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Enantiomerically pure diphosphines play an important role in various homogeneous metalcatalyzed asymmetric reactions. Over the last few years, our group has been involved in the design and synthesis of atropisomeric ligands named SYNPHOS and DIFLUORPHOS with complementary stereoelectronic properties. This paper shows the high catalytic performances of DIFLUORPHOS, SYNPHOS and SYNPHOS analogues for some C–H and C–C bond forming processes as well as for the synthesis of biorelevant targets.

We have extended the methodology developed for the preparation of atropisomeric chiral ligands derived from the MeOBIPHEP ligand to water-soluble ones. The hydrophilic ligands bearing sodium carboxylate and methylammonium chloride moieties were easily synthesized under mild conditions in a short sequence and in high yields. Their solubility and acid/base properties were also determined. The ruthenium(II) catalysts contain- ing 4-CO2Na- and 3,5-(CO2Na)2-substituted MeOBIPHEP analogues showed excellent activities and led to the desired hydrogenated products derived from dimethyl itaconate and 2-(4-fluorophenyl)-3-methylcrotonic acid in ees≥92%. An investigation of the asymmetric hydrogenation of the latter substrate in D2O as solvent afforded an insight into the mechanism.

Applications of electron-deficient DIFLUORPHOS and SYNPHOS analogues in the rhodium-catalyzed asymmetric conjugate addition of boronic acids to α,β-unsaturated ketones afford the 1,4-addition adducts in yields up to 92% and with 99% ee. Particularly, a Rh-catalyzed asymmetric 1,4-addition of arylboronic acids to nonsubstituted maleimide substrates using the (R)-3,5-diCF(3)-SYNPHOS ligand is also reported. This protocol provides access to various enantioenriched 3-substituted succinimide units of biological interest, in high yields and good to excellent ee up to 93%, which could be upgraded up to 99% ee, after a single crystallization.

A highly efficient Pd-catalyzed P-C coupling reaction of easily accessible atropisomeric bisphosphane is described in the presence of various electron-poor aromatic iodides. The reactions are conducted in the presence of a Pd(II)/dppf catalyst in acetonitrile at 80 °C. The reaction conditions are compatible with several electron-withdrawing groups such as esters, cyano, chloro, and trifluoromethyl groups and lead to atropisomeric MeOBIPHEP derivatives in good to excellent yields and high enantiomeric purities.

A highly efficient and general iridium-difluorphos-catalyzed asymmetric hydrogenation of diverse 2-alkyl- and 2-aryl-substituted quinoxalines into biologically and pharmaceutically relevant 2-substituted-1,2,3,4-tetrahydroquinoxaline units has been developed. High isolated yields and excellent enantioselectivities of up to 95% for 2-alkyl-substituted quinoxalines and of up to 94% for 2-aryl-substituted quinoxalines were obtained.

A very simple and efficient catalytic system for the hydroarylation of olefins by aromatic ketones and Michael acceptors using simple and inexpensive ruthenium trichloride as a ruthenium source is described. These very mild conditions (dioxane at 80 degrees C) appeared to be highly compatible, tolerant, and selective toward various functional groups, and the ease of the protocol is highly convenient for synthetic purposes.

Hydrogenation of enantioenriched β-hydroxy ketones promoted by the catalyst generated in situ from commercially available and inexpensive RuCl3 and PPh3 under hydrogen pressure allowed the efficient preparation of a variety of anti-1,3-diols in good yields and with a high level of diastereoselectivity. This method should be an interesting alternative to organoboron reagents for the diastereoselective reduction of β-hydroxy ketones. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

The C1-C7 and C9-C14 subunits of (+)-discodermolide have been synthesized using ruthenium-SYNPHOS-mediated asymmetric hydrogenation reactions of β-keto esters to set the C3, C5 and C11 hydroxy-bearing stereocenters with very high levels of diastereoselectivity.

The efficiency of a Au(III)/chiral ligand system has been studied. The association of several chiral mono- and bidentate phosphanes with gold has been tested in the formal addition of an oxygen nucleophile to an alkene followed by a cyclization process, namely the hydroxycyclization reaction of 1,6-enynes. The use of (R)-4-MeO-3,5-(t-Bu)2-MeOBIPHEP ligand led to clean cycloisomerizations and afforded the highest enantiomeric excesses. The enantiomeric excesses were highly dependant on the substrate/nucleophile combination. A 31P NMR study of the catalytic species tends to prove that Au(III) catalyst may be reduced to Au(I) intermediate in the presence of phosphanes.

