Highly Enantioselective Brønsted Acid Catalyzed Heyns Rearrangement

Herein we report the first method for highly enantioselective Brønsted acid catalyzed Heyns rearrangements. These reactions, catalyzed by a chiral spiro phosphoric acid, afforded synthetically valuable chiral α-aryl-α-aminoketones which cannot be obtained by means of previously reported Heyns rearrangement methods. This method features low catalyst loadings, high yields and high enantioselectivities, making these reactions highly practical. We used the method to efficiently synthesize various chiral amines, including some biologically active molecules. We experimentally proved that these acid-catalyzed Heyns rearrangements proceeded via a proton-transfer process involving an enol intermediate and the stereocontrol was realized during the proton-transfer step.     

Organocatalytic Enantioselective Vinylcyclopropane-Cyclopentene (VCP-CP) Rearrangement

We have demonstrated that the catalytic and enantioselective vinylcyclopropane-cyclopentene rearrangement can be carried out on (vinylcyclopropyl)acetaldehydes through activation via enamine intermediates. The reaction makes use of racemic starting materials that, upon ring opening facilitated by the catalytic generation of a donor-acceptor cyclopropane, deliver an acyclic iminium ion/dienolate intermediate in which all stereochemical information has been deleted. The final cyclization step forms the rearrangement product, showing that chirality transfer from the catalyst to the final compound is highly effective and leads to the stereocontrolled formation of a variety of structurally different cyclopentenes.     

Asymmetric Synthesis of Heterocyclic Chloroamines and Aziridines by Enantioselective Protonation of Catalytically Generated Enamines**

We report a method for the synthesis of chiral vicinal chloroamines via asymmetric protonation of catalytically generated prochiral chloroenamines using chiral Brønsted acids. The process is highly enantioselective, with the origin of asymmetry and catalyst substituent effects elucidated by DFT calculations. We show the utility of the method as an approach to the synthesis of a broad range of heterocycle-substituted aziridines by treatment of the chloroamines with base in a one-pot process, as well as the utility of the process to allow access to vicinal diamines.     

Reductive Asymmetric Aza-Mislow-Evans Rearrangement by 1,3,2-Diazaphospholene Catalysis**

1,3,2-diazaphospholene hydrides (DAP−H) enable smooth conjugate reduction of polarized double bonds. The transiently formed phosphorus-enolate provides a potential platform for reductive α-functionalizations. In this respect, asymmetric C-heteroatom bond forming processes are synthetically appealing but remain elusive. We report a 1,3,2-diazaphospholene-catalyzed three-step cascade reaction of N-sulfinyl acrylamides comprised of conjugate reduction, [2,3]-sigmatropic aza-Mislow-Evans rearrangement and subsequent S−O bond cleavage. The obtained enantio-enriched α-hydroxy amides are formed in good yields and excellent enantiospecificity. The stereo-defined P-bound N,O-ketene aminal ensures an excellent transfer of chirality from the sulfur stereocenter to α-carbon. The transformation operates under mild conditions at ambient temperature. Moreover, DAP−H is a competent reductant for the cleavage of formed sulfenate ester, eliminating the extra step in traditional Mislow-Evans processes.     

Brønsted Acid Catalyzed Asymmetric Synthesis of cis-Tetrahydrocannabinoids**

We report herein the catalytic asymmetric cyclization of 1-aryl terpenols to afford enantiomerically highly enriched Δ⁹-cis-tetrahydrocannabinoid scaffolds in a single step. As powerful chiral catalysts strongly acidic imidodiphosphorimidates (IDPis) have been identified which furnish the products with good yields and excellent enantioselectivity. Upon MOM-deprotection some naturally occurring cannabimimetica such as (−)-cis-Δ⁹-tetrahydrocannabinol and (−)-perrottetinene as well as some unnatural analogues were made accessible along a merely 3-step biomimetic sequence (MOM=methoxymethyl).     

