Enantioselective Cyclization of 4-Alkenoic Acids via an Oxidative Allylic C–H Esterification

Abstract

An enantioselective intramolecular oxidative cyclization of 4-alkenoic acids was developed. The reaction proceeded via a π-allyl Pd intermediate generated by an allylic C-H activation to give γ-lactone derivatives with moderate to good enantioselectivity. Spiro bis(isoxazoline) ligand, SPRIX, was indispensable for this asymmetric transformation.

Structural Features and Asymmetric Environment of i‐Pr‐SPRIX Ligand

“…The same trend was observed for the asymmetric oxidative allylic C À H esterification of 5-methyl-2,2-diphenylhex-4-enoic acid (12) ( Table 2). 20 Thus, the reaction of 12 with a Pd (OAc) 2 /(M,S,S)-1e catalyst system led to the quantitative formation of γ-lactone product 13 with 34% ee, whereas an inferior result was obtained in the presence of (M,S,S)-1 f or (M,S,S)-1a (entries 1-3). Not surprisingly, (M,S,S)-1d promoted the reaction in a highly selective manner to give 13 in quantitative yield with 76% ee (entry 4).…”

“…[14][15][16] Recently, we succeeded in the development of the cyclative diacetoxylation of alkynyl cyclohexadienones involving an unusual Pd enolate umpolung. 17 In addition, 5-endo-trig-type cyclization of 3-alkenoic acids, 18,19 oxidative allylic C À H esterification of 4-alkenoic acids, 20 and other asymmetric Pdcatalyzed reactions [21][22][23][24] are also feasible. In these processes, i-Pr-SPRIX 1d displayed the best performance.…”

Pd‐Catalyzed Synthesis of Oxygen‐Containing Heterocycles

“…An enantioselective oxidative cyclization of 4-alkenoic acids to give γ-lactone derivatives via palladium-catalyzed allylic C-H activation was also disclosed by Sasai in 2011 (Scheme 3.42) [76]. In the presence of 10 mol% Pd(OAc) 2 and 15 mol% spiro bis(isoxazoline) ligand, a variety of five-membered ring lactones could be constructed in moderate to excellent yields.…”

Direct Allylic Functionalization Through Pd‐Catalyzed C–H Activation

“…[62] On the basis of kinetic isotopic effect experiments, the authors favored a mechanism involving C-H allylic activation over the alternative oxypalladative path. The chiral, enantiomerically pure SPRIX ligand controlled the enantioselectivity of the reaction, providing ee values up to 82 % (Scheme 41).…”