Enantioselective Michael addition of α,α-disubstituted aldehydes to maleimides organocatalyzed by chiral primary amine-guanidines

New primary amine-guanidines derived from the monoguanylation of (1S,2S)- and (1R,2R)-cyclohexane-1,2-diamine have been prepared and used as chiral organocatalysts for the enantioselective conjugate addition of α,α-disubstituted aldehydes to maleimides. The corresponding Michael adducts bearing a new stereocenter were generally obtained in high or quantitative yields and with good enantioselectivities (up to 93% ee).     

Enantioselective direct Mannich reactions of 3-substituted oxindoles catalyzed by chiral phosphine via dual-reagent catalysis

A combination of an amino acid-derived chiral phosphine catalyst and methyl acrylate to catalyze the direct Mannich reaction of 3-substituted oxindoles and imines has been reported to afford 3-tetrasubstituted oxindole derivatives which are key structures for biological activities. The products are formed with a quaternary carbon and featured with two adjacent chiral centers. Various N-EDG(electron-donating group) and N-EWG(electron-withdrawing group) protected oxindoles, including 3-aryl and 3-alkyl substituted ones, have been evaluated with aromatic and aliphatic imines under this catalytic system, smoothly giving desired products in good yields as well as excellent diastereo- and enantioselectivities.     

Michael addition-elimination reactions of chiral enolates with ethyl 3-halopropenoates

Key dienoic or dienal substructures of cytotoxic macrolides amphidinolide E and dictyostatin have been prepared via a Michael addition (followed by elimination of X-) of chiral enolates on beta-halo derivatives of ethyl acrylate, with full retention of the initial E or Z configuration. Evans oxazolidin-2-ones and our related thiazolidin-2-ones, as well as a fine-tuning of the reaction conditions, have been essential. Many chiral building blocks are accessible from these adducts.     

Asymmetric Michael reaction involving chiral imines/secondary enamines: stereocontrolled synthesis of 2,2-disubstituted tetrahydrothiophen-3-ones

[reaction: see text] The asymmetric Michael reaction involving a chiral imine derived from 2-methyltetrahydrothiophenone-3-one and enantiopure (R)-1-phenylethylamine with a variety of electrophilic alkenes furnished 2,2-disubstituted tetrahydrothiophenone-3-ones with good yields and excellent stereoselectivity.     

Enantioselective intramolecular [2+2] photocycloaddition reactions of 4-substituted coumarins catalyzed by a chiral Lewis acid

Eight coumarins, which carry a terminal alkene tethered by a CH(2)XCH(2) group to their 4-position (X = CH(2), CMe(2), O, S, NBoc, NZ, NTs, NBn), were synthesized in overall yields of 51-80?%. Starting materials for the syntheses were either commercially available 4-hydroxycoumarin or 4-formylcoumarin. The intramolecular [2+2] photocycloaddition of these coumarins gave diastereoselectively products with a tetracyclic 3,3a,4,4a-tetrahydro-1H-cyclopenta[2,3]cyclobuta[1,2-c]chromen-5(2H)-one skeleton. Direct irradiation at λ = 300?nm in dichloromethane (c = 10?mM) led to product formation in good yields for most substrates, presumably via a singlet excited state intermediate. Due to the low coumarin absorption at λ >350?nm the photocycloaddition was slow upon irradiation at λ = 366?nm. Addition of a chiral oxazaborolidine-based Lewis acid (50?mol?%) increased the reaction rate at λ = 366?nm and induced a significant enantioselectivity in the [2+2] photocycloaddition. Six out of eight coumarin substrates (X = CH(2), CMe(2), O, NBoc, NZ, NTs) gave the respective products in yields of 72-96?% and with 74-90?% enantiomeric excess (ee) upon irradiation in dichloromethane (c = 20?mM) at -75?°C. The Lewis acid presumably acts by coordination to the coumarin carbonyl oxygen atom, which leads to a bathochromic shift (redshift) of the UV absorption and which increases the singlet state lifetime. A second electrostatic interaction of the hydrogen atom at C3 with the oxygen atom of the oxazaborolidine is likely.     

