Copper catalyzed enantioselective methodologies to functionalize oxygen and nitrogen heterocycles towards the synthesis of natural products phomoxanthone A and morphine

Attard, Jonathan W.

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Copper catalyzed enantioselective methodologies to functionalize oxygen and nitrogen heterocycles towards the synthesis of natural products phomoxanthone A and morphine

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In chapter 1, the role of silanediols in Lewis acid catalyst activation was investigated. The BINOL-silanediol and Cu(OTf)2 co-catalyst species enabled an enantioselective Friedel-Crafts alkylation of un-protected indoles by arylidene and alkylidene malonates. The mechanism by which the chiral information is transferred to the products was postulated to be by a hydrogen bond network transition state involving cooperative hydrogen bonding between the heterocyclic indole, the silanediol, and the anion of the Lewis acid catalyst. The model was supported by mechanistic studies. The binding constant determination of silanediol compared to thiourea and squaramide also supported the model, due to the inverse relationship of binding constant to enantiomeric excess. In chapter 2, a novel enantioselective synthesis of tetrahydroxanthone compounds was accomplished by Copper – bis(oxazoline) catalyzed alkynylation of benzopyrylyium triflates. The highly enantioselective alkynylation methodology allows access to a large scope of chromanone substrates with both tri- and tetra-substituted stereocenters. An enantioenriched tetrahydroxanthone compound was synthesized in only 5 steps from starting chromanone using this methodology. This method establishes the groundwork to access the 2-tetrasubstituted stereocenter in chromanone natural products; a key hurdle in the synthesis of the phomoxanthone A and analogues thereof. In Chapter 3, a novel route to cis-hydrodibenzofuran compounds was developed with the goal of achieving the asymmetric formal synthesis of morphine or other related natural products. A key step in the asymmetric synthesis of the key tetrahydroxanthone intermediate was the enantioselective [4+2] cycloaddition of chromone-3-carboxylate esters and Danishefsky’s diene by copper – bis(oxazoline) catalyzed conjugated addition. A novel decarboxylation using trimethyltin hydroxide was utilized to access tetrahydroxanthone. Trace amounts of a model cis-hydrodibenzofuran compound was achieved by subjecting tetrahydroxanthone to semi-pinacol rearrangement conditions. This route has the potential to access this complex class of natural products, and analogues thereof, in few steps and in an enantioselective fashion.

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