Flavin–cyclodextrin conjugates: effect of the structure on the catalytic activity in enantioselective sulfoxidations

A series of flavin–cyclodextrin conjugates has been prepared and tested in the enantioselective oxidations of prochiral aromatic and aliphatic sulfides with hydrogen peroxide. The newly prepared conjugates contain isoalloxazinium or alloxazinium moieties attached to the primary rim of α- and β-cyclodextrins at the C-6 positions. In addition, flavinium units were attached to the secondary rim of the β-cyclodextrin macrocycle. The relationship between the structural features and the catalytic performance of the conjugates, including those recently reported by us, was analyzed. The rate and enantioselectivity of the sulfoxidations catalyzed by flavin–cyclodextrin conjugates are influenced mainly by the size of the cyclodextrin cavity, the type of flavin unit (alloxazine or isoalloxazine), and by the relative orientation of the flavin and cyclodextrin moieties.     

Copper-catalyzed asymmetric oxidation of sulfides

Copper-catalyzed asymmetric sulfoxidation of aryl benzyl and aryl alkyl sulfides, using aqueous hydrogen peroxide as the oxidant, has been investigated. A relationship between the steric effects of the sulfide substituents and the enantioselectivity of the oxidation has been observed, with up to 93% ee for 2-naphthylmethyl phenyl sulfoxide, in modest yield in this instance (up to 30%). The influence of variation of solvent and ligand structure was examined, and the optimized conditions were then used to oxidize a number of aryl alkyl and aryl benzyl sulfides, producing sulfoxides in excellent yields in most cases (up to 92%), and good enantiopurities in certain cases (up to 84% ee).     

Asymmetric sulfoxidation of a β-carbonyl sulfide series by chloroperoxidase

The chloroperoxidase (CPO)-catalyzed oxidation of a series of β-carbonyl sulfides to sulfoxides has been studied at room temperature in aqueous citrate buffer. For dialkyl β-carbonyl sulfides, the products with methyl and ethyl substituents are obtained in ca. 100% yield. However when the alkyl group is n-propyl or i-propyl the yield drops dramatically (25%). An aryl sulfide derivative afforded product in very low yield (4%), but when the phenyl group bears a carbonyl, and the sulfur substituents are methyl or ethyl, the oxidation occurs with high yields (91–95%). Steric control of the sulfoxidation reaction is also confirmed with cyclohexanone derivatives, where a low product yield is observed even at high enzyme concentrations. Noteworthy are the yields obtained with cyclopentanone sulfide (65%) and an unexpected quantitative yield obtained with the γ-butyrolactone sulfide.     

Catalytic asymmetric oxidation of sulfide and styrene derivatives using macroporous resins containing chiral metalloporphyrins (Fe, Ru)

Chiral metalloporphyrin (Fe, Ru) complexes, functionalized with four vinyl groups, have been polymerized with styrene and divinylbenzene (or ethylene glycol) to obtain supported iron and ruthenium complexes. The heterogeneous asymmetric oxidation of sulfides and styrene derivatives was carried out by using these polymers as catalysts. The reaction proceeded under mild conditions and gave sulfoxides and epoxides with good enantiomeric excesses (up to 75–76%). The catalysts keep constant ee values for the recycle tests of up to six times for asymmetric oxidation of styrene derivatives and of up to 14 times for asymmetric oxidation of sulfides with only traces of sulfones.     

First enantioselective iron-porphyrin-catalyzed sulfide oxidation with aqueous hydrogen peroxide

The asymmetric oxidation of sulfides by H(2)O(2) to give optically active sulfoxides (ee up to 90%) was carried out in methanol and water using chiral water-soluble iron porphyrins as catalysts.     

Parallel synthesis of 2,4,5-trisubstituted thiophene-3-carbonitrile derivatives on traceless solid support

A parallel solid-phase synthesis of 2,4,5-trisubstituted thiophene-3-carbonitrile derivatives was developed. The polymer-supported synthetic route progressed using the sulfide linker via a traceless strategy. The initial synthesis utilized the Thorpe–Ziegler type cyclization of α-haloketone and polymer-supported 2,2-dicyanoethene-1,1-bis(thiolate), which was derived from the Merrifield resin. The resulting thiophene resin was introduced to one substitution by N-arylation. After oxidation of sulfides to sulfones in the thiophene resins for subsequent cleavage, nucleophilic desulfonative substitution with amines and thiols afforded the desired thiophene-3-carbonitrile derivatives in good overall yields.     

