Metallophosphite-Catalyzed Asymmetric Acylation of α,β-Unsaturated Amides

Abstract

The l-menthone-derived TADDOL phosphite 6b catalyzes highly enantioselective conjugate additions of acyl silanes to α,β-unsaturated amides. p-Methoxybenzoyl cyclohexyldimethylsilane adds to a variety of N,N-dimethyl acrylamide derivatives in the presence of the lithium salt of 6b. In many instances the α-silyl-γ-ketoamide product undergoes facile enantioenrichment (to 97-99% ee) upon recrystallization. Desilylation with HF·pyr affords the formal Stetter addition products. BaeyerVilliger oxidation of the desilylated γ-ketoamides affords useful ester products. An X-ray diffraction study of 6b reveals that the isopropyl group of the menthone ketal influences the position of the synpseudoaxial phenyl group in the TADDOL structure. Through a crossover experiment, the silicon migration step in the reaction mechanism is shown to be strictly intramolecular.

Lanthanum Tricyanide-Catalyzed Acyl Silane−Ketone Benzoin Additions and Kinetic Resolution of Resultant α-Silyloxyketones

“…In the Stetter-type reaction, the resultant enolate was not sufficiently nucleophilic to undergo silyl transfer and initiate catalyst turnover. This is consistent with previous work in our lab on the metallophosphite-catalyzed alkene silylacylation reaction, where α,β-unsaturated amides were necessary as enolates derived from enones were not sufficiently nucleophilic to initiate silyl transfer and achieve catalyst turnover 16. Thus, the reactions between acyl silanes and some enones became stoichiometric in cyanide and required use of a full equivalent to achieve complete conversion in the cases where substantial 1,4-addition occurred.…”

“…The results of this survey are shown in Table 3. Electron-rich acyl silanes deliver a more nucleophilic (silyloxy)nitrile anion intermediate and performed the best, as expected 10,16. Yields of the coupling product decreased as a function of electron density on the aryl ring, as evidenced by entries 1, 4, and 5.…”

Carbene Catalysts

“…In a related process, Johnson and co-workers have developed an asymmetric metallophosphite-catalyzed intermolecular Stetter-like reaction employing acyl silanes [81, 82]. Acyl silanes are effective aldehyde surrogates which are capable of forming an acyl anion equivalent after a [1,2]-Brook rearrangement.…”

The Catalytic Asymmetric Intramolecular Stetter Reaction

“…Recently, Johnson and co-workers have developed an elegant solution to the enantioselective synthesis of 1,4-dicarbonyls by taking advantage of the umpolung reactivity of acyl silanes catalyzed by chiral metallophosphites 34. Acyl silanes are effective aldehyde surrogates capable of forming an acyl anion equivalent that can add to a variety of electrophiles in the presence of nucleophilic catalysts.…”