The PPh3AuCl/AgSbF6 catalytic system promotes a tandem Friedel–Crafts' type addition of electron-rich aromatic and heteroaromatic derivatives to unactivated alkene followed by a C–C bond cyclization reaction. The efficiency of this system allowed room temperature reactions in a very short time. The scope and limitations of this reaction were investigated. The reaction conditions were compatible with various functional groups on the nucleophiles. Severe limitations were observed when the allylic position of the enyne is substituted by electron-withdrawing groups. The mechanism of the reaction was investigated via the synthesis of a deuterated aromatic ring: we showed that the source of proton involved in the protodemetallation step originates from the acidic activated C–H bond of the nucleophile.

Asymmetric desymmetrization of the diallyl acetals of alkynal (1) by an enantioselective Pauson-Khand-type reaction catalyst was studied. The corresponding 5-oxabicyclo[3.3.0]octenones (2) were obtained as a mixture of diastereomers (2a and 2b), which were hydrolyzed to afford a single enantiomer (3), in high yields (up to 88%) as well as excellent enantioselectivities (up to 97%).

International audience; One trumps two: Monosubstituted chiral bicyclo[2.2.2]octadiene ligands, derived from carvone, form complexes with rhodium to catalyze the asymmetric addition of boronic acid substrates to α,β-unsaturated ketones. The 1,4-adducts are produced in good yield and high enantioselectivity.

In the presence of catalytic amounts of CeCl 3.7H 2O, [RuCl(benzene)(S)-SunPhos]Cl is a highly effective catalyst for the asymmetric hydrogenation of aromatic alpha-ketoesters. A variety of ethyl alpha-hydroxy-alpha-arylacetates have been prepared in up to 98.3% ee with a TON up to 10,000. Challenging aromatic alpha-ketoesters with ortho substituents are also hydrogenated with high enantioselectivities. The addition of CeCl 3.7H 2O not only improves the enantioselectivity but also enhances the stability of the catalyst. The ratio of CeCl 3.7H 2O to [RuCl(benzene)(S)-SunPhos]Cl plays an important role in the hydrogenation reaction with a large substrate/catalyst ratio.

Conjugate addition of potassium trifluoro(organo)borates 2 to dehydroalanine derivatives 1, mediated by a chiral rhodium catalyst and in situ enantioselective protonation, afforded straightforward access to a variety of protected alpha-amino esters 3 with high yields and enantiomeric excesses up to 95%. Among the tested chiral ligands and proton sources, Binap, in combination with guaiacol (2-methoxyphenol), an inexpensive and nontoxic phenol, afforded the highest asymmetric inductions. Organostannanes have also shown to participate in this reaction. By a fine-tuning of the ester moiety, and using Difluorophos as chiral ligand, increased levels of enantioselectivity, generally close to 95%, were achieved. Deuterium labeling experiments revealed, and DFT calculation supported, an unusual mechanism involving a hydride transfer from the amido substituent to the alpha carbon explaining the high levels of enantioselectivity attained in controlling this alpha chiral center.

The high potential of commercially available Au 2 O 3 as a catalyst in the cyclization of alkynes bearing carboxylic acids to the corresponding γ-alkylidene-γ-butyrolactones through a general, efficient and easy procedure is presented. The reaction shows a high degree of chemo-, regio-, and stereoselectivity. The 5- EXO mode of cyclization and ANTI auration are a general trend for the Au 2 O 3 catalyst.

Novel Ir-SYNPHOS and Ir-DIFLUORPHOS catalysts were synthesized and used for the synthesis of tetrahydroquinolines via asymmetric hydrogenation of the corresponding quinoline -derivatives.

A general Au III catalytic system is described for the efficient hydroxy- and alkoxycyclization reactions of 1,6-enynes. The reactions lead to carbo- and heterocyclic alcohols or ethers in good to excellent yields. The cyclizations are conducted in the presence of AuCl 3 /AgSbF 6 /PPh 3 catalyst in dioxane-water or various alcohols at room temperature. The hydroxycyclization reactions of 1,7-enynes afforded either the methyl ketone or a mixture of the methyl ketone and the carbocyclic alcohol.

Direct cross-coupling reactions of aromatic aldehydes with arylboronic acids afforded ketones in high yields and under mild conditions in the presence of a rhodium catalyst, acetone and a base. This new reaction, involving a formal aldehyde C-H bond activation, is believed to proceed via a tandem process involving addition of the organometallic species to the aldehyde followed by oxidation by β-hydride transfer.

