Antonin Jaillet

Christophe Darcel

Jérôme Bayardon

Adrien Schlachter

Christine Salomon

Yoann Rousselin

Pierre D Harvey

Sylvain Jugé
email: sylvain.juge@u-bourgogne.fr

Design of P-Chirogenic Aminophosphine-Phosphinite (AMPP*) Ligands at both Phosphorus Centers: Origin of Enantioselectivities in Pd-Catalyzed Allylic Reactions

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

INTRODUCTION

The chirality in phosphines used in enantioselective metal-catalyzed or organocatalyzed reactions has overwhelmingly been located on the carbon skeleton. [1][2][3] If the efficiency of P-chirogenic ligands is also documented, 4 the design of chiral ligands at the phosphorus centers has largely been neglected due to the lack of versatile methods to efficiently design series of catalysts and to obtain their enantiopure stereoisomers.

Although the use of P-chirogenic compounds in organocatalyzed asymmetric reactions is also known for several decades, 3 their applications also recently increased significantly. 5 Consequently and unsurprisingly, the design of P-chirogenic compounds (and not only phosphines) is still a very active research area for the development of enantioselective catalyzed reactions. So far, the stereoselective synthesis of P-chirogenic organophosphorus compounds was usually achieved by P-C bond formation. This was done using a limited number of P-chirogenic tetracoordinated building blocks, such as tbutylmethylphosphine-borane, secondary phosphine-oxide or phosphinous-borane derivatives. 4 Chiral aminophosphine phosphinites (AMPP) such as 1-8, represent a large family of readily available bidendate ligands in asymmetric catalysis (Chart 1). 6 These ligands are obtained from the reaction between two equivalents of Ph 2 PCl or (c-pent) 2 PCl with commercially available amino alcohols such as ephedrine, threoninol, 7a prolinol, 7b valinol, 7c propranolol, 7d 1,2-diphenyl aminoethanol, 7e,f 2-indoline-methanol 7g,h or azabicyclo[2.2.1]hept-3-ylmethanol. 7i AMPP ligands 2-8 are excellent for the asymmetric hydrovinylation of cyclohexadiene, 7a [2+2+2] cycloaddition, 7b,c hydrogenation of C=C 7d-f,i or

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Chart 1. Representative Chiral Aminophosphine-Phosphinite (AMPP) ligands

The EPHOS ligand 1 derived from (-)-ephedrine, described in pioneering works by B.

Petit and G. Buono, 8a led to moderate enantioselectivities in asymmetric hydrogenation, 8b hydroformylation, 8c,d hydrosilylation 8e and allylation 8f catalyzed by Pt-, Rh-or Pd-complexes, respectively. During the past decade, we and Vogt group have independently described the synthesis of two series of modified EPHOS ligands 13 and 16 with P-chirogenic phosphorus centers (Scheme 1). 9,10 So far, a large series of P-chirogenic modified EPHOS ligands 13 (AMPP*) has been synthesized from the oxazaphospholidine-borane (-)-or (+)-10. They were derived from (+)-or (-)-ephedrine 9 based on a well-established methodology (Scheme 1). 9,10 Thus, the borane complex (-)-10 reacted with organolithium reagents (R 1 Li) to afford the lithium salts

Scheme 1. Stereoselective Synthesis of Modified EPHOS with P-chirogenic P-Centers

[11] by a ring opening reaction upon P-O bond cleavage. The salts [11] were successively trapped with a chlorophosphine R' 2 PCl then with borane to produce the AMPP*-diborane complexes 12, and then isolated as air-stable and storable compounds (Scheme 1a). The free AMPP* 13 finally obtained after borane decomplexation of their corresponding diborane complexes 12 with DABCO, yielded up to 73% from ephedrine (Scheme 1a). This methodology permitted to synthesize numerous P-chirogenic AMPP* ligands 13 with R 1 = alkyl, cycloalkyl, aryl, bisaryl, heteroaryl or ferrocenyl and R' = phenyl-, -naphtyl-or 3,5-

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The Journal of Organic Chemistry xylyl-substituents on the aminophosphine and phosphinite moieties, respectively (Scheme 1a). 9,10 Similarly, the AMPP* ligands 13u-w bearing o-biphenyl, calix [4]arenyl and 1,1'binaphth-2-yl substituents on the P-chirogenic aminophosphine moiety were prepared using the same methodology, but starting from (-)-ephedrine 9 (Scheme 2 and Supporting Information, SI). 9c For instance of their efficiency in asymmetric catalysis, the rhodium(I) complex with the P-chirogenic AMPP* 13a ligand bearing an o-anisyl group on the aminophosphine moiety (i.e. R 1 = o-An), efficiently promoted the asymmetric hydrogenation of dehydrophenylalanine with 99% e.e. 9a When the ring opened products

[11] reacted with P-chirogenic chlorophosphine-boranes 14, the resulting AMPP*diboranes 15 were obtained with inversion of configuration at the phosphorus atom. After decomplexation by DABCO, the free P-chirogenic ligands 16 were diastereoselectively obtained with the chirality located on either the phosphinite or both aminophosphine and phosphinite moieties (Scheme 1b). 9a,b However, the design of the phosphinite moiety in AMPP* 16 based on this methodology is limited. This is because the reaction of the products [11] with P-chirogenic chlorophosphine-boranes 14 bearing other substituents R 2 , R 3 than o-anisyl, phenyl or methyl group was proven to be difficult (Scheme 1b). In this case, the reaction of the secondary alkoxide salts [11] with the chlorophosphine-boranes 14 led to epimeric AMPP* mixtures 16 with low yields due to the poor reactivity and the racemization of 14 in the medium (Scheme 1b). 11 We have recently discovered an unexpected stereospecific intramolecular rearrangement of free P(III)-chirogenic aminophosphine {R 1 R 2 PN(R)-OH} derived from chiral 1,2aminoalcohols into their corresponding phosphinites {R 1 R 2 PO-NH(R)}. 12 This rearrangement obtained by stereospecific N→O phosphinyl migration, has been used for the synthesis of AMPP* ligands 20 bearing a P-chirogenic phosphinite moiety. As proof of the method efficiency, the stereoselective synthesis of four epimers of the o-biphenyl containing AMPP* ligands 13f,i and 20f,i, was herein reported with (R p )-or (S p )configuration either on aminophosphine or phosphinite moieties. Finally, the P-chirogenic AMPP* ligands 13 and 20 has been investigated in asymmetric palladium-catalyzed allylic reactions and the resulting enantioselectivities (R or S), based on the P-chirality in the metal-sphere of coordination, were explained by DFT computations.

