Date of Award
Doctor of Philosophy (PhD)
Dr. Paul Harrison
Oxetan-2-ones (β-lactones) represent important synthetic targets because they are versatile synthetic intermediates and are present in a wide variety of pharmacologically relevant natural products. Using several reported methods, a homologous series of racemic C4-monosubstituted and trans-1,2-disubstituted β-lactones was prepared for investigation as potential inhibitors of yeast 3-hydroxy-3-methylglutaryl-Coenzyme A (HMG-CoA) synthase. However, no general method were then available for the preparation of the corresponding cis-1,2-disubstituted β-lactones.
Using the mercury (II) promoted Masamune lactonization of β-hydroxy thiopyridyl ester 3-7, cis-3-methyl-4-decyloxetan-2-one (3-1) was prepared in high yield. The requisite syn thiol ester was prepared starting from undecanal: (1) in one step using a titanium (IV) promoted Mukaiyama aldol condensation with silyl ketene acetal 1-28; and (2) in three steps using a titanium (IV) promoted Evans-type aldol condensation with N-propionyl thiazolidinethione 4-24, followed by conversion of the thiazolidinethione aldol adduct to thiol ester 3-7 through the corresponding free acid. Substituting N-propionyl thiazolidinethione 4-24 for chiral N-acetyl and N-propionyl thiazolidinethiones 4-26 and 5-16, respectively, the Evans-type aldol condensations with undecanal proceeded with excellent diastereoselectivity (> 90 %de); this is necessary for the preparation of optically active cis-1,20-disubstitutede and C4-monosubstituted β-lactones.
A tandem-Evans aldol-lactonization (TEAL) reaction was developed using the lithium enolates of N-acetyl (5-16) and N-propionyl thiazolidinethione 4-24. Thus far, trisubstituted spiro β-lactones 6-17 and 6-19, and C4-disubstituted spiro β-lactones 6-22, have been successfully prepared in one-pot.
In addition to using aldol condensations to prepare the carbon skeleton for C4-monosubstituted β-lactones, a Claisen-type condensation on a glycoluril template was attempted; the advantage of this route was the potential use of well developed asymmetric reductions of the product β-keto carboxylic acid derivative to introduce optical activity in an enantioselective preparation of C4-monosubstituted β-lactones. Unfortunately, using glycoluril 7-11, racemic 4-nonyloxetan-2-one (2-7v) was produced in poor yield because of difficulties encountered removing the aldol adduct-like β-hydroxy carboxylic acid derivative from the template.
Jenkins, Stephen I., "Preparation of β-Lactones" (2003). Open Access Dissertations and Theses. Paper 821.