Highly Enantioselective Synthesis of 3,3-Diarylpropyl Amines and 4-Aryl Tetrahydroquinolines via Ir-Catalyzed Asymmetric Hydrogenation.

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

Chiral compounds containing nitrogen heteroatoms are fundamental substances for the chemical, pharmaceutical and agrochemical industries. However, the preparation of some of these interesting scaffolds is still underdeveloped. Herein we present the synthesis of a family of P‐stereogenic phosphinooxazoline iridium catalysts from L‐threonine methyl ester and their use in the asymmetric hydrogenation of N‐Boc‐2,3‐diarylallyl amines, achieving very high enantioselectivity. Furthermore, the synthetic utility of the 2,3‐diarylpropyl amines obtained is demonstrated by their transformation to 3‐aryl‐tetrahydroquinolines and 4‐benzyl‐tetrahydroisoquinolines, which have not yet been obtained in an enantioselective manner by direct reduction of the corresponding aromatic heterocycles. This strategy allows the preparation of these types of alkaloids with the highest enantioselectivity reported up to date.

Several chiral sulfonyl compounds were prepared using the iridium catalyzed asymmetric hydrogenation reaction. Vinylic, allylic and homoallylic sulfone substitutions were investigated, and high enantioselectivity is maintained regardless of the location of the olefin with respect to the sulfone. Impressive stereoselectivity was obtained for dialkyl substitutions, which typically are challenging substrates in the hydrogenation. As expected, the more bulky Z-substrates were hydrogenated slower than the corresponding E isomers, and in slightly lower enantioselectivity.

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.

Chiral carboxylic acid moieties are widely found in pharmaceuticals, agrochemicals, flavors, fragrances, and health supplements. Although they can be synthesized straightforwardly by transition-metal-catalyzed enantioselective hydrogenation of unsaturated carboxylic acids, because the existing chiral catalysts have various disadvantages, the development of new chiral catalysts with high activity and enantioselectivity is an important, long-standing challenge. Ruthenium complexes with chiral diphosphine ligands and rhodium complexes with chiral monodentate or bidentate phosphorus ligands have been the predominant catalysts for asymmetric hydrogenation of unsaturated acids. However, the efficiency of these catalysts is highly substrate-dependent, and most of the reported catalysts require a high loading, high hydrogen pressure, or long reaction time for satisfactory results. Our recent studies have revealed that chiral iridium complexes with chiral spiro-phosphine-oxazoline ligands and chiral spiro-phosphine-benzylamine ligands exhibit excellent activity and enantioselectivity in the hydrogenation of α,β-unsaturated carboxylic acids, including α,β-disubstituted acrylic acids, trisubstituted acrylic acids, α-substituted acrylic acids, and heterocyclic α,β-unsaturated acids. On the basis of an understanding of the role of the carboxy group in iridium-catalyzed asymmetric hydrogenation reactions, we developed a carboxy-group-directed strategy for asymmetric hydrogenation of olefins. Using this strategy, we hydrogenated several challenging olefin substrates, such as β,γ-unsaturated carboxylic acids, 1,1-diarylethenes, 1,1-dialkylethenes, and 1-alkyl styrenes in high yield and with excellent enantioselectivity. All these iridium-catalyzed asymmetric hydrogenation reactions feature high turnover numbers (up to 10000) and turnover frequencies (up to 6000 h-1), excellent enantioselectivities (greater than 95% ee with few exceptions), low hydrogen pressure (<12 atm), and operational simplicity. These features make chiral iridium catalysts superior or comparable to well-established chiral ruthenium and rhodium catalysts for asymmetric hydrogenation of unsaturated carboxylic acids. A number of chiral natural products and pharmaceuticals have been prepared by concise routes involving an iridium-catalyzed asymmetric hydrogenation of an unsaturated carboxylic acid as a key step. As part of a mechanistic study of iridium-catalyzed asymmetric hydrogenation of unsaturated acids, we isolated, for the first time, the migratory insertion intermediate in the iridium-catalyzed asymmetric hydrogenation of olefins, and this result strongly supports the involvement of an Ir(III)/Ir(V) catalytic cycle. The rigid, bulky scaffold of the chiral spiro-P,N-ligands of the catalysts not only prevents them from undergoing deactivating aggregation under the hydrogenation conditions but also is responsible for the efficient chiral induction. The carboxy group of the substrate acts as an anchor to ensure coordination of the substrate to the iridium center of the catalyst during the reaction and makes the hydrogenation proceed smoothly.

