Applications of N-hydroxymethyl protected α-amino aldehydes for stereoselective synthesis of threo-β-amino-α-hydroxy acids and Cu-catalyzed one-pot process for acetaminophen

Abstract

This thesis comprises part A and part B. Part A is about the stereoselective synthesis of β-amino-α-hydroxy acids from the N-hydroxymethyl protected α-amino aldehydes. threo-β-Amino-α-hydroxy acids, frequently found in naturally occurring bioactive compounds, have been synthesized via the stereoselective intramolecular conjugate addition of N-hydroxymethyl group, which configurationally stabilizes an α-amino aldehyde by forming the hemiacetal. In this study, the stable α-amino aldehyde was reacted with phenylsulfonylnitromethane (PhSO2CH2NO2) to afford stereoselective trans-oxazolidine, which was a precursor for threo-β-amino-α-hydroxy. The three tandem reactions between phenylsulfonylnitromethane and the α-amino aldehydes and the followed in-situ ozonolysis affored trans-oxazolidine methyl esters (A23) in 65% to 69% yields with more than 20 to 1 stereoselectivity. Bestatin, a well-known aminopeptidase inhibitor, was stereoselectively synthesized in 83% yield from trans-oxazolidine methyl ester A23-Phe, which was derivated from D-Phe-OH. Leucinal and valinal derivatives (A23-Leu, and A23-Val) were successfully applied for the synthesis of the corresponding threo-vicinal amino alcohol embeded dipeptides at N-terminus, which were the first synthesized isobutyl and isopropyl substituted bestatin analogs. Moreover, two stereoselective dipeptides, containing (2S,3R), or (2R,3S)-3-amino-2-hydroxy-4-methylpentanoic acid at N-terminus, were synthesized to elucidate the stereochemistry of naturally occurring another aminopeptidase inhibitor lapstatin from the commercially available Boc-D-Val-OH or Boc-L-Val-OH. trans-Oxazolidine methyl ester from D-Ser-OH (A23-Ser) was stereoselectively converted to the glutamate transporter blocker L-threo-β-benzyloxy aspartic acid (L-TBOA) via the simple functionalization of hydroxymethyl of the oxazolidine A23-Ser and following selective benzyl protection of hydroxyl group. In part B, a new process development for acetaminophen has been presented. In the new proces, two copper catalyzed reactions were applied with p-dihalobenzenes for practical and efficient synthesis of acetaminophen. N-Acetylamidomethyl and hydroxyl group on acetaminophen were regioselectively introduced via Goldberg reaction with acetamide and Ullmann type condensation reactions in the presence of copper catalysts and diamine ligands. Furthermore, the suggested efficient two-step process was successfully simplified as one-pot process by excluding the purification of the intermediate, N-acetyl-p-haloaniline. Under the optimized one-pot process, acetaminophen was obtained in 74% yield from the commercially available p-bromoiodobenzene