The HIV protease inhibitor nelfinavir and a proposed HTLV-1 protease inhibitor are medicinally valuable materials that have been previously been prepared by the application of the asymmetric aldol reaction. In this body of work, a synthetic pathway has been designed that employs the asymmetric aldol reaction of glycolate derivatives. The use of the glycolate aldol addition reaction allows the more efficient introduction of functionality. The work involves the use of the Crimmins' oxazolidine-2-thione derived from L-phenylalaninol as the chiral scaffold for the reaction. Our initial work using this auxiliary with a benzyloxyacetyl side chain were not successful. The asymmetric aldol reactions failed to yield clean product distribution and also resulted in unreacted starting material. This difficulty was coupled with the fact the (-)-sparteine, a key additive for the Crimmins' glycolate aldol reaction, was no longer available. To resolve these matters, the reaction conditions of the aldol reaction were modified and the oxazolidine-2-thione side chain was converted to a 4-methoxyphenoxyacetyl side chain. This side chain gave a superior result in the aldol reaction as determined by 1H NMR spectroscopy and HPLC. Cleavage of the auxiliary to form the Weinreb amide followed by reduction with diisobutylaluminum hydride (Dibal-H) to afford the desired aldehydes. The resultant aldehydes then serve as the scaffolds for building the protease inhibitors.

Asymmetric glycolate aldol addition approach to the synthesis of the HIV protease inhibitor nelfinavir and a proposed HTLV-1 protease inhibitor

248th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.