TY - JOUR
T1 - Solid-phase synthesis of tetrahydro-beta-carbolines and tetrahydroisoquinolines by stereoselective intramolecular N-carbamyliminium Pictet-Spengler reactions
AU - Diness, Frederik
AU - Meldal, Morten
PY - 2006/10/25
Y1 - 2006/10/25
N2 - 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.
AB - 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.
KW - Benzaldehydes
KW - Carbolines
KW - Isoquinolines
KW - Oxazines
KW - Oxidation-Reduction
KW - Stereoisomerism
KW - Tetrahydroisoquinolines
U2 - 10.1002/chem.200600138
DO - 10.1002/chem.200600138
M3 - Journal article
C2 - 16881029
VL - 12
SP - 8056
EP - 8066
JO - Chemistry: A European Journal
JF - Chemistry: A European Journal
SN - 0947-6539
IS - 31
ER -