Consecutive Stereogenic Centers Research Articles

Organocatalytic Desymmetric Spirocyclization of Enone-Tethered 2,5-Cyclohexadienone with Isoxazolines to Access Enantioenriched Spiro-Fused Scaffolds.

Enantioselective desymmetric spirocyclization is a powerful tool for concisely generating intricate 3D molecular architectures from readily accessible substrates. Herein, we report an organocatalytic desymmetric spirocyclization of enone-tethered 2,5-cyclohexadienone with 3-arylisoxazol-5(4H)-one to access enantioenriched spiro-fused scaffolds featuring four consecutive stereogenic centers in high yields and excellent diastereo- and enantioselectivities. This protocol could proceed smoothly under parts per million-level organocatalyst loading. Furthermore, the reusability of the catalyst and various intriguing derivatizations of the title product highlight its synthetic utility.

4+2] Cycloaddition Mediated Stereoselective Synthesis of Tetrahydro‐1H‐Isobenzofuro Chromene Dione Derivatives: Antibacterial Evaluation and Molecular Docking Investigation

AbstractAn efficient stereoselective synthesis of tetrahydro‐1H‐isobenzofuro[4,5‐c]chromene‐1,3(3aH)‐dione derivatives were achieved through a novel [4+2] cycloaddition reaction of 4‐styryl‐2H‐chromenes with cheaply available maleic anhydride. A series of new tetrahydro‐1H‐isobenzofuro[4,5‐c]chromene‐1,3(3aH)‐dione derivatives 21(a–p) were synthesized in good to excellent yield under mild reaction condition with no chromatographic purification. In this reaction, the generation of four new consecutive stereogenic centers were determined by single crystal X‐ray analysis. All the synthesized compounds were investigated further in silico and in vitro for antibacterial activities using two bacterial strain of DNA gyrase. Compounds 21 b and 21 j showed excellent docking score −9.3 kCal/mol and −8.6 kCal/mol with gram negative bacterial strain Escherichia coli (E. coli) with protein data bank (PDB ID) 3G7E. Out of all the tested molecules, 21 b and 21 j displayed good results with minimum inhibitory concentration 10 μg/ml, 10 μg/ml against the bacterial strain Escherichia coli(E. coli) and 10 μg/ml, 20 μg/ml against Staphylococcus aureus (S. aureus) respectively.

Kinetic Resolution of β-Branched Aldehydes through Peptide-Catalyzed Conjugate Addition Reactions.

The catalytic kinetic resolution of racemic β-branched aldehydes offers a straightforward stereoselective entry to aldehydes and addition products. Yet, control over stereoselectivity is difficult due to the conformational flexibility of β-branched aldehydes. Here, we show that the peptide catalyst H-dPro-αMePro-Glu-NH2 resolves β-branched aldehydes through reaction with nitroolefins and provides γ-nitroaldehydes with three consecutive stereogenic centers in high yields and stereoselectivities. Kinetic, NMR spectroscopic, and computational studies provided insights into the selectivity-determining step and origins of the kinetic resolution.

COAP-Pd Catalyzed Asymmetric Formal [3+2] Cycloaddition for Optically Active Multistereogenic Spiro Cyclopentane-Indandiones Bearing Cyclic N-Sulfonyl Ketimine Skeletons.

We reported a chiral oxamide-phosphine ligand (COAP-Ph)-Pd-catalyzed asymmetric [3+2] cycloaddition reaction between vinyl cyclopropane compounds derived from 1,3-indanedione and 2-vinylcyclopropane-1,1-dicarboxylates with cyclic sulfonyl 1-azadienes. The corresponding reactions provided a series of enantiomerically active spiro cyclopentane-indandione and cyclopentane structures bearing three consecutive stereogenic centers in good yields with good diastereo- and enantioselectivity. The COAP-Pd complex serves not only to promote generation of chiral π-allyl-palladium intermediates and induce the asymmetry of the reaction, but also depress the background reaction.

Access to Chiral β-Boryl δ-Lactones via NHC-Catalyzed [4 + 2] Annulation.

We report a carbene-catalyzed [4 + 2] annulation of activated esters and β-borate enones, providing an efficient method to build enantioenriched organoborones with two consecutive stereogenic centers. It is worth noting that this protocol represents a new organocatalytic manner to generate chiral β-C-B bonds. Moreover, it also greatly enriches the structural diversity of the chiral organoboron compounds.

Copper catalyzed diastereoselective and enantioselective hydroborylation of cyclopentenylcarboxyesters

Cu-catalyzed asymmetric hydroborylation of cyclopentenylcarboxyesters.

Nickel-Catalyzed Diastereoselective Cross-Electrophile Ring Opening of 7-Oxabenzonorbornadienes with Aromatic Aldehydes.