RESULTS AND DISCUSSION

Due to the atropoisomery of the binaphtyl substituent, the preparation of the AMPP* 13v warrants a particular attention (Scheme 2). The synthesis was achieved by reacting oxazaphospholidine-borane (+)-10a (prepared from (-)-ephedrine) with the 1,1'-binaphth-2- yllithium reagent (prepared by a metal-halide exchange of (±)-2-bromobinaphtyl 17 with t-BuLi), at -78°C in THF (Scheme 2). The aminophosphine-borane 11v was obtained in 38% yield as a mixture of stereoisomers in 85:15 ratio. The major isomer of 11v was isolated by crystallisation in ethyl acetate and its structure was established by X-ray diffraction. This latter showed that the absolute configuration at the phosphorus center was S p when the atropoisomeric binaphtyl moiety was M (see SI). The diastereoselectivity was explained by the dynamic resolution of the binaphtyllithium reagent during the reaction with the oxazaphospholidine-borane (+)-10a leading to the ring-opened product 11v (Scheme 2). [START_REF]C{ 1 H} NMR (100.6 MHz[END_REF] The aminophosphine-borane (M,S p )-11v was then deprotonated with n-BuLi at -78°C, to afford the corresponding alkoxide salt [11v] which was trapped with Ph 2 PCl then with borane to form the AMPP*-diborane complex 12v in 41% yield. The free diastereomerically pure AMPP* (M,S p )-13v was isolated in 85% yield after decomplexation of the diborane complex 12v upon heating with DABCO in toluene at 50 °C overnight, and purification on a neutral alumina column. The phosphinites 19 could be isolated either under a P-free form or after complexation with borane. They were directly used without purification for the synthesis of the AMPP* 20 bearing a P-chirogenic phosphinite moiety. They reacted with the chlorodiphenylphosphine in presence of triethylamine at room temperature (Scheme 3). The free AMPP* ligands 20

were isolated from the reaction medium, but they were usually complexed by boranedimethylsulfide and then stored as diborane complexes 21 (Scheme 3). The P-chirogenic AMPP* 20 were obtained as free ligands directly usable in asymmetric catalysis, in contrast with the synthetic method reported in Scheme 1. AMPP* 20 , their [START_REF] Holz | P-Chirogenic Xantphos Ligands and related ether diphosphines: Synthesis and application in rhodium-catalyzed asymmetric hydrogenation[END_REF] P NMR chemical shifts and their diborane complexes 21, are reported in Table 1. The efficiency of the method was demonstrated by the stereoselective synthesis of all (R p )-and (S p )-epimers of the free o-biphenyl-containing AMPP* ligands 13f,i and 20f,i, bearing a P-chirogenic center either at the aminophosphine or phosphinite moiety. These epimers were prepared from the oxazaphospholidine-borane complexes (-)-10a and (-)-10b derived from (+)-ephedrine 9 (Scheme 4). The latter complex (-)-10b was prepared in a diastereomerically pure form according to a modified litterature procedure. alkylation led to many elegant applications in organic synthesis and the fine design of efficient chiral ligands is still topical. 16,[START_REF] Fournier | Palladium-catalyzed asymmetric allylic alkylation of cyclic dienol carbonates: efficient route to enantioenriched -butenolides bearing an all-carbon -quaternary stereogenic center[END_REF] This asymmetric catalysis proceeds by nucleophilic attacks to the -allylic moiety formed upon complexation to palladium, which led Trost group to develop efficient pocket-shaped ligands supported by a chiral 1,2-diamine bridge. 16 Although P-chirogenic ligands, such as 22 to 26, led also to highly enantioselective allylic catalyzed allylation with e.e.> 95%, [18][19][20][21][22] the design of phosphines at the P-centers for this reaction was rarely performed and few structural elements allowed the prediction of their stereoselectivity (Chart 2). This outcome could be explained by a limited level of understanding of the influence of chirality located on the P-atoms on the environment of the -allylic moiety. Given the homochirality of the twenty nine P-chirogenic AMPP* 13 and 20 synthesized herein, they were investigated in Pd-catalyzed allylic alkylation reactions. This was to determine the relationship between their structure and the enantioselectivity (R) or (S) obtained. The allylation reaction of dimethyl malonate was first examined with the allylic substrate 27, using 1-2 mol% of [Pd(C 3 H 5 )Cl] 2 and 2-4 mol% of AMPP* 13 or 21 as in situ generated catalyst, in the presence of 2 equiv. of N,O-bis(trimethylsilyl)acetamide (BSA) in dichloromethane, and a catalytic amount of potassium acetate as base (Tables 2 and3).

According to the AMPP* used, the reactions were usually completed within 1 to 48 h at room temperature to afford the mono allylated malonate 28, in isolated yields up to 92%

(Table 2). The dependence of the reaction conditions on the allylation showed a moderate effect on the enantioselectivity (see SI).

The catalyzed allylic substitution of the (E)-1,3-diphenylprop-2-en-1-yl acetate 27 by palladium AMPP* complexes, was also investigated using benzylamine as the nucleophile.

The reactions were performed at room temperature in dichloromethane, using TBAF as base, affording the corresponding allylated benzylamine 29 in 7 h. The results on the catalyzed asymmetric allylations using the P-chirogenic AMPP* 13 and 21 are respectively summarized in Tables 2 and3. Reference 8f. f Test not realized. g Prepared from (-)-ephedrine 9.

EPHOS ligand 1 (R 1 , R, R' = Ph) bearing achiral aminophosphine and phosphinite moieties used in the Pd-catalyzed asymmetric allylation of malonate and benzylamine, exhibited moderate enantioselectivities of 42% 8f and 27% e.e. for products (S)-28 and (R)-29, respectively (Table 2, entry 1). In contrast, the enantioselectivities of the catalyzed reactions exhibited a strong substituent-dependence of the P-chirogenic EPHOS ligands 13, as the allylated products 28 and 29 with (S)-or (R)-configurations were obtained with enantioselectivities up to 95% (entry 8). However, when the AMPP* ligands 13 derived Interestingly, the AMPP* (S p )-13i derived from (+)-ephedrine 9 and bearing an o-biphenyl substituent at the aminophosphine moiety as R group, led to the allylated product (R)-28

from (+)-ephedrine bore R 1 = o-An, -Np, -Np, Fc, Me, c-Hex, o-MEMPh, o-i-PrOPh, o- BnOPh, 3,5-Xyl, 3,5-di(t-Bu)Ph, 3,5-di(t-Bu)-4-
with 91% e.e. (entry 8). In this latter case, the product 28 was obtained with a reversed absolute configuration upon using the epimeric o-biphenyl AMPP* ligand (R p )-13f. This and8). 23 The AMPP* ligands 13a and 13g bearing o-anisyl or ferrocenyl as R 1 substituents at the aminophosphine moiety, also enhanced the enantioselectivity with respect to EPHOS 1 (Table 2, entry 1), for the Pd-catalyzed allylation using benzylamine. In these case, the product (R)-29 was obtained with 33 and 56% e.e., respectively (entries 2 and 6). The epimeric AMPP* ligands (R p )-13f and (S p )-13i bearing an o-biphenyl group either as R 1 or R on the aminophosphine moiety, remarkably, led to the allylated benzylamine 29 with an opposite absolute configuration and with e.e. up to 95% (entries 5 and 8). 23 Results obtained for the catalyzed allylation of dimethyl malonate and benzylamine using palladium complexes derived from AMPP* 20 bearing a P-chirogenic phosphinite moiety, are reported in Table 3. The allylated products 28 and 29 were obtained with moderate enantioselectivities up to 70% e.e. (Table 3). The P-chirogenic phosphinite substituents of the AMPP* ligands 20 in this catalyzed allylic reaction, did not show significant effect on the stereoselectivity. The products (S)-28 and (R)-29 were obtained with low to moderate enantioselectivities of 13-56% e.e., compared to 27-42% for the EPHOS 1 (Table 3, entries 1-6 and 8). This was after changing the R ferrocenyl. However, when R 1 = o-biphenyl, the enantioselectivities obtained for the products (S)-28 and (R)-29 reached 50 and 70% e.e., respectively (entry 7). When R is an o-biphenyl, lower enantioselectivities up to 34% e.e. were obtained using the ligand (S p )- 20i compared to epimer (R p )-20f (entry 9 vs entry 7). Results in Tables 2 and3 show that the enantioselectivities in the palladium catalyzed asymmetric allylic reactions was considerably increased with the AMPP* 13 bearing a P-chirogenic aminophosphine moiety, even if the best asymmetric induction was obtained with the o-biphenyl-containing AMPP* ligand 20f.

