UC Irvine

This body of work revolves around two themes: palladium-catalyzed construction of new carbon–nitrogen (C–N) bonds in an enantioselective fashion, and the total synthesis of naturally occurring indano[2,1-c] chromans of biological interest. The development of new methods to synthesize complex molecules in an efficient and stereocontrolled manner is an essential goal. Transition metal catalysis has broadened the types of disconnections and connections available to synthetic chemists. Palladium carbene intermediates provide a new point of disconnection that has gained popularity. Not only do palladium carbene intermediates generate new carbon–carbon and carbon–heteroatom bonds, but they do so while providing an avenue for chiral control. Many biologically active compounds, such as RYDAPT®, contain aromatic heterocycles attached to chiral centers through a C–N bond. Methods to generate these types of linkages from achiral fragments with control of stereochemistry are invaluable. This work describes a method to access chiral C–N bonds between achiral α-aryl-α-diazocarbonyl compounds and achiral aromatic heterocycles containing N–H bonds.

Naturally occurring indano[2,1-c]chromans, such as (±)-brazilin, (±)-pestalachloride C, and (±)-pestalachloride D, are of analytical or biological importance. The second part of this work describes the synthesis of these three biologically active indano[2,1-c]chromans. (±)-Brazilin, a highly oxygen sensitive species, has been studied for its pharmacological activity since the discovery of its structural framework. Prior syntheses of (±)-brazilin that have utilized a common strategy: an intramolecular Friedel-Crafts-type acylation of an aromatic ring. The total synthesis described in this work takes advantage of palladium-catalyzed carbene insertion reaction to provide the core structure of (±)-brazilin through a non-obvious bond-disconnection. The carbene insertion approach was less efficient when applied to the synthesis of the highly functionalized indano[2,1-c]chroman core of (±)-pestalachloride C and (±)-pestalachloride D which occur in nature as racemates. These compounds exhibit interesting biological activity because pestalachloride C exhibits teratogenic activity whereas pestalachloride D does not. A biomimetic synthesis of these two compounds was developed which seems to support the Knoevenagel/hetero-Diels–Alder cascade reaction proposed for the biosynthesis. This concise synthesis facilitates construction of chemical analogues with higher potency.