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.

A number of cyclic dienes containing the allylsilane moiety were prepared by a Birch reduction and subjected to iridium-catalyzed regioselective and asymmetric hydrogenation, which provided chiral allylsilanes in high conversion and enantiomeric excess (up to 99 % ee). The compounds were successively used in the Hosomi-Sakurai allylation with various aldehydes employing TiCl4 as Lewis acid, providing adducts with two additional stereogenic centers in excellent diastereoselectivity.

Chiral compounds containing nitrogen heteroatoms are fundamental substances for the chemical, pharmaceutical and agrochemical industries. However, the preparation of some of these interesting scaffolds is still underdeveloped. Herein we present the synthesis of a family of P‐stereogenic phosphinooxazoline iridium catalysts from L‐threonine methyl ester and their use in the asymmetric hydrogenation of N ‐Boc‐2,3‐diarylallyl amines, achieving very high enantioselectivity. Furthermore, the synthetic utility of the 2,3‐diarylpropyl amines obtained is demonstrated by their transformation to 3‐aryl‐tetrahydroquinolines and 4‐benzyl‐tetrahydroisoquinolines, which have not yet been obtained in an enantioselective manner by direct reduction of the corresponding aromatic heterocycles. This strategy allows the preparation of these types of alkaloids with the highest enantioselectivity reported up to date.

The Ir-catalyzed asymmetric hydrogenation of olefins is widely used for production of value-added bulk and fine chemicals. The iridium catalysts with chiral spiro phosphine-oxazoline ligands developed in our group show high activity and high enantioselectivity in the hydrogenation of olefins bearing a coordinative carboxyl group, such as α,β-unsaturated carboxylic acids, β,γ-unsaturated carboxylic acids, and γ,δ-unsaturated carboxylic acids. Here we conducted detailed mechanistic studies on these Ir-catalyzed asymmetric hydrogenation reactions by using (E)-2-methyl-3-phenylacrylic acid as a model substrate. We isolated and characterized several key intermediates having Ir-H bonds under the real hydrogenation conditions. Particularly, an Ir(III) migratory insertion intermediate was first isolated in an asymmetric hydrogenation reaction promoted by chiral Ir catalysts. That this intermediate cannot undergo reductive elimination in the absence of hydrogen strongly supports the involvement of an Ir(III)/Ir(V) cycle in the hydrogenation. On the basis of the structure of the Ir(III) intermediate, variable-temperature NMR spectroscopy, and density functional theory calculations, we elucidated the mechanistic details of the Ir-catalyzed hydrogenation of unsaturated carboxylic acids and explained the enantioselectivity of the reactions. These findings experimentally and computationally elucidate the mechanism of Ir-catalyzed asymmetric hydrogenation of olefins with a strong coordinative carboxyl group and will likely inspire further catalyst design.

