A two step synthesis of a key unit B precursor of cryptophycins by asymmetric hydrogenation

The use of frustrated Lewis pairs is an extremely important approach to metal-free hydrogenations. In contrast to the rapid growth of catalytic reactions, asymmetric hydrogenations are far less developed due to a severe shortage of readily available chiral frustrated Lewis pair catalysts with high catalytic activities and selectivities. Unlike the stable Lewis base component of frustrated Lewis pairs, the moisture-sensitive boron Lewis acid component is difficult to prepare. The development of convenient methods for the quick construction of chiral boron Lewis acids is therefore of great interest. In this Account, we summarize our recent studies on frustrated Lewis pair-catalyzed, asymmetric metal-free hydrogenations and hydrosilylations. To address the shortage of highly active and selective catalysts, we developed a novel strategy for the in situ preparation of chiral boron Lewis acids by the hydroboration of chiral dienes or diynes with Piers' borane without further purification, which allows chiral dienes or diynes to act like ligands. This strategy ensures the construction of a useful toolbox of catalysts for asymmetric metal-free hydrogenations and hydrosilylations is rapid and operationally simple. Another strategy is using combinations of readily available Lewis acids and bases containing hydridic and acidic hydrogen atoms, respectively, as a novel type of frustrated Lewis pairs. Such systems provide a great opportunity for using simple chiral Lewis bases as the origins of asymmetric induction. With chiral diene-derived boron Lewis acids as catalysts, a broad range of unsaturated compounds, such as imines, silyl enol ethers, 2,3-disubstituted quinoxalines, and polysubstituted quinolines, are all viable substrates for asymmetric metal-free hydrogenations and give the corresponding products in good yields with high enantioselectivities and/or stereoselectivities. These chiral catalysts are very effective for bulky substrates, and the substrate scope for these metal-free asymmetric hydrogenations has been dramatically expanded. Chiral alkenylboranes were designed to enhance the rigidity of the framework and modify the Lewis acidity through the resulting double bonds. Frustrated Lewis pairs of chiral alkenylboranes and phosphines are a class of highly effective catalysts for asymmetric Piers-type hydrosilylations of 1,2-dicarbonyl compounds, and they give the desired products in high yields and enantioselectivities. Moreover, asymmetric transfer hydrogenations of imines and quinoxalines with ammonia borane as the hydrogen source have been achieved with frustrated Lewis pair of Piers' borane and (R)-tert-butylsulfinamide as the catalyst. Mechanistic studies have suggested that the hydrogen transfer occurs via an 8-membered ring transition state, and regeneration of the reactive frustrated Lewis pair with ammonia borane occurs through a concerted 6-membered ring transition state.

ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTPractical Syntheses of β-Amino Alcohols via Asymmetric Catalytic HydrogenationGuoxin Zhu, Albert L. Casalnuovo, and Xumu ZhangView Author Information Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, and DuPont Agricultural Products, Stine-Haskell Research Center, P.O. Box 30, Building 300, Newark, Delaware 19714 Cite this: J. Org. Chem. 1998, 63, 23, 8100–8101Publication Date (Web):October 29, 1998Publication History Received7 August 1998Published online29 October 1998Published inissue 1 November 1998https://pubs.acs.org/doi/10.1021/jo981590ahttps://doi.org/10.1021/jo981590arapid-communicationACS PublicationsCopyright © 1998 American Chemical SocietyRequest reuse permissionsArticle Views1302Altmetric-Citations76LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (2)»Supporting Information Supporting Information SUBJECTS:Alcohols,Catalysts,Hydrogenation,Ligands,Stereoselectivity Get e-Alerts

Although trifluoromethylthiolated compounds have privileged applications in pharmaceuticals and agrochemicals, efficient strategies for the asymmetric construction of Csp3–SCF3 bonds are limited. S...

Much effort has been devoted to the development of efficient asymmetric synthetic methods for the preparation of enantiomerically enriched compounds.1,2 Among various methods for the enantiomerically selective synthesis of chiral organic compounds from prochiral precursors, enantioselective catalytic hydrogenation of dehydro precursors has been extensively developed.3 In fact, asymmetric hydrogenation is one of the most practical methods in asymmetric synthesis, accounting for 70% of all procedures used on a commercial scale.4 However, most asymmetric catalytic hydrogenation systems only hydrogenate electron-deficient olefins with high enantioselectivity and high reactivity. In contrast, electronrich olefins, such as simple enamides5 and enolates,6 are generally poor substrates for asymmetric hydrogenation with most known systems. Since enamides and enolates upon asymmetric hydrogenation can be converted to enantiomerically pure amines and alcohols,7 it would be extremely desirable to have a general and efficient method for this transformation. Recently, Burk and coworkers have reported that Rh complexes bearing the electron-rich DuPhosand BPE-type ligands were efficient catalysts for the asymmetric hydrogenation of enamides8 and enolates.9 They reported that analogous Rh-chiral bisphosphines bearing diphenylphosphino groups (e.g., BINAP, DIOP, and CHIRAPHOS) led to significantly lower enantioselectivities in the reduction of enamides (<60% ee).8 We have been interested in elucidating the steric and electronic effects10 of various diphenylphosphino-bearing chiral ligands in asymmetric hydrogenation processes. Recently a new chiral 1,4-bisphosphine, 2(R),2′(R)-bis(diphenylphosphino)-1(R),1′(R)-dicyclopentane ((R,R)BICP, Figure 1), was reported from our laboratory as an excellent ligand for the Rh-catalyzed asymmetric hydrogenation of dehydroamino acids.11 The key feature of this new ligand is that four stereogenic centers are introduced in a conformationally rigid bicyclic backbone, which is fundamentally different from either axially dissymmetric BINAP or bisphosphines with two stereogenic centers. Herein, we describe the highly enantioselective Rhcatalyzed hydrogenation of enamides using the BICP ligand. Among the known chiral bisphosphines with diphenylphosphino groups, the BICP ligand gives the highest enantioselectivity for the rhodium-catalyzed asymmetric hydrogenation of simple enamides.

