Asymmetric Synthesis Research Articles

Collective Asymmetric Synthesis of Thiosilvatins.

Thiosilvatins are a family of biologically active sulfenylated diketopiperazine natural products. The first members were reported over 40 years ago, but total synthesis of a thiosilvatin has remained elusive. Here, we describe the first, collective, synthesis of the parent epidithiodiketopiperazine (-)-dithiosilvatin and ten related thiosilvatins. Several of the targets are structurally revised. A catalytic asymmetric sulfenylation of triketopiperazines efficiently controls absolute configuration at the thioaminal units. Further synthetic highlights include a diastereoconvergent installation of the requisite cis-orientation of the sulfur atoms and a tandem epidisulfide formation/O-prenylation under mild Mitsunobu conditions. The described methods for late-stage diversification of sensitive bis(methylthio)diketopiperazines offer a blueprint for systematically exploring this interesting 3D-pharmacophore in stereochemically pure form.

Primary Amine-Functionalized Chiral Covalent Organic Framework Enables High-Efficiency Asymmetric Catalysis in Water.

Aqueous asymmetric catalysis using chiral covalent organic frameworks (COFs) represents a significant advancement but remains to be explored. Herein, we present the first example of aqueous asymmetric catalysis catalyzed by a primary amine-tagged chiral D-ADP-TAPB COF. The D-ADP-TAPB COF was synthesized by the postsynthetic deprotection of D-ADP-TAPB-Boc bearing a protective tert-butoxycarbonyl (Boc) group, which was constructed by a Schiff-base reaction between an alanine-derived chiral building block (D-ADP-Boc) and 1,3,5-tris(4-aminophenyl)benzene (TAPB). The crystalline D-ADP-TAPB COF exhibits a uniform, spherical morphology with abundant, well-distributed chiral primary amines, rendering it highly active in the asymmetric aldol reaction between cyclohexanone and 4-nitrobenzaldehyde. Notably, this reaction is conducted entirely in water, achieving impressive yields and enantiomeric excess (ee) values of up to 90 and 85%, respectively. To the best of our knowledge, D-ADP-TAPB COF represents the first chiral COF catalyst with high reactivity and enantioselectivity for an asymmetric aldol reaction solely in water, eliminating the need for conventional organic solvents. Moreover, a plausible mechanism for D-ADP-TAPB COF-mediated aqueous asymmetric aldol reactions is elucidated. This work not only expands the toolbox for designing rare primary amine-functionalized chiral COFs for asymmetric catalysis but also opens exciting avenues for developing green and water-based enantioselective catalysis.

N-Directed, Radical Relay Enantioconvergent Sulfinylation of Distal C(sp3)-H Bonds via Cobalt Catalysis.

Cobalt-catalyzed enantioconvergent cross-coupling of C(sp3)-H bonds with in situ-generated sulfenate anions is achieved to access chiral sulfoxides, which are found in the structures of many biologically active agents. The more challenging aliphatic C-H bonds as well as sterically hindered substrates containing tertiary C-H bonds could also be tolerated well. Mechanistic studies indicate that the transformation could undergo a CoIIS(O)R-mediated single-electron transfer with N-fluorocarboxamides, followed by a 1,5-hydrogen atom transfer and then a pivotal organocobalt(IV)-controlled enantioselective cross-coupling process. This novel asymmetric radical reaction for C-S bond construction could open a new door for the synthesis of sulfur-centered chiral compounds.

Progress in the Stereoselective Synthesis Methods of Pyrrolidine-Containing Drugs and Their Precursors.

The presented review systematizes and summarizes the data on the synthesis of pyrrolidine derivatives, which are precursors for obtaining drugs. Based on the analysis of published data, the most promising directions in the synthesis of biologically active compounds containing a pyrrolidine ring are identified. Stereoselective synthesis methods are classified based on the source of the pyrrolidine ring. The first group includes methods that use a pyrrolidine ring as the starting compound. The second group combines stereoselective methods of cyclization of acyclic starting compounds, which lead to optically pure pyrrolidine derivatives.

