Abstract
By means of the domino ring-closure reactions of (1S*,1′S*)-1-(1′-aminoethyl)-, (1R*,1′R*)-1(2′-amino-1′-methylethyl)and 1-(2-aminophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline with acyclic and aromatic γor δ-oxo acids, angularly-condensed tetra-, pentaand hexacyclic lactam derivatives were formed with practically full diastereoselectivities (de ~100%), containing the substituents at the annelations of the saturated heterocyclic rings in cis position. The structure and relative stereochemistry of the products were determined with H and C NMR spectroscopy. Further, the tetrahydropyridine ring (ring B) was observed to prefer cis fusion with the condensed imidazolidine or hexahydropyrimidine ring (ring C), with one exception preferring trans fusion (namely, the tetracyclic imidazolidine derivative bearing a methyl substituent at the C/D ring annelation, cmpd. 11). These two conformations can interconvert via simultaneous nitrogen inversion at the B/C annelation and ring inversion of the ring B, and their populations could be roughly estimated from the J-coupling constant data for each lactam derivative. The compounds gave fragment ions that were typical for the structures of the compounds.
Highlights
The cyclocondensation of various 1,2-difunctional compounds (1, amino alcohols, amino thiols or diamines, containing a primary amino group) comprise a well-established method for the preparation of 1,3-heterocycle-fused γ- or δ-lactams with a nitrogen at the annelation (4).[1]
We recently described the domino ring-closures of 1-(aminomethyl)- and 1-(2-aminoethyl)6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline with γ- and δ-oxo acids, whereby tetra- and pentacyclic either angularly or linearly tetrahydroisoquinoline-condensed lactam derivatives were formed with excellent diastereoselectivities.[5]
As a continuation of this work and in connection with our previous studies on the synthesis and structural analysis of tetrahydroisoquinolinecondensed saturated heterocycles,[6] we report on the reactions of 1-substituted 1,2,3,4tetrahydroisoquinoline 1,2- and 1,3-diamines, bearing a methyl substituent or an aromatic ring in the side chain, with γ- and δ-oxo acids
Summary
The cyclocondensation of various 1,2-difunctional compounds (1, amino alcohols, amino thiols or diamines, containing a primary amino group) comprise a well-established method for the preparation of 1,3-heterocycle-fused γ- or δ-lactams with a nitrogen at the annelation (4).[1]. We recently described the domino ring-closures of 1-(aminomethyl)- and 1-(2-aminoethyl)6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline with γ- and δ-oxo acids, whereby tetra- and pentacyclic either angularly or linearly tetrahydroisoquinoline-condensed lactam derivatives were formed with excellent diastereoselectivities.[5] As a continuation of this work and in connection with our previous studies on the synthesis and structural analysis of tetrahydroisoquinolinecondensed saturated heterocycles,[6] we report on the reactions of 1-substituted 1,2,3,4tetrahydroisoquinoline 1,2- and 1,3-diamines, bearing a methyl substituent or an aromatic ring in the side chain, with γ- and δ-oxo acids. Our aim was to investigate the effects of the side chain substituents and the size of the lactam rings formed on the stereochemical outcome of the reactions, and the conformational and mass spectral behaviour of the tetra- and pentacyclic products
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