Bifunctional Thiourea Organocatalysts Research Articles

Synthesis of D-Fructose-Based Bifunctional Primary Amine-Thiourea Organocatalysts and Their Applications in Asymmetric Reactions

The preparation of a new class of six bifunctional thiourea organocatalysts having a D-fructose scaffold and a primary amino group was demonstrated. In the present study, the novel organocatalysts exhibited excellent enantio- and moderate diastereoselectivities in the asymmetric Michael addition of aliphatic ketones and 1,3-diketone to substituted nitroolefins at room temperature. In addition, the direct asymmetric aldol reaction between cyclic aliphatic ketone and aromatic aldehydes was also studied in the presence of the saccharide-thiourea organocatalysts giving excellent yield with moderate enantioselectivity.

Enantioselective Synthesis of 3‐Acetyl Coumarin Substituted 3‐Hydroxy Oxindoles and Pyranocoumarin Fused Spirooxindoles

AbstractEnantioselective construction of bioinspired coumarin and oxindole hybrid structures always enduring challenges in organic chemistry due to the generation of asymmetric quaternary/spiro center at the C3 position of oxindole. Herein, we demonstrated a facile enantioselective synthesis of highly functionalized 3,3’‐disubstituted oxindole derivatives containing 3‐acetyl coumarins and pyranocoumarin fused spirooxindoles using L‐proline derived bifunctional thiourea organocatalyst through Aldol reaction and Michael addition/cyclization. The L‐proline derived thiourea catalyst well performed with broad substrate scope to produce desired products in very good yields (up to 95 %) and excellent enantioselectivities (up to 99 % ee).

The First Highly Enantioselective Synthesis of 3-Sulfinyl-Substituted Isoindolinones Having Adjacent Carbon and Sulfur Stereocenters.

A highly stereoselective access to 3-sulfinyl-substituted isoindolinones has been achieved by a tandem organocatalytic addition/cyclization reaction of 2-carbobenzyloxy-N-tosylbenzylidenimine with thiols and succeeding diastereoselective oxidation with MCPBA. First, enantioenriched isoindolinone N,S-acetals have been obtained through a dynamic kinetic asymmetric transformation induced by a bifunctional chiral thiourea organocatalyst. In turn, the newly created carbon stereocenter enabled a high diastereocontrol in the subsequent sulfoxidation. Based on DFT calculations, a theoretical rationale for the stereoselectivity of the oxidation reaction is also provided.

Organocatalytic Desymmetrization of Meso‐Aziridines Via Asymmetric Intramolecular Rearrangement

AbstractHerein we report the first organocatalytic method for the desymmetrization of meso‐aziridines that does not require the use of an external nucleophilic reagent. The process was designed upon a base promoted rearrangement of bicyclic meso‐cyclopentanone aziridines, that progresses in intramolecular fashion to provide densely functionalized cyclic ketones, key intermediates for the preparation of Active Pharmaceutical Ingredients. The key enantio‐determining step proceeded under the catalysis of a bifunctional thiourea organocatalyst. The process provides an entry to a class of highly functionalized chiral amines, 4‐aminocyclopentenones, not accessible with previous desymmetrization methods. The ambiphilic nature of the products makes them versatile synthetic intermediates in the preparation of natural products and popular antiviral nucleoside inhibitors, for example abacavir.

Stereodivergent Synthesis of Camphor-Derived Diamines and Their Application as Thiourea Organocatalysts.

A series of 18 regio- and stereo-chemically diverse chiral non-racemic 1,2-, 1,3-, and 1,4-diamines have been synthesized from commercial (1S)-(+)-ketopinic acid and (1S)-(+)-10-camphorsulfonic acid. The structures of the diamines are all based on the d-(+)-camphor scaffold and feature isomeric diversity in terms of regioisomeric attachment of the primary and the tertiary amine function and the exo/endo-isomerism. Diamines were transformed into the corresponding noncovalent bifunctional thiourea organocatalysts, which have been evaluated for catalytic activity in the conjugative addition of 1,3-dicarbonyl nucleophiles (dimethyl malonate, acetylacetone, and dibenzoylmethane) to trans-β-nitrostyrene. The highest enantioselectivity was achieved in the reaction with acetylacetone as nucleophile using endo-1,3-diamine derived catalyst 52 (91.5:8.5 er). All new organocatalysts 48–63 have been fully characterized. The structures and the absolute configurations of eight intermediates and thiourea derivative 52 were also determined by X-ray diffraction.

Covalent Poly(lactic acid) Nanoparticles for the Sustained Delivery of Naloxone.

