Recent Advances in Chiral Guanidine‐Catalyzed Enantioselective Reactions

Chiral guanidines have been widely used as Brønsted base catalysts and phase transfer catalysts in enantioselective reactions. Due to their amendable structure and powerful catalytic ability, they have attracted much interest. Several new catalysts containing a guanidinium moiety have been reported over the past decade and many promising outcomes have been achieved. This article illustrates the progress of chiral guanidine catalysis in asymmetric synthesis from 2009 to 2018. It is an update of a review of the same title published in 2009.     

Lewis Base/Brønsted Acid Co‐catalyzed Enantioselective Sulfenylation/Semipinacol Rearrangement of Di‐ and Trisubstituted Allylic Alcohols

An enantioselective sulfenylation/semipinacol rearrangement of 1,1‐disubstituted and trisubstituted allylic alcohols was accomplished with a chiral Lewis base and a chiral Brønsted acid as cocatalysts, generating various β‐arylthio ketones bearing an all‐carbon quaternary center in moderate to excellent yields and excellent enantioselectivities. These chiral arylthio ketone products are common intermediates with many applications, for example, in the design of new chiral catalysts/ligands and the total synthesis of natural products. Computational studies (DFT calculations) were carried out to explain the enantioselectivity and the role of the chiral Brønsted acid. Additionally, the synthetic utility of this method was exemplified by an enantioselective total synthesis of (?)‐herbertene and a one‐pot synthesis of a chiral sulfoxide and sulfone.     

Switchable Stereoselectivity in Bromoaminocyclization of Olefins: Using Brønsted Acids of Anionic Chiral Cobalt(III) Complexes

Brønsted acids of anionic chiral Co^III complexes act as bifunctional phase‐transfer catalysts to shuttle the substrates across the solvent interface and control stereoselectivity. The diastereomeric chiral Co^III‐templated Brønsted acids, with the same chiral ligands, enabled a switch in the enantioselective bromoaminocyclization of olefins to afford the two enantiomers of 2‐substituted pyrrolidines with high enantioselectivities (up to 99:1 e.r.).     

Modulating the acidity: highly acidic Brønsted acids in asymmetric catalysis

Recently, chiral highly acidic Brønsted acids have emerged as powerful catalysts for enantioselective C C and C X bond‐forming reactions. Their strong acidity renders them valuable tools for the activation of imines, carbonyl compounds, and other weakly basic substrates. As a result, new perspectives are opened and highly stereoselective transformations based on the concept of chiral contact‐ion‐pair catalysis can be realized. This Minireview gives an overview of the design and application of these new organocatalysts and presents recent results in this rapidly growing field.     

Chiral Bisphosphoric Acids and Their Applications in Asymmetric Catalysis

Asymmetric Brønsted acid catalysis has been recognized as a powerful concept for asymmetric synthesis. In the process of pursuing more robust and highly effective chiral Brønsted acid catalysts, chiral bisphosphoric acids have received much attention in the last two decades. Their unique catalytic properties are mainly attributed to the inherent intramolecular hydrogen bonding interactions that could increase the overall acidity and tune the conformation property. Integrating hydrogen bonding into the catalyst design, quite a few structurally unique and effective bisphosphoric acids have been synthesized, which frequently exhibited superior selectivity in a broad range of asymmetric transformations. This review summarizes the status quo of chiral bisphosphoric acid catalysts and their applications in catalyzing asymmetric transformations.     

Conformational Control of Organocatalyst in Strongly Brønsted-Acidic Metal-Organic Frameworks for Enantioselective Catalysis

Chiral imidodiphosphates (IDPs) have emerged as strong Brønsted acid catalysts for many enantioselective processes. However, the dynamic transformation between O,O-syn and O,O-anti conformers typically results in low enantioselectivity. Here we demonstrate that topologies of metal-organic frameworks (MOFs) can be exploited to control IDP conformations and local chiral microenvironments for enantioselective catalysis. Two porous Dy-MOFs with different topologies are obtained from an enantiopure 1,1′-biphenol IDP-based tetracarboxylate ligand. While the ligand adopts a 4- or 3-connected (c) binding mode, all IDPs are rigidified to get only a single O,O-syn conformation and display greatly enhanced Brønsted acidity relative to the free IDP. The MOF with the 4-c IDP that has a relatively less compact shape than the 3-c IDP can be an efficient and recyclable heterogeneous Brønsted acid catalysing the challenging asymmetric O,O-acetalization reaction with up to 96 % enantiomeric excess.     