Table 3. Asymmetric Allylation of Dimethylmalonate and Benzylamine Catalyzed Palladium

Complexes of AMPP* 20

From a mechanistic standpoint, the P-chirogenic AMPP* ligands 13 and 20 were useful The seven-membered ring in PdCl 2 -complexes 30-32 adopted a boat-like geometry, with a slight distorsion O1-P2-P1-N1 of -36° and -18°, respectively. This was explained by the required equatorial positions of the methyl and phenyl substituents of the ephedrine chain (here, cis-positioning). A shorter phosphinite-Pd bond was also noted with the Pd1-P2 and Pd1-P1 bond lenghts measured between 2.23-2.25Å and 2.26-2.27Å, respectively (Figure 1 and SI). Very similar structures have already been observed in case of rhodium or ruthenium complexes with AMPP derived from ephedrine. 9b,c, [START_REF] Haquette | A new optically pure half-sandwich Cp-Ru diphosphine complex with a chiral metal centre, (S)-Ru( 5 -C 5 H 5 )-(EPHOS)Cl {EPHOS is (+)-(1R,2S)-2-[(diphenylphosphino)methylamino]-1phenylpropyldiphenyl phosphinite}[END_REF] Here, the structure of the PdCl 2 -complex 30 prepared with the ligand (R p )-13f interestingly showed the o-biphenyl substituent of the aminophosphine moiety placed perpendicular to the palladium square (i.e. P1P2PdCl 2 ) with a dihedral angle Pd1-P1-C7-C8 of 103.5(4)° (Figure 1a). In addition, the biphenyl group adopted a staggered conformation with a dihedral angle C7-C12-C13-C14 of -46.1(5)°. This could explain the strong influence of the ligand (R p )-13f in the palladium sphere of coordination and consequently the high enantioselectivities observed in allylic reactions (Figure 1a; Table 2, entry 5: e.e. up to 82%), By contrast, the -naphtyl substituent in the PdCl 2 -complex 32, located in back area of the Pd-sphere of coordination, might explain the moderate asymmetric induction resulting from ligand (R p )-20b (Figure 1b; or R c = o-biPh, Scheme 5). In total four starting conformations were optimized for the -allyl complexes 33-35, named 33-35M-or 33-35W (boat or half-chair). A maximal energy differences between all these species of 16.1 KJmol -1 was observed (Scheme 5, Table S61, SI). 4. Among all these optimized structures, the -allyl Pd-complexes 33W(boat), 33M(boat), 34M(boat), 34W(boat), 34W(half-chair), 35M(boat), 35W(half-chair) and 35W(boat) exhibited the lowest calculated total energies with differences not exceeding 3.2 KJmol -1 (Tables 4 andSI complexed moiety. The Pd-C3 bond, trans to the phosphinite moiety in the Pd-square planar center was most commonly longer than the Pd-C1 bonds and was observed in similar X-ray structures of the ProNOP ligand 2. 25 However, computations showed that the Pd-C1 and Pd-C3 bond lenghts also depend on the Pd-complex conformation (Table 4).

Even if the electroaffinity values of the C1 and C3 atoms in all -allyl complexes 33-35 are of unequal value, the enantioselectivity of the allylation is much better explained by molecular orbital (MO) than electrostatic interactions between the nucleophile and the allyl moiety (Table 4; see detail Table S61 to S76, SI). 26 The most stable Pd-complexes 33M and 33W, derived from AMPP* ligand (R p )-13f, were in boat conformation and in equilibrium from each other with an energy difference of 2.5

KJmol -1 . This was due to the changing M-or W-shape of the -allyl group (Scheme 6a;

Table 4, entries 1 and 2). In this case, the enantioselectivity was explained by a favored nucleophilic attack at the C3 position of the complex 33M(boat), leading to the products (S)-28 or (R)-29 respectively after reaction with malonate or benzyl amine (Scheme 6a).

This selectivity was possible by a longer Pd-C3 bond length and a larger LUMO relative atomic contribution at the C3 position of the -allyl group, higher in 33M(boat) than 33W(boat). This allows the favored interaction with the nucleophile and consequently the cleavage of the Pd-C3 bond to enantioselectively afford the corresponding allylated product (Table 4, entries 1 and 2). 4, entries 4 and 5). However, the computed Pd-C1 bond length and the LUMO contribution for the complex 34M(boat) were higher at the C1 than C3 position of the -allyl group, i.e. 2.35 Å and 16.52% vs 2.25 Å and 9.06% (Table 4, entry 3). In this case the enantioselectivity was explained by a nucleophilic attack at the C1-position of the -allyl group. It is noteworthy that all stereochemical course from the three lower stable -allyl Pdcomplexes 34 resulted in the same enantioselectivities, justifying the obtained high enantiomeric excesses up to 95% using the ligand (S p )-13i (Scheme 6b).

Finally, the more stable optimized complexes 35 derived from AMPP* ligand (R p )-20f

were either in boat or in half-chair conformation and with a -allyl group in both M-or Wshape (Scheme 6c; Table 4, entries 6, 7 and 8). All these species were in equilibrium from each other with an energy difference of 3.2 KJ.mol -1 . The modest enantioselectivity was explained by a nucleophilic attack at the C1 position of the complexes 35W(boat) or 35W(half-chair), but also in a lesser extent of 35M (boat) which led to reverse enantiomers (R)-28 or (S)-29. This was due in all case to their longer Pd-C1 than Pd-C3 bonds and their higher LUMO contributions at the C1 rather than C3 position, i.e. 2.37 Å and 13.84%, 2.33 Å and 13.71% vs 2.27 Å and 10.63%, respectively (Scheme 6b, Table 4, entries 6, 7 and 8). To conclude, this methodology to prepare P-chirogenic modified EPHOS ligands derived from ephedrine, opens up further possibilities for optimizing and predict enantioselectivities in asymmetric catalyzed processes by designing AMPP* derived from aminoalcohols. and AMPP* 13a-c, 13f-h, 13j-l, 13u and their corresponding diborane complexes 12 were synthesized according to literature procedures. 9a,b,10a The 2-benzyloxy-27a and 2isopropoxybromobenzene 27b were prepared from 2-bromophenol according to reported procedures. The 4-bromo-2,6-bis(t-butyl)anisole was synthesized from 4-bromo-2,6-bis(tbutyl)phenol, according to a modified procedure using K 2 CO 3 as base. 27c The bromo-2,6dimethoxybiphenyl has been prepared and generously provided by Dr F. Leroux (LIMA-Strasbourg). [START_REF] Diemer | Regioselectivity in the aryne cross-coupling of aryllithiums with functionalized 1,2-dibromobenzenes[END_REF] Thin layer chromatography was performed on silica chromagel (60 µm F 254 ) and exposed by UV, potassium permanganate or iodine treatment. Flash chromatography was carried out with the indicated solvents using silica gel 60 (60AAC, 35-70 µm). HPLC analyses were performed on a chromatograph equipped with a UV detector at λ = 210 and 254 nm. The 1 H, [START_REF]C{ 1 H} NMR (100.6 MHz[END_REF] C{ 1 H} and 31 P{ 1 H} NMR spectra were recorded on 600, 500, 400 or 300 MHz spectrometers at ambient temperature, using tetramethylsilane (TMS) as internal reference for 1 H and [START_REF]C{ 1 H} NMR (100.6 MHz[END_REF] C spectra, and phosphoric acid (85%) as external reference for 31 P NMR. Data were reported as s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br.s = broad signal, coupling constant(s) in Hertz. Infrared spectra were recorded on FT-IR instrument and the data are given in cm -1 . Melting points were measured on a Kofler melting points apparatus. Optical rotation values were determined at 20 °C on a polarimeter at 589 nm (sodium lamp). The mass spectra and accurate mass measurements (HRMS) were performed under (ESI) conditions with a micro Q-TOF detector or Orbitrap detector, or in the MALDI/TOF reflectron mode using dithranol as a matrix. Elemental analyses were performed with a precision superior to 0.3% on a CHNS-O instrument apparatus.

