High Regio Research Articles

Total synthesis of (-)-cylindrocyclophane A facilitated by C-H functionalization.

(-)-Cylindrocyclophane A is a 22-membered C2-symmetric [7.7]paracyclophane that bears bis-resorcinol functionality and six stereocenters. We report a synthetic strategy for (-)-cylindrocyclophane A that uses 10 C-H functionalization reactions, resulting in a streamlined route with high enantioselectivity and efficiency (17 steps). The use of chiral dirhodium tetracarboxylate catalysis enabled the C-H functionalization of primary and secondary positions, which was complemented by palladium-catalyzed C(sp2)-C(sp2) cross-couplings, resulting in the rapid formation of the macrocyclic core and all stereocenters with high regio-, diastereo-, and enantioselectivity. The use of a late-stage palladium-catalyzed fourfold C(sp2)-H acetoxylation installed the bis-resorcinol moieties. This research exemplifies how multilaboratory collaborations can produce substantial modernizations of complex total synthesis endeavors.

Silver-Mediated Allylation of Aryl Alkenes to Synthesize 1,4-Dienes.

An efficient silver-mediated allylation of aryl alkenes is described, which provides a variety of skipped 1,4-dienes.Without the need for other traditional transition metals or gold, this AgOTf-mediated allylation proceeds smoothly with high regio- and stereoselectivity. Mechanistic and computational studies suggest that this silver-mediated allylation takes place via a Friedel-Crafts-type pathway of aryl alkenes to the silver-activated allyl acetates.

Ligand-controlled regiodivergent aminocarbonylation of cyclobutanols toward 1,1- and 1,2-substituted cyclobutanecarboxamides

Four-membered carbocycles are among the most sought-after backbones which are commonly found in biologically active molecules. However, difficulties on their producing are existing due to its highly strained ring system. On the other hand, cyclobutanols can be straightforwardly prepared and can serves as precursors for synthesizing cyclobutane derivatives. Here we report an example of regioselective aminocarbonylation of cyclobutanols in which the cyclobutane core remained intact. The method exhibits good functional group compatibility, as well as high regio- and stereoselectivity, offering new pathways for synthesizing several pharmaceuticals. Furthermore, this strategy enables the rapid installation of cyclobutane as a conformational restricted skeleton, greatly facilitating direct access to valuable drug molecules that require conformational restriction.

Interrupted Michael Reaction: Sulfophosphinoylation of α,β-Unsaturated Ketones Catalyzed by Phosphine.

An efficient method for phosphine-catalyzed sulfophosphinoylation of α,β-unsaturated ketones for synthesis allylic organophosphorus compounds has been reported, in which α,β-unsaturated compounds acting as zwitterions react with electrophiles and nucleophiles to form a C-P bond and a C-O bond and obtain allylic organophosphorus with high regio- and stereoselectivity in moderate to excellent yields.

Nickel-Catalyzed Asymmetric (3 + 2) Annulations of Propargylic Carbonates and Vinylogous Donors via an Alkenylation Pathway.

The transition-metal-catalyzed alkenylation strategy of propargylic alcohol derivatives provides an efficient protocol to access multifunctional products in a double-nucleophilic attack pattern. While limited relevant asymmetric examples have been reported via palladium catalysis, here we first demonstrate that a nonprecious Ni(0)-based chiral complex can efficiently promote the tandem substitution process between propargylic carbonates and N-trifluoroethyl ketimines via consecutive aza-vinylogous activations, finally accomplishing a (3 + 2) annulation reaction to afford products embedding a 4-methylene-3,4-dihydro-2H-pyrrole framework with high regio-, diastereo-, and enantiocontrol. Their assemblies with a few all-carbon-based vinylogous precursors are also successful, and enantioenriched adducts containing a 3-methylenecyclopentene scaffold are furnished effectively. The substitution patterns for both types of substrates are substantial, and an array of synthetic elaborations is conducted to deliver more versatile architectures with high application potential. In addition, density functional theory calculations and control experiments have been conducted to rationalize the catalytic pathways and regio- and enantioselectivity control.