Chiron approach toward the synthesis of the fused tricyclic core of epi-parvistemonine A

A stereoselective synthesis of fused tricyclic framework of epi-parvistemonine A from D-glucono-δ-lactone is described. The synthetic strategic is based on the stereoselective construction of the 7-membered cyclic skeleton via a cross-metathesis reaction followed by a Michael type cyclization promoted by Tf2O.

Enantioselective Synthesis of Axially Chiral Silacyclohexylidene Oxime Ethers by Chiral Phosphoric Acid Catalysis

Enantioselective Synthesis of Axially Chiral Silacyclohexylidene Oxime Ethers by Chiral Phosphoric Acid Catalysis

Catalytic Asymmetric Conjugate Addition and Allylic Substitution of Cyclobutenones with Arylzinc Halides

Comprehensive SummaryConjugate addition and allylic substitution are two essential chemical transformations, and they could be competitive for substrates with multiple reactive sites. Herein, we report the diversified enantioselective synthesis of cyclobutenes via the functionalization of cyclobutenones. The conjugate addition of cyclobutenones with arylzinc halides provided enantioenriched cyclobutenes with all‐carbon quaternary centers. On the other hand, when cyclobutenones with gem‐dichloro groups were employed, a chemo‐ and enantioselective allylic substitution occurred. Further synthetic utility was demonstrated for synthesizing versatile cyclobutane derivatives, together with ring‐opening and expansion products.

Catalytic Asymmetric Synthesis of Bicyclic Isothioureas from a Common Enolizable Template.

While bicyclic isothiourea (ITU) moieties are found in biologically active molecules and organocatalysts, a catalytic asymmetric synthesis of ITUs is pending. Here, we report the catalytic, enantioselective functionalization of enolizable template II with a variety of electrophiles, including unsaturated ketones, esters, sulfones, nitro compounds, and thiolating reagents, as an entry to enantioenriched bicyclic ITUs III. Scope and limitations are shown, as well as examples of product derivatization.

Meso- and l,l-Diaminopimelic Acids: A Stereoselective Synthesis from α-Amino Acids

meso- and l,l-Diaminopimelic Acids: A Stereoselective Synthesis from α-Amino Acids

Catalytic Promiscuity of Fatty Acid Photodecarboxylase Enables Stereoselective Synthesis of Chiral α‐Tetralones

AbstractIn the field of biocatalysis, discovering novel reactivity from known enzymes has been a longstanding challenge. Fatty acid photo‐decarboxylase from Chlorella variabilis (CvFAP) has drawn considerable attention as a promising photoenzyme with potential green chemistry applications; however, its non‐natural reactivity has rarely been exploited to date. Herein we report a non‐natural reductive dehalogenation (deacetoxylation) reactivity of CvFAP inspired by its natural oxidative decarboxylation process, enabling the stereoselective synthesis of a series of chiral α‐substituted tetralones with high yields (up to 99 %) and e.r. values (up to 99 : 1). Mechanistic studies demonstrated that the native photoenzyme catalyzed the reductive dehalogenation via a novel mechanism involving oxidized state (FADox)/semiquinone state (FADsq) redox pair and an electron transfer (ET)/proton transfer (PT) process of radical termination, distinct from the previous reports. To our knowledge, this study represents a new example of CvFAP promiscuity, and thus expands the reactivity repertoire of CvFAP and highlights the versatility of CvFAP in asymmetric synthesis.

Simultaneous Determination of the Position and Cis-Trans Configuration of Lipid C═C Bonds via Asymmetric Derivatization and Ion Mobility-Mass Spectrometry.

