Solid‐Phase Synthesis of Tetrahydro‐β‐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‐β‐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‐β‐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‐β‐carboline, a 3,4‐dihydroisoquinoline, or a similar core structure.