Divergent asymmetric reactions of α-alkenyl ketones with β,γ-alkynyl-α-imino esters enabled by chiral phosphoric acids

Divergent asymmetric synthesis provides access to a wide range of isomers from the same starting material by modifying the reaction conditions, which plays an important role in the efficient construction of a structurally diverse molecular library for structure-activity relationship studies. In this work, we present the divergent asymmetric addition of α-alkenyl ketones with β,γ-alkynyl-α-imino esters enabled by chiral phosphoric acid catalysis. Despite the challenging presence of multiple reactive sites in both components, we successfully achieved the regioselective synthesis of both α-1,2-addition α-tertiary amines and γ-1,4-addition allenes with good to high regio-, diastereo- and enantioselectivities by modifying the reaction conditions. Moreover, the stereodivergent asymmetric synthesis of the four allene stereoisomers bearing contiguous central and axial chirality was achieved by adjusting the E/Z configuration of the α-alkenyl ketone substrates.

Recyclable Pd(OAc)2/2P(3-tol)3/PEG-400 System for Regio- and Stereoselective Addition of Boronic Acids to Ynamides

AbstractPd(OAc)2/2P(3-tol)3 in poly(ethylene glycol) (PEG-400) is shown to be a highly efficient catalyst for the regio- and stereoselective addition of boronic acids to ynamides. The reaction proceeds smoothly at 70 °C with Na2CO3 as base, delivering a variety of (Z)-α,β-disubstituted enamides in good to excellent yields with high regio- and stereoselectivity. The isolation of the crude products can be facilely performed by extraction with diethyl ether and more importantly, the Pd(OAc)2/2P(3-tol)3/PEG-400 system could be readily recycled and reused more than six times without any significant loss of its catalytic efficiency.

Nickel‐Catalyzed [2+2+2] Cyclotrimerization of Alkynes and Other Unsaturated Systems: A Literature Overview

Transition metal‐catalyzed [2+2+2] cyclotrimerization provides easy access to carbocycles and heterocycles in a single operation with complete atom economy. In recent years, nickel catalysis has emerged as a powerful tool for constructing fused arenes and heteroarenes with high regio‐/chemoselectivity and functional group tolerance. This review highlights the historical perspective and advances made in recent years in nickel‐catalyzed [2+2+2] cycloadditions of alkynes, diynes, and various unsaturated systems. The catalytic activity of the nickel complexes, such as Ni‐phosphine, Ni‐NHC, Ni‐pincer, Ni‐diimine, etc, and their mechanistic insights have been thoroughly examined. Highly substituted arenes have broad applications in pharmaceuticals and soft materials. The applications of cyclotrimerization in these areas have been illustrated.

Stereoselective Synthesis of anti-2,4-Disubstituted Tetrahydrofurans via a Pd-Catalyzed Hayashi-Heck Arylation and Rh-Catalyzed Hydroformylation Sequence.

A catalytic, two-step protocol for the expedient synthesis of anti-2,4-disubstituted tetrahydrofurans is described. In the first step, an enantioselective and regioselective Pd-catalyzed Hayashi-Heck arylation was developed using (R)-hexaMeOBiphep to generate 5-aryl-2,3-dihydrofurans. A subsequent Rh-catalyzed hydroformylation step proceeds at low Rh loading with high regio- and diastereoselectivity for the anti-2,4-disubstituted tetrahydrofuran isomer. Key to the development of the hydroformylation reaction was the utilization of either (R)-Me-i-Pr-INDOLphos or (R,R)-Ph-BPE to control the regioselectivity and provide the kinetic product isomer.

