Asymmetric Synthesis of α,α‐Disubstituted Allylic Amines through Palladium‐Catalyzed Allylic Substitution

The first asymmetric synthesis of important α,α‐disubstituted N‐alkyl allyl amine scaffolds through allylic substitution is reported. This approach is based on palladium catalysis and features ample scope with respect to both the allylic precursor and amine reagent, and high asymmetric induction with enantiomeric ratios (e.r.) up to 98.5:1.5. The use of less‐reactive anilines is also feasible, providing enantioenriched α,α‐disubstituted N‐aryl allylic amines.     

Silicon‐Directed Rhenium‐Catalyzed Allylic Carbaminations and Oxidative Fragmentations of γ‐Silyl Allylic Alcohols

A highly regioselective allylic substitution of β‐silyl allylic alcohols has been achieved that provides the branched isomer as a single product. This high level of regiocontrol is achieved through the use of a vinyl silane group that can perform a Hiyama coupling providing 1,3‐disubstituted allylic amines. An unusual oxidative fragmentation product was also observed at elevated temperature that appears to proceed by a Fleming–Tamao‐type oxidation–elimination pathway.     

Enantioselective Rhodium‐Catalyzed Allylic Alkylation of β,γ‐Unsaturated α‐Amino Nitriles: Synthetic Homoenolate Equivalents

An enantioselective rhodium‐catalyzed allylic alkylation of β,γ‐unsaturated α‐amino nitriles is described. This protocol provides a novel approach for the construction of β‐stereogenic carbonyl derivatives via the catalytic asymmetric alkylation of a homoenolate equivalent. The particularly challenging nature of this transformation is highlighted by the fact that three modes of selectivity must be manipulated, namely regio‐ and enantioselectivity, in addition to geometrical control. The γ‐stereogenic cyanoenamine products can be readily hydrolyzed in situ to afford the β‐substituted carboxylic acids, which in turn provide expedient access to a number of related carbonyl derivatives. Additionally, control experiments indicate that the chiral rhodium‐allyl intermediate facilitates the selective formation of the E‐cyanoenamine products, which is critical since the Z‐isomer affords significantly lower enantiocontrol.     

Stereospecific Synthesis of α‐Hydroxy‐Cyclopropylboronates from Allylic Epoxides

Herein, we report a catalytic and stereospecific method for the preparation of enantioenriched α‐hydroxy cyclopropylboronates with control in four contiguous stereocenters. The reaction involves the borylation of readily available allylic epoxides using an inexpensive Cu(I) salt and a commercially available phosphine ligand. High diastereocontrol is achieved and different diastereomers can be selectively prepared. Functionalization of the carbon–boron bond provides access to different enantiomerically enriched trisubstituted cyclopropanes from a common intermediate.     

A Facile One‐pot Synthesis of α‐Halo,α‐allylic Aldehydes from α,α‐Dihalo Ketones Utilizing Allylic Zinc Bromide

An efficient synthesis of various α‐halo,α‐allylic aldehydes from α,α‐dihalo ketones using both cyclic (3‐bromocyclohex‐1‐ene zinc bromide and (Z)‐3‐bromocyclobut‐1‐ene zinc bromide) and acyclic (allylzinc bromide and cinnamylzinc bromide) type of allylic organozinc bromide with DMF as base is described. A possible reaction mechanism is also proposed.     

Highly Enantioselective Formation of α‐Allyl‐α‐Arylcyclopentanones via Pd‐Catalysed Decarboxylative Asymmetric Allylic Alkylation

A highly enantioselective Pd‐catalysed decarboxylative asymmetric allylic alkylation of cyclopentanone derived α‐aryl‐β‐keto esters employing the (R,R)‐ANDEN‐phenyl Trost ligand has been developed. The product (S)‐α‐allyl‐α‐arylcyclopentanones were obtained in excellent yields and enantioselectivities (up to >99.9 % ee). This represents one of the most highly enantioselective formations of an all‐carbon quaternary stereogenic center reported to date. This reaction was demonstrated on a 4.0 mmol scale without any deterioration of enantioselectivity and was exploited as the key enantioselective transformation in an asymmetric formal synthesis of the natural product (+)‐tanikolide.     

