DOI: 10.1002/chem.201404731

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Enantiopure Narrow Bite-Angle P OP Ligands: Synthesis and Catalytic Performance in Asymmetric Hydroformylations and Hydrogenations Hctor Fernndez-Prez,[a] Jordi Benet-Buchholz,[a] and Anton Vidal-Ferran*[a, b] In memory of Professor Dr. P. Victory, on the 20th anniversary of his passing. As the PhD supervisor and mentor of A.V.F., his valuable teaching and guidance made a deep and lasting impression on him.

gands enabled very good catalytic properties in the Rhmediated enantioselective hydrogenation and hydroformylation of challenging and model substrates (up to 99 % ee). Whereas for asymmetric hydrogenation the optimal P–OP ligand depended on the substrate, for hydroformylation, a single ligand was the highest-performing one for almost all studied substrates: it contains an R-configured stereogenic carbon atom between the two phosphorus ligating groups, and an S-configured 3,3’-diphenyl-substituted biaryl unit.

Abstract: Herein is reported the preparation of a set of narrow bite-angle P–OP ligands the backbone of which contains a stereogenic carbon atom. The synthesis was based on a Corey–Bakshi–Shibata (CBS)-catalyzed asymmetric reduction of phosphomides. The structure of the resulting 1,1P–OP ligands, which was selectively tuned through adequate combination of the configuration of the stereogenic carbon atom, its substituent, and the phosphite fragment, proved crucial for providing a rigid environment around the metal center, as evidenced by X-ray crystallography. These new li-

Introduction

angle P–OP ligands have received less attention in asymmetric catalysis (Figure 1).[7] The reported examples (1–4) have combined configurationally stable biaryl phosphite groups with diverse phosphine moieties. However, the incorporation of a stereogenic element between the two ligating phosphorus groups remains an understudied structural motif for these ligands; indeed, the only reported examples (ligands 7 a–e) are from a preliminary communication by the present authors, who prepared the key building block 6 for accessing the 1,1P–OP ligands 7 by an unprecedented asymmetric carbonyl re-

The substantial progress made in transition-metal-mediated asymmetric catalysis has been accelerated by the development of new, structurally diverse chiral ligands, which enable high selectivities in myriad transformations.[1] In this context, metal complexes derived from hybrid bidentate phosphorus ligands have proven to be powerful enantioselective catalysts and as such, have undergone major developments in the past decade.[2] Ligands with two different coordinating groups are also very interesting in asymmetric catalysis, as they may enable better stereocontrol than do their C2-symmetric analogues.[3] Amongst these ligands, seminal examples of phosphine–phosphite (P–OP) ligands were described by Takaya[4] and Pringle[5] et al. in the early 1990s. Since then, a rich array of structurally diverse P–OP ligands has been prepared by several research groups, and their unique stereoelectronic properties have been efficiently applied to many homogeneous asymmetric catalytic transformations.[6] However, narrow-bite[a] Dr. H. Fernndez-Prez, Dr. J. Benet-Buchholz, Prof. Dr. A. Vidal-Ferran Institute of Chemical Research of Catalonia (ICIQ) Av. Paı¨sos Catalans 16, 43007 Tarragona (Spain) Fax: (+ 34) 977920228 E-mail: [email protected] [b] Prof. Dr. A. Vidal-Ferran Catalan Institution for Research and Advanced Studies (ICREA) P. Llus Companys 23, 08010 Barcelona (Spain) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201404731. Chem. Eur. J. 2014, 20, 1 – 11

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Figure 1. Reported examples of narrow-bite-angle P–OP ligands.

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Full Paper enantiopure phosphino-alcohol 6, followed by O-phosphorylation, and borane-cleavage. As an extension of their previous work, the authors sought to exploit this strategy to introduce a bulkier tert-butyl substituent at the aforementioned position of the ligand backbone, by using the tert-butyl substituted phosphomide 8[11] as the starting material. Thus, compound 8 was reduced under optimized experimental conditions:[9] slow addition of BH3·DMS to a solution of (R)-Me-CBS catalyst (30 mol %) and 8 in THF at room temperature. This afforded the target borane-protected phosphino-alcohol 9 in 54 % yield and a 59:41 (R/S) enantiomeric ratio (see Scheme 2). The ste-

Scheme 1. Synthetic route to the 1,1-P–OP ligands 7. DABCO = 1,4diazobicyclo[2.2.2]octane.

duction of phosphomide 5, by using the Corey–Bakshi–Shibata (CBS)[8] catalyst and borane as the reducing agent (Scheme 1). The aforementioned methodology enabled the introduction of a stereogenic carbon atom between the phosphine and phosphite groups. The corresponding rhodium complexes of 7 performed efficiently as catalysts in asymmetric hydrogenations and hydroformylations.[9] Seeking to gain a deeper understanding of the catalytic performance of the narrow-bite-angle P–OP ligands in these chemistries and to expand the catalyst diversity,[10] the authors studied the synthesis and catalytic performance of 1,1-P–OP ligands with a stereogenic carbon atom in their backbone. This work, presented here, included: detailed complexation studies of these ligands with standard rhodium precursors for hydrogenations and hydroformylations. Reports on the influence of the different molecular fragments on catalytic performance are also provided.

Scheme 2. Improved synthesis of the 1,1-P–OP ligands 10. BINOL = [1,1’-binaphthalene]-2,2’-diol.

reogenic carbon atom in 9 was unambiguously established to be R-configured by X-ray analysis of the rhodium complex of 1,1-P–OP ligand 11 b, as discussed in the following section.[12] The enantiomeric ratio of 9 could not be further increased by lowering the temperature or through further optimization of the reaction conditions. Thus, 9 was optically enriched by semipreparative HPLC through a chiral stationary phase (Chiralpak IC column): enantiomerically pure borane-protected (R)-9 was obtained in 80 % theoretical yield in gram amounts. Attempts at O-phosphorylation of enantiomerically pure 9 with several enantiopure chlorophosphites by the preliminary synthetic protocol were unsuccessful and led to decomposition of the starting material. Hence, an alternative procedure[7c] was used: one that employs iodophosphites as electrophiles and DABCO both for cleaving the borane complex and for mediating the O-phosphorylation. Thus, through this methodology, the enantiopure BINOL-derived 1,1-P–OP ligands 10 a and 10 b were readily obtained and isolated in good yields (94 and

Results and Discussion Ligand synthesis In the synthetic methodology preliminarily reported by the authors, the 1,1-P–OP ligands 7 were prepared in three synthetic steps (Scheme 1): formation of the borane complex of the &

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Full Paper 80 %, respectively; see Scheme 2). Unfortunately, the O-phosphorylation of the tert-butyl-containing phosphino-alcohol derivative 9 did not proceed with the studied chloro- or iodophosphites derived from sterically hindered 3 and 3’-disubstituted [1,1’-biaryl]-2,2’-diol derivatives. Therefore, analogous ligands to 7 d and 7 e, containing a tert-butyl group rather than a methyl substituent (i.e. 10 c in Scheme 2), were inaccessible from the reported synthetic methodology.

