Vellalath S, Van KN, Romo D * Texas A&M University, College Station, USA
Direct Catalytic Asymmetric Synthesis of N-Heterocycles from Commodity Acid Chlorides by Employing α,β-Unsaturated Acylammonium Salts.
Angew. Chem. Int. Ed. 2013;
DOI:
10.1002/anie.201306050
Key words
asymmetric organocatalysis - γ-lactams - δ-lactams - δ-lactones - radical reaction
Significance
The reported method for the synthesis of lactams and lactones 4 employs quinine- and quinidine-derived catalysts 3 to activate α,β-unsaturated acid chlorides 1 toward reaction with bisnucleophiles 2. A variety of heterocycles relevant to medicinal and natural product chemistry were obtained, including 2-pyrrolidinones, 2-piperidinones, enol δ-valerolactones, and 3,4-dihydro-2-pyridinones. The yields are modest to good and enantioselectivity is good to excellent. The method was demonstrated to provide two intermediates for drug synthesis (one on a gram scale).
Comment
For success of the reported method, significant tuning of the reaction conditions to the substrate, including the use of excess reactant; the choice of base, catalyst, and temperature; and the use of additives, is required. Catalyst 3b affords products of opposite configuration to those obtained using 3a or 3c; although, in our opinion, the publication relies too heavily on assumptions in drawing this conclusion. In the synthesis of piperidinones, a retro-aza Michael side reaction results in low yields of the desired product. Interestingly, Michael addition, not acylation, appears to be the first mechanistic step, a fact essential to explaining the enantioselectivity.