Copper‐Catalyzed γ‐Selective and Stereospecific Allylic Cross‐Coupling with Secondary Alkylboranes

The scope of the copper‐catalyzed coupling reactions between organoboron compounds and allylic phosphates is expanded significantly by employing triphenylphosphine as a ligand for copper, allowing the use of secondary alkylboron compounds. The reaction proceeds with complete γ‐E‐selectivity and preferential 1,3‐syn stereoselectivity. The reaction of γ‐silicon‐substituted allylic phosphates affords enantioenriched α‐stereogenic allylsilanes.     

Iridium‐Catalyzed Enantioselective Allylic Substitution of Unstabilized Enolates Derived from α,β‐Unsaturated Ketones

We report Ir‐catalyzed, enantioselective allylic substitution reactions of unstabilized silyl enolates derived from α,β‐unsaturated ketones. Asymmetric allylic substitution of a variety of allylic carbonates with silyl enolates gave allylated products in 62–94 % yield with 90–98 % ee and >20:1 branched‐to‐linear selectivity. The synthetic utility of this method was illustrated by the short synthesis of an anticancer agent, TEI‐9826.     

Copper‐Catalyzed Enantioselective Allylic Alkylation with a γ‐Butyrolactone‐Derived Silyl Ketene Acetal

Herein, we report a Cu‐catalyzed enantioselective allylic alkylation using a γ‐butyrolactone‐derived silyl ketene acetal. Critical to the development of this work was the identification of a novel mono‐picolinamide ligand with the appropriate steric and electronic properties to afford the desired products in high yield (up to 96 %) and high ee (up to 95 %). Aryl, aliphatic, and unsubstituted allylic chlorides bearing a broad range of functionality are well‐tolerated. Spectroscopic studies reveal that a Cu^I species is likely the active catalyst, and DFT calculations suggest ligand sterics play an important role in determining Cu coordination and thus catalyst geometry.     

Asymmetric Allylic Alkylation of β‐Ketoesters with Allylic Alcohols by a Nickel/Diphosphine Catalyst

Asymmetric allylic alkylation of β‐ketoesters with allylic alcohols catalyzed by [Ni(cod)₂]/(S)‐H₈‐BINAP was found to be a superior synthetic protocol for constructing quaternary chiral centers at the α‐position of β‐ketoesters. The reaction proceeded in high yield and with high enantioselectivity using various β‐ketoesters and allylic alcohols, without any additional activators. The versatility of this methodology for accessing useful and enantioenriched products was demonstrated.     

Concise Synthesis of α‐Methylene‐β‐hydroxy‐γ‐carboxy‐γ‐lactams

A concise protocol for the synthesis of α‐methylene‐β‐hydroxy‐γ‐carboxy‐γ‐lactams has been described via alkylation of amino acid derived iminoesters with α‐bromomethylmethacrylate, followed by allylic hydroxylation. All the synthesized compounds have been evaluated for their cytotoxicity on multiple myeloma cancer cell lines.     

Highly Selective Allylborations of Aldehydes Using α,α‐Disubstituted Allylic Pinacol Boronic Esters

α,α‐Disubstituted allylic pinacol boronic esters undergo highly selective allylborations of aldehydes to give tetrasubstituted homoallylic alcohols with exceptional levels of anti‐Z‐selectivity (>20:1). The scope of the reaction includes both acyclic and cyclic allylic boronic esters which lead to acyclic and exocyclic tetrasubstituted homoallylic alcohols. The use of β‐borylated allylic boronic esters gave fully substituted alkenes bearing a boronic ester which underwent further cross‐coupling enabling a highly modular and stereoselective approach to the synthesis of diaryl tetrasubstituted alkenes. Computational analysis revealed the origin of the remarkable selectivity observed.     

Enantioselective Synthesis of α‐Secondary and α‐Tertiary Piperazin‐2‐ones and Piperazines by Catalytic Asymmetric Allylic Alkylation

The asymmetric palladium‐catalyzed decarboxylative allylic alkylation of differentially N‐protected piperazin‐2‐ones allows the synthesis of a variety of highly enantioenriched tertiary piperazine‐2‐ones. Deprotection and reduction affords the corresponding tertiary piperazines, which can be employed for the synthesis of medicinally important analogues. The introduction of these chiral tertiary piperazines resulted in imatinib analogues which exhibited comparable antiproliferative activity to that of their corresponding imatinib counterparts.