Coordination studies To demonstrate the general ability of bidentate 1,1-P–OP ligands to form stable, well-defined complexes with the rhodium precursors normally used in hydrogenation and hydroformylation reactions, the authors performed coordination studies using P–OP ligands 7 or 10 as model ligands. As rhodium catalyst precursors for hydrogenation, the rhodium complexes derived from the P OP ligands 10 a or 10 b, and [Rh(nbd)2]BF4 (nbd = bicyclo[2.2.1]hepta-2,5-diene) were efficiently synthesized in dichloromethane by using stoichiometric amounts of ligand and rhodium precursor (Scheme 3). The

Figure 2. Crystal structure of the Rh-complex 11 b (ORTEP drawings showing thermal ellipsoids at 30 % probability). The H-atoms and BF4 counterion have been omitted for clarity.

acterized by standard analytical methods (NMR and HRMS) and by single-crystal X-ray analysis (see Scheme 4). However, the complex cis-13 could not be efficiently isolated (yield < 1 %): despite various attempts at recrystallization, only a miniscule amount of material crystalized out from the mother liquor upon standing. Nonetheless, this material was confirmed (by single-crystal X-ray analysis) to be cis13 (see Scheme 4). These coordination studies clearly showed that an excess of 1,1-P–OP ligand relative to rhodium favors formation of the rhodium bischelates 13, which are inactive in hydrogenations.[10c] To elucidate the structure of the active hydroformylation species, the authors performed coordination studies between ligand 7 d (as representative P–OP ligand) and [Rh(k2O,O’-acac)(CO)2] (acac = acetylacetonate). Hydrido–dicarbonyl rhodium complexes [Rh(H)(CO)2(L L’)] (L L’ = bidentate ligand) are generally accepted as the catalytic resting states for the hydroformylation reaction.[14] Hybrid bidentate phosphorus ligands, such as the P–OP ones described here can form four plausible isomers, by coordinating in either a bis-equatorial (A and B) or an equatorial-apical (C and D) fashion (see Figure 3).

Scheme 3. Rh-coordination studies on the 1,1-P–OP ligands 10.

corresponding complexes [Rh(nbd)(10 a)]BF4 (11 a) and [Rh(nbd)(10 b)]BF4 (11 b) were isolated in yields of approximately 90 % (Scheme 3). Furthermore, single crystals of 11 b suitable for X-ray diffraction were obtained, and then analyzed to unambiguously confirm a five-membered chelate coordination mode of the P–OP ligand to the Rh center in a square-planar complex. A narrow bite-angle of 80.76(8)8 was observed (see Figure 2). Also by X-ray analysis, the stereogenic carbon atom attached to the tert-butyl group was unambiguously assigned to have the R-configuration. The authors were also interested in studying the coordination properties of these P–OP ligands at different ligand-torhodium ratios. Thus, studies were done using ligand 7 c as a representative compound. When stoichiometric amounts of P–OP ligand and rhodium precursor were mixed, the only product obtained was the complex [Rh(nbd)(7 c)]BF4 (12), as determined by NMR spectroscopy and X-ray analysis (see Scheme 4). However, the use of a two-fold excess of 7 c with respect to [Rh(nbd)2]BF4 in dichloromethane at room temperature led to a mixture of two rhodium species in a 1.3:1 ratio: the trans- and cis-bischelate complexes [Rh(7 c)2]BF4 (13),[12, 13] respectively, as determined by 31P{1H} and 1H NMR spectroscopy. Interestingly, the complex trans-13 was efficiently isolated in pure form as yellow needles (54 % yield), and then fully charChem. Eur. J. 2014, 20, 1 – 11

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Figure 3. Possible coordination modes of 1,1-P–OP ligands in [Rh(H)(CO)2(P– OP)] complexes.

The desired complex [Rh(H)(CO)2(k2P,P’-7 d)] was generated stepwise. Initially, a slight excess of phosphine–phosphite 7 d was added to a solution of [Rh(k2O,O’-acac)(CO)2] in [D8]toluene under N2. Under these conditions, the neutral rhodium complex [Rh(k2O,O’-acac)(k2P,P’-7 d)] was cleanly formed and characterized by standard spectroscopic techniques. Attempts to isolate this complex by crystallization failed. As 3

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Scheme 4. Rh-coordination studies using the 1,1-P–OP ligand 7 c.

