Enantioselective Cascade Research Articles

Enantioselective Cascade Annulation of α-Amino-ynones and Enals Enabled by Gold and Oxidative NHC Relay Catalysis.

We report herein an unprecedented gold and oxidative NHC relay catalysis that enables highly enantioselective cascade annulation between readily available α-amino-ynones with enals. This method utilizes the in situ-generated pyrrolin-4-ones as a novel and versatile synthon, which engage with α,β-unsaturated acylazolium intermediates generated from enals by oxidative NHC catalysis to produce pyrrole-fused lactones in high yield and excellent enantioselectivity. Synthetic utility of the lactone products is also demonstrated by facile conversion to densely functionalized pyrroles and pyrrolin-4-ones in high yields with excellent stereopurity.

Single‐Operation Decarboxylative Mannich Reaction/Asymmetric Transfer Hydrogenation Cascade Process Directly Accesses 1,3‐Distereocentered β‐Sulfonamido Alcohols

AbstractThe development of cooperative catalysis is of great significance for multi‐step sequential enantioselective organic transformations. However, the complicated subtle environments and inherent mutual deactivations of chiral dual catalysts pose a great challenge in a single operation. To address these issues, we here report the rational design of an integrated Cu/bisoxazoline and Ru/diamine co‐catalyst system, which enables a decarboxylative Mannich reaction/asymmetric transfer hydrogenation enantioselective cascade reaction for the direct preparation of 1,3‐distereocentered β‐sulfonamido alcohols. Through this cascade process, an initial Cu/bisoxazoline‐catalyzed decarboxylative Mannich reaction of a cyclic aldimine and a β‐keto acid to afford a chiral β‐sulfonamido ketone, followed by asymmetric transfer hydrogenation of this in situ generated ketone, produces a wide range of chiral β‐sulfonamido alcohols in 80–95% yields with 86–99% ee and 64:36–99:1 dr. Advantageous feature of this co‐catalyst system lies in the cooperative catalytic process, which greatly enhances the catalytic efficiency compared with the single‐step reactions, making it attractive for gaining direct access to the diastereoselective 1,3‐distereocenter.magnified image

A Chemoenzymatic Cascade Combining a Hydration Catalyst with an Amine Dehydrogenase: Synthesis of Chiral Amines

The combination of biocatalysis and transition-metal catalysis can complement synthetic gaps only in a chemical or biological process. However, the intrinsic mutual deactivation between enzymatic and chemical species is a significant challenge in a single operation. To address the above issue, we developed an encapsulated Au/carbene combined with a free amine dehydrogenase as a co-catalyst system that enables an efficient hydration/amination enantioselective cascade process to be accomplished. The mechanistic investigation discloses dual catalysis comprised of alkyne hydration, followed by a reductive amination process.

A Chemoenzymatic Cascade Combining a Hydration Catalyst with an Amine Dehydrogenase: Synthesis of Chiral Amines

AbstractThe combination of biocatalysis and transition‐metal catalysis can complement synthetic gaps only in a chemical or biological process. However, the intrinsic mutual deactivation between enzymatic and chemical species is a significant challenge in a single operation. To address the above issue, we developed an encapsulated Au/carbene combined with a free amine dehydrogenase as a co‐catalyst system that enables an efficient hydration/amination enantioselective cascade process to be accomplished. The mechanistic investigation discloses dual catalysis comprised of alkyne hydration, followed by a reductive amination process.

Cascade cyclization of 1,2,7,8-tetraones and total synthesis of (±)-nesteretal A

Regio-, stereo- and enantioselective cascade intramolecular aldol cyclization/acetalizations of symmetrical 1,2,7,8-tetraones were developed. The total synthesis of (±)-nesteretal A was accomplished in seven steps by this synthetic strategy.

Asymmetric synthesis of isochromanone derivatives via trapping carboxylic oxonium ylides and aldol cascade.

An efficient asymmetric synthesis of isochromanone derivatives was realized through Z-selective-1,3-OH insertion/aldol cyclization reaction involving acyclic carboxylic oxonium ylides. The combination of achiral dirhodium salts and chiral N,N′-dioxide–metal complexes, along with the use of α-diazoketones instead of α-diazoesters, enables the cascade reaction efficiently. A variety of benzo-fused δ-lactones bearing vicinal quaternary stereocenters were obtained with good to excellent enantioselectivity, bypassing the competitive 1,1-OH insertion and racemic background aldol reaction.

