Modular Syntheses of Phenanthroindolizidine Natural Products

Abstract

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.

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

“…HRMS (ESI + , CH 3 OH/CH 2 Cl 2 , C 24 H 28 NO 4 [M+H] + ) calcd 394.20128, found 394.2010. The analytical data were in agreement with those reported in the literature [10a] …”

“…Finally, the Pictet‐Spengler annulation of both amines 19 was carried out according to a formerly reported procedure in which the amines were refluxed in formic acid in the presence of an excess of paraformaldehyde (up to 9 equivalents) [38] . Under these reaction conditions, the title alkaloids 1 and 2 were obtained in 95 % and 86 % yields, respectively, and the proton and carbon spectroscopy data were found to be consistent with that reported in the literature [10a,18c] …”

Electrophilic Aminating Agents in Total Synthesis

“…There are over sixty reported alkaloids in this family, [270] and many are known to have potent bioactivities. As a result, there have been several reported syntheses; however, very few allow access to a wide array of these alkaloids [271, 272] . In the Wang approach, a radical cascade provides rapid access to the common polyheterocyclic core, thus enabling a general route to many members of the alkaloid family.…”

Possible pharmaceutical applications can be developed from naturally occurring phenanthroindolizidine and phenanthroquinolizidine alkaloids

“…Although tylocrebrine ( 12 ) was advanced to clinical trials but failed due to its central nervous system (CNS) toxicity manifested as disorientation and ataxia, naturally occurring PIA and PQA analogues along with their total or semi synthetic derivatives still attract great attention all along as potent anti-cancer agents because of their excellent biological activities, such as the isolation of new natural analogues (Yap et al 2016 ; Al-Khdhairawi et al 2017 ; Chen et al 2019a ; Thuy et al 2019 ), new synthetic methods and new anti-cancer mechanism on active agents (Chen et al 2016 ; Wang et al 2018 ; Jo et al 2019 ; Shimada et al 2019 ), etc. Therefore, it is worthwhile to carry out further investigations on natural species and organic reactions for more novel PIA and PQA analogues with great bioeffects.…”