Copper(I)‐Catalyzed Asymmetric [3+2]‐Cycloaddition of α‐Substituted Iminoesters with α‐Trifluoromethyl α,β‐Unsaturated Esters

Reported herein is an example of highly regio‐, diastereo‐ and enantioselective Cu(I)‐catalyzed intermolecular [3+2] cycloaddition reaction of α‐substituted iminoesters with α‐trifluoromethyl α,β‐unsaturated esters. This novel strategy provided a facile access to pyrrolidines with two skipped (aza)quaternary stereocenters including a CF₃ all‐carbon quaternary stereocenter. A broad substrate scope was observed and high yields (up to 94%) with excellent diastereoselectivity (up to >20 : 1 d.r.) and enantioselectivity (up to 98% ee) were obtained.     

A Copper(I)‐Catalyzed Enantioselective γ‐Boryl Substitution of Trifluoromethyl‐Substituted Alkenes: Synthesis of Enantioenriched γ,γ‐gem‐Difluoroallylboronates

The first catalytic enantioselective γ‐boryl substitution of CF₃‐substituted alkenes is reported. A series of CF₃‐substituted alkenes was treated with a diboron reagent in the presence of a copper(I)/Josiphos catalyst to afford the corresponding optically active γ,γ‐gem‐difluoroallylboronates in high enantioselectivity. The thus obtained products could be readily converted into the corresponding difluoromethylene‐containing homoallylic alcohols using highly stereospecific allylation reactions.     

B(C6F5)3/Chiral Phosphoric Acid Catalyzed Ketimine–Ene Reaction of 2‐Aryl‐3H‐indol‐3‐ones and α‐Methylstyrenes

The enantioselective ketimine–ene reaction is one of the most challenging stereocontrolled reaction types in organic synthesis. In this work, catalytic enantioselective ketimine–ene reactions of 2‐aryl‐3H‐indol‐3‐ones with α‐methylstyrenes were achieved by utilizing a B(C₆F₅)₃/chiral phosphoric acid (CPA) catalyst. These ketimine–ene reactions proceed well with low catalyst loading (B(C₆F₅)₃/CPA=2 mol %/2 mol %) under mild conditions, providing rapid and facile access to a series of functionalized 2‐allyl‐indolin‐3‐ones with very good reactivity (up to 99 % yield) and excellent enantioselectivity (up to 99 % ee). Theoretical calculations reveal that enhancement of the acidity of the chiral phosphoric acid by B(C₆F₅)₃ significantly reduces the activation free energy barrier. Furthermore, collective favorable hydrogen‐bonding interactions, especially the enhanced N?H???O hydrogen‐bonding interaction, differentiates the free energy of the transition states of CPA and B(C₆F₅)₃/CPA, thereby inducing the improvement of stereoselectivity.     

Chemoselectivity Control in the Asymmetric Hydrogenation of γ‐ and δ‐Keto Esters into Hydroxy Esters or Diols

The asymmetric hydrogenation of aromatic γ‐ and δ‐keto esters into optically active hydroxy esters or diols under the catalysis of a novel DIPSkewphos/3‐AMIQ–Ru^II complex was studied. Under the optimized conditions (8 atm H₂ , Ru complex/t‐C₄H₉OK=1:3.5, 25 °C) the γ‐ and δ‐hydroxy esters (including γ‐lactones) were obtained quantitatively with 97–99 % ee. When the reaction was conducted under somewhat harsh conditions (20 atm H₂ , [t‐C₄H₉OK]=50 mm , 40 °C), the 1,4‐ and 1,5‐diols were obtained predominantly with 95–99 % ee. The reactivity of the ester group was notably dependent on the length of the carbon spacer between the two carbonyl moieties of the substrate. The reaction of β‐ and ?‐keto esters selectively afforded the hydroxy esters regardless of the reaction conditions. This catalyst system was applied to the enantioselective and regioselective (for one of the two ester groups) hydrogenation of a γ‐?‐diketo diester into a trihydroxy ester.     

