Search

Although (+)-catharanthine is an attractive alkaloid for both clinical research and organic synthetic chemistry, only a limited number of approaches for its catalytic asymmetric synthesis exist. Herein, we describe a novel strategy for synthesizing a chiral intermediate of (+)-catharanthine via phosphoric acid-catalyzed asymmetric desymmetrization of a meso-isoquinuclidine possessing a 1,3-diol unit that was synthesized by a formal amide insertion reaction.

The enantioselective formal synthesis of (−)-aurantioclavine is described. The core tricyclic skeleton was synthesized using a Pd-catalyzed Heck insertion–allylic amination cascade. The stereocenter was constructed by a highly enantioselective organocatalytic asymmetric aziridination reaction.

This account describes the development of novel dearomatization reactions of phenols using transition-metal-catalyzed ipso-Friedel–Crafts-type processes. In general, phenols function as O-nucleo­philes in transition-metal-catalyzed allylic substitution reactions, providing the corresponding aryl ethers. We found that, however, an intramolecular ipso-Friedel–Crafts allylic alkylation of phenols proceeded smoothly in the presence of a palladium catalyst, producing various spiro[4.5]cyclohexadienone derivatives. This finding led us to launch detailed investigations into this type of reaction. Pd-catalyzed intramolecular Friedel–Crafts allylic alkylation of phenols was next examined to synthesize 10-vinyl 9,10-dihydrophenanthrene derivatives. This reaction was successfully extended to a catalytic asymmetric process. We also developed a novel synthetic method for spiro[5.5]cyclohexadienones based on a Pd-catalyzed intramolecular ipso-Friedel–Crafts-type addition of phenols to η3-propargylpalladium(II) intermediates. Mechanistic studies revealed that the present reaction proceeds through a rearomatization-assisted oxidative addition. Moreover, a Au-catalyzed intramolecular ipso-Friedel–Crafts alkenylation of phenols with a terminal alkyne is discussed. 1 Introduction 2 Pd-Catalyzed Intramolecular Friedel–Crafts Allylic Alkylation of Phenols 2.1 Synthesis of Spirocyclohexadienone Derivatives by Pd-Catalyzed Intramolecular ipso-Friedel–Crafts Allylic Alkylation of Phenols 2.2 Mechanistic Considerations 2.3 Application to Cascade Reaction Processes 2.4 Asymmetric Synthesis of Dihydrophenanthrene Derivatives by Pd-Catalyzed Asymmetric Intramolecular Friedel–Crafts Allylic Alkylation of Phenols 3 Dearomatization of Phenols by Activation of Propargyl Carbonates with a Pd Catalyst 4 Au-Catalyzed Intramolecular ipso-Friedel–Crafts Alkenylation of Phenols 5 Summary and Outlook

A synthetic study of pactamycin is described. Enantioselective construction of the aminocyclopentitol core of pactamycin bearing five contiguous stereocenters was achieved based on an organocatalytic asymmetric aziridination of 2-cyclopentene-1-one, a regio- and diastereoselective 1,3-dipolar cycloaddition, and a rhodium-catalyzed C-H amination reaction.

We developed a highly effective organocatalytic system for asymmetric aziridination of cyclic enones. Catalytic asymmetric aziridination of 2-cyclopenten-1-one with t-butyl p-toluenesulfonyloxy carbamate proceeded using 20 mol % of (1R,2R)-1,2-diphenylethylenediamine derivative with an N-4,4-dimethylcyclohexyl group 1h, producing chiral aziridine ketone (1R,5R)-4 in 82% yield with 99% ee. Organocatalyst 1h was also an effective catalyst for the asymmetric aziridination of other cyclic enones. The obtained chiral aziridine ketone (1R,5R)-4 could be successfully transformed into the key intermediate for the synthesis of (−)-allosamizoline, demonstrating the utility of this asymmetric aziridination for the synthesis of aminocyclopentitol derivatives.