Immobilization of MoO2Cl2 on polystyrene via different linkers and oxidation of sulfides in the presence of hydrogen peroxide

Chloromethylated polystyrene was oxidized to aldehydic polystyrene and by reaction of this aldehydic polystyrene resin with furfuryl amine and 2-(amino methyl) pyridine, imine-bounded polystyrene resins 1a and 1b were obtained. Amine-bounded polystyrene resins 1c?C1f were also prepared by direct reaction of chloromethylated polystyrene and amines. These functionalized polystyrene resins were used to immobilize MoO₂Cl₂ on polystyrene. These functionalized polystyrene resins were characterized with elemental analysis (CHN) and FT-IR spectrum. Polymer-supported catalysts were characterized with FT-IR and neutron activation analysis (NAA). These catalysts were used in oxidation of methyl phenyl sulfide in the presence of H₂O₂ as oxidant and the results showed that these catalysts were highly active and selective. The reusability of these heterogeneous catalysts was also investigated and the results showed that the supported MoO₂Cl₂ catalyst on polystyrene via imidazole liker was highly reusable as it was used 15 times in oxidation of methyl phenyl sulfide in the presence of environmental benign oxidant (H₂O₂) and solvent (H₂O) without any decrease in its activity. Then the catalytic activity of these supported catalysts was investigated in oxidation of some aliphatic and aromatic sulfides. Almost all of these supported molybdenum-based catalysts were highly active and selective in the conversion of these sulfides to their corresponding sulfoxides.     

Highly enantioselective aldol reaction of acetone with β,γ-unsaturated α-keto esters promoted by simple chiral primary-tertiary diamine catalysts

A series of primary-tertiary diamine catalysts were successfully applied to promote the enantioselective aldol reaction of acetone with β,γ-unsaturated α-keto esters in excellent yields (up to 99%) and enantioselectivities (up to 96% ee).     

Bifunctional cinchona alkaloids-catalyzed asymmetric [4+2] cycloaddition reaction of β,γ-unsaturated α-keto esters with oxazolones

A highly enantioselective [4+2] cycloaddition reaction of β,γ-unsaturated α-keto esters with oxazolones was realized with readily available cinchona alkaloids as the catalysts. Using this reaction, a series of highly functionalized δ-lactones with adjacent α-quaternary-β-tertiary stereocenters were obtained in high yields (up to 97%) and with good-to-excellent enantioselectivities (up to 97% ee).     

Molecular addition compounds. 17. Borane and chloroborane adducts with organic sulfides for hydroboration

The following sulfides have been examined as borane carriers in comparison with dimethyl sulfide and 1,4-oxathiane: tert-butyl methyl sulfide, isoamyl methyl sulfide, ethyl isoamyl sulfide, tert-butyl isoamyl sulfide, diisoamyl sulfide, tetrahydrothiophene, tetrahydro-thiopyran, thioanisole, 3-ethylthiotetrahydrofuran, bis(3-tetrahydrofuryl) sulfide, and bis(2-methoxyethyl) sulfide. Their complexing ability toward borane increases in the following order: thioanisole < ether-sulfides < dialkyl sulfides < dimethyl sulfide. Borane adducts of the sulfides are liquids above 0 degrees C. The thioanisole adduct loses diborane at room temperature. The reactivity of the adducts toward 1-octene increases in the reversed order of the complexing ability of the sulfides. Diisoamyl sulfide has a mild, ethereal, agreeable aroma, its synthesis is economical and the borane adduct, 4.2 M in BH3, is stable over prolonged periods at room temperature. The sulfide can be recovered from hydroboration-oxidation products by distillation. Consequently, diisoamyl sulfide is a new promising borane carrier. Bis(2-methoxyethyl) sulfide, easily synthesized from the low cost thiodiethanol, is three times more soluble in water than 1,4-oxathiane. Its borane adduct is 6.0 M in BH3 and can substitute for more expensive borane-1,4-oxathiane in hydroboration reactions. Applications of these new borane adducts in the synthesis of mono- and dichloroborane adducts was also studied. The equilibrium ratios observed for the new chloroborane adducts were similar to that observed for dimethyl sulfide adducts. However, the hydroboration of 1-octene with these new chloroborane adducts are much faster than the corresponding adducts of dimethyl sulfide, which are currently used extensively.     

