Synthesis of Natural Product-like Polyheterocycles via One-Pot Cascade Oximation, C–H Activation, and Alkyne Annulation

Abstract

An efficient protocol for the direct transformation of chroman-4-ones to tricyclic fused pyridines with the skeleton of cassiarins, a family of alkaloids with antimalarial activity, was developed. Also, a general strategy for modular construction of polyheterocycles with diverse natural product-like skeletons was developed by using ketone-alkyne bifunctional substrates. These reactions involved a one-pot cascade oximation of ketones, rhodium-catalyzed C-H activation, and intermolecular/intramolecular alkyne annulations under mild conditions with high atom, step, and redox economy.

A comprehensive overview of directing groups applied in metal-catalysed C–H functionalisation chemistry

“…Hua and co-workers developed an alkenylation–cyclisation sequence in which the oxime DG is formed in situ via reaction of a carbonyl group with hydroxylamine hydrochloride ( Scheme 58E ). 320 Starting from chroman-4-ones, tricyclic fused pyridines were easily accessible, which allowed rapid access to the skeleton of cassiarins, a family of alkaloids with antimalarial activity. Yields were typically >80% and a hydroxyl and bromine function were tolerated without any loss in efficiency.…”

C–H Activation and Alkyne Annulation via Automatic or Intrinsic Directing Groups: Towards High Step Economy

“…Recently, we extended the oxime DG auto strategy to chroman‐4‐ones for construction of the skeleton of cassiarins, a family of natural product with various bioactivities . Under an enhanced condition of previous isoquinoline synthesis, a library of multi‐substituted tricyclic N ‐heterocycle was obtained (Scheme ) . Both aryl–alkyl and alkyl–alkyl unsymmetrical alkynes were reacted with high regioselectivity, but terminal alkynes were not productive during our effort towards total synthesis of cassiarins using propyne or its surrogates.…”

“…Based on the above success on intermolecular alkyne annulation via oxime DG auto , we embarked on extending the strategy to an intramolecular way (Scheme ) . We designed two types of ketone−alkyne bifunctional substrates with suitable linkers.…”

Regioselective Direct C‐Alkenylation of Indoles

“…The introduction of hydroxylamine hydrochloride in the Rh III ‐catalyzed reaction of differently tethered 3‐acetyl‐ N ‐alknylindoles ultimately affords γ‐carboline derivatives (Scheme ) . The ring closure is preceded by the oxime formation which upon nitrogen coordination with the metal favors the C−H activation and drives the ring closure towards the exo mode .…”

“…[136] In both cases, the CÀHa ctivation at the 2p ositioni sa ssisted by the carbonyl The introduction of hydroxylamine hydrochloride in the Rh IIIcatalyzed reactiono fd ifferently tethered 3-acetyl-N-alknylindoles ultimatelya ffords g-carbolined erivatives (Scheme 64). [137] The ring closure is preceded by the oxime formation which upon nitrogen coordinationw ith the metal favors the CÀHa ctivationa nd drives the ring closuret owards the exo mode. [138] The length of the tether has ac rucial effect on the success of the intramolecular reactions ince short (n = 0) or long alkyl chains( n = 3-4) are ineffective in leadingt ot he g-carboline products.Furthermore, the NÀOb ond of the oxime acts an autocleavablei nternal oxidant increasing the efficency of the whole procedure.…”