Chiral synthesis of (2S,3S)-2-(2-morpholin-2-yl-2-phenylmethoxy)phenol.
Resolution of (2RS,3RS)-2-[alpha-(2-methoxymethoxyphenoxy)phenylmethyl]morpholine, 11, with (+) mandelic acid led to the formation of (+)-(2S,3S)-2-[alpha-(2-methoxymethoxyphenoxy)phenyl methyl] morpholine (11a). Compound 11 was synthesized in seven steps from (2RS,3RS)-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 (+)-(2S,3S)-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 (2S,3S)-2-[alpha-(2-ethoxyphenoxy)phenylmethyl]morpholine (1) and (2S,3S)-2-(2-methoxyphenoxy) benzyl)morpholine (16), two potential norepinephrine reuptake inhibitors under clinical evaluation.
Prabhakaran
Jaya
J
Department of Psychiatry and Division of Neuroscience, NYSPI/Columbia University, 1051 Riverside Drive, New York, NY 10032, USA.
Majo
Vattoly J
VJ
Mann
J John
JJ
Kumar
J S Dileep
JS
D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000737:chemistry; D015195:Drug Design; D008722:Methods; D015394:Molecular Structure; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry*; D014179:Neurotransmitter Uptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry*; D000077593:Reboxetine; D013237:Stereoisomerism
D000928:Antidepressive Agents; D009025:Morpholines; D014179:Neurotransmitter Uptake Inhibitors; D000077593:Reboxetine