Construction of an enantiomerically pure 6-substituted 3,5-syn-dihydroxyhexanoic acid system by an enantioselective deprotonation strategy: formal synthesis of an antiobesity agent, (-)-tetrahydrolipstatin

Preparation of 6-substituted 4-hydroxytetrahydro-2H-pyran-2-one (12), a key intermediate for the synthesis of (-)-tetrahydrolipstatin, was achieved in an optically pure form by employing an enantioselective deprotonation reaction of the prochiral bicyclic derivative (5) as a key step.     

Chemoselective Henry reaction catalyzed by electro-generated base

Chemoselective synthesis of 2-nitroalkanols catalyzed by electro-generated base (EGBs) in the presence of acetonitrile and lithium perchlorate has been studied by cyclic voltammetry and controlled potential electrolysis techniques. Cathodic reduction of nitromethane at platinum cathode produces organic anion which acts as EGBs and undergoes condensation with carbonyl group of substituted aldehydic substrate to produce 2-nitroalkanols in 75–85 % yields. The controlled nucleophilicity of EGBs in organic solvent during electrochemical reaction makes it chemoselective which is a unique feature of this work.     

The molecular weight limiting step in the ring-opening polymerization of 1,1-disubstituted epoxides catalyzed by bis(diisobutylaluminum)oxide

The ring-opening polymerization of 1,2-epoxy-4,4,4-trifluoro-2-methylbutane ( 2 ) and its unfluorinated analogue, 1,2-epoxy-2-methylbutane ( 3 ), gives the expected polyethers when catalyzed by bis(diisobutylaluminum)oxide. However, the molecular weights are low because of a competing deprotonation/ring-opening of the epoxide that produces all three possible alkene end groups and their stereoisomers. With 2 , deprotonation occurs mainly at the methyl group to give the terminal double bond and only minor amounts of the internal double bond. However, 3 gives the opposite regiochemistry. A model is proposed where this reaction occurs within an aluminum(polyether oxide) bound to the least hindered face of the epoxide ring. In this model, the different regiochemistries originate from a concerted and highly directed deprotonation/ring-opening of 2 versus a step-wise deprotonation of 3 through its ring-opened, tertiary-cation.     

Dibenzophenazine derivatives as visible photosensitizers for diaryliodonium salts

The use of two dibenzo[a,c]phenazine derivatives, 10,13‐bis(2,3‐dihydrothieno[3,4‐b][1,4]dioxin‐5‐yl)dibenzo[a,c]phenazine and 10,13‐bis(4‐hexylthiophen‐2‐yl)dibenzo[a,c]phenazine are reported as photosensitizers for diaryliodonium salt photoinitiators. Novel dyes based on the dibenzo[a,c]phenazine skeleton are shown to be efficient in carrying out the cationic photopolymerizations. Representative examples of different types of monomers including epoxide, and vinyl monomers are polymerized in the presence of the photosensitizers and diphenyliodonium hexafluorophosphate (Ph₂I⁺PF). Polymerizations are initiated at room temperature using long wavelength UV and visible light, and monitored by optical pyrometry. The photopolymerization of an epoxide monomer via solar irradiation is also demonstrated. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Stereoselective reactions. XXXIV. Enantioselective deprotonation of prochiral 4-substituted cyclohexanones using chiral bidentate lithium amides having a bulky group instead of a phenyl group on the chiral carbon

Using chiral bidentate lithium amides having a bulky group instead of a phenyl group on the chiral carbon, enantioselective deprotonation of prochiral 4-substituted cyclohexanones in the presence of excess trimethylsilyl chloride was examined in THF in the absence and in the presence of HMPA. It is shown that enantioselectivity of the reactions decreases as the substituent on the chiral carbon of the chiral lithium amides and the substituent at the 4-position of cyclohexanones become reasonably bulky. An eight-membered cyclic transition state model is proposed for this deprotonation reaction.     

New Chiral Ligands with Nonstereogenic Chirotopic Centers for Asymmetric Synthesis

Pseudo- C ₂ -symmetrical ligands have been prepared efficiently: The attachment of the chiral alkyl group to the heteroatom (P or N) through a nonstereogenic, chirotopic carbon center facilitates their synthesis as the configuration at this carbon atom no longer needs to be controlled. Two such ligands were combined, for example, in the base 1 , which is especially useful for asymmetric deprotonation of prochiral ketones [Eq. (a)].     

