Synthesis of Fmoc-Protected Amino Alcohols via the Sharpless Asymmetric Aminohydroxylation Reaction Using FmocNHCl as the Nitrogen Source.

Abstract

The aminohydroxylation of various alkenes using FmocNHCl as a nitrogen source is reported. In general, in the absence of a ligand, the reaction provided racemic Fmoc-protected amino alcohols with excellent regioselectivity but in low to moderate yields. However, in some instances, the yield of an amino alcohol product and the regioselectivity could be altered by the addition of a catalytic amount of triethylamine (TEA). The Sharpless asymmetric variant of this reaction (Sharpless asymmetric aminohydroxylation (SAAH)), using (DHQD)2PHAL (DHQD) or (DHQ)2PHAL (DHQ) as chiral ligands, proceeded more readily and in higher yield compared to the same reaction in the absence of a chiral ligand. The enantiomeric ratios (er) of all but two examples exceeded 90:10 with many examples giving er values of 95:5 or higher, making FmocNHCl a highly practical reagent for preparing chiral amino alcohols. The SAAH reaction using FmocNHCl was used for the preparation of d-threo-β-hydroxyasparagine and d-threo-β-methoxyaspartate, suitably protected for Fmoc solid phase peptide synthesis.