Palladium-catalyzed Asymmetric Allylic Alkylation Reaction Research Articles

Regio- and Enantioselective Synthesis of Dihydropyrido[1,2-a]indoles via Catalytic Asymmetric Annulative Allylic Alkylation.

A palladium-catalyzed asymmetric annulative allylic alkylation reaction of 2-[(1H-indol-2-yl)methyl]malonates with (E)-but-2-ene-1,4-diyl dicarbonates is described, leading to the regio- and enantioselective synthesis of dihydropyrido[1,2-a]indoles with a chiral cyclic allyl stereocenter adjacent to the ring-junction nitrogen atom in moderate to good yields. The salient features of this protocol include mild conditions, a broad substrate scope, and good compatibility with substituents as well as high regio- and stereoselectivities, providing a catalytic asymmetric entry for fabricating chiral pyridoindole scaffolds.

Introducing C2 asymmetry in chromans—a brief story

The Trost group made notable attempts in the 1990s to synthesize several natural products such as vitamin E and its analogs, clusifoliol, rhododaurichromanic acid A, siccanin, and calanolide A and B through the palladium-catalyzed asymmetric allylic alkylation (AAA) reaction.

Palladium-Catalyzed Asymmetric Allylic Alkylation of Alkyl-Substituted Allyl Reagents with Acyclic Amides.

A wide range of alkyl-substituted allyl reagents, as well as nonstabilized carbon nucleophiles, was successfully used for the first time in the palladium-catalyzed asymmetric allylic alkylation reaction, affording the corresponding allylic alkylated products in high yields with high enantioselectivities. The usefulness of the protocol has been demonstrated by the enantioselective synthesis of an important chiral building block and enantiomer of Dubiusamine A.

Asymmetric palladium-catalyzed allylic alkylation using dialkylzinc reagents: a remarkable ligand effect.

A serendipitously discovered palladium-catalyzed asymmetric allylic alkylation reaction with diorganozinc reagents, which displays broad functional group compatibility, is reported. This novel transformation hinges on a remarkable ligand effect which overrides the standard "umpolung" reactivity of allyl-palladium intermediates in the presence of dialkylzincs. Owing to its mild conditions, enantioselective allylic alkylations of racemic allylic electrophiles are possible in the presence of sensitive functional groups.

ChemInform Abstract: The Construction of All‐Carbon Quaternary Stereocenters by Use of Pd‐Catalyzed Asymmetric Allylic Alkylation Reactions in Total Synthesis

AbstractReview: 111 refs.

The Construction of All-Carbon Quaternary Stereocenters by Use of Pd-Catalyzed Asymmetric Allylic Alkylation Reactions in Total Synthesis.

All-carbon quaternary stereocenters have posed significant challenges in the synthesis of complex natural products. These important structural motifs have inspired the development of broadly applicable palladium-catalyzed asymmetric allylic alkylation reactions of unstabilized non-biased enolates for the synthesis of enantioenriched α-quaternary products. This microreview outlines key considerations in the application of palladium-catalyzed asymmetric allylic alkylation reactions and presents recent total syntheses of complex natural products that have employed these powerful transformations for the direct, catalytic, enantioselective construction of all-carbon quaternary stereocenters.

Palladium-Catalyzed Asymmetric Allylic Alkylations of Polynitrogen-Containing Aromatic Heterocycles

We report the palladium-catalyzed asymmetric allylic alkylation (AAA) reaction of a variety of nitrogen-containing aromatic heterocycles, including pyrazine, pyrimidine, pyridazine, quinoxaline, and benzoimidazole derivatives. The mesityl ester, whose steric bulk prevents competitive deacylation of the electrophile from "hard" nucleophiles, is introduced as a new leaving group in allylic alkylation chemistry. In contrast to our previous studies of AAA reactions with pyridine-based substrates, no precomplexation with a Lewis acid is required before deprotonation with LiHMDS, underscoring the relative acidity of these electron-deficient nucleophiles.

Development of a concise synthesis of (-)-oseltamivir (Tamiflu).

We report a full account of our work towards the development of an eight-step synthesis of anti-influenza drug (-)-oseltamivir (Tamiflu) from commercially available starting materials. The final synthetic route proceeds with an overall yield of 30 %. Key transformations include a novel palladium-catalyzed asymmetric allylic alkylation reaction (Pd-AAA) as well as a rhodium-catalyzed chemo-, regio-, and stereoselective aziridination reaction.