Biomimetic approach to the catalytic enantioselective synthesis of tetracyclic isochroman

Polyketide oligomers containing the structure of tetracyclic isochroman comprise a large class of natural products with diverse activity. However, a general and stereoselective method towards the rapid construction of this structure remains challenging due to the inherent instability and complex stereochemistry of polyketide. By mimicking the biosynthetic pathway of this structurally diverse set of natural products, we herein develop an asymmetric hetero-Diels–Alder reaction of in-situ generated isochromene and ortho-quinonemethide. A broad range of tetracyclic isochroman frameworks are prepared in good yields and excellent stereoinduction (up to 95% ee) from readily available α-propargyl benzyl alcohols and 2-(hydroxylmethyl) phenols under mild conditions. This direct enantioselective cascade reaction is achieved by a Au(I)/chiral Sc(III) bimetallic catalytic system. Experimental studies indicate that the key hetero-Diels-Alder reaction involves a stepwise pathway, and the steric hindrance between in-situ generated isochromene and t-Bu group of Sc(III)/N,N’-dioxide complex is responsible for the enantioselectivity in the hetero-Diels–Alder reaction step.

Regio- and Stereoselective Cascade of β,γ-Unsaturated Ketones by Dipeptided Phosphonium Salt Catalysis: Stereospecific Construction of Dihydrofuro-Fused [2,3-b] Skeletons.

Chiral (dihydro)furo-fused heterocycles are significant structural motifs in numerous natural products, functional materials and pharmaceuticals. Therefore, developing efficient methods for preparing compounds with these privileged scaffolds is an important endeavor in synthetic chemistry. Herein, we develop an effective, modular method by a dipeptide-phosphonium salt-catalyzed regio- and stereoselective cascade reaction of readily available linear β,γ-unsaturated ketones with aromatic alkenes, affording a wide variety of structurally fused heterocyclic molecules in high yields with excellent stereoselectivities. Moreover, mechanistic investigations revealed that the bifunctional phosphonium salt controlled the regio- and stereoselectivities of this cascade reaction, particularly proceeding through the initial ketone α-addition followed by O-participated substitution; and the multiple hydrogen-bonding interactions between Brønsted acid moieties of catalyst and nitro group of aromatic alkene were crucial in asymmetric induction. Given the generality, versatility, and high efficiency of this method, we anticipate that it will have broad synthetic utilities.

Integrated Suzuki Cross-Coupling/Reduction Cascade Reaction of meta-/para-Chloroacetophenones and Arylboronic Acids under Batch and Continuous Flow Conditions.

Overcoming the incompatibility of a pair of conflicting catalysts via a flow methodology has great significance in the practical applications for multistep organic transformations. In this study, a multiple continuous-flow system is developed, which can boost the reactivity and selectivity in a sequential enantioselective cascade reaction. During this process, a periodic mesoporous organosilica-supported Pd/carbene species as a Suzuki cross-coupling catalyst is packed in the first column reactor, whereas another periodic mesoporous organosilica-supported Ru/diamine species as an asymmetric transfer hydrogenation catalyst is packed in the second column reactor. As we envisioned, the initially Pd-catalyzed cross-coupling reaction of meta-/para-chloroacetophenones and aryl boronic acids followed by the subsequentially Ru-catalyzed reduction provides chiral biarylols with enhanced yields and enantioselectivities. Furthermore, the advantages of the easy handling and the simple procedure make this system an attractive application in a scale-up preparation of optically pure organic molecules under environmentally-friendly conditions.

Bioproduction of Enantiopure (R)‐ and (S)‐2‐Phenylglycinols from Styrenes and Renewable Feedstocks

AbstractEnantiopure (R)‐ and (S)‐2‐phenylglycinols are important chiral building blocks for pharmaceutical manufacturing. Several chemical and enzymatic methods for their synthesis were reported, either involving multi‐step synthesis or starting from a relatively complex chemical. Here, we developed one‐pot simple syntheses of enantiopure (R)‐ and (S)‐2‐phenylglycinols from cheap starting materials and renewable feedstocks. Enzyme cascades consisting of epoxidation‐hydrolysis‐oxidation‐transamination were developed to convert styrene 2 a to (R)‐ and (S)‐2‐phenylglycinol 1 a, with butanediol dehydrogenase for alcohol oxidation as well as BmTA and NfTA for (R)‐ and (S)‐enantioselective transamination, respectively. The engineered E. coli strains expressing the cascades produced 1015 mg/L (R)‐1 a in >99% ee and 315 mg/L (S)‐1 a in 91% ee, respectively, from styrene 2 a. The same cascade also converted substituted styrenes 2 b–k and indene 2 l into substituted (R)‐phenylglycinols 1 b–k and (1R, 2R)‐1‐amino‐2‐indanol 1 l in 95–>99% ee. To transform bio‐based L‐phenylalanine 6 to (R)‐1 a and (S)‐1 a, (R)‐ and (S)‐enantioselective enzyme cascades for deamination‐decarboxylation‐epoxidation‐hydrolysis‐oxidation‐transamination were developed. The engineered E. coli strains produced (R)‐1 a and (S)‐1 a in high ee at 576 mg/L and 356 mg/L, respectively, from L‐phenylalanine 6, as the first synthesis of these compounds from a bio‐based chemical. Finally, L‐phenylalanine biosynthesis pathway was combined with (R)‐ or (S)‐enantioselective cascade in one strain or coupled strains, to achieve the first synthesis of (R)‐1 a and (S)‐1 a from a renewable feedstock. The coupled strain approach enhanced the production, affording 274 and 384 mg/L (R)‐1 a and 274 and 301 mg/L (S)‐1 a, from glucose and glycerol, respectively. The developed methods could be potentially useful to produce these high‐value chemicals from cheap starting materials and renewable feedstocks in a green and sustainable manner.magnified image