The opioid epidemic currently plaguing the United States has been exacerbated by an alarming rise in fatal overdoses as a result of the proliferated abuse of synthetic mu opioid receptor (MOR) agonists, such as fentanyl and its related analogues. Attempts to manage this crisis have focused primarily on widespread distribution of the clinically approved opioid reversal agent naloxone (Narcan); however, due to the intrinsic metabolic lability of naloxone, these measures have demonstrated limited effectiveness against synthetic opioid toxicity. This work reports a novel polymer-based strategy to create a long-acting formulation of naloxone with the potential to address this critical issue by utilizing covalent nanoparticle (cNP) drug delivery technology. Covalently loaded naloxone nanoparticles (Nal-cNPs) were prepared via the naloxone-initiated, ring-opening polymerization (ROP) of l-lactide in the presence of a bifunctional thiourea organocatalyst with subsequent precipitation of the resulting naloxone-poly(l-lactic acid) polymer. This protocol afforded well-defined nanoparticles possessing a drug loading of approximately 7% w/w. The resulting Nal-cNPs demonstrated excellent biocompatibility, while exhibiting sustained linear release kinetics in vitro and blocking the effects of high dose (10 mg/kg) acute morphine for up to 98 h in an in vivo rodent model of neuropathic pain.

Transition state analysis of an enantioselective Michael addition by a bifunctional thiourea organocatalyst.

The mechanism of the enantioselective Michael addition of diethyl malonate to trans-β-nitrostyrene catalyzed by a tertiary amine thiourea organocatalyst is explored using experimental 13C kinetic isotope effects and density functional theory calculations. Large primary 13C KIEs on the bond-forming carbon atoms of both reactants suggest that carbon-carbon bond formation is the rate-determining step in the catalytic cycle. This work resolves conflicting mechanistic pictures that have emerged from prior experimental and computational studies.

Asymmetric Synthesis of 2,2-Disubstituted Benzofuranones through an Organocatalytic Alkylation with Nitroallylic Acetates

The asymmetric allylic alkylation of benzofuran-3(2H)-ones with nitroallylic acetates has been achieved employing a bifunctional thiourea organocatalyst via SN2′ substitution. A series of 2,2-disubstituted benzofuranones bearing adjacent tetrasubstituted and tertiary stereocenters have been synthesized with moderate to good yields and very good stereoselectivities.

Dynamic Kinetic Resolution of Heterobiaryl Ketones by Zinc-Catalyzed Asymmetric Hydrosilylation.

A diastereo- and highly enantioselective dynamic kinetic resolution (DKR) of configurationally labile heterobiaryl ketones is described. The DKR proceeds by zinc-catalyzed hydrosilylation of the carbonyl group, thus leading to secondary alcohols bearing axial and central chirality. The strategy relies on the labilization of the stereogenic axis that takes place thanks to a Lewis acid-base interaction between a nitrogen atom in the heterocycle and the ketone carbonyl group. The synthetic utility of the methodology is demonstrated through stereospecific transformations into either N,N-ligands or appealing axially chiral, bifunctional thiourea organocatalysts.

Dynamic Kinetic Resolution of Heterobiaryl Ketones by Zinc‐Catalyzed Asymmetric Hydrosilylation

AbstractA diastereo‐ and highly enantioselective dynamic kinetic resolution (DKR) of configurationally labile heterobiaryl ketones is described. The DKR proceeds by zinc‐catalyzed hydrosilylation of the carbonyl group, thus leading to secondary alcohols bearing axial and central chirality. The strategy relies on the labilization of the stereogenic axis that takes place thanks to a Lewis acid–base interaction between a nitrogen atom in the heterocycle and the ketone carbonyl group. The synthetic utility of the methodology is demonstrated through stereospecific transformations into either N,N‐ligands or appealing axially chiral, bifunctional thiourea organocatalysts.

Asymmetric Organocatalytic Approach to 2,4-Disubstituted 1,2,3-Triazoles by N2-Selective Aza-Michael Addition.

Despite the fact that N1-functionalization of NH-1,2,3-triazoles has been known for several decades, enantioselective variants of this reaction have only recently been developed. Nevertheless, functionalization at the N2-position of NH-1,2,3-triazoles leading to optically active N2-substituted triazoles is not yet developed. In this article, we report, for the first time, the asymmetric aza-Michael reaction of 4-aryl-NH-1,2,3-triazoles to cyclic enones under the catalytic influence of chiral bifunctional thiourea organocatalysts for the enantioselective generation of 2,4-disubstituted 1,2,3-triazoles. The cinchonine-derived thiourea catalyst III worked efficiently in the current transformation to produce N2-functionalized 1,2,3-triazoles as major products in optical yields up to >99.9% along with minor 1,4-disubstitued 1,2,3-triazoles.

