Development of Phosphonium Anhydrides for the Synthesis of Heterocycles; Synthesis of Potential Inhibitors of Glycogen Phosphorylase
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The use of several phosphonium anhydride reagents for the synthesis of a range of heterocyclic compounds has been investigated. The structure of a polymer-supported version of the Hendrickson ‘POP’ reagent, prepared by the reaction of polymer-supported triphenylphosphine oxide (57) with triflic anhydride, was established as an equilibrium mixture of polymer-supported triphenylphosphine ditriflate 54 (δ 79.4 ppm) and polymer-supported phosphonium anhydride 76 (δ 73.3 ppm). The 31P NMR chemical shift reported previously for 54 was shown to be incorrect. β-Hydroxy amides 96 and 103 were treated with triphenylphosphonium anhydride trifluoromethane sulfonate (38) or the cyclic analogue 53 to generate 2-oxazolines 92 and 104 under mild conditions. The reaction was optimised by examining the number of equivalents of reagents 38, 53, or diisopropylethyl amine required to effect cyclisation. The effects of altering the reaction temperature, reaction time, concentration, solvent, and addition rate were also investigated. Use of trityl β- hydroxy amide 114 led to a significantly improved yield of 2-oxazoline 92 (94%). Reagent 53 offered significant advantages in purification of products and was used to dehydrate a range of trityl amides to form simple oxazolines (92, 100, 104 and 125), thiazolines (113 and 126), and a dihydro-1,3-oxazine (101), in high yield (85-99%), as well as a tetrahydro-1,3-oxazepine (112, 31%). A serendipitous discovery during the synthesis of thiazoline 113, led to the development of the first reported procedure for selective reduction of bis-phosphine oxides to bis-phosphine monoxides. The mono reduction was performed under exceptionally mild conditions using triflic anhydride and a thiol. The procedure appears to be general, at least for the reduction of bis-phosphine oxides of the type 93, 133, 134 and 135 and selected BINAP bis-phosphine oxides (128 and 142). When the mild dehydrating reagent phosphonium anhydride 38, was used to cyclise amino amides 56 and 144, the corresponding cyclic amidines 24 and 25 were obtained, though in low yields (36% and 29%, respectively). In comparison, by trityl protecting the amide precursors (56 and 144) and subsequently cyclising them with reagent 38, 24 and 25, were obtained in dramatically improved yields (79% and 89%, respectively). The scope of the reaction was explored and a selection of amides and trityl amides were synthesised and cyclised with reagent 38 to form simple tetrahydropyrimidines and imidazolines in high yields (85-95%), as well as a tetrahydrodiazepine 156 (51%). A number of simple analogues of the natural products, hyphodermins A, B and D were synthesised. Addition of a range of nucleophiles to anhydride 167 resulted in regioselective ring opening at C1 of the anhydride, and amide, ester and thioester derivatives 174–180 were obtained (60–99%). The increased electrophilic reactivity of the C1 carbonyl group of anhydride 167 was supported by a competition experiment with phthalic anhydride. Unexpected formation of lactams 184 and 186 from amides 180 and 179 was shown to proceed via the lactamols 185 and 186 and could be controlled by the reaction conditions. The 13 heterocycles and 14 Hyphodermin derivatives all obeyed Lipinskis ‘rule-offive’, and the calculated physicochemical values were within desired limits. All compounds were tested against Glycogen Phosphorylase a (GPa). Four phenyl and benzyl substituted 2-oxo-hexahydro and tetrahydrobenzo[cd]indole carboxylic acids were identified as novel inhibitors of GPa with apparent IC50 values in the range 0.8– 1.3 mM. All of the heterocycles synthesised displayed some inhibition of GPa, with thiazoline 126 (IC50 value of 24.5 μM) being the most active compound identified.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
Eskitis Institute for Cell and Molecular Therapies
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Phosphonium anhydride reagents
Hendrickson 'POP' reagent