EXPERIMENTAL SECTION

Crystal Structure Determination. All experimental data procedure and refinement are detailed in the part B of the Supplementary Information (SI) for each compound. Data CCDC-1982667, 1982668, 1982669, 1982665, 1982666, 1982663, 1982664, 1982661, 1982662, 1982659, 1982660, 1982656, 1982657, 1982658, 1982652, 1982653, 1982654, 1982650 and 1982651

(2S,4R,5S)-3,4-Dimethyl-2-biphenyl-5-phenyl-1,3,2-oxazaphospholidine-2-borane

(-)-10b. This compound was prepared from 2-chloro-1,3,2-oxazaphospholidine according to a modified procedure using o-biphenyllithium as reagent. [START_REF] Den Heeten | Parallel synthesis and screening of polymer-supported phosphorusstereogenic aminophosphane-phosphite and -phosphinite ligands[END_REF][START_REF] Chaux | Enantiodivergent synthesis of P-chirogenic phosphines[END_REF] To a solution of 2-chloro-

Synthesis of aminophosphine-boranes 11:

General procedure. In a 50 mL threenecked flask, equipped with a magnetic stirrer and an argon inlet, 5 mmol of the oxazaphospholidine borane complex 10 were dissolved in 5 mL of anhydrous THF. The mixture was cooled at -78 °C and 2 equiv. (10 mmol) of the organolithium reagent were slowly added. The resulting mixture was stirred and warmed to RT until the starting material was completely consumed, and hydrolyzed at 0 °C with 2 mL of water. The THF was removed under reduced pressure and the aqueous layer was extracted several times with dichloromethane. The combined organic phases were dried over MgSO 4 and the solvent was removed. The residue was purified by chromatography on a column of silica gel, using a mixture of toluene/AcOEt as eluent, to afford aminophosphine-boranes 11. The aminophosphine-boranes 11 were typically recrystallized using a mixture of hexane/isopropanol (7:3). [START_REF] Holz | P-Chirogenic Xantphos Ligands and related ether diphosphines: Synthesis and application in rhodium-catalyzed asymmetric hydrogenation[END_REF] 3,5-xylyl-, [START_REF] Chaux | Enantiodivergent synthesis of P-chirogenic phosphines[END_REF] 3,5-di-t-butylphenyl-, [START_REF] Bayardon | Designing P-chirogenic 1,2diphosphinobenzenes at both P-centers using P(III)-phosphinites[END_REF] 2-(2',6'-dimethoxy)biphenyl-, [START_REF] Grabulosa | P-Stereogenic monophosphines in Pd-catalyzed enantioselective hydrovinylation of styrene[END_REF] calix [4]arenyl-, 9c aminophosphines 11a-h, 11j-m, 11o, 11p, 11u, respectively, were prepared from the appropriate oxazaphospholidine-borane complex (+)-or (-)-10a or (-)-10b, according to the described procedure. These compounds exhibited satisfactory analytical and spectrochemical data in agreement with the literature.

(R p )-(-)-N-[(1R,2S)-2-Hydroxy-1-methyl-2-phenylethyl], N-methylamino(phenyl-p-

tolyl) phosphine-borane 11e. [START_REF] Holz | P-Chirogenic Xantphos Ligands and related ether diphosphines: Synthesis and application in rhodium-catalyzed asymmetric hydrogenation[END_REF] This compound was synthesized by reaction of oxazaphospholidine-borane complex (-)-10a with p-tolyllithium reagent.

(S p )-(+)-N-[(1R,2S)-2-Hydroxy-1-methyl-2-phenylethyl],

N-methylamino(obiphenyl) phenylphosphine-borane 11i. This compound was synthesized by reaction of oxazaphospholidine-borane complex (-)-10b with phenyllithium reagent. White solid (1.91 g, 87% yield); Mp = 56-58 °C; R f = 0.45 (CH 2 Cl 2 ); [α] D 20 = +9.9 (c 0.6, CHCl 3 ). solvent was evaporated. The crude product was purified by chromatography on silica gel and, in some cases, by recrystallization to afford the desired AMPP*-diboranes 12.

From aminophosphine-borane 11 (Method B).

To a solution of aminophosphineborane 11 (0.5 mmol) in THF (1 mL) was slowly added at -78 °C n-BuLi (0.6 mmol). After stirring during one hour at -78 °C, chlorophosphine R' 2 PCl (1.1 mmol) was added and the resulting mixture was stirred until the solution reached room temperature (~ 5 h). Boranedimethylsulfide complex (4 mmol) was added at 0 °C and the solution was stirred overnight before hydrolysis with water (10 mL). The work-up is similar as described above.

4.4.2.

The EPHOS-8 and the AMPP*-diborane complexes 12a-c, 9a,b 12f-h, 9b 12j, 9a,b,10 12k, 12l, 9b 12u 9c and 15e, 9a were synthetized as described in literature.

(S p )-(-)-N-[(1R,2S)-2-(Diphenylphosphinito-borane)-1-methyl-2-phenylethyl], N-

methyl amino(o-biphenyl)phenylphosphine-borane 12i. The synthesis of 12i was achieved using the method A (as described above) by reaction of the complex (-)-10b (1.26 g, 3.5 mmol) in THF (6 mL) at -78 °C with phenyllithium (1.8 M in dibutylether, 3.9 mL, 7 mmol).

The ring opening product [11i] was then trapped by Ph 2 PCl. The purification was achieved by chromatography on silica gel using petroleum ether/CH 2 Cl 2 1:1 as eluent and recrystallization in hexane/dichloromethane to give the AMPP*-diborane 12i as a white solid (1.16 g, 52% yield). X-ray quality crystals were grown by slow evaporation of a

(R p )-(-)-N-[(1R,2S)-2-(Diphenylphosphinito-borane)-1-methyl-2-phenylethyl], Nmethyl amino(2-isopropoxyphenyl)phenylphosphine-borane 12m. The synthesis of 12m

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(S p )-(-)-N-[(1R,2S)-2-(Diphenylphosphinito)-1-methyl-2-phenyl]ethyl], N-methyl

amino(o-biphenyl)phenylphosphine 13i. [START_REF] Holz | P-Chirogenic Xantphos Ligands and related ether diphosphines: Synthesis and application in rhodium-catalyzed asymmetric hydrogenation[END_REF] This compound was synthesized from (-)-ephedrine 9 according to the described procedure. 9a Suitable colorless crystals for X-ray structure were obtained by slow evaporation of CH 2 Cl 2 . Crystallographic data and structure of (1S p , 2R p )-15e were reported in SI.

Synthesis of AMPP*-diborane 21a-i with a P-chirogenic phosphinite moieties.