Enantioselective Construction of Tetrahydroindole Skeletons by Rh‐Catalyzed [2+2+2] Cycloaddition of Homopropargyl Enamides with Alkynes

AbstractWe have developed the Rh‐catalyzed enantioselective [2+2+2] cycloaddition of homopropargyl enamides (tosylamide‐tethered 1,6‐enynes) with alkynes to construct tetrahydroindole skeletons found in natural alkaloids and pharmaceuticals. This cycloaddition proceeds at room temperature in high yields and regio‐ and enantioselectivity with a broad substrate scope. The preparative scale reaction followed by substituent conversion on the nitrogen atom and the diastereoselective [4+2] cycloaddition with singlet O2 affords hexahydroindole‐diols bearing three stereogenic centers and variable substituents on the nitrogen. Mechanistic studies have revealed that the substituents of the enynes change the ratio of intramolecular and intermolecular rhodacycle formation when using terminal alkynes, varying the ee values of the cycloadducts.

Enantioselective Construction of Tetrahydroindole Skeletons by Rh-Catalyzed [2+2+2] Cycloaddition of Homopropargyl Enamides with Alkynes.

We have developed the Rh-catalyzed enantioselective [2+2+2] cycloaddition of homopropargyl enamides (tosylamide-tethered 1,6-enynes) with alkynes to construct tetrahydroindole skeletons found in natural alkaloids and pharmaceuticals. This cycloaddition proceeds at room temperature in high yields and regio- and enantioselectivity with a broad substrate scope. The preparative scale reaction followed by substituent conversion on the nitrogen atom and the diastereoselective [4+2] cycloaddition with singlet O2 affords hexahydroindole-diols bearing three stereogenic centers and variable substituents on the nitrogen. Mechanistic studies have revealed that the substituents of the enynes change the ratio of intramolecular and intermolecular rhodacycle formation when using terminal alkynes, varying the ee values of the cycloadducts.

Papain-Mediated Conjugation of Peptide Nucleic Acids to Delivery Peptides: A Density Functional Theory/Molecular Mechanics Metadynamics Study in Aqueous and Organic Solvent.

Enzymatic peptide synthesis is a powerful alternative to solid-phase methods, as enzymes can have high regio- and stereoselectivity and high yield and require mild reaction conditions. This is beneficial in formulation research due to the rise of nucleic acid therapies. Peptide nucleic acids (PNAs) have a high affinity toward DNA and RNA, and their solubility and cellular delivery can be improved via conjugation to peptides. Here, we designed and assessed the viability of the papain enzyme to conjugate four PNA-peptide models in water and an organic solvent using QM/MM metadynamics. We found that the reactions in water yield better results, where three conjugates could potentially be synthesized by the enzyme, with the first transition state as the rate-limiting step, with an associated energy of 14.53 kcal mol-1, although with a slight endergonic profile. The results highlight the importance of considering the enzyme pockets and different substrate acceptivities and contribute to developing greener, direct, and precise synthetic routes for nucleic acid-based therapies. By exploring the enzyme's potential in conjunction with chemical synthesis, current protocols can be simplified for the synthesis of longer nucleic acids and peptide sequences (and, by extension, proteins) from smaller oligo or peptide blocks.

Chemo-, regio- and enantioselective hydroformylation of trisubstituted cyclopropenes: access to chiral quaternary cyclopropanes

Catalytic asymmetric synthesis of polysubstituted chiral cyclopropane presents a significant challenge in organic synthesis due to the difficulty in enantioselective control. Here we report a rhodium-catalyzed highly chemo-, regio- and enantioselective hydroformylation of trisubstituted cyclopropenes affording chiral quaternary cyclopropanes. Importantly, the easy made sterically bulky ligand L1 can effectively suppress hydrogenation and decomposition reactions and give quaternary cyclopropanes with high regio- and enantioselectivities for both aryl and alkyl functionalized substrates. Control experiments and computational studies reveal the sterically hindered well-defined chiral pocket instead of the substrates bearing electron-withdrawing diester groups is important for controlling the enantioselectivity and regioselectivity. Scale-up reaction and follow-up diverse transformations are also presented. Density Functional theory (DFT) computations suggest that the regio- and enantio-selectivities originate from the cyclopropene insertion to the Rh-H bond. The high regioselectivity is found to benefit from the presence of more efficient noncovalent interactions (NCIs) manifesting in the form of C–H···Cl, C–H···N, and l.p(Cl)···π contacts.

