The stereoselective total synthesis of the antimalarial korupensamines A (1a) and B (1b) by application of the "lactone method" is described. Key steps of this first atropo-selective access to 5,8'-coupled naphthylisoquinoline alkaloids were the regioselective intramolecular coupling of ester 8 to give the configurationally labile lactone-bridged biaryl 9 and its atropisomer-selective cleavage with a variety of chiral and achiral H-nucleophiles, yielding the configurationally stable P-diol 10a or, optionally, the M-product 10b. From the axially chiral phenylisoquinolines thus obtained atropo-diastereodivergently, the authentic natural naphthylisoquinolines with the respective axial configurations, korupensamines A (1a) and B (1b), were obtained by completion of the second naphthalene ring, starting from the previous "bridgehead" C1 unit.

In the forebrain, synaptic glycine concentrations are regulated through the glycine transporter GlyT1. Because glycine is a coagonist of the N-methyl-D-aspartate (NMDA) receptor (NMDAR), which has been implicated in schizophrenia, inhibition of GlyT1 is thought to provide an option for the treatment of schizophrenia.

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Configurationally unstable biaryl lactones of type (M)-1 ⇌ (P)-1 and ring-opened 2-acyl-2‘-hydroxy biaryl compounds of type (M)-4 ⇌ (P)-4 are versatile precursors for the atroposelective preparation of axially chiral biaryls. The activation barriers of their atropisomerization process, which constitutes a fundamental precondition for the dynamic kinetic resolution, were determined by dynamic NMR spectroscopy for rapid processes and by HPLC-monitored racemization of enantiomerically enriched material for smaller interconversion rates. For the lactones, the free activation energies ΔG ⧧ 298 increase with the steric demand of the substituent R ortho to the biaryl axis in the series H < OMe (t 1/2 ≈ ms) < Me (t 1/2 ≈ s) < Et < i-Pr (t 1/2 ≈ min) < t-Bu (t 1/2 ≈ d). The formally ring-opened 2-acyl-2‘-hydroxy biaryls, which interconvert via the lactol isomers 5 as the cyclic (and thus configurationally less stable) intermediates, have a significantly slower atropisomerization rate as a result of the high loss in activation entropy ΔS ⧧ as a consequence of the required intermediate ring closure 4 → 5.