A Novel Asymmetric Synthesis of 3‐(1H‐Pyrrol‐1‐yl)‐Substituted β‐Lactams via a Bismuth Nitrate‐Catalyzed Reaction

The reaction of racemic α‐keto β‐lactams 5a – 5c with the commercially available chiral compound trans‐4‐hydroxy‐L ‐proline ( 6 ) in the presence of a catalytic amount of Bi(NO₃)₃?5 H₂O in EtOH gave a diastereoisomer mixture of β‐lactams with a pyrrole ring at C(3) ( 7 to 12 ). This is the first enantioselective synthesis of optically active β‐lactams (=azetidin‐2‐ones) that possess a pyrrolyl residue at C(3), in a single step.     

Enantioselective Synthesis of α‐Hydroxy Amides and β‐Amino Alcohols from α‐Keto Amides

Synthesis of enantiomerically enriched α‐hydroxy amides and β‐amino alcohols has been accomplished by enantioselective reduction of α‐keto amides with hydrosilanes. A series of α‐keto amides were reduced in the presence of chiral Cu^II/(S)‐DTBM‐SEGPHOS catalyst to give the corresponding optically active α‐hydroxy amides with excellent enantioselectivities by using (EtO)₃SiH as a reducing agent. Furthermore, a one‐pot complete reduction of both ketone and amide groups of α‐keto amides has been achieved using the same chiral copper catalyst followed by tetra‐n‐butylammonium fluoride (TBAF) catalyst in presence of (EtO)₃SiH to afford the corresponding chiral β‐amino alcohol derivatives.     

Secondary Amine‐Catalyzed Asymmetric γ‐Alkylation of α‐Branched Enals via Dienamine Activation

The direct and enantioselective γ‐alkylation of α‐substituted α,β‐unsaturated aldehydes proceeding under dienamine catalysis is described. We have found that the Seebach modification of the diphenyl‐prolinol silyl ether catalyst in combination with saccharin as an acidic additive promotes an S_N1 alkylation pathway, while ensuring complete γ‐site selectivity and a high stereocontrol. Theoretical and spectroscopic investigations have provided insights into the conformational behavior of the covalent dienamine intermediate derived from the condensation of 2‐methylpent‐2‐enal and the chiral amine. Implications for the mechanism of stereoinduction are discussed.     

Microwave‐Assisted Synthesis of β‐Lactams and Cyclo‐β‐dipeptides

Different cyclo‐β‐dipeptides were prepared from corresponding N‐substituted β‐alanine derivatives under mild conditions using PhPOCl₂ as activating agent in benzene and Et₃N as base. To evaluate β³‐substituent influence, the amino acids 7 – 26 were synthesized, and a β‐lactam formation reaction was carried out instead of cyclo‐β‐dipeptide formation. The crystal structures of three derivatives of cyclo‐β‐peptides and one β‐lactam are presented.     

Enantioselective synthesis of 3‐amino‐1‐aryl‐1H‐benzo[f]chromene‐2‐carbonitrile derivatives by Fe3O4@PS‐arginine as an efficient chiral magnetic nanocatalyst

A novel chiral magnetic nanocatalyst was prepared by the surface modification of Fe₃O₄ magnetic nanoparticles (MNPs) with a chloropropylsilane and further by arginine to form Fe₃O₄@propylsilan‐arginine (Fe₃O₄@PS‐Arg). After the structural confirmation of Fe₃O₄@PS‐Arg synthesized MNPs by Fourier transform‐infrared, X‐ray diffraction, field emission‐scanning electron microscopy, transmission electron microscopy, vibrating‐sample magnetometry and thermogravimetric analyses, their catalytic activity was evaluated for one‐pot enantioselective synthesis of 3‐amino‐1‐aryl‐1H‐benzo[f]chromene‐2‐carbonitrile derivatives. The results showed that in the presence of 0.07 g Fe₃O₄@PS‐Arg nanocatalyst and ethanol as solvent, the best reaction yield (96%) was obtained in the least time (5 min). Easy operation, reusability and stability, short reaction time, high reaction yields and good enantioselectivity are the major advantages of the newly synthesized nanocatalyst. Also, this study provides a novel strategy for further research and investigation on the synthesis of new reusable enantioselective catalysts and chiral compounds.     

