Date of Award

5-2009

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Legacy Department

Chemistry

Advisor

Dieter, R. Karl

Committee Member

Hwu , Shiou-Jyh

Committee Member

Bhattacharyya , Gautam

Committee Member

Smith , Dennis

Abstract

ABSTRACT
The δ-lactone moiety comprises structural subunits in a number of natural products. Highly substituted δ-lactones are important both in synthetic applications and also as naturally occurring compounds. We have reported a one-pot procedure for the synthesis of trans-4,5-disubstituted tetrahydropran-2-ones from 3-hydroxy-3,6-dihydropyran-2-one involving sequential cuprate mediated allylic substitution and 1,4-conjugate addition reactions. We have now examined the same protocol for synthesis of 4,5,6-trisubstituted δ-lactones.
The rich functionalities(i.e. the epoxide, olefin and ester functional groups) in ,δ-epoxy-α,β-enoates provide opportunities for SN2-epoxide opening, allylic substitution, and 1,4-conjugated addtion. The opening of the epoxide with AcCl, AcBr, and benzoyl chloride afforded the -acetoxy--halo-,-enoates and-benzoyloxy--halo-,-enoates , and subsequent copper-mediated allylic SN2' substitution afforded 5-acyloxy-2-alkyl-3,4-enoates. Stereoselective reaction of Grignard reagents, in the presence of catalytic CuCN, with these 5-acyloxy-2-alkyl-3,4-enoates afford 2,3-di-alkyl-4,5-enoates. Sequential treatment of δ-acetoxy-γ-halo-α,β-enoates with RCuCNMgBr and then with R2CuMgBr in a one-pot operation afforded 2,3-di-alkyl-4,5-enoates in good chemical yields and excellent diastereoselectivity. Ozonolysis of 2,3-di-alkyl-4,5-enoates, reduction, and then by cyclization furnished 2,3-di-substituted γ-lactones with excellent diastereomeric ratios. An alternative synthesis of γ-lactones can be achieved by hydrolysis of the 2,3-di-alkyl-4,5-enoates followed by iodolactonization.
Although organometallic mediated conjugate addition of alkyl or aryl ligands to 4-pyridones could provide a rapid entry to the highly versatile 2,3-dihydropyridones, the addition of an allyllithium reagent appears to be the only reported example of such a reaction. We now report that a variety of organometallic reagents do undergo conjugate addition reactions with N-carbamoyl-4-pyridones. Asymmetric 1,4-conjugate addition of diethylzinc reagents to N-Boc-4-pyridone was developed. The fully unsaturated 2-pyrones possess aromatic character, and display reactivity patterns characteristic of lactones, 1,3-dienes, and heteroaromatic rings. Although organocopper mediated conjugate addition reactions to 2- and 4-pyrones have not been reported, cuprate reagents could be successfully added by conversion of the pyrones to pyrilium salts with added triflic anhydride. These reactions proceeded with addition of the ligand to the 4-position of the pyrone ring. We now report that organocuprate reagents do indeed undergo 1,4-conjugate addition reactions with 2- and 4-pyrones. With or without the addition of Cu (I) salt, Grignard reagents can also undergo 1,4-conjugate addition reactions to N-carbamoyl-4-pyridones, 2- and 4-pyrones to afford 1,4-adduct in excellent chemical yields in the presence of TMSCl.

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