Recent Advances for the C–C and C–N Bond Formation in the Synthesis­ of 1-Phenethyl-tetrahydroisoquinoline, Aporphine, Homoaporphine­, and β-Carboline Alkaloids

Abstract

Among the existing methods for the synthesis of bioactive and/or complex small molecules, organic transformations such as C–C and C–N bond formation have been significantly developed and exploited for the synthesis of diverse synthetic and natural fused aza-polycycles. The abundance and biological and physical activities of 1-phenethyl-tetrahydroisoquinolines, aporphines, homoaporphines, and β-carbolines have inspired many organic chemists to seek sustainable and efficient protocols for their preparation. However, these methodologies involve multiple steps and in most cases the key reaction step is based on the formation of new C–C and/or C–N bonds, and this is usually the critical step that lowers the yields and selectivity. This review is focused on the advances made in recent years regarding the synthesis of these selected natural fused aza-polycycles, overviewing the substrate scope, limitations, regioselectivity, and chemoselectivity, as well as related control strategies of these reactions, concentrating on developments from 2010 to 2016.1 Introduction2 1-Phenethyl-tetrahydroisoquinolines; Dysoxylum Alkaloids3 Aporphines, Homoaporphines, and Semisynthetic Derivatives4 Harmala and Eudistomin Alkaloids and Their Biological Properties5 Metal-Catalyzed C–C Bond Formation6 Pd-Catalyzed C–C and C–N Bond Formation7 Metal-Catalyzed C–N Bond Formation8 [4+2] Cycloaddition in the Synthesis Of Aporphines9 Tandem C–N/C–C Bond Formation: The Pictet–Spengler Reaction10 Miscellaneous Methods11 Conclusions

Direct C–H functionalization of tetrahydro-γ-carbolines at the α-position

“…Eudistomin U as an important natural product possesses pharmacologic activities. 19 We developed an efficient synthesis of γ-eudistomin U ( 51 ) by using 40 as a substrate, and the related derivatives were obtained in good yield (Scheme 3B).…”

Synthesis, In Silico and In Vivo Toxicity Assessment of Functionalized Pyridophenanthridinones via Sequential MW-Assisted Intramolecular Friedel-Crafts Alkylation and Direct C–H Arylation

“…Phenanthridinone analogs are key scaffolds with a potential activity against neurodegenerative disease [ 12 ], and they are also antitumoral [ 13 ] and anti-HIV [ 14 ], with an immunomodulatory activity [ 15 ]. To the best of our knowledge, the chemistry, synthetic approaches, and biological activities of pyridophenanthridinones 3 – 4 remain unexplored, and just a few reports regarding the synthesis of system 3 have been reported so far [ 16 , 17 ], as they are analogs of aporphine alkaloids [ 18 ]. In the case of derivatives 4 , any attempts for their synthesis have failed or have not been reported yet.…”

Biomimetic Total Synthesis of Dysoxylum Alkaloids

“…Thus, the responsibility of preparing these alkaloids at multigram scale in a laboratory lays on the organic chemist. ( S )-Homolaudanosine was the first synthesized derivative of this family (1987), and although several elegant works have been reported during the last 9 years for the total synthesis of Dysoxylum alkaloids, none of them attempted to mimic their biosynthesis, so these approaches involved many synthetic steps, were directed to obtain one or a few compounds, and resulted in poor overall yields (Table ). − …”