In this protocol, we developed a nickel-catalyzed diastereoselective cross-electrophile ring opening reaction of 7-oxabenzonorbornadienes with aromatic aldehydes as the electrophilic coupling partner utilizing Zn as the stoichiometric reductant. In this reaction, a challenging stereoselective bond formation between two disubstituted sp3-hybridized carbon centers has been achieved, furnishing a variety of 1,2-dihydronaphthalenes with full diastereocontrol of three consecutive stereogenic centers.

Convergent Synthesis of Enantioenriched ortho-Fused Tricyclic Diketones via Catalytic Asymmetric Intramolecular Vinylogous Aldol Condensation.

Herein, we describe a catalytic asymmetric intramolecular vinylogous aldol reaction by taking advantage of dual organocatalysts, which enables convergent synthesis of ortho-fused tricyclic diketones in excellent enantioselectivities and diastereoselectivities. Noteworthy is that the reaction stereoselectively forges three consecutive stereogenic carbon centers including a quaternary one. Density functional theory calculations reveal that the enantioselectivity was facilitated by a transannular hydrogen bonding between the protonated quinuclidine moiety of the chiral aminocatalyst and the diketone fragment of the substrate.

Catalytic [2+2+2] Tandem Cyclization with Alkyl Substituted Methylene Malonate Enabling Concise Total Synthesis of Four Malagasy Alkaloids

Catalytic [2+2+2] Tandem Cyclization with Alkyl Substituted Methylene Malonate Enabling Concise Total Synthesis of Four Malagasy Alkaloids

Synthetic Approach toward Enantiopure Cyclic Sulfinamides.

A synthetic approach toward densely substituted enantiopure cyclic sulfinamides possessing up to four consecutive stereogenic centers was developed based on a completely diastereoselective SN2′ cyclization/tert-Bu cleavage sequence. Diastereospecific transformation of the obtained scaffold into chiral SVI derivatives such as sulfoximines and sulfonimidamides is demonstrated.

Stereocomplementary Synthesis of a Key Intermediate for Tofacitinib via Enzymatic Dynamic Kinetic Resolution‐Reductive Amination

AbstractTofacitinib is an oral protein tyrosine kinase inhibitor approved for the treatment of rheumatoid arthritis, active psoriatic arthritis and ulcerative colitis. Its efficient production remains a challenge due to the two consecutive stereogenic centers associated to the piperidine ring. In this study, an enzymatic dynamic kinetic resolution‐asymmetric reductive amination was developed to prepare enantiomerically complementary cis‐1‐benzyl‐N,4‐ dimethylpiperidin‐3‐amine and its analogues. Two enantiocomplementary imine reductases (IREDs) were identified for the synthesis of (3R,4R)‐ and (3S,4S)‐1‐benzyl‐N,4‐dimethylpiperidin‐3‐amine in high isolated yields (83% and 91%) with excellent stereoselectivity (97% and >99% ee values) and diastereoselectivity (>99:1 dr), providing a green methodology for the production of the key intermediate of tofacitinib.magnified image

Enantioselective Synthesis of Spirocyclopentane Oxindoles Bearing Five Consecutive Stereocenters through Secondary Amine‐Catalyzed [3+2] Cycloaddition

AbstractThis work delineates a Michael‐initiated ring‐closing [3+2] cycloaddition of newly designed 3‐(1‐benzyl‐2‐oxoindolin‐3‐yl)pentane‐2,4‐diones with α,β‐unsaturated aldehydes. During the chiral secondary amine‐catalyzed cascade reaction, highly functionalized spirocyclopentane oxindole derivatives containing five consecutive stereogenic centers were formed, two of which were tetrasubstituted carbon. All the desired products are smoothly obtained in good yields (up to 90 %) with excellent enantioselectivities (up to >99 : 1 er) and diastereoselectivities (up to >95 : 5 dr). Meanwhile, the practicality of this strategy was highlighted by the further gram‐scale experiment and a set of synthetic transformations.

Phosphine-Catalyzed Sequential [3 + 2]/[3 + 2] Annulation between Allenoates and Arylidenemalononitriles for the Enantioselective Construction of Bicyclo[3,3,0]octenes and Cyclopenta[c]quinolinones.

A highly diastereo- and enantioselective phosphine-catalyzed sequential [3 + 2]/[3 + 2] annulation of allenoates with arylidenemalononitriles has been developed. This reaction allows for the facile construction of multifunctionalized cis-fused bicyclic[3,3,0]octene scaffolds, encompassing three consecutive stereogenic centers with one quaternary carbon center, in a one-step operation from readily available materials. The reported protocol is scalable, operates under mild reaction conditions, and creates the core structural motif of a number of natural products.

Asymmetric Synthesis of Chromans Through Bifunctional Enamine-Metal Lewis Acid Catalysis.