Rational tuning of the rigidity of a ligand scaffold: synthesis of diphenylsulfide-linked bis(oxazoline) ligands and their application in asymmetric allylic alkylation

The scaffold rigidity of bis(oxazoline) ligands was rationally tuned on the basis of literature information. Diphenylsulfide-linked bis(oxazoline) ligands with a flexible scaffold were efficiently synthesized to test our hypothesis. The improved enantioselectivity in palladium-catalyzed asymmetric allylic alkylation reaction was achieved as we expected.

Synthesis of (-)-Oseltamivir

A very concise synthesis of (-)-oseltamivir (tamiflu) features a novel palladium-catalyzed asymmetric allylic alkylation reaction using a phthalimide nucleophile to directly open the racemic lactone A.

A Concise Synthesis of (−)‐Oseltamivir

Tackling the supply problem: A short and efficient synthesis of (−)-oseltamivir has been developed which requires eight steps from commercially available starting material and proceeds with an overall yield of 30 %. Key transformations include a novel palladium-catalyzed asymmetric allylic alkylation reaction (Pd-AAA, see scheme) as well as a chemo-, regio-, and stereoselective aziridination reaction. Phth=phthaloyl.

A Convergent Pd‐Catalyzed Asymmetric Allylic Alkylation of dl‐ and meso‐Divinylethylene Carbonate: Enantioselective Synthesis of (+)‐Australine Hydrochloride and Formal Synthesis of Isoaltholactone

The use of a mixture of dl- and meso-divinylethylene carbonate as an electrophile in palladium-catalyzed asymmetric allylic alkylation reactions is reported. From the diastereomeric mixture of meso and chiral racemic starting materials, a single product is obtained in high optical purity employing either oxygen or nitrogen nucleophiles. The resulting dienes have proven to be versatile synthetic intermediates as each carbon is functionalized for further transformation and differentiated by virtue of the reaction. A mechanism for this intriguing transformation is proposed and a concise enantioselective total synthesis of (+)-australine hydrochloride is reported as well as a formal synthesis of isoaltholactone.

Palladium-Catalyzed Regio- and Enantioselective Allylic Alkylation of Bis Allylic Carbonates Derived from Morita−Baylis−Hillman Adducts

Morita-Baylis-Hillman diene adducts are used as substrates in the palladium-catalyzed asymmetric allylic alkylation reaction with oxygen and carbon nucleophiles in good regio- and enantioselectivity.

Origin of enantioselectivity in palladium-catalyzed asymmetric allylic alkylation reactions using chiral N,N-ligands with different rigidity and flexibility

The chiral bidentate-N,N ligands, (S(a))-1, (S(a))-2, (S,S)-3 and (S,S)-4, were synthesized. They were shown to contain rigid 2-pyridinyl or 8-quinolinyl building blocks and the C(2)-symmetric chiral frameworks trans-2,5-dimethylpyrrolidinyl or (S)-(+)-2,2'-(2-azapropane-1,3-diyl)-1,1'-binaphthalene. In the (S(a))-2, and (S,S)-4 ligands pair, the 8-quinolinyl skeleton is directly bonded to the C(2)-symmetric chiral frameworks (S)-(+)-2,2'-(2-azapropane-1,3-diyl)-1,1'-binaphthalene or trans-2,5-dimethylpyrrolidinyl. This feature induces rigidity in this pair of ligands upon the N,N-framework. However, this does not occur for the (S(a))-1 and (S,S)-3 ligands, in which the presence of the -CH(2)- spacer between the frameworks bearing the nitrogen atom donors gives greater flexibility to the ligand. A further difference between the pairs of ligands is significant from the electronic properties of the chiral framework N-donor atom. The coordinating properties and the specific steric structural features of the (S(a))-1, (S(a))-2, (S,S)-3, and (S,S)-4 ligands are explained by their reactions with the [Pd(PhCN)(2)Cl(2)] and [Pd(eta(3)-PhCHCHCHPh)(mu-Cl)](2) substrates, in which the reported ligands form chelate complexes, with the exception of (S(a))-2, which failed to react with [Pd(eta(3)-PhCHCHCHPh)(mu-Cl)](2). The ligands were used in the palladium-allyl catalyzed substitution reaction of 1,3-diphenylallyl acetate with dimethylmalonate, with the best result being obtained using the (S(a))-1 ligand, giving the substitution product 2-(1,3-diphenylallyl)dimethylmalonate with an enantiomeric excess of 82% in the S form and a yield of 96%. The work demonstrates that in the presence of a steric ligand control, the electronic properties of the ligand donor atoms play a role though not significant in determining the enantioselectivity of palladium(II) catalyzed allylic substitution reactions. The results of the catalytic reaction do not provide a convincing explanation considering the coordinated chiral ligand features, as rigidity or flexibility and electronic properties of the N-donor atoms. A rationalization of the results is proposed on the basis of NMR studies and DFT calculation on the cationic complexes [Pd(eta(3)-PhCHCHCHPh)(N-N*)]CF(3)SO(3), (N-N* = (S(a))-1, 9; (S,S)-3, 10; (S,S)-4, 11).

