Part I. Utilization of Ketyl Radical Generated by Pyridine-Boryl Radical on Pinacol Coupling of Diaryl Ketones and Radical Cyclization of 2-Allylic Benzaldehydes Part II. Progress toward Total Synthesis of Hapalonamide G and Hapalindole G

Abstract

Part I. Ketyl radicals formed by pyridine-boryl radical were utilized for pinacol coupling of diaryl ketones and cyclization of allylic benzaldehydes leading to 2-substituted 1-indanols. The inconveniences of the traditional reducing-metal-promoted ketyl radical generation was overcome via the use of stable diboron and pyridine. The pinacol coupling of diaryl ketones afforded the diols in excellent yields, and the reactivity was maintained in a large scope of diaryl ketone. Only a very short time was required for the completion, and the outstanding reactivity was elucidated by DFT calculation. The slow ketyl radical formation of aromatic aldehydes was exploited for a radical cyclization instead of the pinacol coupling via the introduction of a radical-accepting alkene in benzaldehydes. In the presence of γ-terpinene, a naturally occurring 1,4-cyclohexadiene derivative, the reaction smoothly produced 2-substituted indanols. The size of the boron reagent had an effect on the diastereoselectivity, and the trans-selectivity was explained by DFT calculation.

Part II. Total synthesis of hapalonamide G and hapalindole G was studied. An intramolecular photochemical [2+2] cycloaddition of an allylic amide structure was planned to be used for the stereodetermination of the chlorine-substituted carbon center and the next quaternary center. The construction of the tricyclic backbone of hapalonamide G was examined via [4+2] cycloaddition of 1-amido-1,3-butadiene and 4,4-dimethylnaphthalenone. However, neither vigorous heating nor Lewis acid catalysis was effective. Subsequently, a three-step synthetic approach which was applied for the synthesis of the tetracyclic scaffold of hapalindole U by the Baran group was employed for efficient construction of the backbone of hapalindole G. Unfortunately, the last reductive amination did not work, and the efficiencies of the rest steps were considerably inferior to that of the case for hapalindole U. In the examination of the key [2+2] cycloaddition with a model substrate, the desired reaction did not take place. One-carbon-homologation released the ring strain and allowed the [2+2] cycloaddition but the reaction did not occur without aromatic substituent in the substrate.