A convenient approach to the canthin‐4‐one ring system: Total synthesis of the alkaloids tuboflavine and norisotuboflavine

Abstract

in Wiley InterScience (www.interscience.wiley.com).Canthin-4-one, as well as 5-and 6-alkylcanthin-4-ones are readily available through reaction of 1-acyl-b-carbolines with Bredereck's reagent or dimethylacetamide acetals in anhydrous DMF. The intermediate enaminoketones readily undergo cyclization to the canthin-4-ones. The alkaloids tuboflavine and norisotuboflavine were prepared following this methodology.

New approaches to the synthesis of canthin-4-one alkaloids and synthetic analogues

“…In contrast to the tertiary enaminoketone intermediates B ( Fig. 1) in our previous canthin-4-one synthesis 4,8 (Fig. 1) the obtained primary enaminoketones 10aec did not undergo spontaneous cyclization to the desired canthin-4-ones (1aec).…”

“…Mp 298 C (lit. 8 ethan-1-one 6a (179 mg, 1.11 mmol) in THF (0.5 mL) was added dropwise, and the mixture was stirred at 0 C for 2 h and at rt for additional 15 h. Water (30 mL) was added and the mixture was extracted with methylene chloride (3Â15 mL). The combined organic layers were dried over Na 2 SO 4 and the solvents were concentrated under reduced pressure.…”

“…11e13 Another multistep approach to the canthin-4-one backbone was published in a patent. 6 Later, our group developed a versatile approach to the canthin-4-one ring system (1) via a condensation of 1-acyl-b-carbolines (A) with amide acetals or Bredereck's reagent (tert-butoxy-bis(dimethylamino)methane) to give enaminoketones (B), which undergo cyclization under the reaction conditions 4,8 (Fig. 1).…”

“…5,7 Ring transformation reactions of canthin-4-ones with guanidinium salts give 1-(2-aminopyrimidin-4-yl)-b-carbolines, e.g. the anxiolytic alkaloid annomontine, 8,9 and its antimalarial analogue C-117. 10 Multistep total syntheses with very poor overall yields have been worked out decades ago for confirmation of the structures of the three alkaloids.…”

“…Cyclization of the diketones was expected to give the canthin-4-one scaffold (1). In a second approach we intended to find alternatives to the 1-acyl-b-carboline intermediates, since these are accessible only by using laborious methods (radical reactions, 8,14,15 organometallic chemistry 16 ) or expensive organostannane building blocks. 17 1-Isoxazolyl-b-carbolines (D) were considered as versatile intermediates, which should give primary enaminoketones (E) upon reductive ring cleavage, 18 and the latter were expected to cyclize to the canthin-4-one ring system in a similar manner as known for tertiary enaminoketone intermediates (B) (Fig.…”