Studies On Synthesis Of (S)-2-(Hydroxymethyl) Morpholine Intermediates

This thesis describes the asymmetric synthesis of the derivations of (S)-2-(Hydro xymethyl)morpholine in 20% overall yield in six steps. Optically active compounds of 4-Boc-2-hydroxymethylmorpholine were prepared from D-mannitol by practical procedures. These compounds are versatile intermediates for optically active isomers of a number of neuropharmacologically active agents that have 2-morpholinylmethyl group. Actually the S isomer had at least ten times the neuropharmacological and more antidepressive activity than the R isomer.As a frequently used chiral pool, D-mannitol has been found extensively application in the organic synthesis. Our approach was to build the chiral morpholine moiety. Firstly, cleavage of di-O-isopropylidene-1,2:5,6-D-mannitol with sodium metaperiodate, then, follow by reductive amination of the O-isopropylidene-(R)-gly ceraldehyde with benzylamine in the presence of sodium borohydride. Acylation with chloroacetyl chloride, removal of the isopropylidene group in aqueous acetic acid gave the diol which was treated with sodium ethoxide to afford the lactam. Hydride reduction of the lactam successfully, reductive removal of the benzyl group with palladium on carbon in H₂ and subsequent tert-butoxycarbonylation with Boc₂O (di-tert-butyl dicarbonate) prepared the N-tert-butoxycarbonylmorpholine.The paper also studies on the effect of each reaction's parameters on products synthesis. The structures of all products were characterized by elemental analysis, IR, ¹H-NMR, ¹³C-NMR and MS spectra.