Stereoselective synthesis of novel tetrahydroxypyrrolizidines

N-Benzyloxycarbonyl-2,5-dideoxy-2,5-imino-3,4-O-isopropylidene-l-ribose 12a has been converted into (1R,2S,6R,7S,7aS)-5 and (1R,2S,6S,7R,7aR)-1,2,6,7-tetrahydroxypyrrolidin-5-ones 6 and (1R,2S,6S,7S,7aS)-7 and (1R,2S,6R,7R,7aS)-1,2,6,7-tetrahydroxypyrrolizidines 8 following stereoselective paths. These new compounds have been assayed for their inhibitory activities towards 25 glycosidases. Pyrrolizidines 7 and 8 are moderate but selective inhibitors of amyloglucosidase from Rhizopus mold (7: IC₅₀=130 μM, K_i=120 μM; 8: IC₅₀=200 μM, K_i=180 μM, mixed type of inhibition).     

Efficient synthesis of 2,6,7,8-tetrahydroxyindolizidines (castanospermine analogues) via the dipolar cycloadditions of N-benzyl-C-(tetrofuranos-4-yl)nitrones to methyl acrylate

The dipolar cycloaddition of (Z)-N-benzyl-(3-O-benzyl-1,2-O-isopropylidene-α-d-ribofuranos-5-ylidene)amine N-oxide to methyl acrylate gives a 53:16:26:5 diastereomeric mixture of isoxazolidine derivatives. The dipolar cycloaddition of the xylo analogue to methyl acrylate is more diastereoselective, producing a 44:13:43 mixture of only three diastereomers. The ribo-configured adducts have been converted (4 steps only) into the new (2R,6S,7S,8R,8aR)-, (2S,6S,7S,8R,8aR)-, (2S,6S,7S,8R,8aS)- and (2R,6S,7S,8R,8aS)-2,6,7,8-tetrahydroxyindolizidines. Similarly, the two xylo-configured major isoxazolidine derivatives were converted into the known derivatives (2R,6S,7R,8R,8aS)- and (2S,6S,7R,8R,8aR)-2,6,7,8-tetrahydroxyindolizidines. The six isomeric indolizidine derivatives obtained have been evaluated for their inhibiting activities towards 15 glycosidases. Only the (2R,6S,7S,8R,8aR)-configured isomer is a selective inhibitor of amyloglucosidases from Aspergillus niger (IC₅₀ = 350 μM) and from Rhizopus mold (IC₅₀ = 90 μM, K_i = 195 μM, non-competitive), the other indolizidines show very little inhibitory activity at 1 mM concentration.     

Synthesis of rigid and C2-symmetric 18-crown-6 type macrocycles bearing diamide–diester groups: enantiomeric recognition for α-(1-naphthyl)ethylammonium perchlorate salts

A series of rigid and chiral C₂-symmetric 18-crown-6 type macrocycles (S,S)-4, (S,S)-5, (S,S)-6 and (R,R)-2 bearing diamide–ester groups were synthesized. The binding properties of these macrocycles were examined for α-(1-naphthyl)ethylammonium perchlorates salts by an ¹H NMR titration method. Taking into account the host employed, important differences were observed in the K_a values of (R)- and (S)-enantiomers of guests for macrocycles (S,S)-4 and (S,S)-6, K_S/K_R = 3.6, and K_S/K_R = 0.1 (K_R/K_S = 10.3) ΔΔG = 3.19 and ΔΔG = ?5.77 kJ mol^?1, respectively. The results indicated excellent enantioselectivity of macrocyclic (S,S)-6 towards the enantiomers of α-(1-naphthyl)ethylammonium perchlorate salts.     

Heat capacities and derived thermodynamic properties of lithium,sodium, and potassium disilicates from T = (5 to 350) K in both vitreous and crystalline states

Cryogenic heat capacities determined by equilibrium adiabatic calorimetry from T = (6 to 350) K on Li, Na, and K disilicates in both crystalline and vitreous phases are adjusted to end member composition and the vitreous/crystal difference ascertained. The thermophysical properties of these and related phases are estimated, compared, and updated. The values at T = 298.15 K of {S^∘(T) − S^∘(0)}/R for stoichiometric compositions of alkali disilicate (M₂O · 2SiO₂): vitreous, crystal: Li, 16.30, 14.65; Na, 20.67, 19.47; and K, 23.26, 23.00. Entropy differences confirm greater disorder in the vitreous compounds compared with the crystalline compounds. The entropy data also show that disorder increases with decreasing atomic mass of the alkali ion.     