A formal synthesis of anatoxin-a was accomplished by using rhodium-catalyzed formal amide insertion reaction. The key reaction was performed on a gram scale using 0.4 mol % of Rh 2 (NHCO t Bu) 4 catalyst, affording a 9-azabicyclo[4.2.1]nonane derivative in good yield. The nitrogen-bridged molecule was converted to Wiseman's intermediate through diastereoselective reduction, site-selective deoxygenation and functional group interconversions.

A novel platinum-catalyzed cascade cyclization reaction was developed by intramolecular Friedel-Crafts-type C-H coupling of aniline derivatives with a propargyl carbonate unit-allylic amination sequence. Treatment of various propargyl carbonates tethered to meta-aniline derivatives with a Pt(dba)3/DPEphos catalyst system afforded the corresponding 3,4-fused tricyclic 3-alkylidene indolines in 42-99% yield, which were transformed into 3,4-fused indole derivatives by reaction with trifluoroacetic acid. The reaction products exhibited antiproliferative activities against cancer cells, but not normal cells, revealing the potential usefulness of this reaction for medicinal chemistry.

We previously reported a synthetic method of spirocyclohexadienones using an Pd-catalyzed intramolecular ipso-Friedel–Crafts allylic alkylation of para-substituted phenol derivatives. However, the mechanism for the step leading to spirocyclization and driving force behind the remarkably easier formation of the five-membered spirocyclohexadienone as compared with the six-membered spirocyclohexadienone were unclear. Herein, detailed density functional theory (DFT) calculations for the spirocyclization were performed to obtain a plausible reason for the observed behavior. In addition, the mechanistic basis of the characteristic ortho-selectivity in the related Pd-catalyzed intramolecular Friedel–Crafts allylic alkylation of meta-substituted phenol derivatives was elucidated. DFT calculations and experimental studies revealed that the ortho-selective allylation proceeded via an unexpected eleven-membered oxapalladacycle-mediated intramolecular Friedel–Crafts type process.

We have developed a novel method for synthesizing trisubstituted cyclopropane derivatives by a palladium-catalyzed intramolecular allylic alkylation of α-aryl esters. By using α-aryl α-(methoxycarbonyl) γ-vinyl γ-lactones as substrates, decarboxylative formation of π-allylpalladium(II) intermediates followed by an intramolecular allylic alkylation of the ester enolates proceeded in the presence of 5 mol% of a palladium catalyst, producing 1-aryl-1-(methoxycarbonyl)-2-vinylcyclopropanes in good to excellent yields and high diastereoselectivities. The relative configuration of the major isomer was determined by transforming the product into a known intermediate of milnacipran synthesis. When we extended our method to asymmetric catalysis, we obtained methyl (1S,2S)-1-phenyl-2-vinylcyclopropanecarboxylate in up to 55% ee by using (S)-[2′-(diphenylmethoxy)-1,1′-binaphthalen-2-yl](diphenyl)phosphine as a chiral monodentate phosphorus ligand.

Gephyrotoxin 287C, a bioactive alkaloid bearing a perhydropyrrolo[1,2-a]quinoline skeleton with five stereocenters, is an attractive target for synthetic organic chemistry. We achieved an enantioselective total synthesis of (+)-gephyrotoxin 287C, for which the key steps were palladium-catalyzed asymmetric allylic amination using a chiral diaminophosphine oxide (DIAPHOX) preligand, diastereoselective intramolecular Mannich reaction, and tin tetrachloride-catalyzed diastereoselective conjugate addition/protonation.

In this study, the fluidization characteristics for fine cohesive powders under mechanical vibrating conditions were experimentally investigated. In a case of handling of fine cohesive powders with fluidized bed, stable gas channels and cracks were easily formed in the bed due to the strong cohesiveness acting among particles. A mechanical vibration is one of the methods to improve the fluidity of fine cohesive powders. In this study, we focused on the transition of the dominant bed flow pattern induced by mechanical bed vibrating conditions. The powders used in this study were different sizes (0.7 – 20 μm) and materials (silica, alumina, polymer). All powders belonged to group-C in the Geldart classification. The bed expansion ratio was lower in the relatively smaller vibration strengths regardless of the gas velocity, however, it steeply increased with larger a certain vibration strength. Form the visual observation of the bed, the bubble formation appeared with larger than such a critical vibration strength. This implied that the dominant bed fluidization pattern was transitioned from channeling behavior (group-C) to bubbling behavior (group-A or –AC) by the addition of the mechanical vibration.

