The nucleophilic addition of organomagnesium/lithium reagents to aldehydes and ketones has long enabled the synthesis of valuable alcohol derivatives; however, these types of transformations are often plagued by poor functional group tolerance and require harsh reaction conditions. The direct coupling of carbonyls and alcohols with aryl halides is an appealing alternative to access secondary alcohol products. However, this necessitates a formal C-H bond activation which is not well established in the literature. Chapter 1 provides a detailed literature background of the transition metal-catalyzed functionalization of carbonyls and alcohols. The work discussed in Chapter 2 of this thesis demonstrates the addition of aryl halides to aryl and aliphatic aldehydes and alcohols providing secondary alcohol products in moderate to high yields. Key to the success of this transformation was the implementation of underexplored and readily synthesized 1,5-diaza-3,7-diphosphacyclooctane (P2N2) ligands. Chapter 3 extends the methodology established in chapter 2 and aims to get a preliminary understanding of the application and mechanism of the reaction described above. For this purpose, pharmaceutically relevant isatin substrates are derivatized, providing access to substitution at the 3-position. Coupling isatins with aryl halides yields 3-aryl-3-hydroxy-2-oxindole products which are scaffolds for many natural product derivatives. Through high-throughput experimentation (HTE), we were able to discover that 1,2-addition at the carbonyl position of isatins is highly compatible with our established system and led us to develop a modest scope as well as gain useful mechanistic insights for this coupling.

This thesis is divided into six parts, all centered around the development of dynamic (i.e., reversibly interacting) systems of molecules and their applications in dynamic combinatorial chemistry (DCC) and organic synthesis. Part one offers a general introduction, as well as a more detailed description of DCC, being the central concept of this thesis. Part two explores the potential of the nitroaldol reaction as a tool for constructing dynamic systems, employing benzaldehyde derivatives and nitroalkanes. This reaction is then applied in part three where a dynamic nitroaldol system is resolved by lipase-catalyzed transacylation, selecting two out of 16 components. In part four, reaction and crystallization driven DCC protocols are developed and demonstrated. The discovery of unexpected crystalline properties of certain pyridine β-nitroalcohols is used to resolve a dynamic system and further expanded into asynthetic procedure. Furthermore, a previously unexplored tandem nitroaldol-iminolactone rearrangement reaction between 2-cyanobenzaldehyde and primarynitroalkanes is used for the resolution of dynamic systems. It is also coupled with diastereoselective crystallization to demonstrate the possibility to combine several selection processes. The mechanism of this reaction is investigated and a synthetic protocol is developed for asymmetric synthesis of 3-substituted isoindolinones. Part five continues the exploration of tandem reactions by combining dynamic hemithioacetal or cyanohydrin formation with intramolecular cyclization to synthesize a wide range of 3-functionalized phthalides. Finally, part six deals with the construction of a laboratory experiment to facilitate the introduction of DCC in undergraduate chemistry education. The experiment is based on previous work in our group and features an acetylcholinesterase-catalyzed resolution of a dynamic transthioacylation system. / QC 20100628