P-Chirogenic α-Carboxyphosphine Boranes as Effective Pre-Ligands in Palladium-Catalyzed Asymmetric Reactions

P-Chirogenic α-carboxyphosphine boranes have been applied directly as pre-ligands in palladium-catalyzed asymmetric allylic alkylation and amination reactions, with in situ deprotection of the borane moiety. Using dimethylmalonate as the nucleophile afforded the alkylated product in up to 91% ee, while reaction with benzylamine gave amination in up to 94% ee. In both cases, the opposite enantiomer could be accessed in high ee by using the antipode of the ligand, easily accessible by exchanging (-)-sparteine for a (+)-sparteine mimic in the desymmetrization process used for preparing the ligands.

Synthesis of (+)-Agelastatin A

An inhibitor of glycogen synthase kinase-3b, Agelastatin A provides a potential new treatment for Alzheimer’s disease. Noteworthy in this approach are (1) the use of both intra- and intermolecular palladium-catalyzed asymmetric allylic alkylation (AAA) reactions wherein the use of pyrrole and N-methoxyamide nucleophiles are disclosed, and (2) the aziridination of an olefin mediated by NHC-copper complex G.

Modular chiral selenium-containing oxazolines: synthesis and application in the palladium-catalyzed asymmetric allylic alkylation

A new series of modular chiral selenium-containing oxazolines has been synthesized from inexpensive and commercially available l-serine and l-aspartic acid. These new compounds were evaluated as chiral ligands in the palladium-catalyzed asymmetric allylic alkylation reaction, furnishing the product in high enantiomeric excess, using Cs2CO3/CH2Cl2 as the base/solvent system.

A “Chiral Aldehyde” Equivalent as a Building Block Towards Biologically Active Targets

Chiral gamma-aryloxybutenolides, readily accessible through dynamic kinetic asymmetric transformation (DYKAT) of racemic acyloxybutenolides, were utilized as "chiral aldehyde" building blocks for intermolecular cycloadditions and Michael reactions. Unprecedented selectivity in trimethylenemethane cycloadditions with this building block allowed an efficient synthesis of a novel metabotropic glutamate receptor 1 antagonist in development by the Bayer corporation. These studies further inspired work that culminated in the total synthesis of (+)-brefeldin A, a natural product with a range of significant biological properties. All of the stereochemistry in this target molecule was derived from two palladium-catalyzed asymmetric allylic alkylation reactions. The trans-alkenes were synthesized by a Julia olefination and a ruthenium-catalyzed trans-hydrosilylation-protodesilylation protocol. The route to (+)-brefeldin A lends itself to analogue syntheses and was completed in 18 steps in 6 % overall yield.

Solid-phase synthesis of chiral 3,4-diazaphospholanes and their application to catalytic asymmetric allylic alkylation.

Functionalized chiral diazaphospholanes ligate to a variety of transition metals, yielding chiral, catalytically active, metal complexes. Previous work has established that amino acid derivatization of the carboxyl groups of (R,R)-N,N'-phthaloyl-2,3-(2-carboxyphenyl)-phenyl-3,4-diazaphospholane (1) yields phosphines that are excellent ligands for palladium-catalyzed asymmetric allylic alkylation reactions. Alanine functionalization is particularly effective for allylic alkylation of 1,3-dimethylallyl acetate. Standard Merrifield resins and amino acid coupling methods are used to synthesize the bead-attached phosphine having the topology bead-linker-LAla-(R,R)-1-LAla-OMe, as a 1:1 mixture of linkage isomers. Use of this supported phosphine in Pd-catalyzed asymmetric allylic alkylation yields 92% enantiomeric excess, matching prior solution-phase results. A 20-member collection of amino acid-functionalized phosphines on beads with the topology bead-linker-AA(2)-AA(1)-1-AA(1)-AA(2) was synthesized by using parallel solid-state methods and screened for efficacy in allylic alkylation. Resulting enantioselectivities indicate that the AA(1) position has the strongest effect on the reaction. Catalyst activities can vary widely with the nature of the phosphine ligand and the reaction conditions. Meaningful analysis of intrinsic catalytic activities awaits identification of the structure and abundance of the active catalyst.

Polymer-supported C2-symmetric ligands for palladium-catalyzed asymmetric allylic alkylation reactions.

Polymer-supported C2-symmetric ligands for palladium-catalyzed asymmetric allylic alkylation reactions.