Synthetic Studies on Didymeline Using Spirocyclization of Phenols with Diazo Functionality

Abstract

Didymeline is an alkaloid with an azaspiro tricyclic skeleton with various functionalities. Despite the fact that its unique architecture is synthetically attractive, its total synthesis has never been achieved before. Herein, we present synthetic studies on the core structure of didymeline. Accordingly, a spiro ring system was constructed through dearomatization of a phenol derivative with α-diazoamide unit. Based on the resulting 2-azaspiro [4,5]decane variant, a tricyclic molecule was synthesized via base-promoted intramolecular ring closure.For an asymmetric synthesis, an enantioselective dearomatization was also examined under silver catalysis, which led to the formation of an all-carbon substituted quaternary stereogenic center.Didymeline and dihydrodidymeline were isolated from the leaves of Didimeles madagascariensis by Ahond and Poupat group in 1987 (Figure 1). 1 The chemical structure of these alkaloids includes a tricyclic ring system comprising a 2-azaspiro [4,5]decane with multiple contiguous stereocenters; this is a characteristic architecture also found in bioactive steroidal alkaloids, such as (+)-conessine (a histamine H 3 antagonist) 2 and holadienine. However, to date, the total synthesis of didymeline or dihydrodidymeline has not been achieved due to their structural complexity; thus, their pharmaceutical activities have remained unclear.

Development of Novel Methodology Using Diazo Compounds and Metal Catalysts

“…[14][15][16][17] Our group envisioned that chemoselective arene dearomatizations could be designed by applying an electrophilic metal-carbene if the competing C-H insertion and Buchner ring expansion could be suppressed by suitable selection of the metal-center and supporting ligands. Firstly, diazoamide 5a having 1°, 2° and 3° C-H bond near the reaction site was prepared to assess chemoselectivity [18][19][20] (Table 2). The reaction employing a rhodium or copper complex provided a mixture of C-H insertion products 8a and 9a, and tropone variant 7a through a Buchner reaction (entries 1 and 2).…”