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.

Palladium-catalyzed asymmetric allylic alkylation (AAA) with alkyl sulfones as nucleophiles.

An efficient palladium-catalyzed AAA reaction with a simple α-sulfonyl carbon anion as nucleophiles is presented for the first time. Allyl fluorides are used as superior precursors for the generation of π-allyl complexes that upon ionization liberate fluoride anions for activation of silylated nucleophiles. With the unique bidentate diamidophosphite ligand ligated palladium as catalyst, the in situ generated α-sulfonyl carbon anion was quickly captured by the allylic intermediates, affording a series of chiral homo-allylic sulfones with high efficiency and selectivity. This work provides a mild in situ desilylation strategy to reveal nucleophilic carbon centers that could be used to overcome the pK a limitation of "hard" nucleophiles in enantioselective transformations.

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.

Catalytic Asymmetric Synthesis of the Pentacyclic Core of (+)-Citrinadin A.

The synthesis of the pentacylic core of (+)-citrinadin A is described. Our strategy harnesses the power of palladium-catalyzed trimethylenemethane chemistry (Pd-TMM) to form the key spirooxindole motif in a catalytic, asymmetric fashion. Upon the conversion of this spirooxindole to a vinyl epoxide electrophile, the piperidine ring is directly added via a diastereoselective metalation followed by an SN2' addition. The final ring of the pentacyclic core is then formed through an intramolecular SN2 displacement of the resulting activated alcohol.

Pd-Catalyzed Regio-, Diastereo-, and Enantioselective [3 + 2] Cycloaddition Reactions: Access to Chiral Cyclopentyl Sulfones.

The palladium-catalyzed [3 + 2] cycloaddition using in situ generated sulfone-TMM species to construct various chiral cyclopentyl sulfones in a highly regio-, diastereo- (dr >15:1), and enantioselective (up to 99% ee) manner is reported. The present strategy can tolerate different types of sulfone-TMM donors and acceptors, and enables the construction of three chiral centers in a single step, specifically with a chiral center bearing the sulfone moiety. The robust chiral diamidophosphite ligand is the key to the reactivity and selectivities of this transformation.

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.

Pd(0)-Catalyzed Diastereo- and Enantioselective Intermolecular Cycloaddition for Rapid Assembly of 2-Acyl-methylenecyclopentanes.

A highly regio-, diastereo-, and enantioselective trimethylenemethane (TMM) cycloaddition reaction for the rapid assembly of 2-acyl-methylenecyclopentane in an atom-economic fashion is described. This intermolecular protocol allows for facile and divergent access to an array of structurally attractive cyclic adducts. The choice of a robust chiral diamidophosphite ligand, developed by our group, proved to be crucial for the success of this transformation.

Zn-ProPhenol Catalyzed Enantioselective Mannich Reaction of 2H-Azirines with Alkynyl Ketones.

The enantioselective Mannich reaction of 2H-azirines with alkynyl ketones is achieved under Zn-ProPhenol catalysis, delivering various aziridines with vicinal tetrasubstituted stereocenters in high yields with excellent enantioselectivities. The bimetallic Zn-ProPhenol complexes activate both the nucleophile and the electrophile in the same chiral pocket. A unique intramolecular hydrogen bond is observed in the obtained Mannich adducts, which lowers the basicity of the product's aziridine nitrogen thus favoring enantioselective control and allowing catalyst turnover.

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.

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.