Synthesis of acyl cyclohexenes via an aluminium mediated 1,5-hydride shift–aldol cascade

Thesis

Cyclohexenes and their derivatives are important intermediates in the preparation of natural products and medically relevant compounds. Many methodologies have been reported for the synthesis of such materials, including Diels–Alder cycloaddition, ring-closing metathesis and catalytic cyclotrimerisation. Recently, the Donohoe group has developed a new approach to the synthesis of cyclohexenes from readily accessible pyrans. This method employs inexpensive aluminium reagents to promote a 1,5-hydride shift–aldol cascade. By combining Horner– Wadsworth–Emmons (HWE) olefination with the aluminium-mediated 1,5-hydride shift developed, it was possible to selectively functionalise three of the five positions around the acyl cyclohexene core (Scheme I)

In this thesis, alternative strategies, including cross metathesis and cuprate addition were developed in Chapter 2 to construct the intermediate tetrahydropyrans, thereby enabling functionalisation of all five positions around the acyl cyclohexene framework (Scheme II). To gain insight into the reaction mechanism of the aluminium-catalysed 1,5-hydride shift, detailed computational studies supported by experimental validation were conducted in Chapter 3 to identify the nature of the active catalytic species and to determine the corresponding reaction pathway.

An asymmetric variant of the 1,5-hydride shift–aldol cascade was developed in Chapter 4, allowing the synthesis of enantioenriched cyclohexenes from racemic tetrahydropyran substrates in the presence of a chiral BINOL-derived ligand (Scheme III). Future directions include the single-step removal of the Ph* protecting group to afford a variety of carboxylic acid derivatives and the application of this transformation in natural product synthesis.

Authors: Hou, J

• DOI: 10.5287/ora-kzxdq0gpo
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: hydride shift
• Subjects: Chemistry, Organic