Pd-catalyzed Allylic Alkylation Research Articles

ChemInform Abstract: Camphane‐Based Aminophosphine Ligands for Pd‐Catalyzed Asymmetric Allylic Alkylation.

Abstract A practical synthesis of new chiral aminophosphine ligands based on the camphane scaffold bearing alkoxy groups was accomplished. The application of these ligands in the Pd-catalyzed allylic alkylation of ( E )-1,3-diphenyl-2-propenyl acetate proceeded with excellent conversions and ee’s of up to 91%. Variation of the alkoxy substituents did not substantially influence the catalytic performance.

ChemInform Abstract: Enantioselective Synthesis of 2,3‐Disubstituted Indanones via Pd‐Catalyzed Intramolecular Asymmetric Allylic Alkylation of Ketones.

A Pd-catalyzed intramolecular asymmetric allylic alkylation (AAA) reaction with “hard” carbanions has been developed for the first time, affording 2,3-disubstituted indanones with high diastereo- and enantioselectivities. The transformation of these products into other core structures of natural products has been demonstrated.

Enantioselective Pd-catalyzed tandem allylic alkylation reaction using monodentate phosphoramidite ligands for the formal total synthesis of huperzine A

Enantioselective synthesis of a key intermediate to (−)-huperzine A by Pd-catalyzed tandem allylic alkylation using a novel monodentate phosphoramidite ligand.

Rational design of sulfoxide–phosphine ligands for Pd-catalyzed enantioselective allylic alkylation reactions

A new type of chiral sulfoxide-phosphine ligands have been developed by a rational combination of two privileged scaffolds for Pd-catalyzed asymmetric allylic alkylation reactions. Under optimized conditions, generally high yields (up to 97%) and excellent enantioselectivities (up to >99% ee) were obtained.

Pd-catalyzed allylic alkylation of dienyl carbonates with nitromethane with high C-5 regioselectivity

A highly regioselective palladium-catalyzed allylic alkylation of dienyl esters with nitromethane has been developed, providing selective access to the C-5 attacked products. The structures of the ligands as well as the steric effect of the substrates are important factors in determining the regiochemical outcome of the reaction.

Enantioselective Synthesis of 2,3-Disubstituted Indanones via Pd-Catalyzed Intramolecular Asymmetric Allylic Alkylation of Ketones

A Pd-catalyzed intramolecular asymmetric allylic alkylation (AAA) reaction with "hard" carbanions has been developed for the first time, affording 2,3-disubstituted indanones with high diastereo- and enantioselectivities. The transformation of these products into other core structures of natural products has been demonstrated.

Stereoselective Dithiophosphorylation of Cinchona Alkaloids: Easy Approach to Prospective Chiral Ligands and Organocatalysts

The 9-mesylates of Cinchona alkaloids reacted with HSP(S)(OEt)2 in benzene at 50°C to give the corresponding O,O-diethyl-dithiophosphates of the alkaloids with complete inversion of configuration at the 9-C stereogenic centers (3 examples, 42–45% yields). Also O-ethyl-dithiophosphoric acid derivative of 9-epi-quinine was obtained. The configuration of the stereogenic centers were established using homo- and hetero-NOE NMR techniques and comparing the experimental and calculated (GIAO/DFT) spectra. The dithiophosphates of alkaloids were tested as chiral ligands in the Pd-catalyzed allylic alkylation of dimethyl malonate with rac-1,3-diphenylprop-2-enyl acetate and in the Cu-catalyzed asymmetric Henry reaction and gave the respective product with up to 51% ee. Quinine O,O-diethyl-phosphorodithioate was also tested as a novel potential chiral solvating agent for amino acids (N-Boc-phenylglycine) in 31P and 1H NMR spectroscopy. [Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental files: Additional figures]

Camphane-based aminophosphine ligands for Pd-catalyzed asymmetric allylic alkylation

A practical synthesis of new chiral aminophosphine ligands based on the camphane scaffold bearing alkoxy groups was accomplished. The application of these ligands in the Pd-catalyzed allylic alkylation of (E)-1,3-diphenyl-2-propenyl acetate proceeded with excellent conversions and ee’s of up to 91%. Variation of the alkoxy substituents did not substantially influence the catalytic performance.