Enantioselective Cascade Biocatalysis for Deracemization of Racemic β-Amino Alcohols to Enantiopure (S)-β-Amino Alcohols by Employing Cyclohexylamine Oxidase and ω-Transaminase.

Optically active β-amino alcohols are very useful chiral intermediates frequently used in the preparation of pharmaceutically active substances. Here, a novel cyclohexylamine oxidase (ArCHAO) was identified from the genome sequence of Arthrobacter sp. TYUT010-15 with the R-stereoselective deamination activity of β-amino alcohol. ArCHAO was cloned and successfully expressed in E. coli BL21, purified and characterized. Substrate-specific analysis revealed that ArCHAO has high activity (4.15 to 6.34 U mg-1 protein) and excellent enantioselectivity toward the tested β-amino alcohols. By using purified ArCHAO, a wide range of racemic β-amino alcohols were resolved, (S)-β-amino alcohols were obtained in >99 % ee. Deracemization of racemic β-amino alcohols was conducted by ArCHAO-catalyzed enantioselective deamination and transaminase-catalyzed enantioselective amination to afford (S)-β-amino alcohols in excellent conversion (78-94 %) and enantiomeric excess (>99 %). Preparative-scale deracemization was carried out with 50 mM (6.859 g L-1 ) racemic 2-amino-2-phenylethanol, (S)-2-amino-2-phenylethanol was obtained in 75 % isolated yield and >99 % ee.

Asymmetric Dearomative Cascade Multiple Functionalizations of Activated N-Alkylpyridinium and N-Alkylquinolinium Salts

An enantioselective cascade reaction of N-alkylpyridinium and -quinolinium salts with o-hydroxybenzylideneacetones to access fused polyheterocycles through cross dienamine-mediated addition followed by trapping of the dearomatized enamine-type intermediates and aminal formation has been developed. A cascade assembly of N-benzyl-4-methylpyridinium salt and cyclic 2,4-dienones is further disclosed to give bridged frameworks via repetitive dearomatization and aromatization activation.

Umpolung Strategy for the Synthesis of Chiral Dispiro[2-amino-4,5-dihydrofuran-3-carbonitrile]bisoxindoles

Based on a novel umpolung strategy, an efficient and highly enantioselective cascade aldol/cyclization/tautomerization of the 2-(2-oxoindolin-3-yl)malononitrile to active carbonyl compounds with excellent diastereo- and enantioselectivity has been developed. Also, various enantio-enriched multifunctional dispiro[2-amino-4,5-dihydrofuran-3-carbonitrile]bisoxindoles with adjacent spiro-stereocenters were conveniently obtained by this novel methodology. Also, the dispiro[2-amino-4,5-dihydrofuran-3-carbonitrile]bisoxindoles were easily transformed into structurally complex molecules without any effect on the diastereo- and enantioselectivity.

An Experimental Stereoselective Photochemical [1s,3s]-Sigmatropic Silyl Shift and the Existence of Silyl/Allyl Conical Intersections.

We report an experimental discovery and computational investigation of the first photochemical stereoselective [1,3]-sigmatropic silyl shift of an allylsilane. An organocatalytic enantioselective cascade annulation generates a trimethylsilyl-o-isotoluene reactant in >99:1 e.r., and this trimethylsilyl-o-isotoluene contains an allylic silane moiety that undergoes a stereoselective photochemical [1,3]-silyl shift to form a benzylsilane with 96:4 e.r. The mechanism of this unprecedented [1,3]-silyl shift has been elucidated by a series of experimental studies and CASSCF, DFT, and TD-DFT calculations on model systems and the experimental system. The highly stereoselective photoreaction is proposed to occur via a singlet silyl/allyl conical intersection. This is a new demonstration of the role of conical intersections in selective photochemistry.