International audience; The design of a new class of fluorophores is presented. Some push– pull chromophores (D–p–A) containing polyphenylethynyl units and a phosphane oxide moiety were efficiently prepared from common intermediates. Straightforward syntheses gave novel one-armed, rod-shaped and three-armed, star-shaped fluorophores. The optical properties of the resulting star-shaped derivatives were evaluated, showed high fluorescence quantum yields, and their excitation induces very efficient charge redistribution. Moreover, thanks to their push–pull character, the molecules exhibited significant second-order NLO properties with good transparency, up to 67·1030 esu at 1907 nm, with an absorption lmax at 369 nm. The effect of the donor group and of the number of phenylethynyl arms have been studied in this work.

Based on the proposed mechanism, the electronic effects of various ligands on the stereoselectivity and reaction rate of the rhodium(I)-catalyzed asymmetric Pauson-Khand-type reaction were examined. We demonstrated that both the reaction rate and the enantioselectivity are significantly dependent on the electron density of the ligands; when ligands bearing deshielded phosphine were utilized, the reaction rate was slower, but the products were obtained with improved enantioselectivity.

This paper describes an efficient and green access to functionalized and highly constrained heteropolycyclic derivatives via a microwave-accelerated cycloaddition and heterogeneous hydrogenation sequence.

This letter describes an efficient and enantioselective conjugate addition of highly stable potassium trifluoro(organo)borates to α,β-unsaturated esters. This reaction, catalyzed by chiral rhodium(I) complexes, affords Michael adducts with high yields and enantiomeric excesses up to 96%.

The first stereocontrolled synthesis of the C(1)-C(13) fragment of cytotoxic macrolides dolabelides is reported. The C(3), C(7), C(9) and C(11) hydroxyl-bearing stereocenters were installed using ruthenium-mediated asymmetric hydrogenation reactions of the adequate β-keto esters and β-hydroxy ketone.

The detailed procedure for the synthesis of Ru-SYNPHOS® and Ru-DIFLUORPHOS® catalysts are described. These catalysts displayed high rates and are quite effective for the large-scale hydrogenation reactions of unsaturated compounds.

The synthesis of 4/5/6 polycyclic β-lactams by enyne metathesis and Diels−Alder reactions is described. Compared to the synthesis of 4/6/6 and 4/7/6 polycyclic β-lactams previously reported by our laboratory, formation of the strained 4/5/6 compounds requires alternative reaction conditions. Indeed, the synthesis of the 4/5 bicyclic diene 12 was more difficult than those of the 4/6 (13) and 4/7 (14) dienes. The strain of the 4/5 system could be observed by NMR spectroscopy and molecular modelling. Moreover, the reactivity of 4/5 diene 12 towards Diels−Alder cycloaddition was also different from that of the 4/6 (13) and 4/7 (14) dienes. Cycloadditions with 4/5 diene 12 therefore had to be performed in lithium perchlorate/diethyl ether (LPDE) or in an ionic liquid in order to proceed in good yields with various dienophiles. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

The natural (2 R ,3 R )-Boc-dolaproine and its unnatural (2 S ,3 S ) diastereoisomer were synthesized involving as key transformation the Ru(II)-promoted hydrogenation of the β-keto-α-methyl ester derived from ( S )- N -Boc-proline. Interestingly, the asymmetric hydrogenation of this β-keto ester N -protected as an amine hydrochloride salt, provided the corresponding anti (2 S ,3 R )- and (2 R ,3 S )-β-hydroxy-α-methyl esters with significant level of selectivities through dynamic kinetic resolution.

A general and practical synthesis of both syn- and anti-α-amino β-hydroxy esters with high levels of selectivity by the use of Ru-SYNPHOS® catalysts is reported. The key transformations include asymmetric hydrogenations of α-N-substituted β-keto esters protected as α-amido or α-amino hydrochloride derivatives, respectively. The RuII-catalyzed hydrogenation of α-amino β-keto ester hydrochlorides affords the corresponding anti-α-amino β-hydroxy esters with high diastereoselectivities (up to 99%) and enantioselectivities (up to 97%) through dynamic kinetic resolution (DKR). (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

A total synthesis of sulfobacin A, a von Willebrand factor receptor antagonist, is described. Our synthetic approach relies uniquely on catalytic asymmetric reactions for the creation of the three stereogenic centers without using chiral building blocks. The key steps of this short route to sulfobacin A involve ruthenium-mediated asymmetric hydrogenation reactions of a β-keto ester and a racemic β-keto-α-amino ester hydrochloride to afford, respectively, the corresponding enantiomerically pure β-hydroxy ester and the enantioenriched anti β-hydroxy α-amino ester hydrochloride through dynamic kinetic resolution.

