title: Solid-phase synthesis of tetrahydro-beta-carbolines and tetrahydroisoquinolines by stereoselective intramolecular N-carbamyliminium Pictet-Spengler reactions.
abstract: A solid-phase method for the synthesis of tri-, tetra-, and pentacyclic compounds containing tetrahydro-beta-carboline, tetrahydroisoquinoline or analogous scaffolds is presented. The reaction proceeds with high stereoselectivity through an intermediate N-carbamyliminium ion that exclusively converts into Pictet-Spengler-type products with a variety of C-nucleophiles. Amino aldehydes masked with 3-Boc-(1,3)-oxazinane (Box) have been synthesized from amino acids, amino alcohols, or 2-nitro benzaldehydes. The amino moiety of these masked aldehydes has been converted into pentafluorophenyl carbamate to serve as a urea precursor. The building blocks were incorporated at the N-terminal of a resin-supported dipeptide through urea formation. Subsequent treatment with acid liberated the aldehyde quantitatively. A penultimate tryptophan residue gave rise, under the acetic conditions, to a spontaneous intramolecular Pictet-Spengler reaction with the liberated aldehyde. The reaction proceeded with a high degree of stereoselectivity affording tetrahydro-beta-carbolines with a de (de=diastereomeric excess) above 95 % and purity in the range of 90-99 %. This reaction has been extended to a range of other aromatic C-nucleophiles, including substituted indoles, benzenes, pyrene, furan, thiophenes, and benzothiophene with comparable stereoselectivity and purity. Prolonged exposure of the benzaldehyde-derived Pictet-Spengler products to strong acid and air lead to quantitative auto-oxidation which yielded compounds with a 3,4-dihydro-beta-carboline, a 3,4-dihydroisoquinoline, or a similar core structure.
authors.affiliation: Carlsberg Laboratory, Department of Chemistry, Gamle Carlsberg Vej 10, 2500 Valby, Denmark.
authors.forename: Frederik
authors.initials: F
authors.lastname: Diness
authors.forename: Jürgen
authors.initials: J
authors.lastname: Beyer
authors.forename: Morten
authors.initials: M
authors.lastname: Meldal
mesh_terms: D001547:Benzaldehydes; D002243:Carbolines / Q000138:chemical synthesis* / Q000737:chemistry; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry; D010078:Oxazines / Q000737:chemistry; D010084:Oxidation-Reduction; D013237:Stereoisomerism; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D001547:Benzaldehydes; D002243:Carbolines; C109852:G 1616; D007546:Isoquinolines; D010078:Oxazines; D044005:Tetrahydroisoquinolines