Enantiopure trans-1-amino-2-(arylsulfanyl)cyclohexanes: novel chiral motifs for ligands and organocatalysts

In order to obtain the title compounds (1R,2R)-cyclohexane-1,2-diol was stereoselectively converted into cis-(1R,2S)-2-(arylsulfanyl)cyclohexanols and these products were submitted to the nucleophilic substitution via the Mitsunobu reaction (HN₃, DEAD). Reduction of the isolated azides gave the desired trans-(1S,2S)-1-amino-2-(arylsulfanyl)cyclohexanes. The (1S,2S)-1-amino-2-(2-aminophenylsulfanyl)cyclohexanes thus prepared were reacted with 3,5-bis(trifluoromethyl)phenyl isothiocyanate to furnish the respective bis-thiourea compounds. An application of a derivative of this type as an organocatalyst (20 mol %) in the Baylis–Hillman reaction gave the respective product in up to 93% ee.     

The stereocontrolled synthesis of polyfunctional organosulfur compounds via chiral azetidinium salts and epoxyamines

The stereocontrolled synthesis of functionalized organosulfur compounds of a general formula: Bn₂NCH(CH₃)CH(OH)CH₂SX [where: X = SO₃Na or SP(S)(OR)₂] was achieved by a regioselective opening of enantiomerically >98% pure (2S,3R)- and (2S,3S)-N,N-dibenzyl-2-hydroxy-3-methylazetidinium bromides and/or (1R)-[1′(S)-dibenzylamino)ethyl]oxiranes with thiosulfate and dithiophosphate anions. The attack of both nucleophiles was directed exclusively at the less substituted carbon atom of the heterocyclic ring.     

Enthalpic changes on mixing two couples of S- and R-enantiomers of benzyl-(1-phenyl-ethyl)-amine, 1-phenylethylamine, 1-phenyl-ethanol,butyric acid oxiranylmethyl ester, 4-methyl-[1,3]dioxolan-2-one, 2-chloro-methyloxirane and 3-hydroxyisobutyric acid methyl ester at T = 298.15 K

Enthalpies of mixing of (R)- and (S)-enantomers of liquid chiral compounds such as benzyl-(1-phenyl-ethyl)-amine (1), 1-phenylethylamine (2), 1-phenyl-ethanol (3), butyric acid oxiranylmethyl ester (4), 4-methyl-[1,3]dioxolan-2-one (5), 2-Chloromethyloxirane (6) and 3-hydroxyisobutyric acid methyl ester (7) have been measured over the whole range of mole fractions at 298.15 K, albeit very small values. Mixing of heterochiral liquids of R-1 + S-1, R-5 + S-5, and R-7 + S-7 realized enthalpic stabilization over the whole range of mole fractions, whereas that of R-2 + S-2, R-3 + S-3, R-4 + S-4, and R-6 + S-6 realized enthalpic destabilization over entire compositions. The extreme values of enthalpies of mixing and the intermolecular interaction obtained by the molecular mechanics calculations showed a linear correlation, except few the compounds measured.     

The enantiomeric recognition of chiral organic ammonium salts by chiral pyridino-macrocycles bearing aminoalcohol subunits

Pyridine-based macrocycles were prepared by treating 2,6-bis[[2′6′-bis(bromomethyl)-4′-methylphenoxy]methyl]pyridine 3 with the appropriate chiral aminoalcohols. The enantiomeric recognition of these macrocycles bearing aminoalcohol subunits of the pyridinocrown type ligand was evaluated for chiral organic ammonium salts by UV titration. The important differences were observed in the K_a values of (R)-Am2 and (S)-Am2 for (S,S,S)-1, (S,S,S)-2 and (S,S,S)-3 hosts, K_S/K_R = 5.0, K_S/K_R = 2.4 and K_S/K_R = 5.0, respectively. There seems to be a general tendency for hosts to recognise (S)-enantiomers for both Am1 and Am2.     

Sharpless asymmetric dihydroxylation as the key step in the enantioselective synthesis of spirocyclic σ1 receptor ligands

The enantioselective synthesis of fluorinated spirocyclic σ₁ ligands involved three key steps: (1) the Sharpless asymmetric dihydroxylation of 2-bromostyrene 5 provided enantiomerically pure diols (R)-6 and (S)-6 establishing the stereogenic center; (2) the intramolecular opening of the oxirane ring of (R)-11 and (S)-11, which occurred with excellent regioselectivity and complete inversion of configuration giving access to enantiomerically pure alcohols (S)-7a and (R)-7a; (3) the treatment of alcohols (S)-7b and (R)-7b with DAST, which led to the fluoromethyl derivatives (S)-1 and (R)-1 without racemization. X-ray crystal structure analysis of the tosylate (R)-13 confirmed the absolute configuration of the spirocyclic compounds as well as the enantioselectivity during the Sharpless asymmetric dihydroxylation of 5. The (S)-configured fluoromethyl derivative (S)-1 revealed a high σ₁ affinity (K_i = 1.8 nM), high eudismic ratio (factor 8) and high selectivity over the σ₂ subtype (667-fold).     