Pd-catalyzed allylic alkylation of thioamides

This work describes the first Pd-catalyzed allylic alkylation of thioamides. Various thioamides were efficiently α-allylated in high yields and with excellent selectivity for monoallylation under mild reaction conditions. The process not only provides a facile method for the synthesis of functionalized thioamides, but also presents a useful transformation for synthetically important thioamides.

Palladium-catalyzed asymmetric construction of vicinal all-carbon quaternary stereocenters and its application to the synthesis of cyclotryptamine alkaloids.

A twofold Pd-DAAA Pd-catalyzed decarboxylative allylic alkylation (see scheme) was used to construct two vicinal all-carbon quaternary stereocenters (marked in red) in a diastereo- and enantioselective fashion. The products of the Pd-DAAA were further elaborated to complete the formal syntheses of cyclotryptamine alkaloids. The twofold Pd-catalyzed transformation proceeds through an initial matched allylation followed by a second mismatched allylation to deliver the desired product.

Enantioselective Palladium‐Catalyzed Decarboxylative Allylation of Carbazolones: Total Synthesis of (−)‐Aspidospermidine and (+)‐Kopsihainanine A

Functionalized chiral carbazolones with α-quaternary carbon centers are formed through the ligand-controlled Pd-catalyzed enantioselective decarboxylative allylic alkylation of carbazolones (see scheme). This catalytic asymmetric reaction was employed as the key step in the total synthesis of aspidospermidine and (+)-kopsihainanine A.

Pd-Catalyzed Allylic Alkylation of CF3-Containing Esters with Three Electron-Withdrawing Groups

Tsuji–Trost reaction (Pd-catalyzed allylic alkylation) of CF₃-containing esters with three electron-withdrawing groups is reported. The reactions with methyl bis(trifluoromethyl)acetate and dimethyl (trifluoromethyl)malonate were carried out with low-loading catalysts of Pd(0) and XPhos at ambient temperature in THF, giving the products in high yields. This method efficiently overcomes the β-defluorination, which is hard to control in the chemical transformation of α-trifluoromethyl carbanions, and provides versatile fluorinated compounds with quaternary carbon centers, which are highly demanded in drug discovery.

Highly tunable anionic tethered N-heterocyclic carbene of Pd(II) complexes for asymmetric allylic alkylation reaction

The versatility of the anionic tethered NHC ligand system for the Pd-catalyzed allylic asymmetric alkylation (AAA) reaction was investigated. A well defined anionic amidate/NHC–Pd(II) complex catalyzed the AAA reaction of 1,3-diphenylprop-3-en-1-yl acetate (5) with NaCH(CO2Me)2. Similarly, the AAA reaction occurred by employing an NHC–Pd(II) complex that was generated in situ. Screening of a wide variety of NHC ligand precursors revealed that the combination of [Pd(allyl)Cl]2 and the azolium salt 9, containing a 3-pentyl group at N(3) position in the NHC ring, efficiently promoted the AAA reaction to afford the corresponding alkylated product 7 with 67% ee. Furthermore, it was found that the Pd/NHC ratio was an important factor; the AAA reaction with a Pd/NHC ratio of 1:1 took place smoothly, whereas utilization of a Pd/NHC ratio of 1:2 resulted in low conversion of the substrates probably by the formation of the catalytically inert bis(NHC)–Pd(II) complex. In fact, an independent experiment showed that the bis(NHC)–Pd(II) complex was formed by treating [Pd(allyl)Cl]2 with two equivalents of NHC–Ag complex. Further investigations on the catalytic AAA reaction revealed significant improvements in both the product yield (99%) and the enantioselectivity (81% ee) when cyclopentyl methyl ether was used as a solvent. A plausible reaction intermediate was discussed.

Total Synthesis of Aeruginosin 98B

The first total synthesis of aeruginosin 98B was accomplished. The key step is a highly diastereoselective Pd-catalyzed intramolecular asymmetric allylic alkylation reaction of a diastereomeric mixture of allylic carbonates that is enabled by the use of racemic phosphine ligand L1.

