ProPhenol Derived Ligands to Simultaneously Coordinate a Main-Group Metal and a Transition Metal: Application to a Zn-Cu Catalyzed Reaction.

A new bifunctional ligand bearing chiral N-heterocyclic carbene (NHC) and prolinol moieties is presented. Utilizing the designed ligand, an in situ formed Cu/Zn hetero-bimetallic complex unlocks the asymmetric allylic alkylation reactions of allyl phosphates with zinc keto-homoenolates, leading to the formation of various γ-vinyl ketones with good regio- and enantio-selectivity. DF sT calculation supports that the chelation of allyl phosphates with catalyst promotes the SN 2' addition and the ligand-substrate steric interactions account for the stereoselective outcome.

Lipid droplets can promote drug accumulation and activation.

Genetic screens in cultured human cells represent a powerful unbiased strategy to identify cellular pathways that determine drug efficacy, providing critical information for clinical development. We used insertional mutagenesis-based screens in haploid cells to identify genes required for the sensitivity to lasonolide A (LasA), a macrolide derived from a marine sponge that kills certain types of cancer cells at low nanomolar concentrations. Our screens converged on a single gene, LDAH, encoding a member of the metabolite serine hydrolase family that is localized on the surface of lipid droplets. Mechanistic studies revealed that LasA accumulates in lipid droplets, where it is cleaved into a toxic metabolite by LDAH. We suggest that selective partitioning of hydrophobic drugs into the oil phase of lipid droplets can influence their activation and eventual toxicity to cells.

Total Synthesis of Kadcoccinic Acid A Trimethyl Ester.

The first total synthesis of the trimethyl ester of kadcoccinic acid A is described. The central structural element of our synthesis is a cyclopentenone motif that allows the assembly of the natural product skeleton. A gold(I)-catalyzed cyclization of an enynyl acetate led to efficient construction of the cyclopentenone scaffold. In this step, optimization studies revealed that the stereochemistry of the enynyl acetate dictates regioisomeric cyclopentenone formation. The synthesis further highlights an efficient copper-mediated conjugate addition, merged with a gold(I)-catalyzed Conia-ene reaction to connect the two fragments, thereby forging the D-ring of the natural product. The synthetic strategy reported herein can provide a general platform to access the skeleton of other members of this family of natural products.

Forging Odd-Membered Rings: Palladium-Catalyzed Asymmetric Cycloadditions of Trimethylenemethane.

The catalytic asymmetric synthesis of complex molecules has been the focus of our research program for several decades because such strategies have significant utility for the construction of chiral building blocks for drug development as well as the total synthesis of natural products. Cycloaddition reactions are very powerful transformations in organic synthesis providing access to highly functionalized motifs from simple starting materials. In concert with this central interest, four decades ago, we reported the palladium-catalyzed trimethylenemethane (TMM) cycloaddition for forging odd-membered ring systems. In recent years, we focused our attention on the development of powerful ligand scaffolds which enable the preparation of valuable products with complete control of chemo-, regio-, diastereo-, and enantioselectivity, thereby addressing several limitations in the field of palladium-catalyzed asymmetric cycloadditions. The first section of this Account will outline the discovery of a new class of highly modular pyrrolidine-based phosphoramidite and diamidophosphite chiral ligands which facilitate [3 + 2] cycloadditions of TMM donors, opening a new area in asymmetric construction of five-membered rings.The formation of the Pd-TMM zwitterionic intermediates is driven by the unique charge distribution of the cationic π-allyl motif, in which the most electropositive central carbon stabilizes the neighboring carbanion generated by either desilylation or deprotonation. The second section of this Account summarizes the scope of cycloadditions between Pd-TMM zwitterionic intermediates generated via desilylation and a variety of electron-deficient acceptors to access cyclopentanes, pyrrolidines and tetrahydrofurans. This section also includes the use of nitrile-, vinyl-, alkynyl- and allene-substituted TMM donors to rapidly generate cycloadducts with high molecular complexity. The extension of this strategy to include [6 + 3] cycloadditions and dearomative processes will also be presented. The third section will discuss a new generation of TMM donors substituted with electron-withdrawing groups such as nitrile, benzophenone imine, trifluoromethyl, and phosphonate, where the Pd-TMM zwitterionic intermediates are generated via deprotonation of the acidic C-H bond adjacent to the π-allyl motif. This new strategy has enabled the synthesis of heterocycles with increased numbers of functional groups in highly asymmetric and atom-economic fashion.Throughout this Account, we will describe the implementation of these transformations toward the rapid assembly of drug candidates and the total synthesis of natural products such as (-)-marcfortine C. We will also give details of mechanistic studies regarding relevant intermediates within the catalytic cycles of the different strategies, which allowed us to better understand the origin of selectivity with various donors.

