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CRITICAL REVIEW

BINEPINES: chiral binaphthalene-core monophosphepine ligands for multipurpose asymmetric catalysis

Serano Gladiali,*a Elisabetta Alberico,b Kathrin Jungec and Matthias Beller*c
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Received 2nd November 2010 DOI: 10.1039/c0cs00164c The atropisomeric structure of 4,5-dihydro-3H-dinaphtho[2,1-c;1 0 ,2 0 -e]phosphepine is the common axially chiral scaold of a library of monophosphine ligands nicknamed BINEPINES that have shown a quite remarkable stereoselection eciency in a broad variety of enantioselective reactions involving the formation of new CH or CC or CX bonds. In this critical review the properties and scope of this type of chiral ligands are illustrated (70 references).

Introduction
The last decade has witnessed the enormous success of chiral monodentate phosphorus ligands in several metal- and
a

Dipartimento di Chimica, Universita` di Sassari, via Vienna 2, 07100 Sassari, Italy. E-mail: gladiali@uniss.it; Fax: +39 079 229559; Tel: +39 079 229546 b Istituto di Chimica Biomolecolare, CNR, trav. La Crucca 3, 07040, Italy c Leibniz-Institut fur Katalyse e.V. an der Universitat Rostock, Albert-Einstein-Strae 29a, Rostock 18059, Germany. E-mail: Matthias.Beller@catalysis.de; Fax: +49 381 1281 51113; Tel: +49 381 1281 113

organo-catalyzed enantioselective reactions. The renaissance of this class of chiral inducers has turned around the established belief that only bidentate diphosphines could be the ligands of choice for asymmetric catalysis. The breakthrough in the eld was achieved in 2000 when almost simultaneously three independent groups pointed out the exceptional stereoselective ability displayed in Rh-catalyzed asymmetric hydrogenation of a-acyldehydroamino acid derivatives by the phosphoramidites 1,1 phosphites 22 and phosphonites 33 of binaphthol (Fig. 1). Given the presence of polar Pheteroatom bonds (heteroatom = O; N), these compounds are ligands of comparably higher p-acidity than tertiary trialkyl or triaryl phosphines.

Prof. Serano Gladiali was born in Milano. He accomplished his studies in Industrial Chemistry at the University of Milano where he received the laurea in Industrial Chemistry in 1968. After gaining four years of experience in industrial research on steroid chemistry, in 1972 he moved to the University of Sassari, where he is full Professor of Industrial Organic Chemistry at the Faculty of Sciences. His main research interests are Serano Gladiali centred on asymmetric homogeneous catalysis and ligand design. Stereoselective synthesis of optically active organic compounds, mainly nitrogen heterocycles and atropisomeric phosphorus and sulfur derivatives, is a further subject of his research. He has co-authored over 250 papers, patents and communications covering the areas of enantioselective hydroformylation and hydrogen transfer reduction; synthesis and applications to asymmetric catalysis of chiral heterocycles with pyridine nitrogen donors; preparation and catalytic applications of atropisomeric phosphorus and sulfur donor ligands; catalysis for energy production.
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Elisabetta Alberico obtained her degree in Chemistry (Laurea) from the University of Sassari in 1993. From 1993 to 1996 she worked at the University of Sassari in Prof. Gladialis group and for the National Research Council as research assistant in the eld of asymmetric homogeneous catalysis. After spending ten months at the University of Ottawa in 1998 in the group of Prof. Howard Alper, she moved to the Rheinisch-Westfa lische Elisabetta Alberico Technische Hochschule where she obtained her PhD under the supervision of Prof. Albrecht Salzer. Since 2001 she has held a permanent position as researcher at the Institute of Biomolecular Chemistry of the National Research Council in Sassari. Her research interests are in the elds of organometallic chemistry, asymmetric homogeneous catalysis and application of catalytic methods to the synthesis of molecules endowed with biological activity.

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Fig. 1 Selection of chiral monodentate biaryl phosphoramidites 1, phosphites 2 and phosphonites 3 for asymmetric hydrogenations.

Scheme 1 First synthesis of BINEPINES 5 according to Gladiali et al.

BINEPINES 5 are monodentate phosphines which retain the basic structural features of these monodentate binaphthalenecore ligands, i.e. a seven-membered phosphepine ring embedded in a C2-symmetrical environment with an endocyclic P-donor atom and a stereogenic axis as the unique chiral element, but possess a P-donor of comparably higher electron density (Scheme 1). This feature is expected to display a positive eect in several catalytic processes like the hydrogenation of enamides by Rhphosphine complexes where the turn-over limiting step of the catalytic cycle is the oxidative addition of hydrogen.4 Like the other chiral monophosphines, BINEPINES have several advantages over the bidentate counterparts: they are readily accessible from rather inexpensive starting materials via synthetic routes which enable the easy introduction of

structural diversity; they are amenable to combinatorial screening of catalysts;5 they allow the design of catalysts built up on metal complexes containing an unpaired number of chiral ligands. The higher lability of monophosphines as compared to chelating bidentate diphosphines may inuence the dissociation equilibria in favor of unsaturated species. While this may have contrasting eects on the catalytic process, an increase of the rate is anticipated in the case where vacation of a coordination site is required in an early step of the catalytic cycle. The main drawback in the use of monophosphines as chiral ligands follows from the higher number of regioisomers that, depending on the geometry of the complex, can be obtained when two or more ligands are complexed to the metal. The presence of a mixture of catalysts is normally detrimental for the selectivity of the reaction.

Dr Kathrin Junge, born in 1967 in northern Germany, received her PhD degree in Chemistry from the University of Rostock in 1997 (Prof. E. Popowski Laboratory). After a postdoctoral position in the Max-Planck group of Prof. U. Rosenthal she joined the group of Prof. M. Beller in 2000. Since 2008 she is group leader for homogeneous redox catalysis at LIKAT. She has been involved for years on catalysis and has developed Kathrin Junge ecient hydrogenations for ketoesters and other carbonyl compounds. Moreover, new chiral ligands based on the binaphthophosphepine structure were developed by her. Her current main interest is the development of environmentally benign and ecient catalytic reactions based on cheap nonprecious metals.

Matthias Beller, born in 1962, studied chemistry at the University of Gottingen, Germany, where he completed his PhD thesis in 1989 in the group of Prof. Tietze. As a recipient of a Liebig scholarship, he then spent one year in the group of Prof. Sharpless at the MIT. From 1991 to 1995, Beller was an employee of Hoechst AG in Frankfurt, where he directed the Homogeneous Catalysis project in the companys central research Matthias Beller unit. In 1996 he moved to the Technical University of Munchen as Professor for Inorganic Chemistry. In 1998, he relocated to the University of Rostock to head the Institute for Organic Catalysis. Since 2006 Matthias Beller is director of the newly formed Leibniz-Institute for Catalysis. His scientic work has been published in around 450 original publications and review articles. In addition, ca. 100 patent applications have been led.
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Synthesis and structure of BINEPINES

Synthesis The rst preparation of a 4,5-dihydro-3H-dinaphtho[2,1-c;1 0 ,2 0 -e]phosphepine derivative 5 (BINEPINE) was reported in 1994 (Scheme 1).6 A nickel-catalyzed Kumada coupling of 1-bromo-2-methylnaphthalene with its Grignard reagent7 gave racemic 2,2 0 -dimethylbinaphthyl 4 which was selectively double-lithiated on the methyl groups and subsequently quenched with phenyldichlorophosphine to yield racemic P-phenyl-4,5-dihydro-3H-dinaphtho[2,1-c;10 ,20 -e]phosphepine 5a. Resolution of the enantiomers was carried out by fractional crystallization of the diastereomeric complexes with (+)di-m-chloro-bis[(S)-N,N-dimethyl-a-phenylethylamine-2C,-N]dipalladium 6.8 Finally, the enantiopure monodentate phosphine 5a (PhBINEPINE) was liberated by reacting the single diastereomeric complex with bidentate phosphines (e.g. DPPE). Some years later the group of Stelzer reported the synthesis of the secondary phosphepine 5 (R = H) (Scheme 2) in good yields.9 Both these approaches were however unpractical with respect to up-scaling due to the expensive auxiliaries and low overall yields. A more convenient two step pathway starting from enantiomerically pure 2,2 0 -binaphthol (498% ee) was established later when enantiopure 2,2 0 -binaphthol became commercially available on large scale.10,11 This material

