Electrophilic Reactiv­ity Provid­ing Well-Defined Helically Chiral Gold(III) Catalysts for the Asymmet­ric Synthe­sis of Bioac­tive Compounds

The aim of the project led by Hector RCD Awardee Agnieszka Nowak-Król (Univer­sity of Würzburg) and Hector Fellow A. Stephen K. Hashmi (Heidel­berg Univer­sity) is to develop well-defined helically chiral gold(III) complexes, the first examples of helically chiral gold complexes with gold atoms on either an outer or an inner helicene rim. These compounds will be derived from axially chiral C^N and N^N chelate ligands by auration to form five- and seven-membered auracy­cles, thereby induc­ing helical frame­works. The catalytic poten­tial of these unprece­dented complexes and their practi­cal utility will be demon­strated in the enantios­e­lec­tive synthe­sis of small organic compounds and biolog­i­cally or pharma­ceu­ti­cally relevant targets, i.e. natural products and pharma­ceu­ti­cally active compounds.

Chiral­ity plays a major role in life science and in drug design. The term chiral­ity is defined as the poten­tial of a molecule to exist in two distinct, non-super­im­pos­able forms that are mirror images of one another, wherein the atomic compo­si­tion, atom-atom connec­tions, and bond orders remain unaltered. Since enzymes and recep­tors in living organ­isms are also chiral, they can inter­act differ­ently with both enantiomers, i.e. stereoiso­mers differ­ing in the config­u­ra­tion of all stere­ogenic elements. Due to a differ­ent spatial arrange­ment of atoms in the molecule, one enantiomer can bind more strongly and with greater speci­ficity to biolog­i­cal targets than the other enantiomer. These specific inter­ac­tions deter­mine the drug’s pharma­co­dy­nam­ics, pharma­co­ki­net­ics, and toxic­ity. Thus, one form may induce a desired thera­peu­tic effect, while the other remain inactive, show lower potency or cause adverse effects.

The achieve­ments in gold catal­y­sis over the last decades have estab­lished its place in organic chemistry. In general, gold catalysts operate efficiently under milder condi­tions than other transi­tion metal catalysts, includ­ing lower temper­a­tures, which can prevent the degra­da­tion of sensi­tive substrates. This is partic­u­larly benefi­cial in pharma­ceu­ti­cal synthe­sis, where maintain­ing the struc­tural integrity is criti­cal. In addition, gold-catalyzed trans­for­ma­tions offer high atom economy and functional group toler­ance, may exhibit orthog­o­nal reactiv­ity compared to other transi­tion metal catalysts.

The objec­tive of this project is the devel­op­ment of a new class of gold(III) complexes derived from helically chiral chelate ligands that will operate as catalysts in gold-mediated asymmet­ric trans­for­ma­tions. The gold will be incor­po­rated into the helical frame­work. Such complexes are to date unprece­dented. The helicene struc­ture will provide a well-defined, rigid chiral environ­ment around the gold(III) center, creat­ing a chiral pocket that can selec­tively inter­act with prochi­ral substrates. We expect that this will allow to achieve high enantios­e­lec­tiv­ity in gold(III)-mediated reactions. In addition, the π‑conjugated scaffold of a ratio­nally designed aurahe­licene can enhance the stere­oselctive inter­ac­tions with a substrate through non-covalent inter­ac­tions, result­ing in high chiral induc­tion. These inter­ac­tions can be further tuned by modify­ing the electronic proper­ties of the helicene through the incor­po­ra­tion of selected hetero­cy­cles into the helical backbone or its selec­tive function­al­iza­tion with electron-accept­ing or electron-donat­ing groups.