Camphane-based phosphino-carboxamide ligands as P,O-chelates in Pd-catalyzed enantioselective allylic alkylation

A practical synthesis for new chiral phosphino-carboxamide ligands has been accomplished. These ligands were effectively modified both on the amide moiety and the phosphine atom. Application of these ligands in the Pd-catalyzed allylic alkylation of (E)-1,3-diphenyl-2-propenyl acetate proceeded with excellent conversions and with ee’s of up to 92%. The use of a camphane based chiral auxiliary was found to be crucial for the asymmetric induction.

Origin of Selectivity of Tsuji–Trost Allylic Alkylation of Lactones: Highly Ordered Transition States with Lithium‐Containing Enolates

We report computational investigations on the mechanism and the selectivity of Pd-catalyzed allylic alkylation of γ-valerolactone. Density functional calculations using the B3LYP functional are performed on the selectivity-determining nucleophilic addition step of this reaction. The B3LYP results of commonly assumed pathways fail to reproduce the observed selectivity of the reaction. Therefore, alternative pathways are considered for the nucleophilic addition step, to explain the experimentally established role of the additives LiCl and lithium diisopropyl amide (LDA) in the Pd-catalyzed reaction. These pathways involve different approaches of the enolate toward the η(3)-allylpalladium complex that are mainly guided by stabilizing Cl(δ-)···Li(δ+)···O(enolate) interactions in the transition state. In the calculations, the experimentally observed trans-product selectivity for the prototypical reaction with (S)-BINAP ligands is found only when assuming the addition of a "mixed" Li-enolate/LiCl adduct to the η(3)-allylpalladium complex. This mechanism provides a reasonable explanation for the experimental results and sheds light on the role of LiCl in the reaction. The analysis of the different transition-state models allows us to identify steric and electronic factors that stabilize or destabilize the relevant diastereomeric transition states. Calculations for different combinations of substrates (γ-valerolactone and δ-caprolactone) and catalysts (with (R)- and (S)-BINAP ligands) reproduce the experimentally observed selectivities well and thus provide further support for the proposed mechanism.

‘Evans Auxiliary' Based P-N Ligands for Pd-Catalyzed Asymmetric Allylic Alkylation Reactions

A new type of chiral P–N ligands has been prepared which incorporates the Evans auxiliary as chiral ligand. They were found to act as effective ligands in the Pd-catalyzed allylic alkylation reactions. Using these ligands with allylpalladium chloride dimer as catalyst, the coupling of 1,3-diphenyl-3-acetoxyprop-1-ene and dimethyl malonate proceeded smoothly at –10 °C providing the desired product with enantiomeric excess up to 87% and excellent yield.

Total syntheses of mitragynine, paynantheine and speciogynine via an enantioselective thiourea-catalysed Pictet–Spengler reaction

The pharmacologically interesting indole alkaloids (-)-mitragynine, (+)-paynantheine and (+)-speciogynine were synthesised in nine steps from 4-methoxytryptamine by a route featuring (i) an enantioselective thiourea-catalysed Pictet-Spengler reaction, providing the tetrahydro-β-carboline ring and (ii) a Pd-catalysed Tsuji-Trost allylic alkylation, closing the D-ring.

Highly stereoselective modifications of peptides via Pd-catalyzed allylic alkylation of internal peptide amide enolates

Pd-catalyzed allylations are excellent tools for stereoselective peptide modifications, showing several advantages compared to normal alkylations. Reactions of internal peptide amide enolates with Pd-allyl complexes proceed not only with high yields of up to 86%, they show also high regio- and diastereoselectivities (88-99%), giving rise to the trans-configured products. Therefore, this protocol is a powerful synthetic tool for the synthesis of natural product and drug molecules.

C–N Bond Cleavage of Allylic Amines via Hydrogen Bond Activation with Alcohol Solvents in Pd-Catalyzed Allylic Alkylation of Carbonyl Compounds

Hydrogen-bond-activated C-N bond cleavage of allylic amines was realized in Pd-catalyzed allylic alkylation to form the C-C bond product. The method could be expanded to a series of allylic amines and carbonyl compounds with excellent results. It provides a new and convenient access to C-C bond formation based on Pd-catalyzed allylic alkylation of allylic amines by using only inexpensive alcohol solvents.