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can be eciently converted into enantiopure 2,2 0 -dimethylbinaphthyl 4 in more than 90% overall yield via a two step sequence involving a Kumada coupling of the intermediate ditriate (Scheme 2).12,13 Two dierent methodologies were developed for the conversion of 4 into 5. In the rst procedure double metallation of 2,2 0 -dimethylbinaphthyl 4 with n-butyllithium in the presence of TMEDA (N,N,N 0 ,N 0 -tetramethylethylenediamine) followed by quenching with commercially available dichlorophosphines gave ligands 5a (P-phenyl) and 5b (P-tert-butyl) in 6083% yield, which were both synthesised on a scale greater than 10 g.10 In the second procedure the dilithiated 2,2 0 -dimethylbinaphthyl 4 was quenched with diethylaminodichlorophosphine to produce the amino BINEPINE 814 which, upon treatment with gaseous HCl, was converted into the chloro BINEPINE 9 in 80% yield. By coupling with various Grignard or lithium reagents the chlorophosphine provides a broad selection of ligands 5. The limited number of commercially available dichlorophosphines and the large diversity of Grignard reagents make the access through 4-chloro-4,5-dihydro3H-dinaphtho[2,1-c;1 0 ,2 0 -e]phosphepine 9 the route of choice for a library of ligands 5.11 Very recently, Wild and co-workers have added one more member to the ligand family 5. The 2-(methoxymethyl)phenyl derivative 5t was exploited in the enantioselective synthesis of arsenium and bis(arsenium) salts.15

Scheme 2

Synthetic approach to 4,5-dihydro-3H-dinaphtho[2,1-c;1 0 ,2 0 -e]phosphepines developed by Beller et al.

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Scheme 3 Synthesis of 4,5-dihydro-3H-dinaphtho[2,1-c;1 0 ,2 0 -e]phosphepines by a protocol established by Zhang et al.

A synthetic approach to monodentate BINEPINES analogous to the one devised by Beller et al. was reported at the same time by the group of Zhang (Scheme 3).13 The t-Bu derivative 5b was exploited in the preparation of the bidentate ligand with the phosphepine motif 1113 which adds to the bis-phosphepine ligands 1016 and 1217 previously reported by the same group. Structural diversity in the BINEPINE library can be generated in dierent ways and nowadays a vast array of derivatives has been reported. While the group of Beller has focused on the variation of substituents on the P-centre, Widhalm et al. have managed to introduce one or two substituents on the benzylic carbons a- to the phosphorus (Scheme 4).18 The introduction of new stereocentres in the proximity of the P-donor was deemed to improve the transfer of chiral information. The sulde 13, prepared from 5a, was deprotonated with n-butyllithium and then quenched with suitable electrophiles to provide

monosubstituted ligands. Monosubstitution at the benzylic carbon destroys the C2-symmetry of the supporting scaold and generates, at the same time, two new stereogenic centres, at C and at P. The monoalkylated products 14 (Scheme 4) are obtained as a mixture of two diastereoisomers with a relative syn (Sax,S,SP)-14 or anti (Sax,S,RP)-14 arrangement of the substituents on C and P. The latter stereochemistry is favoured in all cases. Dialkylation of the phosphepine sulde (S)-13 is better achieved by a step-wise protocol involving two sequential deprotonationalkylation reactions with the same alkylating agent. t-BuLi is necessary in order to place the second substituent on C(5). This step proceeds with complete diastereoselectivity providing the trans protected phosphepine (Sax,S,S)-16 as the exclusive reaction product and restoring the original C2-symmetry of the supporting scaold. Ligands 15 and 17 are accessible also from the relevant phosphine

Scheme 4 Synthesis of a- and a,a 0 -substituted 4,5-dihydro-3H-dinaphtho[2,1-c;1 0 ,2 0 -e]phosphepines.

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Scheme 5 Synthesis of diphenyl templated phosphepines.

oxide following a similar deprotonation/alkylation protocol followed by deoxygenation.19 The observed stereochemistry was identical and again only one diastereomer is formed. Dimethoxydibenzophosphepine (R)-23 is the unique example of phosphepine where a diaryl template other than binaphthalene has been used for the installation of the phosphepine ring (Scheme 5). The enantiopure (R)-congured product is readily accessible from the phenol 18 through the bisphenol 20 which has been resolved with the aid of menthyl chlorocarbonate.20 Structural and electronic properties of BINEPINE derivatives The 1H- and 13C-NMR spectra of PhBINEPINE 5a (Scheme 1) show the non-equivalence of the methylene and the naphthyl groups of the 1,1 0 -binaphthyl-2,2 0 -bis(methylene) backbone. Accordingly, the diastereotopic CH2 groups show in the 13C{1H} NMR spectrum two doublets with dierent PC coupling constants. In the 1H-NMR spectrum, the diastereotopic hydrogens of the CH2 groups give rise to four sets of partially overlapping double doublets arising from geminal 1H,1H and from 31P,1H couplings. The 31P{1H} NMR spectra of ligands 5 show a single peak whose chemical shift depends on the nature of the R substituent on the phosphorus and varies within the range of d 3 to +28 ppm. These spectral data, which are common to ligands 5, indicate that no atropisomerization of the dinaphthyl framework occurs at room temperature and that the seven membered phosphepine ring is locked in a single conformation which does not undergo any signicant dynamic process. A noticeable feature of BINEPINES is that the phosphorus atom is not a stereogenic centre since it is located on the C2-symmetry axis of the dinaphthyl substituent. As a consequence, if pyramidal inversion at phosphorus had to occur, which however is not the case, this should not aect the chirality of the molecule which is determined exclusively by the atropisomeric dinaphthyl framework. When the C2-symmetry of the dinaphthyl backbone is lost, as it occurs upon introduction of one substituent at the benzylic position (ligands 15ae, Scheme 4), the phosphorus becomes a stereogenic centre. In ligands 17ae (Scheme 4),
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where the two substituents R1 and R2 are identical and have a mutual trans arrangement, the C2-symmetry of the binaphthyl template is restored and the phosphorus is no longer stereogenic. X-Ray structures have been obtained for ligands 5H R = H,9 (S)-5c and (S)-5k (Fig. 2),11 rac-14b and rac-16b (Fig. 3).18 Common features of the BINEPINE ligands resulting from the comparison of these structures are the distorted skewboat conformation of the seven-membered phosphepine ring containing the phosphorus atom and the large dihedral angle (Table 1) existing between the average planes of the naphthalene rings. These torsional angles lie in the range 651701 for BINEPINES 5, lower values being associated to the presence of aryl substituents at the P-centre. Since the amplitude of this angle is almost unchanged in the relevant P-oxide (compare entries 3 and 4, Table 1), it can be condently assumed that the torsional angle

Fig. 2 Crystal structures of (S)-5c (left hand side) and (S)-5k (right hand side). For ligand 5c, only one of the two symmetryindependent molecules of the asymmetric unit is depicted. H-atoms are omitted for clarity.

Fig. 3 Crystal structures600 dpi in TIF format)??4 of rac-16b (left hand side) and rac-14b (right hand side). In both cases, structures having S conguration at the benzylic carbons are depicted. H-atoms are omitted for clarity.

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Dihedral angles of BINEPINE derivatives Compound 5H 5k 5c 5c-oxide 5a-oxide 17b-oxide 16b 14b 24 Torsion angle 67.6(5)1 70.21(5)1 65.11(10)1a 66.20(9)1 65.05(7)1a 66.86(6)1 63.01(7)1 67.39(4)1 71.361 71.431 63.81 Reference 9 11 11 19 19 19 18 18 6 Table 2 31P-NMR chemical shifts for selected BINEPINES and 1 JP,Se coupling constants of the corresponding selenides measured in CDCl3 at room temperature Entry 1 2 3 4 5 6 7 8 9
a

Table 1 Entry 1 2 3 4 5 6 7 8 9
a

Ligand 5d 5r 5c 5l 23 5a 5n 5h 1

d (31P)/ppm 2.3 4.3 5.7a 7.8a 1.7 7.8 8.2a 5.1a 148.7

JP,Se/Hz

711.4 711.4 721.8 723.1 725.0 728.3 739.9 761.7 971.1

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The two values refer to the two symmetry independent molecules present in the asymmetric unit.

