Iridium-Catalyzed Allylic Alkylation Research Articles

Enantioselective Synthesis of Skipped Dienes via Iridium-Catalyzed Allylic Alkylation of Phosphonates.

An enantioselective synthesis of skipped dienes has been developed based on an iridium-catalyzed allylic alkylation of phosphonates and Horner-Wadsworth-Emmons olefination. This two-step protocol uses easily accessible substrates and delivers C2-substituted skipped dienes bearing a C3 stereogenic center, generally with outstanding enantioselectivities (up to 99.5:0.5 er). This is the first catalytic enantioselective allylic alkylation of phosphonates, and the overall process represents a formal enantioselective α-C(sp2)-H allylic alkylation of α,β-unsaturated carbonyls and acrylonitrile.

Ir-Catalyzed Asymmetric Allylic Alkylation of Dialkyl Malonates Enabling the Construction of Enantioenriched All-Carbon Quaternary Centers.

An enantioselective iridium-catalyzed allylic alkylation of malonates with trisubstituted allylic electrophiles to form all-carbon quaternary stereocenters is reported. This reaction proceeds at ambient temperature and enables the preparation of a wide range of enantioenriched products in up to 93% yield and 97% ee. The quaternary products can be readily converted to several valuable building blocks such as vicinal quaternary products and β-quaternary acids.

Enantioselective Iridium-Catalyzed Allylation of Nitroalkanes: Entry to β-Stereogenic α-Quaternary Primary Amines.

The first systematic study of simple nitronate nucleophiles in iridium-catalyzed allylic alkylation is described. Using a tol-BINAP-modified π-allyliridium C,O-benzoate catalyst, α,α-disubstituted nitronates substitute racemic branched alkyl-substituted allylic acetates, thus providing entry to β-stereogenic α-quaternary primary amines. DFT calculations reveal early transition states that render the reaction less sensitive to steric effects and distinct trans-effects of diastereomeric chiral-at-iridium π-allyl complexes that facilitate formation of congested tertiary-quaternary C-C bonds.

Enantioselective Iridium-Catalyzed Allylic Alkylation of Racemic Branched Alkyl-Substituted Allylic Acetates with Malonates.

The regio- and enantioselective allylic substitution of branched alkyl-substituted allylic acetates employing malonates has been achieved through a process that calls for Krische's π-allyliridium C,O-benzoate catalyst. The protocol reported herein can be applied to a diverse set of branched alkyl substrates that are generally not well tolerated in the other two types of Ir-catalyzed allylation.

Sequence-Dependent Stereodivergent Allylic Alkylation/Fluorination of Acyclic Ketones.

The stereodivergent iridium-catalyzed allylic alkylation and fluorination of acyclic ketones is described. α-Pyridyl-α-fluoroketones with vicinal tertiary and quaternary stereocenters were obtained in moderate to excellent yields and stereoselectivities. Distinct from known stereodivergent synthesis, for which two different chiral catalysts are required in general, herein we report a sequence-dependent stereodivergent synthesis. With only a single chiral Ir catalyst, all four possible stereoisomers of the products were prepared from the same starting materials by simply adjusting the sequence of asymmetric allylic alkylation and fluorination and varying the absolute configuration of the Ir catalyst.

Intermolecular Stereoselective Iridium-Catalyzed Allylic Alkylation: An Evolutionary Account.

Our lab has long been interested in the development of methods for the creation of enantioenriched all-carbon quaternary stereocenters. Historically, our interest has centered on palladium-catalyzed allylic alkylation, though recent efforts have moved to include the study of iridium catalysts. Whereas palladium catalysts enable the preparation of isolated stereocenters, the use of iridium catalysts allows for the direct construction of vicinal stereocenters via an enantio-, diastereo-, and regioselective allylic alkylation. This account details the evolution of our research program from inception, which focused on the first iridium-catalyzed allylic alkylation to prepare stereodyads containing a single quaternary center, to our most recent discovery that allows for the synthesis of vicinal quaternary centers.

Enantioselective Synthesis of Vicinal All-Carbon Quaternary Centers via Iridium-Catalyzed Allylic Alkylation.

The development of the first enantioselective transition-metal-catalyzed allylic alkylation providing access to acyclic products bearing vicinal all-carbon quaternary centers is disclosed. The iridium-catalyzed allylic alkylation reaction proceeds with excellent yields and selectivities for a range of malononitrile-derived nucleophiles and trisubstituted allylic electrophiles. The utility of these sterically congested products is explored through a series of diverse chemo- and diastereoselective product transformations to afford a number of highly valuable, densely functionalized building blocks, including those containing vicinal all-carbon quaternary stereocenters.

Iridium-Catalyzed Allylic Alkylation of Hydroxyquinolines

Iridium-Catalyzed Allylic Alkylation of Hydroxyquinolines

Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents.

The first enantioselective iridium-catalyzed allylic alkylation reaction of a masked acyl cyanide (MAC) reagent has been developed. The transformation allows for the use of an umpoled synthon, which serves as a carbon monoxide equivalent. The reaction proceeds with good yield and excellent selectivity up to gram scale for a wide range of substituted allylic electrophiles, delivering products amenable to the synthesis of highly desirable, enantioenriched vinylated α-aryl carbonyl derivatives.

Iridium-Catalyzed Asymmetric Allylic Alkylation of β-Keto Esters

Iridium-Catalyzed Asymmetric Allylic Alkylation of β-Keto Esters

Iridium-Catalyzed Stereoselective Allylic Alkylation Reactions with Crotyl Chloride.

