A General Approach to the Synthesis of β2‐Amino Acid Derivatives via Highly Efficient Catalytic Asymmetric Hydrogenation of α‐Aminomethylacrylates

A new strategy was developed for the synthesis of a valuable class of α‐aminomethylacrylates via the Baylis–Hillman reaction of different aldehydes with methyl acrylate followed by acetylation of the resulting allylic alcohols and S_N2′‐type amination of the allylic acetates. Asymmetric hydrogenation of these diverse olefinic precursors using rhodium(Et‐Duphos) catalysts provided the corresponding β²‐amino acid derivatives with excellent enantioselectivities and exceedingly high reactivities (up to >99.5% ee and S/C=10,000). The first hydrogenation of (Z)‐configurated substrates was studied for the synthesis of β²‐amino acid derivatives. The high influence of the substrate geometry and steric hindrance on the reactivity and enantioselectivity was also disclosed for this reaction. This protocol provides a highly practical, facile and scalable method for the preparation of optically pure β²‐amino acids and their derivatives under mild reaction conditions.     

Enantioselective Synthesis of Optically Active Alkanephos‐ phonates via Rhodium‐Catalyzed Asymmetric Hydrogenation of β‐Substituted α,β‐Unsaturated Phosphonates with Ferrocene‐Based Monophosphoramidite Ligands

A series of chiral β‐substituted alkanephosphonates was synthesized in high enantioselectivities via the first rhodium‐catalyzed asymmetric hydrogenation of the corresponding β‐substituted‐α,β‐unsaturated phosphonates using a ferrocene‐derived monophosphoramidite ligand, with which up to 99.5% ee have been achieved for the hydrogenation of (E)‐substrates and 98.0% ee for (Z)‐substrates.     

Asymmetric Synthesis of the Roche Ester and its Derivatives by Rhodium‐INDOLPHOS‐Catalyzed Hydrogenation

(S)‐3‐Hydroxy‐2‐methylpropionate, known as the Roche ester, and several of its derivatives were successfully synthesized through asymmetric rhodium‐catalyzed hydrogenation, using INDOLPHOS (diisopropyl{1‐[(S)‐3,5‐dioxa‐4‐phosphacyclohepta[2,1‐a;3,4‐a′]dinaphthalen‐4‐yl]‐3‐methyl‐2‐indolyl}phosphine) as the chiral ligand, in excellent yield and the highest ee reported up to now (TOF over 5500 h⁻¹ at 25 °C; up to 98% ee at −40 °C).     

Highly Active and Enantioselective Rhodium‐Catalyzed Asymmetric 1,4‐Addition of Arylboronic Acid to α,β‐ Unsaturated Ketone by using Electron‐Poor MeO‐F12‐BIPHEP

The asymmetric 1,4‐addition of phenylboronic acid to cyclohexenone were performed by using a low amount of rhodium/(R)‐(6,6′‐dimethoxybiphenyl‐2,2′‐diyl)bis[bis(3,4,5‐trifluorophenyl)phosphine] (MeO‐F₁₂‐BIPHEP) catalyst. Because the catalyst shows thermal resistance at 100 °C, up to 0.00025 mol% Rh catalyst showed good catalytic activity. The highest turnover frequency (TOF) and turnover number (TON) observed were 53,000 h⁻¹ and 320,000, respectively. The enantioselectivities of the products were maintained at a high level of 98% ee in these reactions. The Eyring plots gave the following kinetic parameters (ΔΔH^≠=−4.0±0.1 kcal mol⁻¹ and ΔΔS^≠=−1.3±0.3 cal mol⁻¹ K⁻¹), indicating that the entropy contribution is relatively small. Both the result and consideration of the transition state in the insertion step at the B3LYP/6‐31G(d) [LANL2DZ for rhodium] levels indicated that the less σ‐donating electron‐poor (R)‐MeO‐F₁₂‐BIPHEP could be creating a rigid chiral environment around the rhodium catalyst even at high temperature.     

Practical by Ligand Design: A New Class of Monodentate Phosphoramidite Ligands for Rhodium‐Catalyzed Enantioselective Hydrogenations

A new class of low‐cost and easy‐to‐prepare monodentate phosphoramidite ligands (CydamPhos) has been developed from readily accessible and cheap trans‐1,2‐diaminocyclohexane as starting material through a three‐step transformation. This type of ligands exhibited excellent enantioseletivities and high activities in rhodium(I)‐catalyzed asymmetric hydrogenations of dehydro‐α‐amino acid methyl esters 9 (ee: 96.2–99.8 %) and acetylenamides 11 (91.8–98.8 %). The remarkable substituent effects exhibited by the ligands on the enantioselective control of the catalysis are rationalized on the basis of molecular structure of the catalyst precursor.     