MEDT analysis of mechanism and selectivities in non-catalyzed and lewis acid-catalyzed diels–alder reactions between R-carvone and isoprene

Within the context of Molecular Electronic Density Theory (MEDT), this study investigates the Diels–Alder reaction among isoprene (2) and R-carvone (1R) applying DFT simulations, with and without Lewis acid (LA) catalysis. The results show that carvone (1R) acts as an electrophile and isoprene (2) as a nucleophile in a polar process. LA catalysis increases the electrophilicity of carvone, thereby improving the reactivity and selectivity of the reaction by reducing the activation Gibbs free energy. Parr functions reveal that the C5=C6 double bond is more reactive than the C9=C10 double bond, indicating chemoselectivity. The examination of the Electron Localization Function (ELF) reveals high regio- and stereoselectivity, indicating an asynchronous mechanism for the LA-catalyzed DA reaction. Furthermore, it is suggested that cycloadduct 3 has great anti-HIV potential because it exhibits lower binding energies than azidothymidine (AZT) in the docking studies of cycloadducts 3 and 4 amongst a primary HIV-1protein (1A8O plus 5W4Q).

Regio- and Diastereoselective Synthesis of Trisubstituted Alkenes Through Hydroalkylation of Alkynyl Boronamides.

Hydroalkylation of alkynes is a powerful method for alkene synthesis. However, regioselectivity has been difficult to achieve in transformations of internal alkynes hindering applications in the synthesis of trisubstituted alkenes. To overcome these limitations, we explored using boryl groups as versatile directing groups that can control the regioselectivity of the hydroalkylation and subsequently be replaced in a cross-coupling reaction. The result of our exploration is a nickel-catalyzed hydroalkylation of alkynyl boronamides that provides access to a wide range of trisubstituted alkenes with high regio- and diastereoselectivity. The reaction can be accomplished with a variety of coupling partners, including primary and secondary alkyl iodides, α-bromo esters, α-chloro phthalimides, and α-chloro boronic esters. Preliminary studies of the reaction mechanism provide evidence for the hydrometalation mechanism and the formation of alkyl radical intermediates.

Regio‐ and Diastereoselective Synthesis of Trisubstituted Alkenes Through Hydroalkylation of Alkynyl Boronamides

Hydroalkylation of alkynes is a powerful method for alkene synthesis. However, regioselectivity has been difficult to achieve in transformations of internal alkynes hindering applications in the synthesis of trisubstituted alkenes. To overcome these limitations, we explored using boryl groups as versatile directing groups that can control the regioselectivity of the hydroalkylation and subsequently be replaced in a cross‐coupling reaction. The result of our exploration is a nickel‐catalyzed hydroalkylation of alkynyl boronamides that provides access to a wide range of trisubstituted alkenes with high regio‐ and diastereoselectivity. The reaction can be accomplished with a variety of coupling partners, including primary and secondary alkyl iodides, α‐bromo esters, α‐chloro phthalimides, and α‐chloro boronic esters. Preliminary studies of the reaction mechanism provide evidence for the hydrometalation mechanism and the formation of alkyl radical intermediates.

Regioselective and enantioselective propargylic hydroxylations catalyzed by P450tol monooxygenases

Regioselective and enantioselective hydroxylation of propargylic C-H bonds are useful reactions but often lack appropriate catalysts. Here a green and efficient asymmetric hydroxylation of primary and secondary C–H bonds at propargylic positions has been established. A series of optically active propargylic alcohols were prepared with high regio- and enantioselectivity (up to 99% ee) under mild reaction conditions by using P450tol, while the C≡C bonds in the molecule remained unreacted. This protocol provides a green and practical method for constructing enantiomerically chiral propargylic alcohols. In addition, we also demonstrated that the biohydroxylation strategy was able to scaled up to 2.25 mmol scale with the production of chiral propargyl alcohol 2a at a yield of 196 mg with 96% ee, which’s an important synthetic intermediate of antifungal drug Ravuconazole.Graphical

Catalytic Regio- and Enantioselective Remote Hydrocarboxylation of Unactivated Alkenes with CO2.

