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New catalytic strategies for chemical synthesis: Enantioselective Organocatalytic Dearomatization – From flat molecules to complex 3-D architectures in a single step

Final Report Summary - 3DSSS (New catalytic strategies for chemical synthesis: Enantioselective Organocatalytic Dearomatization - From flat molecules to complex 3-D architectures in a single step.)

Despite the changing face of organic chemistry one aspect remains persistent: the ability to make molecules is something that, even now, is still unique to the synthetic chemist. What is changing in synthesis is the way that we go about achieving our goal. The use of catalysts to control the synthesis of architecturally complex and enantiopure molecules is a key aspect for the future of organic chemistry. Not only does this concept impact strongly on all aspects of chemical synthesis but also the continued development of chemical biology, medicinal chemistry and materials science. The challenge for the synthetic chemist is to develop novel strategies for complex molecule synthesis that combine the factors of atom economy, catalysis and stereocontrol.
The continually increasing challenges associated with the treatment of new and existing diseases often demands that potential therapeutics contain higher levels of molecular complexity in order to achieve potency, selectivity and desirable physical properties. Of particular relevance is the emergence of drug candidates with one or more non-racemic asymmetric centres. Single enantiomer compounds, whether they be natural products or therapeutic agents, are however significantly more difficult to synthesize. Although conventional asymmetric synthesis has coped for many years, new enantioselective methods are now required to meet these challenges that are robust, efficient and generally applicable in a range of environments. The rapid generation of molecular complexity through asymmetric catalytic methods has become a key factor in the chemical synthesis of natural products and molecules of biological and medicinal relevance. While enantioselective catalytic methods have unlocked access to a plethora of non-racemic small molecules the formation of more complex architectures is not always straightforward. Chemists have often strived to mimic Nature’s elegant synthesis machinery in achieving this goal but it is an ideal that is rarely achieved. Of particular note are the recent developments of catalyst controlled cascade reactions that have led to a significant advance in this field, however, the molecules that are accessible from such strategies are often small, ‘building block’ type molecules that still require much synthetic endeavour to reach the desired target.
In complex natural product synthesis, phenol ring has been widely used over the years. The richness of the chemistry of phenols is quite remarkable when one realized that it is simply the presence of a hydroxy group on a benzene ring that renders this otherwise quasi-inert aromatic system amenable to many chemical transformations. The relatively weak bond dissociation energy of their O-H bond opens the door to radical reactions via one-electron dehydrogenative oxidation. Then, it is converted into delocalized phenoxy radicals, which notably underlie the (bio)synthetic implications of various phenolic precursors in the structural elaboration of numerous complex natural products, 11 including biopolymers such as lignins. An important asset of a dearomatization of phenols for organic synthesis resides in the fact that one of the sp2 -hybridized carbon centers of a planar achiral starting material is thus transformed into a sp3 -hybridized carbon center and, hence possibly chiral (Scheme 1). If this new created chirality can be enantio- or diastereoselectively controlled, it then offers tremendous opportunities for inducing asymmetry in subsequent reactions.