Abstract
Judicious substrate design allows interruption of the classical Bischler–Napieralski reaction, providing access to a range of diversely substituted tetracyclic spiroindolines. These complex polycyclic scaffolds are valuable building blocks for the construction of indole alkaloids, as showcased in a concise total synthesis of (±)-akuammicine.
Highlights
Judicious substrate design allows interruption of the classical Bischler–Napieralski reaction, providing access to a range of diversely substituted tetracyclic spiroindolines
Cascade reactions allow the rapid generation of molecular complexity through multiple sequential bond-forming events in a one-pot process
These exceptional advantages over traditional stepwise procedures make them suited to efficiently access complex molecules such as natural products.[1]
Summary
Synthesis of tetracyclic spiroindolines by an interrupted Bischler–Napieralski reaction: total synthesis of akuammicine† Judicious substrate design allows interruption of the classical Bischler–Napieralski reaction, providing access to a range of diversely substituted tetracyclic spiroindolines. Following our interest in indole alkaloids and related compounds,[10] we recently discovered that reaction of styrylacetamides 4 under typical Bischler–Napieralski conditions (POCl3, MeCN, Δ) leads to near-quantitative formation of carbazoles 5 instead of the expected dihydro-β-carbolines (Scheme 1A).[11] Our ensuing mechanistic investigation revealed a highly complex cascade pathway (Scheme 2) which proceeds via several intriguing intermediates.[11] In particular, the tetracyclic spiroindoline 10 caught our interest, owing to its wide-spread presence in indole alkaloids.7i our efforts to isolate 10 (R1 = H) were futile, frustrated by an elimination step (Scheme 2A) that always follows.
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