<p> β-Lactones are present in a number of biologically interesting natural products. They also have inherent reactivity due to their strained ring system and act as important synthetic intermediates. In this current work, we focus on the development of an efficient stereoselective route for the synthesis of β-lactones. A Tandem Evans-type Aldol Lactonization (TEAL) method was developed and various di- and tri-substituted β-lactones were successfully synthesized in a one pot process, using the lithium enolates of N-acetyl- (2-8) and N-propionyl- (2-20) thiazolidine-2-thione and a variety of ketones with moderate to good yields. Substitution of these N-acyl thiazolidine-2-thiones with chiral N-acetyl and N-propionyl thiazolidine-2-thiones (2-41 and 2-42 respectively) produced β-lactones with good enantioselectivity (up to 83% e.e.) and also showed an improvement of diastereoselectivity indicating the potential of the developed method. </p> / Thesis / Master of Science (MSc)

β-Lactones are a class of structurally unique compounds. The versatile reactivity patterns offered by β-lactones have enable chemists to utilize them as powerful synthetic vehicles in complex molecule synthesis. In the total syntheses of the naturally occurring, α-glucosidase inhibitors schulzeines B & C, a readily available trichloromethyl β-lactone was used as a versatile masked surrogate for bishomoserine aldehyde, which led to a highly efficient construction of the core structures through a pivotal Pictet-Spengler condensation and a Corey-Link reaction. The first total synthesis of (+)-omphadiol was achieved in ten steps from (R)-carvone. This synthesis features a three-step synthesis of a bicyclic β-lactone, which constitutes the key intermediate for the highly stereocontrolled introduction of the six contiguous stereogenic centers in the natural product. In efforts toward the total syntheses of scabrolides A & B and sinulochmodin C via transannular C-H insertions, β-lactones served as the key intermediates for the synthesis of complex macrocyclic model substrates. These model studies provided valuable insights into the reactivity and selectivity issues for transannular C-H insertion reactions.

<p> 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. </p> <p> 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 ,2-disubstituted and C4-monosubstituted β-lactones. </p> <p> 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-lactone 6-22, have been successfully prepared in one-pot. </p> <p> 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. </p> / Thesis / Doctor of Philosophy (PhD)