Enantioselective intramolecular [2 + 2]-photocycloaddition reactions of 4-substituted quinolones catalyzed by a chiral sensitizer with a hydrogen-bonding motif

Six 2-quinolones, which bear a terminal alkene linked by a three- or four-membered tether to carbon atom C4 of the quinolone, were synthesized and subjected to an intramolecular [2 + 2]-photocycloaddition. The reaction delivered the respective products in high yields (78-99%) and with good regioselectivity in favor of the straight isomer. If conducted in the presence of a chiral hydrogen-bonding template (2.5 equiv) at low temperature in toluene as the solvent, the reaction proceeded enantioselectively (83-94% ee). An organocatalytic reaction was achieved when employing a chiral hydrogen-bonding template with an attached sensitizing unit (benzophenone or xanthone). The xanthone-based organocatalyst proved to be superior as compared to the respective benzophenone. Closer inspection revealed that the reaction of 4-(pent-4-enyloxy)quinolone leading to a six-membered ring, annelated to the cyclobutane, was less enantioselective (up to 41% ee with 30 mol % catalyst) than the reaction of 4-(but-3-enyloxy)quinolone leading to a five-membered ring (90% ee with 5 mol % and 94% ee with 20 mol % catalyst). Photophysical data (emission spectra, laser flash photolysis experiments) proved that the latter photocycloaddition was significantly faster, supporting the idea that the dissociation of the substrate from the catalyst prior to the photocycloaddition is responsible for the decreased enantioselectivity. Under optimized conditions, employing 10 mol % of the xanthone-based organocatalyst at -25 °C in trifluorotoluene as the solvent, three of the other four substrates gave the intramolecular [2 + 2]-photocycloaddition products with high enantioselectivities (72-87% ee). In all catalyzed reactions, the yields based on conversion were moderate to good (40-93%).     

Ion-pair, anion-exchange and ligand-exchange high-performance liquid chromatography of tenuazonic acid and 3-acetyl 5-substituted pyrrolidine-2,4-diones

The ion-pair, ligand-exchange and anion-exchange chromatography of the fungal metabolic tenuazonic acid (TA) and its related 3-acetyl 5-substituted pyrrolidine-2,4-diones were studied. Ion-pair chromatography was performed on a C18 column with a mobile phase composed of cetrimide, phosphate buffer in water-methanol and a metal complexant (ethylenediamine) to improve the peak sharpness. Addition of the same metal complexant to the mobile phase of the anion-exchange chromatographic system also improved its efficiency. TA and its 5-substituted analogues derived from valine and leucine were separated with the ion-pair and anion-exchange chromatographic systems. With ligand-exchange chromatography, TA could only be separated from its valine analogue. These chromatographic systems were used for the detection of TA in the culture filtrates of the fungus Pyricularia oryzae and in infected rice leaves. Deproteinated culture filtrates could be rapidly analysed for their TA content by anion-exchange chromatography. However, this system was not suitable for the detection of TA in the infected rice leaf as interfering compounds were coeluted with TA. Ion-pair and ligand-exchange chromatographic systems allowed the efficient quantification of TA in infected leaves.     

Asymmetric Michael reactions of α-substituted acetates with cyclic enones catalyzed by multifunctional chiral Ru amido complexes

Well-defined 16-electron chiral Ru amido complexes, Ru[(R,R)-diamine](η⁶-arene), efficiently catalyze asymmetric Michael additions of Michael donors to cyclic enones to give adducts in high yields and with excellent ee’s. β-Ketoesters or nitroacetate as Michael donors react with 2-cyclopentenone in toluene or t-butyl alcohol containing the Ru amido catalyst (S/C=50) to afford the Michael adduct in 99% yield and with up to 92% ee. The outcome of the reaction was delicately influenced by the structures of the diamine and arene ligands as well as reaction conditions.     

An unexpected carbon dioxide insertion in the reaction of trans-2, 4-disubstituted azetidine, trans-2,5-disubstituted pyrrolidine, or trans-2,6-disubstituted piperidine with diphenylthiophosphinic chloride and diphenylselenophosphinic chloride

In the reaction of trans-2,4-disubstituted azetidine, trans-2, 5-disubstituted pyrrolidine, or trans-2,6-disubstituted piperidine with diphenylthiophosphinic chloride or diphenylselenophosphinic chloride in acetonitrile in the presence of potassium carbonate at room temperature, an unexpected carbon dioxide insertion produced carbamic diphenylthiophosphinic or diphenylselenophosphinic anhydride in good yield. The same product could be also obtained when the reaction was carried out under carbon dioxide atmosphere using potassium hydroxide or triethylamine as a base. This is a very simple reaction process related to the fixation of carbon dioxide without a metal catalyst.     