ConspectusCatalytic asymmetric hydrogenation is one of the most reliable, powerful, and environmentally benign methods for the synthesis of chiral molecules with high atom economy and has been successfully applied in the industrial production of pharmaceuticals, agrochemicals, and fragrances. The key to achieving highly efficient and highly enantioselective hydrogenation reactions is the design and synthesis of chiral catalysts.Our recent studies involving iridium complexes of bidentate chiral spiro aminophosphine ligands (Ir-SpiroAP) have revealed that adding another coordinating group on the nitrogen atom to form a tridentate ligand can provide catalysts with markedly higher stability, enantioselectivity, and efficiency. Specifically, chiral Ir-SpiroAP catalysts bearing an added pyridine group (designated Ir-SpiroPAP) exhibit high activity and excellent enantioselectivity in the asymmetric hydrogenation of a wide range of carbonyl compounds, including aryl ketones, β- and δ-ketoesters, α,β-unsaturated ketones and esters, and racemic α-substituted lactones, as well as highly electron-deficient alkenes such as α,β-unsaturated malonates and analogues. The efficiency of the Ir-SpiroPAP catalysts is extremely high: in the hydrogenation of aryl ketones, turnover numbers reach 4.5 million, which is the highest value reported to date for a molecular catalyst. Moreover, when a thioether or a bulky triarylphosphine group is added to afford tridentate ligands designated SpiroSAP and SpiroPNP, respectively, the resulting iridium catalysts show high efficiency and enantioselectivity for asymmetric hydrogenation of β-alkyl-β-ketoesters and dialkyl ketones, which are challenging substrates. Furthermore, chiral spiro catalysts containing an added oxazoline moiety (Ir-SpiroOAP) show high enantioselectivity for asymmetric hydrogenation of α-keto amides and racemic α-aryloxy lactones. The above-described catalysts have been used for enantioselective synthesis of chiral pharmaceuticals and other bioactive compounds.We have shown that chiral spiro ligands that combine a rigid skeleton with tridentate coordination stabilize iridium catalysts. The careful tailoring of the substituents on the ligand creates a chiral environment around the active metal center of the catalyst that can precisely discriminate between the two faces of a substrate carbonyl group. These factors are key for controlling the activity, enantioselectivity, and turnover numbers of asymmetric hydrogenation catalysts. We expect that catalysts based on iridium, and other transition metals, coordinated by tridentate chiral ligands with a rigid skeleton will find more applications in asymmetric hydrogenation and other asymmetric transformations.

Continuous-flow synthesis of fine chemicals has several advantages over batch synthesis in terms of environmental compatibility, efficiency and safety. Nevertheless, most preparative methods still rely on conventional batch systems. For instance, chiral amines are ubiquitous functionalities in pharmaceutical compounds, but methods for their continuous synthesis with broad substrate generality remain very challenging. Here we show the development of heterogeneous iridium complexes combined with chiral phosphoric acids for the asymmetric hydrogenation of imines towards the continuous synthesis of chiral amines. Direct asymmetric reductive amination of ketones under a hydrogen atmosphere also proceeded smoothly using the same catalyst systems. Various chiral aromatic and aliphatic amines including pharmaceutical intermediates could be prepared in high yields with high enantioselectivities. It was found that continuous-flow reactions that use columns packed with the heterogeneous iridium complexes afforded chiral amines continuously for more than two days even at pressures lower than those in the corresponding batch reactions. The synthesis of chiral amines is of crucial importance for the pharmaceutical industry, but it remains a challenging task and is often inefficient. Now, a heterogeneous iridium complex is developed for the asymmetric hydrogenation of imines and the asymmetric reductive amination of carbonyl compounds in continuous flow with high yields and enantioselectivities.

