Chemo-, Regio- and Stereoselective Preparation of (Z)-2-Butene-1,4-Diol Monoesters via Pd-Catalyzed Decarboxylative Acyloxylation.

(Z)-alkenes are useful synthons but thermodynamically less stable than their (E)-isomers and typically more difficult to prepare. The synthesis of 1,4-hetero-bifunctionalized (Z)-alkenes is particularly challenging due to the inherent regio- and stereoselectivity issues. Herein we demonstrate a general, chemoselective and direct synthesis of (Z)-2-butene-1,4-diol monoesters. The protocol operates within a Pd-catalyzed decarboxylative acyloxylation regime involving vinyl ethylene carbonates (VECs) and various carboxylic acids as the reaction partners under mild and operationally attractive conditions. The newly developed process allows access to a structurally diverse pool of (Z)-2-butene-1,4-diol monoesters in good yields and with excellent regio- and stereoselectivity. Various synthetic transformations of the obtained (Z)-2-butene-1,4-diol monoesters demonstrate how these synthons are of great use to rapidly diversify the portfolio of these formal desymmetrized (Z)-alkenes.

Rh(I)/Sulfoxide-Imine-Olefin Complex Catalyzed Enantioselective Allylic Alkylation of 2-Fluoromalonate: Synthesis of Chiral α-Fluorolactone Bearing Vicinal Stereogenic Centers.

Highly enantioselective Rh-catalyzed allylic substitution of the racemic branched allylic substrates with 2-fluoromalonate was realized enabled by a novel chiral sulfoxide-imine-olefin ligand under mild reaction conditions. The utilization of CuSO4 is beneficial for improving the enantioselectivity. Notably, the chiral fluoro-containing allyl products can be employed in a selective cyclic esterification to form chiral α-fluorolactone bearing vicinal stereogenic centers.

Enantio- and Regioconvergent Nickel-Catalyzed Etherification of Phenols by Allylation to Access Chiral C(sp3)-O Allyl Aryl Ethers.

An enantio- and regioconvergent allylation of phenols under nickel catalysis with an α-/γ-regioisomeric mixture of racemic silylated/germylated allylic chlorides is reported. The silyl/germyl group governs the regioselectivity, and the transformation affords enantiomerically enriched unsymmetrical 1,3-disubstituted allyl aryl ethers with great regiocontrol in good yields and with excellent enantioselectivities. Notably, no nickel-mediated C-O bond activation is observed at room temperature. The synthetic value of these densely functionalized silicon-containing building blocks is demonstrated in a series of chemoselective transformations, including a [3,3]-sigmatropic rearrangement for the construction of an α-chiral silane.

Transition-Metal-Free Synthesis of Enantioenriched Tertiary and Quaternary α-Chiral Allylsilanes.

Access to enantioenriched tertiary and quaternary α-chiral allysilanes without any transition-metal catalyst is reported. This was achieved by enantioselective allylic displacement of γ-silylated allylic bromides through Lewis base activation of Grignard reagents by a bidentate chiral NHC ligand. The process afforded both high γ-regio- and enantioselectivity and is compatible with a wide range of silyl groups on the substrates.

Desymmetrization of Geminal Difluoromethylenes using a Palladium/Copper/Lithium Ternary System for the Stereodivergent Synthesis of Fluorinated Amino Acids.

Fluorinated amino acids and related peptides/proteins have been found widespread applications in pharmaceutical and agricultural compounds. However, strategies for introducing a C-F bond into amino acids in an enantioselective manner are still limited and no such asymmetric catalysis strategy has been reported. Herein, we have successfully developed a Pd/Cu/Li ternary system for stereodivergent synthesis of chiral fluorinated amino acids. This method involves a sequential desymmetrization of geminal difluoromethylenes and allylic substitution with amino acid Schiff bases via Pd/Li and Pd/Cu dual activation, respectively. A series of non-natural amino acids bearing a chiral allylic/benzylic fluorine motif are easily synthesized in high yields with excellent regio-, diastereo-, and enantioselectivities (up to >20 : 1 dr and >99 % ee). A density functional theory (DFT) study revealed the F-Cu interaction of the allylic substrate and the Cu catalyst significantly influence the stereoselectivity.