Chemo‐ and Enantioselective Oxidative α‐Azidation of Carbonyl Compounds

We report high‐performance I⁺/H₂O₂ catalysis for the oxidative or decarboxylative oxidative α‐azidation of carbonyl compounds by using sodium azide under biphasic neutral phase‐transfer conditions. To induce higher reactivity especially for the α‐azidation of 1,3‐dicarbonyl compounds, we designed a structurally compact isoindoline‐derived quaternary ammonium iodide catalyst bearing electron‐withdrawing groups. The nonproductive decomposition pathways of I⁺/H₂O₂ catalysis could be suppressed by the use of a catalytic amount of a radical‐trapping agent. This oxidative coupling tolerates a variety of functional groups and could be readily applied to the late‐stage α‐azidation of structurally diverse complex molecules. Moreover, we achieved the enantioselective α‐azidation of 1,3‐dicarbonyl compounds as the first successful example of enantioselective intermolecular oxidative coupling with a chiral hypoiodite catalyst.     

Highly Enantioselective Formation of α‐Allyl‐α‐Arylcyclopentanones via Pd‐Catalysed Decarboxylative Asymmetric Allylic Alkylation

A highly enantioselective Pd‐catalysed decarboxylative asymmetric allylic alkylation of cyclopentanone derived α‐aryl‐β‐keto esters employing the (R,R)‐ANDEN‐phenyl Trost ligand has been developed. The product (S)‐α‐allyl‐α‐arylcyclopentanones were obtained in excellent yields and enantioselectivities (up to >99.9 % ee). This represents one of the most highly enantioselective formations of an all‐carbon quaternary stereogenic center reported to date. This reaction was demonstrated on a 4.0 mmol scale without any deterioration of enantioselectivity and was exploited as the key enantioselective transformation in an asymmetric formal synthesis of the natural product (+)‐tanikolide.     

Synthesis of 4‐(trihalomethyl)dipyrimidin‐2‐ylamines from β‐alkoxy‐α,β‐unsaturated trihalomethyl ketones

The synthesis of a novel series of twelve 4‐(trihalomethyl)dipyrimidin‐2‐ylamines, from the cyclo‐condensation reaction of 4‐(trichloromethyl)‐2‐guanidinopyrimidine, with β‐alkoxyvinyl trihalomethyl ketones, of general formula: X₃C‐C(O)‐C(R²)=C(R¹)‐OR, where: X = F, Cl; R = Me, Et, ‐(CH₂)₂‐, ‐(CH₂)₃‐; R¹ = H, Me; R² = H, Me, ‐(CH₂)₂‐, ‐(CH₂)₃‐, is reported. The reactions were carried out in acetonitrile under reflux for 16 hours, leading to the dipyrimidin‐2‐ylamines in 65‐90% yield. Depending on the substituents of the vinyl ketone, tetrahydropyrimidines or aromatic pyrimidine rings were obtained from the cyclization reaction. When X = Cl, elimination of the trichloromethyl group was observed during the cyclization step. The structure of 4‐(trihalomethyl)dipyrimidin‐2‐ylamines was studied in detail by ¹H‐, ¹³C‐ and 2D‐nmr spectroscopy.     

Protonation‐Assisted Conjugate Addition of Axially Chiral Enolates: Asymmetric Synthesis of Multisubstituted β‐Lactams from α‐Amino Acids

β‐Lactams with contiguous tetra‐ and trisubstituted carbon centers were prepared in a highly enantioselective manner through 4‐exo‐trig cyclization of axially chiral enolates generated from readily available α‐amino acids. Use of a weak base (metal carbonate) in a protic solvent (EtOH) is the key to the smooth production of β‐lactams. Use of the weak base is expected to generate the axially chiral enolates in a very low concentration, which undergo intramolecular conjugate addition without suffering intermolecular side reactions. Highly strained β‐lactam enolates thus formed through reversible intramolecular conjugate addition (4‐exo‐trig cyclization) of axially chiral enolates undergo prompt protonation by EtOH in the reaction media (not during the work‐up procedure) to give β‐lactams in up to 97 % ee.     