Values measured in CD2Cl2.

of the parent ligand PhBINEPINE 5a should be very close to that of the relevant P-oxide (631). Unlike the case of P-oxides, the introduction of sulfur in place of oxygen induces a signicant increase of the dihedral angle (compare entries 6 and 7, Table 1) as to span over 711 in rac-14b and in rac-16b. In both these last ligands the methyl substituents at the benzylic carbons hold a pseudo-axial position. A few transition metal complexes containing PhBINEPINE 5a have been isolated and characterized. Cationic [Rh(nbd)(5a)2]+X derivatives, where nbd is norbornadiene and X is a noncoordinating anion (CF3SO3; BF4; PF6; SbF6; BaRF) show in solution a NMR pattern consistent with the presence of two units of P-ligand coordinated to the metal and an overall C2-symmetry of the complex.21 The same structural features can be extracted from the NMR spectra of neutral dichloro and cationic ditriate Pt-complexes synthesized by reacting Pt(cod)Cl2 (cod = 1,5-cycloctadiene) with two equivalents of 5a followed by treatment of the dichloro derivative with aqueous silver triate.22 Crystals suitable for X-ray analysis have been obtained for two metal complexes containing just one unit of (S)-PhBINEPINE 5a: the cyclopalladated complex with the (R)-phenethylamine derivative 246 and the cycloplatinated complex 25a23 (Fig. 4). The measure of the dihedral angle of the BINEPINE is reported only for the cyclopalladated complex 24 and is very close to that of the corresponding phosphepine oxide (compare entries 5 and 9, Table 1). From this it follows that the binding of a metal at the P-centre has only minor consequences on the atropisomeric conformation of the ligand. Tolmans cone angle y of PhBINEPINE as extracted from the crystal structure of (S,R)-24 spans some 1511, slightly larger than that of triphenylphosphine (1451).24

The electron density at the P-donor of a range of BINEPINES has been evaluated by means of the 1JP,Se of the corresponding selenides, prepared in situ by heating the phosphepine derivative and selenium in CDCl3.25 This method is among the most reliable ones for assessing the donating ability of the phosphorus donors, smaller coupling constants corresponding to a higher electron density at the phosphorus and vice versa.26 From the data of Table 2 it is apparent that the electronic eect of the substituents on the phenyl ring is eectively transmitted to the P-donor of aryl substituted BINEPINES and that the dimethoxydibenzophosphepine 23 (1JP,Se = 725 Hz) is slightly more basic than PhBINEPINE 5a (1JP,Se = 728 Hz).3 For the sake of comparison, the 1JP,Se of a typical phosphoramidite such as Monophos (1; R1 = R2 = Me), a ligand much more p-acidic than any BINEPINE 5, is as high as 971.1 Hz (Table 2; entry 9). Formation of CH bonds Hydrogenation of CQC double bonds. Hydrogenation of CQC double bonds is the benchmark reaction for assessing the eciency of a chiral ligand. Driven by the success of monodentate phosphorus ligands based on the binaphthyl backbone (Fig. 1), the ligand tool box 5 was assessed in the asymmetric catalytic hydrogenation of a variety of substrates. A rst set of experiments was dedicated to the rhodium-catalyzed asymmetric hydrogenation of a-aminoacid precursors.10,11 Here, methyl-(Z)-a-acetamidocinnamate 26 and methyla-acetamidoacrylate 27 were chosen as model substrates (Scheme 6). High enantioselectivities (up to 93% ee) and activities (TOF 10006000 h1) were achieved in toluene and in ethyl acetate with 26 as the substrate.11 The use of sodium dodecyl sulfate (SDS) as an additive frequently led to improved enantioselectivities (up to 95% ee in the case of 5a) for the reaction in toluene.10 This result is rather unexpected because aromatic hydrocarbons are known to induce the formation of coordinatively saturated Rh-complexes which are less reactive towards hydrogen.27 A negative eect on the kinetics of the hydrogenation is the expected consequence and this may have an unfavorable impact also on the stereoselectivity. In the present case, however, the decrease in the reaction rate is counterbalanced by a denite increase of the stereoselectivity. The same happens in the hydrogenation in ethyl acetate when the ligand to metal ratio is increased from 2 : 1 to 4 : 1.10 Both these results are most probably related to the stabilization of
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Fig. 4 Crystal structures of cyclometalated Pd (24) and Pt (25a) complexes with (S)-5a. H-atoms are omitted for clarity.

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Scheme 6 Asymmetric hydrogenation of 26 and 27 in the presence of BINEPINE ligands 5.

Scheme 7 Hydrogenation of acetamidocinnamic acid 28 and its methyl ester 26 catalyzed by Rh-complexes of PhBINEPINE 5a and a,a 0 -disubstituted PhBINEPINES 17b and 17d.

the resting state of the catalyst and to the consequent decrease in the rate of its decomposition.27 The best enantioselectivities were obtained with aryl substituted BINEPINES, while alkyl derivatives led, in most cases, to enantiomeric excesses lower than 50%. In the case of asymmetric hydrogenation of methyl a-acetamidocinnamate 26 a detailed study of various ligands with substituted aryl groups at the phosphorus demonstrated no signicant change in enantioselectivity, when electron-donating or electron-withdrawing functionalities were situated in the para-position. Analogous substitution in the ortho-position caused a decrease in the enantioselectivity. The substituents on the P-phenyl group display a signicant inuence on the activity of the catalyst which is increased by electron donating substituents such as p-OMe and reduced by electron-withdrawing ones such as p-F and p-CF3. While the majority of the catalysts gave lower enantioselectivities in the reduction of methyl a-acetamidoacrylate 27 as compared with methyl a-acetamidocinnamate 26, in the case of the best ligand, (S)-5o, the ee was practically the same (9495%). With both substrates, ligand (S)-5o gives also rise to the catalyst with the highest activity. As a general trend, with BINEPINES 5 the handedness of the reaction is opposite (the inducing ligand and the reaction product have opposite congurations). The sole exception to this behavior has been noticed in the reduction of 27 with t-BuBINEPINE 5b, where the inducing ligand and the product have the same congurations. With C-substituted BINEPINES, the best results in the reduction of a-acetamidocinnamic acid 28 (91% ee) and its methyl ester 26 (73% ee) are achieved with ligands (Sax,S,S)17b and (Sax,S,S)-17d respectively (Scheme 7).18 Interestingly, with all these ligands the handedness of the reaction is reversed as compared to the corresponding unsubstituted BINEPINES 5, indicating that axial- and central chiralities are mismatched and that stereoselection is steered by the conguration of the stereogenic centres rather than by that of the stereogenic axis. The hydrogenation of b-aminoacid precursors is attracting increasing interest because the resulting products are useful building blocks for various novel biologically active compounds.28 While investigating the application of ligand class 5 in the rhodium-catalyzed asymmetric hydrogenation of b-dehydroamino acids derivatives, the necessity of dierent reaction conditions
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for the E- and Z-isomers became soon apparent (Scheme 8).29 A good enantioselectivity (79% ee (R)) was obtained for the reduction of (E)-methyl-3-acetamido butenoate E-29 in 2-propanol at 2.5 bar hydrogen pressure, while higher pressures (50 bar) and ethanol as the solvent turned out to be benecial for the Z-isomer Z-29 (92% ee (S)). Notably, a chiral switch in the product conguration was noticed depending on the geometry of the double bond, which had been scarcely reported before.30 Furthermore, a higher reaction rate was monitored for the Z-isomer compared to the E-isomer, in spite of the opposite behavior reported for most other catalysts.31 With Z-29 the highest enantioselectivity was reached with ligand 5a while the tert-butyl-substituted derivative 5b was completely inactive. Surprisingly, ligand 5b gave a good enantioselectivity in the hydrogenation of E-29. Several b-dehydroamino acids derivatives have been screened and in the best case 94% ee was attained when the methyl ester of Z-29 was replaced by the ethyl ester. From the observation of a non-linear dependence of the stereoselectivity of the reduction on the enantiopurity of the used BINEPINES, it was inferred that 2 equiv. of ligand per metal were present in the active catalyst.32 This circumstance gave the chance for a combinatorial screening of catalysts. Unfortunately no positive eect was observed upon combining 5a with dierent achiral phosphorus ligands.29

Scheme 8 Hydrogenation of E-29 and Z-29 with dierent BINEPINES 5.