(S p )-(+)-N-[(1S,2R)-2-(o-Anisylphenylphosphinito-borane)-1-methyl-2-phenylethyl],

N-methylaminodiphenylphosphine-borane 21a. This compound was synthesized from (S p )-

A c c e p t e d M

 d a n u s c r i p t

A c c e p t e d M

 d a n u s c r i p t

A c c e p t e d M a n u s c r i p t

 dt complexes have been reached.

A c c e p t e d M a n u s c r i p t

 d

A c c e p t e d M a n u s c r i p t

 d

A c c e p t e d M a n u s c r i p t

 d

Scheme 2 .A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t

 2dtd Scheme 2. Synthesis of P-chirogenic binaphtyl-AMPP* (M,S p )-13vA c c e p t e d M a n u s c r i p t

A c c e p t e d M a n u s c r i p t

 dt from (-)-ephedrine 9 (entry 2). These AMPP* were characterized by their[START_REF] Holz | P-Chirogenic Xantphos Ligands and related ether diphosphines: Synthesis and application in rhodium-catalyzed asymmetric hydrogenation[END_REF] P NMR chemical shifts at ~ +64 and +100 ppm, corresponding to their trivalent aminophosphine and phosphinite moieties. They were isolated after addition of BH 3 .DMS as diborane complexes (R p )-or (S p )-21a in 68 or 65% yield, respectively (entries 1, 2). The diastereoselectivity (> 99%) was checked by NMR analysis of the free AMPP* 20a and its diborane complex 21a. The free P-chirogenic ligands 20a could be recovered by borane decomplexation of 21a with DABCO (Scheme 3). In addition, the -or -naphtyl-, oor ptolyl-, o-biphenyl-, ferrocenyl-and t-butylphenylphosphinites 19b-i were obtained from the rearrangement of their corresponding aminophosphine-boranes 11b-i previously prepared from (+)-ephedrine 9. Finally, the reaction of the phosphinite-boranes 19b-i with Ph 2 PCl in presence of NEt 3 and then complexation with BH 3 .DMS, led to the AMPP*-diborane complexes 21b-i in yields up to 81% (entries 3-11). The X-ray crystal structures of eight AMPP*-diborane complexes 21a-h have been solved. Their absolute configurations are reported in SI (Figures S8 to S16). Consequently, as the borane complexation and decomplexation proceed with retention of configuration at the P-atom, the resulting stereochemistry of the AMPP* 20 from aminophosphine-borane 11 is consistent with the retention during the N→O phosphinyl migration step (Scheme 3). The ORTEP views of all AMPP*-diborane complexes 12, 15 or 21 exhibited similar aspectsA c c e p t e d M a n u s c r i p t of unfolded conformations of the chain, flattened geometries for the amino groups, and anti orientation of the P-B bonds with P1-B1-P2-B2 dihedral angles up to 165° (Figures S4 to S16, SI).

A c c e p t e d M a n u s c r i p t

 d

MeOPh or 2 -

 2 Pyr on the aminophosphine moiety, the allylated methyl malonate (S)-28 were obtained with 8-70% e.e. (entries 2-4, 6, 9-17). In the case of AMPP* 13u linked at the upper-rim to a calix[4]arene unit, the catalyzed allylic alkylation also led to a low enantioselectivity (27% e.e.; entry 20). On the A c c e p t e d M a n u s c r i p tother hand, when the catalyzed allylation was performed with the AMPP* 13h or 13s prepared from (+)-ephedrine 9 and bearing t-butyl or 2-(2',6'-dimethoxy)biphenyl as R 1 substituent, the observed enantioselectivities were reversed and (R)-28 was obtained with 41 and 28% e.e., respectively (entries 7, 18). When the aminophosphine arm of the AMPP* ligands 13 bore a binaphtyl or a biphenyl substituent, the enantioselectivities were strikingly enhanced. Thus, the binaphtyl AMPP* (M,S p )-13v, derived from (-)-ephedrine 9, was used in the palladium-catalyzed asymmetric allylation of the dimethyl malonate, the product (R)-28 was obtained with 81% e.e. (entry 21). Using the ligand AMPP* 13f derived from (+)ephedrine 9 and bearing an o-biphenyl as R 1 substituent, the palladium catalysed reaction afforded the allylated malonate derivative (S)-28 with 82% e.e. (entry 5). Surprisingly, when the phenyl-of diphenylphosphinite moiety of AMPP* 13f was replaced by a naphtyl-or a 3,5-xylyl-group, the corresponding AMPP* 13t and 13w exhibited a modest change of the enantioselectivities. This was because the asymmetric catalyzed allylation were achieved with 70% and 85% vs 82% e.e., respectively (entries 5, 19 and 22).

A c c e p t e d M a n u s c r i p t

 dt illustrates the key importance of the P-chirality at the aminophosphine moiety on the enantioselectivity of the catalytic transformation (82% e.e. (S) vs 91% e.e. (R); entries 5

A c c e p t e d M a n u s c r i p t a

 dt Reactions were carried out in dichloromethane ([27] = 0.3 M) with 2 mol% of [Pd(C 3 H 5 )Cl] 2 and 4 mol% of AMPP* 20, 2 equiv. of dimethyl malonate or benzylamine as nucleophile, 2 equiv. of N,O-bis(trimethylsilyl)acetamide (BSA) and a catalytic amount of KOAc (10 mol%) or 2 equiv. of TBAF as base, respectively. b The reaction was performed at room temperature to completion in 7 h. c Determined by HPLC on chiral column. d Reference 8f.

A c c e p t e d M a n u s c r i p t

 d

Figure 1 .

 1 Figure 1. ORTEP view of palladium complexes [Pd(13f)Cl 2 ] 30 and [Pd(20b)Cl 2 ] 32

A c c e p t e d M

 d a n u s c r i p t

Scheme 5 .

 5 Scheme 5. Geometry Optimization of the -Allylpalladium-AMPP* Complexes 33-35 A c c e p t e d M a n u s c r i p t

  ). The observed enantioselectivity provided from the nucleophilic attack on either the C1 or C3 of the -allyl Page 27 of 95 ACS Paragon Plus Environment The Journal of Organic ChemistryA c c e p t e d M a n u s c r i p t

A c c e p t e d M a n u s c r i p t

 d

Scheme 6 .

 6 Scheme 6. Computed Stereochemical Course of Pd-Catalyzed Allylations using AMPP*

A c c e p t e d M a n u s c r i p t

 dt In contrast, the computed structures for the Pd-complex derived of the AMPP* ligand (S p )-13i indicated three species 34M(boat), 34W(boat) and 34W(half-chair) with lower energy difference by 2 KJ.mol -1 (Table4, entries 3, 4 and 5). The complex 34 could also be in halfchair conformation (i.e. 34W(half-chair)), due to steric hindrance of the biphenyl substituent when it is in axial position with regard to the Pd-square as in boat form (Scheme 5, R a = biPh, R b,c,d = Ph). The observed enantioselectivities of the products (R)-28 and (S)-29 were again explained by a favored nucleophilic attack at the C3 position of the complexes 34W(half-chair) or 34W(boat). This was due to their longer Pd-C3 bonds and higher LUMO contributions at their C3 positions i.e 2.35 Å, 15.93% and 12.73%, respectively (Scheme