Open AccessCCS ChemistryCOMMUNICATION1 Oct 2019Copper-Catalyzed Asymmetric Formal Hydroaminomethylation of Alkenes with N,O-Acetals to Access Chiral β-Stereogenic Amines: Dual Functions of the Copper Catalyst Yang'en You, Quyet Van Pham and Shaozhong Ge Yang'en You , Quyet Van Pham and Shaozhong Ge *Corresponding author: E-mail Address: [email protected] https://doi.org/10.31635/ccschem.019.20190053 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesTrack Citations ShareFacebookTwitterLinked InEmail Chiral amines are synthetically versatile intermediates used for the preparation of a wide range of biologically active compounds and drugs. Compared with the well-developed synthesis of α-stereogenic amines, the establishment of enantioselective protocols to access β-stereogenic amines are very limited. Herein, we report an asymmetric synthesis of β-stereogenic amines through copper-catalyzed enantioselective formal aminomethylation of alkenes with N,O-acetals of formaldehyde. We carried out series of reactions using a variety of vinylarenes and 1,3-dienes with N,O-acetals of formaldehyde to generate the corresponding chiral β-branched alkylamines and (E)-homoallylamines in high yields, and with excellent enantioselectivity. The copper catalyst promoted not only the formation of alkylcopper nucleophiles from alkenes but also the generation of methylene imine electrophiles from N,O-acetals of formaldehyde. Our experimental design provides an attractive approach for the synthesis of chiral β-stereogenic amines from readily available alkenes and N,O-acetals with a base-metal catalyst under mild conditions. Download figure Download PowerPoint Introduction β-Stereogenic chiral amines are privileged structures found in a variety of bioactive and pharmaceutically relevant molecules and drugs (Figure 1).1–8 Among numerous methods used to prepare chiral amines, the majority has focused on the synthesis of α-stereogenic amines,9–11 while attempts to prepare chiral β-stereogenic amines are rather limited.12–19 Asymmetric hydroamination of 1,1-disubstituted alkenes is an atom-economic approach to synthesize β-stereogenic amines, but the enantioselectivity of this reaction largely depends on the steric difference between two substituents on alkenes.14,17 Catalytic hydroformylation of alkenes with H2/CO, followed by enantioselective reductive amination of aldehydes with amines,13 also yields β-stereogenic amines.18 However, this sequential reaction requires toxic CO gas and noble metal catalysts. Therefore, developing a practical enantioselective protocol, which could combine high enantioselectivity, base-metal catalysts, and easily accessible starting materials to prepare chiral β-stereogenic amines remains a challenge. Figure 1 | Examples of drugs and biologically active compounds containing a β-stereogenic amine moiety. Download figure Download PowerPoint Recently, chiral Cu–H complexes have been emerging as catalysts to convert alkenes to chiral amines via C–N or C–C bond-forming reactions.20–36 For example, chiral alkylcopper species, formed from alkenes, could react with ketimines and aldimines, derived from ketones or aryl-substituted aldehydes to yield chiral amines containing α,β-stereogenic carbons.37–39 Due to their high reactivity toward polymerization and oligomerization, methylene imines have not been isolated in pure forms. Therefore, the reactions of chiral organometallic nucleophiles with formaldehyde imines, which could afford synthetically versatile amines bearing only β-stereogenic centers, have not been studied. Very recently, Yu reported a Cu-catalyzed synthesis of β-stereogenic primary alcohols from alkenes40 and utilization of CO2 as a C1 building block as a key measure in achieving this transformation. In view of the synthetic importance of β-stereogenic amines, we took an interest to develop an enantioselective protocol for the synthesis of these β-stereogenic amines from alkenes. To study this asymmetric reaction, we rationalized that identifying a suitable N-containing C1 building block would be a critical step. N,O-Acetals of formaldehyde are readily accessible via the reactions between paraformaldehyde and carbamates in the presence of acetic anhydride and acetic acid.41 Recently, Luo and co-workers42 used these N,O-acetals as C1 imine surrogates in Mannich reaction to prepare chiral β-amino carbonyl compounds. However, their applications as methylene imine surrogates in transition-metal-catalyzed C–C bond-forming reactions remain largely unexplored. During our efforts, in search to develop Cu-catalyzed hydrofunctionalization of olefins,43–45 we found that copper catalysts could promote the conversion of these N,O-acetals to carbamate methylene imines. Herein, we report the reactions between these in-situ-generated carbamate methylene imines and chiral alkylcopper species derived from vinylarenes and 1,3-dienes, which supported a practical and novel highly enantioselective approach to access synthetically versatile chiral β-stereogenic amines from readily available olefinic substrates. Experimental Method In an argon (Ar)-filled dry box, cupric acetate [Cu(OAc)2] (1.8 mg, 10.0 μmol), (+)-1,2-Bis((2S,5S)-2,5-diphenylphospholano)ethane [(S,S)-Ph-BPE] (6.1 mg, 12.0 μmol), vinylarene (0.200 mmol), N,O-acetal (0.400 mmol), CH3CN (0.2 mL), and tBuOH (29.6 mg, 0.400 mmol) were added to a 4 mL screw-capped vial and stirred with a magnetic stirring bar for 10 min, followed by addition of dimethoxymethyl silane [(MeO)2MeSiH] (106 mg, 1.00 mmol). Then, the vial was sealed with a cap containing a polytetrafluoroethylene (PTFE) septum and removed from the dry box, after which the reaction mixture was stirred at room temperature (RT) for 12 h, and the resultant solution was concentrated in vacuum. Subsequently, the crude product was purified by column chromatography on silica gel with a mixture of ethyl acetate (EtOAc) and hexane (1∶9) as eluent. The enantiopurity of the purified products was analyzed by chiral high-performance liquid chromatography (HPLC). See the for more detailed experimental procedures and the characterization data of all the products. Results and Discussion We initiated our studies by identifying selective copper catalysts and optimal conditions for the reaction between 4-chlorostyrene ( 1a) and methyl 2-(acetylamino)benzoate (AcOCH2NHCbz), which is an N,O-acetal derived from formaldehyde. Copper catalysts, generated in situ by the combination of Cu(OAc)2 and various bisphosphine ligands were employed in the reaction to test their effectiveness. The results from selected experiments are summarized in Scheme 1. In general, these reactions were conducted in acetonitrile (CH3CN) at RT with 1a as a limiting reagent, (MeO)2MeSiH was used as a hydride source and tert-butanol [(CH3)3C-OH] as a proton source in the presence of 5 mol % copper catalyst. We identified β-stereogenic amine 2a as the major product for these reactions, by our established optimal reaction conditions indicated below: Scheme 1 | Evaluation of optimal conditions for formal aminomethylation of 1a. Download figure Download PowerPoint Reaction conditions: 1a (0.100 mmol), AcOCH2NHCbz (0.150 mmol), (MeO)2MeSiH (0.500 mmol), Cu(OAc)2 (5.0 μmol), bisphosphine ligand (6.0 μmol), solvent (0.2 mL), RT, 12 h; aIsolated yields; bee was determined by chiral HPLC analysis; c 1a (0.200 mmol) and AcOCH2NHCbz (0.100 mmol) were employed; dAcOCH2NHCbz (0.200 mmol); (MeO)2MeSiH was added after all other reagents were stirred in acetonitrile (CH3CN) at RT for 10 min. Our results showed that (1) the copper catalysts generated from Cu(OAc)2 and (Ra)-synphos, and (Ra)-DM-segphos were marginally active for this reaction (entries 1 and 2, Scheme 1). (2) The reactions catalyzed by the combination of Cu(OAc)2 and (Ra)-DTBM-segphos or (R,R)-QuinoxP* occurred at low conversions of 1a, and the desired product 2a was obtained in low yields with modest enantioselectivity (entries 3 and 4 in Scheme 1). (3) To our delight, the reaction conducted with 5 mol % of Cu(OAc)2 and 6 mol % (S,S)-Ph-BPE proceeded with high conversion of 1a, affording amine 2a in modest isolated yield, but with excellent enantioselectivity (97% ee, entry 5, Scheme 1). Subsequently, we tested this catalytic reaction in various solvents, such as