Cycloadditions of Oxacyclic Allenes and a Catalytic Asymmetric Entryway to Enantioenriched Cyclic Allenes

The chemistry of strained cyclic alkynes has undergone a renaissance over the past two decades. However, a related species, strained cyclic allenes, especially heterocyclic derivatives, have only recently resurfaced and represent another class of valuable intermediates. We report a mild and facile means to generate the parent 3,4‐oxacyclic allene from a readily accessible silyl triflate precursor, and then trap it in (4+2), (3+2), and (2+2) reactions to provide a variety of cycloadducts. In addition, we describe a catalytic, decarboxylative asymmetric allylic alkylation performed on an α‐silylated substrate, to ultimately permit access to an enantioenriched allene. Generation and trapping of the enantioenriched cyclic allene occurs with complete transfer of stereochemical information in a Diels–Alder cycloaddition through a point‐chirality, axial‐chirality, point‐chirality transfer process.     

Chirality Transfer in Gold(I)‐Catalysed Direct Allylic Etherifications of Unactivated Alcohols: Experimental and Computational Study

Gold(I)‐catalysed direct allylic etherifications have been successfully carried out with chirality transfer to yield enantioenriched, γ‐substituted secondary allylic ethers. Our investigations include a full substrate‐scope screen to ascertain substituent effects on the regioselectivity, stereoselectivity and efficiency of chirality transfer, as well as control experiments to elucidate the mechanistic subtleties of the chirality‐transfer process. Crucially, addition of molecular sieves was found to be necessary to ensure efficient and general chirality transfer. Computational studies suggest that the efficiency of chirality transfer is linked to the aggregation of the alcohol nucleophile around the reactive π‐bound Au–allylic ether complex. With a single alcohol nucleophile, a high degree of chirality transfer is predicted. However, if three alcohols are present, alternative proton transfer chain mechanisms that erode the efficiency of chirality transfer become competitive.     

General approach to allenes through copper-catalyzed γ-selective and stereospecific coupling between propargylic phosphates and alkylboranes

Copper-catalyzed γ-selective coupling between propargylic phosphates and alkylboron compounds (alkyl-9-BBN, prepared by hydroboration of alkenes with 9-BBN-H) affords multisubstituted allenes with various functional groups. The reaction of enantioenriched propargylic phosphates to give axially chiral allenes proceeds with excellent point-to-axial chirality transfer with 1,3-anti stereochemistry.     

Organocatalytic Atroposelective Aldol Condensation: Synthesis of Axially Chiral Biaryls by Arene Formation

Axially chiral compounds are of significant importance in modern synthetic chemistry and particularly valuable in drug discovery and development. Nonetheless, current approaches for the preparation of pure atropisomers often prove tedious. We demonstrate here a synthetic method that efficiently transfers the stereochemical information of a secondary amine organocatalyst into the axial chirality of tri‐ortho‐substituted biaryls. An aromatic ring is formed during the dehydration step of the described aldol condensation cascade, leading to highly enantioenriched binaphthyl derivatives. The fundamental course of the reaction is related to the biosynthesis of aromatic polyketides.     

Stereoselective Arene‐Forming Aldol Condensation: Synthesis of Axially Chiral Aromatic Amides

The increasing awareness of the importance of amide atropisomers prompts the development of novel strategies for their selective preparation. Described herein is a method for the enantioselective synthesis of atropisomeric aromatic amides by an amine‐catalyzed arene‐forming aldol condensation. The high reactivity of the glyoxylic amide substrates enables a remarkably efficient construction of a new aromatic ring, which proceeds within minutes at ambient temperature to afford products with excellent stereoselectivity. The high rotational barriers of the reduced products highlight the utility of this stable, spatially organized chiral scaffold.     

Sequential Ir‐Catalyzed Allylation/2‐aza‐Cope Rearrangement Strategy for the Construction of Chiral Homoallylic Amines†

Sequential Ir‐catalyzed asymmetric allylation/2‐aza‐Cope rearrangement of arylidene aminomalonates with allylic carbonates was successfully developed, and a variety of enantioenriched homoallylic amine derivatives were obtained in high yields with good chirality transfer and excellent E/Z‐geometry control (up to 99% yield, 96% ee). Compared with previous dual catalytic system established for this transformation, the current mono metal catalytic system provides a simpler and more practical protocol employing the readily available starting materials.     

Exploiting Atropisomerism to Increase the Target Selectivity of Kinase Inhibitors

Many biologically active molecules exist as rapidly interconverting atropisomeric mixtures. Whereas one atropisomer inhibits the desired target, the other can lead to off‐target effects. Herein, we study atropisomerism as a possibility to improve the selectivities of kinase inhibitors through the synthesis of conformationally stable pyrrolopyrimidines. Each atropisomer was isolated by HPLC on a chiral stationary phase and subjected to inhibitor profiling across a panel of 18 tyrosine kinases. Notably different selectivity patterns between atropisomers were observed, as well as improved selectivity compared to a rapidly interconverting parent molecule. Computational docking studies then provided insights into the structure‐based origins of these effects. This study is one of the first examples of the intentional preorganization of a promiscuous scaffold along an atropisomeric axis to increase target selectivity, and provides fundamental insights that may be applied to other atropisomeric target scaffolds.     