a continuation of the synthesis towards the hydroformylationdrido–dicarbonyl complex, and the presence of variable active complexes, a freshly prepared solution of the aforemenamounts of nonhydrido containing rhodium complexes, are tioned rhodium chelate in [D8]toluene was subjected to 10 bar consistent with literature reports for bisphosphite ligands.[15] of 1:1 CO/H2 (hereafter, syngas) at 40 8C for 18 h. In situ Regardless, the authors reasoned that the rhodium complex 31 byproduct would not be problematic in hydroformylations, in P HP NMR analysis of the resulting solution revealed two sets which it is inactive because it lacks hydrido ligands: its presof signals for two different complexes:[12] one corresponding to ence might simply translate to a lower concentration of the efthe major compound, which was assigned to the desired comfective catalyst than the initial concentration of [Rh(k2O,O’plex [Rh(H)(CO)2(k2P,P’-7 d)]; and the other one associated with a less abundant compound, established as the complex acac)(CO)2]). The coordination experiments are summarized in [Rh(k2O,O’-acac)(CO)(k2P,P’-7 d)]. The structure of each species Scheme 5. was also confirmed by MALDI-MS analysis (positive ionization mode) of the freshly prepared samples. Under the aforementioned reaction conditions, the two rhodium complexes were obtained in a 66:34 ratio, respectively, as measured by 31P NMR spectroscopic analysis. Accordingly to the proposed mixture of rhodium complexes, HP-IR analysis of the sample Scheme 5. Formation of [Rh(H)(CO) {k2P,P’-(P–OP)}] species from [Rh(k2O,O’-acac)(CO) ] 2 2 in toluene under the same conditions showed three and P–OP ligands. CO absorptions (at 1978, 2006, and 2020 cm 1).[12] Attempts at selective formation of the desired hydrido– 1 dicarbonyl rhodium complex, by either extending the catalyst H HP NMR analysis (at 40 8C) of the desired active species incubation time (from 18 to 36 h; product ratio = 83:17) or infor hydroformylations (i.e. [Rh(H)(CO)2(k2P,P’-7 d)]) revealed only creasing the syngas pressure (20 bar of 1:1 CO/H2 ; product one hydrido signal. It appears at high field (d = 8.7 ppm), as a well-resolved doublet-of-doublets-of-doublets.[12] This signal ratio = 74:26), were unsuccessful, although they each led to a moderately higher amount of the target product. The partial showed a very large coupling constant for the trans arrangeconversion of [Rh(k2O,O’-acac)(k2P,P’-7 d)] into the desired hyment between the hydrido and the phosphino groups (the &

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J(H,P) coupling constant values for the phosphine and phosphite groups were determined to be 111 and 26 Hz, respectively). The authors reasoned that, as hydrido ligands normally occupy one of the two apical coordination sites,[16] the phosphino group must be coordinated to the other apical position (isomer C in Figure 3). Accordingly, complexes with the P–OP ligand coordinated to the equatorial–equatorial sites (species A and B in Figure 3) were also excluded.[16]

Rhodium complexes of the 1,1-P OP ligands 7 a or 10 a displayed very good catalytic properties, providing both high catalytic activity (full conversion in most cases) and enantioselectivity (up to 99 % ee) for the substrates tested. Therefore, introduction of a stereogenic carbon atom between the two phosphorus functionalities, together with use of the appropriate phosphite fragment, afforded highly efficient rhodium catalysts for asymmetric hydrogenation of the set of functionalized alkenes. Interestingly, for the substrates 14 a and 14 b, the 1,1P OP ligands 7 d and 7 a gave much higher enantioselectivity Asymmetric hydrogenation of functionalized olefins than did the 1,1-P–OP ligands 1 and 2, which do not contain a stereogenic carbon atom at the oxymethylene bridge.[7b,d] After having succeeded in preparing 1,1-P–OP ligands 7 and These results highlight the extent to which catalyst per10, and having studied their coordination properties with stanformance is dictated by the alkyl substituent in the ligand dard rhodium precursors for this chemistry, the authors then backbone. sought to assess the performance of these ligands in the RhAs revealed by Table 1, the optimal 1,1-P–OP in terms of mediated enantioselective hydrogenation of various prochiral enantioselectivity varied with the substrate. For substrates olefins 14 a–e. The hydrogenation reactions were run under 14 a–e, the best results were obtained by combining an R-constandard screening conditions (1.0 mol % of preformed or in figured stereogenic carbon atom in the ligand backbone, with situ-prepared [Rh(nbd)(P–OP)]BF4 complex as the catalyst prea (Sa)-[1,1’-biaryl]-2,2’-diol-derived phosphite fragment (ee: cursor, 20 bar of H2, THF as solvent, room temperature, and from 94 to 99 %; see Table 1 in the columns for ligands 7 a, 18 h reaction time; see Scheme 6). The results of this compara10 a, and 7 d). However, whilst the highest ee in the hydrogetive study are summarized in Table 1. nation of 14 a was obtained with the ligand 7 d, which contains two phenyl substituents in the 3 and 3’ positions of the phosphite moiety, for substrates 14 b–e the best ligands were 7 a and 10 a, which incorporate a (Sa)-BINOL-derived phosphite fragment. In general terms, the enantioselectivities herein described are high and close to those described for high-performing five-membered RhI-catalysts derived from electron-rich bisphosphines[17] (e.g. tBu-bisP* and QUINOXP* ligands) as well as for other “milestone” ligands[18] in hydrogenation (e.g. DIPAMP or DUPHOS). These results emphasize the importance of the structure of each 1,1-P OP ligand to the enantioselectivity that it provides in the hydrogenation of a given substrate: these ligands showed substrate specificity. This trend contrasts with what was observed with the lead 1,2-P–OP ligand (16) for this Scheme 6. Rhodium-mediated asymmetric hydrogenation of functionalized alkenes mediated by 1,1-P–OP ligands. chemistry (see Figure 4), which consistently provided very high enantioselectivities for substrates 14 a–e.[10a,c] The authors also assessed the same 1,1-P–OP ligands on a b(acylamino)acrylate (14 f). Table 1. Asymmetric hydrogenation of the substrates 14 a–f with the 1,1-P–OP ligands 7 a–e and 10 a–b[a] Though hydrogenation was not Entry Subs. Ligand 7 a[b] Ligand 7 b[b] Ligand 10 a[c] Ligand 10 b[c] Ligand 7 d[b] Ligand 7 e[b] complete under screening condi1 14 a 90 % ee (R) 5 % ee (S) 96 % ee (R) 16 % ee (S) 99 %[d] ee (R) 98 % ee (S) tions (Table 1, entry 6), a notable 84 % ee (R) 95 % ee (S) 95 % ee (R) 83 % ee (S) 85 % ee (R) 2 14 b 97 %[d] ee (S) enantioselectivity of 80 % ee in [d] 80 % ee (S) 98 % ee (R) 94 % ee (S) 93 % ee (R) 61 % ee (S) 3 14 c 94 % ee (R) favor of the (R)-configured hy[e] [d] 4 14 d 93 % ee (R) 50 % ee (S) 94 % ee (R) 80 % ee (S) 79 % ee (R) 56 % ee (S) drogenation product was ob88 %[d] ee (R) 46 % ee (S) 79 % ee (R) 62 % ee (S) 70 % ee (R) 64 % ee (S) 5 14 e[f] 9 % ee (S) 18 % ee (R) 14 % ee (R) 58 % ee (R) 40 % ee (S) 80 % ee (R) 6 14 f[g] tained when ligand 7 e was used. Importantly, this was the [a] The values shown are the average values of at least two independent runs. Hydrogenations were run in a parallel reactor: RT, 20 bar H2, substrate concn = 0.20 m in THF, 18 h. Complete conversions were determined only substrate for which a ligand by 1H NMR spectroscopy unless otherwise indicated (footnotes f–h). ee values were determined by GC or HPLC incorporating an (Ra)-BINOL-deanalysis on chiral stationary phases, as indicated in the Supporting Information. Absolute configurations were rived phosphite fragment proassigned by comparison of the specific rotation with reported data, as indicated in the SI. [b] Reaction condivided the highest enantioselections: [Rh(nbd)2]BF4/P–OP ligand/substrate = 1.0:1.1:100. [c] Reaction conditions: [Rh(nbd)(P–OP)]BF4/substrate = 1.0:100. [d] Results published in reference [9]. [e] Conv.: 92 % for 7 a, 48 % for 7 b, 83 % for 7 d, and tivity. 69 % for 7 e. [f] Conv.: 84 % for 7 e. [g] Substrate 14 f was hydrogenated as a mixture of E/Z isomers in a ratio Computational studies on the 1:2.8. Conv.: 69 % for 7 a, 51 % for 7 b, 54 % for 10 a, 59 % for 10 b, 54 % for 7 d, and 58 % for 7 e. reactivity of rhodium complexes Chem. Eur. J. 2014, 20, 1 – 11