The position and cis-trans configuration of C═C bonds in unsaturated lipids significantly affect their biological activities. Simultaneous identification of the position and cis-trans configuration of C═C bonds in unsaturated lipids is important; nonetheless, it still remains a challenging task. Herein, a stereoselective asymmetric reaction was used to recognize cis-trans isomers of the C═C bonds, and the derivatized precursor ions and product ions were subjected to tandem ion mobility-mass spectrometry (IM-MS) analysis. The theoretical calculation revealed that the formation of intramolecular hydrogen bonds after the cyclization reaction amplified the structural difference between diastereomers and increased the separation efficiency in IM. Consequently, a simple, sensitive, and highly selective platform for simultaneous determination of the position and cis-trans configuration of various C═C bonds in unsaturated lipids was established. It was then successfully applied to pinpoint the cis-trans geometry conversion of the located C═C bonds in lipids of the bacterial membrane under environmental stress and track the heterogeneous distribution of unsaturated lipids in rats after spinal cord injury. The present study also offers new insights into the application of IM-MS technology in resolving molecular structures and demonstrates the potential as a platform for a broad range of applications.

Photoinduced Asymmetric Alkene Aminohetarylation with Chiral Sulfoximine Reagents.

Given the pivotal role of β-(het)arylethylamine moiety in bioactive molecules, the direct amino(het)arylation of alkenes occupies a privileged position in the construction of (het)arylethylamine derivatives. Herein we devise chiral sulfoximines as novel bifunctional reagents which exhibit remarkable efficiency in the challenging asymmetric alkene aminohetarylation reaction, particularly in terms of reactivity and stereo-control. The chiral reagents can be conveniently accessed in gram scale, and efficiently generate N-centered radicals under mild photochemical conditions. The transformation proceeds through enantioselective 1,4-hetaryl migration, ensuring precise chirality transfer from sulfur- to carbon-centers, rendering wide applicability to both aromatic and aliphatic alkenes. Furthermore, the method is straightforward to operate and does not require transition metals or photosensitizers, making it an attractive and practical option.

One‐Pot Synthesis of (S)‐Flavanones by a Double‐Face Promiscuous Chemo‐Enzymatic Cascade of Lipases

AbstractThe one‐pot stereoselective synthesis of (S)‐flavanones from 2′‐hydroxyacetophenone and substituted aromatic aldehydes was obtained by a double‐face promiscuous chemo‐enzymatic cascade of porcine pancreas and Mucor javanicus lipases. The reaction pathway comprises: A) cross‐aldol condensation catalysed by porcine pancreas lipase to yield chalcone intermediates; B) unprecedented intramolecular oxa‐Michael addition of chalcone intermediates to (S)‐flavanones. Mucor javanicus lipase was the most effective enzyme in step B. Imidazole and 2‐methylimidazole were studied as additive in order to improve the efficacy of the overall transformation. The sustainability of the chemo‐enzymatic cascade was increased by immobilization of lipases on cross‐linked hydroxy‐methylated kraft lignin nanoparticles, by use of concanavalin A. Immobilization conferred considerable stability and reusability at the system for 4 runs. Noteworthy, the reaction mixture was significantly enriched in (S)‐flavanones under both homogeneous and heterogeneous conditions. Computational studies encompassing docking and molecular dynamic analyses showed the role played by evolutionary conserved oxyanion holes and catalytic triad of Mucor javanicus lipase in the stereocontrol of the intra‐molecular oxa‐Michael addition.

Enantioselective Synthesis of 2-Oxazolidinones Using Organoselenium Catalysis

Enantioselective Synthesis of 2-Oxazolidinones Using Organoselenium Catalysis

Asymmetric Synthesis of 3,3′-Pyrrolidonyl Spirooxindole-5’-Carboxylic Ester from L-Tryptophan

A highly efficient, multi-gram scale asymmetric synthesis of 3,3'-pyrrolidonyl spirooxindole-5'-carboxylic ester, which could be a potential precursor for the synthesis of cyanogramide, is accomplished from commercially available L-1-methyl-tryptophan in two pots. Fluoride-promoted desilylative spiro-cyclization of (semi) in situ generated isocyanate derived from (L)-1-methyl tryptophan is the key reaction. Further, a variety of arene-substituted 3,3′-pyrrolidonyl spirooxindole-5’-carboxylxic acid ester were synthesized by late stage functionalization of easily accessible 3,3'-pyrrolidonyl spirooxindole-5'-carboxylic ester.

Controlling (E/Z)-Stereoselectivity of -NHC=O Chlorination: Mechanism Principles for Wide Scope Applications.

