Douglas C. Behenna

Enantioselective Decarboxylative Alkylation Reactions: Catalyst Development, Substrate Scope, and Mechanistic Studies

α-Quaternary ketones are accessed through novel enantioselective alkylations of allyl and propargyl electrophiles by unstabilized prochiral enolate nucleophiles in the presence of palladium complexes with various phosphinooxazoline (PHOX) ligands. Excellent yields and high enantiomeric excesses are obtained from three classes of enolate precursor: enol carbonates, enol silanes, and racemic β-ketoesters. Each of these substrate classes functions with nearly identical efficiency in terms of yield and enantioselectivity. Catalyst discovery and development, the optimization of reaction conditions, the exploration of reaction scope, and applications in target-directed synthesis are reported. Experimental observations suggest that these alkylation reactions occur through an unusual inner-sphere mechanism involving binding of the prochiral enolate nucleophile directly to the palladium center.

Enantioselective construction of quaternary N -heterocycles by palladium-catalysed decarboxylative allylic alkylation of lactams

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.

The Biology and Chemistry of the Zoanthamine Alkaloids

Marine natural products have long played an important role in natural products chemistry and drug discovery. Mirroring the rich variety and complicated interactions of the marine environment, the substances isolated from sea creatures tend to be incredibly diverse in both molecular structure and biological activity. The natural products isolated from the polyps of marine zoanthids are no exception. The zoanthamine alkaloids, the first of which were isolated over 20 years ago, are of particular interest to the synthetic community because they feature a novel structural framework and exhibit a broad range of biological activities. In this Review, we summarize the major contributions to understanding the zoanthamine natural products with regard to their isolation and structure determination, as well as studies on their biological activity and total synthesis.

Unusual Allylpalladium Carboxylate Complexes: Identification of the Resting State of Catalytic Enantioselective Decarboxylative Allylic Alkylation Reactions of Ketones†

Palladium pop rocks: Hold on to your CO2! Enantioselective palladium-catalyzed decarboxylative alkylation of ketone enolates proceeds via 1-σ-allyl palladium-carboxylate complexes, such as 1 (Pd yellow, O red, N blue, P purple), by slow loss of CO_2. Reminiscent of pop rock candy, impure samples of 1 expel a gas (presumably CO_2) in the solid state and effervesce in solution.

The Reaction Mechanism of the Enantioselective Tsuji Allylation: Inner-Sphere and Outer-Sphere Pathways, Internal Rearrangements, and Asymmetric C−C Bond Formation

We use first principles quantum mechanics (density functional theory) to report a detailed reaction mechanism of the asymmetric Tsuji allylation involving prochiral nucleophiles and nonprochiral allyl fragments, which is consistent with experimental findings. The observed enantioselectivity is best explained with an inner-sphere mechanism involving the formation of a 5-coordinate Pd species that undergoes a ligand rearrangement, which is selective with regard to the prochiral faces of the intermediate enolate. Subsequent reductive elimination generates the product and a Pd(0) complex. The reductive elimination occurs via an unconventional seven-centered transition state that contrasts dramatically with the standard three-centered C-C reductive elimination mechanism. Although limitations in the present theory prevent the conclusive identification of the enantioselective step, we note that three different computational schemes using different levels of theory all find that inner-sphere pathways are lower in energy than outer-sphere pathways. This result qualitatively contrasts with established allylation reaction mechanisms involving prochiral nucleophiles and prochiral allyl fragments. Energetic profiles of all reaction pathways are presented in detail.

Enantioselective Synthesis of α-Secondary and α-Tertiary Piperazin-2-ones and Piperazines by Catalytic Asymmetric Allylic Alkylation†

The asymmetric palladium-catalyzed decarboxylative allylic alkylation of differentially N-protected piperazin-2-ones allows the synthesis of a variety of highly enantioenriched tertiary piperazine-2-ones. Deprotection and reduction affords the corresponding tertiary piperazines, which can be employed for the synthesis of medicinally important analogues. The introduction of these chiral tertiary piperazines resulted in imatinib analogues which exhibited comparable antiproliferative activity to that of their corresponding imatinib counterparts.

Simple Enantioselective Approach to Synthetic Limonoids

An enantioselective and short approach to the synthesis of limonoids has been applied successfully to the simplest limonoid, 2. The carbon atoms of the tetracyclic framework were assembled in a single operation from the acylsilane 3 and the acetylenic sulfone 4 to form the chiral epoxide 5. Successive cationic and free-radical cyclizations starting with 5 generated the tetracyclic intermediates 9a, which was transformed into limonoid 2 by a sequence consisting of (1) oxidative cleavage of the exocyclic double bond, (2) stereoselective alpha-methylation, (3) furyl attachment, and (4) introduction of a 16-keto function.

Development of (Trimethylsilyl)ethyl Ester Protected Enolates and Applications in Palladium-Catalyzed Enantioselective Allylic Alkylation: Intermolecular Cross-Coupling of Functionalized Electrophiles

The development of (trimethylsilyl)ethyl ester protected enolates is reported. The application of this class of compounds in palladium-catalyzed asymmetric allylic alkylation is explored, yielding a variety of α-quaternary six- and seven-membered ketones and lactams. Independent coupling partner synthesis engenders enhanced allyl substrate scope relative to traditional β-ketoester substrates; highly functionalized α-quaternary ketones generated by the union of (trimethylsilyl)ethyl β-ketoesters and sensitive allylic alkylation coupling partners serve to demonstrate the utility of this method for complex fragment coupling.

Expanding Insight into Asymmetric Palladium-Catalyzed Allylic Alkylation of N-Heterocyclic Molecules and Cyclic Ketones

Eeny, meeny, miny ... enaminones! Lactams and imides have been shown to consistently provide enantioselectivities substantially higher than other substrate classes previously investigated in the palladium-catalyzed asymmetric decarboxylative allylic alkylation. Several new substrates have been designed to probe the contributions of electronic, steric, and stereoelectronic factors that distinguish the lactam/imide series as superior alkylation substrates (see scheme). These studies culminated in marked improvements on carbocyclic allylic alkylation substrates.

Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones

The first general method for the enantioselective construction of all-carbon quaternary centers on cyclopentanones by enantioselective palladium-catalyzed decarboxylative allylic alkylation is described. Employing the electronically modified (S)-(p-CF3)3-t-BuPHOX ligand, α-quaternary cyclopentanones were isolated in yields up to >99% with ee’s up to 94%. Additionally, in order to facilitate large-scale application of this method, a low catalyst loading protocol was employed, using as little as 0.15 mol % Pd, furnishing the product without any loss in ee.