Stereochemical course in water addition during LUP1-catalyzed triterpene cyclization

Arabidopsis thaliana LUP1 (At1g78970) catalyzes the cyclization of oxidosqualene into lupeol and 3beta,20-dihydroxylupane (lupanediol). The stereochemical course of water addition to the lupanyl cation was studied. The X-ray crystal structure of lupanylepoxide 3,5-dinitrobenzoate established the configuration of epoxide as 20S. LiAlD4 reduction of the epoxide enabled the chemical shift assignment of prochiral methyl groups at C20 of lupanediol. Correlation of these methyl groups with biosynthetic lupanediol from [1,2-(13)C(2)] acetate established the stereochemical course of water addition. [reaction: see text].     

Enantioselective deprotonation reactions using polymer-supported chiral magnesium amide bases

Novel and readily accessible polymer-supported chiral magnesium amide reagents have been prepared and shown to be effective in the asymmetric deprotonation of a series of prochiral cyclohexanones, affording good to excellent levels of both conversion and enantiomeric ratio (up to 93:7); the Merrifield-based chiral amine species has been shown to be readily recyclable.     

Mild,fast, and stereoselective epoxide opening by ketone enolate anions. Application to synthesis of the norlignan curculigine

We report here that (1) enolate anions of five- to seven-membered cycloalkanones nucleophilically open cyclopentene and cyclohexene oxides in 57-76% yields and with 4-8:1 diastereoselectivity; (2) enolate anions formed regiospecifically via kinetic deprotonation of 2-cyclohexenone and 2-cycloheptenone open cyclohexene oxide in 60-62% yields and with 32-95:1 diastereoselectivity; and (3) an aryl methyl ketone enolate anion opens a monosubstituted epoxide as the key step in a short synthesis of the gamma-hydroxyketone (GHK) aglycon of the natural product curculigine.     

Asymmetric alkene epoxidation catalysed by a novel family of chiral metalloporphyrins: effect of structure on catalyst activity,stability and enantioselectivity

A selection of alkenes has been epoxidised with iodosylbenzene, catalysed by three related iron(III) tetraarylporphyrins: 1*, 2* and 3* with four 2,6-di(1-phenylbutoxy)phenyl groups, with one pentafluorophenyl and three 2,6-di(1-phenylbutoxy)phenyl groups and with two pentafluorophenyl and two 2,6-di(1-phenylbutoxy)phenyl groups, respectively. 1* is very sterically hindered and prone to self-oxidation which makes it a relatively poor epoxidation catalyst. Introducing the smaller pentafluorophenyl groups, in place of 2,6-di(1-phenylbutoxy)phenyl, increases catalyst reactivity, stability and selectivity. This change allows easier access of the substrates to the active oxidant and also, by decreasing the electron density on the porphyrin ligand, increases the reactivity of the oxoiron intermediate and its stability towards self-oxidation. A family of five homochiral catalysts, 1, 2 and 3, [the analogues of 1*, 2* and 3*, prepared from (R,R)-2,6-di(1-phenylbutoxy)benzaldehyde] and catalyst 4 with three pentafluorophenyl and one (R,R)-2,6-di(1-phenylbutoxy)phenyl group and 5 the manganese(III) analogue of 3 have been used to epoxidise three prochiral alkenes. All the reactions give low enantioselectivities. Using styrene as the substrate, (S)-styrene epoxide is the major enantiomer obtained with all the catalysts except 1 which leads to the (R)-styrene epoxide being preferred. In contrast cis-hept-2-ene and 2-methylbut-2-ene give the same major epoxide enantiomer with all the catalysts. The dependence of the ee values on catalyst and substrate structure, temperature and solvent is examined and discussed.     

Transition state studies on the dioxirane-mediated asymmetric epoxidation via kinetic resolution and desymmetrization

This paper describes an efficient kinetic resolution process of trisubstituted cyclic olefins via a chiral dioxirane generated in situ from a fructose-derived ketone and Oxone. The substrates presented include a variety of 1,3-disubstituted and 1,6-disubstituted cyclohexenes with the stereogenic centers at allylic positions. A sequential desymmetrization and kinetic resolution of 1,4-cyclohexadienes by the chiral dioxirane was also found to be feasible. The initially formed monoepoxides can be kinetically resolved by continuing the reaction, leading to the increase or decrease of the ee values of monoepoxides depending on the diene systems. In some cases, a prochiral directing group is not required and the first formed epoxide stereoselectively directs the second epoxidation. When the coupled desymmetrization and kinetic resolution is used synergistically, high enantiopurity can be obtained for an epoxide from an intrinsically less enantioselective substrate. The observed absolute and relative stereochemistry as well as the changing optical purity can be effectively rationalized by transition state analysis.     

