Design and Synthesis of 3-D Building Blocks for Medicinal Chemistry

This thesis describes the design and synthesis of two 3-D building blocks for potential use in medicinal chemistry. The design and synthesis of normorphan-derived 3-D building block A and morphan-derived 3-D building block B is outlined. Further functionalisation of the normorphan-derived 3-D building block into lead-like compounds is also presented.

Section 2.1 describes the design consideration, vector analysis and proposed route for the synthesis of normorphan-derived 3-D building block A. Section 2.2 presents the racemic synthesis of normorphan-derived building block A which was achieved with a 30% overall yield on a multi-gram scale via a seven-step sequence. Section 2.3 describes the investigation of routes for the synthesis of enantioenriched normorphan-derived 3-D building block A by asymmetric cyclisation and diastereomeric resolution approaches.

The design, vector analysis and proposed route for morphan-derived 3-D building block B are presented in Section 3.1. Initial approaches for the synthesis of morphan-derived building block B using sulfonamide protecting groups are presented in Section 3.2. Further approaches for the synthesis of morphan-derived building block B using an N-Boc protecting group are then outlined in Section 3.3. However, unfortunately, both these routes were ultimately unsuccessful in providing the desired 3-D building block B.

Finally, Chapter 4 showcases the functionalisation potential of normorphan-derived building block A for the synthesis of medicinally-relevant lead-like compounds. Section 4.1 presents the Suzuki-Miyaura arylation of 3-D building block A with a variety of aryl bromides while Section 4.2 shows further functionalisation of the building block into compounds such as normorphan lactams C and D and amine-based scaffold E.