  We have developed an important series of chiral aminophosphine-phosphinite ligands bearing a chirality at the phosphorus atom of the aminophosphine or phosphinite moiety (AMPP*). Until now the design of AMPP* with a P-chirogenic phosphinite center has been poorly investigated. We synthetized this series with the ephedrine methodology used in stereoselective synthesis of P-chirogenic phosphines. The synthesis of AMPP* ligands with P-chirogenic aminophosphine moieties is based on the stereospecific ring opening of an oxazaphospholidine-borane by reaction with organolithium reagents, trapping the broader design of AMPP* ligands notably on phosphinite center was achieved thank to an unprecedented stereospecific N→O phosphinyl migration process recently developed in our group. When the aminophosphine-boranes were heated at 50°C in the presence of DABCO, P-chirogenic phosphinites were obtained by N→O phosphinyl migration. Their reaction with chlorophosphines led then to the corresponding free AMPP* with P-chirogenic phosphinite moiety. Synthesis efficiency was demonstrated by the stereoselective synthesis of the four epimers of the o-biphenyl containing AMPP* ligands, with (S)-or (R)-absolute configuration at the P-centers. Twenty nine AMPP* including eight with a P-chirogenic phosphinite moiety were investigated in palladium-catalyzed Page 32 of 95 ACS Paragon Plus Environment The Journal of Organic ChemistryA c c e p t e d M a n u s c r i p t asymmetric allylic reactions. The enantioselectivities varied from 91% (R) to 95% e.e. (S), according to the spatial position of the P-substituents in the palladium sphere of coordination. The best asymmetric inductions were obtained with AMPP* bearing Pchirogenic aminophosphine moieties. The (S)-or (R)-enantioselectivity depends on the absolute configuration at the phosphorus atom. X-ray crystallographic data for relevant Pd-AMPP* complexes and computer modeling explained enantioselectivities origin, based on MO interactions of the most stable conformers with nucleophiles. The selectivity provided from the nucleophilic attack at the C3 or C1 position of the complexed -allyl group. It was favorized by the interaction of the nucleophile with the LUMO having the larger contribution in one of those positions, and also by the cleavage of the corresponding longer Pd-C3 or Pd-C1 bond.

A c c e p t e d M a n u s c r i p t

 d

4. 4 . 4 . 4 . 1 .

 4441 Synthesis of the AMPP*-diboranes 12a-w with P-chirogenic aminophosphine moieties. Typical procedures: AMPP*-diborane complexes 12 were obtained either according to a one-pot procedure from the oxazaphospholidine-2-borane 10 (Method A), or by deprotonation of the isolated aminophosphine-borane 11 (Method B).4.4.1.1. From oxazaphospholidine borane 10 (Method A). To a solution of 3,4-dimethyl-5-phenyl-1,3,2-oxazaphospholidine-2-borane 10 (3.5 mmol) in THF (6 mL) was slowly added at -78 °C the organolithium reagent (7 mmol). The temperature reaction was slowly warmed to 0 °C and the solution was stirred until the starting material was completely consumed. Chlorophosphine R' 2 PCl (7 mmol; R' = Ph, -Np or 3,5-Xyl) was added and the mixture was stirred for 2 h. Borane-dimethylsulfide complex (2.7 mL, 28 mmol) was slowly added at 0 °C and the reaction mixture was stirred overnight until the solution reached room temperature. Water (20 mL) was added and the aqueous phase was extracted with CH 2 Cl 2 (3 x 20 mL). The organic extracts were dried over anhydrous MgSO 4 and the

A c c e p t e d M a n u s c r i p t

 d

A c c e p t e d M a n u s c r i p t mixture of CH 2

 d2 Cl 2 and hexane. The structure and the data were reported in the SI. R f = 0.62 (petroleum ether/CH 2 Cl 2 1:1); Mp = 206-208 °C; [α] D 20 = -52.2 (c 0.4, CHCl 3 ). 1 H NMR (500 MHz, CD 2 Cl 2 ): δ 0.56-1.73 (m, 6H), 1.03 (d, J = 6.6 Hz, 3H), 2.19 (d, J = 7.7 Hz, 3H), 4.69-4.77 (m, 1H), 5.42 (t, J = 9.1 Hz, 1H), 6.27 (ddd, J = 12.2, 2.1, 1.2 Hz, 1H), 6.89-6.96 (m, 4H), 7.07-7.24 (m, 8H), 7.32-7.42 (m, 9H), 7.48-7.56 (m, 5H), 7.73-7.78 (m, 2H). 13 C{ 1 H} NMR (125.8 MHz, CD 2 Cl 2 ): δ 15.2, 29.2 (d, J = 4.9 Hz), 57.2 (dd, J = 10.0, 8.9 Hz), 83.5 (dd, J = 10.4, 2.7 Hz), 126.8, 126.9, 127.1 (d, J = 9.5 Hz), 127.4 (d, J = 10.1 Hz), 127.7, 127.9, 128.0, 128.3, 128.5 (d, J = 10.7 Hz), 128.7, 129.0, 129.0 (d, J = 54.1 Hz), 130.0, 130.1 (d, J = 2.4 Hz), 130.5 (d, J = 1.8 Hz), 131.0 (d, J = 10.7 Hz), 131.4 (d, J = 1.8 Hz), 131.5, 131.6, 131.7 (d, J = 1.8 Hz), 132.0 (d, J = 59.4 Hz), 132.3 (d, J = 8.9 Hz), 132.5 (d, J = 10.1 Hz), 132.8, 132.9 (d, J = 7.7 Hz), 138.4, 140.5 (d, J = 2.6 Hz), 146.4 (d, J = 11.0 Hz).

A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t

 dtd

4. 4 . 5 .

 45 (R p )-(-)-N-[(1R,2S)-2-(Diphenylphosphinito-borane)-1-methyl-2-phenylethyl], Nmethyl amino(2-benzyloxyphenyl)phenylphosphine-borane 12n. The synthesis of 12n was achieved using the method A (as described above), by reaction of the complex (-)-10a (1.0 g, 3.5 mmol) with the 2-benzyloxyphenyllithium reagent, previously prepared using 2benzyloxybromobenzene (1.8 g, 7 mmol) in THF (3.5 mL) and s-BuLi (1.4 M in cyclohexane, 5.0 mL, 7 mmol). The ring opening product [11n] was then trapped by Ph 2 PCl. The purification was achieved by column chromatography on silica gel using petroleum ether/toluene (1:1) as eluent. White crystals (1.05 g, 45% yield). R f = 0.10 (petroleum ether/toluene 1:1); Mp = 140-142 °C; [α] D 20 = -36.5 (c 1.9, CHCl 3

4. 4

 4 .8. (R p )-(-)-N-[(1R,2S)-2-(Diphenylphosphinito-borane)-1-methyl-2-phenylethyl], N-methyl amino(3,5-di-t-butyl-4-methoxyphenyl)phenylphosphine-borane 12q. The synthesis of 12q was achieved using the method A (as described above), by reaction of the complex (-)-10a (1.0 g, 3.5 mmol) with the 3,5-di-t-butyl-4-methoxyphenyllithium previously prepared from bromo-3,5-di(t-butyl)-4-methoxybenzene (2.1 g, 7 mmol) in THF (3.5 mL) and s-BuLi (1.4 M in hexane, 5.0 mL, 7 mmol). The ring opening product [11q] was then trapped by

A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t 4 . 4 .

 dtdtd44 10. (R p )-(-)-N-[(1R,2S)-2-(Diphenylphosphinito-borane)-1-methyl-2-phenylethyl], Nmethyl amino-2-(2',6'-dimethoxy-1,1'-biphenyl)phenylphosphine-borane 12s.The synthesis of 12s was achieved using the method A (as described above), by reaction of the complex (-)-10a (1.0 g, 3.5 mmol) with the 2',6'-dimethoxy-1,1'-biphenyllithium previously prepared from 2-bromo-2',6'-dimethoxy-1,1

4. 4 .