Synthesis of Polymer-supported Chiral Lithium Amide Bases and Application in Asymmetric Deprotonation of Prochiral Cyclic Ketones

Polymer-supported chiral amines were effectively prepared from amino acid derivatives and Merrifield resin. Treatment of polymer-supported amines with n-butyllithium gave the corresponding polymer-suppported chiral lithium amide bases, which were tested in the asymmetric deprotonation reactions of prochiral ketones. The trimethylsilyl enol ethers were obtained in up to 82% ee at room temperature. The polymer-supported chiral lithium amides can be readily recycled and reused without any significant loss of reactivity or selectivity.     

Investigation of site selectivity of the stereoselective deprotonation of cyclohexene oxide using kinetic resolution of isotopic enantiomers in natural abundance

Stereoselective deprotonation of epoxides with lithium amides can occur by abstraction of protons from more than one site. The site selectivity of the deprotonation of cyclohexene oxide by several chiral and achiral lithium amides has been investigated. ²H NMR has been used to measure the relative abundances of the isotopomers of the epoxide containing one deuterium. An isotopic stereoisomer, with deuterium in the site undergoing abstraction, reacts slower than its enantiomer and other isotopomers having protium in the same site due to a kinetic isotope effect. This results in a kinetic resolution yielding a relative excess of the less reactive isotopic stereoisomer. Thus, the relative abundance of such an enantiomer increases when compared with those having protium at the site in question as the reaction proceeds. It can be concluded that deprotonation of cyclohexene oxide using some chiral- and non-chiral lithium amides occurs by β_syn-deprotonation.     

Shifting the equilibrium of a biocatalytic cascade synthesis to enantiopure epoxides using anion exchangers

Hydroxide-loaded anion exchangers have been successfully employed to shift the equilibrium of a one-pot, two-step, two-enzyme cascade reaction affording enantiopure epoxides starting from prochiral α-chloroketones. The α-chloroketones were asymmetrically reduced employing an alcohol dehydrogenase and then transformed further to the corresponding epoxides employing halohydrin dehalogenases. Each epoxide enantiomer could be obtained with up to 93% conversion in enantiomerically pure form (>99% ee). In contrast to previous studies the amount of hydride donor (2-propanol) could be reduced due to favoured halohydrin formation in the reduction of α-chloroketones.     

Deprotonation-electrophile trapping of terminal epoxides

Organolithium-induced deprotonation of terminal epoxides in the presence of appropriate diamine ligands allows trapping with a range of electrophiles, yielding functionalised di- and tri-substituted epoxides in good yields and with control of stereochemistry at the epoxide.     

有机磷试剂在不对称反应中的应用

由于其结构多样性,有机磷化合物作为配体、催化剂、辅助剂、添加剂、底物以及试剂等在不对称反应中均获得了成功的应用,从而使有机磷试剂在不对称反应研究领域占有举足轻重的地位.本文全面介绍了本课题组近几年来围绕有机磷试剂在不对称反应中的应用,在醛的不对称硅氰化反应、内消旋环氧烷不对称开环反应、潜手性酮的不对称硼烷还原、不对称Friedel-Crafts烷基化、对映选择Mitsunobu、不对称aza-Morita-Baylis-Hillman、不对称aza-Henry以及硝基烯的不对称Michael加成反应等方面所取得的一些研究结果.     

Complexes of functionalized dipyrido[3,2-a:2',3'-c]-phenazine: a synthetic, spectroscopic, structural, and density functional theory study

