Isothiourea-mediated acylative kinetic resolution of heterocyclic and acyclic tertiary alcohols
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This thesis describes the isothiourea-catalyzed acylative kinetic resolution (KR) of heterocyclic and acyclic tertiary alcohols. The protocols developed for the resolution of these challenging substrates provide access to biologically-relevant small molecules in highly enantioenriched form. Chapter 2 describes the acylative KR of a range of 3-hydroxy-3-substituted oxindole substrates, bearing up to three potential recognition motifs at the stereogenic tertiary carbinol centre. Experimental and computational studies have identified a C=O•••isothiouronium interaction as the key stabilizing interaction for efficient enantiodiscrimination. This interaction was exploited in reactions using the isothiourea catalyst, (2S,3R)-HyperBTM, generally at low catalyst loadings (1 mol %) and isobutyric or acetic anhydride as acylating agent, enabling s values of up to > 200 (30 examples). Chapter 3 focuses on extending the KR protocol to 3-hydroxypyrrolidinone substrates, which do not possess the benzannulation present in the core structure of the substrates resolved in Chapter 2. Re-optimization of the previous KR conditions found (2S,3R)-HyperBTM (2 mol %) as catalyst, acetic anhydride (0.7 equiv.) as acylating agent, in toluene at 0 °C as optimal, enabling s values of up to > 200 to be obtained (27 examples). Variation of the substitution patterns and electronic nature of the pyrrolidinone substrates were investigated, including extension of the protocol for the KR of α-hydroxy-β- and δ-lactam derivatives. Chapter 4 investigates the complete removal of the cyclic structure of the substrate through the KR of a range of acyclic tertiary alcohols. No acylation was observed for acyclic α-hydroxy amides, and poor reactivity and selectivity was observed for α-hydroxy ketones and α-hydroxy phosphonates. However, acylation is readily achieved when using α-hydroxy esters, and this chapter focuses on the KR of these substrates. Optimization studies found (2S,3R)-HyperBTM (5 mol %) as catalyst, isobutyric anhydride (2.0 equiv.) as acylating agent in diethyl ether at rt as optimal, enabling s values of up to 140 (21 examples). The protocol is currently limited to the KR of α-hydroxy esters bearing an aromatic substituent and a methyl group at the carbinol stereocentre, with alkyl substituents larger than methyl leading to either low conversion or selectivity.
Thesis, PhD Doctor of Philosophy
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Description of related resourcesData underpinning Samuel Smith's thesis (Title and description redacted), Smith, S.M., University of St Andrews, DOI: https://doi.org/10.17630/e1e170df-9006-4348-bc1e-1c57a3c032be
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