Chapter 1 provides a rationale for the development of sp3-sp2 Suzuki-Miyaura cross-
coupling (SMCC) methodology. An overview of the reported carbocyclic and
heterocyclic alkyl-boron SMCC reactions is presented and methods to control the
stereochemical pathway of transmetallation are discussed.
In Chapter 2, the synthesis and SMCC of racemic and enantioenriched 2-Bpin
tetrahydrothiophene is described. A highly robust SMCC with 28 racemic examples
(13-84%) and 10 enantioenriched examples (40-72%, 14-99% es) is developed, with
the reactions proceeding predominantly with inversion of configuration.
In Chapter 3, the synthesis and SMCC of a series of 4-boryl N-R pyrrolidones is
detailed. Reaction screening with 4-BF₃K N-PMP pyrrolidone improves the yield from
39% to 50%. A racemic scope of 17 examples (18-80%) is developed alongside a
representative lactam deprotection scope of five examples (56-74%). The
stereochemical pathway is shown to proceed with retention of configuration and an
enantioenriched scope of six examples in high er is exhibited (14-60%, 96:4 to 97:3
er). Finally, the synthesis of (R,R)-Tetflupyrolimet is achieved in six steps with an
overall yield of 21% using the newly developed sp3-sp2 SMCC methodology.
In Chapter 4, the SMCC of 3-BF3K pyrrolidine is optimised using a combination of
Design of Experiments and one-factor at a time screening approaches. The formation
of an inseparable regioisomer is discovered and the cross-coupled products are
consistently isolated as impure mixtures of 3- and 2-aryl pyrrolidines. Although no
method is found to remove the regioisomer, the SMCC yield is rapidly optimised and
a preliminary scope of 10 examples achieved (total yield 27-67%) with varying
regioisomeric ratios.
In Chapter 5, the experimental and characterisation data for chapters 2-4 is presented.
In Chapter 6, the supporting references from in text citations are detailed.