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The mechanistic details of the hydrogenation of b-aminoacid precursors are still to be claried. This does not allow us to draw any sound conclusion from the results obtained in the RhBINEPINE catalyzed hydrogenation. In the asymmetric hydrogenation of dimethyl itaconate 31 with BINEPINES 5 the best results (enantioselectivities up to 88% ee) were obtained in dichloromethane (Scheme 9).11 The hydrogenation of itaconic, acetamidocinnamic and acetamidoacrylic acids and of the relevant methyl esters proceeds at a fast rate and with a high ee, up 96%, even in the presence of dimethoxydibenzophosphepine (R)-23 as the chiral inducer. In this case dichloromethane is the solvent of choice and a preformed cationic Rh-complex containing two units of the ligand (R)-23 has been used as the catalyst.20 PhBINEPINE (S)-5a and related BINEPINES were applied to the rhodium-catalyzed reduction of enamides, an atom economic and straightforward route for the synthesis of chiral amines (Scheme 10).33 As a general trend, with these substrates aryl-substituted phosphepines are much better suited chiral inducers than the alkyl-substituted ones and, among them, (S)-5a is the most ecient. Electron-rich substrates such as 33 were hydrogenated in somewhat higher enantioselectivity compared to N-(1-phenylvinyl)acetamide, the opposite behaviour being observed with electron-poor substrates. Under optimized conditions an enantioselectivity as high as 93% has been obtained in the reduction of N-(1-phenylvinyl)acetamide 32 (Scheme 10) with ligand (S)-5a. This is the highest stereoselectivity obtained up to now with monodentate phosphine ligands in this reaction. The enantioselective reduction of enol carbamates oers an alternative approach for the preparation of chiral benzylic alcohols.19 Pioneering work in this eld has been reported by Feringa and co-workers who have obtained enantioselectivities up to 98% ee with rhodium-catalysts containing monodentate phosphoramidites (MonoPhos-family).34 Utilizing compound 34 as a model substrate, various reaction parameters were investigated in detail and enantioselectivities up to 96% ee

Scheme 11 Hydrogenation of enolcarbamate 34 in the presence of BINEPINE 5a.

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were achieved with a catalyst made up in situ from [Rh(cod)2]+BF4 and ligand 5a (Scheme 11).19 Notably, the catalyst gave a similar enantioselectivity (9496% ee) over the entire temperature range 1090 1C. The inuence of a,a 0 -substitution in the ligand was also explored in a comparative study. Ligand (Sax,S,S)-17b was the best chiral inducer for some enolcarbamates and caused in most cases a switch of conguration compared to the parent ligand 5a.19 Transfer hydrogenation of CQX bonds. Phenyl BINEPINE 5a is an excellent chiral inducer in the hydrogen transfer reduction of the CQC double bond of a,b-unsaturated acid derivatives, a reaction which had no other precedent for the use of chiral monodentate P-donors. In the presence of preformed and well-dened cationic [Rh(nbd)(5a)2]+X complexes (X = non-coordinating anion) a range of a,b-unsaturated acids and esters have been selectively reduced to the corresponding saturated products using formic acid as the hydrogen donor (Scheme 12).21 While with most substrates the stereoselectivities were moderate, an excellent enantioselectivity (97% ee), denitely higher than that obtained in the reduction with hydrogen, was attained in the reduction of itaconic acid 35 where 5a outperformed by far all the other monodentate P-donors screened. Notably, while the corresponding a-methyl monoester (R1 = H; R2 = Me) was quantitatively reduced to the saturated derivative of the same conguration with respectable ee (81%), under the same conditions the dimethyl 31 and the b-methyl monoester (R1 = Me; R2 = H) gave modest yields of the opposite enantiomer in low ees (13% and 28%, respectively). This chiral switch stresses the role played in the catalytic process by the free b-COOH group in the substrate. This structural feature not only dictates the conguration of the reduction product, but is as well needed for high conversions and stereoselectivities to be obtained. We may speculate that the b-COOH can be involved in the intramolecular oxidative addition to the metal centre facilitating the formation of the rst Rh(III)-intermediate of the catalytic cycle. Replacement of the carboxylato ligand at the metal centre by formate anion provides the conditions for carbon dioxide extrusion, leading to a Rh(III)dihydride. Such a species

Scheme 9 Asymmetric hydrogenation of dimethyl itaconate 31 in the presence of BINEPINE ligands 5.

Scheme 10 Asymmetric hydrogenation of N-acyl enamides.

Scheme 12 Transfer hydrogenation of itaconic acid derivatives.

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Scheme 13 Transfer hydrogenation of acetophenone in the presence of Pybim ligand and ligand 5a. Scheme 15 Ruthenium-catalyzed hydrogenation of b-ketoesters in the presence of p-anisylBINEPINE 5c.

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has been proposed as the intermediate in the highly enantioselective asymmetric hydrogenation of itaconic acid by chiral Rhdiphosphine complexes.35 Ligands 5 in association with chiral pyridinebisimidazoline ligands have been used in the Ru-catalyzed hydrogen transfer reduction of ketones yielding enantioselectivities up to 95% ee (Scheme 13).36 The role of the P-ligand in this reaction, however, is of scarce signicance since the ees obtained in the presence of 5 are equal or sometimes even lower than those observed when the chiral pyridinebisimidazolines are associated with triphenylphosphine. In the same reaction stereoselectivities lower than 30% were obtained using a catalyst prepared in situ from [Ru(cod)(methallyl)2] and PhBINEPINE 5a. Hydroboration of CQC bonds. The rhodium-catalyzed hydroboration of styrene with catechol borane proceeds smoothly with ligands 5a, 15, and 17 aording predominately the branched product (Scheme 14).18 The stereoselectivities are rather modest with a top value of 42% ee obtained with ligand 17b. A switch of the product conguration may occur depending on the nature of the substituents on the benzylic carbons of the phosphepine ring. This may be indicative of a mismatched combination of the stereogenic elements present in the ligands. Hydrogenation of CQO bonds. The asymmetric hydrogenation of carbonyl groups provides a straightforward route to chiral alcohols and a number of Ru- or Rh-complexes modied with chiral bidentate phosphine have been successfully employed in the reduction of ketones. The rst successful application of monodentate phosphines to the catalytic asymmetric hydrogenation of b-ketoesters was described in 2004 when it was shown that BINEPINES 5 in combination with [Ru(cod)(methallyl)2] complexes give rise in situ to a catalytic system capable of hydrogenating b-ketoesters 36 in a high stereoselectivity of up to 95% (Scheme 15) even at fairly high temperatures (100120 1C).37

Interestingly, other monodentate ligands of excellence in hydrogenation such as phosphites, phosphonites and phosphoramidites were much less ecient than BINEPINES 5 in this reaction. When the enantioselective hydrogenation of b-ketoesters was run in a homogeneous solution made up of ionic liquids (IL) and methanol,38 the reaction rate was higher than in pure ILs but the enantioselectivity was lower than that observed in plain methanol.39 These dierences have been attributed to the concurrent formation of ketal and hemiketal that is suppressed to a signicant extent in the mixed system IL/methanol. Nature and performance of the catalysts heavily depend on the structure of the cationic part of IL.38 With bis(triuoromethylsulfonyl)-imide anions [NTf2] hydroxyalkylammonium salts display the best catalytic activity and the induction time for the generation of the active species is short. In these systems the enantioselectivities were found to be in the same range as for pure methanol (9096% ee). Very recently it has been reported that the asymmetric hydrogenation of CQO double bonds can be eciently performed in the presence of a Cu-catalyst generated in situ from Cu(OAc)2 and 5.40 A wide array of aryl- and alkyl-substituted ketones including cyclic and heterocyclic ones were successfully hydrogenated with enantioselectivities of up to 89% ee under optimized reaction conditions (50 bar H2, 1030 1C, i-PrOH, KO-t-Bu) (Scheme 16). A base is essential for the formation of an active copper catalyst, presumably a hydridic species. Although the model reaction is run with a base in i-PrOH, the transfer hydrogenation pathway is not operating since without hydrogen no reaction at all is observed. The same catalytic system is eective also in the hydrosilylation of ketones where slightly higher enantiomeric excesses have been reported (next section). Hydrosilylation of CQO bonds. Although asymmetric hydrogenation shows excellent enantioselectivities and yields for a wide range of ketones, high pressure and temperatures

Scheme 14 Asymmetric hydroboration of styrene with catechol borane.