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

The main aim of the research presented in this thesis was to expand the substrate scope of the iridium-catalyzed asymmetric hydrogenation, which represents an extremely useful methodology for the enantioselective synthesis of chiral molecules.&#13;\nWhile this chemistry has been developed and investigated mainly for the hydrogenation of unfunctionalized olefins, so far only little attention has been given to functionalized olefins. Therefore, the different research projects presented in this thesis dealt with the application of iridium catalysts to the reduction of particularly valuable substrates that are difficult to hydrogenate enantioselectively with other methods. &#13;\nThe first chapter of this thesis gives a general introduction on asymmetric hydrogenation and the role of iridium catalysts in this context. The following two chapters deal with the investigation of new substrates in the iridium-catalyzed asymmetric hydrogenation using various N,P ligands developed in the Pfaltz group, and give an account of the superior results that have been obtained with such catalysts compared to those representing the state-of-the-art. In particular, chapter two concerns the reduction of vinylsilanes, for which the judicious choice of the best catalyst for each specific substrate was required to achieve good results in term of both chemical and optical yield. On the contrary, a pyridinyl phosphitine bearing a 2,6-difluorophenyl group on the oxazoline ring was best suited for a broad array of 2-alkyl- and aryl- substituted maleic acid dimethyldiester, as reported in chapter three. Such process turned out to be enantioconvergent, allowing the hydrogenation of mixtures of maleates and fumarates in high enantiomeric excesses.&#13;\nIn chapter four the deployment of environmentally friendly solvents such as THF and 2-MeTHF in the iridium-catalyzed asymmetric hydrogenation of 3,3-disubstituted allylic alcohols is described. Finally, chapter five of this dissertation deals with the development of new NHC ligands for the iridium-catalyzed asymmetric hydrogenation of acid-labile substrates such as tert-butyloxycarbonyl protected allylic alcohols. Experimental details and characterization of the substances discussed in the main body of this manuscript is reported in the experimental section that constitutes chapter six.

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.

The presence of a remote directing group on terminal 1,1-diaryl and 1,1-dialkyl alkenes led to high and unprecedented enantioselectivity in iridium-catalyzed asymmetric hydrogenation (see scheme). This strategy offers efficient synthetic pathways towards valuable enantiomerically enriched 1,1-diaryl and 1,1-dialkyl alkanes. Moreover, the directing group can be further functionalized.

The main focus of the research presented in this dissertation was to broaden the substrate scope of the iridium-catalyzed asymmetric hydrogenation of heterocyclic compounds. In view of the fact that a widely applicable hydrogenation system for the reduction of structurally diverse furans and benzofurans is to date not available, a thorough investigation of furan, benzofuran and thiophene 1,1-dioxide derivatives was carried out. Mono- and disubstituted furan derivatives were synthesized and submitted to iridium-catalyzed hydrogenation reactions. While 3-substituted furans were reduced using a catalyst based on a cyclopentane-annulated bicyclic pyridine-phosphine ligand with high enantiomeric excess (95–99% ee) and conversion (83–99%), 2-substituted counterparts proved to be less reactive (80–97% conv., 65–82% ee) with the same catalyst. Asymmetric hydrogenation of 2,4-disubstituted furans proved to be challenging for several reasons, not least because of the problem of controlling the cis/trans selectivity. Surprisingly, in the iridium-catalyzed hydrogenation of 3-substituted benzofurans only one catalyst, based on the cyclohexane-annulated pyridine-phosphinite ligand, showed high activity and enantioselectivity (75–89% conv., 91–92% ee), whereas the five-membered ring analog suffered from moderate activity and enantioselectivity. In contrast, the 2-alkyl substituted benzofurans gave superior results (99% conv., 97–99% ee). Disubstituted thiophene 1,1-dioxides were also investigated in the iridium-catalyzed asymmetric hydrogenation. The hydrogenation of 3,4 disubstituted thiophene 1,1 dioxides using a catalyst based on a cyclopentane-annulated bicyclic pyridine-phosphine ligand gave inferior results to those obtained with their 2,5 disubstituted counterparts.

A novel highly enantioselective two step access to a unit B precursor of cryptophycins in good yields from commercially available starting materials has been developed. The key step is an asymmetric hydrogenation using the commercially available [(COD)Rh-(R,R)-Et-DuPhos]BF4 catalyst. The synthetic route provides the advantage of less synthetic steps, proceeds with high yields and enantioselectivity, and avoids hazardous reaction conditions.