Efficient asymmetric addition of diethylzinc to aldehydes using C2‐novel chiral pyridine β‐amino alcohols as chiral ligands

A series of novel C₂‐symmetric chiral pyridine β‐amino alcohol ligands have been synthesized from 2,6‐pyridine dicarboxaldehyde, m‐phthalaldehyde and chiral β‐amino alcohols through a two‐step reaction. All their structures were characterized by ¹H NMR, ¹³C NMR and IR. Their enantioselective induction behaviors were examined under different conditions such as the structure of the ligands, reaction temperature, solvent, reaction time and catalytic amount. The results show that the corresponding chiral secondary alcohols can be obtained with high yields and moderate to good enantiomeric excess. The best result, up to 89% ee, was obtained when the ligand 3c (2S,2′R)‐2,2′‐((pyridine‐2,6‐diylbis(methylene))bisazanediyl))bis(4‐methyl‐1,1‐diphenylpentan‐1‐ol) was used in toluene at room temperature. The ligand 3g (2S,2′R)‐2,2′‐((1,3‐phenylenebis(methylene))bis(azanediyl))bis(4‐methyl‐1,1‐diphenylpentan‐1‐ol) was prepared in which the pyridine ring was replaced by the benzene ring compared to 3c in order to illustrate the unique role of the N atom in the pyridine ring in the inductive reaction. The results indicate that the coordination of the N atom of the pyridine ring is essential in the asymmetric induction reaction. Copyright © 2014 John Wiley & Sons, Ltd.     

Highly Enantioselective Synthesis of α‐Stereogenic Esters through Catalytic Asymmetric Michael Addition of 4‐Oxo‐4‐arylbutenoates

Highly enantioselective Michael addition of 1,3‐dicarbonyl compounds and nitromethane to 4‐oxo‐4‐arylbutenoates catalyzed by N,N′‐dioxide–Sc(OTf)₃ complexes has been developed. Using 0.5–2 mol % catalyst loading, various α‐stereogenic esters were obtained regioselectively with excellent yields (up to 97 %) and enantioselectivities (up to >99 % ee). Moreover, the reaction performed well under nearly solvent‐free conditions. The products with functional groups are ready for further transformation, which showed the potential value of the catalytic approach. According to the experimental results and previous reports, a plausible working model has been proposed to explain the origin of the activation and the asymmetric induction.     

Fragmentation Mechanism of Trans—α—Aryl—β—enamino Esters

Electron impact-induced fragmentation mechanism of Trans-α-Aryl-β-enamino esters were investigated using mass-analyzed ion kinetic energy (MIKE) spectrometry and high resolution accurate mass data It was found that the main characteristic fragmentations of compounds studied were:an odd electron ion M^ -EtOH was formed by losing a neutral molecule of ethanol;and the skeletal rearrangements took place;and the ring opening reaction happened after losing a carbon monoxide;and the typical McLafferty rearrangement underwent in ester group.The cycliztion reation caused by losing neutral molecule of TsNH2 due to the ortho-effects of substituted group of gromatic ring was also observed.     

Enantioselective Nitroso‐Diels–Alder Reaction and Its Application for the Synthesis of (−)‐Peracetylated Conduramine A‐1

Cu^I‐catalyzed enantioselective nitroso‐Diels–Alder reactions (NDA reactions) of 2‐nitrosopyridine with various dienes are presented. The [CuPF₆(MeCN)₄]/Walphos‐CF₃ catalyst system is best suited to catalyze the NDA reaction of various dienes by using 2‐nitrosopyridine as a dienophile. In most of the cases studied, cycloadducts are obtained in quantitative yield with very good to excellent enantioselectivities. Based on DFT calculations, a model to explain the stereochemical outcome of the NDA reaction is presented. Finally, an efficient short synthesis of (?)‐peracetylated conduramine A‐1 by applying the enantioselective NDA reaction as a key step is described.     

Oxidative Fragmentations of the 5α‐ and 5β‐Hydroxy‐B‐norcholestan‐ 3β‐yl Acetates