Stereodivergent Construction of 1,3-Chiral Centers via Tandem Asymmetric Conjugate Addition and Allylic Substitution Reaction.

Herein, we report a synthesis of cyclohexanones bearing multi-continuous stereocenters by combining copper-catalyzed asymmetric conjugate addition of dialkylzinc reagents to cyclic enones with iridium-catalyzed asymmetric allylic substitution reaction. Good to excellent yields, diastereoselectivity and enantioselectivity can be obtained. Unlike the stereodivergent construction of adjacent stereocenters (1,2-position) reported in the literature, the current reaction can achieve the stereodivergent construction of nonadjacent stereocenters (1,3-position) by a proper combination of two chiral catalysts with different enantiomers.

Metal catalyst-free N-allylation/alkylation of imidazole and benzimidazole with Morita-Baylis-Hillman (MBH) alcohols and acetates.

A highly α-regioselective N-nucleophilic allylic substitution of cyclic MBH alcohols and acetates with imidazole or benzimidazole, in toluene at reflux with an azeotropic distillation, was successfully carried out with no catalysts or additives, affording the corresponding N-substituted imidazole derivatives in good yields. On the other hand, in refluxing toluene or methanol, the aza-Michael addition of imidazole onto acyclic MBH alcohols was performed using DABCO as an additive, leading to the corresponding 1,4-adducts in 70-84% yields.

Stereodivergent Desymmetrization of Simple Dicarboxylates via Branch-Selective Pd/Cu Catalyzed Allylic Substitution.

Asymmetric desymmetrization has been demonstrated to be a powerful strategy for building stereocenters in asymmetric synthesis. Herein, a Pd/Cu catalyzed asymmetric desymmetrization reaction with a simple geminal dicarboxylate is reported. A wide scope of imino esters bearing an aryl or heteroaromatic group were compatible with this bimetallic catalytic system. The reactions proceeded smoothly, giving the desired products in good yields with high to excellent regio-, diastereo-, and enantioselectivity (up to 20 : 1 branched:linear, >20 : 1 dr, >99 % ee). Notably, the reaction favored branched selectivity, which is unusual for the Pd-catalyzed allylic alkylation reaction. In addition, the standard product could be easily transformed to other valuable molecules such as chiral allylic alcohols, carbamates, and organic boron compounds. Furthermore, DFT calculations were conducted to explain the origin of the branched selectivity.

Stereoretentive Regio- and Enantioselective Allylation of Isoxazolinones by a Planar Chiral Palladacycle Catalyst.

The catalytic allylic substitution is one of the most important tools in asymmetric synthesis to form C-C bonds in an enantioselective way. While high efficiency was previously accomplished in terms of enantio- and regiocontrol using different catalyst types, a strong general limitation is a very pronounced preference for the formation of allylic substitution products with (E)-configured C=C double bonds. Herein, we report that with a planar chiral palladacycle catalyst a diastereospecific reaction outcome is achieved using isoxazolinones and allylic imidates as substrates, thus maintaining the C=C double bond geometry of the allylic substrates in the highly enantioenriched products. DFT calculations show that the reactions proceed via an SN 2 mechanism and not via π-allyl Pd complexes. Crucial for the high control is the stabilization of the allylic fragment in the SN 2 transition state by π-interactions with the phenyl substituents of the pentaphenylferrocenyl catalyst core.

Stepwise Asymmetric Allylic Substitution-Isomerization Enabled Mimetic Synthesis of Axially Chiral B,N-Heterocycles.