Organic halogen compounds are cornerstones of applied chemical sciences. Halogen substitution is a smart molecular design strategy adopted to influence reactivity, membrane permeability and receptor interaction. Chiral bioreceptors may restrict the stereochemical requirements in the halo-ligand design. Straightforward (but expensive) catalyzed stereospecific halogenation has been reported. Historically, PCl5 served access to uncatalyzed stereoselective chlorination although the stereochemical outcomes were influenced by steric parameters. Nonetheless, stereochemical investigation of PCl5 reaction mechanism with carbamoyl (RCONHX) compounds has never been addressed. Herein, we provide the first comprehensive stereochemical mechanistic explanation outlining halogenation of carbamoyl compounds with PCl5; the key regioselectivity-limiting nitrilimine intermediate (8-Z.HCl); how substitution pattern influences regioselectivity; why oxadiazole byproduct (P1) is encountered; stereo-electronic factors influencing the hydrazonoyl chloride (P2) production; and discovery of two stereoselectivity-limiting parallel mechanisms (stepwise and concerted) of elimination of HCl and POCl3. DFT calculations, synthetic methodology optimization, X-ray evidence and experimental reaction kinetics study evidence all supported the suggested mechanism proposal (Scheme 2). Finally, we provide mechanism-inspired future recommendations for directing the reaction stereoselectivity toward elusive and stereochemically inaccessible (E)-bis-hydrazonoyl chlorides along with potentially pivotal applications of both (E/Z)-stereoisomers especially in medicinal chemistry and protein modification.

Enantioselective Synthesis of Chiral Isoindolines via Palladium-Catalyzed Asymmetric Allylic C-H Amination

Enantioselective Synthesis of Chiral Isoindolines via Palladium-Catalyzed Asymmetric Allylic C-H Amination

Enantioselective Synthesis of 3-Hydroxy-2-Oxindoles via Ni-Catalyzed Asymmetric Addition of Aromatic Bromides to α-Ketoamides.

Nickel-catalyzed asymmetric intramolecular addition of aryl halides to α-ketoamides has been achieved to afford chiral 3-substituted-3-hydroxy-2-oxindoles in excellent yields and high enantioselectivities (up to 99% yield and 98% ee), which provides efficient access to valuable molecules containing 3-hydroxy-2-oxindole core. The gram-scale reaction proved the potential utility of the methodology.

N‐Heterocyclic Carbene Enabled Copper Catalyzed Asymmetric Synthesis of Pyrimidinyl Phosphine with both Axial and P‐Stereogenicity

AbstractP‐stereogenic phosphines, renowned for their utility as ligands and catalysts, have been instrumental in the field of asymmetric catalysis. However, the catalytic asymmetric synthesis of chiral ligands possessing both axial and phosphine chirality remains a significant challenge. Here, we present the successful demonstration of a Cu‐catalyzed asymmetric C−P construction using in situ generated secondary phosphine and heteroaryl chloride. By introducing a chiral NHC ligand and an achiral diphosphine auxiliary ligand, we effectively alleviated the poisoning effect caused by phosphine(III) compounds and suppressed the nonenantioselective background reaction. The reaction exhibited excellent enantioselectivity, with up to 96 % ee, and good diastereoselectivity, with up to 14 : 1 dr, when employing less sterically hindered secondary phosphines. This particular substrate poses a significant challenge due to its strong poisoning effect in copper catalysis.

Chiral SPINOL‐derived Boro‐phosphate‐Catalyzed Asymmetric 1,4‐Reduction of Exocyclic α,β‐Unsaturated Ketones

An asymmetric 1,4‐reduction of exocyclic α,β‐unsaturated ketones leading to the formation of diverse optically active α‐substituted tetralones has been realized by chiral SPINOL‐derived boro‐phosphate. The enantios‐elctivity‐determining step of the reaction is the protonation of a highly active boron enolates intermediate. The catalytic reduction system composed of chiral SPINOL‐derived boro‐phosphate and pinacolborane may be widely used in other asymmetric reduction reactions.