synthesis of fluorogypsetin and fluorobrevianamide E. Various levels of diastereocontrol were obtained with best results observed when the cyclization step precedes the fluorination. To date, asymmetric fluorocyclizations have not been explored, with the exception of a Nazarov fluorination process. In essence, this process features a catalytic asymmetric cyclization followed by a diastereoselective fluorination. Asymmetric fluoroheterocyclizations are, however, not known. For this methodology to serve medicinal chemistry, conceptual advances are essential to access fluorinated pharmacophores with programmable stereocontrol as and when necessary.
含氟有机化合物构成了当今市场上销售的药物的重要组成部分。由于杂环是先导化合物中经常遇到的子基元，因此具有增加结构复杂性的偶联官能团的相应氟化分子是备受追捧的构建块，特别是那些具有手性元素的构建块。为了获得氟代杂环化合物，氟环化反应是一种重要的反应类别，可以在一锅反应中构建多个键。具有亲核和亲电氟源的反应已被证明对提供氟化碳和杂环化合物非常有价值。从机理上讲，已经验证了两种情况，即氟代反应发生在环化反应之前或之后。通过采用氟环化方案制备的具有生物活性的氟化分子很少，只有两个例外，即氟代 gypsetin 和氟代 brevianamide E 的合成。通过环化步骤先于氟代反应，可以获得不同程度的非对映选择性控制，观察到最佳结果。迄今为止，除了 Nazarov 氟环化反应外，尚未探索不对称氟环化反应。该过程的本质是催化不对称环化，然后是立体选择性氟代反应。然而，不对称氟杂环化反应是未知的。为了使该方法服务于药物化学，需要概念上的进步，以便在需要时以可编程的立体控制方式获得氟化药效团。