Catalytically Generated Vanadium Enolates Formed via Interruption of the Meyer-Schuster Rearrangement as Useful Reactive Intermediates.

Enolate chemistry is one of the most fundamental strategies for the formation of carbon-carbon and carbon-heteroatom bonds. Classically, this has been accomplished through the use of stoichiometric quantities of strong base and cryogenic reaction temperatures. However, these techniques present issues related to enolate regioselectivity and functional group tolerance. While more modern methods utilizing stoichiometric activating agents have overcome some of these limitations, these processes add additional steps and suffer from poor atom economy. While certain classes of highly acidic nucleophiles have enabled the development of elegant and general catalytic solutions to address all of these limitations, functionalizing less acidic nucleophiles remains difficult.To overcome these challenges, we developed an alternative general approach for the formation and subsequent functionalization of metal enolates that leverages catalytic amounts of Lewis acid and entirely avoids the need for exogenous base or stoichiometric additives. To do so, we re-engineered the classical Meyer-Schuster rearrangement, which normally converts propargylic alcohols into α,ß-unsaturated carbonyl compounds. By careful control of reaction conditions and by selection of an appropriate vanadium-oxo catalyst, the transient metal enolates formed via the 1,3-transposition of propargylic or allenylic alcohols can be guided away from simple protonation reaction pathways and toward more synthetically productive carbon-carbon, carbon-halogen, and carbon-nitrogen bond-forming processes.By utilizing readily available propargylic and allenylic alcohols as our starting materials and relying on a catalytic 1,3-transposition to generate metal enolates in situ, all issues related to the regioselectivity of enolate formation are resolved. Likewise, utilization of a simple isomerization for enolate formation results in a highly efficient process that can be 100% atom economical. The mild reaction conditions employed also allow for remarkable chemoselectivity. Functional groups not typically conducive to enolate chemistry, such as alkynyl ketones, methyl ketones, free alcohols, and primary alkyl halides, are all well tolerated. Finally, by varying the substitution patterns of the alcohol starting materials, enolates of ketones, esters, and even amides are all accessible.Utilizing this strategy starting from propargylic alcohols, we have developed functionalization reactions that produce highly substituted and geometrically defined α-functionalized α,ß-unsaturated carbonyl compounds. Such processes include aldol, Mannich, and electrophilic halogenation reactions, as well as dual catalytic reactions wherein catalytically generated vanadium enolates are trapped with catalytically generated palladium π-allyl electrophiles. In the case of allenylic alcohols, we have developed complementary aldol, Mannich, halogenation, and dual catalytic processes to generate α'-functionalized α,ß-unsaturated carbonyl products.The results described in this work showcase the power and generality of our alternative approach to enolate chemistry. Additionally, we point out unaddressed challenges in the field and invite other groups to help innovate in these areas.

Regiodivergent Synthesis of Spirocyclic Compounds through Pd-Catalyzed Regio- and Enantioselective [3+2] Spiroannulation.

A novel Pd0 -catalyzed highly regio- and enantioselective [3+2] spiroannulation reaction has been developed for rapid assembly of a new class of [5,5] spirocyclic carbo- and heterocycles. Notably, the regioselectivity could be dominated by fine-tuning of the Pd-π-allyl intermediate. An array of coupling partners could be well-tolerated with excellent regio-, and enantioselectivities. Moreover, the potential application of this reaction was exemplified by several further transformations.