The catalytic regio- and enantioselective hydrocarboxylation of alkenes with carbon dioxide is a straightforward strategy to construct enantioenriched α-chiral carboxylic acids but remains a big challenge. Herein we report the first example of catalytic highly enantio- and site-selective remote hydrocarboxylation of a wide range of readily available unactivated alkenes with abundant and renewable CO2 under mild conditions enabled by the SaBOX/Ni catalyst. The key to this success is utilizing the chiral SaBOX ligand, which combines with nickel to simultaneously control both chain-walking and the enantioselectivity of carboxylation. This process directly furnishes a range of different alkyl-chain-substituted or benzo-fused α-chiral carboxylic acids bearing various functional groups in high yields and regio- and enantioselectivities. Furthermore, the synthetic utility of this methodology was demonstrated by the concise synthesis of the antiplatelet aggregation drug (R)-indobufen from commercial starting materials.

Ligand Effects in Carboxylic Ester- and Aldehyde-Assisted β-C-H Activation in Regiodivergent and Enantioselective Cycloisomerization-Hydroalkenylation and Cycloisomerization-Hydroarylation, and [2 + 2 + 2]-Cycloadditions of 1,6-Enynes.

Herein, we report room temperature, atom-economic protocols for high regio- and enantioselective tandem cycloisomerization-hydroarylation and cycloisomerization-hydroalkenylation of 1,6-enynes leading to vicinal carba-functionalized pyrrolidines, tetrahydrofurans, and cyclopentanes. The latter steps in these processes involve carbonyl-coordination-assisted ortho-C-H activation of aromatic aldehydes and esters, and, a similar, yet rarely seen, β-C-H activation in the case of the acrylates. Synthetically useful enantioselective versions of such reactions are rare and are limited to the C2-H activation of indoles and pyrroles. A similar reaction is also observed with N-vinylphthalimide, which also has a carbonyl group suitable for C-H activation. A dibenzooxaphosphole ligand, (2S,2S',3S,3S')-MeO-BIBOP was uniquely identified as crucial to achieving the challenging regio- and enantioselectivity. This methodology gives access to substituted five-membered carbo- and heterocyclic compounds in good yields and excellent enantioselectivities under a low catalyst loading. A primary KIE of 3.5 is observed in an intermolecular competition experiment with methyl benzoate and d5-methyl benzoate, which indicates that the C-H cleavage is the turnover-limiting step of this process. Unlike the acrylates, which undergoes exclusive hydroalkenylation, a β, γ-unsaturated ester, methyl but-3-enoate, undergoes the highly enantioselective cycloisomerization-coupling sequence with a 1,6-enyne giving either a [2 + 2 + 2]-cycloaddition with (S, S)-BDPP or hydroalkenylation with (2S,2'S,3S,3'S)-MeO-BIBOP depending on the ligand employed. The (E)-configuration of the newly formed double bond at the terminal alkynyl carbon (of the starting enyne) in the hydroalkenylation product of β,γ-unsaturated ester suggests a more classical migratory insertion-β-hydride elimination route for the formation of this product.

Copper-Catalyzed Directed Hydroindolation/Annulation Sequence of Alkynes with Indoles via Copper Carbenes.

Described herein is an efficient copper-catalyzed tandem alkyne indolylcupration-initiated 1,2-indole migration/6π-electrocyclic reaction of allene-ynamides with indoles by the in situ-generated metal carbenes. This method allows the efficient synthesis of valuable indole-fused spirobenzo[f]indole-cyclohexanes with high regio- and stereoselectivity. In addition, this reaction affords rapid access to the functionalized spirobenzo[f]indole-cyclohexanes in the absence of indoles by a presumable 5-exo-dig cyclization/Friedel-Crafts alkylation via copper-containing all-carbon 1,4-dipoles.