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Figure 4. Structure of the highest-performing 1,2-P–OP ligand (16) for asymmetric hydrogenation.

derived from 1,2-P–OP ligand 16 in asymmetric hydrogenation[10c] have provided a quantitative base to a rationalization of the origin of enantioselection for 1,1-P–OP ligands by quadrant analysis (Figure 5). The 3D structures (provided by X-ray analysis)[19] of the rhodium complexes derived from 1,1-P–OP ligands 7 a and 7 b (i.e. [Rh(nbd)(7 a)]BF4 (17 a) and [Rh(nbd)(7 b)]BF4 (17 b)) have been drawn in octant diagrams, with the rhodium atoms in the center of the two diagrams and the ligands drawn in the back (Figure 5). These diagrams clearly reveal the differences in the conformation of the respective backbones of the ligands 7 a and 7 b, as well as the different orientations of the phenyl groups of the phosphine in each ligand. In the precatalyst 17 a with matched effects, one of the phenyl substituents from the phosphine adopts a face-on pseudo-axial position in the front-upper-right octant, whereas the other has an edge-on pseudo-equatorial orientation in the front-lower-right one (see Figure 5). Interestingly, in the precatalyst 17 b with mismatched effects, the phenyl groups at the phosphine have different orientations: one of them is fixed in a face-on pseudo-equatorial position in the front-upper-right octant, whereas the other occupies an edge-on pseudo-axial orientation in the front-lower-right octant. Theoretical investigations into the reactivity of the 1,2-P–OP &

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Figure 5. Octant diagram models rationalizing the results on Rh-mediated asymmetric hydrogenation of the substrates 14 by using the 1,1-P–OP ligands 7 a–b. a) X-ray structures of complexes [Rh(nbd)(7 a)]BF4 (17 a) and [Rh(nbd)(7 b)]BF4 (17 b), in which the norbornadiene ligands, Csp2 H atoms and BF4 counterions have been removed for clarity. b) Rationalization of the stereochemical outcome of the hydrogenations mediated by [Rh(nbd)(7 a)]BF4 (17 a) and [Rh(nbd)(7 b)]BF4 (17 b). www.chemeurj.org 6  2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Full Paper ligand 16[10c] indicated that asymmetric hydrogenation follows the generally accepted “unsaturated mechanism”[20] instead of the “dihydride”[21] one. Assuming that 1,1-P–OP ligands have the same reactivity than their 1,2-analogues, the two front-right-hand octants would be electronically disfavored for placement of the Ca and Cb olefin carbon atoms of the alkene (double-bond coordination trans to the phosphino group is more favorable).[10c] Steric hindrance in the transition state of the rate- and stereodetermining step (oxidative addition in P–OP-mediated hydrogenations)[10c] arises in the quadrant originally occupied by the Ca olefin carbon.[20] Therefore, placement of this carbon atom in the more accessible lower-left octant—far from the steric congestion of the binaphthyl group—is strongly favored in hydrogenations mediated by rhodium complexes of ligand 7 a (see the left side of Figure 5). The authors would like to emphasize that these octant diagrams only represent a simplified view of the hydrogenation process, or a mnemonic rule, that mainly serves for predicting the sense of stereoinduction: hydrogenation of a-(acylamino)acrylate (14 a), dimethyl itaconate (14 b), the a-arylenamides 14 c and 14 e, and 1-phenylvinyl acetate (14 d) afforded R-, S-,[22] R- and R-configured products, respectively (see Table 1) in high enantioselectivities.[23] On the contrary, in ligand 7 b, placement of the Ca olefin carbon atom in the front-upper-left octant—far from the steric congestion of the binaphthyl group—is favored (see the right side of Figure 5), which accounts for obtaining hydrogenation products with opposite configurations to those obtained with ligand 7 a (see Table 1). Additionally, enantioselectivities obtained with the rhodium catalysts derived from 7 b are consistently lower (and in favor of the other enantiomer) with respect to those observed for 7 a (see Table 1 in the columns corresponding to ligands 7 a and 7 b). This effect reached its maximum when ligand 7 b was used with substrate 14 a (see entry 1 in Table 1). Its substituent at the b-position (R = Ph) sterically interacts with the phenyl substituent of the phosphine group in the front-lower-right octant (see the right side of Figure 5), which could account for the enormous drop in enantioselectivity obtained with the ligands presenting matched and mismatched effects (i.e. 7 a and 7 b, respectively).

