Regioselective monochloro substitution in carbohydrates and non-sugar alcohols via Mitsunobu reaction: applications in the synthesis of reboxetine.
A regioselective high yielding monochloro substitution (chlorohydrin formation) via Mitsunobu reaction is reported. In carbohydrates and sterically hindered non-sugars, only the primary hydroxyl group is chlorinated, whereas in the non-sugar 1,2- and 1,3-alcohols, predominantly the secondary chloride substitution occurs. The versatile methodology provides indirect access to epoxides with the retention of configuration, as against conventional Mitsunobu reaction which generates epoxides with inversion. The methodology was successfully used as a key step in the synthesis of optically active diastereoisomers of the antidepressant drug reboxetine from (R)-2,3-O-cyclohexylidene-d-glyceraldehyde in ∼43% overall yields.
CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India.
Abdul Rouf
AR
Dar
Mushtaq A
MA
Aga
Brijesh
B
Kumar
Syed Khalid
SK
Yousuf
Subhash Chandra
SC
Taneja
D000438:Alcohols / Q000737:chemistry*; D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000737:chemistry; D002241:Carbohydrates / Q000737:chemistry*; D002728:Chlorohydrins / Q000138:chemical synthesis* / Q000737:chemistry; D008968:Molecular Conformation; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry; D000077593:Reboxetine; D013237:Stereoisomerism
D000438:Alcohols; D000928:Antidepressive Agents; D002241:Carbohydrates; D002728:Chlorohydrins; D009025:Morpholines; D000077593:Reboxetine