Synthesis of chiral C/N-functionalized morpholine alcohols: study of their catalytic ability as ligand in asymmetric diethylzinc addition to aldehyde

• Published in: Tetrahedron: asymmetry 2006-02, Vol.17 (3), p.388-401
• Main Authors: Dave, Rajesh, Sasaki, N. André
• Format: Article
• Language: English
• Subjects: Chemical Sciences; Organic chemistry
• ISSN: 0957-4166; 1362-511X; 0957-4166
• DOI: 10.1016/j.tetasy.2005.12.027

A broad variety of chiral C/N-functionalized morpholine alcohols sharing a common structural motif in the 3-(hydroxymethyl)morpholine 6 were prepared from enantiomerically pure serine for the purpose of studying their catalytic ligand properties. The asymmetric addition of diethylzinc to benzaldehyde in the presence of 10 mol % of chiral C/N-functionalized morpholine alcohols gave 1-phenyl-1-propanol in 59–81% yield with 10–30% ee. The addition of 10 mol % of n-butyl lithium to the reaction mixture resulted in a significant enhancement of the stereoselectivity in the case of ligands bearing the two geminal phenyl substituents on the backbone. In the presence of n-butyl lithium and using ( S)-3-(hydroxydiphenylmethyl)morpholine ( S)- 19 as the chiral promoter, ( S)-1-phenyl-1-propanol was obtained in 81% yield with 76% ee. The geminal diphenyl-class of morpholine ligands was examined for the diethylzinc addition to four different aldehydes in the presence of n-butyl lithium. ( S)- N-Benzyl-3-(hydroxydiphenylmethyl)morpholine ( S)- 27 was found to be most enantioselective in the case of 4-methoxybenzaldehyde to give ( R)-alcohol in 87% yield with 80% ee. Catalysts ( S)- 19 and its N-methyl derivative ( S)- 26 gave alcohols with an ( S)-absolute configuration while the N-benzylated derivative ( S)- 27 gave the opposite enantiomeric products. The tentative transition state models to account for the observed product stereoselectivity with morpholine ligands holding the geminal diphenyl group on the β-amino alcohol segment are proposed.