Oxidations of 5α‐hydroxy‐B‐norcholestan‐3β‐yl acetate ( 8 ) with Pb(OAc)₄ under thermal or photolytic conditions or in the presence of iodine afforded only complex mixtures of compounds. However, the HgO/I₂ version of the hypoiodite reaction gave as the primary products the stereoisomeric (Z)‐ and (E)‐1(10)‐unsaturated 5,10‐seco B‐nor‐derivatives 10 and 11 , and the stereoisomeric (5R,10R)‐ and (5S,10S)‐acetals 14 and 15 (Scheme 4). Further reaction of these compounds under conditions of their formation afforded, in addition, the A‐nor 1,5‐cyclization products 13 and 16 (from 10 ) and 12 (from 11 ) (see also Scheme 6) and the 6‐iodo‐5,6‐secolactones 17 and 19 (from 14 and 15 , resp.) and 4‐iodo‐4,5‐secolactone 18 (from 15 ) (see also Scheme 7). Oxidations of 5β‐hydroxy‐B‐norcholestan‐3β‐yl acetate ( 9 ) with both hypoiodite‐forming reagents (Pb(OAc)₄/I₂ and HgO/I₂) proceeded similarly to the HgO/I₂ reaction of the corresponding 5α‐hydroxy analogue 8 . Photolytic Pb(OAc)₄ oxidation of 9 afforded, in addition to the (Z)‐ and (E)‐5,10‐seco 1(10)‐unsaturated ketones 10 and 11 , their isomeric 5,10‐seco 10(19)‐unsaturated ketone 22 , the acetal 5‐acetate 21 , and 5β,19‐epoxy derivative 23 (Scheme 9). Exceptionally, in the thermal Pb(OAc)₄ oxidation of 9 , the 5,10‐seco ketones 10, 11 , and 22 were not formed, the only reaction being the stereoselective formation of the 5,10‐ethers with the β‐oriented epoxy bridge, i.e. the (10R)‐enol ether 20 and (5S,10R)‐acetal 5‐acetate 21 (Scheme 8). Possible mechanistic interpretations of the above transformations are discussed.     

Four oxoindole‐linked α‐alkoxy‐β‐amino acid derivatives

Four structures of oxoindolyl α‐hydroxy‐β‐amino acid derivatives, namely, methyl 2‐{3‐[(tert‐butoxycarbonyl)amino]‐1‐methyl‐2‐oxoindolin‐3‐yl}‐2‐methoxy‐2‐phenylacetate, C₂₄H₂₈N₂O₆, (I), methyl 2‐{3‐[(tert‐butoxycarbonyl)amino]‐1‐methyl‐2‐oxoindolin‐3‐yl}‐2‐ethoxy‐2‐phenylacetate, C₂₅H₃₀N₂O₆, (II), methyl 2‐{3‐[(tert‐butoxycarbonyl)amino]‐1‐methyl‐2‐oxoindolin‐3‐yl}‐2‐[(4‐methoxybenzyl)oxy]‐2‐phenylacetate, C₃₁H₃₄N₂O₇, (III), and methyl 2‐[(anthracen‐9‐yl)methoxy]‐2‐{3‐[(tert‐butoxycarbonyl)amino]‐1‐methyl‐2‐oxoindolin‐3‐yl}‐2‐phenylacetate, C₃₈H₃₆N₂O₆, (IV), have been determined. The diastereoselectivity of the chemical reaction involving α‐diazoesters and isatin imines in the presence of benzyl alcohol is confirmed through the relative configuration of the two stereogenic centres. In esters (I) and (III), the amide group adopts an anti conformation, whereas the conformation is syn in esters (II) and (IV). Nevertheless, the amide group forms intramolecular N—H...O hydrogen bonds with the ester and ether O atoms in all four structures. The ether‐linked substituents are in the extended conformation in all four structures. Ester (II) is dominated by intermolecular N—H...O hydrogen‐bond interactions. In contrast, the remaining three structures are sustained by C—H...O hydrogen‐bond interactions.     

Enantioselective Copper‐Catalyzed Decarboxylative Propargylic Alkylation of Propargyl β‐Ketoesters with a Chiral Ketimine P,N,N‐Ligand

The first enantioselective copper‐catalyzed decarboxylative propargylic alkylation has been developed. Treatment of propargyl β‐ketoesters with a catalyst, prepared in situ from [Cu(CH₃CN)₄BF₄] and a newly developed chiral tridentate ketimine P,N,N‐ligand under mild reaction conditions, generates β‐ethynyl ketones in good yields and with high enantioselectivities without requiring the pregeneration of ketone enolates. This new process provides facile access to a range of chiral β‐ethynyl ketones in a highly enantioenriched form.