Functionalized quinolizidin-4-ones and indolizidin-3-ones were synthesized from mixed N,O-acetals with a terminal alkyne unit and nucleophiles with two reactive sites by a gold(I)/Bronsted acid relay catalysis with 40–90% yield. The reactions are proposed to proceed through gold-catalyzed carboalkoxylation of the alkynes with the internal mixed N,O-acetals, giving the corresponding cyclic enols, which are transformed to spirocyclic compounds by a Bronsted acid catalyst. The latter spirocyclization process occurs under thermodynamic control, providing polycyclic quinolizidin-4-one and indolizidin-3-one derivatives diastereoselectively.

We developed a novel synthetic method of the core structure of dragmacidin E bearing a 7-membered ring-fused bis(indolyl)pyrazinone skeleton. Formation of the 7-membered ring-fused tricyclic indole skeleton was accomplished using a palladium-catalyzed Heck insertion–allylic amination cascade. Vicinal difunctionalization of the 7-membered ring was realized via a rhodium-catalyzed aminoacetoxylation.

Herein we report an enantioselective synthesis of ( R )-Sumanirole wherein an organocatalytic asymmetric aziridination of 2-nitrocinnamaldehyde was the key step.

A new method to synthesize spiro[4.5]cyclohexadienone derivatives with an exo-cyclic olefin unit is developed.

We developed a novel method for synthesizing fused-tricyclic indole derivatives with a 3-aminomethyl indole motif through a reaction cascade involving ipso -Friedel–Crafts alkylation of phenols, rearomatization of the spirocyclohexadienone unit, and iso -Pictet–Spengler reaction. Using TFA as an acid promoter, six-, seven-, and eight-membered ring-fused indoles were obtained in 31–99% yield.

This review describes our recent works on the diastereo- and enantioselective synthesis of anti-β-hydroxy-α-amino acid esters using transition-metal-chiral-bisphosphine catalysts. A variety of transition metals, namely ruthenium (Ru), rhodium (Rh), iridium (Ir), and nickel (Ni), in combination with chiral bisphosphines, worked well as catalysts for the direct anti-selective asymmetric hydrogenation of α-amino-β-keto ester hydrochlorides, yielding anti-β-hydroxy-α-amino acid esters via dynamic kinetic resolution (DKR) in excellent yields and diastereo- and enantioselectivities. The Ru-catalyzed asymmetric hydrogenation of α-amino-β-ketoesters via DKR is the first example of generating anti-β-hydroxy-α-amino acids. Complexes of iridium and axially chiral bisphosphines catalyze an efficient asymmetric hydrogenation of α-amino-β-keto ester hydrochlorides via dynamic kinetic resolution. A homogeneous Ni-chiral-bisphosphine complex also catalyzes an efficient asymmetric hydrogenation of α-amino-β-keto ester hydrochlorides in an anti-selective manner. As a related process, the asymmetric hydrogenation of the configurationally stable substituted α-aminoketones using a Ni catalyst via DKR is also described.

Formal meta-specific intramolecular Friedel–Crafts allylic alkylation of phenols was achieved based on spirocyclization–dienone–phenol rearrangement cascades. Systematic screening of acid catalysts revealed that Sc(OTf)3 was a highly effective catalyst for dienone–phenol rearrangement of spiro[4.5]cyclohexadienones. Using 5 mol % of Sc(OTf)3 as the promoter, various spirocyclic substrates were transformed into the corresponding phenol derivatives in good to excellent yield. Furthermore, the one-pot sequential spirocyclization–dienone–phenol rearrangement proceeded using a palladium and scandium multi-catalytic system or a triphenylmethyl cation single-catalyst system, providing the corresponding meta-allylated phenol derivatives in excellent yield.

