Applications of chiral allenylzinc additions and Noyori asymmetric reductions to an enantioselective synthesis of a C3-C13 precursor of the polyketide phosphatase inhibitor cytostatin

A 12-step synthesis of a C3-C13 precursor of the protein phosphatase inhibitor cytostatin is described. Key stereocenters were introduced by a chiral allenylzinc addition and Noyori asymmetric-transfer hydrogenation.     

New organocatalysts for the asymmetric reduction of imines with trichlorosilane

Asymmetric reduction of prochiral ketimines 1a-f with trichlorosilane can be catalyzed by the Lewis-basic formamides (S)-4a,b, derived from N-methyl valine, with ≤91% enantioselectivity and low catalyst loading (≤5 mol %) at room temperature in toluene.     

Structure investigation of TiIV-BODOLates involved in the catalytic asymmetric reduction of ketones using catecholborane

The complexes formed by the reaction of [Ti(OiPr)(4)] and bicyclo-octanediols (BODOLs) 1 and 2 (1:1) are useful as chiral catalysts in asymmetric reductions and were investigated by (1)H NMR spectroscopy and computational methods. A consistent picture emerged of head-to-tail dimers being kept together via a Ti-O-Ti-O micro-oxo bridge similar to the Ti-tartrates but different from the corresponding Ti-BINOLates and Ti-TADDOLates.     

A convenient route to chiral γ-lactones via asymmetric hydrogenation of γ-ketoesters using the RuCl3-BINAP-HCl catalytic system

A convenient one-step synthesis of chiral γ-lactones has been performed. The method is based on enantioselective hydrogenation of γ-ketoesters using the RuCl₃-BINAP-HCl catalytic system. Chiral γ-lactones (91-99% ee) have been isolated in 57-88% yield.     

Chiral imidates as a new class of nitrogen-based chiral ligands: synthesis and catalytic activity in asymmetric aziridinations and diethylzinc additions

Chiral imidates were efficiently synthesized in one step and with high yields (seven examples). These chiral imidates were used as ligands in the Cu(I)-catalyzed asymmetric aziridination of methyl cinnamate and in the asymmetric diethylzinc additions to benzaldehyde as a proof of principle. The imidate catalyst system showed high catalytic activities and induced encouraging selectivities. An X-ray structure analysis of an imidate-Cu(I) complex is included, showing a distorted tetrahedral arrangement with two bidentate ligand molecules surrounding the metal.     

Recent advances in the asymmetric catalytic synthesis of chiral 3-hydroxy and 3-aminooxindoles and derivatives: Medicinally relevant compounds

Several oxindole derivatives, of natural or synthetic origin, have been identified as medicinally appealing compounds, with a plethora of bioactivities reported. Chiral 3-hydroxy and 3-aminooxindole scaffolds have captured the attention of several research groups, due to their importance in drug discovery. In this review, we systematically address the wide variety of asymmetric catalytic methodologies employed in the preparation of these relevant chiral scaffolds, present in many biologically active compounds and/or natural products. Special focus will be given to the nature of the catalyst used.     

Rh(II)-Cp-TsDPEN catalyzed aqueous asymmetric transfer hydrogenation of chromenones into saturated alcohol: CC and CO reduction in one step

As an efficient catalyst for asymmetric transfer hydrogenation reaction (ATH reaction) of α,β-unsaturated ketones, Rh-Cp^∗-TsDPEN (Cp^∗ = 1,2,3,4,5-pentamethylcyclopenta-1,3-diene, TsDPEN = N-(p-toluenesulfonyl)-1,2-diphenyl- ethylenediamine) shows high chemoselectivity on CO and CC reduction. In our method, both CO and CC bonds in a variety of chromenone derivatives were reduced efficiently in aqueous media, resulting in at least 98% ee and up to 99% yields in a convenient way without further purification. The product was a useful intermediate for deriving chiral chroman-4-amine, which was reported as an effective agent against hypotension and inflammatory pain by inhibiting human bradykinin B1 receptor.     

Relationship between the structure and enantioselectivity in the asymmetric reduction of 2,6-disubstituted acetophenones with DIP-Chloride. An ab initio study

Using computational and chemical studies, a relationship between the % ee achieved and the dihedral angles between the plane of the aromatic ring and the plane containing the carbonyl group has been established for asymmetric reductions with B-chlorodiisopinocampheylborane.     

