High Diastereoselectivity Research Articles

Diastereoselective Synthesis of Phosphinyl Peptides via Rh-Catalyzed 1,4-Addition in Coparticipation of a P-Chiral Moiety and Difluorphos.

The asymmetric Rh-catalyzed 1,4-addition of aryl/heteroaryl moieties to α,β-unsaturated esters was achieved in high diastereoselectivity via the coparticipation of a P-chiral phosphinyl moiety at Cβ to the prochiral center and (R)- or (S)-Difluorphos. This methodology expands the synthetic toolbox available for the preparation of structurally diverse chiral phosphinyl peptides.

Base-Mediated Chemodivergent [4 + 1] and [2 + 1] Cycloadditions of N-Alkylpyridiniums and Enones.

Divergent synthesis of structurally different products from the same kinds of starting materials is highly synthetically useful but very challenging. Herein, we reported a base-mediated chemodivergent [4 + 1] and [2 + 1] cycloaddition of N-alkylpyridinium and enone under mild conditions, leading to furan-fused bicycles with high diastereoselectivity and spirobicycles, respectively, from moderate to high yields. N-Alkylpyridinium salts were modular nucleophilic transfer reagents and C1 synthons, which underwent tandem Michael addition to the α,β-unsaturated ketones and cyclization under the base conditions. Late-stage derivatization of 4-propyldicyclohexylanone from an important industrial raw of liquid crystal display (LCD) screens was realized. In vitro, compound 3f exhibited good activities against human colon cancer cells (HCT116) with IC50 values in 9.82 ± 0.27 μM. Further biological evaluations investigated the mechanism of the effective inhibition of cell growth, including apoptosis ratio detection, cell cycle analysis, and migration capacity of HCT116 cells. In apoptosis effect studies, complex 3f increased the percentage of apoptotic HCT116 cells to 26.8% (15 μM).

Reaction under Ball-Milling: Solvent- and Metal-Free One-Pot Diastereoselective Synthesis of Tetrahydroquinoline Derivatives as Potential Antibacterial and Anticancer Agents

AbstractA mild and efficient one-pot, three-component ball-mill-assisted reaction of aldehydes, anilines, and dihydrofuran (or dihydropyran and cyclohexenone) has been described for the first time in the presence of the catalytic amount of aqueous perchloric acid (8 mol%) at room temperature under organic solvent- and metal-free conditions. The reactions are fast (1 h), providing the products with excellent yields and high diastereoselectivity. This procedure endows a simple, efficient, and cost-effective method for the diastereoselective synthesis of furano- and pyrano-tetrahydroquinolines and phenanthridinone derivatives, which are important biological compounds. The diastereomers with cis configuration were isolated as major products. The H–H COSY, NOESY experiments and X-ray crystallographic analysis of selected compounds were performed to confirm the cis isomer. The synthesized tetrahydroquinolines have been evaluated in vitro for their antibacterial and anticancer activities, and it was found that both the prepared compounds showed significant antibacterial and anticancer properties.

Regio- and Diastereoselective Synthesis of Polysubstituted Piperidines Enabled by Boronyl Radical-Catalyzed (4+2) Cycloaddition.

Piperidines are widely present in small molecule drugs and natural products. Despite many methods have been developed for their synthesis, new approaches to polysubstituted piperidines are highly desirable. This work presents a radical (4+2) cycloaddition reaction for synthesis of piperidines featuring dense substituents at 3,4,5-positions that are not readily accessible by known methods. Using commercially available diboron(4) compounds and 4-phenylpyridine as the catalyst precursors, the boronyl radical-catalyzed cycloaddition between 3-aroyl azetidines and various alkenes, including previously unreactive 1,2-di-, tri-, and tetrasubstituted alkenes, has delivered the polysubstituted piperidines in generally high yield and diastereoselectivity. The reaction also features high modularity, atom economy, broad substrate scope, metal-free conditions, simple catalysts and operation. The utilization of the products has been demonstrated by selective transformations. A plausible mechanism, with the ring-opening of azetidine as the rate-limiting step, has been proposed based on the experimental and computational results.