A novel method for synthesizing 4,5-fused tricyclic quinoline derivatives based on an acid-promoted intramolecular Friedel–Crafts allenylation of anilines. Using aryl group-substituted propargyl alcohol derivatives with a meta-substituted N-Boc aniline unit as substrates, a four-step reaction sequence involving an acid-promoted intramolecular Friedel–Crafts allenylation of anilines, an acid-promoted intramolecular C–N bond formation, deprotection of the Boc group, and air oxidation proceeded in a single pot, producing the corresponding 4,5-fused tricyclic quinoline derivatives in 31–84% yield.

A novel and efficient synthetic method for functionalized spiro[4.5]cyclohexadienones was developed based on the palladium-catalyzed sequential process: Heck insertion to an allene–intramolecular ipso-Friedel–Crafts allylic alkylation cascade. Using 5 mol% of palladium catalyst, a wide variety of spirocycles was obtained in good to excellent yields. The developed cascade process was also applicable to the synthesis of tetrahydronaphthalene derivatives.

We report the first enantioselective total syntheses of cedrelin A and methylated paralycolin B, wherein Pd-catalyzed asymmetric intramolecular Friedel–Crafts allylic alkylation of phenols was the key step.

We developed a novel synthetic method for allenyl spiro[4.5]cyclohexadienone derivatives based on a base-promoted intramolecular ipso-Friedel–Crafts addition of phenols to propargyl bromides. The present spirocyclization proceeded in a CH2Cl2–tert-BuOH mixed solvent system using potassium tert-butoxide as the base, and produced the corresponding spiro[4.5]cyclohexadienone derivatives with an allene motif in up to 99% yield. This-type allenyl spirocycle was also accessible through Pd-catalyzed intramolecular ipso-Friedel–Crafts alkylation when a propargyl carbonate derivative with a naphthol unit was used as a substrate. Acid-promoted skeletal rearrangement of the reaction adducts was also examined.

A novel method for synthesizing 3-arylpyrrolidine and 4-arylpiperidine derivatives through an acid-promoted skeletal rearrangement is described. Using trifluoroacetic acid as the acid promoter, an intramolecular ipso -Friedel–Crafts-type addition of phenols to allyl cations, formation of iminium cations through rearomatization of the spirocyclohexadienone units, and an intramolecular aza-Prins reaction, proceeded sequentially to afford 3-arylpyrrolidine and 4-arylpiperidine derivatives in good yield with high diastereoselectivity.

For the total synthesis of novel cyclodepsipeptide homophymine A, (2R,3R,4R)-2-amino-3-hydroxy-4,5-dimethylhexanoic acid was successfully synthesized by Evans' asymmetric alkylation and the anti-selective asymmetric hydrogenation of a chiral α-amino-β-keto ester as the key steps.

We have developed a novel method for synthesizing trisubstituted cyclopropane derivatives by a palladium-catalyzed intramolecular allylic alkylation of α-aryl esters. By using α-aryl α-(methoxycarbonyl) γ-vinyl γ-lactones as substrates, decarboxylative formation of π-allylpalladium(II) intermediates followed by an intramolecular allylic alkylation of the ester enolates proceeded in the presence of 5 mol% of a palladium catalyst, producing 1-aryl-1-(methoxycarbonyl)-2-vinylcyclopropanes in good to excellent yields and high diastereoselectivities. The relative configuration of the major isomer was determined by transforming the product into a known intermediate of milnacipran synthesis. When we extended our method to asymmetric catalysis, we obtained methyl (1S,2S)-1-phenyl-2-vinylcyclopropanecarboxylate in up to 55% ee by using (S)-[2′-(diphenylmethoxy)-1,1′-binaphthalen-2-yl](diphenyl)phosphine as a chiral monodentate phosphorus ligand.

The Rh-catalyzed formal carbenoid insertion into an amide C—N bond delivers azabicyclo[X.Y.Z.]alkane derivatives in good to high yields and proceeds via the formation of Rh-associated N-ylides, followed by an acyl group-selective Stevens [1,2]-shift through a concerted addition/elimination process on the sp2-hybridized carbon.