手性药物催化β-酮酸酯不对称α-羟基化反应研究

以商业化易得的具有碱性氮原子的手性药物为有机催化剂,用于催化β-酮酸酯不对称α-羟基化反应,发现以噻吗洛尔或普萘洛尔为催化剂,反应对映选择性分别可达32%和18%.对噻吗洛尔和普萘洛尔进行结构修饰,合成了12个洛尔药物类似物,并考察了其催化效果,发现在优化的反应条件下,以30mol%(R)-1-叔丁胺基-3-(2-萘氧基)-2-丙醇(7f)为催化剂,20mol%β-环糊精为助催化剂,叔丁基过氧化氢为氧化剂,正己烷为溶剂,反应对映选择性最高可达57%,收率92%.不对称α-羟基化产物(S)-5-氯-2-羟基-1-茚酮-2-甲酸甲酯(2a)在乙酸乙酯中一次重结晶后,对映体光学纯度可达99%,收率68%.     

A novel 5-thioglycosylation method with 1,5-dithioglycosyl donors: relevance to exo- versus endocyclic activation

5-Thioglucosylation of a 1,6-anhydro-2-azido-2-deoxy-β-d-glucopyranose derivative was carried out with various 1,5-dithioglucosyl donors. The use of per-O-acetyl donors resulted in poor yields of an α-disaccharide. On the other hand, per-O-benzyl donors selectively gave an α-disaccharide in good to excellent yields regardless of the anomeric configuration of the donors. To study the relevance of the glycosylation results to the pre-equilibrium of exo- versus endocyclic sulfide activation, the relative nucleophilicities of exo- and endocyclic sulfides were estimated from the regioselectivities in the electrophilic oxidation of the per-O-benzyl donors with m-chloroperbenzoic acid. The results obeyed stereoelectronic effects and the endocyclic sulfides were more nucleophilic than the exocyclic sulfides for both anomers of per-O-benzyl-1,5-dithioglucosyl donors, the relative nucleophilicities of the endocyclic over exocyclic sulfides being 67% and 100%, respectively, for the α- and β-anomers. The results of the glycosidation and oxidation suggest that the glycosidation proceeded through an exocyclic cleavage mechanism despite the preferential endocyclic activation of 1,5-dithioglucosides.     

Distinct Selectivity Control in Solar-Driven Bio-Based α-Hydroxyl Acid Conversion: A Comparison of Pt Nanoparticles and Atomically Dispersed Pt on CdS

Solar-driven photocatalytic lignocellulose conversion is a promising strategy for the sustainable production of high-value chemicals, but selectivity control remains a challenging goal in this field. Here, we report efficient and selective conversion of lignocellulose-derived α-hydroxyl acids to tartaric acid derivatives, α-keto acids, and H₂ using Pt-modified CdS catalysts. Pt nanoparticles on CdS selectively produce tartaric acid derivatives via C−C coupling, while atomically dispersed Pt on CdS switches product selectivity to the oxidation reaction to produce α-keto acids. The atomically dispersed Pt species stabilized by Pt−S bonds promote the activation of the hydroxyl group and thus switch product selectivity from tartaric acid derivatives to α-keto acids. A broad range of lignocellulose-derived α-hydroxyl acids was applied for preparing the corresponding tartaric acid derivatives and α-keto acids over the two Pt-modified CdS catalysts. This work highlights the unique performance of metal sulfides in coupling reactions and demonstrates a strategy for rationally tuning product selectivity by engineering the interaction between metal sulfide and cocatalyst.     

Organocatalytic asymmetric conjugate addition and cascade acyl transfer reaction of α-nitroketones

Organocatalytic asymmetric conjugate addition of α-nitroketones to β,γ-unsaturated α-keto esters has been developed. A pyrrolidine-based thiourea-tertiary amine was identified as the best catalyst. The reaction was found to proceed via cascade conjugate addition and acyl transfer reaction. A number of α-nitroketones and β,γ-unsaturated α-keto esters were examined in this transformation. 5-Nitro-2-acyloxypent-2-enoates were obtained in good yields (up to 99%) and enantioselectivities (up to 99% ee). The products could be hydrolyzed to provide 5-nitro-2-oxopentanoates, which are not available from the direct addition of nitromethane to β,γ-unsaturated α-keto esters.     