Cobalt‐Catalyzed Enantioselective Synthesis of Chiral gem‐Bis(boryl)alkanes

We report an asymmetric synthesis of enantioenriched gem‐bis(boryl)alkanes in an enantioselective diborylation of 1,1‐disubstituted alkenes catalyzed by Co(acac)₂/(R)‐DM‐segphos. A range of activated and unactivated alkenes underwent this asymmetric diborylation in the presence of cyclooctene as a hydrogen acceptor, affording the corresponding gem‐bis(boryl)alkanes with high enantioselectivity. The synthetic utility of these chiral organoboronate compounds was demonstrated through several stereospecific derivatizations and the synthesis of sesquiterpene and sesquiterpenoid natural products.     

Chirality Transfer and Memory of Chirality in Gold‐Catalyzed Reactions

Over the last few years, gold‐catalyzed reactions that involved chirality transfer and memory of chirality (MOC) have emerged as a powerful tool in enantioselective synthesis. This technique has allowed for the single‐step synthesis of enantioenriched compounds from readily available starting materials. This Focus Review discusses this emerging field with an emphasis on mechanistic aspects and their applications in synthetic organic chemistry.     

Design and Atroposelective Construction of IAN analogues by Organocatalytic Asymmetric Heteroannulation of Alkynes

An organocatalytic atroposelective strategy for accessing enantioenriched axially chiral IAN analogues was developed for the first time. A class of novel atropisomeric C2-arylquinoline skeletons were synthesized with high enantiocontrol via chiral phosphoric-acid-catalyzed heteroannulation of in situ generated vinylidene ortho-quinone methide (VQM) intermediates with ortho-aminophenones. The strategy tolerated a broad substrate scope, providing a facile organocatalytic approach to IAN analogues in good yields and excellent enantioselectivities under mild reaction conditions. Moreover, the synthetic utility of this methodology was illustrated through further transformations into IAN-type ligand and axially chiral thiourea.     

Aldehyde-catalyzed epoxidation of unactivated alkenes with aqueous hydrogen peroxide

The organocatalytic epoxidation of unactivated alkenes using aqueous hydrogen peroxide provides various indispensable products and intermediates in a sustainable manner. While formyl functionalities typically undergo irreversible oxidations when activating an oxidant, an atropisomeric two-axis aldehyde capable of catalytic turnover was identified for high-yielding epoxidations of cyclic and acyclic alkenes. The relative configuration of the stereogenic axes of the catalyst and the resulting proximity of the aldehyde and backbone residues resulted in high catalytic efficiencies. Mechanistic studies support a non-radical alkene oxidation by an aldehyde-derived dioxirane intermediate generated from hydrogen peroxide through the Payne and Criegee intermediates.

An atropisomeric two-axis aldehyde is capable of catalysing the organocatalytic epoxidation of unactivated alkenes using hydrogen peroxide as the oxidant.     

Access to Aryl‐Naphthaquinone Atropisomers by Phosphine‐Catalyzed Atroposelective (4+2) Annulations of δ‐Acetoxy Allenoates with 2‐Hydroxyquinone Derivatives

Although asymmetric phosphine catalysis is a powerful tool for the construction of various chiral carbon centers, its synthetic potential toward an enantioenriched atropisomer has not been explored yet. Reported herein is a phosphine‐catalyzed atroposelective (4+2) annulation of δ‐acetoxy allenoates and 2‐hydroxyquinone derivatives. The reaction provides expedient access to aryl‐naphthaquinone atropisomers by the de novo construction of a benzene ring. The two functionalities of the catalyst, a tertiary phosphine (Lewis base) and a tertiary amine (Brønsted base), cooperatively enable this process with high regio‐ and enantioselectivities.     

Silicon‐Based Bulky Group‐Induced Remote Control and Conformational Preference in the Synthesis and Application of Isolable Atropisomeric Amides with Secondary Alcohol or Amine Moieties

Remote stereocontrol through conformational transmission along a carbon chain is highly important in synthetic systems and molecular architectures. In this work, the interactional reactivity between a remote silicon‐based bulky group and an O‐/N‐containing functional group has been revealed and determined by lateral lithiation–substitution, desilylation, as well as desilylation–olefination with benzaldehyde. The results suggest considerable information transmission and steric hindrance that can be exploited for the controllable synthesis of atropisomeric molecules. Based on the remote steric effect of a functional group across the aromatic ring of an amide, the construction of isolable atropisomeric amides with functional groups, such as alcohol, amine, and olefin was successfully achieved. All these new atropisomers were obtained in reasonable yield in pure diastereomeric form, and the specific configuration of representative products was confirmed by X‐ray crystallography.     