A novel catalytic asymmetric synthetic method for making spirocyclohexadienones with an all-carbon quaternary spirocenter was developed based on the Pd-catalyzed intramolecular ipso -Friedel–Crafts allylic alkylation of phenols. When 5 mol % of the Pd catalyst and 12 mol % of (−)-9-NapBN (−)- 3e were used, the spirocyclic adduct was obtained with up to 93% ee, albeit with low chemical yield. On the other hand, when using 6 mol% of the Trost ligand ( R , R )- 3k , the spirocyclic adducts were obtained in good yields with up to 89% ee (diastereoselectivity = 9.2:1).

A novel method of the enantioselective synthesis of 2-substitutedhexahydroquinolin-4-ones is described. The method relies on a Pd-catalyzedasymmetric allylic amination using a chiral diaminophosphine oxide(DIAPHOX) preligand and diastereoselective intramolecular Mannichreaction. The developed synthetic method could be applied to thecatalytic asymmetric synthesis of (+)-2- EPI- CIS-195A.

Novel chiral hydrogen bond donor catalysts based on a 4,5-diamino-9,9′-dimethylxanthene skeleton were designed and synthesized. Among the phenylurea-amide hybrid molecules prepared from various natural/unnatural chiral amino acids, the phenylalanine-derived catalyst, and the proline-derived catalyst were successfully applied to enantioselective conjugate addition of 1,3-dicarbonyl compounds to nitroalkenes. Using 2-acetylcyclopentanone and 2-methoxycarbonylcyclopentanone as prochiral nucleophiles, asymmetric conjugate addition to β-aryl nitroalkenes proceeded with good diastereoselectivity to provide the corresponding products bearing an all-carbon quaternary stereocenter in excellent yield with up to 95% ee.

This review describes the development of a new class of chiral secondary phosphine oxide preligands: Amino acid-derived P-chiral diaminophosphine oxides, DIAPHOXs, and their application to several transition metal-catalyzed asymmetric reactions. The Pd-DIAPHOX catalyst system was successfully applied to enantioselective construction of quaternary stereocenters through Pd-catalyzed asymmetric allylic alkylation with β-keto esters as prochiral nucleophiles, asymmetric allylic substitutions with nitromethane, asymmetric allylic amination with various substrates, and enantioselective synthesis of axially chiral allenes. Ir-catalyzed asymmetric allylic amination and alkylation of terminal allylic carbonates were also examined using structurally optimized DIAPHOX preligands, and the corresponding branched products were obtained in a highly regio- and enantioselective manner. Furthermore, the developed processes were successfully applied to the enantioselective synthesis of biologically active compounds.

The Shi-type epoxidation of O-tert-butyldiphenylsilyl (TBDPS) protected o-allylphenols serves as an efficient strategy to construct the dihydrobenzofurans and dihydrobenzopyrans in up to 97% ee. This methodology led to the enantioselective synthesis of (+)-marmesin, (−)-(3′R)-decursinol, and (+)-lomatin.

The first enantioselective total synthesis of tangutorine has been achieved, wherein a Pd-catalyzed asymmetric allylic amination using a chiral diaminophosphine oxide (DIAPHOX) preligand was the key step.

(2S,3R)- and (2R,3R)-2,3-Diaminobutanoic acid (Dab) derivatives were efficiently synthesized from Cbz-(R)-alanine using the proline-catalyzed diastereoselective α-hydrazination reaction and the SmI2-promoted reductive cleavage of the N–N bond as the key steps.

An enantioselective synthesis of allenes through palladium-catalyzed asymmetric allylic alkylation using a chiral diaminophosphine oxide is described. The asymmetric allylic alkylations proceeded in the presence of a catalytic amount of lithium acetate at 4 °C, affording the chiral allenes in excellent yield with up to 99% ee.

