Stereoselective Synthesis of Constrained Oxacyclic Hydroxyethylene Isosteres of Aspartic Protease Inhibitors: Aldol and Mukaiyama Aldol Methodologies for Branched Tetrahydrofuran 2-Carboxylic Acids

The synthesis of diastereomeric 3-substituted-tetrahydrofuran 2-carboxylic acids in enantiopure
form was achieved relying on aldol condensations of N-substituted α-amino aldehydes with enolates
and enol silyl ethers of γ-butyrolactone. Catalytic YbFOD leads to a high yield of a syn/syn-α-amino alcohol isomer. This was used as a constrained THF subunit in the synthesis of a
peptidomimetic intended as an inhibitor of the enzyme BACE1, which is implicated in the cascade
of events leading to plaque formation in Alzheimer's disease.

本研究依托N-取代α-氨基醛与γ-丁内酯的烯醇负离子及烯醇硅醚的羟醛缩合反应，成功合成了对映纯的非对映异构3-取代四氢呋喃-2-羧酸。采用催化型氟化镱（YbFOD）可高产率获得syn/syn型α-氨基醇异构体。该异构体被用作受限型四氢呋喃（THF）结构单元，用于合成一款拟作为β-分泌酶1（BACE1）抑制剂的肽模拟物；而BACE1参与了阿尔茨海默病中引发斑块形成的级联反应过程。