Novel and highly efficient bifunctional calixarene thiourea derivatives as organocatalysts for enantioselective Michael reaction of nitroolefins with diketones

New bifunctional calixarene thiourea organocatalysts were synthesized and applied in catalytic asymmetric Michael addition of acetylacetone to various nitroolefins at room temperature. The corresponding adducts were obtained in good to excellent yields with excellent enantioselectivities (up to 92% ee). The present research demonstrates the advantages of incorporating two stereocontrolling structures into a single catalyst. Notably, it offers a simple and convenient doubly stereocontrolled approach for the catalytic asymmetric synthesis of a chiral organic molecule.

Organocatalytic Stereoconvergent Synthesis of α-CF3 Amides: Triketopiperazines and Their Heterocyclic Metamorphosis.

The highly enantioselective alkylation of α-CF3 enolates, generated from triketopiperazines, has been accomplished through use of a bifunctional thiourea organocatalyst to facilitate 1,4-addition to varied enone acceptors. On treatment with appropriate nitrogen nucleophiles, the chiral triketopiperazine products undergo a metamorphosis, to provide novel fused heterocyclic lactams such as extended pyrazolopyrimidines.

Organocatalytic Domino Oxa‐Michael/1,6‐Addition Reactions: Asymmetric Synthesis of Chromans Bearing Oxindole Scaffolds

AbstractAn asymmetric organocatalytic domino oxa‐Michael/1,6‐addition reaction of ortho‐hydroxyphenyl‐substituted para‐quinone methides and isatin‐derived enoates has been developed. In the presence of 5 mol % of a bifunctional thiourea organocatalyst, this scalable domino reaction affords 4‐phenyl‐substituted chromans bearing spiro‐connected oxindole scaffolds and three adjacent stereogenic centers in good to excellent yields (up to 98 %) and with very high stereoselectivities (up to >20:1 d.r., >99 % ee).

Organocatalytic Domino Oxa-Michael/1,6-Addition Reactions: Asymmetric Synthesis of Chromans Bearing Oxindole Scaffolds.

An asymmetric organocatalytic domino oxa-Michael/1,6-addition reaction of ortho-hydroxyphenyl-substituted para-quinone methides and isatin-derived enoates has been developed. In the presence of 5 mol % of a bifunctional thiourea organocatalyst, this scalable domino reaction affords 4-phenyl-substituted chromans bearing spiro-connected oxindole scaffolds and three adjacent stereogenic centers in good to excellent yields (up to 98 %) and with very high stereoselectivities (up to >20:1 d.r., >99 % ee).

Development of Bifunctional Thiourea Organocatalysts Derived from a Chloramphenicol Base Scaffold and their Use in the Enantioselective Alcoholysis of meso Cyclic Anhydrides

AbstractThe synthesis of new chloramphenicol‐base‐derived thiourea organocatalysts, (1S,2R)‐12 a–f and (1R,2R)‐15 a–c, and their use in the enantioselective alcoholysis of meso‐anhydrides are described. In particular, hemiesters afforded excellent enantioselectivities if low loadings of (1S,2R)‐12 a–f were used. Almost no enantioselectivities were achieved with the use of (1R,2R)‐15 a–c. This technique was used to synthesize (R)‐(−)‐baclofen.

ChemInform Abstract: Novel Efficient Bifunctional Calixarene Thiourea Organocatalysts: Synthesis and Application in the Direct Enantioselective Aldol Reactions.

AbstractA novel bifunctional calixarene thiourea CLXA is prepared and successfully applied as chiral catalyst for enantioselective aldol reactions of aryl aldehydes with acetone.

Novel efficient bifunctional calixarene thiourea organocatalysts: synthesis and application in the direct enantioselective aldol reactions

Novel efficient bifunctional calixarene thiourea organocatalysts have been designed as efficient organocatalysts for direct asymmetric aldol reactions between acetone and aromatic aldehydes. The reactions generated the corresponding products in satisfactory isolated yields (up to 96%) and with excellent enantiomeric excesses (up to 99%) in the presence of catalyst (10mol %).

ChemInform Abstract: Enantioselective Synthesis of Highly Substituted Chromans via the Oxa‐Michael—Michael Cascade Reaction with a Bifunctional Organocatalyst.

A highly enantioselective synthesis of chiral chroman derivatives via an oxa-Michael–Michael cascade reaction has been developed using a bifunctional thiourea organocatalyst. The products were obtained with excellent enantioselectivities (up to >99%), good yields (up to 95%), and diastereoselectivities (up to 5:1).

ChemInform Abstract: Iterative Coupling of Two Different Enones by Nitromethane Using Bifunctional Thiourea Organocatalysts. Stereocontrolled Assembly of Cyclic and Acyclic Structures.

AbstractVarious unsaturated aldehydes and ketones are utilized for the highly diastereoselective and enantioselective construction of cyclic syn‐ketols and acyclic compounds with multiple contiguous stereocenters.