We have found that the use of [Rh(cod)OH]2 associated with the water-soluble ligand m-TPPTC was highly efficient for the Rh-catalyzed arylation of alkynes. Aryl and alkyl alkynes were transformed to alkenes using 3 mol % rhodium catalyst and 2.5 equiv of boronic acid at 100 °C in a biphasic water/toluene system in 80–99% yield. The reaction was found to be totally regioselective for alkyl arylalkynes and alkyl silylated alkynes. The Rh/m-TPPTC system was for the first time recycled with no loss of the activity and with excellent purity of the desired alkene.

This paper is dedicated to a study of properties of the following novel optically active organoaluminium compounds (OACs): (1S,2S)-l,7,7-trimethyl-2-[(dialkylalumina)oxy]-bicyclo[2.2.1]heptanes and (1S)-N-(dialkylalumina)-6,7-dimethoxy-1-methyl-1,2,3,4tetrahydroisoquinolines. The synthesis of the chiral OACs was carried out in the reaction of either natural camphor or salsolidine with both AlEt3 and i-Bu2AlH. The main goal of the research was to investigate the stereodifferentiating activity of the chiral OACs in the olefin carbo- and cycloalumination reactions, catalyzed by Cp2ZrCl2. 2003 Elsevier B.V. All rights reserved.

One-pot ring-closing enyne metathesis and Diels-Alder reactions led to efficient synthesis of tricyclic and tetracyclic (3-lactams.

A total synthesis of the von Willebrand factor receptor antagonist sulfobacin A is described. Key steps for this short route to sulfobacin A include ruthenium-catalyzed asymmetric hydrogenation and diastereoselective electrophilic amination for the construction of the three stereogenic centers.

A new, optically active, atropisomeric diphosphane ligand, (2,3,2′,3′-tetrahydro-5,5′-bi(1,4-benzodioxin)-6,6′-diyl)bis-(diphenylphosphane) (SYNPHOS®), has been synthesized, characterized, and used in ruthenium-catalyzed asymmetric hydrogenations. This new ligand has been compared with other atropisomeric diphosphanes (BINAP and MeO-BIPHEP) with respect to their dihedral angles calculated by molecular modeling and the enantioselectivity of their ruthenium-mediated hydrogenation reactions. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

A new optically active diphosphine ligand, [(5,6),(5‘,6‘)-bis(ethylenedioxy)biphenyl-2,2‘-diyl]bis(diphenylphosphine) (SYNPHOS) has been synthesized. Laboratory-scale synthesis and scale-up development of this ligand are described herein. This new atropisomeric diphosphine was also used in ruthenium-catalyzed asymmetric hydrogenation.

Enantiomerically pure phosphetanes are easily obtained from primary phosphines and chiral, symmetrically substituted anti-1,3-diols. The synthetic approach has been applied to the preparation of both monodentate and C2-symmetric bidentate derivatives. Applications of these ligands in rhodium- and ruthenium-promoted hydrogenations of unsaturated substrates have been reported: peculiar catalytic properties and high enantioselectivities have been noticed. To cite this article: A. Marinetti, J.-P. Genet, C. R. Chimie 6 (2003).

The synthesis of chiral 1,2,3,5-substituted tetrahydropyrans has been realized via an asymmetric hetero Diels–Alder (HDA) reaction. The key step that involved a trisubstituted chiral enol ether derived from (R)-mandelic acid as the dienophile promoted the creation of three stereogenic centers with a remarkable and unprecedented endo and facial stereocontrol. The hydrogenation of the heteroadduct 2 was optimized by using Pd on charcoal and diisopropylethylamine, leading to a unique isomer. The chiral inductor was cleanly and stereoselectively removed via an acetal reduction, which demonstrated the potential of this methodology for the efficient construction of key intermediate of biologically active molecules.

The stereocontrolled synthesis of a C15C24 fragment of dolabelides is reported. The C19 and C21 hydroxyl-bearing stereocenters were installed using ruthenium-mediated asymmetric hydrogenations of cyclic hemiketal 4 and β-keto ester 7 . The C25C30 portion of dolabelides was prepared as well by ring opening of chiral epoxy alcohol 12 to set up the C27 stereogenic center.

Different mechanisms have been proposed for the cyclization of enynes catalyzed by electrophilic metal halides or complexes. We present evidence to indicate that the previously reported “carbohydroxypalladation” and the “hydroxycyclization catalyzed by PtII” are closely related reactions. Thus, palladium complexes formed in situ from PdCl2 and trisulfonated phosphane TPPTS or cyclic phosphite P(OCH2)3CEt as the ligands catalyze the methoxy- or hydroxycyclization of enynes with selectivities similar to those observed with PtII complexes. Deuteration studies indicate that activation of the alkyne by PdII promotes an anti-addition of the alkene.

