A Short Synthesis of (±)‐3‐Demethoxyerythratidinone by Ligand‐Controlled Selective Heck Cyclization of Equilibrating Enamines

Abstract

As hort, 5-step total synthesis of (AE)-3-demethoxyerythratidinone from as imple pyrrole derivative is described. Features include the formation of gram quantities of ak ey tricylic aziridine from ac hallenging photochemical cascade reaction through the use of flowphotochemistry.The final step involved ah ighly unusual Heckc yclization whereby ligand control enabled efficient formation of the natural product in 69 %y ield from the minor isomer present in an equilibrating mixture of labile enamines.The alkaloid (+ +)-3-demethoxyerythratidinone 1 is one of over 100 natural products produced by the Erythrina genus of flowering plants. [1] The Erythrina alkaloids display ab road range of pharmacological activities including hypotensive, sedative,n euromuscular blocking,C NS depressing and curare-like activities.T he key structural feature of this family is the tetracyclic tetrahydroisoquinoline core.S ince the first total synthesis of 1 by Tsuda in 1984, [2] this tetracyclic alkaloid has been used by others in order to demonstrate the utility of various synthetic methodologies.[3] Av ery elegant synthesis was recently reported by Reisman, where chiral sulfinyl imine chemistry was used to control the stereochemistry of the key quaternary center, [3d] giving (À)-3-demethoxyerythratidinone in just six steps overall (Figure 1).Individually both photochemical and Pd-catalyzed crosscoupling methodologies have been shown to be powerful techniques in organic synthesis as well as valuable tools in the synthesis of complex molecular architectures.[4] We have previously reported the photochemical transformation of simple N-butenyl-substituted pyrroles into complex tricyclic aziridines 2.[5] We recently demonstrated that these strained photochemical products undergo arange of thermal and Pdcatalyzed ring-opening/annulation reactions to produce ab road range of fused polyheterocycles,i nj ust two steps from simple pyrroles (Scheme 1).[6] We were therefore keen to exploit the functionality and inherent strain in these aziridines as part of an alkaloid synthesis,i np articular the aziridine carboxylates 3.H erein we report as hort total synthesis of (AE)-1 utilizing ah ighly unusual and selective, ligand controlled intramolecular Heck-reaction onto one of apair of equilibrating enamine intermediates. Our initial strategy to 1 (Scheme 1) involved aryl cyclization onto the iminium ion 4 which itself would be generated by in situ decarboxylation of the amino acid 5.[7] Although iminium ion cyclizations are one of the most frequently used approaches to such alkaloids, [8] these have usually involved the intermediary of N-acyliminium ions.[9] Ther equisite amino-acid 5 should be obtained by Pd 0 -catalyzed acetate ring-opening of the aziridine 3 followed by N-alkylation with the iodide 6.Irradiation of pyrrole 7 (254 nm) gave the aziridine (AE)-8 in a39% yield (Scheme 2). As before,wefound that this two- photon process suffers from low productivity due to al ikely low overall quantum yield and as such was limited to ca. 60 ...

Insights into the Regioselectivity of Metal-Catalyzed Aryne Reactions

“…Inspired by ligand-controlled selectivity in other metal-mediated transformations, 49 50 51 52 53 54 55 56 57 we postulated that ligands could be used to control the binding and subsequent functionalization of the aryne. We selected a palladium-catalyzed annulation developed by Larock and co-workers for the synthesis of phenanthridinones as our model reaction.…”

Intramolecular Heck Reaction in Total Synthesis of Natural Products: An Update

“…Finally, the methylation of alcohol 102 using the Tsuda procedure, furnished the targeted natural product in an excellent yield (96 %). In 2017, Booker‐Milburn et al [33a] . reported the total synthesis of another erythrina alkaloid (+)‐3‐demethoxyerythratidinone ( 108 ) (Scheme 11) where it was shown an interesting outcome of Heck cyclization based on the electron‐donating ability of phosphine ligand.…”

Flow Chemistry for Cycloaddition Reactions

“…What is more, the same group described a 5‐step total synthesis of (±)‐3‐demethoxyerythratidinone, a natural alkaloid, from a simple pyrrole derivative, being the key step the formation of the tricyclic aziridine in flow. This was produced in gram quantities, which would have been very difficult to achieve in batch due to the high dilution and irradiation times required …”