Short and stereoselective synthesis of manzacidins A and C, and their enantiomers

A short and stereoselective synthesis of manzacidins A and C, and their enantiomers was achieved via stereoselective hydrogenation reactions of dehydroamino acid esters 5-8 using a chiral Rh catalyst.     

Novel stereoselective synthesis of all four diastereomers of 3a-methyl-pyrrolo[3,4-c]piperidine from glycine ethyl ester

Asymmetric synthesis of all four diastereomers of 3a-methyl-pyrrolo[3,4-c]piperidine is described herein. The key steps in this synthesis are the highly diastereoselective hydrogenation of an alkenyl nitrile through a hydroxyl-directed or sterically controlled hydrogenation, and the resolution of enantiomers using a chiral auxiliary.     

过渡金属/磷配体催化不对称氢化反应研究进展

正手性过渡金属配合物催化的不对称氢化是合成手性药物、农药和精细化工中间体的重要方法.到目前为止,已经有一些过渡金属/配体配合物催化的不对称氢化反应得到工业化应用,典型的实例如孟山都公司采用手性双齿膦配体DIPAMP生产L     

芳香酮的高效对映选择性转移氢化

手性芳香醇在制药工业上有重要的应用,因而利用芳香酮的对映选择性氢化制备相应的手性醇已引起人们极大关注.近10年来,用手性金属配合物为催化剂,利用种种有机物作氢源,实现芳香酮的不对称氢转移氢化取得了很大进展.但这些反应过程的催化活性仍然较低,底物酮与催化剂.     

Asymmetric catalysis in fragrance chemistry: a new synthetic approach to enantiopure Phenoxanol®, Citralis® and Citralis Nitrile®

A new approach to the synthesis of the single stereomers of the fragrances Phenoxanol^®, Citralis^® and Citralis Nitrile^® is reported. The key step of the synthesis is the asymmetric hydrogenation of (Z)- or (E)-3-methyl-5-phenyl-pent-2-en-1-ol, which leads to the single enantiomers of Phenoxanol^® from which both enantiomers of Citralis^® are obtained by oxidation. Treatment of these compounds with hydroxylamine finally led to Citralis Nitrile^® without any loss of enantiopurity. The odour profiles of the single enantiomers of these fragrances are reported as well.     

Concise Synthesis of Both Enantiomers of Pilocarpine

Furan-2-carboxylic acid was used as a starting material for the synthesis of dehydro-homopilopic acid. Esterification, hydrogenation and enzymatic hydrolysis followed by the reduction of Weinreb amides and a single-step attachment of a 1-methyl-imidazole residue allowed for the concise synthesis of both enantiomers of pilocarpine.     

A General Regioselective Synthesis of Alcohols by Cobalt-Catalyzed Hydrogenation of Epoxides

A straightforward methodology for the synthesis of anti-Markovnikov-type alcohols is presented. By using a specific cobalt triphos complex in the presence of Zn(OTf)₂ as an additive, the hydrogenation of epoxides proceeds with high yields and selectivities. The described protocol shows a broad substrate scope, including multi-substituted internal and terminal epoxides, as well as a good functional-group tolerance. Various natural-product derivatives, including steroids, terpenoids, and sesquiterpenoids, gave access to the corresponding alcohols in moderate-to-excellent yields.     

Asymmetric Catalysis by Architectural and Functional Molecular Engineering: Practical Chemo- and Stereoselective Hydrogenation of Ketones

Hydrogenation is a core technology in chemical synthesis. High rates and selectivities are attainable only by the coordination of structurally well-designed catalysts and suitable reaction conditions. The newly devised [RuCl(2)(phosphane)(2)(1,2-diamine)] complexes are excellent precatalysts for homogeneous hydrogenation of simple ketones which lack any functionality capable of interacting with the metal center. This catalyst system allows for the preferential reduction of a C=O function over a coexisting C=C linkage in a 2-propanol solution containing an alkaline base. The hydrogenation tolerates many substituents including F, Cl, Br, I, CF(3), OCH(3), OCH(2)C(6)H(5), COOCH(CH(3))(2), NO(2), NH(2), and NRCOR as well as various electron-rich and -deficient heterocycles. Furthermore, stereoselectivity is easily controlled by the electronic and steric properties (bulkiness and chirality) of the ligands as well as the reaction conditions. Diastereoselectivities observed in the catalytic hydrogenation of cyclic and acyclic ketones with the standard triphenylphosphane/ethylenediamine combination compare well with the best conventional hydride reductions. The use of appropriate chiral diphosphanes, particularly BINAP compounds, and chiral diamines results in rapid and productive asymmetric hydrogenation of a range of aromatic and heteroaromatic ketones and gives a consistently high enantioselectivity. Certain amino and alkoxy ketones can be used as substrates. Cyclic and acyclic alpha,beta-unsaturated ketones can be converted into chiral allyl alcohols of high enantiomeric purity. Hydrogenation of configurationally labile ketones allows for the dynamic kinetic discrimination of diastereomers, epimers, and enantiomers. This new method shows promise in the practical synthesis of a wide variety of chiral alcohols from achiral and chiral ketone substrates. Its versatility is manifested by the asymmetric synthesis of some biologically significant chiral compounds. The high rate and carbonyl selectivity are based on nonclassical metal-ligand bifunctional catalysis involving an 18-electron amino ruthenium hydride complex and a 16-electron amido ruthenium species.     

