Palladium Catalyzed Alkene Difunctionalization Reactions for the Synthesis of Polycyclic Nitrogen Heterocycles and Functionalized Carbocycles

Abstract

Saturated heterocycles are structures commonly found in pharmaceutically relevant compounds and natural products. From a synthetic perspective, controllable and efficient syntheses of such motifs are highly desirable. Over the past decade, our group has found that Pd-catalyzed alkene difunctionalization reactions are a powerful means to generate valuable heterocycles from simple starting materials. A number of protocols have been reported that detail the synthesis of a variety of heterocyclic motifs that are commonly found in bioactive compounds. Importantly, these transformations proceed with high stereoselectivity and yield. Furthermore, relatively mild reaction conditions are used, and starting materials are readily accessible in few steps. Our continued interest in the development of new alkene difunctionalization reactions to provide synthetic access to motifs which are found in natural products and pharmaceuticals has led to the development of a new cascade Pd-catalyzed alkene carboamination/Diels-Alder reaction. In contrast to the majority of reported alkene difunctionalization reactions that generate 2 new bonds and 1 ring, this reaction generates 4 bonds, 3-5 stereocenters, and 3 rings in a single synthetic operation. Detailed in Chapter 2 are our efforts in the design and optimization of coupling reactions between dienyl halides and amino-alkene substrates that contain two pendant alkenes which undergo consecutive Pd-catalyzed carboamination/[4+2]-cycloaddition reactions to rapidly access polycyclic nitrogen heterocycles in moderate to good yield and up to >20:1 dr. In addition to our interests in the development of new methods for the synthesis of heterocycles, we have recently pointed our efforts towards investigating a new class of alkene difunctionalization reactions which may be used to synthesize high-value carbocyclic building blocks. In stark contrast to the majority of reported alkene difunctionalization protocols which utilize alkenes that are appended to a nucleophile, these reactions utilize exogenous nucleophiles that are completely separate from the alkene and electrophile components of the reaction. This approach led to the design of new substrates which bear an olefin that is appended to the electrophile constituent (i.e. aryl or alkenyl triflate). The implementation of this design strategy has led to asymmetric intermolecular carboamination reactions of aliphatic amines for the synthesis of chiral 2-aminoindane derivatives (Chapter 3), stereocontrolled syntheses of amino-substituted carbocycles (Chapter 4), intermolecular phenol or alcohol carboalkoxylation reactions (Chapter 5), and intermolecular Pd-catalyzed dialkylation reactions of in situ generated enolates (Chapter 6). Overall, these novel transformations should provide a strong foundation for the design of future methodology which utilize external nucleophiles in order to generate valuable functionalized rings in high efficiency and selectivity.