Investigating Asymmetric Catalytic Dihalocyclopropanation

注：在本摘要中，方括号中的脚注仅供非专业科学读者阅读。那些有化学学术背景的人应该忽略它们。2012年是氯仿(CHCl3)与氢氧化钠反应150周年。这个反应是卡宾CCL2的多种来源，它很容易与烯烃进行环丙烷化[a]。不幸的是，尽管60年来的“现代”研究试图“捕获”游离的CCL2(或其近亲CF2和CBr2)，或在合适的手性[b]环境中释放它们，但在前手性烯烃的两个面上选择性手性加成CX2单元[c]方面绝对没有成功。人们普遍认为，这种反应是不可能的，因为与其任何衍生物相比，游离CX2的反应活性非常高。缺乏合适的催化不对称反应是非常令人遗憾的，因为衍生的手性环丙烷通常具有生物活性，这与它们的手性‘形状’密切相关。迫切需要推翻这一既定的教条，找到一种替代方法，在这些反应中不分青红皂白地使用‘CX2’卡宾--通过获得一种根本的新机制来完全避免它们。初级文献中的暗示表明这是一个前进的方向-CX2的直接前体是CX3-阴离子，这些阴离子具有可观的寿命和对某些烯烃的适当反应活性。在适当的催化作用下，这些阴离子加成缺电子烯烃[d]的速度比形成游离态CX2或直接环丙烷化此类烯烃的速度快。我们的研究将集中于设计新的催化循环，其中CX3-或CX2(LeavingGroup)-阴离子与缺电子的烯烃发生共轭加成，导致中间体失去离开的基团间接生成环丙烷[e]。这种方法以前没有被尝试过，用于二卤环丙烷，但文献中有足够的线索表明它是有效的想法。如果这一机制可以转变为一个非常有效的过程，使用合适的手性衍生物，那么有效的不对称二卤环丙烷合成的新途径将成为药物化学的可用途径[f]。[A]卡宾是一个只有2个取代基的碳原子(与正常的4个取代基相反)。环丙烷化是三元环的形成(在这种情况下来自CCL2和CH2=CH2的导数)。[B]手性物体被关联为非超不可能的镜像--你的手就是一个很好的例子。许多药物分子是手性的，两个镜像可以有非常不同的效果，例如乙胺丁醇的一个镜像可以治愈结核病，另一个镜像导致失明。[C]取代的烯烃(例如RCH=CH2)的中心pi(=)键有两个等价的表面。其中一个与CX2的反应产生与另一个相反的镜像；控制这一点非常具有挑战性。[d][c]中的烯烃从中心pi(=)键中移除电子密度。[e]‘离开基团’是分子的一部分，很容易被取代。将CX3-(或实际上，许多其他阴离子)加到缺电子烯烃的末端。[F]药物化学是利用化学来产生对人类健康有益的‘药物’分子。

Note: in this summary the footnotes, shown in square brackets thus [a] etc.., are only for lay scientific readers. Those with an academic chemistry background should ignore them.2012 is the 150th anniversary of the reaction of chloroform (CHCl3) with sodium hydroxide. This reaction is a versatile source of the carbene CCl2, that readily undergoes cyclopropanation with alkenes [a]. Unfortunately, despite 60 years of 'modern' research attempting to 'entrap' free CCl2 (or its cousins CF2 and CBr2), or to release them in suitable chiral [b] environments, absolutely no success has been realised in selective chiral addition of CX2 units to one of the two faces of prochiral alkenes [c]. There is a general belief that such reactions are 'impossible' due to the exceptionally high reactivity of free CX2 compared to any of its derivatives. The lack of a suitable catalytic asymmetric reaction is highly regrettable as the derived chiral cyclopropanes often have biological activity, that is intimately dependent on their chiral 'shape'. There is a pressing need to overturn this established dogma by finding an alternative approach to using indiscriminate 'CX2' carbenes in these reactions - by attaining a fundamental new mechanism that avoids them completely. Hints in the primary literate indicate that this is a way forward - the immediate precursors to 'CX2' are CX3- anions and these have appreciable lifetimes and suitable reactivity to certain alkenes. Under appropriate catalysis these anions add to electron deficient alkenes [d] faster than free CX2 is formed or direct cyclopropanation of such alkenes. Our research will focus on designing new catalytic cycles whereby CX3- or CX2(LeavingGroup)- anions undergo conjugate addition to electron deficient alkenes leading to an intermediate that loses the leaving group generating the cyclopropane indirectly [e]. This approach has not been attempted before, for dihalocyclopropanation, but there are sufficient clues in the literature to show it is valid idea. If this mechanism can be turned into a very efficient process, with suitable chiral derivatives, then new routes for effective asymmetric dihalocyclopropanation will become available to pharmaceutical chemistry [f].[a] A carbene is a carbon atom with only 2 attached substituents (as opposed to the normal 4). Cyclopropanation is the formation of 3-membered rings (in this case from CCl2 and a derivative of CH2=CH2).[b] Chiral objects are related as non super imposable mirror images - your hands are a good example. Many drug molecules are chiral and the two mirror images can have profoundly different effects, e.g. one mirror image of Ethambutol cures TB, the other causes blindness.[c] A substituted alkene (e.g. RCH=CH2) has two equivalent surfaces to its central pi (=) bond. Reaction at one with CX2 generates the opposite mirror image to the other; controlling this is very challenging.[d] An alkene as in [c] were the R group removes electron density from the central pi (=) bond.[e] A 'leaving group' is part of the molecule that can be easily displaced. Addition of CX3- (or indeed, many other anions) to the terminus of an electron deficient alkene.[f] Pharmaceutical chemistry is the use of chemistry to produce 'drug' molecules primerily for human health.