Dimethylformamide Acetals and Bredereck’s Reagent as Building Blocks in Natural Products Total Synthesis

Abstract

Dimethylformamide acetals and Bredereck’s reagent (tert-butoxy-bis(dimethylamino) methane) are versatile C1 building blocks due to their ability to undergo condensation reactions with CH-acidic methyl and methylene moieties. Subsequent modulation of the resulting condensation products enables the preparation of open-chain products like aldehydes, ketones, enones, enol ethers, methyl groups, and, most important in alkaloid total synthesis, the annulation of heterocyclic rings like pyridines, pyridine-N-oxides, bromopyridines, aminopyridines, aminopyrimidines, pyrroles and chromenones. In certain cases, these reagents can act as alkylating agents. The applications of these building blocks in natural products total synthesis are reviewed here.

Synthesis of 1,4‐Disubstituted and 1‐Substituted β‐Carbolines via 3‐Substituted 2‐Acylindoles

“…Due to the limited availability of these intermediates and their lachrymator properties, protocols utilizing alternative building blocks were desirable. Cyclizations of intermediates of type B into 3‐substituted 2‐acylindoles C have only been performed for diketones and ketoesters (Z=keto group or ester) until now, hence the extension to other Z groups was to be explored. Most desirably, our previously described one‐pot approach [11b] consisting of N ‐oxomethylation of sulfonamides of type A , directly followed by cyclization to give indoles of type C should be extended to the new target compounds containing various Z groups. The final operation, the cyclization of 2,3‐disubstituted indoles C under regioselective aminomethylenation with formamide derivatives (dimethylformamide (DMF) dialkyl acetals, Bredereck's reagent [14] ) to give enamines of type D , followed by ring closure with ammonium salts. This final step was challenging as well, since undesired side‐reactions of these formylating agents with other CH‐acidic methyl(ene) groups (as present if R was an alkyl residue or if Z contained a second acidic group, like alkyl ketones or alkyl sulfones) and NH‐acidic amide groups of the intermediates C could not be ruled out.…”

Nucleophilic Vinylic Substitution in Perfluoroacylchromenes. Diastereoselective Synthesis of Push–Pull Enamino Ketones

“…Enamino ketones [1] exhibit ambident nucleophilicity of enamines and ambident electrophilicity of enones and are widely used in the synthesis of various heterocycles [2][3][4] and natural compounds [5][6][7], primarily alkaloids with a broad spectrum of biological activity [8][9][10]; they can also act as multidentate ligands capable of coordinating many transition metals [11]. On the other hand, the reactivity of enamino ketones fairly strongly differs from the reactivity of enamines and α,β-unsaturated ketones themselves.…”