A uronic acid analogue of isofagomine lactam as a nanomolar glucuronidase inhibitor

The synthesis of (3S,4R,5R)-3,4-dihydroxypiperidin-2-one-5-carboxylic acid (‘isofagomine lactam uronate’) from d-arabinose is reported. The product is a potent inhibitor in the low nanomolar range (K_i 36 nM) for bovine liver β-glucuronidase.     

TpRu complexes as recoverable Lewis acid catalysts for enantioselective solvent-free cycloaddition reactions (Tp = hydrotris(pyrazolyl)borate)

The enantiomerically and diastereomerically pure dinitrogen-bridged complexes [{TpRu(L)}₂(μ-N₂)][PF₆]₂ (L = R,R- or S,S-1,2-bis(diphenylphosphinoamino)cyclohexane (R,R- or S,S-dppach)) were prepared by reaction of the corresponding chloro-complexes [TpRuCl(L)] with NaPF₆ in dichloromethane under dinitrogen. The dinitrogen adducts react with neat methacrolein furnishing the labile complexes [TpRu(methacrolein)(L)][PF₆] (L = R,R- or S,S-dppach). Both the dinitrogen and methacrolein derivatives are catalysts for the solvent-free regio- and enantioselective Diels–Alder reactions between methacrolein and cyclopentadiene or pentamethylcyclopentadiene, with moderate enantiomeric excesses ranging from 36 to ca. 70%. The metal complex can be easily recovered and re-utilised for further reactions. The dinitrogen complexes also catalyse the 1,3-dipolar cycloaddition reaction between methacrolein and benzylidenephenylamine N-oxide to yield 5-methyl-2-N-3-diphenyl-isoxazolidine-5-carbaldehyde with very high regioselectivity and 32% enantiomeric excess.     

Co-crystal of (R,R)-1,2-cyclohexanediol with (R,R)-tartaric acid,a key structure in resolution of the (±)-trans-diol by supercritical extraction,and the related ternary phase system

A novel co-crystal of trans-(R,R)-1,2-cyclohexanediol and (R,R)-tartaric acid (with 1:1 molar ratio, 1) has been found to be a key crystalline compound in the improved resolution of (±)-trans-1,2-cyclohexanediol by supercritical fluid extraction. The molecular and crystal structure of this co-crystal, which crystallizes in orthorhombic crystal system (space group P2₁2₁2₁, a = 6.7033(13) Å, b = 7.2643(16), c = 24.863(5), Z = 4), has been solved by single crystal X-ray diffraction (R = 0.064). The packing arrangement consists of two dimensional layers of sandwich-like sheets, where the inner part is constructed by double layers of tartaric acids which hydrophilicity is “covered” on both upper and bottom side by cyclohexanediols with the hydrophobic cyclohexane rings pointing outward. Thus, a rather complex hydrogen bonding pattern is constructed. The relatively high melting point (133 °C) observed by both simultaneous TG/DTA and DSC, and the main features of FTIR-spectrum of 1 are explained by the increased stability of this crystal structure. DSC studies on binary mixtures of co-crystal 1 with (R,R)-1,2-cyclohexanediol or (R,R)-tartaric acid, revealed eutectic temperatures of T_eu = 100 or 131 °C, respectively. Between (S,S)-1,2-cyclohexanediol and (R,R)-tartaric acid a eutectic temperature of T_eu = 85 °C have also been observed. The phase relations have been confirmed by powder X-ray diffraction, as well.     

Spontaneous resolution of a novel chiral coordination polymer through supramolecular interactions and solvent symmetry breaking

