Development of novel enantioselective transition metal-catalysed 1,4- and 1,6-additions
Roy, Iain David
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1. ENANTIOSELECTIVE RHODIUM-CATALYSED 1,4-ARYLATION OF ALKENYLAZAARENES An extended study on the enantioselective rhodium-catalysed 1,4-arylation of alkenylazaarenes has been conducted. The 1,4-arylation of various alkenylazaarenes was performed with an extended range of arylboronic acids using a modified catalytic system with a superior chiral diene ligand. The result is the generation of a large number of b-stereocentre-containing azaarene compounds in high enantiopurity. Further studies also enabled the completion of a reactivity index between alkenylazaarenes and more traditional α,β-unsaturated carbonyl compounds and the incorporation of the arylation into arylation-aldol domino processes. 2. ENANTIOSELECTIVE RHODIUM-CATALYSED 1,4-ALKENYLATION OF ALKENYLAZAARENES An extensive study on the enantioselective rhodium-catalysed 1,4-alkenylation of alkenylazaarenes has been performed. Development of the reaction parameters identified novel heterogeneous reaction conditions in pure water with sub-stoichiometric SDS. Subsequent ligand development identified an anilide-based chiral diene that provided the best balance between conversion and enantiopurity. Using the novel conditions, a selection of alkenylazaarenes underwent enantioselective rhodium-catalysed 1,4-alkenylation with two alkenyl MIDA boronates to provide the alkenylation products in good to excellent yields and moderate to excellent enantioselectivities. 3. ENANTIOSELECTIVE COPPER-CATALYSED 1,6-BORATION OF ELECTRON-DEFICIENT DIENES The development of an enantioselective copper-catalysed 1,6-boration of electrondeficient dienes using B2(pin)2 has been achieved. The reactions provide chiral allylboronic esters that, after oxidation, result in secondary allylic alcohols in moderate to high yields with excellent enantioselectivities and 1,6:1,4-regioselectivities. The 1,6-borations proceed efficiently employing catalyst loadings as low as 0.0049 mol% and their scalability has been demonstrated up to 40.4 mmol. The methodology was applied to a concise synthesis of atorvastatin, in which the key 1,6-boration was performed using a catalyst loading of 0.02 mol%.