We describe the asymmetric total syntheses of naphthylisoquinoline alkaloids. Atroposelective biaryl coupling reaction between naphthyl pinacol boronate and an aryl iodide, bearing (S)-2-aminopropyl group at the ortho-position using the existing central chirality as an atroposelectivity-controlling group, provided the desired biaryl product with high atroposelectivity, without the use of an external chiral source. From the resulting biaryl product, several naphthylisoquinoline alkaloids were prepared via the stereoselective formation of the isoquinoline framework with the appropriate oxidation state and stereochemistry.

A highly concise strategy for the total synthesis of phenanthroindolizidines was developed. The one-pot iterative Suzuki−Miyaura reaction of aryl boronic acids with ortho-bromoaryl N-methyliminodiacetate (MIDA) boronate followed by a second Suzuki−Miyaura reaction with a suitable pyridyl bromide provided ortho-aza-terphenyls. Subsequent saturation of the triple bond, treatment with mesyl chloride, and reduction of the resulting dihydroindolizidinium ring afforded the hexahydroindolizines. A final vanadium-catalyzed oxidative electrocyclization provided the desired alkaloids in only three column-separation operations.

A new protocol for the enantioselective synthesis of 3,3'-disubstituted-1,1'-bi-6-methoxy-2-phenol (BIPhOL) derivatives is described. Diastereomeric resolution of racemic BIPhOL boronic acid using a boronic acid moiety as a resolving group generated two diastereomers and subsequent Suzuki-Miyaura coupling reaction of the resulting diastereomers with aryl halides provided BIPhOL derivatives without any loss of enantioselectivity. In addition, the absolute stereochemistry of chiral BIPhOL was determined by comparison of the optical rotation with the reported value.

A concise and general strategy for the total synthesis of the phenanthroquinolizidine alkaloids has been developed. An iterative Suzuki−Miyaura coupling reaction between the requisite aryl boronic acid, 2-bromo-4,5dimethoxyphenyl N-methyliminodiacetate (MIDA) boronate derived from boronic acid, and a suitable bromopyridine substrate bearing a homopropargyl alcohol at the 2-position generated the desired ortho-aza-terphenyl compounds. Hydrogenation of the triple bond followed by treatment with methanesulfonyl chloride afforded their corresponding tetrahydroquinolizinium ion intermediates, which were subsequently reacted with NaBH 4 to provide the desired hexahydroquinolizine products. A final oxidative electrocyclization reaction gave the target phenanthroquinolizidine natural products. This synthetic approach only requires the use of three chromatographic separations throughout the entire synthesis.