Scheme 16 Copper-catalyzed enantioselective hydrogenation of ketones with BINEPINE 5n.

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Scheme 17 Copper-catalyzed enantioselective hydrosilylation of ketones using PhBINEPINE 5a.

Scheme 18 Rhodium-catalyzed asymmetric hydroformylation of styrene using ligands 5a and 5r.

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and special equipment are often required. Asymmetric hydrosilylation oers an attractive alternative due to smooth reaction conditions and easy to handle starting materials. Various copper-based catalysts have been investigated for the asymmetric hydrosilylation of carbonyl compounds, but there was no report on the use of copper complexes with chiral monodentate phosphorus ligands until 2010 when the rst copper-catalyzed asymmetric hydrosilylation of carbonyl compounds using monodentate BINEPINE ligands 5 has been described (Scheme 17).41 These CuBINEPINE catalysts have been successfully used in the hydrosilylation of a broad range of carbonyl compounds including aryl alkyl, cyclic, heterocyclic and aliphatic ketones. The reaction proceeds under mild conditions without any base providing, after desilylation with tetrabutylammonium uoride (TBAF), the expected carbinols in high yields and enantioselectivities (up to 96% ee).

selectivity of the reaction was investigated in some detail (Scheme 18).25 This study conrmed that Rh/BINEPINE complexes are quite active catalysts for this reaction and that they show a pronounced preference towards the branched isomer (8596%). The enantiomeric purity of 2-phenylpropanal improved substantially from the rst report (48% ee obtained with the phosphepine 5r) but was still far away from an acceptable threshold so as to make the process a viable tool for the enantioselective synthesis of arylpropionic acids.25 Allylic alkylation of 1,3-diphenylallyl esters The asymmetric allylic alkylation of 1,3-diphenylallyl esters by dimethylmalonate anions has been performed in the presence of palladium/BINEPINE complexes prepared in situ from [Pd(allyl)Cl]2 and the appropriate ligand (Scheme 19).42 The outcome of the reaction is strongly aected by the solvent, the base, the ligand and the temperature. In this reaction aryl substituted BINEPINES are by far better chiral inducers than the P-alkyl derivatives which leads to low stereoselectivities. By proper choice of the reaction conditions and of the substituent on the phosphorus, stereoselectivities up to 92% have been achieved in the alkylation of 1,3-diphenylprop-2-enyl1-acetate using the p-anisyl substituted ligand 5d, while phenyl BINEPINE 5a ranked the second in eciency (86% ee) among the ligands tested. Similar enantioselectivities have been recorded with 1,3-diphenylprop-2-enyl-1-carbonate as the substrate. These results are among the best ones recorded in this reaction with a monodentate P-donor. Allylation of aldehydes by p-allyl Pd-complexes (umpolung of reactivity) The rst ever documented example of catalytic asymmetric aldehyde allylation by umpolung of a p-allyl palladium complex

Formation of CC bonds
Addressing the stereochemistry in the formation of CC bonds is frequently the most challenging task to be faced in the synthesis of an organic product of medium complexity. Asymmetric transition metal catalysis provides one of the most powerful instruments for driving the reaction towards the desired stereoisomer. Due to the huge number of CC bond-forming reactions, chiral ligands of broad general scope are extremely helpful in sorting out the best synthetic strategy and the sequence of CC bonds to be formed. Hydroformylation The Rh-catalyzed hydroformylation of styrene was the rst asymmetric catalytic reaction where PhBINEPINE 5a was screened as a chiral inducer.6 The catalyst, prepared in situ from [Rh(CO)2(acac)] and 5a, displayed a good activity and the reaction proceeded at a satisfactory rate even at temperatures as low as 30 1C. Under standard conditions (benzene; substrate/P/Rh, 500 : 4 : 1, CO/H2, 1 : 1, 50 bars) the reaction was completely chemoselective towards aldehydes and aorded a 64% conversion in 3 h. The branched isomer accounted for 95% of the aldehydic product, but the enantioselectivity was very poor, 20% ee.6 Several years later, a systematic screening of the potential of BINEPINES in Rh-catalyzed asymmetric hydroformylation of styrene was undertaken and the inuence of the structure of the substituent at the P-centre on catalytic activity and
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Scheme 19 Allylic alkylation of 1,3-diphenylallyl esters catalyzed by PdBINEPINE complexes.

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was accomplished in 2004 when it was demonstrated that upon addition of an excess of diethylzinc, an electrophilic Pdallyl complex undergoes transmetallation and is turned into a nucleophilic metalallyl species, supposedly an allyl zinc reagent, which can then deliver the allyl fragment to a carbonyl electrophile.43 Preliminary evidence suggests that transmetallation involves the transfer of an ethyl group from zinc to palladium and that elimination of diethylpalladium eventually occurs. The structure of the nucleophilic reagent and its binding to the chiral ligand, however, have not been determined. The net result is the addition of an allyl fragment to the aldehyde group with formation of a homoallylic alcohol (Scheme 20). Remarkably chiral bidentate phosphines are not well suited ligands for this catalysis as they fail to produce optically active products. When the reaction of benzaldehyde with cinnamyl acetate is performed in the presence of a catalytic amount of [Pd(allyl)Cl]2 and 5a at 30 1C, the allylation reaction is completely diastereoselective and aords only the anti homoallylic alcohol in 77% yield and in 70% enantioselectivity. Even if this value can be hardly considered in the range of excellence, this ee was by far the best one scored in an extensive screening where some twenty dierent chiral monodentate phosphorus donors were compared as chiral inducers. Addition of organoaluminium reagents to aldehydes The 1,2-addition of AlMe3 or its air-stable analogue DABCO (AlMe3) to aldehydes proceeds with high stereoselectivity in the presence of Ni-complexes containing chiral P-donors. In this catalysis monodentate phosphines enable the enantioselective preparation of secondary alcohols in high ee, whereas chelating diphosphines aord very low enantioselectivities.44 The complex prepared in situ by addition of a suitable amount of phosphoramidite 1 to Ni(acaca)2 is the catalyst of choice for this transformation: on a range of aromatic and a few aliphatic aldehydes it enables high turnover numbers and frequencies even at 25 1C with stereoselections in between 85% and 94%. Cinnamaldehyde, however, turned out to be a poor substrate for the phosphoramidite complex, possibly due to competition in CQC vs. CQO p-bonding to the metal centre. In this case the BINEPINE ligand 5a was by far more

Scheme 21 Ni-catalyzed 1,2-addition of AlMe3 to cinnamaldehyde.

ecient, aording the relevant methyl carbinol in a gratifying 80% ee (Scheme 21). SuzukiMiyaura coupling of aryl boronic acids PhBINEPINE 5a and its 3-mono- and 3,5-disubstituted congeners (Sax,S,RP)-15b and (Sax,S,S)-17b respectively, have been tested in the palladium-mediated SuzukiMiyaura coupling of 1-iodo-2-methoxynaphthalene with o-tolyl boronic acid.18 A good yield of the expected biaryl derivative (76%) was obtained with ligand 17b (Scheme 22), but the stereoselectivities were poor, lower than 20% ee whichever the ligand employed. Conjugate addition The Rh-complex [RhCl(Sax,S,Sp)-15f]2 containing the phosphepine alkene ligand 15f has proved to be an ecient chiral ligand for the Rh-promoted conjugate addition of aryl boronic acids to cyclohex-2-enone (Scheme 23).45 A range of aryl boronic acids, with either electron-rich or electron-poor aryl substituents, were used and in all cases the reactions proceeded in fair to good yields (6478%) and excellent enantioselectivities (9298% ee). These results compare favourably with the previous ones which have been obtained with dierent chiral diolen or phosphanealkene ligands. The high eciency displayed by the catalytic system supports the view that, despite the comparably high degree of conformational freedom of the ligand, the catalytic active species is quite robust and endowed with an ecient chiral bias. The conjugate addition to open chain a,b-unsaturated ketones or to nitroolens can be performed under completely dierent conditions using copperphosphepine complexes as catalysts and alkylzinc as a nucleophile.46a This reaction gives good yields, but the enantioselectivities are not exceptional and by far lower than those obtained with the analog phosphoramidite-based catalysts.46b The best ee was obtained with 5a as the ligand and was not higher than 74% (Scheme 24).

