Chiral synthesis of (2 S ,3 S )‐2‐(2‐morpholin‐2‐yl‐2‐phenylmethoxy)phenol

Resolution of (2 RS ,3 RS )‐2‐[α‐(2‐methoxymethoxyphenoxy)phenylmethyl]morpholine, 11 , with (+) mandelic acid led to the formation of (+)‐(2 S ,3 S )‐2‐[α‐(2‐methoxymethoxyphenoxy)phenyl methyl] morpholine ( 11a ). Compound 11 was synthesized in seven steps from (2 RS ,3 RS )‐cinnamyl alcohol‐2,3‐epoxide ( 4 ), with an overall yield of 17%. Cleavage of the methoxymethyl group of the Fmoc derivative 12 with catalytic amounts of p ‐toluenesulfonic acid in methanol afforded (+)‐(2 S ,3 S )‐2‐(2‐morpholin‐2‐yl‐2‐phenylmethoxy)phenol 2 . The synthetic utility as well as the configuration of compound 2 has been demonstrated by converting ( S,S )‐2‐(2‐morpholin‐2‐yl‐2‐phenylmethoxy)phenol 2 to (2 S ,3 S )‐2‐[α‐(2‐ethoxyphenoxy)phenylmethyl]morpholine ( 1 ) and (2 S ,3 S )‐2‐(2‐methoxyphenoxy) benzyl)morpholine ( 16 ), two potential norepinephrine reuptake inhibitors under clinical evaluation. Chirality 16:168–173, 2004. © 2004 Wiley‐Liss, Inc.