Dynamic Covalent Resolution: Applications in System Screening and Asymmetric Synthesis

University dissertation from Stockholm : KTH

Abstract: Combined thermodynamic/kinetic events amount to a kinetically controlled Dynamic Combinatorial Resolution (DCR) process, where the lability of themolecules/aggregates are used to generate dynamics, and the species experiencing the lowest activation energy is selected via kinetic process. Bothinter- and intramolecular processes can be performed using this concept,resulting in complete resolution and associated amplification of the selected species. When intermolecular processes are resolved using this method, an additional advantage is that only a catalytic amount of selector is required tocontrol the system.In this thesis, the Henry and Strecker reactions were developed as efficient C–C bond-forming routes to single and multi-level dynamic covalent systems.These methods efficiently provided a vast variety of substrates from smallnumbers of starting compounds. These dynamic systems, generated underthermodynamic control at mild conditions, were coupled in one-pot processes with kinetically controlled lipase-mediated transacylation. The enzym emediated resolution of the dynamic nitroaldol system led to enantiomericallypure ?-nitroacetates in high yield. Furthermore, combination of multi-leveldynamic Strecker systems and lipase-mediated acylation resulted in theresolution of specific ?-aminonitriles from the pool.In addition, the asymmetric synthesis of discrete ?-nitroalkanol derivatives wassimply achieved, resulting in high yields and high enantiomeric purities through the direct one-pot procedure. Moreover, racemase type activity oflipase enzyme through N-substituted ?-aminonitrile structure has been discovered. By use of control experiments together with molecular modeling,the mechanism of the racemization process has been established. Asymmetric synthesis of N-methyl ?-aminonitriles was also performed through the dualfunction of lipase, resulting in high yield and good enantio selectivity.