手性方酸衍生物的合成及在前手性酮的不对称催化还原反应中的应用研究进展

本文评述手性方酸衍生物的研究进展，包括多个系列的新型手性方酰化氨基醇及氨基酸配体的设计合成以及它们在前手性单酮和二酮的不对称催化还原反应中的应用。     

Highly Enantio- and s-trans C=C bond selective catalytic hydrogenation of cyclic enones: alternative synthesis of (-)-menthol

A highly enantioselective catalytic hydrogenation of cyclic enones was achieved by using the combination of a cationic Rh(I) complex, (S)-5,5'-bis{di(3,5-di-tert-butyl-4-methoxyphenylphosphino)}-4,4'-bi-1,3-benzodioxole (DTBM-SEGPHOS), and (CH2CH2PPh3Br)2. The presence of an s-cis C=C bond isopropylidene moiety on the cyclic enone influenced the enantioselectivity of the hydrogenation. Thus, the hydrogenation of 3-alkyl-6-isopropylidene-2-cyclohexen-1-one, which contains both s-cis and s-trans enones, proceeded in excellent enantioselectivity (up to 98 % ee). To obtain high enantio- and s-trans selectivities, the addition of a halogen source to the cationic Rh complex was the essential step. With the key step of the s-trans selective asymmetric hydrogenation of piperitenone, we demonstrated a new synthetic method for optically pure (-)-menthol via three atom-economical hydrogenations. Moreover, we found that the complete s-trans and s-cis C=C bond selective reactions were also realized by the proper choice of both the chiral ligands and halides.     

Practical, catalytic, asymmetric synthesis of beta-lactones via a sequential ketene dimerization/hydrogenation process: inhibitors of the thioesterase domain of fatty acid synthase

The recent finding that the FDA-approved antiobesity agent orlistat (tetrahydrolipstatin, Xenical) is a potent inhibitor of the thioesterase domain of fatty acid synthase (FAS) led us to develop a concise and practical asymmetric route to pseudosymmetric 3,4-dialkyl-cis-beta-lactones. The well-documented up-regulation of FAS in cancer cells makes this enzyme complex an interesting therapeutic target for cancer. The described route to 3,4-dialkyl-beta-lactones is based on a two-step process involving Calter's catalytic, asymmetric ketene dimerization of acid chlorides followed by a facial-selective hydrogenation leading to cis-substituted-beta-lactones. Importantly, the ketene dimer intermediates were found to be stable to flash chromatography, enabling opportunities for subsequent transformations of these optically active, reactive intermediates. Subsequent alpha-epimerization and alpha-alkylation or acylation led to trans-beta-lactones and beta-lactones bearing alpha-quaternary carbons, respectively. Several of the ketene dimers and beta-lactones displayed antagonistic activity (apparent Ki in the low micromolar range) in competition with a fluorogenic substrate toward a recombinant form of the thioesterase domain of fatty acid synthase. The best antagonist, a simple phenyl-substituted cis-beta-lactone 3d, displayed an apparent Ki (2.5 +/- 0.5 microM) of only approximately 10-fold lower than that of orlistat (0.28 +/- 0.06 microM). In addition, mechanistic studies of the ketene dimerization process by ReactionView infrared spectroscopy support previous findings that ketene formation is rate determining.     

Chiral monooxazolines as modular copper(I)-heterocomplex building blocks: investigations on the catalytic asymmetric cyclopropanation of alkenes

Novel chiral monodentate oxazoline ligands have been synthesized in good yields. The catalytic activity of these monodentate oxazoline/Cu catalysts was evaluated in the catalytic asymmetric cyclopropanation of styrene and α-methylstyrene, giving moderate to good enantioselectivities (up to 74% ee for the trans-cyclopropane product) and full conversions (up to 100%). In an attempt to enhance the enantioselectivities of the cyclopropanations, heterocombinations of these ligands were used. Unfortunately, with the data set that was used in this study, no improvements were observed. However, to gain an insight into the nature of the active catalyst present under these circumstances, NMR, mass spectrometric and computational studies were carried out and indicated the presence of bidentate heterocomplexes in the equilibrium mixture. Analysis of the stereoselectivities (ees and des) did not prove very useful in pin-pointing the identity of the active chiral catalyst and only afforded a very weak conclusion. In order to ascertain the importance of the π-π interactions, the monodentate oxazoline ligands 3a and 3b were synthesized and screened in these reactions, and the resulting stereoselectivities were compared to the results obtained using ligands 1a and 1b. There seemed to be very weak π-π interactions at work.     