Table 2. Optimization of the Rh-mediated asymmetric hydroformylation of vinyl acetate with P–OP ligands 7 a and 7 d.[a]

Entry Lig. L/[Rh] ratio S/C ratio T [8C] Conv. [%][b] b:l ratio[c] ee [%][c] 1 2 3 4 5[d] 6 7

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200 200 100 200 200 200 100

40 40 40 40 40 60 25

53 0 > 99 > 99 94 > 99 61

92:8 n.d. 99:1 99:1 99:1 99:1 99:1

29 (S) n.d. 72 (R) 74 (R) 74 (R) 69 (R) 75 (R)

Interestingly, incubation of the catalyst was not required, which meant that future catalyst screening experiments would be operationally easier (compare entries 4 and 5 in Table 2). Regarding temperature, the authors considered that 40 8C provided the optimal balance between enantioselectivity and conversion (entries 5–7 in Table 2). Thus, based on the aforementioned results, the reaction conditions indicated in entries 1 or 4 in Table 2 were chosen as the optimal ones for future hydroformylation studies. The authors then systematically tested the set of available 1,1-P–OP ligands in the hydroformylation of three benchmark substrates: vinyl acetate (18 a), styrene (18 b), and (allyloxy)trimethylsilane (18 c) (Table 3).[24] Concerning reactivity, for all substrates except styrene (18 b), the rhodium complexes derived from ligands 7 d–e (those of which contain a 3,3’-substituted-octahydrobinol-derived phosphite fragment) performed better than did those derived from 7 a–b or 10 a–b. Regarding the regio- and enantioselectivity, the best results were achieved with ligand 7 d (74 % ee, see entry 1 in Table 3). Moreover, the branched hydroformylation products obtained with P–OP ligands 7 d and 7 e had opposite configurations. This finding indicates that stereodifferentiation by the catalyst is predominantly controlled by the phosphite fragment. The authors also investigated the asymmetric hydroformylations of the challenging 1,2-disubstituted alkenes 18 d and 18 e (Table 3). Briefly, in terms of catalytic performance, the rhodium complexes derived from the 1,1-P–OP ligands generally followed the same trend for substrates 18 d–e as that previously observed for substrates 18 a–c. Ligands 7 d and 7 e provided the best results in terms of activity and regio- and stereoselectivity. For instance, hydroformylation of 18 d with ligand 7 d yielded the 2-carbaldehyde 19 d as the major isomer with good conversion (83 %) and high enantioselectivity (up to 80 % ee; see entry 4 in Table 3), which is close to the highest reported stereoselectivities in the literature (90 % ee by Landis

The authors also evaluated the catalytic properties of the prepared set of 1,1-P–OP ligands in rhodium-mediated asymmetric hydroformylations. A first round of experiments was completed, in which the aim was to identify optimal reaction conditions using 1,1-P–OP ligands 7 a or 7 d, and vinyl acetate (18 a) as a model substrate. The reactions were run using catalysts that had been preformed in situ by mixing [Rh(k2O,O’acac)(CO)2] with either ligand. As reflected in Table 2, the ligand/[Rh] ratio affected the reaction differently for each ligand: increasing it from 1.1 to 4 proved detrimental to catalytic activity for ligand 7 a (compare entries 1 and 2 in Table 2), yet did not affect catalytic activity for ligand 7 d (compare entries 3 and 4 in Table 2). www.chemeurj.org

1.1 4 1.1 4 4 4 1.1

[a] Hydroformylations were run in a parallel reactor under the specified conditions. [b] Determined by 1H NMR spectroscopic analysis. [c] Determined by GC analysis on chiral stationary phases. Absolute configurations were assigned by comparison of the elution orders in GC with reported data, as indicated in the Supporting Information. [d] Incubation time: 23 h at 40 8C under CO/H2 (1:1, 10 bar).

Asymmetric hydroformylation

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7a 7a 7d 7d 7d 7d 7d

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Full Paper Table 3. Asymmetric hydroformylation of substrates 18 a–e with the 1,1-P–OP ligands 7 d–e and 10 a–b.[a]

Entry

Subs.

Ligand 10 a[b]

Ligand 10 b[b]

Ligand 7 d[c]

Ligand 7 e[c]

1

18 a[d]

2

18 b

3

18 c[e]

4

18 d[f]

5

18 e[g]

19 a/20 a: 96:4 19 a: 39 % ee (S) 19 b/20 b: 98:2 19 b: 24 % ee (S) 19 c/20 c: 52:48 19 c: 3 % ee (S) 19 d/20 d: 47:53 19 d: 7 % ee (S) 20 d: 16 % ee (R) 19 d/20 d: 2:98 19 d: 10 % ee (S) 20 d: 4 % ee (S) 18 d: 16 % isom.

19 a/20 a: 97:3 19 a: 47 % ee (S) 19 b/20 b: 96:4 19 b: 34 % ee (R) 19 c/20 c: 65:35 19 c: 20 % ee (R) 19 d/20 d: 48:52 19 d: 30 % ee (S) 20 d: 24 % ee (S) 19 d/20 d: 2:98 19 d: 31 % ee (S) 20 d: 28 % ee (R) 18 d: 14 % isom.

19 a/20 a: 99:1 19 a: 74 % ee (R) 19 b/20 b: 99:1 19 b: 54 % ee (S) 19 c/20 c: 81:19 19 c: 36 % ee (S) 19 d/20 d: 58:42 19 d: 80 % ee (R) 20 d: 78 % ee (R) 19 d/20 d: 1:99 19 d: n.d. 20 d: 60 % ee (S) 18 d: 0 % isom.

19 a/20 a: 99:1 19 a: 69 % ee (S) 19 b/20 b: 99:1 19 b: 30 % ee (R) 19 c/20 c: 82:18 19 c: 43 % ee (R) 19 d/20 d: 55:45 19 d: 78 % ee (S) 20 d: 76 % ee (S) 19 d/20 d: 1:99 19 d: n.d. 20 d: 72 % ee (R) 18 d: 0 % isom.

suming that the hydrogen and formyl groups add across the olefin from the metal side (see Figure 6). For monosubstituted olefins (18 a–c) R2 is an H atom and R1 occupies the front-lowerleft octant, which yields the experimentally observed configurations in the resulting aldehydes. Moreover, the octant diagram in Figure 6 is also consistent with the direction of approach of the cyclic olefins 18 d–e, in which R1 and R2 are either an alkyl or oxygen substituent, as indicated for each substrate in Figure 6.

