Rapid Synthesis of theN-Methylwelwitindolinone Skeleton

Abstract

An efficient, convergent synthesis of the core bicyclo[4.3.1]decane ring system of welwitindolinones is described. Key steps in the synthesis include an intramolecular palladium-catalyzed enolate arylation reaction to create the desired bicyclic skeleton and a Curtius rearrangement to install the bridgehead isocyanate unit. [reaction: see text]

Transition Metal-Catalyzed Direct Arylation of Substrates with Activated sp3-Hybridized C−H Bonds and Some of Their Synthetic Equivalents with Aryl Halides and Pseudohalides

“…263 An interesting example of palladium-catalyzed intramolecular arylation of a -ketoester was reported by Rawal et al in 2005. 264 The reaction (Scheme 84), which was used as a key step in an efficient convergent synthesis of the bicyclo[4.3.1]decane ring system of welwitindolinones, a new class of indole alkaloids, gave the best result when Pd(OAc) 2 , the P(t-Bu) 3 ligand, and the base were premixed at room temperature, followed by addition of a toluene solution of substrate 204. 264 Intriguing examples of syntheses of ethyl arylacetates via palladium-catalyzed intermolecular arylation of ethyl acetoacetate with aryl bromides and chlorides, followed by deacylation under the reaction conditions, were described by Parkinson et al in 2004.…”

Transition metals in organic synthesis: Highlights for the year 2005

“…Both C-and O-alkylation was observed upon arylation of 6,8-dimethoxybenzofuran-3-one [368]. Intramolecular palladium-catalyzed ␣-alkenylations or -arylations of ketones were used to polycyclic indole alkaloids [369], Nmethylwelwitindolinone skeleton [370,371], ABC ring system of calyciphylline A [372], gardnerine and gardnutine [373], and lennoxamine, 13-deoxychilenine, and chilenine [374]. Palladium catalyzed an intramolecular ␣-arylation of an imine (Eq.…”

“…(50)) [489]. (50) Palladium-catalyzed oxidative addition to 2-iodobenzenamine derivatives followed by alkyne insertion and intramolecular amino-palladation producing indoles were used to prepare a variety of alkaloids [370,490,491,373]. Palladium catalyzed the reaction of 2-iodopyrroles with 4-ynoic acids (Eq.…”

Synthetic studies on the ambiguine family of alkaloids: construction of the ABCD ring system

“…Tetracycle 15 was formed in 58% over two steps, whereas tetracycle 11 was formed in 27% over eleven steps clearly showing the advantage of the tin-mediated chemistry. It was thought that utilizing this methodology, which has been used in a variety of alkaloid syntheses,10,11,12,13 we could gain rapid access to the ABCD ring system of the ambigiunes in a more efficient manner than that extant.…”