An organocatalytic enantioselective aziridination reaction of α,β-unsaturated aldehydes including aromatic substrates using N-arenesulfonyloxycarbamates in the presence of diphenylprolinol triethylsilyl ether and sodium carbonate or sodium acetate is described.

The asymmetric hydrogenation of α-amino-β-keto esters using ruthenium (Ru) anti -selectively proceeds via a dynamic kinetic resolution to afford anti -β-hydroxy-α-amino acids with high enantiomeric purities, which are important chiral building blocks for the synthesis of medicines and natural products. A mechanistic investigation has revealed that the Ru-catalyzed asymmetric hydrogenation takes place via the hydrogenation of the double bond in the enol tautomer of the substrate.

The martinelline chiral core 3 and its diastereomer were synthesized by using the asymmetric tandem Michael–aldol reaction as the key step from 4-methoxycarbonylanthranilaldehyde and the α,β-unsaturated aldehyde.

Asymmetric allylic aminations with aromatic amine nucleophiles using Pd–DIAPHOX catalyst systems are described. The asymmetric allylic aminations of various allylic carbonates proceeded using 2–5 mol % of the catalyst and BSA, providing the corresponding N-aryl chiral allylic amines in up to 99% ee for cyclic substrates, and in up to 97% ee for acyclic substrates.

A Pd-catalyzed asymmetric allylic alkylation of 2-substituted cycloalkenyl carbonates using a chiral diaminophosphine oxide is described. Asymmetric allylic substitution of various cyclic substrates proceeded using 5 mol % of Pd catalyst, 10 mol % of (S,RP)-Ph-DIAPHOX 1, 10 mol % of LiOAc, and N,O-bis(trimethylsilyl)acetamide (BSA), to afford the corresponding products in excellent yields with up to 92% ee.

Asymmetric hydrogenation of α-amino-β-keto esters using ruthenium (Ru), rhodium (Rh), and iridium (Ir)-chiral phosphine catalysts proceeds anti-selectively through dynamic kinetic resolution to afford anti-β-hydroxy-α-amino acids with high enantiomeric purity, which are important intermediates for the synthesis of medicines and natural products. The mechanistic investigation has revealed that the Ru-catalyzed asymmetric hydrogenation takes place through the hydrogenation of the double bond in the enol tautomer of the substrate and the Rh- and Ir-catalyzed asymmetric hydrogenations proceed through the reduction of the keto tautomer of the substrate.

The synthesis of novel P-stereogenic phenylphosphonamides 3 and 11 via an intramolecular nucleophilic substitution of P-stereogenic phosphoramide 8 is described. These compounds were used as chiral Lewis basic catalysts for the asymmetric allylation of benzaldehyde, providing the corresponding homoallylic alcohol derivatives in up to 54% ee.

Synthesis of 2,6-dimethyl-9-aryl-9-phosphabicyclo[3.3.1]nonanes from 1,5-cyclooctadiene and their application to asymmetric cyclization leading to chiral tetrahydroquinolines and relatives through palladium-catalyzed allylic alkylation are described.

Various nitrogen-bridged bicyclic skeletons are found in bioactive natural products and pharmaceuticals. The development of a new reaction to construct these molecular frameworks has attracted considerable attention in synthetic organic chemistry. We developed a novel synthetic method for obtaining a wide variety of nitrogen-bridged bicyclic compounds with a catalytic process, Rh-catalyzed formal carbenoid insertion into an amide C-N bond. Using 0.1-0.4 mol % Rh2(NHCO(t)Bu)4 catalyst, various azabicyclo[X.Y.Z]alkane derivatives were obtained in good to excellent yield, successfully demonstrating the broad substrate scope of the developed process. Experimental and computational studies to elucidate the reaction mechanism revealed that the formal insertion reaction of a carbenoid into an amide C-N bond proceeded via the formation of Rh-associated N-ylides, followed by an acyl group-selective Stevens [1,2]-shift through a concerted addition/elimination process on the sp(2)-hybridized carbon.

A novel protocol for the cascade cyclization of allenes derivatives to form three types of 3,4-fused tricyclic indoles is reported.