UC Berkeley

This dissertation describes the application of molecular complexity analysis to the synthesis of Daphniphyllum alkaloids and strained bicyclic scaffolds. Chapter 1 outlines foundational work in molecular complexity quantification, its application to retrosynthetic analysis and natural product total synthesis, and the development of MolComplex, a python package for automating complexity analysis in the context of retrosynthesis planning. Chapter 2 reviews the historical, biosynthetic, and synthetic background of the Daphniphyllum alkaloids. This Chapter introduces the calyciphylline A-type alkaloids, their structural variations, and outlines the previous synthetic approaches to himalensine A and daphenylline.

In Chapter 3, a synthetic approach to himalensine A based on a key transannular disconnection is described. Beginning with the complexity analysis, transannular disconnections are identified to be maximally simplifying for polycyclic skeletons despite the synthetic challenge of macrocyclic intermediates. A series of targeted macrocyclic intermediates containing various degrees of unsaturation were pursued. Next, a saturated macrocyclic intermediate was successfully prepared by Mitsunobu alkylation, and a series of 1,2- and 1,4-oxidation strategies were explored for promoting the desired transannulation over undesired transannular pathways.

Chapter 4 discusses the counterintuitive aspects of “excess complexity” and its relevance for the efficient total synthesis of daphenylline through bond cleavage strategies. Dearomative entry into this calyciphylline A-type alkaloid was achieved by pyridinium dearomatization followed by a Buchner cycloaddition/C–C cleavage sequence to form the pentacyclic core. Challenges associated with installation of the quaternary methyl group are extensively described. This led to the development of a thia-Paternò-Büchi [2+2] photocycloaddition, followed by a thietane reduction sequence, to install the requisite methyl group. The total synthesis of daphenylline was ultimately completed in 11 steps in racemic fashion, which was then rendered formally enantioselective by a Rh-catalyzed pyridone conjugate addition.

Finally, Chapter 5 describes the application of bond cleavage tactics to performing a “scaffold hop” between aza-bicyclo[2.1.1]hexanes and bicyclo[1.1.1]pentanes, two strained bicyclic scaffolds relevant to medicinal chemistry. The photochemical preparation of aza- bicyclo[2.1.1]hexanes, followed by deaminative C–C bond formation, provides access to bridge- substituted bicyclo[1.1.1]pentanes, which might serve as bioisosteres for ortho- or meta- substituted arenes. The application of this skeletal editing strategy to a host of heteroarene- containing, bridge-substituted scaffolds is described.