Conclusion

A synthesis of 1,1-P–OP ligands, which differ by the substituent at the stereogenic carbon atom in their backbone and by their [a] Hydroformylations were run in a parallel reactor under the specified conditions. Complete conversions were determined by 1H NMR spectroscopic analysis unless otherwise indicated (see footnotes d–g). ee values were phosphite fragment, has been determined by GC analysis on chiral stationary phases. Absolute configurations were assigned by comparison developed. The intermediates for of the elution orders in GC analysis with reported data, as indicated in the Supporting Information. [b] Reaction their preparation are obtained 2 2 conditions: [Rh(k O,O’-acac)(CO)2]/P–OP ligand/substrate = 0.5:0.55:100. [c] Reaction conditions: [Rh(k O,O’by asymmetric carbonyl reducacac)(CO)2]/P–OP ligand/substrate = 0.5:2.0:100. [d] Conv.: 64 % for 10 a and 73 % for 10 b. [e] Conv.: 60 % for 10 a, and 42 % for 10 b. [f] Conv.: 39 % for 10 a, 50 % for 10 b, 83 % for 7 d, and 84 % for 7 e. [g] Conv.: 97 % for tion of the corresponding phos10 a and 98 % for 10 b. phomides by using the Corey– Bakshi–Shibata catalyst and borane as the reducing agent. Coordination studies on the 1,1-P–OP ligands used with rhoet al.[25a] and 92 % ee by Zhang et al.[25b]). In another example, dium precursors afforded several rhodium complexes. The Xhydroformylation of 18 e by using ligand 7 e proceeded ray crystal structure of these complexes confirmed their smoothly, forming 3-carbaldehyde 20 d with complete regiosenarrow natural bite-angle, which provides a congested asymlectivity and decent enantioselectivity (72 % ee; see entry 5 in Table 3), though lower than the highest one reported for this metric environment around the metal center. The catalytic performance of the rhodium complexes desubstrate (95 % ee by Landis et al.[25a]). In summary, rhodium rived from the 1,1-P–OP ligands has been investigated in enancomplex of 7 d, which combines a methyl substituent at the tioselective hydrogenations and hydroformylations of various stereogenic carbon atom and a (Sa)-3,3’-diphenylstructurally diverse alkenes. Overall, very high enantioselectivi5,5’,6,6’,7,7’,8,8’-octahydro-[1,1’-binaphthalene]-2,2’-diol-derived ties were obtained. For asymmetric hydrogenation, the best phosphite, consistently provided the highest regio- and stereocatalyst (i.e. the optimal combination of substituent at the steselectivities for the whole set of studied substrates. reogenic carbon atom of the ligand, and phosphite moiety) In the previous section, the authors report that the reaction was substrate-dependent. In contrast, for enantioselective hyof ligand 7 d and [Rh(k2O,O’-acac)(CO)2] under CO/H2 pressure droformylation the best catalyst was always the one based on at 40 8C gave only one detectable rhodium hydride complex ligand 7 d, regardless of the substrate. In both cases, the sub([Rh(H)(CO)2(k2P,P’-7 d)]), in which the hydrido and the phosphistituent at the stereogenic carbon atom proved to be crucial no groups are coordinated to the apical positions; the phosfor high stereoselectivity. phite group is coordinated to one of the equatorial coordinaSimple octant analysis was used to identify the accessible tion sites, and two carbonyl groups occupy the remaining co(and inaccessible) directions of approach of the substrate to ordination sites (see Figure 6). The stereochemical outcome for the metal center during the catalytic event in hydrogenation asymmetric hydroformylation can be qualitatively rationalized or hydroformylation. This mnemonic rule enables prediction of through simple octant analysis, which should be regarded as the stereochemical outcome of the reactions. purely mnemonic. The two front-upper octants are blocked by In conclusion, the authors of this article have validated a set electronic factors that control the regioselectivity and favor of catalysts derived from 1,1-P–OP ligands that contain a stealignment of the Ca and Cb olefin carbon atoms with the rhodireogenic carbon atom at their backbone in hydrogenations um center and the hydrido ligand, respectively.[26] The absolute and hydroformylations. They are currently screening these liconfigurations of the branched aldehydes can be predicted as&

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Full Paper Experimental Section General procedure for Rh-mediated asymmetric hydrogenations In a glove box, a solution of [Rh(nbd)2]BF4, the P–OP ligand (10 % molar excess relative to the rhodium precursor), and the corresponding functionalized alkene (one of substrates 14 a–f; 0.10 mmol) in anhydrous degassed THF (0.50 mL) was prepared inside a glass vessel under a N2 atmosphere. In all cases the molar concentration of a given substrate in the reaction medium was adjusted to 0.20 m. Once the reaction mixture had been loaded, the glass vessel was placed into one of the holes of a steel autoclave reactor (HEL Cat-24 parallel pressure multi-reactor). The autoclave was purged three times with H2 (at a pressure not higher than the selected one) and finally, the autoclave was pressurized under the required pressure of H2 gas (20 bar H2). The reaction mixture was stirred at room temperature for 18 h (overnight reaction). The autoclave was subsequently depressurized slowly, and the reaction mixture was filtered through a short pad of SiO2 and eluted with EtOAc (1.0 mL). The resulting solution was concentrated under vacuum. The conversion was determined by 1H NMR spectroscopy, and the enantiomeric excess was determined by GC or HPLC analysis on chiral stationary phases.