Scheme 20 Enantioselective catalytic allylation of aldehydes by umpolung of p-allyl palladium complexes.

Scheme 22 SuzukiMiyaura coupling catalyzed by palladiumBINEPINE complexes.

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Scheme 23 Rh-catalyzed conjugate addition of aryl boronic acids to cyclohex-2-enone.

Scheme 24 Cu-catalyzed conjugate addition of diethylzinc to trans-chalcone.

nucleophilic species, either a reactant or a solvent, ring opening of the cyclopropane and reorganization of the multiple bonds take place in such a way as to lead to the incorporation of a unit of the nucleophile in the nal product (Scheme 25). If the metal catalyst promoting this transformation is capable of driving the reaction cascade with high selectivity and in an enantioselective manner, the synthetic utility of such atom-economic sequence of events is immediately apparent for the preparation of cyclic compounds of signicant molecular complexity. Platinum complexes with P-donors are quite active and chemoselective catalysts for this transformation both in the presence and in the absence of nucleophiles. This gives the choice to terminate the transformation at the stage of the bicyclocyclopropane derivative or to push it further until incorporation of the nucleophile occurs. In a rst paper on this topic, PhBINEPINE 5a was shown to outperform by far any other mono- or bidentate chiral inducer of the pool of P-donors screened for this process in the Pt-catalyzed tandem cycloisomerizationoxyaddition, providing the corresponding oxy-cycloadduct in high chemical yield and in up to 85% ee (Scheme 26: i).47 In this reaction the BINEPINEPt catalyst shows a remarkable substrate tolerance

Platinum catalyzed cycloisomerization and tandem cycloisomerizationoxyaddition or hydroarylation of 1,6-enynes Noble metal complexes are able to promote the cycloisomerization of 1,6-enynes via a sequential multi-step reaction path proceeding through a cyclopropylcarbene intermediate that, in suitable conditions, may terminate in a bicyclic derivative featuring a cyclopropane ring (Scheme 25). While in apolar solvents and in the absence of nucleophiles, this species is the terminal product, when the reaction is run in the presence of a

Scheme 25 Platinum catalyzed cycloisomerization of 1,6-enynes: reaction path.

Scheme 26 Platinum catalyzed cycloisomerization and tandemcycloisomerization of 1,6-enynes.

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and a range of diverse functionalities can be admitted in the starting 1,6-enynes without compromising the outcome of the reaction to a major extent. The specicity of PhBINEPINE 5a in this process is unique and, more important, is not limited to this single case. More recent work has shown that very high enantioselectivities, up to 96% ee, can be obtained when the cycloisomerization is performed in the presence of electron rich arenes or heterocycles such as indoles. In this case the nal product arises from a tandem cycloadditonhydroarylation involving an electrophilic aromatic substitution as the terminal step of the sequence (Scheme 26: ii).48 In this study evidence has been provided that the Pt-catalyst might contain three P-donors in the coordination sphere of the metal and that in principle one equivalent of BINEPINE might suce to enable high stereoselectivities to be obtained. This assumption is corroborated by a report by Marinetti et al. who have performed the Pt-catalyzed cycloisomerization of 1,6-enynes in apolar solvent (toluene) using a preformed cyclometalated carbenePt complex 25 containing one unit of PhBINEPINE 5a as the sole chiral fragment.23 Under these conditions the reaction stops at the stage of the bicyclic cyclopropane derivative (Scheme 26: iii) that can be isolated in good chemical yields and excellent enantioselectivity, up to 97% (absolute conguration was not assigned).

Asymmetric platinum-catalyzed BayerVilliger oxidation of cycloalkanones: regiodivergent kinetic resolution of cyclobutanones The ability of platinum complexes with chiral diphosphines to catalyze the enantioselective BayerVilliger oxidation of ketones with moderate to high stereoselectivities is well documented in the literature.49 Monodentate phosphines are much less ecient chiral inducers than the bidentate chelating counterparts when used in the BV oxidation of achiral ketones. With tert-butylcyclohexanone, for instance, the ee obtained with the preformed bis-aquo cationic Pt-complex containing PhBINEPINE 5a is as low as 16% to be compared with 92% ee of the relevant BINAP complex (Scheme 27).22 In the BV oxidation of unsymmetrical ketones two parallel reaction paths are available for the substrate which lead either to the normal or to the abnormal lactone (NL and AL, respectively). In the presence of Pt-chiral phosphine catalysts, chiral racemic substrates are expected to undergo kinetic resolution and rate dierentiation may be convergent or divergent, meaning that the same enantiomer of the substrate might react at a faster rate in both the competitive reactions leading to NL and to AL (regioconvergent process) or vice versa (regiodivergent process). In the case of Pt/5a complexes, the BV oxidation of two racemic cyclobutanones does proceed through a regiodivergent process, thus enabling very high stereoselectivities for both the lactones to be attained. Notably, in this transformation monodentate P-donors are better suited than bidentate derivatives and PhBINEPINE 5a is better than phosphoramidite 1 (Scheme 28).

Organocatalysis
The use of monophosphines as chiral organocatalysts has become more and more frequent in recent years and the subject has been recently reviewed.50

Scheme 27 Pt-catalyzed BayerVilliger oxidation of achiral ketones.

Scheme 28 Regiodivergent kinetic resolution in BayerVilliger oxidation of chiral racemic cyclobutanones catalyzed by Pt/PhBINEPINE complexes.

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Cycloaddition reactions of activated allenes and alkynes [3+2] cycloaddition. Phosphines are able to catalyze the [3+2] cycloaddition of activated alkynes and allenes to suitable dipolarophiles such as b-substituted a,b-unsaturated enones and N-tosylimines. The reaction involves addition of the phosphorus nucleophile to the central carbon atom of the allene moiety or to the b-carbon of the alkyne as the key step, followed by reaction of the resulting zwitterionic intermediate I (Scheme 29) with an electron-decient unsaturated substrate. The products of the annulation are, respectively, cyclopentenes and 3-pyrrolines which, due to the presence of the double bond, are prone to further, often highly stereoselective, derivatization. Two regioisomers A and B are possible, which arise from a Michael-type addition of the phosphine-adduct I to the electrophilic partner through its g or a carbon respectively (Scheme 29). Synthesis of carbocycles. t-BuBINEPINE 5b catalyzes the asymmetric [3+2] cycloaddition of ethyl-2,3-butadienoate with a wide array of b-substituted a,b-unsaturated enones to give substituted cyclopentenes (Scheme 30).51 These products are generated in good ee (7590%) from both electron-rich and electron-poor chalcone derivatives. In line with the known reactivity of allenes towards nucleophiles, with

Table 3 Selected results obtained in the t-Bu-BINEPINE 5b catalyzed asymmetric [3+2] annulation of ethyl-2,3-butadienoate with b-substituted a,b-unsaturated enones (see Scheme 30) Entry 1 2 3 4 5 R C6H5 C6H5 C6H5 C6H5 C5H11 R0 C6H5 4-ClC6H5 4-OMeC6H5 2-Thienyl C6H5 Yielda (%) 64 76 54 74 39 eeb (%) 88 82 88 90 75 A : Bc 13 : 1 7:1 420 : 1 6:1 420 : 1

a Yield of isolated A and B. b Enantiomeric excess of A. c Absolute conguration of B not assigned.

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electron rich-substrates (entries 3 and 5, Table 3) the reaction is less ecient and two equivalents of allenes instead of 1.2 are required for the reaction to proceed. The prevailing regioisomer A shows the opposite regioselectivity compared to b-unsubstituted a,b-unsaturated enones for which the prevailing regioisomer is B.51 This protocol can be applied to trisubstituted olens thus generating adjacent quaternary and tertiary stereocentres. t-BuBINEPINE 5b is as well ecient when 2-aryl-1,1dicyanoethylenes are used as substrates.52 The corresponding cyclopentenes are obtained as single regioisomers in high yield and with over 70% enantioselectivity in most cases (Scheme 31). Best substrates are olens with heteroaromatic substituents: within this class, 95% ee was scored when 1,1-dicyano-2(2-N-methylindolyl)ethene was reacted with ethyl-2,3-butadienoate at 0 1C.52 Allenylphosphonates represent another class of substrates suitable for the construction of carbocycles through t-Bu BINEPINE 5b promoted [3+2] cycloadditon with a,b-unsaturated esters (Scheme 32).53 Even if the lower reactivity of allenylphosphonates compared to allenic esters requires the application of more drastic conditions, the expected products are obtained with very good selectivity and in moderate yield.53 Synthesis of heterocycles. When arylimines bearing electronwithdrawing N-substituents are used in place of activated olenes, the phosphine promoted [3+2] cycloaddition gives access to functionalized 3-pyrrolines (Scheme 33). In this process Ph and t-BuBINEPINES 5a and 5b were by far more eective in terms of conversion rates and enantioselectivities than any other mono- or bidentate chiral inducer of the pool of P-donors screened.54 The preferred regioisomer arises from electrophilic addition of the imine to the a-position of the zwitterionic phosphonium intermediate followed by cyclisation.55 By proper combination

Scheme 29 Reaction pathway of [3+2] cycloaddition promoted by phosphine catalysts.

