Formation of Non-Natural α,α-Disubstituted Amino Esters via Catalytic Michael Addition

Abstract

<p class="first" id="P1">The enolate monoanion of amino esters is explored, and the first catalytic Michael addition of α-amino esters is demonstrated. These studies indicate that the acidity of the αC–H is the primary factor determining reactivity. Thus, polyfluorophenylglycine amino esters yield novel α-amino esters in the presence of a catalytic amount of a guanidine derived base and Michael acceptors. Reactivity requires an acidic N–H, which is accomplished using common protecting groups such as N-Bz, N-Boc, and N-Cbz. Calculations and labeling experiments provide insight into the governing principles, in which a key C-to-N proton transfer occurs, resulting in an expansion of the scope to include a number of natural amino esters. The study culminates with a late-stage functionalization of peptidic γ-secretase inhibitor, DAPT. </p><p id="P2"> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/40f0f0cc-7327-46e2-95cc-6d8afa8dd959/PubMedCentral/image/nihms-1034798-f0001.jpg"/> </div> </p>