Catalytic asymmetric epoxidation of alkenes with arabinose-derived uloses

Four l-erythro-2-uloses were readily prepared from l-arabinose via a reaction sequence involving Fischer glycosidation, acetalization and oxidation. Bulky steric sensors at the anomeric center could enhance the stereoselectivity of the dioxirane epoxidation and one of the uloses performed with good enantioselectivity towards trans-stilbene (up to 90% ee). However, the catalysts decomposed during the epoxidation and the maximum chemical yield was only 13% under the basic conditions. Three l-threo-3-uloses could overcome the decomposition problem based on the electron withdrawing effect of the ester group(s) α to the ketone functionality. The best chemical yield was up to 93% using a ketone with two flanking ester groups. One of the improved uloses displayed moderate enantioselectivity towards trans-disubstituted and trisubstituted alkenes (40-68% ee).     

Catalytic enantioselective epoxidation with arabinose-derived uloses containing tunable steric sensors

Readily available arabinose-derived 4-uloses, containing a tunable butane-2,3-diacetal as the steric sensor, displayed increasing enantioselectivity (up to 93% ee) with the size of the acetal alkyl group in catalytic asymmetric epoxidation of trans-disubstituted and trisubstituted alkenes.     

Arabinose-derived ketones as catalysts for asymmetric epoxidation of alkenes

[reaction: see text] Readily available arabinose-derived ketones, containing a tunable butane-2,3-diacetal as the steric blocker, displayed increasing enantioselectivity (up to 90% ee) with the size of the acetal alkyl group in catalytic asymmetric epoxidation of trans-disubstituted and trisubstituted alkenes. The stereochemical communication between our ketone catalysts and the alkene substrates is mainly due to steric effect, and electronic effect involving pi-pi interaction between phenyl groups of substrate and of catalyst did not appear to be operative in our system.     

Chiral fluoro ketones for catalytic asymmetric epoxidation of alkenes with oxone

Two structurally dissimilar, chiral fluoro ketones have been prepared and their potential as enantioselective catalysts for asymmetric epoxidation with Oxone has been evaluated. The tropinone-based ketone (-)-5 was easily prepared and showed excellent reactivity but only modest enantioselectivity. The biphenyl-based ketone (-)-6 was prepared in a somewhat lengthy synthesis (along with its monofluoro and geminal fluoro analogues). This ketone exhibited only modest reactivity; 30 mol % of (-)-6 was needed to bring about complete conversion in a reasonable time. The enantioselectivity of this catalyst was generally much higher, but again very substrate dependent.     

Catalytic asymmetric allylation of ketones and a tandem asymmetric allylation/diastereoselective epoxidation of cyclic enones

A simple procedure is reported for the catalytic asymmetric allylation of ketones, utilizing titanium tetraisopropoxide, BINOL, 2-propanol additive, and tetraallylstannane as allylating agent. A variety of ketone substrates, including acetophenone derivatives and alpha,beta-unsaturated cyclic enones, reacted to form tertiary homoallylic alcohols in good yields (67-99%) and with high levels of enantioselectivity (generally >80%). A novel one-pot enantioselective allylation/diastereoselective epoxidation has also been introduced. Thus, upon completion of the allyl addition to conjugated cyclic enones, 1 equiv of tert-butyl hydroperoxide is added and the directed epoxidation of the allylic double bond ensues to afford the epoxy alcohol with high diastereoselectivity.     

Zinc-mediated asymmetric epoxidation of nitro alkenes with oxygen

The asymmetric epoxidation of nitro alkenes using oxygen in the presence of diethylzinc and N-methyl pseudo-ephedrine as a chiral additive is reported. This method provides an access to 3-substituted trans-2-nitro oxiranes of excellent diastereomeric purity (de≥98%) and with medium to good enantiomeric excesses (ee=36–82%).     

Catalytic asymmetric vinylation of ketones

This communication describes the catalytic asymmetric 1,2-addition of vinylzinc reagents to aromatic, alpha,beta-unsaturated, and dialkyl ketones with enantioselectivities between 79 and 97% and with yields ranging from 84 to 98%. The products of these reactions are tertiary allylic alcohols with chiral quaternary centers that are useful in organic synthesis. The reaction involves hydrozirconation of a terminal alkyne, transmetalation to zinc, and addition to a ketone in the presence of a chiral titanium-based Lewis acid catalyst. The reactions proceed smoothly at room temperature in under 24 h.     