The ligands 11-bromodipyrido[3,2-a:2',3'-c]phenazine and ethyl dipyrido[3,2-a:2',3'-c]phenazine-11-carboxylate have been prepared and coordinated to ruthenium(II), rhenium(I), and copper(I) metal centers. The electronic effects of substitution of dipyrido[2,3-a:3',2'-c]phenazine (dppz) have been investigated by spectroscopy and electrochemistry, and some photophysical properties have been studied. The crystal structures of [Re(L)(CO)(3)Cl] (L = ethyl dipyrido[3,2-a:2',3'-c]phenazine-11-carboxylate or 11-bromodipyrido[3,2-a:2',3'-c]phenazine) are presented. Density functional theory calculations on the complexes show only small deviations in bond lengths and angles (most bonds within 0.02 Angstroms, most angles within 2 degrees) from the crystallographic data. Furthermore, the vibrational spectra of the strongest Raman and IR bands are predicted to within an average 6 cm(-1) for the complexes [Re(L)(CO)(3)Cl] and [Cu(L)(triphenylphosphine)(2)]BF(4) (in the 1000-1700 cm(-1) region). Spectroscopic and electrochemical evidence suggest that reduction of the complex causes structural changes across the entire dppz ligand. This is unusual as dppz-based ligands typically have electrochemical properties that suggest charge localization with reduction on the phenazine portion of the ligand. The excited-state lifetimes of the complexes have been measured, and they range from ca. 200 ns for the [Ru(L)(2,2'-bipyridine)(2)](PF(6))(2) complexes to over 2 mus for [Cu(11-bromodipyrido[3,2-a:2',3'-c]phenazine)(PPh(3))(2)](BF(4)) at room temperature. The emission spectra suggest that the unusually long-lived excited states of the copper complexes result from metal-to-ligand charge transfer (MLCT) transitions as they are completely quenched in methanol. Electroluminescent films may be fabricated from these compounds; they show MLCT state emission even at low doping levels [<0.1% by weight in poly(vinylcarbazole) polymer matrix].     

Catalytic double carbonylation of epoxides to succinic anhydrides: catalyst discovery, reaction scope, and mechanism

The first catalytic method for the efficient conversion of epoxides to succinic anhydrides via one-pot double carbonylation is reported. This reaction occurs in two stages: first, the epoxide is carbonylated to a beta-lactone, and then the beta-lactone is subsequently carbonylated to a succinic anhydride. This reaction is made possible by the bimetallic catalyst [(ClTPP)Al(THF)2]+[Co(CO)4]- (1; ClTPP = meso-tetra(4-chlorophenyl)porphyrinato; THF = tetrahydrofuran), which is highly active and selective for both epoxide and lactone carbonylation, and by the identification of a solvent that facilitates both stages. The catalysis is compatible with substituted epoxides having aliphatic, aromatic, alkene, ether, ester, alcohol, nitrile, and amide functional groups. Disubstituted and enantiomerically pure anhydrides are synthesized from epoxides with excellent retention of stereochemical purity. The mechanism of epoxide double carbonylation with 1 was investigated by in situ IR spectroscopy, which reveals that the two carbonylation stages are sequential and non-overlapping, such that epoxide carbonylation goes to completion before any of the intermediate beta-lactone is consumed. The rates of both epoxide and lactone carbonylation are independent of carbon monoxide pressure and are first-order in the concentration of 1. The stages differ in that the rate of epoxide carbonylation is independent of substrate concentration and first-order in donor solvent, whereas the rate of lactone carbonylation is first-order in lactone and inversely dependent on the concentration of donor solvent. The opposite solvent effects and substrate order for these two stages are rationalized in terms of different resting states and rate-determining steps for each carbonylation reaction.     

Alkynylated phenazines: synthesis, characterization, and metal-binding properties of their bis-triazolyl cycloadducts

We have synthesized a series of ethynylated phenazines and their bis-triazolyl cycloadducts to serve as metal ion sensors. Binding of metal ions is achieved through coordination to the phenazine nitrogen atom and the triazole ring. To allow metal sensing in aqueous solution, the triazole units are substituted with water-soluble ethylene glycol chains. These phenazine cycloadducts exhibit a selective affinity for binding silver ions. Examination of the halogenated analogues reveals a lowering of the band gap and the corresponding bathochromic shifts in the absorption and emission spectra. The electron-withdrawing properties of these halogens also result in significantly decreased metal-binding activity of the phenazine cycloadducts.     

手性氨基酸及其衍生物配体在酮不对称氢转移反应中的应用进展

前手性酮的不对称氢转移反应(ATH)是获得手性醇的重要方法.近年来氨基酸及其衍生物在金属Ru,Rh,Ir催化酮的ATH中的应用引起人们关注.就氨基酸、氨基酸酰胺、氨基酸硫代酰胺、氨基酸羟胺酸、氨基酸酰肼、氨基醇及氨基酸羟基酰胺等为配体的金属络合物在ATH中的催化性能进行了综述.