UC San Diego

Atropisomerism is a form of dynamic chirality arising from hindered bond rotation, most typically in a Csp2-Csp2 σ bond, in which the adjacent substitutions contribute energy differences caused by steric strain. While prevalent in many different molecules like natural products and catalysis, atropisomerism has largely been implicated in many important pharmaceuticals in drug discovery. While there has been interest in medicinal chemistry within these last two decades, there are many challenges to creating stable atropisomerism – in which there is significant steric strain to give rise to two isolable enantiomers.1 However, in stabilizing the atropisomeric axis towards these two enantiomers can lead to profound effects on target selectivity. Within the last decade, the Gustafson group at San Diego State University2–4 has since focused on leveraging atropisomerism5,6 to increase selectivity (and later potency) of promiscuous pharmaceutically relevant compounds. Particularly focused on kinase inhibitors, we have shown that curated designs of stable atropisomeric analogues were able to successfully “lock the molecule” in the most bioactive conformation and preorganize the molecules’ atropisomeric axes into preferred dihedral angles which bind to the kinase of interest.One of the major drawbacks to stable atropisomerism is the difficulties attributed to accessing enantiomerically pure samples. Traditional resolution methods like chiral separation (e.g., HPLC or SFC) can be inconducive in time and resources and sometimes impractical for scaffold exploration. For this reason, the Gustafson group began a marital chemistry program towards developing new chemical reactions that expedite access to these atropisomeric compounds. Finding effective atroposelective synthetic methods to obtain pharmaceutically relevant N-heterocyclic scaffolds has been a long-standing challenge in drug discovery. Further elaboration of this work was covered in our seminar reviews. Specific works from these reviews were highlighted in Chapter 17,8 that pertain to the research featured in this dissertation. To address this limitation, we have developed several atroposelective synthetic strategies via nucleophilic substitutions. These are a class of reactions which are among the most widely used in medicinal chemistry towards ethers (i.e., C-O bonds), amines (i.e., C-N bonds), and sulfides (i.e., C-S bonds) towards pharmaceutically relevant N-heterocyclic scaffolds. I and my colleagues developed an atroposelective nucleophilic aromatic substitution (SNAr) strategy which was used in facile access towards pharmaceutically relevant 3-aryl pyrrolopyrimidines (PPYs) and 3-aryl quinolines. A thorough discussion of this atroposelective SNAr research is covered in Chapter 29,10 of this dissertation. Further studies to apply these synthetic strategies has found recent success, wherein post-functionalization after our subsequent atroposelective SNAr methods lead to compounds that have potential to be used for chemical probes, which is briefly discussed in Chapter 3. Furthermore, nucleophilic substitutions outside of SNAr have also been widely used for the synthesis of pharmaceutically relevant compounds. Chapter 4 of this dissertation unveils other types of enantioselective functionalization of various N-heterocyclic scaffolds which sample other unique chemical space, such as enantioselective vicarious nucleophilic substitution (VNS) and atroposelective alkylation by acid-catalyzed directed ‘nucleophilic radicals’ (otherwise known as Minisci chemistry). While the findings shared are preliminary as the current enantioselectivity and yields are not yet optimal, it is quite promising and serves as a strong foundation for future pursuit of these new atroposelective nucleophilic substitution methodologies by the current Gustafson lab. We firmly believe that this research will impact the current need for atroposelective nucleophilic substitution strategies towards pharmaceutically relevant scaffolds in the field of asymmetric catalysis. It is with hope to then springboard new developments in enantioselective reactions towards N-heterocyclic atropisomers relevant to drug discovery. Lastly, we shared that these chemistries furnished enantioenriched pharmaceutically relevant scaffolds in desired yields that would be useful to ongoing medicinal chemistry efforts.