Materials and Methods. Unless otherwise stated, reactions were performed in flame-dried glassware under an argon atmosphere using dry, deoxygenated solvents. Solvents were dried by passage through an activated alumina column under argon. Tetrabutylammonium triphenyldifluorosilicate (TBAT) was purchased from Sigma-Aldrich Chemical Company and azeotropically dried five times from acetonitrile prior to use. Trimethylsilyl chloride (TMSCl) and triethyl amine (TEA) were distilled from sodium hydride immediately prior to use. Sodium iodide was dried by heating at 90

Enantioconvergent catalysis is a powerful synthetic method that converts a racemic stereogenic substrate into an enantiomerically enriched product with a theoretical yield of 100 % in a single operation.[1] Conceptually, a catalytic system for such a reaction must achieve a stereomutation [2] or stereoablation [3,4] of the substrate (or an intermediate), followed by an enantioselective conversion into product (Figure 1, compare pathways I and II). A number of catalytic processes of this type have been developed, including chemical, enzymatic, and chemoenzymatic strategies. [1,2,4] Racemic compounds that contain quaternary carbon centers are typically unsuitable substrates for enantioconvergent catalysis because of the difficulty associated with CÀC bond cleavage in the stereomutative or stereoablative process. [5,6] Herein, we describe the first catalytic system for the deracemization of quaternary carbon stereocenters. Our enantioconvergent method converts racemic a-substituted 2-carboxyallylcyclohexanones into highly enantioenriched cycloalkanones that bear quaternary stereocenters through catalytic asymmetric decarboxylative allylation.We recently reported the first catalytic asymmetric allylation methods for the synthesis of 2-alkyl-2-allylcycloalkanones (Scheme 1).[7] These reactions, based on racemic transformations reported in the early 1980s by Tsuji, [8] use enol carbonates and silyl enol ethers along with various allyl carbonates and a Pd 0 catalyst supported by a chiral phosphinooxazoline ligand (e.g., 1). [9][10][11] To demonstrate the utility of this methodology, we have started to employ these allylations as the key enantioselective reaction in multistep syntheses. In one such project, we required the substituted cyclohexenone 6 (Scheme 2). Unfortunately, the preparation of the allylation precursor 4 (R = CO 2 allyl or SiMe 3 ) was hampered by nonselective enolization of 3 to form inseparable mixtures of 4 and 5, which resulted in significant amounts of 7 after allylation.Prompted by the need for better position control in these synthetic sequences, we sought mechanistically guided alternatives to the reactions depicted in Scheme 1. To this end, we synthesized dideuterated carbonate 8 and trideuterated carbonate 9. When 8 was subjected to our standard conditions for allylation, the deuterium label was almost evenly scrambled between the termini of the allyl fragment in the product (Scheme 3 a).[12] In a separate crossover experiment, the reaction of equimolar amounts of carbonates 8 and 9 was performed under our standard allylation conditions. As expected, NMR spectroscopic analysis of the product showed deuterium scrambling between the allyl termini, but interestingly, mass spectrometric analysis of the product showed an almost perfect statistical distribution of enolate and allyl fragment pairs with four possible masses (Scheme 3 b).[12] Thus, all six possible products were formed in the reaction including those derived from crossover reactions. Although the specific details associated with the en...

The enantioselective synthesis of Nitrogen-containing heterocycles (N-heterocycles) represents a substantial chemical research effort and resonates across numerous disciplines including the total synthesis of natural products and medicinal chemistry. In this manuscript, we describe the highly enantioselective palladium-catalyzed decarboxylative allylic alkylation of readily available lactams to form 3,3,-disubstituted pyrrolidinones, piperidinones, caprolactams, and structurally related lactams. Given the prevalence of quaternary N-heterocycles in biologically active alkaloids and pharmaceutical agents, we envision that our method will provide a synthetic entry into the de novo asymmetric synthesis of such structures. As an entry for these investigations we demonstrate how the described catalysis affords enantiopure quaternary lactams that intercept synthetic intermediates previously employed in the synthesis of the Aspidosperma alkaloids quebrachamine and rhazinilam, but that were previously only available by chiral auxiliary approaches or as racemic mixtures.

We propose an inner-sphere mechanism explaining the unique performance of the Tsuji asymmetrical allylation reaction using hard prochiral enolate nucleophiles and non-prochiral allyl groups. Using first principles quantum mechanics (B3LYP density functional theory), we find that the pathway for this reaction involves nucleophilic attack followed by interconversion from a five-coordinate Pd complex to a four-coordinate complex. This intermediate is trapped in a potential well and escapes via reductive elimination that proceeds through a seven-membered transition state to generate the product and a Pd0 complex. This seven-membered transition state contrasts dramatically from the usual three-centered C−C reductive elimination paradigm generally associated with C−C coupling reactions. This inner-sphere asymmetric allylation pathway involving hard enolates is energetically more favorable than outer-sphere nucleophilic attack, a process understood to occur in asymmetric allylic alkylations with soft enolates.

Palladium poprocks: Hold on to your CO2! Enantioselective Pd-catalyzed decarboxylative alkylation of ketone enolates proceeds via η1-σ-allyl Pd-carboxylate complexes by slow loss of CO2.