Search

The use of enzymes in preparative biocatalysis often requires tailoring enzyme selectivity by protein engineering. Herein we explore the use of computational library design and molecular dynamics simulations to create variants of limonene epoxide hydrolase that produce enantiomeric diols from meso‐epoxides. Three substrates of different sizes were targeted: cis‐2,3‐butene oxide, cyclopentene oxide, and cis‐stilbene oxide. Most of the 28 designs tested were active and showed the predicted enantioselectivity. Excellent enantioselectivities were obtained for the bulky substrate cis‐stilbene oxide, and enantiocomplementary mutants produced (S,S)‐ and (R,R)‐stilbene diol with >97 % enantiomeric excess. An (R,R)‐selective mutant was used to prepare (R,R)‐stilbene diol with high enantiopurity (98 % conversion into diol, >99 % ee). Some variants displayed higher catalytic rates (k cat) than the original enzyme, but in most cases K M values increased as well. The results demonstrate the feasibility of computational design and screening to engineer enantioselective epoxide hydrolase variants with very limited laboratory screening., Overcoming bottlenecks: This paper describes the use of computational design to obtain limonene epoxide hydrolase variants that show regioselective attack of water and thereby form enantiomeric diols from meso‐epoxides. Most of the 28 designs that were examined in the laboratory carried multiple mutations, retained stability, and gave diols with the predicted chirality.

Enantiomerically pure biheteroaromatic diphosphine oxides were synthesised and tested as organocatalysts in two different reactions involving trichlorosilyl compounds. The allylation of aldehydes with allyl(trichloro)silane afforded homoallylic alcohols in fair to good yields and up to 95% ee. Preliminary experiments showed that this new class of metal-free catalysts was able also to promote the stilbene oxide opening by addition of tetrachlorosilane with enantioselectivity higher than 80%. The interesting results in terms of chemical and stereochemical efficiency open the way to further studies towards the development of new chiral heteroaromatic Lewis bases as efficient metal-free catalysts.

Chiral oxathianes were designed, synthesized, and successfully used for asymmetric sulfur ylide mediated epoxidation. A considerable emphasis has been placed upon the design of sulfides with suitable architecture in a small number of steps (three or four). The use of (4aR,6S,8aR)-6-isopropenyl-8a-methyloctahydro-1,4-benzoxathiane in asymmetric epoxidation resulted in good diastereo- and enantioselectivity in the formation of stilbene oxide, and (2S,6S)-2-allyl-2,3,3,6-tetramethyl-1,4-oxathiane produced even better results. Moderate to good diastereoselectivities with essentially complete enantioselectivities were observed in the formation of alkyl-aryl-, vinyl-aryl-, and propargyl-aryl-substituted epoxides. The selectivities were rationalized and supported by density functional theory calculations.

trans -Stilbene oxide was oxidatively converted to 2-phenyl-1,3-dioxanes with phenyltrimethylammonium tribromide in the presence of various 1,3-diols and a catalytic amount of SbBr 3 in DMSO at room temperature. Aromatic 1,2-diol, such as hydrobenzoin, was similarly converted to 2-aryl-1,3-dioxane derivatives under the same reaction conditions.

We describe a general method for elaboration of the ethyl sidechain of tamoxifen and its primary 4-hydroxy metabolite. Novel lipidic tamoxifen and a functionalized B-ring analog were synthesized from a common stilbene oxide intermediate for potential liposomal applications including estrogen receptor targeting.

have been developed for therearrangement of epoxides to carbonyl compounds. How-ever, there has been little success in the selective rearrange-ment of epoxides, being plagued by the formation ofbyproducts and low yield.In studying the carboxylation of sterically hindered ep-oxides, we have found that in the absence of carbon dioxidethese epoxides rearranges to carbonyl compounds. Forexample

Deprotonation of PH spirophosphorane 4 bearing Martin ligands with n -BuLi followed by reaction with trans -stilbene oxide gave a pair of anti - β -hydroxy-α,β-diphenylethylspirophosphoranes 5-S P ∗ R ∗ S ∗ and 5-S P ∗ S ∗ R ∗ , whereas treatment with cis -stilbene oxide yielded syn - β -hydroxy-α,β-diphenylethylspirophosphoranes 5-S P ∗ S ∗ S ∗ . The remaining diastereomer 5-S P ∗ R ∗ R ∗ was obtained selectively by α-benzoylation of benzylspirophosphorane 3 followed by reduction with LiBH 4 . Deprotonation of the diastereomers with t -BuOK or t -BuONa lead to the stereospecific formation of stilbenes. The anti diastereomers gave cis -stilbene ( Z : E =99:1) and the syn diastereomers furnished trans -stilbene ( Z : E =1:99).

The relationship between hepatic metallothionein (MT) and glutathione (GSH) in the Red Sea bream, Pagrus major , following treatment with cadmium (Cd), zinc (Zn), buthionine sulfoximine (BSO), and trans -stilbene oxide (TSO) was sought. Cd and Zn caused an increase in total GSH concentration and induced MT. BSO greatly decreased total GSH but apparently caused no synthesis of MT. TSO treatment resulted in a slight decrease in GSH concentration and a significant increase in MT. Pretreatment with BSO had no effect on MT synthesis caused by Cd, Zn and TSO. The total GSH level thus appears to be not directly involved in the regulation of MT concentration in Red Sea bream liver. MT induced by Cd, Zn and TSO was noted to have two isoforms. Their ratio when induced by Zn was different from that in the case of induction by Cd or TSO. The isoforms of MT may thus have different biological functions.

