Synthesis of fused tricyclic amines unsubstituted at the ring-junction positions by a cascade condensation, cyclization, cycloaddition then decarbonylation strategy

Abstract

SummaryHeating aldehydes that contain a protected hydroxymethyl group, a tethered alkyl chloride and a tethered alkenyl group at the α-position of the aldehyde with an amine sets up a cascade (tandem) reaction sequence involving condensation to an intermediate imine, then cyclization and formation of an intermediate azomethine ylide and then intramolecular dipolar cycloaddition. The fused tricyclic products are formed with complete or very high stereochemical control. The hydroxymethyl group was converted into an aldehyde – which could be removed to give the tricyclic amine products that are unsubstituted at the ring junction positions – or was converted into an alkene, which allowed the formation of the core ring system of the alkaloids scandine and meloscine.

Application of Transition Metal‐Catalyzed Decarbonylation of Aldehydes in the Total Synthesis of Natural Products

“…Coldham's group succeeded in synthesizing a tricyclic amine core ring system [53] which can be found in alkaloids such as meloscine and scandine (Scheme 23). [54] Swern oxidation was used to oxidize alcohol 77 to aldehyde 78 , which was then decarbonylated with retention of configuration using a stoichiometric amount of Wilkinson's catalyst in benzonitrile as solvent.…”

A Domino Aza-Piancatelli Rearrangement/Intramolecular Diels–Alder Reaction: Stereoselective Synthesis of Octahydro-1H-cyclopenta[cd]isoindole

“…The efficiency of this process has inspired much interest among the synthetic community to design and develop novel cascade strategies . The angularly fused 5–6–5 aza-tricyclic core is very common in numerous natural products, exhibiting a broad spectrum of biological activities such as antipyretic, antihypertensive, anti-inflammatory, antitumor, anti-HIV, and anticancer (Figure ). Synthesis of alkaloids having an angularly fused aza-tricyclic core has attracted significant attention due to their structural complexity coupled with the broad spectrum of biological activities. − …”

“…Natural alkaloids such as dendrobine, gracilamine, deethylibophyllidine, and epimeloscine possess the 5–6–5 aza-tricyclic core (Figure ). As a consequence of their remarkable structural frameworks, various approaches have been developed for the construction of the 5–6–5 aza-tricyclic core, using intramolecular [3+2] cycloaddition, Diels–Alder reaction, Mannich reaction, and radical cyclization as a key step. − Nevertheless, new synthetic strategies for the construction of functionalized the aza-tricyclic core with remarkable efficiency and exquisite selectivity are urgently being sought.…”

Radical [3 + 2]-Annulation of Divinylcyclopropanes: Rapid Synthesis of Complex Meloscine Analogs

“…We have recently reported a short total synthesis of the pentacyclic alkaloid meloscine 1a that featured a tandem [3 + 2] radical annulation reaction of a divinylcyclopropane (DVCP) to assemble the C-ring and the adjacent bonds (represented in red in Figure ). − The two examples reported in that synthesis are shown in Scheme . Radical cyclization of sec -amide 4 provided lactam 6 (R = H) in 38% yield while tert -amide 5 gave the corresponding lactam 7 (R = Bn) in 55% yield.…”