Highly enantioselective synthesis of α,α-dialkylmalonates by phase-transfer catalytic desymmetrization

A novel enantioselective synthetic method for the construction of a quaternary carbon center from malonates via phase-transfer catalytic (PTC) alkylation has been developed. The asymmetric α-alkylation of diphenylmethyl tert-butyl α-alkylmalonates with alkylating agents under phase-transfer catalysis conditions (aq 50% KOH, toluene, 0 °C) in the presence of (S,S)-3,4,5-trifluorophenyl-NAS bromide (8) as PTC catalyst afforded the corresponding α,α-dialkylmalonates in high chemical (up to 99%) and optical yields (up to 97% ee) which could be readily converted to versatile chiral intermediates. Notably, the direct double α-alkylations of diphenylmethyl tert-butyl malonate also provided the corresponding α,α-dialkylmalonates without loss of enantioselectivity. The synthetic potential of this method has been demonstrated by the preparation of α,α-dialkylamino acid and oxindole systems.     

Highly enantioselective copper-catalyzed electrophilic trifluoromethylation of β-ketoesters

Enantioselective Cu-catalyzed trifluoromethylation of β-ketoesters using commercially available trifluoromethylating reagents is reported. A number of α-CF(3) β-ketoesters are obtained with up to 99% ee. The trifluoromethylated products were then transformed diastereoselectively to α-CF(3) β-hydroxyesters with two adjacent quaternary stereocenters via a Grignard reaction.     

Investigation of steric and electronic effects in the copper-catalysed asymmetric oxidation of sulfides

Steric and electronic effects in the copper-catalysed asymmetric oxidation of aryl benzyl, aryl alkyl and alkyl benzyl sulfides have been investigated. The presence of an aryl group directly attached to the sulfur is essential to afford sulfoxides with high enantioselectivities, with up to 97% ee for 2-naphthyl benzyl sulfoxide, the highest enantioselectivity achieved to date for copper-catalysed asymmetric sulfoxidation. In contrast, the benzyl substituent can be replaced by sterically comparable groups with no effect on enantioselectivity. Copper-mediated oxidation of substituted aryl benzyl sulfides display modest steric and electronic effects resulting in comparable or lower enantioselectivities to those obtained with the unsubstituted benzyl phenyl sulfide.     

Enantioselective oxysulfenylation and oxyselenenylation of olefins catalyzed by chiral Brønsted acids

This paper describes Brønsted acid catalyzed enantioselective oxysulfenylation and oxyselenenylation of olefins. Enantiomerically enriched tetrahydrofurans are formed with up to 63% ee with dibenzoyl-d-tartaric acid and its derivatives as catalyst. Chiral β-carboxyl sulfides and selenides have also been obtained with up to 50% and 84% ee, respectively, via enantioselective desymmetrization of thiiranium and seleniranium ions in the presence of catalytic amounts of chiral binaphthol derived N-triflyl phosphoramide.     

Asymmetric copper-catalyzed

The asymmetric copper-catalyzed generation and subsequent [2,3]-sigmatropic rearrangement of sulfur ylides is strongly dependent on the structure of the starting allyl sulfide. A series of alkyl and aryl substituted allyl sulfides (2a-i) were reacted with ethyl diazoacetate in the presence of copper triflate (CuOTf) and a C2-symmetric bis-oxazoline ligand (5a-c). The degree of asymmetric induction ranged from 2.8% for allyl methyl sulfide (2a) to 60% for (1S,2S,5R)-(+)-allyl menthyl sulfide (2d). The enantioselectivity of the reactions was also dependent on the electronic nature of the sulfide; allyl phenyl sulfide (2e) gave a 14% ee, whereas allyl p-methoxyphenyl sulfide (2i) produced only an 8% ee. The stereochemistry of 2d and (1R,2S,5R)-(+)-allyl menthyl sulfide (7) was assigned on the basis of NMR spectroscopic experiments.     

新型手性相转移催化剂的合成及其催化作用研究

以金鸡纳生物碱和2-氯甲基苯并咪唑为原料方便地合成了四种新型的手性相转移催化剂. 该类催化剂在相转移催化的二苯亚胺甘氨酸叔丁酯的对映选择性烷基化反应中, 可有效地催化多种卤代烃的不对称烷基化反应, 化学产率最高达85%, 对映体过量值最高达95% ee.