Stereochemistry of the [4 + 2] cycloadditions of trans,trans- and cis,trans-2,4-hexadiene to C(60)

The [4 + 2] cycloaddition of trans,trans-2,4-hexadiene with C(60) proceeds via a concerted mechanism with retention of stereochemistry in the cycloadduct 1a. However, when cis,trans-2,4-hexadiene reacts with C(60), isomerization of the cis,trans to the thermodynamically more stable trans,trans isomer occurs. Subsequently, the cis,trans diene isomerized to the trans,trans isomer and cycloadds to C(60), to form adduct 1a. When the reaction is carried out at higher temperatures, the formation of cycloadduct 1b is also obtained. This result is consistent with a concerted cycloaddition of cis,trans-2,4-hexadiene with C(60), which is more reactive at elevated temperatures and leads to the formation of the Diels-Alder adduct 1b.     

Kinetics and mechanism of the reactions of S-2,4-dinitrophenyl 4-substituted thiobenzoates with secondary alicyclic amines

[reaction: see text] The title reactions, in 44 wt % ethanol-water at 25.0 degrees C, exhibit slightly curved Br?nsted-type plots (log kN versus pKa of amines) with slopes beta1 = 0.1-0.44 (at high pKa) and beta2 ca. 0.7 (at low pKa). The magnitude of some of these slopes, together with the fact that the curvature center (pKa(0) = 9.5-10.8) does not change with the electronic effects of the benzoyl substituent, suggests that these reactions are not stepwise, but concerted.     

4-hydroxy-2-quinolones. 109. Alkylation of 4-substituted ethyl 2-oxo-1,2-dihydro-quinoline-3-carboxylates

The alkylation of the ethyl esters of 4-methyl, 4-chloro-, and 4-amino substituted 2-oxo-1,2-dihydroquinoline-3-carboxylic acid by ethyl iodide in the system DMF/K₂CO₃ has been studied. Features of the structure of the starting compounds and their effect on the ratio of the N-and O-alkyl products formed are discussed. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1502–1507, October, 2006.     

Chiral amine thiourea-promoted enantioselective Michael addition reactions of 3-substituted benzofuran-2(3H)-ones to maleimides

A highly diastereo- and enantioselective Michael addition reaction with respect to prochiral 3-substituted benzofuran-2(3H)-ones and maleimides by a chiral bifunctional thiourea-tertiary amine catalyst was investigated. The corresponding adducts, containing a quaternary center at the C3-position of the benzofuran-2(3H)-one as well as a vicinal tertiary center, were generally obtained in high yields (up to 99%) with very good diastereo- (up to >20:1 dr) and enantioselectivities (up to 97% ee).     

Enantioselective Michael reaction of 1,3-dicarbonyl compounds to 3-nitro-2H-chromenes catalyzed by chiral nickel complexes

A chiral nickel complexes-catalyzed enantioselective Michael addition of 1,3-dicarbonyl compounds to 3-nitro-2H-chromenes has been developed; the products could be obtained in high yields and good enantioselectivities.     

CeCl3·H2O/NaI-Promoted stereoselective synthesis of 2,4-disubstituted chiral tetrahydroquinolines

d-Glycals readily undergo cyclization with aryl amines in the presence of CeCl₃·7H₂O-NaI under mild and neutral conditions to afford a novel sugar derived tetrahydroquinoline derivatives in good yields with high stereoselectivity. The stereochemistry of the products was assigned by using various NMR studies.     

4+2] Cycloaddition of 2-substituted 1,2-dihydropyridines with nitrosobenzene: asymmetric synthesis of trans-2-substituted 3-amino-1,2,3,6-tetrahydropyridines

[reaction: see text] A new methodology for the stereoselective synthesis of trans-2-substituted 3-amino-1,2,3,6-tetrahydropyridines is reported. The preparation of these 3-aminopiperidines is achieved by cycloaddition of nitrosobenzene with 2-substituted 1,2-dihydropyridines followed by chemoselective reduction of the cycloadducts. Enantioenriched 1,2-dihydropyridine derivatives are easily prepared from pyridine and a chiral amide following a previous report from our laboratories. Moreover, the in situ hydrogenation of these cycloadducts over palladium in a solution of hydrogen chloride in methanol led to tetrahydropyrroloimidazoles.     

Asymmetric Michael reactions of α,α-disubstituted aldehydes with maleimides using a primary amine thiourea organocatalyst

Primary amine thiourea organocatalyst 8 was used to promote Michael additions of bulky α,α-disubstituted aldehydes, such as isobutyraldehyde with maleimides to afford the corresponding adducts in high to excellent yields and with up to 91% ee.