cyclohexane, toluene, and tetrahydrofuran (THF). Nonetheless, these reactions proceeded with low conversions of 1a, with very low isolated yields (<5% to 21%) of 2a (entries 6–8, Scheme 1). In addition, when we performed the reaction with AcOCH2NHCbz, as a limiting reagent, we found that the process occurred with a higher yield (72%), but with a slightly diminished enantioselectivity (92% ee; entry 9, Scheme 1). Thus to further improve the reaction conditions, we conducted the experiment by stirring Cu(OAc)2, the ligand, 1a, N,O-acetal, and tBuOH for 10 min to allow ligand coordination, prior to the addition of (MeO)2MeSiH. This reaction proceeded with a full conversion of 1a to 2a, obtaining a 79% yield with excellent enantioselectivity (97%; entry 10, Scheme 1). With the identified copper catalyst and optimal conditions in hand, we studied the scope of vinylarenes that undergo this Cu-catalyzed asymmetric transformation. The results of these reactions are summarized in Scheme 2. In general, we observed that a wide range of vinylarenes containing various substituted phenyl groups ( 1c– 1j) or polyaromatic groups ( 1m– 1p) reacted with AcOCH2NHCbz readily in the presence of 5 mol % Cu(OAc)2 and 6 mol % (S,S)-Ph-BPE at RT, yielding the corresponding enantioenriched-β-stereogenic amines ( 2a– 2p) in moderate to high yields (55–97%) with high enantioselectivities (92% to >99% ee). Noticeably, vinylarenes containing ortho-substituted aryl groups ( 1g and 1h) reacted to give amine products 2g and 2h in relatively lower yields (41–43%), but with high enantioselectivity (93–99% ee). These low yields occurred, possibly due to the incomplete conversions of vinylarenes 1g and 1h as we were able to recover the unreacted substrates. Besides, Boc- and Fmoc-protected N,O-acetals reacted with 1p under our standard conditions, affording the desired amines 2p′ and 2p″ in high yields (95% and 83%) with excellent enantioselectivity (99% and 98%), respectively (Scheme 2). Scheme 2 | Scope of vinylarenes for the Cu-catalyzed formal aminomethylation. Download figure Download PowerPoint (1) Reaction conditions with lower N,O-acetal derivative but higher tBuOH concentrations: Vinylarene (0.200 mmol), AcOCH2NHR (0.400 mmol), (MeO)2MeSiH (1.00 mmol), tBuOH (0.400 mmol), Cu(OAc)2 (10.0 μmol), (S,S)-Ph-BPE (12.0 μmol), CH3CN (0.2 mL), RT, 12 h, yields of isolated products; ee was determined by chiral HPLC analysis. bThe absolute configuration of 2b was assigned as (S), see the for the details. (2) Reaction conditions with higher N,O-acetal derivative but lower tBuOH concentrations: Vinylarene (0.200 mmol), AcOCH2NHR (0.400 mmol), (MeO)2MeSiH (1.60 mmol), tBuOH (0.200 mmol), Cu(OAc)2 (10.0 μmol), (S,S)-Ph-BPE (12.0 μmol), CH3CN (0.2 mL), RT, 12 h, yields of isolated products; ee was determined by chiral HPLC analysis. Subsequently, we tested 1,3-dienes for this Cu-catalyzed asymmetric reaction. Different from vinylarenes, the presence of two double bonds in 1,3-dienes poses additional challenges to the study of formal hydroaminomethylation of 1,3-dienes, such as the control over 1,2-/1,4-regioselectivity and Z-/E-stereochemistry of the remaining double bond. After modifying reaction conditions (entry 10 in Scheme 1) with 8-gram, instead of 5-gram equivalent of (MeO)2MeSiH, we found that aryl-substituted 1,3-dienes reacted with N,O-acetals to yield chiral homoallylic amines with excellent 1,4-regioselectivity, E-selectivity, and enantioselectivity. Scheme 3 summarizes the scope of 1,3-dienes that undergo this Cu-catalyzed formal hydroaminomethylation reaction. Typically, a variety of 1,3-dienes containing electronically varied aryl groups reacted to afford the corresponding (E)-homoallylic amines ( 4a– 4m) in high isolated yields with high enantioselectivity (95% to >99% ee). Our standardized reaction tolerated various aryl groups with substituents at para ( 4b– 4g), meta ( 4h), and ortho ( 4i and 4j) positions, as well as oxygen- and sulfur-containing heteroaryl groups ( 4k– 4m). The absolute configuration of 4b′ was assigned as (R) by comparison of optical rotation with a reported value.46 Scheme 3 | Scope of 1,3-dienes for the Cu-catalyzed formal aminomethylation. Download figure Download PowerPoint The formal hydroaminomethylation reactions of vinylarene 1p and 1,3-diene 3a with AcOCH2NHCbz were run on a gram scale with 1–2 mol % of Cu(OAc)2/(S,S)-Ph-BPE, which occurred in good yields with excellent enantioselectivity (Scheme 4a,b). Thus these reactions could also be conducted on a scale that allows practical applications in synthesis. We also showed that the Cbz, Boc, and Fmoc groups in 2a, 2p′, and 2p″ could be readily removed under neutral, acidic, and basic conditions,47–53 respectively, yielding β-stereogenic primary amines 5 and 6 in high yields (87% and 92%), while maintaining excellent enantiopurity (95% and 98% ee), respectively (Scheme 4c). Scheme 4 | Gram-scale reactions and deprotection of carbamates to access β-stereogenic primary amines. Download figure Download PowerPoint Further, we conducted several experiments to elucidate the mechanism of this Cu-catalyzed reaction (Scheme 5). First, we showed that the N-Cbz methylene imine 6 was generated from AcOCH2NHCbz in the presence of the copper catalyst, as indicated by gas chromatography–mass spectrometry (GC-MS) and high-resolution mass spectrometry (HRMS) analysis (Scheme 5a). Second, we demonstrated that in contrast to copper catalyst reaction, the corresponding reaction in the absence of the copper catalyst failed to yield the imine 6. Indeed, our results are consistent with previous studies which showed that N,O-acetals of formaldehyde could form imines in the presence of Lewis acids.41 Third, our study revealed that formal hydroaminomethylation of vinylarene 1p in the presence of biphenylhydrosilane (Ph2SiD2), instead of (MeO)2MeSiH yielded the chiral amine 2p-d1 in 51% yield with 98% ee, and the deuterium label localized in the methyl group of 2p (Scheme 5b). Similarly, deuterium incorporation was observed for 4a-d1 when the reaction of 1,3-diene 3a was run with Ph2SiD2 (Scheme 5c). Scheme 5 | Deuterium-labeling experiments and the proposed catalytic pathway for the Cu–H-catalyzed hydroaminomethylation of alkenes. Download figure Download PowerPoint Based on the results of the aforementioned experiments on imine detection, deuterium labeling, and previous studies on Cu–H-catalyzed reactions of alkenes,23 we proposed a plausible catalytic cycle for this Cu-catalyzed hydroaminomethylation of alkenes (Scheme 5d), as follows: Activation of Cu(OAc)2 with hydrosilane in the presence of (S,S)-Ph-BPE ( L*) generates a chiral Cu–H species, ( L*)Cu–H. Insertion of alkenes into ( L*)Cu–H, in turn, formed chiral alkylcopper species A.54 Intermediate A reacted with the N-Cbz imine 6, generated in situ from N,O-acetal, in the presence of a copper catalyst, to produce an amidocopper complex B. Consequently, B was protonated by tBuOH to yield the chiral β-stereogenic amine product 2 and copper tert-butoxide ( L*)CuOtBu, which was reacted with hydrosilane to regenerate the catalytically active Cu–H species, ( L*)Cu–H. Conclusion We have developed an effective and highly enantioselective protocol for the synthesis of chiral β-stereogenic amines through Cu-catalyzed asymmetric formal hydroaminomethylation of alkenes with N,O-acetals. A wide range of vinylarenes and 1,3-dienes reacted with N,O-acetals of formaldehyde to afford the corresponding alkylamines and homoallylic amines in high yields with excellent enantioselectivity in the presence of a chiral copper catalyst generated in situ from Cu(OAc)2 and (S,S)-Ph-BPE ligand. Mechanistic studies revealed dual functions of the copper catalyst, involving the formations of both the chiral alkylcopper nucleophile from alkenes and the N-Cbz imine electrophile from N,O-acetals of formaldehyde. Further studies to determine the detailed mechanism of this transformation and to expand the scope of this aminoalkylation reaction is the focus of future work in our laboratory. Supporting Information Supplemental Information is available online. Conflict of Interest There is no conflict of interest to report. Acknowledgment This work was supported by the Ministry of Education (MOE) of Singapore (no. R-143-000-A93-112).