Catalytic asymmetric epoxidation of cyclic enones

A highly enantioselective epoxidation of cyclic enones with hydrogen peroxide has been developed that is catalyzed by chiral primary amine salts.     

Catalytic asymmetric thiofunctionalization of unactivated alkenes

Catalytic asymmetric sulfenylation of double bonds has been achieved using a BINAM-based phosphoramide catalyst and an electrophilic sulfur source. Simple alkenes as well as styrenes afforded sulfenylated tetrahydrofurans and tetrahydropyrans by closure with pendant hydroxyl or carboxyl groups. Intermolecular thiofunctionalizations were also achieved with simple alcohols or carboxylic acids as the nucleophiles.     

Asymmetric epoxidation of cis-alkenes with arabinose-derived ketones: enantioselective synthesis of the side chain of Taxol

The ee values of asymmetric epoxidation of cis-ethyl cinnamate 15 with arabinose-derived ketones as catalyst and Oxone^® as the terminal oxidant were found to increase inversely with the size of the catalyst acetal blocking group. Ketone catalyst 2, with the least bulky methoxy acetal group, displayed the best enantioselectivity and afforded ethyl (2R,3R)-3-phenylglycidate 16 in 68% ee. Epoxide 16 was readily converted into a protected side chain of Taxol^® in five steps with an overall yield of 89%. The enantioselectivity of the epoxidation of other cis-alkenes was moderate to poor.     

Carbohydrate-derived iminium salt organocatalysts for the asymmetric epoxidation of alkenes

A new family of carbohydrate-based dihydroisoquinolinium salts has been prepared and tested for potential as asymmetric catalysts for the epoxidation of unfunctionalized alkene substrates, providing up to 57% ee in the product epoxides.     

Catalytic asymmetric cyanosilylation of ketones with chiral Lewis base

The development of broadly applicable and practical catalytic approaches for the enantioselective creation of quaternary stereocenters remains a highly desirable yet challenging goal. In this Communication, we describe a highly enantioselective cyanosilylation of acetal ketones (alpha,alpha-dialkoxy ketones) catalyzed by modified cinchona alkaloids. This reaction is the first highly enantioselective cyanosilylation of ketones catalyzed by an organic chiral Lewis base and is found to be highly efficient with acetal ketones bearing a broad range of alkyl, aryl, alkenyl, and alkynyl substituents. This new catalytic asymmetric reaction, coupled with the versatility of the acetal functionality, provides a broadly useful synthetic method for chiral building blocks bearing quaternary stereocenters. Acetal ketones, readily accessible but previously unexplored in asymmetric synthesis, demonstrate unusual reactivity and selectivity toward the nucleophilic cyanosilylation, thereby suggesting that they may be interesting substrates for other catalytic enantioselective reactions.     

Catalytic asymmetric vinylation and dienylation of ketones

A solution to the long-standing problem of catalytic asymmetric vinylation of ketones is reported. Vinylzinc reagents are generated via hydrozirconation of terminal alkynes followed by transmetalation to zinc. In the presence of our catalyst, which is formed in situ from a bis(sulfonamide) diol ligand (1) and titanium tetraisopropoxide, the vinylzinc reagent undergoes 1,2-addition to a variety of ketones and enones with enantioselectivities (typically >90%) and high yields. This method is tolerant of functional groups, including alkyl, aryl and vinyl halides, esters, silyl protected alcohols, sulfides, and alkenes. Thus, enantioenriched tertiary allylic alcohols bearing a variety of functional groups can be prepared. It has also been found that 2,2-disubstituted vinylzinc reagents, substitution patterns not accessible through hydrozirconation, can be added to ketones with high enantioselectivities to generate trisubstituted allylic alcohols. Furthermore, we have developed an asymmetric addition of dienyl groups to ketones in the presence of our catalyst. This method enables the synthesis of dienols in high yields with enantioselectivities as high as 94%.     

New chiral binaphthalene-derived iminium salt organocatalysts for asymmetric epoxidation of alkenes

A series of binaphthalene-fused azepinium salts has been generated and used as organocatalysts in the asymmetric epoxidation of unfunctionalized alkenes, giving rise to ees of up to 84%.     

