Total Synthesis of Phenanthroquinolizidine Alkaloids Using a Building Block Strategy

Abstract

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.

A Stereodivergent Strategy for Total Syntheses of Antirhine Alkaloids

“…Because direct hydrogenation of the pyridine ring in compounds 15 and 17 provided cis -indoloquinolizidine compounds ( 16 and 18 ) as the major products regardless of the protection of the indolic N-H group, the preparation of the trans -indoloquinolizidine core was attempted through a two-step reduction of the pyridinyl ring (Scheme c). It was envisaged that the pyridinium ring in 14 could be reduced to tetrahydropyridine 19 and subsequent trans -selective reduction of the double bond in the resulting tetrahydropyridine 19 could afford trans -indoloquinolizidine 12 . , Based on this new strategy, 15 was first converted into the corresponding indoloquinolizidinium 14 in a quantitative yield by the treatment with HCl. However, the α-proton of the 1,3-dicarbonyl group in 14 was still sufficiently acidic to undergo deprotonation during purification on silica.…”

Design, Synthesis, Antivirus Activity, and SARs of Phenanthroquinolizidine Alkaloid Derivatives

“…Although the antiviral activity and SARs of phenanthro indo lizidine alkaloids have been well studied, ,,,,, their siblings, phenanthro quino lizidine alkaloids, were almost ignored until our recent studies on the influence of the skeleton and conformation of D/E rings on the anti-TMV activity (Figure ). These studies demonstrated that although phenanthro indo lizidine and phenanthro quino lizidine alkaloids have similar structures, the same change on the original skeleton of the D/E rings might cause a totally different influence on the activity. , Because fewer phenanthroquinolizidine alkaloids were reportedonly nine members are known by now, much less synthetic methodology was developed. − In addition, all of the synthesis was designed for the 14a- H phenanthroquinolizidine alkaloids, and the approach to the synthesis of 14a-substituted analogues was unknown. Herein, we report the design, synthesis, and antiviral evaluation of phenanthroquinolizidine alkaloid derivatives for the first time.…”

Total Synthesis of Phenanthropiperidine Alkaloids by Sequential Alkylation of N,N‐Dibenzylaminoacetonitrile

“…[9] These significant biological properties have incited chemists to propose numerous syntheses. The most recent racemic approaches to alkaloids 1 and 2 rely on various methodologies, including iterative Suzuki-Miyaura reaction of boronic acids, [10] intramolecular aza-Diels-Alder condensation, [11] free radical cyclizations, [12] Cp*Co III or Rh III -catalyzed annulation of terminal alkynes, [13] Pd-catalyzed aryne annulation by o-halostyrenes, [14] Stevens rearrangement of a nitrile stabilized ylide, [15] or Negishi cross-coupling reaction. [16] Several well-designed approaches utilizing chiral catalysts have also led to the synthesis of title alkaloids with high enantiomeric ratios.…”