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Title: Isothiourea-promoted O- to C-carboxyl transfer reactions
Author: Joannesse, Caroline
ISNI:       0000 0004 2722 467X
Awarding Body: University of St Andrews
Current Institution: University of St Andrews
Date of Award: 2011
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This thesis describes an extensive investigation of the O- to C-carboxyl transfer of oxazolyl carbonates using isothioureas as Lewis base catalysts. The structural requirements of simple bicyclic amidines and isothioureas to promote this transformation have been investigated, showing that the catalytic efficiency and product distribution of these reactions are markedly affected by the catalyst structure. The optimal isothiourea catalyst was efficiently applied to the rearrangement of a wide range of oxazolyl, benzofuranyl and indolyl carbonates. The structural motif of tetrahydropyrimidine-based isothioureas has then been evaluated in order to develop an asymmetric variant of the O- to C-carboxyl transfer of oxazolyl carbonates. A number of chiral isothioureas bearing stereodirecting groups in C(2) and/or C(3) have been synthesised and used in this rearrangement, showing that a C(2)-stereodirecting unit is essential for high enantioselectivity, with an additional C(3)-substituent increasing the reactivity. The optimal chiral C(2)-substituted isothioureas identified are general and efficient asymmetric catalysts for O- to C-carboxyl transfer of oxazolyl carbonates, generating a quaternary stereocentre with high enantioselectivity (up to 94% ee). The origin of the enantioselectivity of this process has been probed mechanistically and rationalised computationally. Having gained an insight into the structural motifs of isothioureas required to impart good catalytic activity and asymmetric induction in the O- to C-carboxyl transfer of oxazolyl carbonates, the mechanism of this reaction was probed using kinetic and mechanistic experiments. ¹⁹F NMR spectroscopic analysis allowed the evolution of product, by-product and intermediate throughout the reaction to be monitored while a number of crossover and stability experiments gave additional information about the catalytic cycle. Extension to a related system has been demonstrated with the O- to C-carboxyl transfer of furanyl carbonates, producing a mixture of α- and γ-butenolides depending on the nature of the Lewis base employed. DMAP gives a mixture of both regioisomers with a preference for the α-regioisomer, while NHCs lead predominantly to the γ-regioisomer. Chiral isothioureas have been used to promote this rearrangement, giving the major α-regioisomer with good enantioselectivity (up to 83% ee). To quantify the different reactivities observed with these isothioureas, their nucleophilicities and Lewis basicities using the stopped-flow technique have been determined. Finally, model studies toward the synthesis of the natural product calcaridine A, using the methodology developed herein, have been investigated.
Supervisor: Smith, Andrew D. Sponsor: EPSRC
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Organocatalysis ; Isothiourea ; Asymmetric catalysis ; Steglich rearrangement