We describe a general method for elaboration of the ethyl sidechain of tamoxifen and its primary 4-hydroxy metabolite. Novel lipidic tamoxifen and a functionalized B-ring analog were synthesized from a common stilbene oxide intermediate for potential liposomal applications including estrogen receptor targeting.

Chiral and C2-symmetric seven-membered cycloalkanones 2--6 bearing 1,2-diphenylethane-1,2-diamine and cyclohexane-1,2-diamine backbones were synthesized and evaluated their asymmetry inductive behaviours in an asymmetric epoxidation of stilbene with oxone. Although the reaction of the ketones 2 and 3 of a 1,2-diphenylethane-1,2-diamine backbone gave stilbene oxide in trace to 31% yield, those of the ketones 4-6 of a cyclohexane-1,2-diamine backbone gave the epoxide in satisfactorily high yield up to 98%. It is noteworthy that both reactions with use of stoichiometric and substoichiometric amounts of a ketone 4 gave the epoxide in the essentially same enantioselectivity, 17 and 18%. Eleven-membered cyclic ketones 7 and 8 bearing a binaphthalene backbone were also synthesized and examined their behaviours, while the enantioselectivity turned out to be marginal.

The synthesis of enantiomerically pure C2-symmetric dipyridylmethane ligands and related N,N′-dioxides is reported. A procedure for the synthesis of a few new enantiomerically pure C2-symmetric pyridine N-oxides and the preparation of four pyridine N-oxides with oxygen and nitrogen atoms as further coordinating elements in the heterocycle framework is described. All compounds were prepared from naturally occurring monoterpenes. These new compounds were assessed as organocatalysts in two different reactions, namely the allylation of aldehydes with allyltrichlorosilane that afforded homoallylic alcohols in good yields and up to 85% ee and the stilbene oxide opening by the addition of tetrachlorosilane that gave chlorohydrin in quantitative yield and up to 70% ee.

Enantiomerically pure biheteroaromatic diphosphine oxides were synthesised and tested as organocatalysts in two different reactions involving trichlorosilyl compounds. The allylation of aldehydes with allyl(trichloro)silane afforded homoallylic alcohols in fair to good yields and up to 95% ee. Preliminary experiments showed that this new class of metal-free catalysts was able also to promote the stilbene oxide opening by addition of tetrachlorosilane with enantioselectivity higher than 80%. The interesting results in terms of chemical and stereochemical efficiency open the way to further studies towards the development of new chiral heteroaromatic Lewis bases as efficient metal-free catalysts.

The synthesis of enantiomerically pure C2-symmetric dipyridylmethane ligands and related N,N′-dioxides is reported. A procedure for the synthesis of a few new enantiomerically pure C2-symmetric pyridine N-oxides and the preparation of four pyridine N-oxides with oxygen and nitrogen atoms as further coordinating elements in the heterocycle framework is described. All compounds were prepared from naturally occurring monoterpenes. These new compounds were assessed as organocatalysts in two different reactions, namely the allylation of aldehydes with allyltrichlorosilane that afforded homoallylic alcohols in good yields and up to 85% ee and the stilbene oxide opening by the addition of tetrachlorosilane that gave chlorohydrin in quantitative yield and up to 70% ee.

A series of structurally simple compounds belonging to thestilbene family were synthesized by means of a Ti(III)-mediated methodology that allows access, in an efficient manner, to derivatives of dihydrostilbene, E-stilbene, and stilbene oxide, with high yields. The antioxidant activity of these compounds has been evaluated by means of two electrochemical assays, which provide complementary information, showing that the majority of these stilbene analogs exhibit significant antioxidant activity dependent on the electronic structure and functionalization of the molecule in each case.

The lithiation of trans- and cis-stilbene oxides (+/-)-1 and 8 has been investigated. While with 8, lithiation occurred exclusively at the benzylic position, with the trans isomer (+/-)-1, ortho-lithiation competed with alpha-lithiation depending upon the experimental conditions. The configurational stability of the alpha-lithiated cis- and trans-stilbene oxides (+/-)-2 and (+/-)-9, respectively, was proved as well as that of scalemic stilbene oxide (R,R)-2.

Sonication of aromatic esters, benzil, benzoin, cis - and trans -stilbene, and trans -stilbene oxide with excess lithium in the presence of catalytic amounts of 4,4′-di- t -butylbiphenyl (DBB) in dry THF afforded bibenzyl derivatives in high yields.

The presence of epoxidase and epoxide hydrase enzymes in cell suspension culture of Phaseolus vulgaris is demonstrated. Results indicate high levels of enzyme activity using stilbene and stilbene oxide as substrates.

The cyclic oxalate esters from meso - and d , 1 -hydrobenzoin were prepared and photolyzed. Meso -hydrobenzoin oxalate gave only cis -stilbene oxide upon photolysis while the d , 1 isomer gave trans -stilbene oxide.