The spontaneous resolution reaction of racemic trans-2,3-dihydro-2,3-dipyridyl-benzo[e]indole 1 with Cd(ClO₄)₂·6H₂O in the presence of 2-butanol under solvothermal reaction conditions favors the formation of crystal 2 [P-Cd(R,R,-1)₂(ClO₄)₂], while a similar reaction in the presence of ethanol only favors the formation of crystal 3 [M-Cd(S,S,-1)₂(ClO₄)₂]. The crystal structural determination shows that both 2 and 3 crystallize in chiral enantiomorphous space groups (P6₁22 and P6₅22) and their structures are 1D infinite chain, and are just enantiomorphous pairs most like. The spontaneous resolution process displays estimated ee values of ca. +0.6 for 2-butanol and ca. −0.4 for ethanol. Enantiomerically pure (S,S)-trans-2,3-dihydro-2,3-dipyridyl-benzo[e]indole (S,S,-1) can be obtained through the decomposition of mechanically separated 3. Additionally (S,S,-1) also crystallizes in a chiral space group (P2₁). The CD (circular dichroism) spectra of both 2 and 3 in the solid state are also approximately enantiomorphous pairs. However, their fluorescent spectra in the solid state display a moderate difference in maximum emission peaks (Δλ = 19 nm). Crystal data for 2: C₄₄H₃₄Cl₂N₆O₈Cd, M = 958.07, hexagonal, P6₁22, a = 10.5488(5), c = 68.256(4) Å, α = γ = 90°, β = 120°, V = 6577.8(6) Å³, Z = 6, D_c = 1.451 mg m⁻³, R₁ = 0.0498, wR₂ = 0.1124, μ = 0.679 mm⁻¹, S = 0.623, Flack χ = −0.02(6). For space group P6₅22, R₁ = 0.0670, wR₂ = 0.1602, S = 0.725 with a Flack value of 1.03(7); Crystal data for 3, C₄₄H₃₄Cl₂N₆O₈Cd, M = 958.07, hexagonal, P6₅22, a = 10.5446(3), c = 68.265(3) Å, V = 6573.3(4) Å³, Z = 6, D_c = 1.452 mg m⁻³, R₁ = 0.0444,wR₂ = 0.1002, μ = 0.679 mm⁻¹, S = 0.558, Flack χ = 0.01(5). For space group P6₁22, R₁ = 0.0501, wR₂ = 0.1178, S = 0.599 with a Flack value of 1.00(5). The low Flack parameter indicates that the absolute configurations of 2 and 3 are stated; Crystal data for (S,S)-1, C₂₂H₁₇N₂, M = 323.39, orthorhombic, P2₁2₁2₁, a = 9.2598(7), b = 9.4617(8), c = 19.1452(16) Å, V = 1677.4(2) Å³, Z = 4, D_c = 1.281 mg m⁻³, R₁ = 0.0417, wR₂ = 0.1191, T = 293 K, μ = 0.077 mm⁻¹, S = 0.862.     

Stereocontrolled self-assembly of luminescent lanthanide helicates and their enantiodifferentiation using Δ-TRISPHAT as the NMR resolving agent

Self-assembled supramolecular lanthanide constructs have great potential in luminescent bioprobes/sensors. Stereoselectivity on the lanthanide assemblies is needed to facilitate chiroptical probes and sensors. Herein we report the stereocontrolled synthesis of M₂L₃-type (M = metal ion, L = organic ligand) lanthanide triple-helicates using a chiral-induction strategy, where the periphery point-chirality [(R,R) or (S,S)] of the organic ligands was transferred into the metal centered chirality (ΔΔ or ΛΛ), thus leading to the formation of topological chiral (P or M) helicates. Moreover, commercially available Δ-TRISPHAT proved to be an effective NMR chiral resolving agent to differentiate between the two enantiomers of the helicate.     

Hydrocarbon (π- and σ-) complexes of nickel,palladium and platinum: Synthesis,reactivity and applications

With the exception of metallocenes, transition metal complexes with hydrocarbon ligands only are rare. However, complexes of this type containing Group 10 metals are known and have been shown to be quite stable. These complexes are versatile precursors for many organometallic compounds. In addition, such compounds can play an important role in many reactions including C–H or C–C activation reactions and have useful applications in the thermal and photochemical production of metal films by chemical vapour deposition (CVD). The present review summarizes the synthesis, properties and chemistry of hydrocarbon complexes of Group 10 metals of the type L_nM or L_nMR₁R₂ (where L_n = σ- or π-hydrocarbon ligands; M = Ni, Pd and Pt; R₁, R₂ = σ-hydrocarbon ligands) without the involvement of any hetero donor ligands such as N, P, O and S in the metal coordination spheres.     

