An Efficient Protocol for the Palladium‐Catalyzed Asymmetric Decarboxylative Allylic Alkylation Using Low Palladium Concentrations and a Palladium(II) Precatalyst

Abstract

Enantioselective catalytic allylic alkylation for the synthesis of 2-alkyl-2-allylcycloalkanones and 3,3-disubstituted pyrrolidinones, piperidinones and piperazinones has been previously reported by our laboratory. The efficient construction of chiral all-carbon quaternary centers by allylic alkylation was previously achieved with a catalyst derived in situ from zero valent palladium sources and chiral phosphinooxazoline (PHOX) ligands. We now report an improved reaction protocol with broad applicability among different substrate classes in industry-compatible reaction media using loadings of palladium(II) acetate as low as 0.075 mol % and the readily available chiral PHOX ligands. The novel and highly efficient procedure enables facile scale-up of the reaction in an economical and sustainable fashion.

The Enantioselective Synthesis of Eburnamonine, Eucophylline, and 16′‐epi‐Leucophyllidine

“… [15] Benzoyl protection of δ‐valerolactam ( 11 → 12 ) is followed by C‐acylation to yield β‐amidoester 14 and alkylation to generate racemic quaternary lactam 15 . An enantioselective decarboxylative allylic alkylation using low loadings [17] of a Pd(II) precatalyst and ( R )‐CF 3 ‐ t ‐BuPHOX ligand 16 forges the all‐carbon quaternary center of lactam 17 in 91 % yield and 92 % ee . Finally, Bz cleavage affords divergent intermediate 10 , completing the five‐step sequence on a decagram scale and providing enough material to synthesize both monomers.…”

Recent Advances in Enantioselective Pd-Catalyzed Allylic Substitution: From Design to Applications

“…Stoltz’s group later demonstrated that the use of ligand L122 allowed the Pd-catalyzed DAAA using low Pd concentrations. 562 …”

Synthesis of a 4‐Vinyltetrahydrocarbazole by Palladium‐Catalyzed Asymmetric Allylic Alkylation of Indole‐Containing Allylic Carbonates

“…Using toluene as the solvent, the reaction optimization was continued by varying the ( S )‐ L1 /Pd(OAc) 2 ratio, as shown in Table 5. Full conversion was obtained with ( S )‐ L1 /Pd(OAc) 2 ratios of 3:1, 2:1, and even 1:1, which thus showed that in this case, unlike in previous reports,12,14,15 the use of a large excess amount of the phosphite ligand was not necessary to achieve Pd II → Pd 0 reduction. As the best ee was obtained with a ( S )‐ L1 /Pd(OAc) 2 ratio of 2:1, this L/Pd ratio was kept for subsequent experiments.…”

“…The AAA of ( E )‐ 1 in the presence of Pd(OAc) 2 and ligand ( S )‐ L1 was repeated several times and was found to be reproducible in terms of both conversion and enantioselectivity. Therefore, Pd(OAc) 2 was selected as the Pd source to complete this study 12…”