title: A synthetic route to highly substituted 1,2,3,4-tetrahydroisoquinolines via Yb(OTf)3 -catalyzed diastereoselective ring opening of bridged oxazolidines: asymmetric synthesis of 2-azapodophyllotoxin.
abstract: We herein report a robust and efficient synthetic route to highly functionalized enantiopure 1,2,3,4-tetrahydroisoquinolines (THIQs) from Garner aldehyde. We utilized the inherent chirality of Garner aldehyde through 1,2- and 1,3-/1,4-asymmetric inductions iteratively to obtain 1,2,3,4-tetrasubstitued THIQs using rigid and isolable bridged oxazolidines without any external chiral sources. All possible stereoisomers of bridged oxazoliodines were efficiently synthesized from L- and D-Garner aldehydes and transformed into fully functionalized THIQs via diastereoselective ring opening with various nucleophiles in the presence of Yb(OTf)(3). This methodology furnished four out of eight possible diastereomers of 1,2,3,4-tetrasubstituted THIQs despite the electronic nature of substituents on the aryl rings. Finally, the enantioselective synthesis of 2-azapodophyllotoxin was achieved with an overall yield of 35.4% (eight steps) from D-Garner aldehyde using this synthetic route.
authors.affiliation: Department of Chemistry, Seoul National University, Seoul, 151-747, Korea.
authors.forename: Ajay Kumar
authors.initials: AK
authors.lastname: Srivastava
authors.forename: Minseob
authors.initials: M
authors.lastname: Koh
authors.forename: Seung Bum
authors.initials: SB
authors.lastname: Park
mesh_terms: D001952:Bridged-Ring Compounds / Q000737:chemistry*; D002384:Catalysis; D058116:Lewis Acids / Q000737:chemistry*; D015394:Molecular Structure; D010080:Oxazoles / Q000737:chemistry*; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D013237:Stereoisomerism; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis* / Q000737:chemistry*; D015018:Ytterbium / Q000737:chemistry*
chemical_list: C558765:2-azapodophyllotoxin; D001952:Bridged-Ring Compounds; D058116:Lewis Acids; D010080:Oxazoles; D044005:Tetrahydroisoquinolines; C064210:oxazolidine; C014843:1,2,3,4-tetrahydroisoquinoline; D011034:Podophyllotoxin; D015018:Ytterbium