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This review outlines the most recent papers describing the stereoselective synthesis of γ-amino acids. In this update, the γ-amino acids have been classified according to the type of compounds, position and number of substituents, and depending on the type of substrate, acyclic, carbocyclic or azacyclic derivatives, following in the first case an order related to the strategy used, whereas in the second and third cases the classification is based on the ring size., The authors thank CONACYT-Mexico for financial support via projects 181816 and 248868. Ministerio de Ciencia e Innovación–FEDER-Spain (grant CTQ2010-17436) and Gobierno de Aragón–FSE (research group E40).

The synthesis and resolution of the first 3,3′-disubstituted BINAP ligands containing C -bonded substituents are described. An ortho -metallation/electrophile capture sequence was used to obtain the key trisubstituted naphthalene intermediate available and this intermediate was successfully converted into the desired ligands. Minor changes in the steric and stereoelectronic components of the 3,3′-substituents on the enantioselectivity and product enantiosense were also assessed in the context of the Rh-catalyzed asymmetric hydrogenation of enamides. A comparison of the absolute stereochemistry of the products derived from 3,3′-disubstituted BINAPs containing C -bonded substituents with their O -bound counterparts indicated that the product enantiosense could be dictated by increased steric bulk due to the 3 and 3′-substituents.

Lewis acid platinum and palladium complexes of ( S )-Me 2 -CATPHOS catalyse the carbonyl-ene reaction between allylbenzene derivatives and ethyl trifluoropyruvate to give the expected α-hydroxy esters with ee’s up to 97%, while the corresponding reaction involving 2-allylfuran and thiophene was exclusively selective for Friedel–Crafts-type reactivity and gave the corresponding 2-hydroxy-trifluoromethyl ethyl esters in good yield and moderate to good enantioselectivity.

A synthetic route to BINAP disulfide analogues with chirality on one of the phosphorus atoms was developed. The synthesis of these ligands was achieved by step-wise palladium and nickel-catalysed coupling reactions of the precursor binaphthyl triflate with secondary phosphines and phosphine oxides, respectively. C2-Unsymmeric BINAP bissulfide analogues with the same aryl substituents were also synthesized for the sake of comparison. Preliminary studies of the reduction of these sulfides to the free phosphines are also described.

The conformations of two classes of 7-ring diphosphine metal chelate have been analysed, based on DIOP- or BINAP-type structures. A combination of X-ray analysis, DFT calculations, data analysis based on the CDS structure database and solution NMR studies has been employed. The conformational flexibility of DIOP-type structures has been endorsed, and the scope of BINAP complex flexibility defined. BINAP complexes possess an intrinsic conformational mobility. Analysis of the metal-adjacent torsion angles C-P-M-P′ and C′-P′-M-P provides a useful probe for the ligand-metal environment, and may be more generally useful. © 2010 Elsevier Ltd. All rights reserved.

The complexes [Rh((S)-BINAP)(COD)]BF4 1, [Rh((S)-BINAP)(NBD)]BF4 2, [Rh((R)-BINAP)(COD)]OTf 3, [Rh((R)-BINAP)(NBD)]OTf 4, and [Rh((R)-BINAP)(COD)]BArF 5 were synthesized, and 1–4 were analyzed by single crystal X-ray crystallography. The transformation of these precatalysts into hydrogenation-active species was investigated as well as the hydrogenation of prochiral olefins. In particular, this series of transformations was investigated with regard to solvent and counterions.

International audience; Industrial developments of asymmetric catalysis are slowed down by cost and toxicity of the soluble transition metal complexes which are used as catalysts. This problem could be solved by using homogeneous supported catalysis among other technologies. The article analyzes recent results obtained in the fields of catalysis using transition metal complexes grafted on organic or inorganic materials. Two types of ligand are considered: BINAP and BOX. In these two cases several approaches are still under investigations and some of them appear to give a higher performance, such as the polymer with ligand in the main chain and with rigid spacer in case of the BINAP and the ligand grafted on silica particles in the case of BOX.

A series of optically active cyclic trans-?-amido alcohols were obtained by the non-enzymatic kinetic resolution of the corresponding racemic amido alcohols using commercially available (S)-BINAP and NCS by SN2 halogenation of the hydroxy group. The product, cis-?-amido chloride, was also obtained in optically active form with an inversion of stereochemistry. � 2010 Elsevier Ltd. All rights reserved.

