Diastereoselective Allylic Alkylation Research Articles

Synergistic Ir/Cu Catalysis for Asymmetric Allylic Alkylation of Oxindoles: Enantio- and Diastereoselective Construction of Quaternary and Tertiary Stereocenters.

3,3-Disubstituted oxindoles bearing quaternary and tertiary stereogenic centers are privileged structural motifs, which widely exist in pharmaceutical and natural products. Herein, a highly regio-, enantio-, and diastereoselective allylic alkylation of 3-alkyl oxindoles through synergistic iridium and copper catalysis is described, which provides a series of 3,3-disubstituted oxindole derivatives containing adjacent quaternary and tertiary stereogenic centers in excellent yields, enantiomeric excess, and diastereomeric ratio (for 30 examples, up to 97 % yield, >99 % ee, and >20 : 1 dr). This method provides exclusive branched selectivity, excellent enantio- and diastereoselectivities, and good functional compatibility. Control experiments suggested that the chiral copper catalyst is required for achieving high reactivities and diastereoselectivities under mild reaction conditions.

Chloroalkene dipeptide isosteres as peptidomimetics.

To date various biologically active peptides have been discovered, characterized and modified for drug discovery. However, the utilization of peptides as therapeutics involves some limitation due to several factors, including low metabolic stability owing to proteolysis and non-specific interactions with multiple off-target molecules. Hence, the development of "peptidomimetics," in which a part or whole of a molecule is modified, is a desirable strategy to enhance the stability or bioactivity of peptide-based drugs. In this situation, we have designed and developed a synthetic method for chloroalkene dipeptide isosteres (CADIs), which involves replacement of an amide bond in peptides with a chloroalkene structure and are classified as peptidomimetics. By a developed synthetic method, an N-tert-butylsulfonyl protected CADI can be obtained utilizing diastereoselective allylic alkylation with organocopper reagents as a key reaction. This CADI can be transformed into an N-fluorenylmethoxycarbonyl protected CADI in short steps. In addition, CADIs are used in Fmoc-based solid-phase peptide synthesis and introduced into a bioactive peptide. Protocols for practical preparation of some CADIs and peptide mimetics containing a CADI are described as detailed recipes.

Asymmetric Organocatalysis Combined with Palladium Catalysis: Synergistic Effect on Enantioselective Mannich/α-Allylation Sequential Reactions of Pyrazolones in Constructing Vicinal Quaternary Stereocenters.

In this letter, an efficient one-pot asymmetric sequential reaction is achieved by organo/transition metal relay catalysis in constructing two consecutive C-C bonds, which involves enantioselective amino squaramide catalytic Mannich-type addition of pyrazolones to isatin-derived ketimines and a subsequent palladium catalyzed diastereoselective allylic alkylation of pyrazolones with allylic acetates. An array of novel pyrazolone-aminooxindole-propylene structural motifs are obtained in a high level of yield and with excellent enantio- and diastereoselectivity (up to 95% yield, >20:1 dr, >99% ee). This methodology features the formation of vicinal quarternary carbon-stereocenters, and the second all-carbon tetrasubstituted stereogenic center is induced by joint action of the achiral palladium catalysis and the chiral environment generated from the Mannich step. Moreover, the usefulness of this methodology is highlighted by converting the allylic product into the carbonyl compound.

Synthesis of a Chloroalkene Dipeptide Isostere-Containing Peptidomimetic and Its Biological Application.

The first rapid and efficient chemical synthesis of a cyclic Arg-Gly-Asp (RGD) peptide containing a chloroalkene dipeptide isostere (CADI) is reported. By a developed synthetic method, an N-tert-butylsulfonyl protected CADI was obtained utilizing diastereoselective allylic alkylation as a key reaction. This CADI was also transformed into an N-Fmoc protected CADI in a few steps. The CADI was used in Fmoc-based solid-phase peptide synthesis. The first synthesis of a CADI-containing cyclic RGD peptide was successful, and the synthesized CADI-containing peptidomimetic was found to be a more potent inhibitor against integrin-mediated cell attachment than the parent cyclic peptide.

Catalytic Enantioselective and Diastereoselective Allylic Alkylation with Fluoroenolates: Efficient Access to C3-Fluorinated and All-Carbon Quaternary Oxindoles.

Synthetically versatile 3,3-disubstituted fluorooxindoles exhibiting vicinal chirality centers were obtained in high yields and with excellent enantio-, diastereo-, and regioselectivity through catalytic asymmetric fluoroenolate alkylation with allylic acetates. The reaction proceeds under mild conditions and can be scaled up without compromising the asymmetric induction. The unique synthetic usefulness of the products is highlighted by the incorporation of additional functionalities and the formation of 3-fluorinated oxindoles exhibiting an array of four adjacent centers of chirality. A new C-F bond functionalization path that provides unprecedented possibilities for the stereoselective generation of a chiral quaternary carbon center in the alkaloid scaffold is introduced.