Phosphoric Acid-Catalyzed Enantioselective Synthesis of Axially Chiral Anthrone-based Compounds

Anthrones and analogues are structural cores shared by diverse pharmacologically active natural and synthetic compounds. The sp²-rich nature imposes inherent obstruction to introduce stereogenic element onto the tricyclic aromatic backbone. In our pursuit to expand the chemical space of axial chirality, a novel type of axially chiral anthrone-derived skeleton was discovered. This work establishes oxime ether as suitable functionality to furnish axial chirality on symmetric anthrone skeletons through stereoselective condensation of the carbonyl entity with long-range chirality control. The enantioenriched anthrones could be elaborated into dibenzo-fused seven-membered N-heterocycles containing well-defined stereogenic center via Beckmann rearrangement with axial-to-point chirality conversion.     

Regiochemical control in the metal-catalyzed transposition of allylic silyl ethers

A novel mode of regiochemical control over the allylic [1,3]-transposition of silyloxy groups catalyzed by Re2O7 has been developed. This strategy relies on a cis-oriented vinyl boronate, generated from the Alder-ene reaction of homoallylic silyl ethers and alkynyl boronates, to trap out the allylic hydroxyl group. The resulting cyclic boronic acids are excellent partners for cross-coupling reactions. High chirality transfer is observed for the rearrangement of enantioenriched allylic silyl ethers.     

Hydrogen‐Bond‐Enabled Dynamic Kinetic Resolution of Axially Chiral Amides Mediated by a Chiral Counterion

Non‐biaryl atropisomers are valuable in medicine, materials, and catalysis, but their enantioselective synthesis remains a challenge. Herein, a counterion‐mediated O‐alkylation method for the generation of atropisomeric amides with an er up to 99:1 is outlined. This dynamic kinetic resolution is enabled by the observation that the rate of racemization of atropisomeric naphthamides is significantly increased by the presence of an intramolecular O?H???NCO hydrogen bond. Upon O‐alkylation of the H‐bond donor, the barrier to rotation is significantly increased. Quantum calculations demonstrate that the intramolecular H‐bond reduces the rotational barrier about the aryl–amide bond, stabilizing the planar transition state for racemization by approximately 40 kJ mol^?1, thereby facilitating the observed dynamic kinetic resolution.     

Combining Organocatalysis with Central‐to‐Axial Chirality Conversion: Atroposelective Hantzsch‐Type Synthesis of 4‐Arylpyridines

Suitably substituted enantioenriched 4‐aryl‐1,4‐dihydro‐pyridines prepared by an organocatalytic enantioselective Michael addition were oxidized with MnO₂ into axially chiral 4‐arylpyridines with central‐to‐axial chirality conversion. Moderate to complete percentages (cp) were observed, and a model for the conversion of chirality is discussed.     

Dynamic resolution of atropisomeric amides using proline-derived imidazolines and ephedrine-derived oxazolidines

Condensation of atropisomeric tertiary 2-formyl naphthamides or 2-formyl benzamides with some chiral diamines and amino alcohols leads, via a dynamic resolution process, to single atropisomers of tertiary amides bearing chiral imidazolidines or oxazolidines. Hydrolysis of the new heterocycle competes a dynamic thermodynamic resolution of the starting aldehyde, and rapid reduction allows the isolation of atropisomeric amides bearing 2-hydroxymethyl substituents in enantiomerically enriched form. Evidence that the reactions are under thermodynamic control is presented.     

Palladium‐Catalyzed Enantioselective Cacchi Reaction: Asymmetric Synthesis of Axially Chiral 2,3‐Disubstituted Indoles

We report herein the first examples of a palladium‐catalyzed enantioselective Cacchi reaction for the synthesis of indoles bearing a chiral C2‐aryl axis. In the presence of a catalytic amount of Pd(OAc)₂ and (R,R)‐QuinoxP* ligand, reaction of N‐aryl(alkyl)sulfonyl‐2‐alkynylanilides with arylboronic acids under oxygen atmosphere afforded enantioenriched 2,3‐disubstituted indoles in high yields and enantioselectivity. The indole ring is constructed de novo in this process and a complexation‐induced chirality transfer is proposed to account for the observed enantioselectivity.     

Regio‐ and Stereoselective Homologation of 1,2‐Bis(Boronic Esters): Stereocontrolled Synthesis of 1,3‐Diols and Sch 725674

1,2‐Bis(boronic esters), derived from the enantioselective diboration of terminal alkenes, can be selectively homologated at the primary boronic ester by using enantioenriched primary/secondary lithiated carbamates or benzoates to give 1,3‐bis(boronic esters), which can be subsequently oxidized to the corresponding secondary‐secondary and secondary‐tertiary 1,3‐diols with full stereocontrol. The transformation was applied to a concise total synthesis of the 14‐membered macrolactone, Sch 725674. The nine‐step synthetic route also features a novel desymmetrizing enantioselective diboration of a divinyl carbinol derivative and high‐yielding late‐stage cross‐metathesis and Yamaguchi macrolactonization reactions.