Chiral phosphoric acid-catalyzed enantioselective three-component Mannich reaction of acyclic ketones,aldehydes and anilines

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Enantioselective Synthesis of Spiro Heterocyclic Compounds Using a Combination of Organocatalysis and Transition-Metal Catalysis

Over the last ten years, the combination of organocatalysis with transition metal (TM) catalysis has become one of the most important toolboxes used for synthesizing optically pure compounds containing chiral quaternary centers, including spiro heterocyclic molecules. The dominant method in the enantioselective synthesis of spiro heterocyclic compounds based on synergistic catalysis includes chiral aminocatalysis and NHC catalysis, as already established covalent organocatalytic strategies. Another area of organocatalysis widely combined with TM catalysis producing enantiomerically enriched spiro heterocyclic compounds is non-covalent catalysis, dominated by chiral phosphoric acids, thiourea, and squaramide derivatives. This review article aims to summarize enantioselective methods used for constructing spirocyclic heterocycles based on a combination of organocatalysis and transition metal catalysis.     

One-Pot Synthesis of Enantioenriched β-Amino Secondary Amides via an Enantioselective [4+2] Cycloaddition Reaction of Vinyl Azides with N-Acyl Imines Catalyzed by a Chiral Brønsted Acid

A catalytic enantioselective synthesis of β-amino secondary amides was achieved using vinyl azides as the enamine-type nucleophile and chiral N-Tf phosphoramide as the chiral Brønsted acid catalyst through a five-step sequential transformation in one pot. The established sequential transformation involves an enantioselective [4+2] cycloaddition reaction of vinyl azides with N-acyl imines as the key stereo-determining step that is efficiently accelerated by a chiral N-Tf phosphoramide catalyst in a highly enantioselective manner in most cases. Further generation of the iminodiazonium ion intermediate through ring opening of the cycloaddition product and subsequent skeletal rearrangement involving Schmidt-type 1,2-aryl group migration followed by recyclization of the resulting nitrilium ion were also initiated by the same acid catalyst. Final acid hydrolysis of the recyclized products in the same pot gave rise to enantioenriched β-amino amides through C−C bond formation at the α-position of the secondary amides.     

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.     

Asymmetric synthesis of novel spirocycles via a chiral phosphoric acid catalyzed desymmetrization

A straightforward method for the asymmetric preparation of novel lactone and lactam spirocycles is described. An initial desymmetrization via a chiral Brønsted acid yields enantioenriched lactones which readily undergo a second cyclization to give the desired spirocycle.     

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.     

Catalytic Enantioselective Synthesis of Heterocyclic Vicinal Fluoroamines by Using Asymmetric Protonation: Method Development and Mechanistic Study

A catalytic enantioselective synthesis of heterocyclic vicinal fluoroamines is reported. A chiral Brønsted acid promotes aza-Michael addition to fluoroalkenyl heterocycles to give a prochiral enamine intermediate that undergoes asymmetric protonation upon rearomatization. The reaction accommodates a range of azaheterocycles and nucleophiles, generating the C−F stereocentre in high enantioselectivity, and is also amenable to stereogenic C−CF₃ bonds. Extensive DFT calculations provided evidence for stereocontrolled proton transfer from catalyst to substrate as the rate-determining step, and showed the importance of steric interactions from the catalyst's alkyl groups in enforcing the high enantioselectivity. Crystal structure data show the dominance of noncovalent interactions in the core structure conformation, enabling modulation of the conformational landscape. Ramachandran-type analysis of conformer distribution and Protein Data Bank mining indicated that benzylic fluorination by this approach has the potential to improve the potency of several marketed drugs.     

A Spiro Phosphamide Catalyzed Enantioselective Proton Transfer of Ylides in a Free Carbene Insertion into N−H Bonds

Free carbene readily causes multiple side reactions due to its high energy, thus its asymmetric transformation is very difficult. We present here our findings of high-pK_a Brønsted acid catalysts that enable free carbene insertion into N−H bonds of amines to prepare chiral α-amino acid derivatives with high enantioselectivity. Under irradiation with visible light, diazo compounds produce high-energy free carbenes that are captured by amines to form free ylide intermediates, and then the newly designed high-pK_a Brønsted acids, chiral spiro phosphamides, promote the proton transfer of ylides to afford the products. Computational and kinetic studies uncover the principle for the rational design of proton-transfer catalysts and explain how the catalysts accelerate this transformation and provide stereocontrol.     

