Diastereoselective Synthesis of N-Methylspiroindolines by Intramolecular Mizoroki–Heck Annulations

Abstract

Spiroindolines represent a privileged structure in medicinal chemistry, although stereocontrol around the spirocarbon can be a synthetic challenge. Here we present a palladium(0)-catalyzed intramolecular Mizoroki–Heck annulation reaction from ( + )-Vince lactam-derived cyclopentenyl-tethered 2-bromo- N -methylanilines for the formation of N -methylspiroindolines. A series of 14 N -methylspiroindolines were synthesized in 59–81% yield with diastereoselectivity >98%, which was rationalized by density functional theory calculations and confirmed through X-ray crystallography. One spiroindoline was converted to an N- and C-terminal protected rigidified unnatural amino acid, which could be orthogonally deprotected.

Two-Chamber Aminocarbonylation of Aryl Bromides and Triflates Using Amino Acids as Nucleophiles

“…The study was initiated by conducting a reaction with bromobenzene ( 1a , 0.64 mmol, 1 equiv) and l -phenylalanine tert -butyl ester hydrochloride ( 2a ) with 5 mol % Pd(OAc) 2 , 10 mol % XantPhos and triethylamine (3 equiv) in the first chamber of the H-tube and molybdenum hexacarbonyl ((Mo(CO) 6 ), 2 equiv) and DBU (2 equiv) in the other chamber with DMF (2 mL per chamber) used as solvent with heating at 100 °C for 2 h. 33 The results of this initial experiment, which resulted in a 75% isolated yield of 3a ( Table 1 , entry 1), prompted us to continue screening the reaction conditions, beginning with altering the palladium ligand. From the tested ligands (entries 2–5), none performed as well as XantPhos.…”

Convenient One-Pot Synthesis of L2Pd(0) Complexes for Cross-Coupling Catalysis

“…The merits on the use of preformed catalysts versus the limitations of in situ catalysis have been reviewed extensively. − These Pd(0) precatalysts are utilized in both academia and chemical industry for the synthesis of complex molecules with applications in pharmaceutical, electronic, and polymer areas. Among the L n Pd­(0) based catalysts, L 2 Pd­(0) complexes are very suitable precatalysts for various cross-coupling applications such as Mizoroki–Heck, − Negishi, − Suzuki–Miyaura, − carbo-halogenations, , and Murahashi–Feringa reactions. − These catalysts are also very effective for C–H activation, − Buchwald–Hartwig aminations, alpha arylations, − and silylation reactions. , …”