 4 11. (R p )-(-)-N-[(1R,2S)-(2-(Di--naphtylphosphinito-borane)-1-methyl-2-phenylethyl],N-methylamino(o-biphenyl)phenylphosphine-borane 12t. The synthesis of the 12t was achieved using the method A (as described above) by reaction of the complex (-)-10a (1.0 g, 3.5 mmol) with the 1,1'-biphenyllithium previously prepared from 2-bromo-1,1'-biphenyl (1.3 mL, 7 mmol) in THF (3.5 mL) and s-BuLi (1.4 M in cyclohexane, 5.0 mL, 7 mmol). The ring opening product [11t] was then trapped by -Np 2 PCl. The purification was achieved by column chromatography on silica gel using petroleum ether/CH 2 Cl 2 (2:1) as eluent. White solid (1.65 g, 64% yield). R f = 0.27 (petroleum ether/ CH 2 Cl 2 , 2:1); [α] D 20 -93.2 (c 0.3, CHCl 3 ).

A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t 4 . 5 .

 dtdtdtd45 Typical procedure for the decomplexation of aminophosphine-phosphinitediboranes 12. A solution of aminophosphine-phosphinite-diborane 12 (1 mmol) and DABCO (4 mmol) in toluene (3 mL) was heated at 50°C with an oil bath and was stirred under argon overnight. After removing the solvent under vacuum, the residue was purified by chromatography on neutral aluminium-oxide using a mixture of petroleum ether/ethyl acetate (4:1) or toluene as eluent, to afford the free AMPP* 13.4.5.1.The EPHOS 19a and the free o-anisyl-,9a

A c c e p t e d M a n u s c r i p t 4 . 5 4 . 6 .

 d4546 .10. (R p )-N-[(1R,2S)-(2-(Di--naphtylphosphinito)-1-methyl-2-phenylethyl], Nmethylamino (o-biphenyl)phenylphosphine 13t. 31 P{ 1 H} NMR (121.5 MHz, CDCl 3 ): δ +56.0, +97.2. 4.5.11. (M,S p )-(+)-N-[(1S,2R)-2-(Diphenylphosphinito)-1-methyl-2-phenylethyl], Nmethylamino-2-(1,1'-binaphtyl)phenylphosphine 13v. 31 P{ 1 H} NMR (202.5 MHz, CDCl 3 ): δ +53.8, +109.9.4.5.12. (S p )-N-[(1S,2R)-2-Bis(3,5-dimethylphenyl)phosphinito]-1-methyl-2-phenylethyl],N-methyl amino(o-biphenyl)phenylphosphine-borane 13w.[START_REF] Holz | P-Chirogenic Xantphos Ligands and related ether diphosphines: Synthesis and application in rhodium-catalyzed asymmetric hydrogenation[END_REF] P{ 1 H} NMR (121.5 MHz, CDCl 3 ): δ +56.0, +114.0. AMPP*-diborane (1S p , 2R p )-15e bearing P-chirogenic aminophosphine and phosphinite moieties. (S p )-(+)-N-{(1S, 2R)-2-[(R p )-o-Anisylphenylphosphinito-borane]-1methyl-2-phenylethyl}, N-methylamino-o-anisylphenylphosphine-borane 15e.

A c c e p t e d M a n u s c r i p t 4 . 7 . 1 .

 d471 Typical procedure.12 To a solution of the aminophosphine-borane 11 (1 mmol) in toluene (3 mL) was added 0.6 mmol (2.0 mmol for 11 with R 1 = alkyl) of DABCO. The solution was heated at 50°C with an oil bath and was stirred overnight.Chlorodiphenylphosphine (2 mmol) and triethylamine (5 mmol) were added at room temperature. The solution was stirred for 4 h before addition of BH 3 .DMS (8 mmol) at 0 °C and the mixture was again stirred for 4 h. After hydrolysis, the aqueous phase was extracted with dichloromethane and the organic phase was washed with saturated NaCl solution, dried over MgSO 4 and evaporated. The residue was purified by chromatography on silica gel with toluene as eluent to afford the AMPP*(BH 3 ) 2 21 which was recrystallized in a mixture of hexane/CH 2 Cl 2 .

  C{ 1 H} NMR (125.8 MHz, CDCl 3 ): δ 16.0, 29.4 (d, J = 4.5 Hz), 57.5 (dd, J = 11.2, 7.7 Hz), 83.6 (dd, J = 8.9, 3.0 Hz), 124.7 (d, J = 13.5 Hz), 126.3, 126.8 (d, J = 5.0 Hz), 127.1, 127.7 (d, J = 63.7 Hz), 128.0 (d, J = 5.7 Hz), 128.1 (d, J = 6.1 Hz), 128.3, 128.4, 128.6, 128.9, 129.0, 129.7 (d, J = 71.6 Hz), 130.4 (d, J = 2.0 Hz), 130.9, 130.9 (d, J = 11.8 Hz), 131.1 (d, J = 1.7 Hz), 131.7 (d, J = 10.3 Hz), 132.3 (d, J = 6.4 Hz), 132.5 (d, J = 10.2 Hz), 133.0 (d, J = 63.3 Hz), 133.5 (d, J = 2.4 Hz), 133.8 (d, J = 7.6 Hz), 133.9, 134.0, 138.5. 31 P{ 1 H} NMR (202.5 MHz, CDCl 3 ): δ +71.3 (br.s), +110.0 (br.s). HRMS (ESI/Q-TOF) calcd for C 38 H 41 B 2 NOP 2 Na [M+Na] + : 634.27472; found: 634.27398. HRMS (ESI/Q-TOF) calcd for C 38 H 42 B 2 NOP 2 [M+H] + : 612.29278; found: 612.29213. )-(+)-N-[(1R,2S)-2-(-Naphtylphenylphosphinito-borane)-1-methyl-2phenylethyl], N-methylaminodiphenylphosphine-borane 21b. This enantiomer was synthesized from (R p)-(+)-N-[(1R,2S)-2-hydroxy-1-methyl-2-phenylethyl], N-methylamino(-naphtyl)phenylphosphine-borane 11c previously prepared from (+)-ephedrine 9. 11b,29 (0.39 g, 63% yield).[START_REF] Holz | P-Chirogenic Xantphos Ligands and related ether diphosphines: Synthesis and application in rhodium-catalyzed asymmetric hydrogenation[END_REF] P{ 1 H} NMR (202.5 MHz, CDCl 3 ): δ +71.5 (br.s), +110.2 (br.s). 4.7.6. (R p )-(-)-N-[(1R,2S)-2-(-Naphtylphenylphosphinito-borane)-1-methyl-2phenylethyl], N-methylaminodiphenylphosphine-borane 21c. This compound was synthesized from (R p )-(-)-N-[(1R,2S)-2-hydroxy-1-methyl-2-phenylethyl], N-methylamino(naphtyl)phenylphosphine-borane 11d previously prepared from (+)-ephedrine 9. 11b,29b Xray quality crystals were grown by slow evaporation of cyclohexane. The structure and the data were reported in the SI. Colorless crystals (0.49 g, 81% yield); R f = 0.60 (toluene); Mp = 151 °C. [α] D 20 = -66.3 (c 0.6, CHCl 3 ). 1 H NMR (300 MHz, CDCl 3 ): δ 0.38-1.81 (m, 6H), 1.35 (d, J = 6.5 Hz, 3H), 2.33 (d, J = 7.5 Hz, 3H), 4.58-4.74 (m, 1H), 5.46 (t, J = 9.4 Hz, 1H), 6.59-6.71 (m, 2H), 7.05-7.23 (m, 6H), 7.26-7.66 (m, 14H), 7.68-7.77 (m, 1H), 7.86-8.00 (m, 3H), 8.33 (d, J = 12.7 Hz, 1H). 13 C{ 1 H} NMR (75.5 MHz, CDCl 3 ): δ 16.0, 29.4 (d, J = 4.5 Hz), 57.5 (dd, J = 11.2, 8.6 Hz), 83.6 (dd, J = 8.8, 3.0 Hz), 126.1 (d, J = 10.3 Hz), 126.9, 127.9 (d, J = 3.5 Hz), 128.0 (d, J = 2.8 Hz), 128.2 (d, J = 2.9 Hz), 128.3, 128.4 (d, J = 10.0 Hz), 128.4, 128.6, 128.8, 129.0, 129.2, 130.2 (d, J = 7.5 Hz), 130.4 (d, J = 2.2 Hz), s c r i p t butyl)phenylphosphine-borane 11h previously prepared from (+)-ephedrine 9. 11b,32 X-ray quality crystals were grown by slow evaporation of hexane. The structure and the data were reported in the SI. Colorless crystals; (0.32 g, 59% yield); R f = 0.55 (toluene); Mp = 234 °C. [α] D 20 = -93.6 (c 1.0, CHCl 3 ). 1 H NMR (300 MHz, CDCl 3 ): δ 0.25-1.77 (m, 6H), 1.13 (d, J = 14.6 Hz, 9H), 1.51 (d, J = 6.5 Hz, 3H), 2.23 (d, J = 7.5 Hz, 3H), 4.63-4.76 (m, 1H), 5.26 (t, J = 9.5 Hz, 1H), 6.53-6.63 (m, 2H), 6.96-7.62 (m, 18H). 13 C{ 1 H} NMR: (75.5 MHz, CDCl 3 ): δ 16.7, 24.4 (d, J = 2.9 Hz), 29.2 (d, J = 4.8 Hz), 32.5 (d, J = 44.7 Hz), 57.1 (dd, J = 11.1, 8.6 Hz), 82.4 (dd, J = 9.2, 5.1 Hz), 126.9 (d, J = 10.0 Hz), 128.0 (d, J = 10.8 Hz), 128.1, 128.3, 128.5 (d, J = 5.0 Hz), 128.7, 129.1, 129.3 (d, J = 6.8 Hz), 130.3 (d, J = 2,4 Hz), 130.4 (d, J = 19.2 Hz), 130.8 (d, J = 2.6 Hz), 131.1 (d, J = 2.1 Hz), 131.6 (d, J = 10.4 Hz), 132.5 (d, J = 10.1 Hz), 132.5 (d, J = 10.4 Hz), 138.2. 31 P{ 1 H} NMR (121.5 MHz, CDCl 3 ): δ +71.