Palladium-Catalyzed Enantioselective Cycloaddition of Carbonylogous 1,4-Dipoles: Efficient Access to Chiral Cyclohexanones.

A novel palladium-mediated carbonylogous 1,4-dipole was developed by in situ deprotonation. By using our own-developed C2-unsymmetric phosphoramidite as supporting ligand, this dipole was applied to the asymmetric synthesis of chiral cyclohexanones via a catalytic [4+2] cycloaddition. Electron-deficient allylic carbonate was used to generate the highly reactive palladium-mediated dipoles for the first time, and a diverse array of stable dipole precursors was explored for the elaboration of chiral cyclohexanones. A general mechanism for the reaction process and stereochemical outcome was proposed, which can be useful in designing and predicting future transformation.

Ruthenium-Catalyzed Intermolecular Coupling of Vinylic 1,2-Bisboronates with Alkynes: Stereoselective Access to Boryl-Substituted Homoallylic Alcohols.

The ruthenium catalytic addition of alkenes to alkynes has been demonstrated as a powerful synthetic tool to form diene motifs and widely applied in the synthesis of complex molecules. However, except for the intramolecular coupling, trisubstituted alkenes are unsatisfactory coupling partners with alkynes, presumably due to the increased steric hindrance. Herein, we discovered that substituted vinyl 1,2-bisboronate derivatives can serve as the trisubstituted alkene equivalents to couple with alkynes, generating various boryl-substituted homoallylic alcohol motifs with good stereoselectivity through the sequential allylboration with aldehydes. In contrast to carbon substituents on the double bond, boron substituents accelerate the alkyne coupling.

Palladium-Catalyzed Enantioselective Cycloadditions of Aliphatic 1,4-Dipoles: Access to Chiral Cyclohexanes and Spiro [2.4] heptanes.

Design and exploration of new intermediates for chemo-, regio-, and stereoselective cycloadditions remain a formidable challenge in modern organic synthesis. Compared to the well-developed 1,3-dipolar cycloadditions, Pd-catalyzed1,4-dipolar cycloadditions are generally limited to specialized substrates due to the inherent nature of the thermodynamically driven intramolecular transformations and undesired isomerizations. Herein, we demonstrate the use of ligated palladium catalysts to control and modulate the intermolecular reactivity of aliphatic 1,4-dipoles, enabling two distinctive cycloaddition pathways with a broad scope of acceptors. This atom-economic process also features an eco-friendly in situ deprotonation strategy to generate the corresponding active palladium-mediated dipoles. Overall, a diverse array of chiral 6-membered rings and spiro [2.4] heptanes were prepared in high yield and selectivity. In addition, an unexpected property of cyano-stabilized carbanions was discovered and investigated, which can be useful in designing and predicting future transformations.

Annulative Allylic Alkylation Reactions between Dual Electrophiles and Dual Nucleophiles: Applications in Complex Molecule Synthesis.

Metal-catalyzed allylic alkylation reactions between dual nucleophiles and dual electrophiles represent a powerful set of methods for the synthesis of small-, medium-, and even large-sized rings. Using this strategy, a handful of simple allylic diol derivatives can be transformed into a broad array of complex carbo- and heterocycles of varying ring sizes in just a single step. Because of their ability to rapidly generate complexity, annulative allylic alkylation reactions between dual nucleophiles and dual electrophiles have been extensively employed in the total synthesis of both natural products and pharmaceutical compounds.

Transition-Metal-Catalyzed Cycloaddition Reactions to Access Seven-Membered Rings.