Electronically enriched chiral BINAP derivatives were synthesized incorporating electron-donating substituents at the para-phenyl position and evaluated for the Ru-catalyzed homogeneous asymmetric hydrogenation of α-ketoesters with up to 92% ee. These diphophosphines were also excellent ligands for the iridium-catalyzed asymmetric hydrogenation of quinolines.

Asymmetric 1,4-addition of arylzinc chlorides to (E)-3-arylpropenals proceeded with high enantioselectivity in the presence of a rhodium/(R)-binap catalyst and chlorotrimethylsilane to give, after hydrolysis, high yields of the corresponding 3,3-diarylpropanals of 98–99% ee. The presence of the chlorosilane is essential for high yields of the 1,4-addition products.

New ( R )- or ( S )-4,4 ′ - and 5,5 ′ -perfluoroalkylated BINAP have been synthesized in four steps from enantiomerically pure BINAP. These new ligands were used in the homogeneous asymmetric hydrogenation of ethyl acetoacetate in ethanol and in the asymmetric hydrogenation of methyl-2-acetamidoacrylate in supercritical carbon dioxide. In the supercritical media, the addition and nature of a co-solvent have been discussed. Very good conversion and selectivity were obtained in each case.

A short and efficient enantioselective synthesis of ( R )-(−)-baclofen, a selective GABA B agonist has been described with an overall yield of 26% and 90% ee. Ru(II)–( S )-BINAP catalyzed asymmetric hydrogenations of CC and CO groups constitute the key steps in introducing stereogenic centers into the molecule.

New BINAP derivatives (polyamide, polyureas or ureas) were synthesized and employed in the ruthenium-catalyzed asymmetric heterogeneous hydrogenation of methyl acetoacetate. Enantiomeric excesses in the range 48–100% were observed. Furthermore, the most efficient have been recovered and the recycled catalysts were shown to maintain their efficiency in subsequent reactions.

(2R,3R)- and (2S,3S)-3-Hydroxyleucines, components of cyclodepsipeptides, papuamides and polyoxypeptins, were efficiently synthesized along with their diastereomers from the corresponding β-keto-α-amino acid ester through dynamic kinetic resolution using RuCl2(binap)-catalyzed hydrogenation.

Palladium-catalyzed amination of o- dibromobenzene provided chiral N , N′- disubstituted 1,2-benzenediamines in good to excellent yields. The amination was executed stepwise and in one pot to give unsymmetrically and symmetrically substituted 1,2-benzenediamines. Incorporation of chiral primary amines was possible without racemization using catalytic Pd 2 dba 3 –BINAP.

The short and high yielding synthesis of a new cis -configured bissteroidal phosphine 7 is reported. The comparison of these new phosphines as ligands in ruthenium-based hydrogenation catalysts with the previously synthesized diastereomeric trans -configured phosphines 20 shows that the steroid backbone exerts only a minor influence on the enantioselection of the ruthenium catalysts and confirms that the bissteroidal phosphines behave as ‘pseudo’-enantiomers in spite of their diastereomeric nature. Evidence is presented that the mode of catalyst preparation, i.e. catalyst structure, is the crucial reaction parameter which mainly determines the enantiomeric excess of the hydrogenation products.

Complexes of ( R )-BINAP (BINAP=2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) derived from the available rhodium precursors Rh(acac)(CO) 2 and [Rh(μ-OMe)(cod)] 2 are used for the asymmetric hydroformylation of vinyl acetate. Enantiomeric excesses of up to 60% are achieved with regioselectivities of up to 99%. Only a BINAP/Rh ratio of 2 is required. Effects of pressure and temperature on catalyst stability, enantio- and chemoselectivity are discussed.

The regiochemistry of the reduction of mono-ethyl fumarate using bis (carboxylato){2,2′- bis (diphenylphosphino)-[R]-1,1-binapthyl}-ruthenium(II) (Ru[BINAP]) in H 2 /CH 3 OD is reported and occurs opposite to the regiochemistry observed in the reduction of tiglic acid. Reduction of mono-ethyl maleate with D 2 /CH 3 OD is very sluggish but produces meso -dideuteriosuccinic acid with high stereoselectivity. Reduction of mono-ethyl maleate with Ru[BINAP](O 2 CR) 2 and H 2 /CH 3 OD results in mono-ethyl succinate-d 1 with nearly complete loss of regiochemistry.

An optically active 1-hydroxymethyl-substituted tetrahydroisoquinoline alkaloid, ( S )-calycotomine 1 , was conveniently synthesized by using catalytic asymmetric hydrogenation of 1-benzyloxymethyl-3,4-dihydro-6,7-dimethoxyisoquinoline 6 with 0.5 mol % of an iridium(I) complex of ( R )-BINAP in the presence of 3,4,5,6-tetrafluorophthalimide.