Regio‐ and Diastereoselective Synthesis of Polysubstituted Piperidines Enabled by Boronyl Radical‐Catalyzed (4+2) Cycloaddition

AbstractPiperidines are widely present in small molecule drugs and natural products. Despite many methods have been developed for their synthesis, new approaches to polysubstituted piperidines are highly desirable. This work presents a radical (4+2) cycloaddition reaction for synthesis of piperidines featuring dense substituents at 3,4,5‐positions that are not readily accessible by known methods. Using commercially available diboron(4) compounds and 4‐phenylpyridine as the catalyst precursors, the boronyl radical‐catalyzed cycloaddition between 3‐aroyl azetidines and various alkenes, including previously unreactive 1,2‐di‐, tri‐, and tetrasubstituted alkenes, has delivered the polysubstituted piperidines in generally high yield and diastereoselectivity. The reaction also features high modularity, atom economy, broad substrate scope, metal‐free conditions, simple catalysts and operation. The utilization of the products has been demonstrated by selective transformations. A plausible mechanism, with the ring‐opening of azetidine as the rate‐limiting step, has been proposed based on the experimental and computational results.

Phosphazene-Catalyzed Cascade Esterification/Stereoselective Aza-Michael Addition of Chiral β-Trifluoromethyl-α,β-unsaturated N-Acylated Oxazolidin-2-ones

AbstractUpon treatment of chiral β-trifluoromethyl-α,β-unsaturated N-acylated oxazolidin-2-ones with a range of alcohols using phosphazene base as a catalyst, the unexpected cascade esterification/stereoselective aza-Michael addition was observed. The reactions proceeded with high diastereoselectivities (up to >99:1) to give a series of enantioenriched aza-Michael addition products in good to high yields. The structure and stereochemistry of the representative aza-Michael adduct were confirmed by X-ray crystal structure analysis. The plausible mechanism was proposed on the basis of the experimental results.The synthetic transformations of chiral aza-Michael addition products were also demonstrated highlighting the synthetic application of the present work.

Construction of Diverse Fused Chromene Frameworks via Isocyanide-Based Three-Component Reaction.

A convenient synthetic protocol for diverse fused chromenes was successfully developed by a three-component reaction of alkyl isocyanides, dialkyl but-2-ynedioates, and various cyclic 1,3-dipolarophiles containing o-hydroxyphenyl group. In the absence of any catalyst, the three-component reaction of alkyl isocyanides, dialkyl but-2-ynedioates, and 3-(o-hydroxyarylidene)indolin-2-ones in tetrahydrofuran at 60 °C resulted in unique functionalized spiro[cyclobuta[c]chromene-1,3'-indolines] in good yields and with high diastereoselectivity. However, the similar three-component reaction with 2-(5-halo-2-hydroxyarylidene)indolin-2-ones afforded unexpected chain products in satisfactory yields. In addition, the three-component reaction of alkyl isocyanides, dialkyl but-2-ynedioates, and 2-(o-hydroxyarylidene)-1,3-indanediones in tetrahydrofuran at 60 °C resulted in complex indeno[2',1':5,6]pyrano[3,4-c]chromene derivatives in high yields and with high diastereoselectivity.

Phosphoric Acid-Catalyzed Alkene Difunctionalization of 2-Vinylpyridines via HOMO/LUMO Biactivated Diels-Alder Reaction.

The difunctionalization of vinylpyridines based on the cyclization strategy remains rare and underdeveloped, in contrast to the well-developed hydrogen functionalization. Current exploration on [4 + 2] cyclization of vinylpyridines mainly relies on extremely high temperatures and the LUMO activation of vinylpyridines using boron trifluoride as a strong Lewis acid. Herein, we established a phosphoric acid-catalyzed [4 + 2] cyclization reaction of 3-vinyl-1H-indoles and 2-vinylpyridines by means of the LUMO/HOMO bifunctional activation model. This protocol features mild reaction conditions, high functional group tolerance, broad substrate compatibility, and high diastereoselectivity, enabling the efficient construction of various functionalized pyridine-substituted tetrahydrocarbazoles with prominent potential in drug discovery.

