Abstract
Chapter 1 introduces the concept of chemical space and addresses current challenges in identifying lead compounds. Furthermore, Chapter 1 argues for the adoption of new synthetic approaches aimed at enhancing molecular three-dimensionality, proposing the use of alkene reactivity in aromatic molecules as a viable solution. To this end, dearomatization is proposed as a means to convert planar aromatic compounds into complex three-dimensional small molecules. The Chapter otulines the different synthetic approaches to dearomatization, such as enzymatic, photochemical/thermal, and transition metal-mediated. Lastly, emphasis is given on transition-metal mediated dearomatization reactions, specifically those promoted via dihapto-coordination of electron-deficient aromatic substrates to transition metals.
Chapter 2 looks at different ways to synthesize y-lactams and hydroindolone cores, which can be found in drugs and Lycorine-type natural products. Moreover, it introduces how the technology developed throughout my PhD using electron deficient arenes allows for the synthesis of novel hydroindolone cores (Chapter 4) and novel multicyclic molecules (Chapter 5).
In Chapter 3 A novel process is described for the synthesis of di- and trisubstituted cyclohexenes from an arene. These compounds are prepared from three independent nucleophilic addition reactions to a phenyl sulfone (PhSO2R; R = Me, Ph, and NC4H8) dihapto-coordinated to the tungsten complex {WTp(NO)(PMe3)}(Tp = trispyrazolylborate). The resulting arenium species readily reacts with the first nucleophile to form a dihapto-coordinated sulfonylated diene complex. This complex can again be protonated, and the subsequent nucleophilic addition forms a trisubstituted cyclohexene species bearing a sulfonyl group at an allylic position. Loss of the sulfinate anion forms a π-allyl species, to which a third nucleophile can be added. The trisubstituted cyclohexene can then be oxidatively decomplexed, either before or after substitution of the sulfonyl group. Of the 12 novel functionalized cyclohexenes prepared as examples of this methodology, nine compounds meet five independent criteria for evaluating drug likeliness.
In Chapter 4 a synthetic strategy for functionalized cis-hydro-2-oxindoles is described. This involves the initial coordination of phenyl sulfones to the tungsten fragment WTp(NO)(PMe3), followed by a tandem protonation and addition of an ester nucleophile. The resulting species is then protonated and a primary amine is introduced. Dihydro-2-oxindoles are formed through the construction of -lactam followed by elimination of sulfinic acid to form the η2-diene complex. Finally, cis-hydro-2-oxindoles are obtained via oxidative decomplexation of the tungsten complex. The methodology described offers a modular approach for accessing functionalized cis-hydro-2-oxindole derivatives. The reported approach provides a robust alternative to existing methodologies for the construction of these biologically relevant skeletons.
Chapter 5, the field of dearomatization seeks to leverage the synthetic potential of aromatic molecules through approaches ranging from photoactivation, high pressures, enzymatic protocols, to activation through transition metals. The aim of this study is to develop heteropolycyclic molecules that resemble cores of natural products from a phenylsulfone. In this approach the aromatic ring is dihapto-coordinated to a π-basic tungsten complex, and through a series of additions to the ring carbons, a wide array of chemically diverse polycyclic systems is prepared. These compounds resemble the size, shape and polarity of known biologically active compounds, yet these polycyclic cores are completely unique, having virtually no reported counterparts.