The development of methodologies for efficient asymmetric synthesis is one of the most important areas of synthetic organic chemistry.1 The syntheses of biologically relevant natural and unnatural organic molecules in optically pure form are of central interest in medicinal chemistry and related disciplines. Variations in the stereochemistry of molecular probes for a target enzyme or receptor sites very often display dramatic differences in their binding properties and biological activities. For meaningful biological studies it is important, if not mandatory, to synthesize such agents in enantiomerically pure form. Recent advances in molecular biology and modern instrumentation techniques have led to a better understanding of many complex human diseases at the molecular level. Concurrent with these remarkable achievements have come new challenges and opportunities for asymmetric synthesis. Thus, from the design of enzyme inhibitors to the synthesis of receptor agonists or antagonists and bioactive natural products, asymmetric synthesis is of fundamental significance in biology and medicine. The advances in asymmetric synthesis have now reached the point that many organic molecules can be prepared with near complete enantioselectivity. This technology is particularly sophisticated in the generation of new stereogenic centers in the presence of existing chiral centers. A number of asymmetric catalysts or so called ‘abiological catalysts’ are approaching an efficiency and selectivity comparable to enzymes such as in the asymmetric hydrogenation of dehydroamino acids utilizing chiral bisphosphine–rhodium complexes,2 asymmetric isomerization of allylic amines with rhodium(I)–BINAP complexes,3 asymmetric epoxidation of allylic alcohols,4 asymmetric epoxidation of unfunctionalized olefins,5 asymmetric reductions with chiral oxazaborolidenes6 and asymmetric dihydroxylation reactions.7 The advantage of abiological catalysts, however, is the availability of either enantiomer of the catalyst which enables one to synthesize either enantiomer of the target molecule. Today there is enormous emphasis on the design and development of efficient chiral catalysts for enantioselective synthesis and this field has become one of the most intense areas of organic chemical research. In recent years, C2-symmetric chiral bis(oxazoline) ligand–metal complexes have received a great deal of attention through their use in various catalytic process.1c The bis(oxazoline) ligands are structurally related to C2-symmetric semicorrins pioneered by Pfaltz and co-workers.8a–c The inception of bis(oxazoline) ligands, however, added a new dimension in terms of flexibility in ligand design, convenient synthesis and availability of ligands in both enantiomeric forms. Since the early 1990s, many impressive enantioselective carbon–carbon bond forming reactions, aziridination reactions, hydrosilylations, oxidations and reductions have been recorded using bis(oxazoline)–metal complexes. The present review is intended to focus on the recent developments of bis(oxazoline) ligand–metal catalyzed asymmetric reactions and their applications in organic synthesis. The authors do not intend to provide an exhaustive review of this area since earlier developments have been reviewed by Pfaltz8a–c and Bolm.9 Applications of mono- and tris(oxazoline) ligand–metal complex catalyzed reactions are not included in this review.

The rates of the asymmetric hydrogenation of prochiral diketones catalyzed by Ru(BINAP) catalysts were substantially accelerated in the presence of small amounts of a strong acid.

The synthesis of three new families of monomeric carboxylato(diphosphine)iridium(III) complexes is described (e.g. diphosphine = diop, binap, bdpp). Some of these complexes catalyse the asymmetric hydrogenation of prochiral imines to amines in good activity and enantioselectivity.

We herein describe a novel example of a palladium-catalysed asymmetric allylic elimination leading to enantiomerically enriched dienes. The use of chiral ligands such as BINAP or DIOP allows the catalyst to discriminate between the enantiotopic hydrogens H and H' and leads to e.e. up to 37 %. Higher degrees of asymmetric induction was possible by the introduction of a chiral auxiliary (R ∗ ) in the substrate (89: 11 diastereomeric ratio).

New (Binap)Ru(carboxylate)2 have been prepared and used for the enantioselective hydrogenation of 2′-chloroacetophenone. Both enantiomers of 2′-chlorophenylethanol can be selectively prepared with the same optically active catalyst precursor simply by changing the solvent, and the carboxylate groups have an influence on the enantioselectivity only in aprotic solvents.

The synthesis of (2R,3R) and (2S,3S) dideuteriosuccinic acid in 63 ± 10% enantiomeric excess by reduction of the half acid ester of ethyl fumarate from (R) and (S) BINAP ruthenium (II) diacetate complex, respectively, is reported. (2R,3R) and (2S,3S)-Dideuteriosuccinic acid has also been prepared from (R)-BINAP ruthenium (II) dicarboxylate complex directly in similar optical purity by reversing the sequence of introduction of the isotopic label.