Axially chiral molecules bearing multiple stereogenic axes are of great importance in the field of organic chemistry. However, the efficient construction of atropisomers featuring two different types of stereogenic axes has rarely been explored. Herein, we report the novel atroposelective synthesis of configurationally stable axially chiral B,N-heterocycles. By using stepwise asymmetric allylic substitution-isomerization (AASI) strategy, diaxially chiral B,N-heterocycles bearing B-C and C-N axes that are related to the moieties of axially chiral enamines and arylborons were also obtained. In this case, all four stereoisomers of diaxially chiral B,N-heterocycles were stereodivergently afforded in high enantioselectivities. Density functional theory (DFT) studies demonstrated that the NH⋅⋅⋅π interactions played a unique role in the promotion of stereospecific isomerization, thereby leading to the highly efficient central-to-axial chirality transfer.

Bimetallic Catalysis in Stereodivergent Synthesis.

Bimetallic catalysis has emerged as an efficient strategy for the development of new chemical reactions. Importantly, this strategy also provides a simple and powerful platform for stereodivergent synthesis, whereby all the possible stereoisomers of products bearing two stereocenters can be easily prepared from the same set of starting materials. In this Minireview, the development of stereodivergent allylic substitution, propargylic substitution, hydrofunctionalization, and annulation based on bimetallic catalysis has been summarized. It is expected that more bimetallic catalytic systems will be developed and applied for the stereodivergent synthesis of valuable molecules.

Secondary Phosphine Sulfide-Enabled Iridium-Catalyzed Asymmetric Allylic Substitution.

An iridium-catalyzed asymmetric synthesis of branched allylic phosphine compounds under mild conditions is reported. Products bearing various functional groups can be synthesized with excellent stereoselectivity (up to 99.9 % ee) and regioselectivity. The employment of phosphine sulfides with relatively low deactivation capacity against metal catalysts is crucial for the success of this reaction.

Asymmetric α-Allylation of Glycinate with Switched Chemoselectivity Enabled by Customized Bifunctional Pyridoxal Catalysts.

Owing to the strong nucleophilicity of the NH2 group, free-NH2 glycinates react with MBH acetates to usually deliver N-allylated products even in the absence of catalysts. Without protection of the NH2 group, chiral pyridoxal catalysts bearing an amide side chain at the C3 position of the naphthyl ring switched the chemoselectivity of the glycinates from intrinsic N-allylation to α-C allylation. The reaction formed chiral multisubstituted glutamic acid esters as SN 2'-SN 2' products in good yields with excellent stereoselectivity (up to 86 % yield, >20 : 1 dr, 97 % ee). As compared to pyridoxal catalysts bearing an amide side arm at the C2 position, the pyridoxals in this study have a bigger catalytic cavity to enable effective activation of larger electrophiles, such as MBH acetates and related intermediates. The reaction is proposed to proceed via a cooperative bifunctional catalysis pathway, which accounts for the high level of diastereo- and enantiocontrol of the pyridoxal catalysts.

Catalytic Asymmetric Allylic Substitution with Copper(I) Homoenolates Generated from Cyclopropanols.

By using copper(I) homoenolates as nucleophiles, which are generated through the ring-opening of 1-substituted cyclopropane-1-ols, a catalytic asymmetric allylic substitution with allyl phosphates is achieved in high to excellent yields with high enantioselectivity. Both 1-substituted cyclopropane-1-ols and allylic phosphates enjoy broad substrate scopes. Remarkably, various functional groups, such as ether, ester, tosylate, imide, alcohol, nitro, and carbamate are well tolerated. Moreover, the present method is nicely extended to the asymmetric construction of quaternary carbon centers. Some control experiments argue against a radical-based reaction mechanism and a catalytic cycle based on a two-electron process is proposed. Finally, the synthetic utilities of the product are showcased by means of the transformations of the terminal olefin group and the ketone group.

Palladium-Catalyzed Dearomative Methoxyallylation of 3-Nitroindoles with Allyl Carbonates.

Herein we report a Pd-catalyzed dearomative methoxyallylation of 3-nitroindoles with readily available allyl carbonates. Good yields (up to 86 %) and diastereoselectivity (up to >20:1 dr) are obtained for a wide range of substrates. The compatibility of gram-scale synthesis and the relatively low catalyst loading (down to 1 mol % of [Pd]) enhance the practicality of this method. The kinetic experiments indicate that the rate-determining step of this reaction is the nucleophilic attack of the alkoxide anion.

