Rhodium-catalysed enantio- and diastereoselective C(sp2)-C(sp3) cross-coupling reactions

Thesis

In this thesis, we describe a series of Rhodium-catalysed enantio- and diastereoselective C(sp2)–C(sp3) cross-coupling reactions and perform brief mechanistic studies in order to understand their underlying mechanisms.

In Chapter 1, cross-coupling reactions are introduced and recent developments in catalytic asymmetric Suzuki–Miyaura type cross-coupling reactions are summarised.

In Chapter 2, a series of asymmetric Rh-catalysed Suzuki–Miyaura type cross-coupling reactions between racemic allyl chlorides and aryl- and alkenylboronic acids are presented. These dynamic kinetic transformations (DYKATs) proceed via the stereoselective formation of pseudomeso Rh-π-allyl complex, followed by enantiodetermining reductive elimination. This allows for the control of multiple stereogenic centres in a single reaction step. Synthetic applicability of this method was demonstrated with a concise synthesis of the prostaglandin analogue Tafluprost.

In Chapter 3, we contribute to the long-standing problem of asymmetric cyclobutane synthesis and present Rh-catalysed cross-coupling reactions between cyclobutenes and arylboronic acids. After an initial asymmetric carbometallation step, the Rh-cyclobutyl intermediates can undergo chain-walking or C–H insertion enabling reductive Heck reactions, 1,5-additions and homoallylic substitution reactions. The synthetic applicability of these highly enantioselective transformations is demonstrated with formal syntheses of the drug candidates Belaperidone and PF-04862853. This work represents the first asymmetric carbometallation of cyclobutenes, which occurs despite a very small release in olefinic strain.

In Chapter 4, an asymmetric hydroacylation of cyclobutenes with salicylaldehydes is presented. Acyl cyclobutanes can be obtained with excellent enantio- and diastereoselectivity. Further, this reaction serves as a proof-of-concept that Rh-catalysed hydrometallation of cyclobutenes is feasible and will likely guide the development of other Rh-catalysed hydrofunctionalisation reactions.

Authors: Goetzke, FW

• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English