Cooperative enamine-metal Lewis acid catalysis has emerged as a powerful tool to construct carbon-carbon and carbon-heteroatom bond forming reactions. A concise synthetic method for asymmetric synthesis of chromans from cyclohexanones and salicylaldehydes has been developed to afford tricyclic chromans containing three consecutive stereogenic centers in good yields (up to 87 %) and stereoselectivity (up to 99 % ee and 11 : 1 : 1 dr). This difficult organic transformation was achieved through bifunctional enamine-metal Lewis acid catalysis. It is believed that the strong activation of the salicylaldehydes through chelating to the metal Lewis acid and the bifunctional nature of the catalyst accounts for the high yields and enantioselectivity of the reaction. The absolute configurations of the chroman products were established through X-ray crystallography. DFT calculations were conducted to understand the mechanism and stereoselectivity of this reaction.

Metal-Free Diastereo- and Enantioselective Dearomative Formal [3 + 2] Cycloaddition of 2-Nitrobenzofurans and Isocyanoacetate Esters.

The diastereo- and enantioselective dearomative formal [3 + 2] cycloaddition of 2-nitrobenzofurans and α-aryl-α-isocyanoacetate esters provides tricyclic compounds bearing the 3a,8b-dihydro-1H-benzofuro[2,3-c]pyrrole framework with three consecutive stereogenic centers. The reaction was enabled by a cupreine-ether organocatalyst. The reaction products were obtained with almost full diastereoselectivity and with excellent enantiomeric excesses for a number of substituted 2-nitrobenzofurans and isocyanoacetates.

Copper-catalyzed cascade reaction of tryptamines with diazo compounds to access hexahydropyrroloindoline derivatives.

A domino reaction sequence of cyclopropanation/ring-opening/iminium cyclization of tryptamine derivatives with donor-acceptor diazo compounds is developed to furnish pyrroloindolines, creating three consecutive stereogenic centers in a single step. The copper-catalyzed reaction provides pyrroloindolines at room-temperature with good substrate scope.

Synthesis of novel chiral spiro-β-lactams from nitrile oxides and 6-(Z)-(benzoylmethylene)penicillanate: batch, microwave-induced and continuous flow methodologies.

The first examples of the diastereoselective 1,3-dipolar cycloaddition reaction of nitrile oxides and 6-alkylidene penicillanates leading to chiral spiroisoxazoline-penicillanates are reported. The synthesis of this new type of penicillanate involved the selective generation of two consecutive stereogenic centers, including a quaternary chiral center. Furthermore, the present work also describes the outcomes of these 1,3-dipolar cycloaddition reactions under three distinct reaction conditions (conventional heating, microwave irradiation and continuous flow). The successful use of the continuous flow technique as well as the proper selection of the reaction media allowed the development of a sustainable route to chiral spiroisoxazoline-penicillanates.

Rhodium-Catalyzed Enantioselective and Desymmetrizative Pauson-Khand Reaction: Access to Tricyclo[6.2.1.04,11]undecenes.

Rhodium-catalyzed asymmetric desymmetrization Pauson-Khand reaction of C4-alkynyl-tethered cyclohexadienones has been developed as a novel strategy for access to fused 6-5-5 tricycles bearing three consecutive stereogenic centers. An array of chiral tricyclo[6.2.1.04,11]undecenes have been synthesized in high yields and enantioselectivities in a single step under mild conditions. This strategy employs readily accessible internal-olefin-containing 1,6-enynes, providing a potentially powerful tool for constructing chiral polycyclic scaffolds of complex molecules containing cyclopentenones and cyclohexenones.

Ruthenium-Catalyzed Asymmetric Transfer Hydrogenation of β-Substituted α-Oxobutyrolactones.

A concise and effective ruthenium-catalyzed asymmetric transfer hydrogenation of β-substituted α-oxobutyrolactones has been developed, delivering a series of cis-β-substituted α-hydroxybutyrolactone derivatives with excellent yields, enantioselectivities, and diastereoselectivities. Two consecutive stereogenic centers were constructed in one step through dynamic kinetic resolution under basic conditions. The reaction could be conducted on a gram scale without loss of activity and enantioselectivity. The reductive products could be easily transformed into useful building blocks.

Copper(I)‐Catalyzed Asymmetric Interrupted Kinugasa Reaction: Synthesis of α‐Thiofunctional Chiral β‐Lactams

AbstractA copper(I)‐catalyzed asymmetric, three‐component interrupted Kinugasa reaction has been developed. Diverse chiral sulfur‐containing chiral β‐lactams with two consecutive stereogenic centers were synthesized in one step from readily available starting materials in good yields and with excellent diastereo‐ and enantioselectivity. The key is the interception of in situ formed chiral four membered copper(I) enolate intermediate with sulfur electrophiles.