<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)
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/19522 |
| Date | 08 1900 |
| Creators | Jenkins, Stephen |
| Contributors | Harrison, Paul, Chemistry |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
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