Regioconvergent Nucleophilic Substitutions with Morita-Baylis-Hillman Fluorides.

Lithium iodide enables regioconvergent C-F bond functionalization of isomeric Morita-Baylis-Hillman fluorides with carbon, sulfur, and nitrogen nucleophiles. The defluorinative carbon-carbon and carbon-heteroatom bond formations give multifunctional compounds in excellent yields and with good to high diastereoselectivities at room temperature. The possibility of catalytic enantioselective allylation is also discussed.

Template-Directed Selective Photodimerization Reactions of 5-Arylpenta-2,4-dienoic Acids.

We developed an efficient method that enables selective photodimerization of 5-arylpenta-2,4-dienoic acids (i.e., vinylogous cinnamic acids). The use of 1,8-dihydroxynaphthalene as a template ensures proximity of the two reacting olefins so that irradiation of template-bound dienoic acids gives mono [2 + 2] cycloaddition products in good to excellent yields (up to 99%), as single regioisomers, and with high diastereoselectivities (dr = 3:1 to 13:1). The geometrical and stereochemical features of compounds 12a, 16a, and 22a were analyzed by X-ray crystallography.

Chemoselective and Stereoselective Allylation of Bis(alkenyl)boronates

AbstractBis(alkenyl)boronates react with optically active Ir(π‐allyl) species in a process that involves allylation of the more substituted olefin and 1,2‐metalate shift of the less substituted olefin. The method constructs valuable enantioenriched tertiary allylic boronic esters with high chemoselectivity, enantioselectivity and diastereoselectivity. Allylic functionalization reactions transform the 1,3‐stereodiad to 1,5‐ and 1,6‐stereochemical relationships.

Iridium-catalysed synthesis of C,N,N-cyclic azomethine imines enables entry to unexplored nitrogen-rich 3D chemical space

Three-dimensional nitrogen-rich bridged ring systems are of great interest in drug discovery owing to their distinctive physicochemical and structural properties. However, synthetic approaches towards N–N-bond-containing bridged heterocycles are often inefficient and require tedious synthetic strategies. Here we delineate an iridium-catalysed reductive approach to such architectures from C,N,N-cyclic hydrazide substrates using IrCl(CO)[P(OPh)3]2 and 1,1,3,3-tetramethyldisiloxane (TMDS), which provided efficient access to the unstabilized and highly reactive C,N,N-cyclic azomethine imine dipoles. These species were stable and isolable in their dimeric form, but, upon dissociation in solution, reacted with a broad range of dipolarophiles in [3 + 2] cycloaddition reactions with high yields and good diastereoselectivities, enabling the direct synthesis of nitrogen-rich sp3-hybridized pyrazoline polycyclic ring systems. Density functional theory calculations were performed to elucidate the origin of the diastereoselectivity of the cycloaddition reaction, and principal moment of inertia (PMI) analysis was conducted to enable visualization of the topological information of the dipolar cycloadducts.

Chemoselective and Stereoselective Allylation of Bis(alkenyl)boronates.

Bis(alkenyl)boronates react with optically active Ir(π-allyl) species in a process that involves allylation of the more substituted olefin and 1,2-metalate shift of the less substituted olefin. The method constructs valuable enantioenriched tertiary allylic boronic esters with high chemoselectivity, enantioselectivity and diastereoselectivity. Allylic functionalization reactions transform the 1,3-stereodiad to 1,5- and 1,6-stereochemical relationships.

Desymmetrization-Addition Reaction of Cyclopropenes to Imines via Synergistic Photoredox and Cobalt Catalysis.

