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Chiral synthesis of (2 S ,3 S )‐2‐(2‐morpholin‐2‐yl‐2‐phenylmethoxy)phenol
Author(s) -
Prabhakaran Jaya,
Majo Vattoly J.,
Mann J. John,
Dileep Kumar J. S.
Publication year - 2004
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.20004
Subject(s) - morpholine , chemistry , methanol , stereochemistry , yield (engineering) , phenol , epoxide , medicinal chemistry , organic chemistry , catalysis , materials science , metallurgy
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.