An efficient synthesis of diltiazem has been developed using dynamic kinetic resolution (DKR) as a key step. The methyl (2S,3S)-2-chloro-3-hydroxy-3-(4-methoxyphenyl)propionate was synthesized from a racemic mixture of α-chloro-β-keto ester, with high anti diastereoselectivity (92%) and enantioselectivity (95%), based on an asymmetric hydrogenation reaction with a chiral ruthenium(II) catalyst, simply prepared by mixing Ru(cod)(2-methylallyl) 2 with the atropisomeric ligand (S)-MeO-BIPHEP. By treatment of this α-chloro-β-hydroxy ester with a base, the corresponding trans methyl glycidate, a key intermediate of diltiazem, was easily obtained.

A new optically active diphosphine ligand, [(5,6),(5′,6′)-bis(ethylenedioxy)biphenyl-2,2′-diyl]bis(diphenylphosphine) (SYNPHOS®) has been synthesized and used in ruthenium-catalyzed asymmetric hydrogenation. This new ligand has been compared to other diphosphines (BINAP and MeO-BIPHEP), regarding their dihedral angles and the enantioselectivity in the ruthenium mediated hydrogenation reaction.

Enantioselective hydrogenation using chiral complexes between atropisomeric diphosphines and ruthenium is a powerful tool for producing chiral compounds. Using a simple and straightforward in situ catalyst preparation, the conditions were optimized using molecular hydrogen for both academic and industrial purposes. This led to the best conditions and the lowest catalytic ratio required for the pressure used. Hydrogenation of various β-keto esters was efficiently performed at atmospheric and higher pressures, leading to the use of very low catalyst-substrate ratios up to 1/20,000. Asymmetric hydrogenations were used in key-steps towards the total synthesis of corynomycolic acid, Duloxetine and Fluoxetine.

Rh-catalyzed CC bond formation in neat water under basic conditions has been efficiently performed. The addition of various boronic acids to styrene, 2-vinylpyridine, and cyclic α,β-unsaturated ketones has been realized with high selectivity and yield. We have shown that m -TPPTC (tris( m -carboxyphenyl)phosphane trilithium salt) exhibited a higher reactivity compared to TPPTS. These couplings could also be conducted very efficiently under basic and phosphaneless conditions to give functionalized aryl derivatives. The benefits of the additional anionic ligand m -TPPTC lied in the successful recycling experiments of 1,4-addition of phenylboronic acid to cyclohexenone, with no loss of the water-soluble catalyst.

The reaction of compounds 6a – i , readily available from α-amino acids, with an excess of lithium diisopropylamide, leads to new 3-substituted-2 H -1,2-naphthothiazin-4(3 H )-one 1,1-dioxides 7a – i , with yields ranging between 21 and 70%. The key steps are: the naphthylsulfonyl ortho-deprotonation based on the directed ortho-metalation reaction followed by a regiospecific intramolecular cyclisation reaction. Lithiation–deuteration experiments carried out on the naphthylsulfonamides 8 and 9 using n -BuLi and LDA demonstrated the regioselectivity of the deprotonation of the H-3 over the H-1 one of the naphthalene ring.

A new Pd-catalyzed route to (±)-podophyllotoxin is disclosed. The strategy is based on an efficient organoaqueous reaction that diastereoselectively introduces the C-4 hydroxyl group and the furan ring. Further functionalization led to an iododerivative, which was cyclized under optimized conditions either to the aryltetralin of (±)-podophyllotoxin or to a five-membered ring isomer.

The versatile preparation of new anionic water-soluble ligands derived from triphenylphosphane is described based on halogen-lithium exchange followed by CO2 quenching. Efficient inter- and intramolecular Heck reactions have been disclosed. Comparison with other anionic and cationic ligands showed that meta substitution on the aromatic ring enhanced the reactivity.

CODRu(h3methylallyl)2 is a versatile starting material for the preparation of a wide range of chiral bisphosphines ruthenium(II) complexes: (P*P)Ru(h3methylallyl)2 2, Ru[X4(P*P)2] 3, and cationic monohydride ruthenium complex 4. A facile synthesis of new C2 electron-rich chiral phosphines, bis(phosphetano)benzene 8 and 1,1¢bis(phosphetano)ferrocene 10 is presented. Dynamic kinetic resolution was used for efficient syntheses of key components of the hexahydroazepane core 16 of balanol and of optically pure Boc-(2S,3R,3S)-iso-dolaproïne 19. Catalyst 4 was used in asymmetric hydrogenation of 22 to give (+)-cis-methyl dihydrojasmonate in high enantioselectivity.