Biomimetic iron-catalyzed asymmetric epoxidation of aromatic alkenes by using hydrogen peroxide

A novel and general biomimetic non-heme Fe-catalyzed asymmetric epoxidation of aromatic alkenes by using hydrogen peroxide is reported herein. The catalyst consists of ferric chloride hexahydrate (FeCl(3)6 H(2)O), pyridine-2,6-dicarboxylic acid (H(2)(pydic)), and readily accessible chiral N-arenesulfonyl-N'-benzyl-substituted ethylenediamine ligands. The asymmetric epoxidation of styrenes with this system gave high conversions but poor enantiomeric excesses (ee), whereas larger alkenes gave high conversions and ee values. For the epoxidation of trans-stilbene (1 a), the ligands (S,S)-N-(4-toluenesulfonyl)-1,2-diphenylethylenediamine ((S,S)-4 a) and its N'-benzylated derivative ((S,S)-5 a) gave opposite enantiomers of trans-stilbene oxide, that is, (S,S)-2 a and (R,R)-2 a, respectively. The enantioselectivity of alkene epoxidation is controlled by steric and electronic factors, although steric effects are more dominant. Preliminary mechanistic studies suggest the in situ formation of several chiral Fe-complexes, such as [FeCl(L*)(2)(pydic)]HCl (L*=(S,S)-4 a or (S,S)-5 a in the catalyst mixture), which were identified by ESIMS. A UV/Vis study of the catalyst mixture, which consisted of FeCl(3)6 H(2)O, H(2)(pydic), and (S,S)-4 a, suggested the formation of a new species with an absorbance peak at lambda=465 nm upon treatment with hydrogen peroxide. With the aid of two independent spin traps, we could confirm by EPR spectroscopy that the reaction proceeds via radical intermediates. Kinetic studies with deuterated styrenes showed inverse secondary kinetic isotope effects, with values of k(H)/k(D)=0.93 for the beta carbon and k(H)/k(D)=0.97 for the alpha carbon, which suggested an unsymmetrical transition state with stepwise O transfer. Competitive epoxidation of para-substituted styrenes revealed a linear dual-parameter Hammett plot with a slope of 1.00. Under standard conditions, epoxidation of 1 a in the presence of ten equivalents of H(2) (18)O resulted in an absence of the isotopic label in (S,S)-2 a. A positive nonlinear effect was observed during the epoxidation of 1 a in the presence of (S,S)-5 a and (R,R)-5 a.     

Catalytic asymmetric cyanosilylation of ketones by a chiral amino acid salt

In this Communication, we describe the first highly enantioselective cyanosilylation of ketones catalyzed by simple chiral amino acid salt. A broad range of aromatic, alpha,beta-unsaturated, heterocyclic ketones catalyzed by l-phenylglycine sodium salt gave the corresponding trimethylsilyl ethers of cyanohydrins in 75-96% yields with 86-97% enantioselectivities. A catalytic cycle based on experimental phenomena and studies has been proposed to explain the origin of this activation. The reaction employed commercially available and fully recyclable catalysts and involves a simple experimental procedure.     

Practical synthesis of Shi's diester fructose derivative for catalytic asymmetric epoxidation of alkenes

[reaction: see text] A practical synthesis of Shi's diester 3 for catalytic asymmetric epoxidations has been developed. The catalyst has been prepared in multigram quantities from D-fructose in four steps with a 66% overall yield. Efficiency, cost, and selectivity aspects of the reagents involved for its preparation have been taken care of during its preparation. The workup procedures have been simplified to the bare minimum, rendering a very practical preparation method. The well-known high efficiency of this catalyst 3 in the epoxidation of alpha,beta-unsaturated carbonyl compounds has also proved to be high in unfunctionalized alkenes.     

A new class of chiral tetrahydropyran-4-one catalyst for asymmetric epoxidation of alkenes

A new class of chiral α-oxygenated-tetrahydropyran-4-ones for asymmetric epoxidation of alkenes using Oxone^® is described, affording epoxides with up to 83% ee.     

Catalytic and asymmetric vinylogous mukaiyama reactions on aliphatic ketones: formal asymmetric synthesis of taurospongin a

Catalytic asymmetric vinylogous Mukaiyama reactions on ketones, leading to the formation of alpha,beta-unsaturated lactones with tertiary alcohols, have been described (11 examples, up to 93% ee). This methodology has been applied in a formal enantioselective synthesis of taurospongin A (12 steps, 6% overall yield).