Syntheses of (Chiral) Hetero- and Carbocycles Using Ammonium Enolates

The development of powerful, generally applicable, and highly efficient synthetic transformations is one of the ultimate goals in (organic) chemistry, especially considering the increasing demand for complex molecules with a variety of different functions in our society nowadays (pharmaceutical applications, agrochemicals, material science,..). Amongst the frequently found structural motives, highly functionalized small and medium ring size chiral (hetero)-cycles are of uttermost importance, as they present the key-scaffold in a large variety of biologically active (natural) products. In addition they serve as versatile intermediates in the synthesis of biologically active molecules. Accordingly, novel powerful strategies to access them in an efficient, economic, and direct fashion are an important task, not only for organic chemists working academia, but also for medicinal chemists searching for new lead compounds or for industrial (pharmaceutical) applications. The use of (chiral) ammonium enolates (either preformed or generated in situ by using a catalyst) to carry out demanding stereoselective reactions is a powerful and unique strategy, giving access to transformations that are not possible using any other (catalytic) methods. However, having a closer look at the use of this unique strategy to facilitate (stereoselective) organic reactions it is fair to say that, although impressive (stereoselective) examples have been reported recently, it seems reasonable that this methodology holds much more promise for further investigations and the development of significantly more complex and outstanding applications. Thus, it is the main target of this project to address transformations that will give access to a variety of highly important cyclic structural motives that represent major synthesis challenges, as other commonly employed methods are still not powerful enough. Accordingly, this project will introduce versatile strategies to facilitate the activation und use of easily available starting materials in a unique and unprecedented fashion and thus will provide new powerful methodologies to the standard toolbox employed by chemists to obtain important highly functionalized cyclic compounds straightforwardly.

The development of novel synthesis methods to access chiral carbo- and heterocycles in an efficient and highly selective manner is an important field of research. The primary goal of this project was to introduce new (asymmetric) strategies to access important cyclic structural motives by relying on the use of (in situ formed) ammonium enolates. Hereby we focused on three fundamentally different approaches, the use of so-called Type 1, 2, or 3 ammonium enolates as key-intermediates for asymmetric reactions. These three classes differ in the nature/structure of the employed starting materials, which then upon reaction with a suited (usually amine-based) catalyst give a certain class of highly reactive ammonium enolates. These three classes of ammonium enolates then have quite characteristic and complementary reactivities which we explored in much detail in the context of this project. Hereby especially the use of chiral Type 2 ammonium enolates (also known as ammonium ylides) turned out to be very successful, resulting in several new and highly selective synthesis methods. On the other hand, the work carried out in the other two parts (Type 1 and Type 3 enolates) interestingly opened some new (surprising) pathways, leading into initially unexpected and very promising future research directions. These new observations have been explored further to some extent within this project and will also be followed up in the future. Altogether this project resulted in development of several new synthesis methods and we have also recently been granted a new follow-up FWF stand-alone project on the use of Type 1 ammonium enolates for asymmetric a-functionalization reactions (P 31784).