Selective reduction without metals: An imidazolidinone salt effectively catalyzes the highly enantioselective biomimetic transfer hydrogenation of α,β-unsaturated aldehydes to give the saturated analogues using a synthetic dihydropyridine cofactor (see scheme). Remarkably only one enantiomer forms regardless of the configuration of the enal starting material. Asymmetric catalytic hydrogenations are used in the large-scale industrial production of pharmaceuticals and fine chemicals and also by all living organisms. While chemical hydrogenations require metal catalysts or the use of stoichiometric amounts of metal hydrides,1 living organisms typically rely on organic cofactors such as nicotinamide adenine dinucleotide (NADH) in combination with metalloenzymes.2 Until now, metal-free catalytic asymmetric hydrogenations have been unknown in chemical synthesis and seem to be rare in nature.3 Here we show that a small organic molecule effectively catalyzes a highly enantioselective biomimetic transfer hydrogenation of α,β-unsaturated aldehydes using a synthetic dihydropyridine cofactor. This reaction is the first example of a completely metal-free transfer hydrogenation of olefins.7 We could also show that enantioselective iminium catalysis of the reaction is in principle possible. Iminium catalysis has recently been introduced as a powerful organocatalytic method for carbonyl transformations such as conjugate additions and cycloadditions.8 We have now completed an extensive screening of several synthetic and commercially available Hantzsch dihydropyridines and chiral ammonium salt catalysts and report here on an efficient enantioselective variant of our transfer hydrogenation. Entry Starting Product Yield [%] e.r. material 1 1 1 77[a] 95:5 2 1 1 89 98:2 3 1 1 83 (from (E)-5 c) 97:3 80 (from (Z)-5 c) 97:3 81 (from (E)/(Z)- 5 c (1:1)) 97:3 4 1 1 90 97:3 5 1 1 85 97:3 6 1 1 86 96:4 Like our nonasymmetric variant, the enantioselective reactions are generally clean and highly chemoselective, and carbonyl reduction or aldolization products were not detected. We also investigated the influence of the stereochemistry at the double bond. Remarkably, when we subjected both the isolated pure E or Z isomers of 4-nitro-substituted derivative 5 c to our reaction conditions, the same R enantiomer of product 8 c was obtained and with the same enantiomeric ratio of 97:3. Similarly, (E)/(Z)-5 c mixtures always gave the same result and, independent of their exact ratio, all furnished (R)-8 c in 97:3 e.r. Thus, our process is enantioconvergent, a highly desirable yet rare feature of a catalytic asymmetric reaction, where a mixture of stereoisomers furnishes only one product enantiomer. As a practical consequence of this feature, the unsaturated aldehyde starting material of our reaction may be used as a mixture of E and Z isomers as obtained from common synthetic procedures such as the Wittig reaction. Mechanistically, we assume the reaction to proceed by formation of iminium ion 9, which presumably isomerizes quickly via dienamine 10 (Scheme 1). The following rate-determining hydride transfer from dihydropyridine 6 to enal (E)-9 via transition state A proceeds faster than to (Z)-9 [k(E)>k(Z)] and, as a result, saturated aldehyde (R)-8 is formed predominantly. Proposed mechanism of the organocatalytic asymmetric transfer hydrogenation. In summary we have described the first completely metal-free catalytic asymmetric transfer hydrogenation. In our iminium catalytic reaction α,β-unsaturated aldehydes are highly efficiently reduced by means of transfer hydrogenation from a dihydropyridine. Attractive features of the process are 1) its high yields, chemo-, and enantioselectivities, 2) its enantioconvergence, and 3) its simplicity and practicability. Applications in the synthesis of natural products, pharmaceuticals, and fine chemicals may be envisioned. General procedure for the asymmetric transfer hydrogenation reaction: To a stirred solution of α,β-unsaturated aldehyde 5 (0.5 mmol) in dioxane (7 mL) at 13 °C was added catalyst 7 (20.4 mg, 0.05 mmol, 10 mol %) and, after five minutes, crystalline dihydropyridine 6 (129.2 mg, 0.51 mmol). After a reaction time of 48 h the mixture was poured into distilled water (20 mL) and extracted with dichloromethane (2×15 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The product was isolated by flash chromatography (SiO2, ethyl acetate/hexane) to give the saturated aldehyde product 8. Aldehydes 5 a–f were synthesized according to previously reported methods and their analytical data as well of those of aldehydes 8 match literature values.9 The absolute configuration of (R)-8 f was determined by measurement of its optical rotation and comparision to the literature value.10 Enantiomeric ratios were determined by chiral stationary phase GC-analysis.