The development of the first enantio-, diastereo-, and regioselective iridium-catalyzed allylic alkylation reaction of prochiral enolates to form an all-carbon quaternary stereogenic center with an aliphatic-substituted allylic electrophile is disclosed. The reaction proceeds with good to excellent selectivity with a range of substituted tetralone-derived nucleophiles furnishing products bearing a newly formed vicinal tertiary and all-carbon quaternary stereodyad. The utility of this protocol is further demonstrated via a number of synthetically diverse product transformations.

Syntheses of the Hexahydroindene Cores of Indanomycin and Stawamycin by Combinations of Iridium‐Catalyzed Asymmetric Allylic Alkylations and Intramolecular Diels–Alder Reactions

Short and concise syntheses of the hexahydroindene cores of the antibiotics indanomycin (X-14547 A) and stawamycin are presented. Key methods used are an asymmetric iridium-catalyzed allylic alkylation, a modified Julia olefination, a Suzuki-Miyaura coupling, and an intramolecular Diels-Alder reaction.

Iridium-Catalyzed Allylic Alkylation Reaction with N-Aryl Phosphoramidite Ligands: Scope and Mechanistic Studies

A series of N-aryl phosphoramidite ligands has been synthesized and applied to iridium-catalyzed allylic alkylation reactions, offering high regio- and enantioselectivities for a wide variety of substrates. These ligands feature the synthetic convenience and good tolerance of the ortho-substituted cinnamyl carbonates. Mechanistic studies, including DFT calculations and X-ray crystallographic analyses of the (π-allyl)-Ir complexes, reveal that the active iridacycle is formed via C(sp(2))-H bond activation.

Iridium-catalyzed allylic alkylation of monosubstituted allylic acetates with azlactone, and separation of diastereoisomers by sequential aza-Cope rearrangement

The iridium-catalyzed allylic alkylation with azlactone and sequential aza-Cope rearrangement was demonstrated. The sequential reaction was effective in separating of diastereoisomers and afforded a diastereomerically pure azlactone derivative and oxazolinone derivative.

Enantioselective Modular Synthesis of Cyclohexenones: Total Syntheses of (+)-Crypto- and (+)-Infectocaryone

A modular synthesis of cyclohexenones is described and applied to the first enantioselective total syntheses of (+)-crypto- and (+)-infectocaryone. Key steps in the synthesis of cyclohexenones are an iridium-catalyzed allylic alkylation, nucleophilic allylation, and ring-closing metathesis. On the way to (+)-cryptocaryone, a catch and release strategy involving an iodolactonization/elimination and a regioselective C-acylation were used.

Synthesis of 2-Methylindoline- and 2-Methyl-1,2,3,4-tetrahydroquinoline-Derived Phosphoramidites and Their Applications in Iridium-Catalyzed Allylic Alkylation of Indoles

A series of novel phosphoramidite ligands were synthesized from enantiopure BINOL and 2-methylindoline or 2-methyl-1,2,3,4-tetrahydroquinoline. These ligands were found to be efficient in iridium-catalyzed Friedel-Crafts reaction of indoles with allylic carbonates, affording branched products with high regio- and enantioselectivities. Strikingly, these ligands were demonstrated to be superior to the Feringa ligands when the ortho-substituted cinnamyl carbonates were used.

Preparation of 2,4‐Disubstituted Cyclopentenones by Enantioselective Iridium‐Catalyzed Allylic Alkylation: Synthesis of 2′‐Methylcarbovir and TEI‐9826

A broadly applicable synthesis of chiral 2- or 2,4-substituted cyclopent-2-enones has been developed by combining asymmetric iridium-catalyzed allylic alkylation reactions and ruthenium-catalyzed ring-closing metathesis. Enantiomeric excesses (ee values) in the range of 95-99 % ee have been achieved. This method offers a straightforward access to biologically active prostaglandins of the PGA type. As an example, an enantioselective synthesis of the prostaglandin-analogue 13,14-dihydro-15-deoxy-Delta(7)-prostaglandin-A1-methyl ester (TEI-9826) has been carried out. Furthermore, the carbonucleoside 2'-methylcarbovir has been prepared from O-protected 4-hydroxymethyl-2-methyl-cyclopent-2-enone by Pd-catalyzed allylic amination.

Salt-Free Enantioselective Iridium-Catalyzed Allylic Alkylations

Previous systems involving iridium-catalyzed allylic alkylations with β-carbonyl compounds require the use of the corresponding ­alkali-metal salt. The authors report iridium complexes of several phosphorus amidite ligands activated by the base TBD [1,5,7-triazabicyclo[4.4.0]dec-5-ene] which accommodate neutral β-carbonyl compounds. Further, the authors illustrate the utility of this method by providing a key intermediate in Stork’s quinine synthesis, the Ta­niguchi lactone, in high enantiomeric purity. Additionally, the catalytic system is applied to the intramolecular cyclization of 6 to yield cyclopropane 7 in high ee.

Enantioselective Iridium-Catalyzed Allylic Alkylations - Improvements and Applications Based on Salt-Free Reaction Conditions

Simplified procedures for the Ir-catalyzed asymmetric allylic alkylation reaction are described that often allow substitution products to be obtained with ≥99% ee. Applications to syntheses of important chiral building blocks, such as the Taniguchi lactone and dimethyl 2-vinylcyclopropane-1,1 -dicarboxylate, are presented.

Enantioselective Modular Synthesis of 2,4‐Disubstituted Cyclopentenones by Iridium‐Catalyzed Allylic Alkylation

Classy combo: Together, the asymmetric iridium-catalyzed allylic alkylation and ruthenium-catalyzed ring-closing metathesis lead to an efficient synthesis of chiral cyclopentenones (see scheme). One example is the synthesis of the antitumor agent TEI-9826 with high enantiomeric purity.