Synthesis and asymmetric catalytic application of chiral imidazolium–phosphines derived from (1R,2R)-trans-diaminocyclohexane

Reaction between a chiral imidazole–amine precursor derived from (1R,2R)-trans-diaminocyclohexane and P¹Cl (where P¹ = PPh₂, P(1,3,5-Me₃C₆H₃)₂, P(2,2′-O,O′-(1,1′-biphenyl), P((R)-(2,2′-O,O′-(1,1′-binaphthyl))) and P((S)-(2,2′-O,O′-(1,1′-binaphthyl)))) followed by RX (where R = ⁿPr, ⁱPr, CHPh₂, X = Br; R = ⁱPr, X = I), respectively, gives a selection of chiral imidazolium–phosphine compounds. Deprotonation of the imidazolium salt gives the corresponding NHC–P ligands that can be used in metal-mediated asymmetric catalytic applications. Catalytic reactions show that NHC–P ligands give a significantly greater rate of reaction for a palladium catalysed allylic substitution reaction in comparison to analogous di-NHC or NHC–imine ligands and that NHC–P hybrids are also effective for iridium catalysed transfer hydrogenation.     

Approaches to (R)- and (S)-1′-(1-aminoethyl)ferrocene-1-carboxylic acid derivatives

Lipase-catalyzed esterification of (±)-methyl 1′-(1-hydroxyethyl)ferrocene-1-carboxylate 4 afforded its (R)-acetate (−)-5 (ee = 99%) and (S)-(+)-4 (ee = 90%). Stereoretentive azidation/amination/acetylation of (R)-(−)-5 gave (R)-(+)-methyl 1′-(1-acetamidoethyl)ferrocene-1-carboxylate (R)-3 (ee = 98%). In a similar manner (S)-(+)-4 was converted into (S)-(−)-3 (ee = 84%). Both enantiomers of 3 were obtained in high chemical yields without a loss of enantiomeric purity. The title compounds can be coupled with natural amino acids and peptides on both C- and N-termini.     

Insight into the mechanism of diazocompounds transformation catalyzed by hetero cuboidal clusters [Mo3CuQ4(MeBPE)3X4]+, (Q = S,Se; X = Cl,Br): The catalytically active species

Two enantiomerically pure trinuclear compounds of formula (P)-[Mo₃S₄{(R,R)-Me–BPE}₃Br₃]Br and (P)-[Mo₃Se₄{(R,R)-Me–BPE}₃Cl₃]Cl, (P)-1b.Br and (P)-1c.Cl, respectively, have been synthesized in a good yield and a stereospecific manner by excision of polymeric [Mo₃Q₇X₄]_n (Q = S or Se, X = Cl or Br) phases with (R,R)-Me–BPE{1,2-bis[(2R,5R)-2,5-(dimethylphospholan-1-yl)]ethane}. They have been transformed into chiral hetereo cuboidal compounds [Mo₃S₄{(R,R)-Me–BPE}₃Br₃]PF₆, (P)-2b.PF₆, and [Mo₃Se₄{(R,R)-Me–BPE}₃Cl₃]PF₆, (P)-2c.PF₆, by reaction with copper salts. All these compounds have been characterized by ³¹P NMR, IR, UV–Vis, mass spectrometry, elemental analysis, and chiral dichroism. The catalytic potential of tetranuclear cuboidal compounds has been assessed in the paradigm intermolecular cyclopropanation reaction of styrene with ethyl diazoacetate. Results are compared with those obtained for the analogue [Mo₃S₄{(R,R)-Me–BPE}₃Cl₃]PF₆, (P)-2a.PF₆. The catalytic data demonstrate that the Se derivative (P)-2c.PF₆ is less reactive than the S analogues, but it leads to a similar product distribution as the sulfide analogue (P)-2a.PF₆. By contrast, exchange of chlorine by the bulky bromine gives rise to a catalyst which makes the carbene dimerization more competitive. These data agree with temporal breaking of one of the Cu–Q bonds to generate an active catalytic species.     

Chiral polyamino alcohols and polyamino thiols for asymmetric heterogeneous catalysis

A series of macroporous copolymer beads were synthesized by THE free radical suspension copolymerization of (S)-glycidylmethacrylate (GMA), (S)-thiiranylmethylmethacrylate (TMA), or (R,R)-phenylglycidylmethacrylate (Ph-GMA) with ethyleneglycol dimethacrylate (EDMA) or divinylbenzene (DVB). This allowed for the evaluation of their chemical and physical properties (polymer matrix nature or the structure of the heterocyclopropane) and their influence on the catalytic efficiency. These chiral polymers were subsequently transformed into polyamino alcohol or polyamino thiol derivatives by the facile ring opening of the oxirane or thiirane group with benzylamine and methylamine. Complexed with [RuCl₂(p-cymene)]₂, these derivatives were shown to be effective in the asymmetric hydrogen transfer reduction of acetophenone. The best results (conversion: 94%, ee: 71%) were obtained with benzylamine grafted onto poly(GMA-co-EDMA) (30/70 % wt/wt).