Cascade Annulation Reactions To Access the Structural Cores of Stereochemically Unusual Strychnos Alkaloids

Abstract

A new cascade annulation reaction has been developed to access the core structures of a novel family of strychnos alkaloids with a unique stereochemical arrangement. The new annulation cascade is facilitated by the development of a ro-

Synthesis of Spirocyclic Indolines by Interruption of the Bischler–Napieralski Reaction

“…Heating the reaction to 45 °C in an oil bath afforded (±)- 8h in excellent yield 14 (Scheme 2, 91% yield), while brief heating in a microwave 15 to 130 °C provided (±)- 8h in quantitative yield. While similar cascades have been reported previously, the lack of any requirement of large excesses of activating agents 3a,c,d and the ability to completely avoid Wagner–Meerwein rearrangement 3d are specific advantages to the chemistry described here, and highlight the importance of nitrogen lone pair deactivation by the highly electronegative trifluoromethanesulfonyl group. Not surprisingly, electron-rich 3,4-dimethoxyphenylacetamide 1i provided pentacycle (±)- 8i in 98% yield as a single regio- and diastereomer 9 under 45 °C conditions on half-gram scale (Scheme 2).…”

“…Consistent with this hypothesis, the use of excess Tf 2 O (2.1 equiv) and 2-ClPyr (3.2 equiv) increased the yield of (±)- 3a to 30% together with a complex mixture of side products and none of the Bischler–Napieralski product 2a . Given the propensity of spiropyrrolidinoindoleninium intermediates to undergo Wagner–Meerwein rearrangement unless a strongly nucleophilic trap is present during spirocyclization, 2c,g,3a–f,h–k we hypothesized that the reduction at C2 may have been the result of a rapid hydride transfer reaction between two intermediates along the reaction pathway (Scheme 1). 8 …”

“…The exceptional resilience of the intermediates, accessed under the described reaction conditions, to Wagner–Meerwein rearrangement allows for efficient intra- and intermolecular trapping with nucleophiles, including weak nucleophiles such as deactivated arenes, even after activation and spirocyclization. The use of urea and tertiary amides under our conditions allows for the direct and highly diastereoselective synthesis of spiropyrrolidinoindolines without competitive rearrangement 2c,3a,c–e,h,k or the need for an electron-withdrawing group 2c,3a,c,d,g,j on the aliphatic or indole nitrogen atoms.…”

Highly Efficient Formal [2+2+2] Strategy for the Rapid Construction of Polycyclic Spiroindolines: A Concise Synthesis of 11‐Demethoxy‐16‐epi‐myrtoidine

“…The only known example was reported by Delgado and Blakey, who have developed an elegant intramolecular annulation reaction starting from diketene [Scheme , Eq. (1)] …”

Synthetic Approaches to Tetracyclic Indolines as Versatile Building Blocks of Diverse Indole Alkaloids

“…The intriguing biological activities exhibited by malagashanine combined with its unprecedented trans ‐ring fusion stereochemistry between ring C and ring D have intrigued chemists to develop a new synthetic method to construct the uncommon tetracyclic indoline scaffold. In 2009, Blakey and co‐workers developed a Lewis acid catalyzed tandem cyclization strategy for the construction of the novel tetracyclic framework of the Strychnos system (Scheme a) . The amide 41 was synthesized by a condensation between tryptamine 40 and carboxylic acid 39 , which was prepared by a nickel‐catalyzed Kumada coupling.…”