Synthesis of substituted β3-amino acid derivatives utilising the 4-substituted-1,3-oxazinan-6-one scaffold

Submission note: A thesis submitted in total fulfilment of the requirements for the degree of Doctor of Philosophy to the School of Molecular Sciences, Faculty of Science, Technology and Engineering, La Trobe University, Victoria.

In recent years beta-amino acids have gained considerable attention due to their applications in medicinal chemistry, particularly in peptidomimetics. As a result, a plethora of synthetic methods for accessing beta-amino acids have been developed. However, a majority of these methods have shortcomings. As a result there is an ongoing requirement to develop new methodologies to produce beta-amino acids that possess multifunctional substitution. Herein presented are novel strategies to produce known and novel beta-amino acid derivatives. A novel multi step pathway was developed to access beta 3 -amino acids. In this approach, a set of N-protected alpha-amino acids were converted to N-protected amino nitroalkanes. The nitroalkanes were then subjected to the Nef reaction to afford a variety of enantiomerically pure N-protected beta3 -amino acids. The beta 3 -amino acids were then used to produce the 1,3-oxazinan-6-one scaffold, which was used as a synthon to access a variety of functionally substituted beta 2,2,3 -amino acids, cyclic beta 2,3 -amino acids and beta-amino ketones. Firstly, 1,3-oxazinan-6-ones were enolised and trans-selectively intercepted with various electrophiles. The resulting 5-substituted adducts were enolised again, and then intercepted with different electrophiles to form differentially 5,5-disubstituted products with high diastereoselectivity. The 5,5-dialkylated 1,3-oxazinan-6-ones were then transformed into a variety of beta2,2,3 -substituted amino acids. In addition, the enolates of the 4-vinyl, 4-allyl and 4-butenyl-1,3-oxazinan-6-ones were allylated with various alkenyl electrophiles diastereoselectively. The resulting 4,5-bisalkene adducts were subjected to ring closing metathesis to provide the 4,5-cyclic-1,3- oxazinan-6-ones. The metathesis products were subsequently converted into a variety of 5-, 6- and 7-membered cyclic beta2,3 -amino acids. And lastly, the 4-substituted 1,3-oxazinan-6-one was enolised and then intercepted with various acyl halides. The acylated products were subjected to acidic conditions to give enantiomerically pure N-protected beta-amino ketones. The methodology described has provided novel avenues to a variety of functionalised beta-amino acids and beta-amino ketones that have important applications in the design of medicinal therapeutics.