Iridium‐Catalyzed Regio‐ and Enantioselective Allylic Substitution of Silyl Dienolates Derived from Dioxinones

Reported herein is the iridium‐catalyzed regio‐ and enantioselective allylic substitution reactions of unstabilized silyl dienolates derived from dioxinones. Asymmetric allylic substitution of a variety of allylic trichloroethyl carbonates with these silyl dienolates gave γ‐allylated products selectively in 60–84 % yield and 90–98 % ee.     

Iridium‐Catalyzed Regio‐ and Enantioselective Allylic Substitution of Trisubstituted Allylic Electrophiles

The first Ir‐catalyzed enantioselective allylation of trisubstituted allylic electrophiles has been developed. Through modification of the leaving group of allylic electrophiles, we found that trisubstituted allylic phosphates are suitable electrophiles for asymmetric allylation. The reaction of allylic phosphates with enol silanes derived from dioxinones gave allylated products in good yields with high enantioselectivities.     

Highly Regio‐ and Enantioselective Synthesis of N‐Substituted 2‐Pyridones: Iridium‐Catalyzed Intermolecular Asymmetric Allylic Amination

The first iridium‐catalyzed intermolecular asymmetric allylic amination reaction with 2‐hydroxypyridines has been developed, thus providing a highly efficient synthesis of enantioenriched N‐substituted 2‐pyridone derivatives from readily available starting materials. This protocol features a good tolerance of functional groups in both the allylic carbonates and 2‐hydroxypyridines, thereby delivering multifunctionalized heterocyclic products with up to 98 % yield and 99 % ee.     

Enantioselective Synthesis of Tertiary Allylic Fluorides by Iridium‐Catalyzed Allylic Fluoroalkylation

Few allylic electrophiles containing two different substituents at a single allyl terminus and none in which one of the two substituents is a heteroatom, have been shown previously to react with iridium catalysts to form substitution products. We report that iridium‐catalysts are uniquely suited to form tertiary allylic fluorides enantioselectively by the addition of a diverse range of carbon‐centered nucleophiles at the fluorine‐containing terminus of 3‐fluoro‐substituted allylic esters. The products contain tertiary stereogenic centers bearing a single fluorine, which are isosteric with common tertiary stereocenters containing a single hydrogen. Computational studies reveal the principal steric interactions influencing the stability of endo and exo π‐allyl intermediates formed from 3,3‐disubstituted allylic electrophiles.     

Direct Asymmetric Dearomatization of Pyridines and Pyrazines by Iridium‐Catalyzed Allylic Amination Reactions

The first iridium‐catalyzed intramolecular asymmetric allylic dearomatization reaction of pyridines and pyrazines has been realized. 2,3‐Dihydroindolizine and 6,7‐dihydropyrrolo[1,2‐a]pyrazine derivatives were obtained with excellent yields and enantioselectivity. This methodology features dearomatization by direct N‐allylic alkylation of pyridines or pyrazines under mild reaction conditions.     

Enantioselective Synthesis of Pyrrole‐Based Spiro‐ and Polycyclic Derivatives by Iridium‐Catalyzed Asymmetric Allylic Dearomatization and Controllable Migration Reactions

The first highly diastereo‐ and enantioselective synthesis of five‐membered spiro‐2H‐pyrroles was achieved using an Ir‐catalyzed asymmetric allylic dearomatization reaction. The spiro‐2H‐pyrrole derivatives readily undergo a controllable and stereospecific allylic migration under acid catalysis, providing polycyclic pyrrole derivatives in excellent yields and ee values. Additionally, the novel Ir‐complex K1 , derived from [Ir(cod)Cl]₂ (cod=1,5‐cyclooctadiene) and N‐benzhydryl‐N‐phenyldinaphthophosphoramidite (BHPphos), showed excellent control of both diastereo‐ and enantioselectivities.     

Immobilized Catalysts for Iridium‐Catalyzed Allylic Amination: Rate Enhancement by Immobilization

The first immobilized catalyst for Ir‐catalyzed asymmetric allylic aminations is described. The catalyst is a cationic (π‐allyl)Ir complex bound by cation exchange to an anionic silica gel support. Preparation of the catalyst is facile, and the supported catalyst displayed considerably enhanced activity compared with the parent homogeneous catalyst. Up to 43 consecutive amination runs were possible in recycling experiments.     

An Iridium(I) N‐Heterocyclic Carbene Complex Catalyzes Asymmetric Intramolecular Allylic Amination Reactions

A chiral iridium(I) N‐heterocyclic carbene complex was reported for the first time as the catalyst in the highly enantioselective intramolecular allylic amination reaction. The current method provides facile access to biologically important enantioenriched indolopiperazinones and piperazinones in good yields (74–91 %) and excellent enantioselectivities (92–99 % ee). Preliminary mechanistic investigations reveal that the C?H activation occurs at the position ortho to the N‐aryl group of the ligand.     