Enantio‐ and Diastereoselective Access to Distant Stereocenters Embedded within Tetrahydroxanthenes: Utilizing ortho‐Quinone Methides as Reactive Intermediates in Asymmetric Brønsted Acid Catalysis

A protocol for the highly enantioselective synthesis of 9‐substituted tetrahydroxanthenones by means of asymmetric Brønsted acid catalysis has been developed. A chiral binol‐based N‐triflyphosphoramide was found to promote the in situ generation of ortho‐quinone methides and their subsequent reaction with 1,3‐cyclohexanedione to provide the desired products with excellent enantioselectivities. In addition, a highly enantio‐ and diastereoselective Brønsted acid catalyzed desymmetrization of 5‐monosubstituted 1,3‐dicarbonyl substrates with ortho‐quinone methides gives rise to valuable tetrahydroxanthenes containing two distant stereocenters.     

Chiral Iminophosphoranes—An Emerging Class of Superbase Organocatalysts

Chiral Brønsted base catalysis is a fascinating and highly explored field of research. For many years catalysts based on chincona alkaloid chiral scaffolds have constituted privileged systems widely employed in numerous base‐promoted organic transformations. Recently, a novel group of chiral base catalysts has been successfully introduced. The application of organosuperbases, namely cyclopropenimines, guanidines, and iminophosphoranes, as chiral catalysts is receiving increasing attention. The aim of this Concept article is to summarize recent progress in the field of chiral iminophosphorane superbase organocatalysis. Catalysts design, different approaches to their synthesis, and applications in asymmetric synthesis are outlined and discussed in detail.     

Enantioselective Direct Mannich‐Type Reactions Catalyzed by Frustrated Lewis Acid/Brønsted Base Complexes

An enantioselective direct Mannich‐type reaction catalyzed by a sterically frustrated Lewis acid/Brønsted base complex is disclosed. Cooperative functioning of the chiral Lewis acid and achiral Brønsted base components gives rise to in situ enolate generation from monocarbonyl compounds. Subsequent reaction with hydrogen‐bond‐activated aldimines delivers β‐aminocarbonyl compounds with high enantiomeric purity.     

Exploiting the Multidentate Nature of Chiral Disulfonimides in a Multicomponent Reaction for the Asymmetric Synthesis of Pyrrolo[1,2‐a]indoles: A Remarkable Case of Enantioinversion

A new multicomponent coupling reaction for the enantioselective synthesis of pyrrolo[1,2‐a]indoles under the catalysis of a chiral disulfonimide is described. The high specificity of the reaction is a consequence of the multidentate character of the Brønsted acid catalyst. Insights from DFT calculations helped explain the unexpected high enantioselectivity observed with the simplest 3,3′‐unsubstituted binaphthyl catalyst as a result of transition‐state stabilization by a network of cooperative noncovalent interactions. The remarkable enantioinversion resulting from the simple introduction of substituents at 3‐ and 3′‐positions, the first reported example of this phenomenon in the context of binaphthalene‐derived Brønsted acid catalysis, was instead attributed to destabilizing steric interactions.     

Enantioselective Formal [3+2] Cycloaddition of Epoxides with Imines under Brønsted Base Catalysis: Synthesis of 1,3‐Oxazolidines with Quaternary Stereogenic Center

The formal [3+2] cycloaddition of epoxides and unsaturated compounds is a powerful methodology for the synthesis of densely functionalized five‐membered heterocyclic compounds containing oxygen. Described is a novel enantioselective formal [3+2] cycloaddition of epoxides under Brønsted base catalysis. The bis(guanidino)iminophosphorane as a chiral organosuperbase catalyst enabled the enantioselective reaction of β,γ‐epoxysulfones with imines, owing to its strong basicity and high stereocontrolling ability, to provide enantioenriched 1,3‐oxazolidines having two stereogenic centers, including a quaternary one, in a highly diastereo‐ and enantioselective manner.     

Palladium(II)/Brønsted Acid‐Catalyzed Enantioselective Oxidative Carbocyclization–Borylation of Enallenes

An enantioselective oxidative carbocyclization–borylation of enallenes that is catalyzed by palladium(II) and a Brønsted acid was developed. Biphenol‐type chiral phosphoric acids were superior co‐catalysts for inducing the enantioselective cyclization. A number of chiral borylated carbocycles were synthesized in high enantiomeric excess.     

Organocatalytic Enantioselective Protonation for Photoreduction of Activated Ketones and Ketimines Induced by Visible Light

The first catalytic asymmetric photoreduction of 1,2‐diketones and α‐keto ketimines under visible light irradiation is reported. A transition‐metal‐free synergistic catalysis platform harnessing dicyanopyrazine‐derived chromophore (DPZ) as the photoredox catalyst and a non‐covalent chiral organocatalyst is effective for these transformations. With the flexible use of a chiral Brønsted acid or base in H⁺ transfer interchange to control the elusive enantioselective protonation, a variety of chiral α‐hydroxy ketones and α‐amino ketones were obtained with high yields and enantioselectivities.     