A General Regioselective Synthesis of Alcohols by Cobalt‐Catalyzed Hydrogenation of Epoxides

A straightforward methodology for the synthesis of anti‐Markovnikov‐type alcohols is presented. By using a specific cobalt triphos complex in the presence of Zn(OTf)₂ as an additive, the hydrogenation of epoxides proceeds with high yields and selectivities. The described protocol shows a broad substrate scope, including multi‐substituted internal and terminal epoxides, as well as a good functional‐group tolerance. Various natural‐product derivatives, including steroids, terpenoids, and sesquiterpenoids, gave access to the corresponding alcohols in moderate‐to‐excellent yields.     

Synthesis of 7-cyano- and 7-acetamido-indoles via cyanocarbonation/hydrogenation of 7-formyl indole

A procedure for the synthesis of 7-cyano and 7-acetamido indoles via cyanocarbonation/hydrogenation of 7-formyl indole is presented. The process can be efficiently scaled up to provide multigram quantities of the desired compounds in good yield. A small survey of substrate scope indicates that the reaction may prove generally useful for the synthesis of aryl acetonitriles.     

Chemoenzymatic synthesis of trans-dihydrodiol derivatives of monosubstituted benzenes from the corresponding cis-dihydrodiol isomers

Enantiopure trans-dihydrodiols have been obtained by a chemoenzymatic synthesis from the corresponding cis-dihydrodiol metabolites, obtained by dioxygenase-catalysed arene cis-dihydroxylation at the 2,3-bond of monosubstituted benzene substrates. This generally applicable, seven-step synthetic route to trans-dihydrodiols involves a regioselective hydrogenation and a Mitsunobu inversion of configuration at C-2, followed by benzylic bromination and dehydrobromination steps. The method has also been extended to the synthesis of both enantiomers of the trans-dihydrodiol derivatives of toluene, through substitution of a vinyl bromine atom of the corresponding trans-dihydrodiol enantiomers derived from bromobenzene. Through incorporation of hydrogenolysis and diMTPA ester diastereoisomer resolution steps into the synthetic route, both trans-dihydrodiol enantiomers of monohalobenzenes were obtained from the cis-dihydrodiols of 4-haloiodobenzenes.     

Enzymatic resolution and evaluation of enantiomers of cis-5'-hydroxythalidomide

The straightforward synthesis of both enantiomers of cis-5'-hydroxythalidomide, a major metabolite of thalidomide, has been accomplished by enzymatic kinetic resolution of a racemic substrate catalyzed by Pseudomonas stutzeri lipase TL. cis-5'-Hydroxythalidomide shows resistance to racemization (and epimerization) at physiological pH. A tube formation assay to assess the ability to inhibit angiogenesis revealed that cis-5'-hydroxythalidomides are inactive.     

Inverting External Asymmetric Induction via Selective Energy Transfer Catalysis: A Strategy to β‐Chiral Phosphonate Antipodes

Enantiodivergent, catalytic reduction of activated alkenes relays stereochemical information encoded in the antipodal chiral catalysts to the pro‐chiral substrate. Although powerful, the strategy remains vulnerable to costs and availability of sourcing both catalyst enantiomers. Herein, a stereodivergent hydrogenation of α,β‐unsaturated phosphonates is disclosed using a single enantiomer of the catalyst. This enables generation of the R‐ or S‐configured β‐chiral phosphonate with equal and opposite selectivity. Enantiodivergence is regulated at the substrate level through the development of a facile E → Z isomerisation. This has been enabled for the first time by selective energy transfer catalysis using anthracene as an inexpensive organic photosensitiser. Synthetically valuable in its own right, this process enables subsequent Rh^I‐mediated stereospecific hydrogenation to generate both enantiomers of the product using only the S‐catalyst (up to 99:1 and 3:97 e.r.). This strategy out‐competes the selectivities observed with the E‐substrate and the R‐catalyst.     

Separation of enantiomers by high performance liquid chromatography using chiral eluents

Simple procedures are presented for separating the enantiomers of α-methyldopa, 5-hydroxytryptophan, tryptophan, triiodothyronine and thyroxine, which require neither special sorbents nor difficult-to-obtain or unstable reagents. The method for α-methyldopa, 5-hydroxytryptophan and tryptophan is based on the use of L-phenylalanine copper complex as the chiral constituent of the mobile phase; LiChrosorb® RP-18 serves as the stationary phase. The procedure for triiodothyronine and thyroxine is grounded on the L-proline copper complex as the chiral reagent and LiChrosorb® Si 60 as the stationary phase. In all observed cases, the D-enantiomer is eluted prior to the respective L-enantiomer. Chirality inversion of the mobile phase (application of the D-phenylalanine copper complex) reverses the order of elution; a racemic eluent (DL-phenylalanine copper complex) leads to no separation. In addition to the enantiomers of α-amino acids, the enantiomers of α-hydroxy acids (mandelic acid) can be separated.     