General procedure for Rh-mediated asymmetric hydroformylations In a glove box, a solution of the required amount of [Rh(k2O,O’acac)(CO)2], the P–OP ligand, and the corresponding substrate (0.15 mmol) in anhydrous degassed toluene (0.30 mL) was prepared inside a glass vessel under a N2 atmosphere. In all cases the molar concentration of a given substrate in the reaction medium was adjusted to 0.50 m. Once the reaction mixture had been loaded, the glass vessel was placed into one of the holes of a steel autoclave reactor (HEL Cat-24 parallel pressure multi-reactor). The autoclave was purged three times with syngas (1:1 H2/CO at a pressure not higher than the selected one), and then the autoclave was pressurized under the required pressure of syngas (10 bar syngas). The reaction mixture was stirred at 40 8C (oil bath) for 18 h. The reaction was cooled, and the pressure was carefully released in a well-ventilated hood. The conversion was determined by 1H NMR spectroscopy, and the enantiopurity and regioselectivities for the hydroformylation products were determined by GC analysis on chiral stationary phases (without further sample treatment).

Crystallography Single crystals of enantiopure compounds 11 b, 12, trans-13, and cis-13 suitable for X-ray diffraction analysis were grown by slow diffusion of Et2O into DCM solutions of each compound at room temperature. CCDC 1017556, 1017557, 1017558 and 1017559 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

Figure 6. Octant diagram model rationalizing the results on Rh-mediated asymmetric hydroformylation of 18 a–e by using 1,1-P–OP ligand 7 d.

Acknowledgements

gands in new and challenging metal-mediated transformations, and will report the relevant results in due course.

The authors thank MINECO (grant CTQ2011–28512), DURSI (grant 2014SGR618), and the ICIQ Foundation for financial support. Dr. S. Curreli is acknowledged for her assistance in semipreparative HPLC and Dr. J. L. NuÇz-Rico for 3D graphics. Chem. Eur. J. 2014, 20, 1 – 11

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Full Paper [14] a) D. Evans, J. A. Osborn, G. Wilkinson, J. Chem. Soc. A 1968, 3133 – 3142; b) C. K. Brown, G. Wilkinson, J. Chem. Soc. A 1970, 2753 – 2764; c) G. Yagupsky, C. K. Brown, G. Wilkinson, J. Chem. Soc. A 1970, 1392 – 1401; d) R. Franke, D. Selent, A. Boerner, Chem. Rev. 2012, 112, 5675 – 5732. [15] G. J. H. Buisman, E. J. Vos, P. C. J. Kamer, P. W. N. M. van Leeuwen, J. Chem. Soc. Dalton Trans. 1995, 409 – 417. [16] a) A. van Rooy, P. C. J. Kamer, P. W. N. M. van Leeuwen, K. Goubitz, J. Fraanje, N. Veldman, A. L. Spek, Organometallics 1996, 15, 835 – 847; b) S. H. Chikkali, J. I. van der Vlugt, J. N. H. Reek, Coord. Chem. Rev. 2014, 262, 1 – 15. [17] a) T. Imamoto, J. Watanabe, Y. Wada, H. Masuda, H. Yamada, H. Tsuruta, S. Matsukawa, K. Yamaguchi, J. Am. Chem. Soc. 1998, 120, 1635 – 1636; b) T. Imamoto, K. Tamura, Z. Zhang, Y. Horiuchi, M. Sugiya, K. Yoshida, A. Yanagisawa, I. D. Gridnev, J. Am. Chem. Soc. 2012, 134, 1754 – 1769. [18] a) B. D. Vineyard, W. S. Knowles, M. J. Sabacky, G. L. Bachman, D. J. Weinkauff, J. Am. Chem. Soc. 1977, 99, 5946 – 5952; b) M. J. Burk, J. Am. Chem. Soc. 1991, 113, 8518 – 8519. [19] The X-ray structures of [Rh(nbd)(7 a)]BF4 and [Rh(nbd)(7 b)]BF4 have previously been published (see ref. [9]). However, suitable crystals for X-ray analysis of [Rh(nbd)(7 d)]BF4 and [Rh(nbd)(7 e)]BF4 could not be obtained; consequently, there were no X-ray data on which to discuss rhodium precatalysts derived from ligands with substituents at the 3 and 3’ positions of the [octahydro-1,1’-biaryl]-2,2’-diol moiety. Furthermore, the structure-activity relationships based on X-ray data for the tert-butyl containing rhodium precatalyst [Rh(nbd)(10 b)]BF4 have been omitted, as they were redundant with those mentioned in the manuscript for the methyl-substituted analogue [Rh(nbd)(7 b)]BF4. [20] a) C. R. Landis, P. Hilfenhaus, S. Feldgus, J. Am. Chem. Soc. 1999, 121, 8741 – 8754; b) S. Feldgus, C. R. Landis, J. Am. Chem. Soc. 2000, 122, 12714 – 12727; c) C. R. Landis, S. Feldgus, Angew. Chem. Int. Ed. 2000, 39, 2863 – 2866; Angew. Chem. 2000, 112, 2985 – 2988; d) S. Feldgus, C. R. Landis, Organometallics 2001, 20, 2374 – 2386. [21] For a review on this alternative mechanism for rhodium-mediated hydrogenations, see: I. D. Gridnev, T. Imamoto, Acc. Chem. Res. 2004, 37, 633 – 644. The “dihydride” route is favored in hydrogenations involving electron-rich alkyl-phosphines, and is not related to hydrogenations involving P – OP ligands. [22] The change to the S-configuration in the hydrogenation product of dimethyl itaconate is due to an inversion in the CIP priority rules. [23] The aforementioned mechanistic premises are no longer valid for (bacylamino)acrylates. See references [20a–d]. [24] Hydroformylation results for ligands 10 a and 10 b are reported for the first time in the present manuscript, whereas the remaining results were already published in the preliminary communication but have been included here for the sake of comparison. [25] a) T. T. Adint, G. W. Wong, C. R. Landis, J. Org. Chem. 2013, 78, 4231 – 4238; b) K. Xu, X. Zheng, Z. Wang, X. Zhang, Chem. Eur. J. 2014, 20, 4357 – 4362. [26] A. L. Watkins, C. R. Landis, J. Am. Chem. Soc. 2010, 132, 10306 – 10317.