Scheme 30 t-BuBINEPINE 5b catalyzed asymmetric [3+2] annulation of ethyl-2,3-butadienoate with b-substituted a,b-unsaturated enones.

Scheme 31 Asymmetric [3+2] cycloaddition of allenes with dicyanoethylenes (absolute conguration of product not assigned).

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Scheme 32 [3+2] cycloaddition of allenylphosphonates with a,b-unsaturated esters.

Scheme 34 Synthesis of spirocyclic compound 40 via asymmetric [3+2] cycloaddition of enones 39.

Table 4 Results obtained in the synthesis of spirocyclic compound 40 via asymmetric [3+2] cycloaddition of enones 39 (see Scheme 34) Entry Cat. 1 2 3 4
a

Product R1 40a 40b 40c 40c

R2

Yield (%) dr 85 : 15 80 : 20 495 : 5 495 : 5

eea (%) 82 86 92 92

(S)-5b (S)-5b (S)-5b (S,S)-41

Et Me 75 t-Bu Me 20 Et t-Bu 50 Et t-Bu 98

The two catalysts display the same sense of chiral induction.

Scheme 33 Asymmetric [3+2] cycloaddition of N-tosyl arylimines with unsaturated esters.

of allenic ester, aryl-substituted tosylimines and BINEPINE, 3-pyrrolines can be obtained with ee up to 86%. The best ees are obtained when the aryl substituent on the imine is either a phenyl or an electron-rich aryl. High levels of asymmetric induction (7392% ee), but at the expenses of reactivity, are obtained by applying t-BuBINEPINE nucleophilic catalyst 5b to the cycloaddition of N-diphenylphosphino (DPP) arylimines and 2-butynoates. The DPP protecting group oers the advantage of being more easily removed than the Ts group from the reaction product.56 3-Pyrrolines can be prepared also from allenylphosphonates under t-BuBINEPINE catalysis 5b but with modest results (2545% yield, 5768% ee).53 Synthesis of spirocyclic compounds. Electron-poor allenes participate in the phosphine-catalyzed [3+2] cycloaddition with 4-substituted 2,6-bis(benzylidene)cycloesanone 39 to aord spirocyclic compounds. Upon reaction with an alkyl allenoate in the presence of either (S,S)-FerroPHANE 41 or t-BuBINEPINE (S)-5b, the substrate undergoes desymmetrization providing the product 40 via a regio-, diastereo- and enantioselective process (Scheme 34).57
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The product 40 results from the formation of a new CC bond at the b-olenic carbon of the substrate and is obtained as a mixture of two diastereomers. The stereoselectivity obtained with BINEPINE (S)-5b compares well with those obtained with FerroPHANE. The latter one, however, is a more ecient catalyst and promotes higher yields (compare entries 3 and 4, Table 4) probably in consequence of a higher electron-donating ability and nucleophilicity. As evinced from the X-ray structure, the major diastereomer of 40a comes from the addition of the allenoate syn to the R2 substituent. Likely, the latter group rests in the equatorial position of the most stable conformer of the substrate and the syn approach of the nucleophile minimizes steric interactions with the axial H-substituent. This might explain the improved enantioselectivities observed with FerroPHANE when increasing the steric bulk of the R2 group from Me-, to i-Pr to t-Bu. The phosphine-mediated [3+2] cycloaddition of alkyl 2,3-butadienoate to 3-alkylideneindolin-2-ones 42 is a valuable procedure for the highly enantioselective synthesis of 3-spirocyclopentane-2-oxindoles 43 (Scheme 35). This scaold is found in several natural alkaloid derivatives and bioactive compounds.58 The stereochemistry of the quaternary carbon at position 3 is the main synthetic challenge in this reaction and the

Scheme 35 Synthesis of spirocyclic compounds 43 via asymmetric [3+2] cycloaddition of 3-alkylideneindolin-2-ones 42.

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Table 5 Selected results obtained in the synthesis of spirocyclic compounds 43 via asymmetric [3+2] cycloaddition of 3-alkylideneindolin2-ones 42: variations of the olen substituent R1 (see Scheme 35) Entry 1 2 3 4 5 6 7 8 9 10 Product 43a 43b 43c 43d 43e 43f 43g 43h 43i 43l R1 C6H5 1-naphthyl 4-C6H4C6H4 4-CF3C6H4 4-ClC6H4 3-BrC6H4 4-MeC6H4 2-Furyl 2-Quinolyl CRCC5H11 Yield (%) 95 98 20 (61) 62 80 82 99 25 (80) 75 38 (56) 43/44 495 : 5 495 : 5 90 : 10 85 : 15 92 : 8 85 : 15 88 : 12 76 : 24 90 : 10 74 : 26 43 ee (%) 499 499a 99 (92) 99 499 499 499 97 (90) 97 97 (86) Scheme 37 Phosphepine catalyzed cycloaddition of phenyl ethyl ketene to dimethyl azodicarboxylate and nitrosobenzene.

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Values within parentheses refer to the use of FerroPHANE 41 under otherwise identical reaction conditions.a (1S,5R) conguration according to X-ray data.

BINEPINE (S)-5b stood out as the most eective catalyst among all the other chiral P-donors screened in this task. The low yields obtained with some of the substrates (entries 3, 8, 10, Table 5) could be improved by the use of FerroPHANE although at the expense of the enantioselectivity. From the X-ray absolute conguration of product 43b it is established that the substrate double bond retains the E-geometry during the cycloaddition. [4+2] cycloadditions Heterocycles. BINEPINE 5b is an eective nucleophilic catalyst for the synthesis of functionalized piperidine derivatives through the Kwon [4+2] cycloaddition59 of imines with 2-allyl substituted 2,3-butadienoate (Scheme 36).60 A range of aryl imines with either electron-rich (Table 6, entry 2), electronpoor (Table 6, entries 3 and 4) or ortho-substituted aromatic groups have been successfully reacted (Table 6, entry 4). Heteroaryl imines are also suitable substrates for this reaction (Table 6, entries 6 and 7). The desired heterocycles are obtained in good yield with excellent enantio- and diastereoselectivity.

[2+2] cycloadditions. t-BuBINEPINE 5b has been tested in the catalytic asymmetric cycloaddition of phenyl ethyl ketene to dimethyl azodicarboxylate and nitrosobenzene to generate aza-b-lactams61 and 1,2-oxazetidin-3-ones62 respectively (Scheme 37). The BINEPINE ligand is able to catalyze this reaction, but in both cases the product is almost racemic. The catalyst of choice for this process turned out to be a planar-chiral ferrocene-based 4-dimethylaminopyridine derivative. Additions of nucleophiles to the c-position of activated alkynes and allenes. Phosphines can catalyze the addition of some carbon, nitrogen and oxygen nucleophiles to the g-position of 2-butynoates and 2,3-butadienoates.63 On suitable substrates the formation of the new bond may generate a new stereogenic centre (Scheme 38). The synthetic utility of these processes may be impaired by the competitive phosphine-catalyzed isomerization of the substrates to the corresponding dienones. C-Nucleophiles. Formation of CC bonds has been achieved using nitromethane and 1,3-dicarbonyl compounds as C-based nucleophiles.

Scheme 36 t-BuBINEPINE 5b promoted Kwon [4+2] annulation of imines with 2-allyl substituted 2,3-butadienoate. Scheme 38 BINEPINE-catalyzed addition of nucleophiles to the g-position of activated alkynes and allenes.