Highly Modular P‐O‐P Ligands for Asymmetric Hydrogenation

The preparation of a library of new P‐O‐P ligands (phosphine‐phosphites and phosphine‐phosphinites), easily available in two synthetic steps from enantiopure Sharpless epoxy ethers, is reported. The “lead” catalyst of the series has proven to have outstanding catalytic properties in the rhodium‐catalysed asymmetric hydrogenation of a wide variety of functionalised alkenes (16 examples). The excellent performance and modular design of the catalysts makes them attractive for future applications.     

DiPAMP’s Big Brother “i‐Pr‐SMS‐Phos” Exhibits Exceptional Features Enhancing Rhodium(I)‐Catalyzed Hydrogenation of Olefins

Switching Knowles DiPAMP’s {DiPAMP=1,2‐bis[(o‐anisyl)(phenyl)phosphino]‐ ethane} MeO groups with i‐PrO ones led to the i‐Pr‐SMS‐Phos {i‐Pr‐SMS‐Phos=1,2‐bis[(o‐isoprop‐ oxyphenyl)(phenyl)phosphino]ethane} ligand which displayed a boosted catalyst activity coupled with an enhanced enantioselectivity in the rhodium(I)‐catalyzed hydrogenation of a wide‐range of representative olefinic substrates (dehydro‐α‐amido acids, itaconates, acrylates, enamides, enol acetates, α,α‐diarylethylenes, etc). The rhodium(I)‐(i‐Pr‐SMS‐Phos) catalytic profile was investigated revealing its structural attributes and robustness, and in contrast to the usual trend, ³¹P NMR analysis revealed that its methyl (Z)‐α‐acetamidocinnamate (MAC) adduct consisted of a reversed diastereomeric ratio of 1.4:1 in favour of the most reactive diastereomer.     

Iridium‐Catalyzed Enantioselective Hydrogenation of Cyclic Imines

A catalytic complex made from [Ir(COD)Cl]₂ [di‐μ‐chloro‐bis(1,5‐cyclooctadiene)diiridium(I)] precursor and (S,S)‐f‐Binaphane ((R,R)‐1,1′‐bis{(R)‐4,5‐dihydro‐3H‐dinaphtho[1,2‐c:2′,1′‐e]phosphepino}ferrocene) ligand effectively catalyzed the enantioselective hydrogenation of cyclic imines with high reactivity and good enantioselectivity.     

Fluorinated Alcohols as Solvents for Enantioselective Hydrogenation with Chiral Self‐Assembling Rhodium Catalysts

We herein describe the beneficial effect of fluorinated alcohols on asymmetric hydrogenation using chiral self‐assembling rhodium complexes. Previously, the application of these catalysts has been hampered by low reaction rates in non‐polar solvents, which are essential for establishing the self‐assembling architecture via hydrogen bonding. Excellent reaction rates are usually observed in alcohols as solvents, but the characteristic hydrogen bonds are cleaved in those media, resulting in poor ee values. We now show for the first time that the disadvantageous properties of both solvent classes on the catalytic reaction can be overcome by using fluorinated alcohols. Due to this key finding, homogeneous catalysis with self‐assembling catalysts is much closer to practical application.     

Optically Pure 1,2‐Bis[(o‐alkylphenyl)phenylphosphino]ethanes and Their Use in Rhodium‐Catalyzed Asymmetric Hydrogenations of α‐(Acylamino)acrylic Derivatives

Optically pure (S,S)‐1,2‐bis[(o‐alkylphenyl)phenylphosphino]ethanes 1a–d were prepared in four steps from phenyldichlorophosphine via phosphine‐boranes as the intermediates. The rhodium complexes 5a–d of these diphosphines were used for the asymmetric hydrogenations of α‐(acylamino)acrylic derivatives including β‐disubstituted derivatives. Markedly high enantioselectivity (78–>99%) was observed for the reduction of β‐monosubstituted derivatives. β‐Disubstituted derivatives were also reduced in considerably high enantioselectivity (up to 90%). The single crystal X‐ray analysis of the rhodium complex 5c of (S,S)‐1,2‐bis[phenyl(5′,6′,7′,8′‐tetrahydronaphthyl)phosphino]ethane ( 1c) revealed its δ‐type structure with face orientation of the two tetrahydronaphthyl groups and edge orientation of the two phenyl groups. This conformation corresponds to that of the rhodium complex of 1,2‐bis[(o‐methoxyphenyl)phenylphosphino]ethane (DIPAMP); the rhodium complex of (R,R)‐DIPAMP, whose chirality at phosphorus is opposite that of 5c , exhibits a λ‐type structure with the face orientation of the two o‐methoxyphenyl groups and the edge orientation of the two phenyl groups. The conformational similarity of these rhodium complexes as well as the stereochemical outcome in the asymmetric hydrogenations means that the coordinative interaction of the methoxy group of DIPAMP with rhodium metal is not the main factor that affects asymmetric induction.     