Iridium‐Catalyzed Enantioselective Allylic Alkylation with Functionalized Organozinc Bromides

Iridium‐catalyzed enantioselective allylic alkylation of branched racemic carbonates with functionalized alkylzinc bromide reagents is described. Enabled by a chiral Ir/(P,olefin) complex, the method described allows allylic substitution with various primary and secondary alkyl nucleophiles with excellent regio‐ and enantioselectivities. The developed reaction was showcased in a concise, asymmetric synthesis of (?)‐preclamol.     

Iridium‐Catalyzed Enantioselective Allyl–Allylsilane Cross‐Coupling

An enantioselective allyl–allylsilane cross‐coupling involving racemic branched allylic alcohols and allylsilanes is reported. An iridium‐(P,olefin) phosphoramidite complex enables the transformation with high regio‐ and stereoselectivity under operationally simple conditions. The utility of the coupling is demonstrated in a concise catalytic, enantioselective synthesis of a pyrethroid insecticide protrifenbute.     

Regio‐ and Enantioselective Synthesis of Sulfone‐Bearing Quaternary Carbon Stereocenters by Pd‐Catalyzed Allylic Substitution

Chiral sulfones are of great importance in medicinal chemistry and chemical synthesis. Efficient methods for preparing enantiomerically enriched sulfone‐containing molecules can therefore be of significant value; such methods, however, are uncommon. Herein, we report the first general palladium‐catalyzed sulfonylation of vinyl cyclic carbonates with sodium sulfinates. A series of enantiomerically enriched tertiary allylic sulfones were synthesized in good yields with excellent enantiomeric ratios. Both aliphatic‐ and aryl‐substituted vinyl cyclic carbonates are suitable reactants with excellent results. This reaction features broad substrates scope, readily available starting materials, excellent regio‐ and enantioselectivity, and synthesis of sulfone‐bearing quaternary carbon stereocenters. Through the sulfonylation of geranyl derived cyclic carbonate 1 h , we achieve the formal total synthesis of (+)‐agelasidine A.     

Iridium‐Catalyzed Asymmetric Isomerization of Primary Allylic Alcohols

Nothing to sm(Ir)k at : Under appropriate reaction conditions, iridium hydride catalysts promote the isomerization of primary allylic alcohols. The best catalysts, like (R)‐ 1 (P green, O red, N blue, Ir yellow), deliver the desired chiral aldehydes with excellent enantioselectivity and good yields. Mechanistic hypotheses have been developed on the basis of preliminary investigations.

     

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.     

Rhodium‐Catalyzed Sequential Allylic Amination and Olefin Hydroacylation Reactions: Enantioselective Synthesis of Seven‐Membered Nitrogen Heterocycles

Dynamic kinetic asymmetric amination of branched allylic acetimidates has been applied to the synthesis of 2‐alkyl‐dihydrobenzoazepin‐5‐ones. These seven‐membered‐ring aza ketones are prepared in good yield with high enantiomeric excess by rhodium‐catalyzed allylic substitution with 2‐amino aryl aldehydes followed by intramolecular olefin hydroacylation of the resulting alkenals. This two‐step procedure is amenable to varied functionality and proves useful for the enantioselective preparation of these ring systems.     

Regio‐ and Enantioselective Synthesis of N‐Substituted Pyrazoles by Rhodium‐Catalyzed Asymmetric Addition to Allenes

The rhodium‐catalyzed asymmetric N‐selective coupling of pyrazole derivatives with terminal allenes gives access to enantioenriched secondary and tertiary allylic pyrazoles, which can be employed for the synthesis of medicinally important targets. The reaction tolerates a large variety of functional groups and labelling experiments gave insights into the reaction mechanism. This new methodology was further applied in a highly efficient synthesis of JAK 1/2 inhibitor (R)‐ruxolitinib.     

Enantioselective Synthesis of Allylboronates and Allylic Alcohols by Copper‐Catalyzed 1,6‐Boration

Chiral secondary allylboronates are obtained in high enantioselectivities and 1,6:1,4 ratios by the copper‐catalyzed 1,6‐boration of electron‐deficient dienes with bis(pinacolato)diboron (B₂(pin)₂). The reactions proceed efficiently using catalyst loadings as low as 0.0049 mol %. The allylboronates may be oxidized to the allylic alcohols, and can be used in stereoselective aldehyde allylborations. This process was applied to a concise synthesis of atorvastatin, in which the key 1,6‐boration was performed using only a 0.02 mol % catalyst loading.