Synthesis of (+)-boronolide, (+)-sesbanimide A, and design and synthesis of inhibitors of memapsin 2.

摘要

This thesis begins with a discussion of the previous syntheses of (+)-boronolide. This is followed by a detailed discussion of our synthesis which begins with (−)-diethyl-D-tartrate and uses these key steps for its completion: elaboration of the butyl side chain through Grignard addition to a Weinreb amide, a stereocontrolled reduction of the resulting ketone to set the 3 ′ chiral center, a stereoselective allylation of an aldehyde and ring-closing olefin metathesis to afford the α,β-unsaturated δ-lactone moiety of the target molecule. Protecting group manipulation is performed to complete the synthesis.; The formal synthesis of (+)-sesbanimide A starting from (−)-diethyl-D-tartrate is described in part two. This synthesis employs many interesting reactions including a directed epoxidation of an olefin followed by a reductive transposition to set one stereocenter of the target molecule. Ring-closing olefin metathesis is used to generate an α,β-unsaturated-γ-lactone. Michael addition of t-butylacetate, aminolysis and cyclization are used to form the glutarimide A ring of (+)-sesbanimide A. The dioxane B ring is synthesized by treatment of a methoxymethyl ether with a catalytic amount of acid. Deprotection of the resulting product will complete the formal synthesis of (+)-sesbanimide A.; Part three details the design and synthesis of inhibitors of memapsin 2 which is speculated to have an important role in the progression of Alzheimer's disease. Structure-activity studies of inhibitors of this aspartic protease are described followed by the detailed synthesis of the Leu-Ala dipeptide isostere portion of these inhibitors. This synthesis begins with transformation of N-Boc-leucine into the corresponding Weinreb amide. Reduction of the Weinreb amide and addition of a propiolate anion to the resulting aldehyde are followed by saturation of the alkyne and lactonization. Selective α-methylation of the lactone followed by hydrolysis and protection of the resulting hydroxy acid lead to completion of the synthesis of the silyl-protected Leu-Ala isostere. Incorporation of this isostere into the corresponding inhibitors follows a common scheme of deprotection and peptide coupling with HOBt and EDCI. This process is reiterated to incorporate as many residues as are desired for each inhibitor. Many potent inhibitors of memapsin 2 have been synthesized using this methodology.