Threonine‐Derived Phosphinite‐Oxazoline Ligands for the Ir‐Catalyzed Enantioselective Hydrogenation

A series of chiral phosphinite‐oxazolines was synthesized in four steps starting from carboxylic acids and threonine methyl ester. In the asymmetric hydrogenation of a number of alkenes, iridium complexes of these ligands induced significantly higher enantioselectivities than the corresponding serine‐derived complexes. Enantiomeric excesses of 89 to 99% were obtained for unfunctionalized alkenes with turnover numbers of up to 5000.     

Iridium‐Catalyzed Enantioselective Hydrogenation of β,β‐Disubstituted Nitroalkenes

A highly efficient, iridium‐catalyzed, enantioselective hydrogenation of β,β‐disubstituted nitroalkenes has been developed. Using a complex consisting of iridium and (S,S)‐f‐spiroPhos as the catalyst, a variety of β,β‐disubstituted nitroalkenes were successfully hydrogenated to the corresponding chiral nitroalkanes with excellent enantioselectivities (up to 98% ee) and high turnover numbers (TON=1000).

     

Rhodium‐BisbenzodioxanPhos Complex‐Catalyzed Homogeneous Enantioselective Pauson–Khand‐Type Cyclization in Alcoholic Solvents

The chiral atropisomeric diphosphane ligand (S)‐BisbenzodioxanPhos was found to be highly effective in the co‐operative processeses of aldehyde decarbonylation and cascaded enantioselective Pauson–Khand‐type reactions. Various 1,6‐enynes were transformed to the corresponding bicyclic cyclopentenones in good yields and enantiomeric excesses (up to 96% ee). The attractive feature of this new Rh‐catalyzed homogeneous dual catalysis system is that the reaction can be performed in alcoholic solution.     

Rhodium‐Catalyzed Homogeneous Reductive Amidation of Aldehydes

The catalytic reductive amidation of an aldehyde (hexanal) with an amide (acetamide) is reported. Apart from the desired N‐hexylacetamide, the two isomeric unsaturated intermediates as well as hexanol are produced together with higher mass products that arise from aldol condensation and diamide coupling of the aldehyde. Screening of different catalyst precursor salts, ligands and reaction conditions led to the finding that the catalytic system based on the (cyclooctadiene)rhodium chloride dimer, [Rh(cod)Cl]₂, in combination with the ligand xantphos and an acid co‐catalyst results in high selectivity for the desired product. Under optimized conditions nearly full conversion is reached with high selectivity to the desired N‐alkylamide and with a very high N ‐ alkylamide/alcohol ratio, while producing only small amounts of by‐products. The scope of the reaction has been investigated using different amides as well as aldehydes; the results show the general applicability of this novel reaction, but with electron‐withdrawing amides the selectivity to N‐alkylamide is lower. NMR studies showed that the nucleophilic addition of acetamide to hexanal is acid catalyzed, forming N‐(1‐hydroxyhexyl)acetamide in equilibrium with both hexanal and the dehydrated unsaturated imides. A catalytic mechanism is proposed in which a strong acid such as HOTs acts as a co‐catalyst by establishing a rapid chemical equilibrium between the aldehyde, acetamide and the intermediates. Furthermore, it is proposed that the presence of acid causes a change in catalytic species, enabling a cationic Rh/xantphos hydrogenation catalyst to selectively hydrogenate the intermediates to N‐hexylacetamide in the presence of hexanal.     

