First Atroposelective Total Synthesis of Enantiomerically Pure Ancistrocladidine and Ancistrotectorine

Abstract

The first regio- and stereoselective total synthesis of the axially chiral 7,3'-coupled naphthylisoquinoline alkaloids ancistrocladidine (1) and ancistrotectorine (2) has been described. Both possess a 7,3'-coupled axis, which before now, was difficult to attain synthetically. Moreover, target 2 has a sensitive relative cis-array of the two methyl groups at C1 and C3 in the tetrahydroisoquinoline part. The key step in the chosen strategy was the construction of the biaryl axis in accordance with the "lactone method": the two molecular halves, which were activated in an "inverse-halogenated" form, were prefixed by an ester bridge, followed by intramolecular coupling, and atroposelective cleavage of the lactone auxiliary bridge delivered the desired biaryl scaffold.

Dioncophyllines C2, D2, and F and Related Naphthylisoquinoline Alkaloids from the Congolese Liana Ancistrocladus ileboensis with Potent Activities against Plasmodium falciparum and against Multiple Myeloma and Leukemia Cell Lines

“…The absolute configuration at C-3 in the tetrahydroisoquinoline moiety was determined by ruthenium-mediated oxidative degradation. 30 The formation of R-3-aminobutyric acid proved the alkaloid to be R-configured at C-3. The relative configuration at C-1 versus C-3 was evidenced to be cis from a NOESY interaction between H-1 (δ 4.80) and H-3 (δ 3.32) (Figure 3B), which, given the above-determined absolute Rconfiguration at C-3, indicated C-1 to be S-configured.…”

Concise Total Synthesis of Dioncophylline E through an ortho‐Arylation Strategy

“…The first synthesis of a 7,3′‐linked alkaloid was that of ancistrocladidine ( 2 ) by our group, but the long endgame of this synthesis limits the utility for further work on analogue production . Bringmann and co‐workers recently developed an atropselective synthesis of 2 by making an advancement in his impressive “lactone method”, but the key biaryl‐bond‐forming step in this sequence could only be achieved in 32 % yield . There have been no reports of syntheses of the 5,3′‐linked members.…”

“…[10] Bringmann and co-workers recently developed an atropselective synthesis of 2 by making an advancement in his impressive "lactone method", but the key biaryl-bondforming step in this sequence could only be achieved in 32 % yield. [11] There have been no reports of syntheses of the 5,3'-linked members.T hus,there is room for improvement in the synthesis of these valuable scaffolds.…”

Cu-Catalyzed Enantioselective Atropisomer Synthesis via Thiolative Ring Opening of Five-Membered Cyclic Diaryliodoniums

“…Thus, much effort has been made in this area, and several elegant ligands and catalysts have been developed to realize highly enantioselective aryl–aryl cross-coupling. , Moreover, alternative methods, namely de novo aryl ring synthesis, asymmetric aromatic substitution, desymmetrization or (dynamic) kinetic resolution, , and chirality transfer, have been established, and the diversity of these axially chiral biaryl analogues has significantly improved. Recently, organocatalysis has emerged as a powerful method for the preparation of axially chiral biaryl compounds. , Through the lactone strategy, Bringmann and co-workers realized efficient syntheses for a series of axially chiral biaryls, including many atropisomeric natural products . Hayashi and co-workers reported a Ni-catalyzed ring-opening/cross-coupling reaction of dinaphthothiophene for the asymmetric synthesis atropisomeric (1,1′-binaphthalene)-2-thiol analogues …”