Iridium-Catalyzed Enantioselective Intermolecular Indole C2-Allylation.

The enantioselective intermolecular C2-allylation of 3-substituted indoles is reported for the first time. This directing group-free approach relies on a chiral Ir-(P, olefin) complex and Mg(ClO4 )2 Lewis acid catalyst system to promote allylic substitution, providing the C2-allylated products in typically high yields (40-99 %) and enantioselectivities (83-99 % ee) with excellent regiocontrol. Experimental studies and DFT calculations suggest that the reaction proceeds via direct C2-allylation, rather than C3-allylation followed by in situ migration. Steric congestion at the indole-C3 position and improved π-π stacking interactions have been identified as major contributors to the C2-selectivity.

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.

Enantioselective Intramolecular Allylic Substitution via Synergistic Palladium/Chiral Phosphoric Acid Catalysis: Insight into Stereoinduction through Statistical Modeling.

The mode of asymmetric induction in an enantioselective intramolecular allylic substitution reaction catalyzed by a combination of palladium and a chiral phosphoric acid was investigated by a combined experimental and statistical modeling approach. Experiments to probe nonlinear effects, the reactivity of deuterium-labeled substrates, and control experiments revealed that nucleophilic attack to the π-allylpalladium intermediate is the enantio-determining step, in which the chiral phosphate anion is involved in stereoinduction. Using multivariable linear regression analysis, we determined that multiple noncovalent interactions with the chiral environment of the phosphate anion are integral to enantiocontrol in the transition state. The synthetic protocol to form chiral pyrrolidines was further applied to the asymmetric construction of C-O bonds at fully substituted carbon centers in the synthesis of chiral 2,2-disubstituted benzomorpholines.

Regio- and Stereoselective Allylic Substitutions of Chiral Secondary Alkylcopper Reagents: Total Synthesis of (+)-Lasiol, (+)-13-Norfaranal, and (+)-Faranal.

Chiral secondary alkylcopper reagents were prepared from chiral secondary alkyl iodides by a retentive I/Li exchange followed by a retentive transmetalation with CuBr⋅P(OEt)3 . Switching the solvent to THF significantly increased their configurational stability and made these copper reagents suitable for regioselective allylic substitutions. The optically enriched copper species underwent SN 2 substitutions with allylic bromides (up to >99 % SN 2 regioselectivity). The addition of ZnCl2 and the use of chiral allylic phosphates allowed to switch the regioselectivity towards SN 2' substitution (up to >99 % SN 2' regioselectivity) and to perform highly selective anti-SN 2' substitutions with absolute control over two adjacent stereocenters. This method was applied in the total synthesis of the three ant pheromones (+)-lasiol, (+)-13-norfaranal, and (+)-faranal (up to 98:2 dr, 99 % ee).

A Mechanistic Analysis of the Palladium-Catalyzed Formation of Branched Allylic Amines Reveals the Origin of the Regio- and Enantioselectivity through a Unique Inner-Sphere Pathway.

A recently reported palladium-catalyzed allylic substitution of vinyl-substituted cyclic carbonates (VCCs) with aryl amines represents a rare example of a regio- and enantioselective synthesis of α,α-disubstituted allylic N-aryl amines. However, the underlying reasons for this unusual selectivity profile remain elusive. In the present work, density functional theory (DFT) calculations in combination with mechanistic control experiments were performed to elucidate in detail this allylic amination manifold and the origin of the regio- and enantioselectivity. The combined data show that after oxidative addition of the VCC to Pd0 , the nucleophilic attack via an originally proposed outer-sphere pathway gives, however, the opposite regioisomer compared to the experimental results. Instead, nucleophilic attack of the amine reagent via a unique type of chelation-assisted, inner-sphere pathway accounts for the experimentally observed "branched" regioselectivity and high enantio-control.