Rigid P-chiral phosphine ligands with tert-butylmethylphosphino groups for rhodium-catalyzed asymmetric hydrogenation of functionalized alkenes

Both enantiomers of 2,3-bis(tert-butylmethylphosphino)quinoxaline (QuinoxP*), 1,2-bis(tert-butylmethylphosphino)benzene (BenzP*), and 1,2-bis(tert-butylmethylphosphino)-4,5-(methylenedioxy)benzene (DioxyBenzP*) were prepared in short steps from enantiopure (S)- and (R)-tert-butylmethylphosphine-boranes as the key intermediates. All of these ligands were crystalline solids and were not readily oxidized on exposure to air. Their rhodium complexes exhibited excellent enantioselectivities and high catalytic activities in the asymmetric hydrogenation of functionalized alkenes, such as dehydroamino acid derivatives and enamides. The practical utility of these catalysts was demonstrated by the efficient preparation of several chiral pharmaceutical ingredients having an amino acid or a secondary amine component. A rhodium complex of the structurally simple ligand BenzP* was used for the mechanistic study of asymmetric hydrogenation. Low-temperature NMR studies together with DFT calculations using methyl α-acetamidocinnamate as the standard model substrate revealed new aspects of the reaction pathways and the enantioselection mechanism.     

Synthesis of enantioenriched propargylic alcohols related to polyketide natural products. A comparison of methodologies

[reaction: see text] Applications of methodology for the synthesis of propargylic alcohols related to polyketide natural products were examined. Noyori's asymmetric transfer hydrogenation of alpha-chiral alkynones was found to be highly selective and catalyst controlled. Additions of TMS acetylene to alpha-chiral aldehydes, catalyzed by a Ti(O-i-Pr)(4)-BINOL complex, were diastereoselective but substrate dependent.     

Catalyst-controlled asymmetric synthesis of fostriecin and 8-epi-fostriecin

Catalytic asymmetric synthesis of the natural antibiotic fostriecin (CI-920) and its analogue 8-epi-fostriecin and evaluation of their biological activity are described. We used four catalytic asymmetric reactions to construct all of the chiral centers of fostriecin and 8-epi-fostriecin; cyanosilylation of a ketone, Yamamoto allylation, direct aldol reaction, and Noyori reduction, two of which were developed by our group. Catalytic enantioselective cyanosilylation of ketone 13 produced the chiral tetrasubstituted carbon at C-8. Both enantiomers of the product cyanohydrin were obtained with high enantioselectivity by switching the center metal of the catalyst from titanium to gadolinium. Yamamoto allylation constructed the C-5 chiral carbon in the alpha,beta-unsaturated lactone moiety. A direct catalytic asymmetric aldol reaction of an alkynyl ketone using LLB catalyst constructed the chirality at C-9 with the introduction of a synthetically versatile alkyne moiety, which was later converted to cis-vinyl iodide, the substrate for the subsequent Stille coupling for the triene synthesis. Noyori reduction produced the secondary alcohol at C-11 from the acetylene ketone 6 with excellent selectivity. Importantly, all the stereocenters were constructed under catalyst control in this synthesis. This strategy should be useful for rapid synthesis of stereoisomers of fostriecin.     

Synthèse racémique et énantiosélective d’énol-lactones et leur évaluation comme inhibiteurs de la protéase du VIH-1

Racemic and enantioselective synthesis of enol-lactone and their biological activity as potent HIV-1 protease inhibitors. A series of enol-lactones was prepared and evaluated for its activity against HIV-1 protease. The preparation of (R,S)-5,6-dihydro-4-hydroxy-6-phenyl-2H-pyran-2-one (3) is the key intermediate for the synthesis. The synthesized enol-lactones (5 and 8–11) were kinetically evaluated against a HIV-1 protease substrate and were found to exhibit moderate inhibitory activity. The enantioselective synthesis of enol-lactone is achieved to give the two enantiomers. To cite this article: S. Ibrahimi et al., C. R. Chimie 8 (2005).     

Chemoenzymatic asymmetric synthesis of harzia lactone A stereomers

A facile chemoenzymatic synthesis of the harzia lactone A enantiomers was developed. A lipase-catalyzed acylation and an enantio-controlled substrate and reagent-controlled Sharpless’ asymmetric dihydroxylation are the key features of the synthesis.     

Efficient synthesis of enantiomerically pure beta2-amino acids via chiral isoxazolidinones

We report a practical and scalable synthetic route for the preparation of alpha-substituted beta-amino acids (beta(2)-amino acids). Michael addition of a chiral hydroxylamine, derived from alpha-methylbenzylamine, to an alpha-alkylacrylate followed by cyclization gives a diastereomeric mixture of alpha-substituted isoxazolidinones. These diastereomers are separable by column chromatography. Subsequent hydrogenation of the purified isoxazolidinones followed by Fmoc protection affords enantiomerically pure Fmoc-beta(2)-amino acids, which are useful for beta-peptide synthesis. This route provides access to both enantiomers of a protected beta(2)-amino acid.