Herein, we designed a reaction for the desymmetrization-addition of cyclopropenes to imines by leveraging the synergy between photoredox and asymmetric cobalt catalysis. This protocol facilitated the synthesis of a series of chiral functionalized cyclopropanes with high yield, enantioselectivity, and diastereoselectivity (44 examples, up to 93% yield and >99% ee). A possible reaction mechanism involving cyclopropene desymmetrization by Co-H species and imine addition by Co-alkyl species was proposed. This study provides a novel route to important chiral cyclopropanes and extends the frontier of asymmetric metallaphotoredox catalysis.

Synthesis of Nonclassical Heteroaryl C-Glycosides via Decarboxylative C-H Glycosylation.

A photoredox-promoted decarboxylative C-H glycosylation for the synthesis of nonclassical heteroaryl C-glycosides is reported. This methodology is characterized by an exceedingly simple reaction system, high diastereoselectivity, and good functional group tolerance. Moreover, the operational procedure is simple, and the gram-scale reaction highlights the practical applicability of this protocol.

Organocatalytic Dearomative Spirocyclization Reaction of Enone-Tethered α-and β-Naphthols and Dearomatization Reaction of In Situ Generated Nitro-Olefin-Tethered α-Naphthols.

Herein, we report a catalytic dearomative spirocyclization reaction of new substrates having aryl/alkyl enone tethered α- and β-naphthols and a dearomatization reaction of in situ generated nitro-olefin-tethered α-naphthols. The spirocarbocycles were obtained in moderate to good yields with high diastereoselectivities. A preliminary catalytic asymmetric variant was reported. A few applications such as hydrogenations and epoxidation reaction have also been demonstrated. Theoretical study has also been performed to understand high diastereoselectivity in the triethylamine catalyzed spirocyclization reaction.

Diastereoselective Aldol Reaction of α‐Azido Ketones with α‐CF3 Pyruvate to Organoazides with Vicinal Tetrasubstituted Carbons

AbstractA direct diastereoselective aldol reaction of cyclic or acyclic α‐azido ketones with α‐trifluoromethyl (CF3) pyruvate catalysed by DABCO is developed, which allowed the facile access of CF3‐containing multifunctional organoazides with vicinal tetrasubstituted carbons in good to high yields and diastereoselectivities. Moreover, phenylethynyl trifluoro‐ and difluoromethyl ketones are also viable substrates. Up to 50 % enantioselectivity could be obtained in the initial exploration of the catalytic asymmetric variant.

Synthesis of Complex Tetracyclic Fused Scaffolds Enabled by (3 + 2) Cycloaddition.

We describe the single-step formation of complex tetracyclic fused scaffolds enabled by (3 + 2) cycloaddition of azomethine ylides. Various indoles, N-protecting groups, and amino acids are well tolerated. The products are obtained in a catalyst-free manner with moderate to excellent yield and high diastereoselectivity. Representing a new scaffold that is not yet found in nature, the construction of pyrrolidine-fused cyclohepta-, azepino-, or oxepinoindoles could be found valuable in the synthesis of new pseudo-natural products.

Decatungstate‐Photocatalyzed Diastereoselective Dearomative Hydroalkylation of Indoles

AbstractIn this study, we present an efficient and straightforward dearomative hydroalkylation of indoles. By utilizing alkanes or ethers as alkyl radical sources and employing TBADT as a cost‐effective photocatalyst for direct hydrogen atom transfers (HAT), we achieved successful conversion of these heterocyclic derivatives into 2‐alkylindolines with good to excellent yields and high diastereoselectivity under mild reaction conditions.

Proline-derived carboxylic acid as a bifunctional organocatalyst for highly efficient asymmetric Michael addition of aldehydes to nitroalkenes

A novel bifunctional proline amide–carboxylic acid catalyst was used for the highly stereoselective Michael reaction of various aldehydes with different nitroalkenes. This catalyst was easily prepared using commonly available anhydrides and proline linked with a diamine spacer. The asymmetric catalytic Michael reactions afforded high yields (up to 98 %), diastereoselectivities (syn/anti ratio: up to 86:14), and enantioselectivity (up to 99 % ee) when 5 mol% of the catalyst is used with N-methylmorpholine as a base in a dichloromethane solvent at room temperature.