Table 6 Selected results obtained in the t-Bu-BINEPINE 5b promoted Kwon [4+2] annulation of imines with 2-allyl substituted 2,3-butadienoate: scope with respect to the imines (see Scheme 36) Entry 1 2 3 4 5 6 7
a

Ar C6H5 3-MeC6H4 4-ClC6H4 2-(NO2)C6H4 2-Naphthyl 2-Furyl 3-Pyridyl

Yielda (%) 93 98 99 98 96 98 76

cis : trans 91 : 9 93 : 7 91 : 9 96 : 4 93 : 7 87 : 13 91 : 9

eeb (%) 98 98 96 68 99 97 97 Scheme 39 Asymmetric g-addition of a nitromethane to allenes catalyzed by chiral BINEPINES.

Isolated yields.

The ee-value is for the cis diastereomer.

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Scheme 40 PhBINEPINE 5a promoted asymmetric g-addition of malonate esters to g-substituted 2,3-allenoate.

Table 7 Selected results obtained in the Ph-BINEPINE 5a promoted asymmetric g-addition of malonate esters to g-substituted 2,3-allenoate (see Scheme 40)

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Entry 1 2 3 4 5

R1 Me

Yielda (%) 94 88

ee (%) 94 92 93 87 90

Scheme 41 Possible mechanism for the phosphine catalyzed asymmetric g-addition of malonate ester to an activated allene.

(CH2)3Cl (CH2)4TLPS (CH2)4OBn

91 78 78

6 7 8
a

71 (CH2)3CO2Me 77 71 Yield of puried products. Only the E product is observed.

94 94 86

In the addition of nitromethane to a variety of racemic electron-poor allenes (Scheme 39), the amine-substituted BINEPINE 8 aorded the best results in terms of enantioselectivity among several bis- and monophosphines tested as catalysts.64 The reactions proceed with good to excellent yields and stereoselectivities (7397%) under mild conditions. Several functional groups in the R substituent of the allenamides are tolerated and in all cases only the E isomer of the product is observed. Since no kinetic resolution of the starting racemic allene has been noticed in the course of the reaction, the stereochemical bias is determined by enantioface selection. PhBINEPINE 5a turned out to be the catalyst of choice for the asymmetric g-addition of malonate esters to g-substituted 2,3allenoate (Scheme 40) and 2,3-allenamides (Weinreb allenamides) where very high yields (6598%) and enantioselectivities (8595%) have been achieved.65 The formation of the CC bond is compatible with the presence of diverse functional groups in the substrate such as alkynes, halides, ethers, acetals, esters and alkenes (Table 7). At variance with other phosphine catalyzed enantioselective g-addition reactions, in this process kinetic resolution of the allene is observed. From mechanistic investigations a reaction path where addition of the phosphine catalyst to the substrate is the turnover-limiting step can be proposed (Scheme 41). O-Nucleophiles. Chiral tetrahydrofurans and tetrahydropyrans are accessible from a variety of substrates possessing a hydroxy2-alkynoate motif through phosphine-catalyzed intramolecular
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Scheme 42 Asymmetric g-addition of an oxygenated nucleophile catalyzed by chiral monophosphines.

g-addition (Scheme 42).66 Substituents a, b or g to the hydroxy group are tolerated in the reaction thus allowing for structural diversity. In this transformation, t-Bu and PhBINEPINES (S)-5b and (S)-5a are ranked the best eective ligands immediately after the spirophosphocin (S)-45 among a range of mono- and bisphosphines. BINEPINE-promoted intramolecular Michael addition Monophosphines have been exploited by Fu et al. as nucleophilic catalysts in the synthesis of diquinanes 50 from properly functionalized alicyclic substrates through a double-cyclization process (Scheme 43).67 Following a reactivity manifold discovered by Tomita,68 the synthesis is triggered by the conjugated addition of the phosphine to the ynone subunit of the substrate to give intermediate 46 (Scheme 43), which by cross-tautomerization turns into the zwitterionic enolate 47. The latter undergoes intramolecular Michael addition to the unsaturated ester subunit to generate the rst ring as in 48. A second intramolecular addition aords intermediate 49 and eventually, after catalyst release, the desired diquinane 50. In optimal conditions and using PBu3 as nucleophile, the products are obtained with very high diastereoselectivity (dr 4 20 : 1). By applying t-BuBINEPINE 5b, a moderate but encouraging enantioselectivity, 60% ee, could be achieved.67 This is the sole
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Scheme 43 Enantioselective phosphepine-promoted synthesis of diquinanes 50.

Scheme 45 Asymmetric phase transfer catalyzed amination of b-ketoesters.

Scheme 44 Enantiotopo-dierentiating acylation of meso-diols promoted by monodentate phosphines.

example of the enantioselective version of this reaction which provides for the elaboration of fused-ring systems featuring three vicinal stereocentres and one double bond. Desymmetrization of meso-diols. PhBINEPINE 5a has been tested as organocatalyst in the enantiotoposelective monoacylation of cis-1,2-cyclohexane-diol and meso-hydrobenzoin (Scheme 44). In this transformation BINEPINE 5a was a poor inducer and much less ecient than (2S,5S)-dimethyl-1-phenyl-phospholane (S,S)-51, which in this reaction gave the best conversion (up to 84%) and selectivity (up to 81% ee), outperforming the chiral bidentate phosphines used in the screening test.69 Asymmetric phase-transfer catalysts. Quaternary tetraalkylphosphonium salts 52 and 53, prepared by alkylation of the
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Scheme 46 BINEPINE-assisted enantioselective As-stereogenic trisubstituted arsine.

synthesis

of

corresponding phosphepines with butyl bromide, have been used as phase transfer catalysts to mediate the asymmetric amination of cyclic b-keto esters and b-diketones with di-tertbutyl azodicarboxylate (Scheme 45). Under optimized conditions, the expected products have been obtained in quantitative yields and ee ranging from 73 to 95%.70 Chiral auxiliary. The BINEPINE 5t has been exploited as the chiral auxiliary to assist the generation of a stereogenic arsenic centre in the chiral tertiary arsine 54 (Scheme 46).15 The key step in this preparation is the irreversible nucleophilic addition of n-butyllithium to the corresponding diastereomeric phosphepine-stabilized methylphenylarsenium hexauorophosphate salts (Scheme 46). When the reaction is carried out
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at 95 1C in dichloromethane, the chiral arsine 54 is obtained with 70% enantioselectivity. The 2-methoxymethyl substituent in 5t is crucial for a good selectivity to be achieved as with PhBINEPINE 5a the diastereoselectivity in the complex formation is only 16%.

Conclusions and outlook

More than fteen years have passed since the rst preparation of PhBINEPINE 5a was reported in the literature. From that rst report, this fairly simple P-ligand has tremendously expanded its elds of application which at present comprise a wide variety of asymmetric reactions covering metal catalyzed, organocatalyzed, phase transfer catalyzed and stoichiometric asymmetric processes. The versatility displayed by the parent ligand is further supported by the size and the diversity of the library of BINEPINE derivatives built up in recent times and that is still growing. The number of dierent asymmetric processes where BINEPINES have demonstrated their stereorecognitive eciency is pretty wide and for this reason BINEPINE can be considered a multipurpose chiral ligand. Based on previous results, specic elds of transition metal catalyzed reactions where the use of BINEPINES can be recommended are the Rh-catalyzed hydrogenation and transfer hydrogenation of CC double bond; the Pt-catalyzed cycloaddition of 1,6-enynes and the BayerVilliger oxidation of strained ketones; the Pd-catalyzed allylation of aldehydes by umpolung of reactivity. Due to the peculiar electronic properties of these ligands which are characterized by a fairly high electron density at the P-donor in these reactions BINEPINES are expected to perform at the highest level of eciency. The second area where BINEPINES can be recommended for their versatility and their eciency in chiral recognition is in organocatalysis. Their use as chiral catalysts has led to very high yields/stereoselectivities in several cases, particularly in a variety of [3+2] and [4+2] cycloaddition reactions, both in the intra- and inter-molecular fashion. There is little doubt that these good performances are strictly related to the basicity of the P-centre that substantially increases the nucleophilicity of BINEPINES as compared to other monodentate P-donors derived from binaphthol 1, 2 and 3. We can reasonably expect that good results will be achieved by the application of these chiral ligands in similar reactions.

Acknowledgements
EA acknowledges nancial support from the Regione Autonoma della Sardegna, L.R. 7 Agosto 2007, n. 7.

Notes and references

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