We have successfully developed a highly enantioselective hydrogenation of various 3-aryl and 3-methyl maleinimides to access enantiomerically pure 3-substituted succinimides catalyzed by Rh/bisphosphine-thiourea (ZhaoPhos). This efficient catalytic system furnished the desired 3-substituted succinimide products with high yields and enantioselectivities (up to 99% yield, full conversions, almost all 3-aryl succinimide products up to 99% ee, and 3-methyl succinimide with 83% ee). Our catalytic system has a strong substrate tolerance and generality. Whether the N-substituted group of maleinimides is H or other protecting groups, the maleinimides were hydrogenated well (up to >99% ee, 99% yield). Moreover, the hydrogenation succinimide products can be readily utilized for the construction of biologically active molecules, such as chiral amides and pyrrolidines.

The condensation of β‐phenylpyruvic acid with amides gave olefinic intermediates in good yields (75‐80%). The asymmetric catalytic hydrogenation of α‐acetamidocinnamic acid with high enantioselectivity is described.

We have developed Cu(II)-catalyzed enantioselective conjugate-addition reactions of boron to α,β-unsaturated carbonyl compounds and α,β,γ,δ-unsaturated carbonyl compounds in water. In contrast to the previously reported Cu(I) catalysis that required organic solvents, chiral Cu(II) catalysis was found to proceed efficiently in water. Three catalyst systems have been exploited: cat. 1: Cu(OH)2 with chiral ligand L1; cat. 2: Cu(OH)2 and acetic acid with ligand L1; and cat. 3: Cu(OAc)2 with ligand L1. Whereas cat. 1 is a heterogeneous system, cat. 2 and cat. 3 are homogeneous systems. We tested 27 α,β-unsaturated carbonyl compounds and an α,β-unsaturated nitrile compound, including acyclic and cyclic α,β-unsaturated ketones, acyclic and cyclic β,β-disubstituted enones, acyclic and cyclic α,β-unsaturated esters (including their β,β-disubstituted forms), and acyclic α,β-unsaturated amides (including their β,β-disubstituted forms). We found that cat. 2 and cat. 3 showed high yields and enantioselectivities for almost all substrates. Notably, no catalysts that can tolerate all of these substrates with high yields and high enantioselectivities have been reported for the conjugate addition of boron. Heterogeneous cat. 1 also gave high yields and enantioselectivities with some substrates and also gave the highest TOF (43,200 h(-1) ) for an asymmetric conjugate-addition reaction of boron. In addition, the catalyst systems were also applicable to the conjugate addition of boron to α,β,γ,δ-unsaturated carbonyl compounds, although such reactions have previously been very limited in the literature, even in organic solvents. 1,4-Addition products were obtained in high yields and enantioselectivities in the reactions of acyclic α,β,γ,δ-unsaturated carbonyl compounds with diboron 2 by using cat. 1, cat. 2, or cat. 3. On the other hand, in the reactions of cyclic α,β,γ,δ-unsaturated carbonyl compounds with compound 2, whereas 1,4-addition products were exclusively obtained by using cat. 2 or cat. 3, 1,6-addition products were exclusively produced by using cat. 1. Similar unique reactivities and selectivities were also shown in the reactions of cyclic trienones. Finally, the reaction mechanisms of these unique conjugate-addition reactions in water were investigated and we propose stereochemical models that are supported by X-ray crystallography and MS (ESI) analysis. Although the role of water has not been completely revealed, water is expected to be effective in the activation of a borylcopper(II) intermediate and a protonation event subsequent to the nucleophilic addition step, thereby leading to overwhelmingly high catalytic turnover.