Synthesis and exploration of electronically modified (R)-5,5-dimethyl-(p-CF3)3-i-PrPHOX in palladium-catalyzed enantio- and diastereoselective allylic alkylation: a practical alternative to (R)-(p-CF3)3-t-BuPHOX

The synthesis of the novel electronically modified phosphinooxazoline (PHOX) ligand, (R)-5,5-dimethyl-(p-CF3)3-i-PrPHOX, is described. The utility of this PHOX ligand is explored in both enantio- and diastereoselective palladium-catalyzed allylic alkylations. These investigations prove (R)-5,5-dimethyl-(p-CF3)3-i-PrPHOX to be an effective and cost-efficient alternative to electronically modified PHOX ligands derived from the prohibitively expensive (R)-t-leucine.

Transition metal-free asymmetric and diastereoselective allylic alkylation using Grignard reagents: construction of vicinal stereogenic centers via kinetic resolution

The first transition metal-free catalyzed diastereoselective and enantioselective asymmetric allylic alkylation (AAA) has been disclosed leading to the construction of vicinal tertiary/quaternary centers via a kinetic resolution protocol starting from readily available starting materials.

ChemInform Abstract: Highly Enantio‐ and Diastereoselective Allylic Alkylation of Morita—Baylis—Hillman Carbonates with Allyl Ketones.

AbstractIn the presence of the alkaloid (ALK) the title reaction allows an efficient, regio‐ and stereoselective access to hexadienes of type (III).

Highly Enantio- and Diastereoselective Allylic Alkylation of Morita–Baylis–Hillman Carbonates with Allyl Ketones

The asymmetric allylic alkylation of Morita-Baylis-Hillman (MBH) carbonates with allyl ketones has been developed. The α-regioselective alkylation adducts, containing a hexa-1,5-diene framework with important synthetic value, were achieved in up to 83% yield, >99% ee, and 50:1 dr by using a commercially available Cinchona alkaloid as the catalyst. From the allylic alkylation adduct, a cyclohexene bearing two adjacent chiral centers was readily prepared.

ChemInform Abstract: Palladium‐Catalyzed Regio‐ and Diastereoselective Allylic Alkylation in Ionic Liquids.

AbstractPerforming the allylic alkylation of alkene (II) using ammonium salts as solvents realizes the recyclable use of the palladium catalyst while maintaining regio‐ and diastereoselectivity.

Palladium-catalyzed Regio- and Diastereoselective Allylic Alkylation in Ionic Liquids

Abstract Palladium-catalyzed regio- and diastereoselective allylic alkylations using ionic liquids (ILs) as a solvent were demonstrated. The reaction using diethyl(2-methoxyethyl)methylammonium bis(trifluoromethanesulfonyl)amide ([N221ME][NTf2]) or ethylhexyldimethylammonium bis(trifluoromethanesulfonyl)amide ([N6211][NTf2]) as solvent realized the recyclable use of the palladium catalyst while maintaining excellent regioselectivity and diastereoselectivity.

Palladium‐Catalyzed Regio‐ and Diastereoselective Allylic Alkylation Using 2‐(Diphenylphosphino)benzoic Acid: Construction of Vicinal Quaternary and Tertiary Carbon Centers.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Palladium-catalyzed regio- and diastereo-selective allylic alkylation using 2-(diphenylphosphino)benzoic acid: construction of vicinal quaternary and tertiary carbon centers

The palladium-catalyzed regio- and diastereo-selective allylic alkylation of allyl acetates with carbon nucleophiles occurred. The stereochemistry was highly controlled by the palladium catalyst with 2-(diphenylphosphino)benzoic acid as the ligand, and vicinal quaternary and tertiary carbon centers were constructed.

Palladium‐Catalyzed Regio‐ and Diastereoselective Allylic Alkylation with Azlactones Using Triphenylarsine.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Palladium-Catalyzed Regio- and Diastereoselective Allylic Alkylation with Azlactones Using Triphenylarsine

The palladium-catalyzed regio- and diastereoselective allylic alkylation of (R)-2-acetoxy-4-phenyl-3-butene with azlactones using AsPh3 successfully occurred. The stereochemistries were highly controlled, and the reaction produced a coupling product which possessed vicinal chiral quaternary and tertiary carbon centers.

Palladium‐Catalyzed Construction of Amino Acid Derivatives Possessing Vicinal Chiral Quaternary and Tertiary Carbon Centers at the α and β Positions.

Abstract The palladium catalyzed regio- and diastereo-selective allylic alkylation of ( R )-2-acetoxy-4-aryl-3-butene with N -(diphenylmethylidene)glycinate and N -(diphenylmethylidene)alaninate occurred. The stereochemistry was controlled by the use of o -(diphenylphosphino)carboxylic acid, and produced new amino acid derivatives possessing vicinal chiral quaternary and tertiary carbon centers at the α and β positions.

Palladium-catalyzed construction of amino acid derivatives possessing vicinal chiral quaternary and tertiary carbon centers at the α and β positions

The palladium catalyzed regio- and diastereo-selective allylic alkylation of ( R)-2-acetoxy-4-aryl-3-butene with N-(diphenylmethylidene)glycinate and N-(diphenylmethylidene)alaninate occurred. The stereochemistry was controlled by the use of o-(diphenylphosphino)carboxylic acid, and produced new amino acid derivatives possessing vicinal chiral quaternary and tertiary carbon centers at the α and β positions.