Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of Enol Carbonates

Abstract

Palladium-catalyzed decarboxylative asymmetric allylic alkylation (DAAA) of allyl enol carbonates as a highly chemo-, regio-and enantio-selective process for the synthesis of ketones bearing either a quaternary or a tertiary α-stereogenic center has been investigated in detail. Chiral ligand L4 was found to be optimal in the DAAA of a broad scope of cyclic and acyclic ketones including simple aliphatic ketones with more than one enolizable proton. The allyl moiety of the carbonates has been extended to a variety of cyclic or acyclic di-substituted allyl groups. Our mechanistic studies reveal that, similar to the direct allylation of lithium enolates, the DAAA reaction proceeds through an "outer sphere" S N 2 type of attack on the π-allylpalladium complex by the enolate. An important difference between the DAAA reaction and the direct allylation of lithium enolates is that in the DAAA reaction, the nucleophile and the electrophile were generated simultaneously. Since the π-allylpalladium cation must serve as the counterion for the enolate, the enolate probably exists as a tight-ion-pair. This largely prevents the common side reactions of enolates associated with the equilibrium between different enolates. The much milder reaction conditions as well as the much broader substrate scope also represent the advantages of the DAAA reaction over the direct allylation of preformed metal enolates.

Metal catalyzed allylic alkylation: its development in the Trost laboratories

“…68 Initial studies showed that allylation of cyclic ketones to form both tertiary (eq 66) and quaternary (eq 67) centers works well. 69 The ligand of choice is that which has the largest bite angle, the anthracenyl derived one L A . Acyclic substrates work equally well.…”

“…Acyclic substrates work equally well. 69,70 Enolate geometry controls facial selectivity as shown in eq 68 and 69 wherein switching from a Z to an E enolate inverts the stereochemistry of the newly formed stereocenter. No enolate equilibration occurs nor does any polyalkylation.…”

Synthesis of the Tetrahydropyran Fragment of Bistramide D

“…[33] While good yields were be obtained, the ee was too low to be useful, even when the ANDEN ligand 36 was used (Table 2). [34] Thus, the acyl oxazolidinone allylation route remains the most effective route to this series of compounds. …”

Palladium-Catalyzed Enantioselective Allylic Substitution

“…A noteworthy discovery was made during a study by Trost [33]: the base used in the generation of the nucleophile was found to influence the overall allylic alkylation (Table 3). The originally proposed mechanism suggests that in the case of an enolate obtained with Cs 2 CO 3 as base, the Si face attack generates less steric hindrance than the Re face attack.…”

“…For example, L5 is a very powerful ligand for the palladium-catalyzed decarboxylative asymmetric allylic substitution (DAAS) of enol carbonates 12 (Scheme 10). It afforded the desired product 13 without the formation of the corresponding unsubstituted ketone 14 by simple decarboxylation [33].…”