The Full Monty? Stripping a catalyst down to its bare essentials gives a neutral iridium complex containing only one monodentate phosphoramidite ligand that is an efficient catalyst for the enantioselective hydrogenation of α-dehydroamino acids (see picture). Bidentate chiral ligands were the rule in metal-catalyzed asymmetric hydrogenation for more than 30 years1 as chelation was believed to be necessary to impart the necessary rigidity to the metal complex for an efficient transfer of chirality. Recently, however, a few groups have demonstrated that monodentate ligands can also induce high enantioselectivity2 as long as two of these ligands are present in the active species. Herein, we describe the first example of a highly asymmetric hydrogenation that is induced by a metal catalyst containing only one monodentate ligand.3 Iridium is an important metal in hydrogenation. The Crabtree catalyst,4 its enantioselective version, developed by Pfaltz, based on chiral P,N ligands,5 or the celebrated Metolachlor process catalyst6 are prime examples of Ir-based hydrogenation catalysts (Scheme 1). We were interested in investigating whether iridium complexes of chiral monodentate phosphoramidites could also act as efficient enantioselective hydrogenation catalysts. Although such Ir complexes have already been reported,7 which has led to the discovery of new cyclometalated species that are active in allylic substitution,8 there are no reports of their use in enantioselective hydrogenation. Iridium catalysts. Our initial studies were aimed at the preparation of cationic iridium complexes that are analogues of the Crabtree catalyst containing a phosphoramidite ligand L, and either the same phosphoramidite, a phosphine, or pyridine as the secondary ligand L′ (Scheme 1). Based on literature precedents,9 two equivalents of Monophos were treated with [{Ir(cod)Cl}2] to immediately give [Ir(cod)(L)Cl]7b which, upon chloride abstraction in the presence of another equivalent of L, should form a cationic complex of the type [Ir(cod)LL′]+. Although we screened several phosphoramidites in combination with different ancillary ligands and counteranions, we did not obtain an efficient hydrogenation catalyst. The breakthrough came with the observation that an active but also enantioselective catalyst is obtained with bulky phosphoramidites based on Binol with substituents in the 3,3′ positions without abstraction of the chloride ligand, that is, from the non-cationic catalyst precursor [Ir(cod)(L)Cl] containing only one phosphoramidite ligand per metal.10 The drastic effect of the substitution in the 3,3′ positions of the diol backbone of the ligand can be visualized by comparing the hydrogen uptake curves obtained during the hydrogenation of methyl (Z)-2-acetamidocinnamate (Figure 1). 1Figure 1 1clearly shows that increasing the bulkiness of the chiral backbone in the 3,3′ positions leads to a substantial increase not only in activity but also in enantioselectivity (average TOFs of 6, 24, 50, and 150 h−1 and ee values of 28, 67, 93, and 98 % for R1=H, Me, Ph, and R2=tBu, respectively; see also Scheme 1). For practical reasons, namely that the diol precursor is commercially available, the bulkiest ligand with the tBu substituents is based on biphenol while the other ligands are based on binaphthol.12 Increasing the bulkiness of the phosphoramidite by changing its amino moiety does not, however, produce the same effect, and the catalytic performance of the complex remained poor when the dimethylamino group was substituted by a bis(α-methylbenzyl)amino group with unsubstituted binaphthol as backbone. This indirectly reinforces our assumption about the major role played by substitution in the 3,3′ positions of the ligand diol backbone. A similar effect has also been reported by Ojima for rhodium-catalyzed hydroformylation reactions.12 Hydrogen consumption during the hydrogenation of methyl (Z)-2-acetamidocinnamate with various Ir/phosphoramidite catalysts (Ir/L/substrate=0.01/0.01/0.5 mmol).11 In order to confirm that the catalyst precursor contains only one phosphoramidite ligand per metal ion, we undertook a full characterization of the complex by NMR spectroscopy, X-ray diffraction, and elemental analysis. The addition of two equivalents of L4 to [Ir(cod)Cl]2 (Ir/L=1/1) led to the complete disappearance of the 31P NMR signal of the free ligand L4 at δ=141.1 ppm and the appearance of a single peak at δ=107.8 ppm (bound L4). If more L4 is added, no change is observed except for the appearance of the free-ligand peak. The behavior of L1 is different. Thus, if more than two equivalents of L1 per [Ir(cod)Cl]2 is used, a new Ir complex exhibiting two sets of doublet (δ=94.5 and 88.6 ppm, J=38.6 Hz) is observed in addition to a singlet at δ=117.6 ppm for [Ir(cod)(L1)Cl]. This pattern is consistent with an iridium complex containing two nonequivalent L1 moieties. Crystals of the complex formed upon reaction of [Ir(cod)Cl]2 with L4 were obtained from a dichloromethane/heptane solution and studied by X-ray diffraction. The crystal structure of this complex is presented in Figure 2.213 ORTEP representation of the structure of [Ir(cod)(L4)Cl]; selected bond lengths [Å] with estimated standard deviations: Ir-Cl 2.362(2), Ir-P 2.265(3), Ir-C1 2.126(9), Ir-C4 2.224(10), Ir-C5 2.232(10), Ir-C8 2.143(9), C1-C8 1.435(16), C4-C5 1.397(17). Although the catalyst precursor was fully characterized as a complex containing a single phosphoramidite ligand, the ligand-to-iridium ratio may be more than one in the active species responsible for the hydrogenation. However, several facts seem to prove that this is not the case: Bulky ligands are necessary for activity and enantioselectivity: As we have seen previously, the less bulky L1, which is more suitable for formation of an [Ir(L1)2]+ complex, does not lead to an active catalyst although it is electronically equivalent to L4. This seems to demonstrate that a bulky ligand is necessary to stabilize an [IrL] species. It might also help to prevent dimerization, which is a common cause of deactivation of iridium hydrogenation catalysts.4b No acceleration is observed in the presence of additional ligand: If one additional equivalent of ligand L4 is added to isolated [Ir(cod)(Cl)L4] prior to the hydrogenation, the hydrogenation reaction proceeds slightly slower. The opposite would be observed if the active species were of the type [IrLn] (n>1) as more of this species would be present in solution. The absence of a nonlinear effect:14 The ee value of 2 varies linearly with that of the ligand L4.15 For phosphoramidites16a and phosphonites,16b a positive nonlinear effect has been observed in the case of Rh, where it is accepted that the active species contains two ligand molecules per metal ion. The absence of a ligand mixture effect: One of the advantages of monodentate ligands in an ML2 complex is the possibility of using mixtures of ligands La and Lb to form new catalysts of the type MLaLb.17 The addition of one equivalent of (R)-L1 to [Ir(cod)((S)-L4)Cl] prior to the hydrogenation does not decrease the ee value of 2. Although this chiral poisoning experiment does not constitute a definite proof, it shows that the active hydrogenation species containing L4 does not accommodate an extra phosphoramidite ligand L1 to form the cation [Ir((S)-L4)((R)-L1)]+. We briefly investigated the scope of the catalyst with various amino acid precursors (Table 1). The catalyst exhibits high activity and enantioselectivity with both electron-poor and electron-rich substituted methyl (Z)-2-acetamidocinnamates (Table 1, entries 2 and 3). A high ee value is also obtained upon hydrogenation of the acid, although the catalysis becomes rather slow (Table 1, entry 4). With smaller substrates such as methyl 2-acetamidoacrylate (Table 1, entry 5), the ee value drops to 50 %. A further drop is observed when the N-acetyl group is replaced by an N-formyl group (Table 1, entry 6).18 However, increasing the bulk of the alkyl residue of the substrate again leads to a high ee value (Table 1, entry 7). A standard enamide (N-(1-phenylvinyl)acetamide) was also tested under the same conditions. It gave full conversion but only a low ee value (10 %). These results are quite informative. First of all, they show that a single-ligand catalyst is more efficient with relatively bulky substrates. Such substrates might form a more rigid assembly with the catalyst because of steric congestion, thus allowing an efficient transfer of chirality. Secondly, although we cannot rule out η6 coordination in the case of the phenylalanine precursor19 as an explanation for the ee value obtained with this substrate, this is not a prerequisite, as observed in entry 7 of Table 1. Entry Substrate Conv. [%] TOF [h−1][b] ee [%] R R′ R′′ 1[c] Ph Me Me 100 150 98 2 p-MeOC6H4 Me Me 100 25 98 3 p-ClC6H4 Me Me 100 25 98 4 Ph H Me 50 9 98 5 H Me Me 100 273 50 6 H Me H 89 30 39 7[d] iPr Me H 89 1 88 Although the true nature of the active species in homogeneous catalysis is often difficult to ascertain unambiguously, our observations point towards an iridium complex with a single monodentate ligand as the active species. We believe this is a unique example of high enantioselectivity induced by a catalyst that has been pared down to the bare essentials. It is conceivable, though, that secondary interactions between iridium and the monodentate ligand are induced either due to an η2 interaction20 or CH insertion8, 21 upon hydrogenation of cod, which would transform our monodentate ligand into a bidentate ligand. We are currently investigating the structure of the catalyst during hydrogenation by NMR spectroscopy and mass spectrometry. General procedures: All reactions were performed under dry nitrogen using standard Schlenk techniques or in a glove box. Anhydrous solvents dried over molecular sieves (Fluka) were used systematically. [{Ir(cod)Cl}2] and Biphen were purchased from Strem. The hydrogenation substrates were synthesized following published procedures. Preparation of [Ir(cod)(L4)Cl]: [{Ir(cod)Cl}2] (65 mg, 0.096 mmol) was placed in a 10-mL Schlenk flask and the entire apparatus was evacuated and back-filled with N2 three times to establish an inert atmosphere. Dry, degassed dichloromethane (1 mL) and (S)-L4 (82 mg, 0.192 mmol) were added and the reaction mixture was stirred at room temperature for 10 min. X-ray quality crystals were obtained upon layering with n-heptane. 1H NMR (300 MHz, CDCl3): δ=7.22 (s, 1 H), 7.09 (s, 1 H), 5.40–5.29 (m, 1 H), 5.24–5.13 (m, 1 H), 3.57–3.47 (m, 1 H), 2.83–2.74 (m, 1 H), 2.61 (br, 3 H), 2.58 (br, 3 H), 2.26 (s, 3 H), 2.24 (s, 3 H), 1.80 (s, 3 H), 1.71 (s, 3 H), 1.65 (s, 9 H), 1.37 ppm (s, 9 H); 31P NMR (121.5 MHz, CDCl3): δ=107.8 ppm; elemental analysis calcd (%) for C34H50ClIrNO2P: C 53.49, H 6.60, N 1.83; found: C 53.4, H 6.8, N 1.8. Hydrogenation experiments: The hydrogenation experiments with monitoring of the H2 consumption were performed in an Endeavor reactor. The Endeavor is an autoclave that contains eight reactors equipped with glass reaction vessels. Substrate (0.5 mmol), [{Ir(cod)Cl}2] (0.01 mmol), and ligand (0.02 mmol) were weighed into these reaction vessels. The vessels were placed in the reactors and CH2Cl2 (5 mL) was added. The reactors were purged for 30 min with N2 before applying a hydrogen atmosphere of 5 bar. The pressure was kept constant during the reaction and the hydrogen uptake was monitored. After completion of the reaction, the reactors were opened and samples were taken for ee determination by GC. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2007/z603930_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

