Synthesis Study Of (S)-N-Fmoc-2-(4’-pentenyl)-alanine And Key Intermediates Of HIV Protease Inhibitors

The first part of this thesis is the synthesis of key intermediates of HIV protease inhibitors(PIs). The key intermediates--(2S,3S)-N-Boc-3-amino -1, 2-expoxy -4 -phenylbutane (intermediate A) and (2R,3S)-N-Boc-3-amino -1,2- expoxy -4-phenyl butane (intermediate B) are widely used in synthesizing PIs medicines. Therefore it is significant to develop efficient synthetic routes for these two intermediates . Starting from L-phenylalanine, intermediate (A) was synthesized in six steps. First, N,N-dibenzyl -L-phenylalaninal was prepared from L-phenylalanine via reduction, dibenzylation and oxidation. Then the aldehyde group of N,N-dibenzyl -L- phenylal aninal was chloromethylated stereoselectively to form the desired erythro aminoalcohol--N,N-dibenzyl- (S)-3-amino-(S)- 2 -hydroxy -4-phenyl -1- chlorobutane,which led to intermediate (A) after ring closure.A novel route for synthesizing intermediate (B) was also displayed in this paper. In this newly designed synthetic route , L-phenylalanine was employed as the starting material again to bring in the first chiral center. In order to construct the other chiral center, we initially converted the carboxyl group of the starting material toα-chloro methyl ketone, and then reduced the ketone high-selectively under the control of the first chiral center. Finally, we obtained the desired threo aminoalcohol—N,N-dibenzyl- (S)-3- amino-(R)-2-hydroxy-4-phenyl- 1- chlorobutane , which led to intermediate (B) via additional two reaction steps.The second part of this thesis is the synthesis of a newα,α-disubstituted amino acid--(S)-N-Fmoc-2-(4’-pentenyl)-alanine. A synthetic route for this target compound was designed and completed. Starting from (1R,2S)-1, 2-diphenyl -2-amino-ethanol, all seven steps were completed including substitution, esterification, alkylation and so on. It is worth mentioning that Williams’chiral template was employed as the chiral auxiliary in this synthetic route, and it showed excellent chiral induction capability.