The Allylic Alkylation of Ketone Enolates

Abstract

The palladium‐catalyzed allylic alkylation of non‐stabilized ketone enolates was thought for a long time to be not as efficient as the analogous reactions of stabilized enolates, e. g. of malonates and β‐ketoesters. The field has experienced a rapid development during the last two decades, with a range of new, highly efficient protocols evolved. In this review, the early developments as well as current methods and applications of palladium‐catalyzed ketone enolate allylations will be discussed.

Enantioselective Formation of Quaternary Centers by Allylic Alkylation with First-Row Transition-Metal Catalysts

“…Of particular interest are transformations that lead to the enantioselective formation of quaternary centers next to a carbonyl group, as the additional functional handle can provide a means for further functionalization of the enantioenriched building blocks generated from these reactions. Traditionally, transition-metal-catalyzed allylic alkylation for the formation of such α-quaternary products involves the use of an enolate-derived nucleophile in combination with a second- or third-row transition metal. − ,− An alternative approach has been described by Murphy and Hoveyda, which utilizes α,β-unsaturated esters bearing a phosphate leaving group at the γ-position as the electrophiles 14a – h and alkylzinc reagents as nucleophiles (Scheme ). Depending upon the identity of the substituent at the α-position of the carbonyl group (R 2 ), two efficient dipeptide-based ligands were identified.…”

“…Moreover, transition-metal-catalyzed allylic alkylation with prochiral nucleophiles provides an opportunity to simultaneously generate two adjacent stereogenic centers in the branched products. Further investigations of the asymmetric formation of vicinal quaternary and tertiary centers, as briefly described by Li, could be an efficient and inexpensive alternative to the well-established iridium-catalyzed methods in this field. ,− In this context, the construction of two vicinal quaternary centers, which to date has not yet been reported, could be achieved in the near future through further developments in this field. Meeting these challenges will require continuous efforts in ligand and catalyst improvements, which ideally are based on a deep mechanistic understanding of the allylic alkylation.…”

“…While this powerful transformation is dominated by the utilization of second- and third-row transition metals, in particular, by palladium, − rhodium, , and iridium, ,− which has been applied in several total syntheses of natural products, ,,− the use of first-row transition metals is much less common, despite the fact that these catalysts would be cheaper and more abundant alternatives to their second- and third-row counterparts. In addition, these first-row metals often afford alternative reactivity and distinct mechanistic possibilities relative to the second- and third-row counterparts.…”

The Enantioselective Intermolecular Saegusa Allylation

“…Here we focus on the enantioselective α-allylation of ketones, an area that was recently reviewed by Kazmaier and Junk. 11 As can be seen in their review, there are many different types of systems, and one of the most highly utilized is the catalytic enantioselective Tsuji allylation developed initially by Stoltz 12 and Trost. 13 These methods utilize substrates such as 1 and 2, where πallylpalladium formation precedes decarboxylative enolate formation followed by allylation to form the α-allyl carbonyl bearing a quaternary stereocenter (Figure 1).…”

“…Metal-catalyzed allylic alkylation reactions constitute an important class of catalytic enantioselective reactions that have contributed to state-of-the-art syntheses by providing highly useful compounds for transformation in a variety of different ways. − Since Tsuji’s pioneering 1965 report, these methods have seen continuous development for more than half a century, and the contributions cover a broad range of catalysts, ligands, and substrate types. Here we focus on the enantioselective α-allylation of ketones, an area that was recently reviewed by Kazmaier and Junk . As can be seen in their review, there are many different types of systems, and one of the most highly utilized is the catalytic enantioselective Tsuji allylation developed initially by Stoltz and Trost .…”