Ruthenium–BINAP catalysts are commonly used in asymmetric hydrogenations and provides high enantioselectivity over a wide range of substrates. Herein we focus on a single Ru(II)–BINAP catalyst prepared from cyclooctadienyl ruthenium dichloride and (R)-BINAP in the presence of triethylamine and report on the structure identified using NMR as the diethylammonium salt [(C2H5)2NH2]+[Ru2Cl5((R)-BINAP)2]−.

Enantioselective hydrogenation of acyclic aromatic ketones PhCOR (R = alkyl or cycloalkyl group) has been accomplished by using the catalytic systems derived from [Ir(( S )-binap)(cod)]BF 4 or [Ir(( S )-H 8 -binap)(cod)]BF 4 [H 8 -BINAP = 2,2′-bis(diphenylphosphino)-5,5′,6,6′,7,7′,8,8′-octahydro-1,1′-binaphthyl] and bis( o -dimethylaminophenyl)phenylphosphine. The enantiomeric excesses as well as the absolute configurations of the corresponding alcohols depend markedly on the steric size of the alkyl or cycloalkyl groups, and the highest ee 's are obtained when the alkyl groups R are i -Pr (84%, R ) and c -C 6 H 11 (80%, R ), respectively.

The new class of 2-methylallyl ruthenium chiral diphosphines 1 are efficient in asymmetric hydrogenation of α,β unsaturated acids and allylic alcohols. The related chiral halogen-containing ruthenium catalysts 2 are prepared from 1 or in situ from (COD)Ru(η) 3 -(CH 2 ) 2 CHCH 3 ) 2 by ligand exchange with the chelating diphosphine followed by protonation (HX) in acetone. This procedure allows rapid screening of chiral phosphines, such as Diop, Chiraphos, Cbd, Bppm, Binap, β-glucophos, Biphemp, MeO-Biphep, Me-Duphos, in ruthenium mediated hydrogenations of prochiral substrates. A high efficiency is displayed by Ru-catalysts having atropisomeric ligands (e.e. up to 99%), and a C 2 symmetric bis(phospholane) has also emerged as a valuable ligand (Me-Duphos, e.e. up to 87% not optimized). Asymmetric hydrogenation of β-keto esters can be conducted under quite mild conditions (4 atm. of H 2 , 50°C, e.e. up to 99%), β-keto esters having a disubstituted double bond are also hydrogenated chemoselectively to unsaturated chiral alcohols under controlled conditions with excellent optical purities.

A general and new synthesis of hexacoordinate chiral 1-[2-methylallyl]Ru II 2 complexes is presented. This synthesis uses the very accessible CODRu(2-methylallyl) 2 complex as starting material. These complexes (P*P)Ru(η 3 -(CH 2 ) 2 CCH 3 ) 2 (e.g. P*P=DIOP, CBD, DEGUPHOS, BINAP, BIPHEMP, CHIRAPHOS, PROPHOS, DIMPC, BPPM, BDPP, DIPAMP, DIPAMPSi, β-PO-OP) have been characterized spectroscopically. X-Ray structures were obtained for (S,S)-DIOP and (S,S)-CHIRAPHOS. They are suitable for the preparation of chiral dihalide ruthenium (II) catalysts. In addition, we have found that it was possible to prepare these same catalysts directly in situ from (COD)Ru(η 3 -(CH 2 ) 2 CCH 3 ) 2 by adding 1-1.3 equiv. of the appropriate chiral ligand in the presence of HX in acetone at room temperature.

L - and D -isoserine were synthesized enantioselectively via asymmetric hydrogenation of 3-amino-2-oxoester 5 catalyzed by [RuCl(binap)(benzene)]CI. Recrystallization and deprotection of (S)-6 (81% ee) afforded enantiomerically pure L -isoserine. The enantioface selection by the catalyst was opposite to that observed in asymmetric hydrogenation of other 2-oxoesters, such as methyl phenylglyoxylate and methyl 2-oxocyclohexylacetate.

Ruthenium (II)-sulfonated-BINAP has been synthesized and this novel water-soluble complex is shown to be an excellent asymmetric hydrogenation catalyst for 2-acylamino acid precursors and methylenesuccinic acid in both methanolic as well as in neat water solvent systems. Enantiomeric excesses approaching 90% have been obtained in aqueous and methanolic solvents. Effects of solvent, pressure and the addition of organic base on enantioselectivity are described.