Asymmetric Vinylogous Diels–Alder Reactions Catalyzed by a Chiral Phosphoric Acid

An unprecedented way to extend the synthetic utility of the Diels–Alder reaction to include a vinylogous reactivity space is described. A commercially available chiral phosphoric acid catalyst effectively activates cyclic 2,4‐dienones towards a vinylogous [4+2] cycloaddition with 2‐vinylindoles, which leads to stereochemically dense tetrahydrocarbazoles. The reaction proceeds with a high level of remote stereocontrol and exclusive chemoselectivity for the more distant double bond of the dienone.     

Chiral Phosphoric Acid Catalyzed Asymmetric Hydrolysis of Biaryl Oxazepines for the Synthesis of Axially Chiral Biaryl Amino Phenol Derivatives

The development of catalytic asymmetric reaction with water as the reactant is challenging due to the reactivity- and stereoselectivity-control issues resulted from the low nucleophilicity and the small size of water. We disclose herein a chiral phosphoric acid (CPA) catalyzed atroposelective ring-opening reaction of biaryl oxazepines with water. A series of biaryl oxazepines undergo the CPA catalyzed asymmetric hydrolysis in a highly enantioselective manner. The key for the success of this reaction is the use of a new SPINOL-derived CPA catalyst and the high reactivity of biaryl oxazepine substrates towards water under acidic conditions. Density functional theory calculations suggest that the reaction proceeds via a dynamic kinetic resolution pathway and the CPA catalyzed addition of water to the imine group is both enantio- and rate-determining.     

Chiral Brønsted Acid Catalyzed Enantioconvergent Propargylic Substitution Reaction of Racemic Secondary Propargylic Alcohols with Thiols

Despite the significant progress of the enantioselective reaction using chiral catalysts, the enantioselective nucleophilic substitution reaction at the chiral sp³-hybridized carbon atom of a racemic electrophile has not been largely explored. Herein, we report the enantioconvergent propargylic substitution reaction of racemic propargylic alcohols with thiols using chiral bis-phosphoric acid as the chiral Brønsted acid catalyst. The substitution products were formed in high yields with high enantioselectivities in most cases. The cation-stabilizing effect of the sulfur functional group introduced at the alkynyl terminus is the key to achieving the efficient enantioconvergent process, in which chiral information originating from not only the racemic stereogenic center but also the formed contact ion pair is completely eliminated from the present system.     

Double Asymmetric Induction as Method for the Synthesis of Chiral Organophosphorus Compounds

New examples of multistereoselective syntheses of organophosphorus compounds are described.     

Asymmetric (4+n) Cycloadditions of Indolyldimethanols for the Synthesis of Enantioenriched Indole-Fused Rings

Catalytic asymmetric construction of chiral indole-fused rings has become an important issue in the chemical community because of the significance of such scaffolds. In this work, we have accomplished the first catalytic asymmetric (4+2) and (4+3) cycloadditions of 2,3-indolyldimethanols by using indoles and 2-naphthols as suitable reaction partners under the catalysis of chiral phosphoric acids, constructing enantioenriched indole-fused six-membered and seven-membered rings in high yields with excellent enantioselectivities. In addition, this approach is used to realize the first enantioselective construction of challenging tetrahydroindolocarbazole scaffolds, which are found to show promising anticancer activity. More importantly, theoretical calculations of the reaction pathways and activation mode offer an in-depth understanding of this class of indolylmethanols. This work not only settles the challenges in realizing catalytic asymmetric cycloadditions of indolyldimethanols but also provides a powerful strategy for the construction of enantioenriched indole-fused rings.