Total Synthesis of Hyphodermins A-D and Other Potential Inhibitors of Glycogen Phosphorylase
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The Hyphodermin A-H natural products were isolated in 1997. This thesis reports the first total synthesis of Hyphodermins A-D (47-50). The reaction sequence to Hyphodermin B, 48, involved conversion of dione 58 to a methoxy enolether followed by vinyl Grignard addition to give diene 54. A Diels-Alder cyclo-addition reaction with dimethyl acetylenedicarboxylate followed by dehydrogenation with Pd/C gave diester 66. Conversion of the ester to the corresponding phthalic acid, cyclisation with acetic anhydride and reduction of the anhydride moiety to the lactol with LiAlH(t-BuO)3 gave (±)-Hyphodermin B, 47. (±)-Hyphodermin B, 48, was synthesised in six steps and with an overall yield of 38%. A key step in this synthesis was the regioselective reduction of anhydride 56 at C1 to (±)-Hyphodermin B, 48. The total synthesis of Hyphodermins A, C and D (47, 49 and 50) used diester 66 as a common starting material. Installation of a double bond ?,? to the ketone moiety of 66 via ?-bromination and dehydrohalogenation gave unsaturated diester 110. Ester hydrolysis, cyclisation with acetic anhydride and reduction of C1 (as per the synthesis of (±)-Hyphodermin B, 47) resulted in the formation of lactol 113. In the synthesis of Hyphodermins C, 49, and D, 50, lactol 113 was converted to the corresponding methyl ether and epoxidised to give Hyphodermins C, 49, and D, 50. Hyphodermins C, 49, and D, 50, were synthesised in eleven steps in unoptimised overall yields of 49, 0.33% and 50, 1.5% respectively. The synthesis of Hyphodermin A, 47, was achieved by protection of lactol 113 as a THP ether followed by epoxidation and selective deprotection under mild acidic conditions. (±)-Hyphodermin A, 47, was synthesised in twelve steps from diketone 58, and in an unoptimised overall yield of 1.55%. Hyphodermin analogues 47, 48, 50, 66, 70, 108, 109, 110, 113, 117 and 130 were assayed for potential inhibitory activity against GPa. None of the analogues inhibited GPa at a concentration less than 100 µM. This thesis also reports preliminary investigations into the synthesis of a spiro-proline scaffold 136, in an effort to develop a library of amino acid mimetics for the C-terminal sequence of the GL subunit of PP-1 which binds to GPa.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
Eskitis Institute for Cell and Molecular Therapies
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