Bioinspired Ether Cyclizations within a π-Basic Capsule Compared to Autocatalysis on π-Acidic Surfaces and Pnictogen-Bonding Catalysts

While the integration of supramolecular principles in catalysis attracts increasing attention, a direct comparative assessment of the resulting systems catalysts to work out distinct characteristics is often difficult. Herein is reported how the broad responsiveness of ether cyclizations to diverse inputs promises to fill this gap. Cyclizations in the confined, π-basic and Brønsted acidic interior of supramolecular capsules, for instance, are found to excel with speed (exceeding general Brønsted acid and hydrogen-bonding catalysts by far) and selective violations of the Baldwin rules (as extreme as the so far unique pnictogen-bonding catalysts). The complementary cyclization on π-acidic aromatic surfaces remains unique with regard to autocatalysis, which is shown to be chemo- and diastereoselective with regard to product-like co-catalysts but, so far, not enantioselective.     

Copper(II)‐Catalyzed Nitroaldol (Henry) Reactions: Recent Developments

Self‐assembled copper(II) complexes are described as effective catalysts for nitroaldol (Henry) reactions on water. The protocol involves a heterogeneous process and the catalysts can be recovered and recycled without loss of activity. Further, C2‐symmetric N,N′‐substituted chiral copper(II) salan complexes are found to be more effective catalysts than chiral copper(II) salen complexes for reactions in homogeneous catalysis, with high enantioselectivities. The reactions involve bifunctional catalysis, bearing the properties of a Brønsted base, as well as a Lewis acid, to effect the reaction in the absence of external additives.     

A Cooperative N‐Heterocyclic Carbene/Chiral Phosphate Catalysis System for Allenolate Annulations

The highly enantioselective NHC‐catalyzed [3+2] annulation reaction with α,β‐alkynals and α‐ketoesters has been developed. A new mode of cooperative catalysis involving the combination of a chiral Brønsted acid and a C₁‐symmetric biaryl saturated‐imidazolium precatalyst was required to generate the desired γ‐crotonolactones in high yields and levels of enantioselectivity.     

Brønsted Acid versus Phase-Transfer Catalysis in the Enantioselective Transannular Aminohalogenation of Enesultams

We have studied the enantioselective transannular aminohalogenation reaction of unsaturated medium-sized cyclic benzosulfonamides by using both chiral Brønsted acid and phase-transfer catalysis. Under optimized conditions, a variety of bicyclic adducts can be obtained with good yields and high enantioselectivities. The mechanism of the reaction was also studied by using computational tools; we observed that the reaction involves the participation of a conformer of the nine-membered cyclic substrate with planar chirality in which the stereochemical outcome is controlled by the relative reactivity of the two pseudorotational enantiomers when interacting with the chiral catalyst.     

Asymmetric Brønsted Acid‐Catalyzed Nazarov Cyclization of Acyclic α‐Alkoxy Dienones

A Brønsted acid‐catalyzed asymmetric Nazarov cyclization of acyclic α‐alkoxy dienones has been developed. The reaction offers access to chiral cyclopentenones in a highly enantioselective manner. The reaction is complementary to our previously reported Brønsted acid‐catalyzed electrocyclization reactions, which provided differently substituted optically active cyclopentenones with a fused tetrahydropyrane ring in good yields and with excellent enantioselectivities.     

Formal Umpolung Addition of Phosphites to 2-Azaaryl Ketones under Chiral Brønsted Base Catalysis: Enantioselective Protonation Utilizing [1,2]-Phospha-Brook Rearrangement

The formal enantioselective umpolung addition of dialkyl phosphites to 2-azaaryl ketones was developed under Brønsted base catalysis. The reaction involves the enantioselective protonation of the transient α-oxygenated (2-azaaryl)methyl anion generated through the 1,2-addition of the anion of dialkyl phosphite to the 2-azaaryl ketone and the subsequent [1,2]-phospha-Brook rearrangement. A chiral bis(guanidino)iminophosphorane organosuperbase efficiently catalyzed the reaction to provide enantio-enriched phosphates in high yields with good to high enantioselectivities. This is a rare example of the catalytic enantioselective protonation of transient carbanions other than enolates, constructing a trisubstituted stereogenic center α to 2-azaarenes.     

Catalytic Enantioselective Protonation/Nucleophilic Addition of Diazoesters with Chiral Oxazaborolidinium Ion Activated Carboxylic Acids

A new chiral Brønsted acid derived from carboxylic acid and a chiral oxazaborolidinium ion (COBI), as an activator, is introduced. This acid was successfully applied as a catalyst for the highly enantioselective protonation/nucleophilic addition of diazoesters with carboxylic acids.