SummaryOver the past decades, asymmetric catalysis has been intensely investigated as a powerful tool for the preparation of numerous chiral biologically active compounds. However, developing general and practical strategies for preparation of both enantiomers of a chiral molecule via asymmetric catalysis is still a challenge, particularly when the two enantiomers of a chiral catalyst are not easily prepared from natural chiral sources. Inspired by the biologic system, we report herein an unprecedented catalytic enantiodivergent Michael addition of pyridazinones to enones by subtle adjustment of achiral amino moiety of dipeptide phosphine catalysts. These two dipeptide phosphine catalysts, P5 and P8, could deliver both enantiomers of a series of N2-alkylpyridazinones in good yields (up to 99%) with high enantioselectivities (up to 99% ee) via the catalyst-controlled enantiodivergent addition of pyridazinones to enones.

This work was dedicated to the development and evaluation of new chiral catalysts for asymmetric C-C and C-H bond forming reactions. In this context ESI-MS was used as a powerful tool for reactivity- and selectivity-studies. In the first part an ESI-MS screening method is described, which allows the determination of the selectivity of a chiral catalyst in the palladium catalyzed asymmetric allylic alkylation by testing its racemic form. It was shown that, by reacting a racemic mixture of the with a scalemic mixture of quasi-enantiomeric mass-labeled substrates, the selectivity of the chiral catalyst can be calculated from the ratio of the formed mass-labeled reaction intermediates. The value of this new method was demonstrated when different new aryl-PHOX-type ligands, which are not easily accessible in enantiopure form, were synthesized and evaluated in the allylic alkylation reaction. In this way a more selective member of this class was found compared to the previously reported phenyl-PHOX ligand. Since PHOX ligands are suitable ligands in the iridium-catalyzed asymmetric hydrogenation of C-C and C-N double bonds, the new PHOX ligands were then tested as well in the iridium-catalyzed asymmetric hydrogenation of different unsaturated compounds. Although low activities and selectivities were found in most cases, one ligand showed some promising results in the hydrogenation of allylic alcohols and imines. Furthermore air- and moisture-stable secondary phosphine oxide (SPO) containing bidentate ligands were tested in the palladium-catalyzed asymmetric allylic alkylation reaction. SPO,N-ligands bearing a PHOX type backbone were inactive in this transformation as they tend to form inactive palladium-bis-ligand complexes stabilized by hydrogen-bonding between the two ligands. SPO,P ligands however, were able to promote the desired reaction in a highly selective fashion although only low activities were found. During this work as well a new organo-catalyst, based on the structure of 2,3-dihydrobenzo[1,4]oxazine, was developed which allows for the asymmetric transfer-hydrogenation of alpha, beta-unsaturated aldehydes. Especially in the reduction of beta, beta-diaryl acrylaldehydes very good activities and high enantioselectivities were achieved. It was shown that for this particular substrate this catalyst outperformed the previously described ones. Thus it proved to be a useful extension to the limited known catalysts for this reaction and especially for this interesting class of products, which can act as precursors for many natural products or drugs. Another organo-catalyzed reaction which was studied in this work was the conjugate addition reaction catalyzed by a tripeptidic organo-catalyst. As in the literature two different mechanistically pathways were hypothesized, via an enamine- or via an enol-intermediate, ESI-MS studies were carried out to clarify the actual mechanism for this transformation. All reaction intermediates which are postulated for the enamine-pathway could be found in both the forward- and the back-reaction. Furthermore the enantioselectivity of enamine-attack onto a nitroolefin was determined by an ESI-MS screening and it was shown that this enantioselectivity equals the selectivity of the preparative reaction. All of these findings strongly support the suggestion of an enamine-catalysis mechanism to be true in this reaction. The last part of this work aimed for the asymmetric alpha-allylation of carbonyl compounds by a tandem-catalysis approach. An intensive screening of both the organo-catalyst and the palladium-ligand led to reaction conditions which allowed for the selective mono-allylation of ketones in high yields. The formation of a quaternary center by alpha-allylation of alpha-branched aldehydes was also achieved. However, only low enantiomeric excesses were obtained in this transformation for the different catalyst systems tested.

Organoselenium compounds, due to their high structural diversity, special function, and biological activities, have drawn attention in synthetic chemistry. Herein, a novel example of chiral N,N′-di...