The efficient and selective synthesis of functionalized seven-membered rings remains an important pursuit within synthetic organic chemistry, as this motif appears in numerous drug-like molecules and natural products. Use of cycloaddition reactions remains an attractive approach for their construction within the perspective of atom and step economy. Additionally, the ability to combine multiple components in a single reaction has the potential to allow for efficient combinatorial strategies of diversity-oriented synthesis. The inherent entropic penalty associated with achieving these transformations has impressively been overcome with development of catalysis, whereby the reaction components can be pre-organized through activation by transition-metal-catalysis. The fine-tuning of metal/ligand combinations as well as reaction conditions allows for achieving chemo-, regio-, diastereo- and enantioselectivity in these transformations. Herein, we discuss recent advances in transition-metal-catalyzed construction of seven-membered rings via combination of 2-4 components mediated by a variety of metals. An emphasis is placed on the mechanistic aspects of these transformations to both illustrate the state of the science and to highlight the unique application of novel processes of transition-metals in these transformations.

Highly Regio-, Diastereo-, and Enantioselective Synthesis of Tetrahydroazepines and Benzo[b]oxepines through Palladium-Catalyzed [4+3] Cycloaddition Reactions.

A novel Pd0 -catalyzed asymmetric [4+3] annulation reaction of two readily accessible starting materials has been developed for building seven-membered heterocyclic architectures. The potential [3+2] side pathway could be suppressed though fine tuning of the conditions. A broad scope of cycloaddition donors and acceptors participated in the transformation with excellent chemo-, regio-, diastereo-, and enantioselectivtities, leading to valuable tetrahydroazepines and benzo[b]oxepines.

Dinuclear Metal-ProPhenol Catalysts: Development and Synthetic Applications.

The ProPhenol ligand is a member of the chiral aza-crown family that spontaneously forms a bimetallic complex upon treatment with alkyl metal reagents, such as Et2 Zn and Bu2 Mg. The resulting complex features Lewis acidic and Brønsted basic sites, enabling simultaneous activation of both nucleophile and electrophile in the same chiral environment. Since the initial report in 2000, metal-ProPhenol catalysts have been used to facilitate a broad range of asymmetric transformations, including aldol, Mannich, and Henry reactions, as well as alkynylations and conjugation additions. By promoting such a diverse array of reactions, these complexes provide rapid and atom-economical access to valuable complex building blocks. In this Review, we describe in detail the development and synthetic applications of these versatile catalysts with a special focus on recent efforts to improve reactivity and selectivity through ligand design and structural modification.

Acyclic Branched α-Fluoro Ketones for the Direct Asymmetric Mannich Reaction Leading to the Synthesis of ß-Tetrasubstituted ß-Fluoro Amines.

The preparation of acyclic ß-fluoro amines bearing tetrasubstituted fluorine stereocenters is described via a direct Zn/ProPhenol-catalyzed Mannich reaction. The reaction utilizes branched vinyl or alkynyl α-fluoro ketones that can be coupled with a range of aryl, heteroaryl, vinyl, or cyclopropyl aldimines in high yield and with excellent diastereo- (up to >20:1) and enantioselectivity (up to 99 %). The use of readily cleaved tert-butoxycarbonyl (Boc) or carboxybenzyl (Cbz) imine protecting groups adds utility to the reaction by allowing for easy access to the free amine products under mild and chemoselective reaction conditions.

Palladium-Catalyzed Asymmetric Allylic Fluoroalkylation/Trifluoromethylation.

The first palladium-catalyzed asymmetric allylic trifluoromethylation is disclosed. The methodology evokes a fundamental principle by which the synergistic interplay of a leaving group and its subsequent activation of the nucleophilic trifluoromethyl group enabled the reaction. Allyl fluorides have been shown to be superior precursors for generation of π-allyl complexes, which lead to trifluoromethylated products with high selectivities and functional group tolerance. This study highlights the unique role of a bidentate diamidophosphite ligand class in palladium-catalyzed reactions that allow a challenging transformation to proceed.

Enantioselective Divergent Syntheses of (+)-Bulleyanaline and Related Isoquinoline Alkaloids from the Genus Corydalis.