Carbene-Catalyzed Reaction of Indolyl Methylenemalononitriles and Enals for Access to Complex Tetrahydrocarbazoles.

A carbene-catalyzed enantioselective cascade reaction of substituted methylenemalononitriles and α-bromoenals is disclosed. Key steps of this cascade process include a formal [4 + 2] cycloaddition, aldol reaction, and intramolecular lactonization. Our reaction offers streamlined and highly stereoselective access to complex tetrahydrocarbazole derivatives, with simultaneous formation of four chemical bonds and four chiral centers.

Organocatalyzed asymmetric cascade Mannich/cyclization of 3-isothiocyanato oxindoles with cyclic ketimines for the synthesis of polycyclic spiro-thioimidazolidine-oxindoles

The first diastereo- and enantioselective cascade Mannich/cyclization reaction of 3-isothiocyanato oxindoles with cyclic ketimines has been successfully developed. By using chiral bifunctional organocatalysts, a range of structurally diverse chiral polycyclic spiro-thioimidazolidine-oxindoles, bearing two contiguous tetrasubstituted stereocenters, could be obtained in excellent yields (up to 99%) with good diastereo- and enantioselectivities (up to >20:1 dr and 94.5:5.5 er) under mild reaction conditions.

Highly Enantioselective Ruthenium-Catalyzed Cascade Double Reduction Strategy: Construction of Structurally Diverse Julolidines and Their Analogues

A direct and facile construction of optically pure julolidine derivatives through ruthenium-catalyzed enantioselective cascade hydrogenation and reductive amination of 2-(quinolin-8-yl)ethyl ketones has been developed. By means of this protocol, various chiral julolidine compounds were obtained in high isolated yields (up to 94%) with excellent diastereoselectivities (up to >20:1 dr) and enantioselectivities (up to 99% ee) under mild conditions. Furthermore, the synthetic practicality of this protocol was illustrated by the preparation of hexahydrojulolidines and a chiral fluorescent molecular rotor.

Highly Enantioselective Iridium-Catalyzed Cascade Double Allylation Strategy: Synthesis of Pyrrolidinoindolines with an All-Carbon Quaternary Stereocenter.

Highly enantioselective cascade double allylations of 1-alkyl-3-alkylindolin-2-imine hydrochlorides with (E)-but-2-ene-1,4-diyl dimethyl dicarbonate leading to tetrahydropyrrolo[2,3-b]indoles with an all-carbon quaternary stereocenter have been developed. This transformation was catalyzed by an iridium catalyst together with our developed chiral cyclic phosphoramidite ligand. The method shows some advantages including an operationally simple protocol, fast reaction, and excellent diastereoselectivity and enantioselectivity. Furthermore, reduction of the obtained products with diisobutyl aluminum hydride provided the pyrrolidinoindolines with three chiral centers in high yields with excellent diastereoselectivity and enantioselectivity.

Generation of Donor/Donor Copper Carbenes through Copper-Catalyzed Diyne Cyclization: Enantioselective and Divergent Synthesis of Chiral Polycyclic Pyrroles.

The generation of metal carbenes from readily available alkynes represents a significant advance in metal carbene chemistry. However, most of these transformations are based on the use of noble-metal catalysts and successful examples of such an asymmetric version are still very scarce. Here a copper-catalyzed enantioselective cascade cyclization of N-propargyl ynamides is reported, enabling the practical and atom-economical construction of diverse chiral polycyclic pyrroles in generally good to excellent yields with wide substrate scope and excellent enantioselectivities (up to 97:3 e.r.). Importantly, this protocol represents the first copper-catalyzed asymmetric diyne cyclization. Moreover, mechanistic studies revealed that the generation of donor/donor copper carbenes is presumably involved in this 1,5-diyne cyclization, which is distinctively different from the related gold catalysis, and thus it constitutes a novel way for the generation of donor/donor metal carbenes.

Total Asymmetric Synthesis of Quinine, Quinidine, and Analogues via Catalytic Enantioselective Cascade Transformations

A catalytic asymmetric strategy for the total synthesis of quinuclidine natural products, which includes the completed enantioselective synthesis of the classical targets quinine and quinidine is disclosed. It is based on catalytic asymmetric cascade transformations, which paves the road for the synthesis of both enantiomers of the crucial C4 stereocenter with high enantioselectivity (up to 99 % ee) in one pot. Next, developing a route to all possible stereoisomers of a common early‐stage intermediate sets the stage for the total synthesis of different enantiomers or epimers of quinine, quinidine and analogues with high selectivity.