Enantioselective Construction of the ABCDE Pentacyclic Core of the Strychnos Alkaloids

Abstract

An efficient enantioselective 12-step synthesis of the ABCDE pentacyclic core of the Strychnos alkaloids is described. A key feature of this approach is an organocatalyzed enantioselective desymmetrization to generate the morphan core in high ee and dr. After palladium-catalyzed installation of the indole moiety, a subsequent 5-exo-trig dearomatizing atom transfer radical cyclization was developed to construct the C-ring. Following a series of functional group interconversions, the pentacyclic amine core was obtained with all the relevant architecture including five stereocenters pertaining to the Strychnos alkaloids.

Catalytic Reductive Functionalization of Tertiary Amides using Vaska’s Complex: Synthesis of Complex Tertiary Amine Building Blocks and Natural Products

“…Succeeding the above studies, in early 2017, Dixon et al reported the use of the Vaska/TMDS system in their synthesis of the pentacyclic core of the Strychnos alkaloids. 65 The authors constructed the tetracyclic precursor in 10 steps from a 4substituted cyclohexanone derivative, using an organocatalytic intramolecular Michael addition as the key enantioselective step, setting three stereogenic centers with excellent absolute and relative stereocontrol (Scheme 17). Tetracycle 3 was then smoothly converted to the tertiary amine.…”

Radical Heterocyclization and Heterocyclization Cascades Triggered by Electron Transfer to Amide‐Type Carbonyl Compounds

“…For example, recent advances in the one‐step construction of polycyclic systems possessing bridgehead nitrogen atoms include the [4+2]/[3+2] cycloaddition cascades of Boger, the rhodium(II)‐catalyzed cyclization/[3+2] cycloaddition cascades of Padwa and Zhai, and Movassaghi's double intramolecular trapping of iminium ions . Perhaps because of the challenge associated with the control of selectivity in the reactions of highly reactive open‐shell intermedates, the otherwise desirable use of radical cyclizations and cyclization cascades to assemble such systems is rare …”

An Environmentally Benign Multicomponent Cascade Reaction of 3-Formylchromones, 2-Naphthols, and Heterocyclic Ketal Aminals: Site-Selective Synthesis of Functionalized Morphan Derivatives

“…The synthetic strategies for producing morphan derivatives include nitroso-ene cyclization, aza-Wacker annulation, radical cyclization, Michael or double Michael reaction, [3+3] annulation, α-arylative desymmetrization of cyclohexanones, and others . Although these protocols have made vital contributions to the synthesis of these types of compounds, they also have some shortcomings, such as the requirement of a metal catalyst under strict anhydrous conditions, basing the prefunctionalized substrates, and using a two-component rather than a multicomponent reaction that limits the structural diversity of the target compounds, especially the highly functionalized products.…”