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

ABSTRACT: The enolate monoanion of amino esters is explored, and the first catalytic Michael addition of ?-amino esters is demonstrated. These studies indicate that the acidity of the ?C-H is the primary factor determining reactivity. Thus, polyfluorophenylglycine amino esters yield novel ?-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 ?-secretase inhibitor, DAPT.

SUBMITTER: Teegardin KA

PROVIDER: S-EPMC6581451 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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

Teegardin Kip A KA Gotcher Lacey L Weaver Jimmie D JD

Organic letters 20181102 22

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-C ...[more]

PMID: 30387616

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