The isoquinoline alkaloids isolated from the genus Corydalis possess potent and diverse biological activities. Herein, a concise, divergent, and enantioselective route to access these natural products is disclosed. Key transformations of our approach include a challenging Zn-ProPhenol-catalyzed asymmetric Mannich reaction to build a quaternary stereogenic center and a rapid cationic Au-catalyzed cycloisomerization to the common structural skeleton of these natural products. Subsequent late-stage oxidations and modifications allow efficient access to the targeted alkaloids. Overall, seven natural products have been successfully synthesized in 6 to 10 steps from readily available starting materials, including (+)-corynoline, (+)-anhydrocorynoline, (+)-12-hydroxycorynoline, (+)-12-hydroxycorynoloxine, (+)-corynoloxine, (+)-6-acetonylcorynoline, and (+)-bulleyanaline.

Desymmetrization of Phosphinic Acids via Pd-Catalyzed Asymmetric Allylic Alkylation: Rapid Access to P-Chiral Phosphinates.

The synthesis of P-chiral compounds is challenging, especially since useful catalytic methods for preparing such molecules are scarce. Herein we disclose a desymmetrization that employs phosphinic acids as prochiral nucleophiles in a Pd-catalyzed asymmetric allylic alkylation reaction, furnishing phosphinates with high enantio- and diastereoselectivity. This new method has broad scope and is applied to the synthesis of an enantioenriched tertiary phosphine oxide.

Enantioselective Divergent Synthesis of C19-Oxo Eburnane Alkaloids via Palladium-Catalyzed Asymmetric Allylic Alkylation of an N-Alkyl-α,ß-unsaturated Lactam.

The C19-oxo-functionalized eburnane alkaloids display unique chemical structure and interesting biological activity. Herein, we report a divergent enantioselective strategy to access these alkaloids by use of a challenging palladium-catalyzed asymmetric allylic alkylation of an N-alkyl-α,ß-unsaturated lactam. 19-( S)-OH-Δ14-vincamone (phutdonginin), (-)-19-OH-eburnamine, (+)-19-oxoeburnamine, and (+)-19-OH-eburnamonine (1-4) have been concisely synthesized for the first time in 11 to 13 steps.

New Catalytic Asymmetric Formation of Oxygen Heterocycles Bearing Nucleoside Bases at the Anomeric Carbon.

Pyrimidine nucleosides are an important class of compounds with versatile applications across many fields, including biology and medicinal chemistry. Synthesis of nucleoside analogs in optically pure form via traditional glycosylation has always been a challenge, especially for unnatural carbohydrate motifs which do not have C2 substitution to dictate the stereochemical outcome of the newly formed glyosidic bond. Herein, we report an asymmetric Pd-catalyzed synthesis of nucleoside analogs enabled by the development of a series of chiral ligands. A variety of 5-substituted pyrimidine nucleobases, ranging from 5- to 12-membered ring nucleoside analogs, are generated in excellent yield (up to 96%) as well as diastereo- (>20:1) and enantioselectivity (up to 99.5% ee). These nucleoside analogs bearing an iodide functional group handle allow for rapid transformation to a variety of other interesting pyrimidine nucleoside structures.

Chemo-, Regio-, Diastereo-, and Enantioselective Palladium Allylic Alkylation of 1,3-Dioxaboroles as Synthetic Equivalents of α-Hydroxyketones.

We describe the development of a Pd-catalyzed asymmetric allylic alkylation (Pd-AAA) of acyclic α-hydroxyketones using boronic acids as traceless templates. Condensation of boronic acids with hydroxyketones generates 1,3-dioxaboroles, which can be used directly as pronucleophiles in Pd-AAA reactions. This strategy enables control of the enolate geometry, while removing the issue of O-alkylation. Allylic alcohols can be directly ionized in the presence of Pd(0) and chiral ligands to afford alkylation products with regio- and enantioselectivity. Additionally, a dynamic kinetic asymmetric transformation of allenyl electrophiles affords C-alkylation products in high regio-, diastereo-, and enantioselectivity. To the best of our knowledge, this method represents the first example in Pd-AAA for setting point chirality on a nucleophile simultaneous to stereoinduction on an axial chiral allene.