Dendronized Poly(Ru‐BINAP) Complexes: Highly Effective and Easily Recyclable Catalysts For Asymmetric Hydrogenation

A new kind of dendronized polymeric chiral BINAP ligands has been synthesized and applied to the Ru‐catalyzed asymmetric hydrogenation of simple aryl ketones and 2‐arylacrylic acids. These dendronized poly(Ru‐BINAP) catalysts exhibited high catalytic activity and enantioselectivity, very similar to those obtained with the corresponding parent Ru(BINAP) and the Ru(BINAP)‐cored dendrimers. It was found that the pendant dendrons had a major impact on the solubility and the catalytic properties of the polymeric ligands. These polymeric catalysts could be easily recovered from the reaction solution by using solvent precipitation, and the reused catalyst showed no loss of activity or enantioselectivity.     

General Enantioselective Synthesis of Butyrolactone Natural Products via Ruthenium‐SYNPHOS®‐Catalyzed Hydrogenation Reactions

Enantioselective syntheses of several paraconic acids have been achieved using catalyzed asymmetric hydrogenation of β‐keto esters with SYNPHOS^® as a ligand. This strategy allowed the short synthesis of biologically active (−)‐methylenolactocin 1 , (−)‐protolichesterinic acid 2 , (−)‐phaseolinic acid 3 and (+)‐roccellaric acid 4 .     

Impact of Incorporating Substituents onto the P‐o‐Anisyl Groups of DiPAMP Ligand on the Rhodium(I)‐Catalyzed Asymmetric Hydrogenation of Olefins

The introduction of 1,2‐bis[(o‐anisyl)(phenyl)phosphino]ethane (DiPAMP) as a P‐stereogenic ligand for rhodium(I)‐catalyzed hydrogenation by Knowles et al. came after their evaluation of several diphosphines. However, no in‐depth study was carried out on incorporating various substituents on its P‐o‐anisyl groups. In this work, we have prepared a large series of enantiopure and closely related DiPAMP analogues possessing various substituents (MeO, TMS, t‐Bu, Ph, fused benzene ring) on the o‐anisyl rings. The new ligands were evaluated in rhodium‐catalyzed hydrogenation of several model substrates: methyl α‐acetamidoacrylate, methyl (Z)‐α‐acetamidocinnamate, methyl (Z)‐β‐acetamidocrotonate, dimethyl itaconate, and atropic acid. They displayed enhanced activities and increased enantioselectivities, particularly the P‐(2,3,4,5‐tetra‐MeO‐C₆H)‐substituted ligand (4MeBigFUS). Interestingly enough, 88% ee was obtained in the hydrogenation of atropic acid using the Rh‐(4MeBigFUS) catalyst under mild conditions (10 bar H₂, room temperature) versus 7% ee using Rh‐DiPAMP. Conversely, the ligand possessing P‐(2,6‐di‐MeO‐C₆H₃) groups proved to slow down considerably the hydrogenation. X‐Ray structures of their corresponding Rh complexes are presented and discussed.     

Synthesis of Chiral 2‐Hydroxy‐1‐methylpropanoates by Rhodium‐Catalyzed Stereoselective Hydrogenation of α‐(Hydroxymethyl)‐acrylate Derivatives

The synthesis of chiral 3‐hydroxy‐2‐methylpropanoic acid esters (e.g., “Roche ester” 3a ) based on the rhodium‐catalyzed stereoselective hydrogenation of Baylis–Hillman reaction products was investigated. Full conversions and enantioselectivities of up to 99% at a substrate/catalyst ratio of up to 500/1 were achieved by application of bisphospholanes of the catASium M series as ancillary ligands. An interesting kinetic resolution was observed by the diastereoselective hydroxy‐directed hydrogenation of related racemic β‐branched precursors affording mainly anti‐isomers with up to 96%ee.     

Low‐Pressure Hydrogenation of Arenecarboxylic Acids to Aryl Aldehydes

A highly effective palladium catalyst has been developed that allows the selective hydrogenation of arenecarboxylic acids to the aryl aldehydes in the presence of pivalic anhydride already at 5 bar hydrogen pressure. With the new catalyst, diversely functionalized aromatic and heteroaromatic aldehydes are conveniently accessible from the corresponding carboxylic acids in a single reaction step without any overreduction to the alcohols.     

Enantioselective Rhodium‐Catalyzed Addition of Arylboronic Acids to Trifluoromethyl Ketones

A new C₂‐symmetrical, chiral bisphosphorus ligand proved to be efficient for the rhodium‐catalyzed nucleophilic addition of arylboronic acids to trifluoromethyl ketones, providing a series of chiral trifluoromethyl‐substituted tertiary alcohols in high yields (up to 93%) and excellent enantioselectivities (>99%).