Towards perfect catalytic asymmetric synthesis: dual activation of the electrophile and the nucleophile

The design and development of new high-performance catalysts for applications in asymmetric catalytic reactions is of ongoing interest in organic chemistry. The combination of a Lewis acid and a Lewis base working in concert is now considered state of the art in stereoselective syntheses. The synergistic activation by two or more reactive centers allows high reaction rates and excellent transfer of stereochemical information. Despite the self-quenching reaction between Lewis acids and Lewis bases that might lead to an inactive catalyst, considerable effort has been directed towards the development of the dual-activation concept. The ultimate goal is to mimic nature by the discovery of catalytic systems analogous to enzymatic processes that involve metal-ion cocatalysts. With this aim, the dual activation concept greatly broadens the range of artificial catalysts. The most efficient catalytic systems are reviewed, and the mechanisms of action are discussed.     

Silver metal nanoparticles: Facile dendrimer‐assisted size‐controlled synthesis and selective catalytic reduction of chloronitrobenzenes

A simple and versatile synthetic methodology to silver metal nanoparticles that utilizes 3,5‐dihydroxybenzyl alcohol‐based dendrimers as templates and does not necessitate the addition of any external reducing agent is reported. An evaluation of the role of addition rate of the silver acetate solution, and the dendrimer to silver acetate molar ratio, as well as the dendritic effect on nanoparticle growth, suggests that the size of these metal nanoparticles can be controlled by simple variations of these parameters. A probe of the mechanism of the nanoparticle formation and growth indicates that the terminal hydroxyl groups of the dendrimers play a major role in metal ion isolation and reduction, in addition to providing stabilization to the growing metal particles. These silver metal nanoparticles are highly active catalysts for the selective reduction of chloronitrobenzenes to chloroanilines. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 4482–4493, 2009     

Stereoselective synthesis of the C7C21 segment of epothilone A via asymmetric alkoxyallyl- and crotylboration

The synthesis of the C₇C₂₁ fragment of epothilone A involving asymmetric alkoxyallyl- and crotylboration using α-pinene-derived reagents is described.     

Synthesis of three novel chiral diamines derived from (S)-proline and their evaluation as precursors of diazaborolidines for the catalytic borane-mediated enantioselective reduction of prochiral ketones

A series of chiral diazaborolidine catalysts are readily prepared in situ at 75 °C in toluene solvent and under microwave irradiation (100 W, 15 min, air cooling) using chiral diamines derived from inexpensive and commercially available (S)-proline and borane-dimethyl sulfide. Special mention deserves the synthesis of potentially versatile diamine (S)-8 [(S)-(pyrrolidin-2-yl)diphenylmethanamine], with the key step being the conversion of tertiary alcohol (S)-(1-benzylpyrrolidin-2-yl)diphenyl methanol, (S)-12, to azide (S)-13. The chiral diazaborolidine/BH₃ reagent system was successfully employed in the enantioselective reduction of prochiral ketones to give the corresponding secondary alcohols in excellent yield and with up to 96% enantiomeric purities.     

Selective reaction of camphor-derived exo-formyl [2.2.1]bicyclic carbinol with alkyl primary amines: application to the preparation of new chiral catalysts for asymmetric reduction of aryl ketones

Reaction of camphor-derived exo-formyl [2.2.1]bicyclic carbinol with various alkyl primary amines gave regio- and stereo-specific [3.2.1]bicyclic α-amino ketones. A detailed mechanism of the reaction was discussed. This reaction was further applied to the preparation of some camphor-derived oxazaborolidines, one of which proved to be an efficient chiral catalyst for the asymmetric borane reduction of prochiral aryl ketones at room temperature.