The ruthenium BINAP complex, [RuX(arene)[(R)-BINAP]]X, can catalyze the hydrogenation of oximes to amines in moderate enantiomeric excess.

Palladlum-catalyzed asymmetric allylic alkylatlon of 1,3-dlphenyl-2-propenyl acetate with sodium salt of dimethyl malonate and its derivatives has been successfully carried out in the presence of optically active diphosphine, such as (S)-BINAP. High enantioselectivity of up to 90% ee was obtained with dimethyl malonate.

BINAP—Ru(II) catalyzed hydrogenation of β-substituted ( E )-β-(acylamino)acrylic acids allows efficient enantioselective synthesis of β-amino acids. The Z double bond isomers which possess an intramolecular hydrogen bond between amide and ester groups are more reactive but are hydrogenated with poor enantioselectivity. BINAP—Rh(I) complexes afford only moderate stereoselectivity with the opposite sense of enantioselection.

Enantioselective syntheses of D and L threonine are described. Racemic methyl and ethyl 2-acylamino-3-oxobutyrate 1 were synthesized from the corresponding acetoacetates 6 and then hydrogenated stereoselectivety via dynamic kinetic resolution with various chiral P * P Rh (I) 8 and Ru (II) 10 catalysts to give syn optically active alcohols which could be converted by hydrolysis and treatment with propylene oxide into threonine. The best results were obtained using (−) CHIRAPHOS Ru and (+) BINAP Ru as catalysts, in the hydrogenation step leading respectively to D threonine (ee: 99 %) and L threonine (ee: 94 %) in 26–34 % overall yields.

Reaction of styrene with catecholborane in the presence of 1 mol % of a cationic phosphine-rhodium catalyst prepared in situ from [Rh(COD)2]BF4 and 1,4-bis(diphenyl-phosphino)butane proceeded regioselectively to give, after oxidation, 1-phenylethanol in a quantitative yield. The regioselectivity forming benzylic alcohols was also observed in the reaction of substituted styrenes. Use of (R)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) as a chiral ligand for the rhodium-catalyzed hydroboration of substituted styrenes (ArCHCH2) gave optically active (R)-1-arylethanols (ArCH(OH)Me) in high yields. The enantiomeric purities of the alcohols are 96% ee, 94% ee, 91% ee, 85% ee, 89% ee, and 82% ee for Ar = Ph, 4-MeC6H4,4-ClC6H4, 3-Cl6H4, 4-MeOC6H4, and 2-MeOC6H4, respectively.

The first general synthesis of mononuclear hexacoordinate chiral ruthenium-complexes is presented. Four chiral ruthenium(II)(2-methylallyl) 2 complexes containing Diop, Chiraphos, Norphos, and Binap were prepared in 50–71% yield under mild conditions, and were found to be effective for asymmetric hydrogenation of unsaturated carboxylic acids to give the corresponding saturated derivatives attaining 90% optical purity.

Hydrogen transfer from the formic acid/triethylamme (5:2) azeotrope to α,β-unsaturated carboxylic acids is effectively catalyzed by ruthenium complexes of general formula [Ru(acac-F 6 )(η 3 - C 3 H 5 )(diphosphine)]. If a chiral diphosphine is employed, the saturated acids are obtained in up to 93% ee, the most active and selective catalyst being formed with BINAP.

Enantioselective hydroborations of alkenes 1 - 4 with catecholborane were performed via catalysis with complexes containing the chiral ligands DIOP, BINAP, CHIRAPHOS , DIPAMP , BDPP , 2-MeODIOP , and 3-McODIOP . Alkenes 1 - 3 were also hydroborated with catecholborane derivatives 5 - 8 in the presence of Rh(+l)/ DIOP catalysts. Trends in the observed optical purities are discussed.

BINAP—Ru catalyzed hydrogenation allows efficient dynamic kinetic resolution of certain 2-substituted 3-oxo carboxylic esters having cyclic structures to lead to the alcoholic products in high enantiomeric and diastereomeric excesses.

The [RuCl2-(S)-BINAP]2.NEt3 catalyst precursor dissolved in 1-n-butyl-3-methylimidazolium tetrafluoroborate molten salt is able to hydrogenate 2-arylacrylic acids (aryl=Ph or 6-MeO-naphthyl) with enantioselectivities similar or higher than those obtained in homogeneous media. Moreover, the hydrogenated products can be quantitatively separated from the reaction mixture and the recovered ionic liquid catalyst solution can be reused several times without any significant changes in the catalytic activity or selectivity.