Keywords: hydroformylation · hydrogenation · ligand design · P ligands · rhodium [1] a) Comprehensive Asymmetric Catalysis, Vol. I-III (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer-Verlag, Heidelberg, 1999; b) Comprehensive Chirality, Vol. 1 – 9 (Eds.: E. M. Carreira, H. Yamamoto), Elsevier Science Oxford, 2012. [2] a) Phosphorus Ligands in Asymmetric Catalysis, Vol. I-III (Ed.: A. Boerner), Wiley-VCH, Weinheim, 2008; b) J. Wassenaar, J. N. H. Reek, Org. Biomol. Chem. 2011, 9, 1704 – 1713; c) S. Lhr, J. Holz, A. Boerner, ChemCatChem 2011, 3, 1708 – 1730. [3] A. Pavlov, T. N. Pavlova, Russ. Chem. Rev. 2012, 81, 823 – 854. [4] N. Sakai, S. Mano, K. Nozaki, H. Takaya, J. Am. Chem. Soc. 1993, 115, 7033 – 7034. [5] M. J. Baker, P. G. Pringle, J. Chem. Soc. Chem. Commun. 1993, 314 – 316. [6] H. Fernndez-Prez, P. Etayo, A. Panossian, A. Vidal-Ferran, Chem. Rev. 2011, 111, 2119 – 2176 and the references cited therein. [7] a) C. G. Arena, D. Drommi, F. Faraone, Tetrahedron : Asymmetry 2000, 11, 2765 – 2779; b) G. Farkas, S. Balogh, J. Madarasz, A. Szoellosy, F. Darvas, L. Uerge, M. Gouygou, J. Bakos, Dalton Trans. 2012, 41, 9493 – 9502; c) G. M. Noonan, J. A. Fuentes, C. J. Cobley, M. L. Clarke, Angew. Chem. Int. Ed. 2012, 51, 2477 – 2480; Angew. Chem. 2012, 124, 2527 – 2530; d) P. Kleman, M. Vaquero, I. Arribas, A. Suarez, E. Alvarez, A. Pizzano, Tetrahedron: Asymmetry 2014, 25, 744 – 749; e) J. R. Lao, J. Benet-Buchholz, A. Vidal-Ferran, Organometallics 2014, 33, 2960 – 2963. [8] a) E. J. Corey, R. K. Bakshi, S. Shibata, J. Am. Chem. Soc. 1987, 109, 5551 – 5553; b) In the last stages of the preparation of this manuscript, Hayashi et al. published an analogous asymmetric reduction of phosphomides, see: M. Hayashi, H. Ishitobi, Y. Matsuura, T. Matsuura, Y. Watanabe, Org. Lett. 2014, DOI: 10.1021/ol5024757. [9] H. Fernndez-Prez, J. Benet-Buchholz, A. Vidal-Ferran, Org. Lett. 2013, 15, 3634 – 3637. [10] a) H. Fernndez-Prez, M. A. Perics, A. Vidal-Ferran, Adv. Synth. Catal. 2008, 350, 1984 – 1990; b) S. M. A. Donald, A. Vidal-Ferran, F. Maseras, Can. J. Chem. 2009, 87, 1273 – 1279; c) H. Fernndez-Prez, S. M. A. Donald, I. J. Munslow, J. Benet-Buchholz, F. Maseras, A. Vidal-Ferran, Chem. Eur. J. 2010, 16, 6495 – 6508; d) H. Fernndez-Prez, P. Etayo, J. L. NfflÇez-Rico, A. Vidal-Ferran, Chim. Oggi 2010, 28, XXVI – XXVIII; e) J. L. NfflÇez-Rico, H. Fernndez-Prez, J. Benet-Buchholz, A. Vidal-Ferran, Organometallics 2010, 29, 6627 – 6631; f) A. Panossian, H. Fernndez-Prez, D. Popa, A. Vidal-Ferran, Tetrahedron: Asymmetry 2010, 21, 2281 – 2288; g) P. Etayo, J. L. NfflÇez-Rico, H. Fernndez-Prez, A. Vidal-Ferran, Chem. Eur. J. 2011, 17, 13978 – 13982; h) P. Etayo, J. L. NfflÇez-Rico, A. VidalFerran, Organometallics 2011, 30, 6718 – 6725; i) J. L. NfflÇez-Rico, P. Etayo, H. Fernndez-Prez, A. Vidal-Ferran, Adv. Synth. Catal. 2012, 354, 3025 – 3035; j) P. Etayo, A. Vidal-Ferran, Chem. Soc. Rev. 2013, 42, 728 – 754; k) J. L. NfflÇez-Rico, A. Vidal-Ferran, Org. Lett. 2013, 15, 2066 – 2069; l) J. L. NfflÇez-Rico, H. Fernndez-Prez, A. Vidal-Ferran, Green Chem. 2014, 16, 1153 – 1157. [11] E. Lindner, G. Vordermaier, Chem. Ber. 1979, 112, 1456 – 1463. [12] See the Supporting Information for further details. [13] The cis notation indicates a cis-arrangement of the phosphine atom in one P–OP molecule in the bischelate with the phosphine group of the other P–OP molecule, whilst the trans notation indicates a trans- arrangement of these groups.

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Full Paper

FULL PAPER & Catalysis H. Fernndez-Prez, J. Benet-Buchholz, A. Vidal-Ferran* && – && Ligand design: Narrow-bite-angle P–OP ligands incorporating a stereogenic carbon atom in their backbone have been synthesized by Corey–Bakshi–Shibata (CBS)-catalyzed asymmetric reduction of the corresponding intermediates

followed by O-phosphorylation. Rhodium complexes of these ligands provided very good catalytic performance in hydroformylations and hydrogenations (see scheme).

Enantiopure Narrow Bite-Angle P OP Ligands: Synthesis and Catalytic Performance in Asymmetric Hydroformylations and Hydrogenations

Narrow-bite-angle 1,1-P–OP ligands… …containing a stereogenic carbon atom in the backbone have been developed. In their Full Paper on page && ff., A. Vidal-Ferran et al. describe the application of these ligands in rhodium-catalyzed hydroformylations and hydrogenations.

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Enantiopure narrow bite-angle P-OP ligands: synthesis and catalytic performance in asymmetric hydroformylations and hydrogenations.

Herein is reported the preparation of a set of narrow bite-angle P-OP ligands the backbone of which contains a stereogenic carbon atom. The synthesis ...
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