4. 7

 7 .13. (S p )-(-)-N-[(1R,2S), 2-(Phenyl-o-biphenylphosphinito-borane)-1-methyl-2-phenylethyl], N-methylamino-diphenylphosphine-borane 21i. This compound was synthesized from(S p )-(+)-N-[(1R,2S)-2-hydroxy-1-methyl-2-phenylethyl],Nmethylamino(phenyl-o-biphenyl)phosphine-borane 11i previously prepared from (+)-

A c c e p t e

  Palladium-catalyzed asymmetric allylic alkylation of 3-substituted 1H-indoles and tryptophan derivatives with vinylcyclopropanes. J. Am. Chem. Soc. 2018, 140, 6710-6717. (f) Song, T.; Arseniyadis, S.; Cossy, J. Asymmetric synthesis of α-quaternary γ-lactams through palladium-catalyzed asymmetric allylic alkylation. Org. Lett. 2019, 21, 603-607. (18) Nettekoven, U.; Widhalm, M.; Kalchhauser, H.; Kamer, P. C. J.; van Leeuven, P. W. N. M.; Lutz, M.; Spek, A. L. Steric and electronic ligand perturbations in catalysis: asymmetric allylic substitution reactions using C 2 -symmetrical phosphorus-chiral (bi)ferrocenyl donors. J. Org. Chem. 2001, 66, 759-770.

( 19 )

 19 Oohara, N.; Katagiri, K.; Imamoto, T. A novel P-chirogenic phosphine ligand, (S,S)-1,2-bis-[(ferrocenyl)methylphosphino]ethane: synthesis and use in rhodium-catalyzed asymmetric hydrogenation and palladium-catalyzed asymmetric allylic alkylation. Tetrahedron: Asymmetry 2003, 14, 2171-2175. (20) (a) Tsuruta, H.; Imamoto, T. P-Chirogenic monodentate phosphine ligands bearing 2-biphenyl group. Synlett 2001, 999-1002. (b) Imamoto, T.; Nishimura, M.; Koide, A.; Yoshida, K. t-Bu-QuinoxP* ligand: Applications in asymmetric Pd-catalyzed allylic substitution and Ru-catalyzed hydrogenation. J. Org. Chem. 2007, 72, 7413-7416.

Table 1 . Synthesis of AMPP* and Diborane Complexes with P-chirogenic Phosphinite

 1

	Page 11 of 95		The Journal of Organic Chemistry
			M a n u s c r i p t
	Moieties A c c e p t e d
	entry	ephedrine 9	R 1	AMPP* 20 R	AMPP*(BH 3 ) 2 a 21 R'
			ACS Paragon Plus Environment

a Isolated yield from aminophosphine-borane 11. b  in ppm. c Diastereoselectivity (> 99%) checked by NMR. The o-anisyl-aminophosphine-borane 11a (R 1 = o-An, R = Ph), prepared from (+)ephedrine, afforded the o-anisylphosphinite 19a upon heating at 50°C overnight with two equivalents of DABCO in toluene. It reacted with Ph 2 PCl in presence of NEt 3 to provide the free AMPP* (R p )-20a (

Table

1, entry 1). The AMPP* (S p )-20a was similarly synthesized

Scheme 4. Diastereodivergent Synthesis of P-chirogenic AMPP* bearing an o-biphenyl Group

	Oxazaphospholidine complex (+)-10a reaction with the o-biphenyllithium reagent led first
	to the (R p )-aminophosphine-borane 11f in 81% yield (Scheme 4). This latter was reacted
	with Ph 2 PCl either directly followed by decomplexation, or after rearrangement upon
	14,15 It uses successive reactions of (+)-ephedrine 9 with PCl 3 , then with o-biphenyllithium reagent and heating with DABCO to afford the free P-chirogenic AMPP* (R P )-13f or (R P )-20f in 40% and 67% yields, respectively (Scheme 4a,b). The X-ray structures of the diborane complexes (R p )-12f and (R p )-21f of the AMPP* (R P )-13f and (R p )-20f, are showed in Figures S4 and S14 (SI). Concurrently, the oxazaphospholidine complex (-)-10b reacted with the phenyllithium reagent to form the (S p )-aminophosphine-borane 11i with a yield of 87% a n u s c r i p t M (Scheme 4). The reaction of 11i with Ph 2 PCl followed by decomplexation, or after
	finally with BH 3 . DMS for complexation (Scheme 4). rearrangement upon heating with DABCO, led to the free AMPP* (S P )-13i and (S P )-20i with respective yield of 44% and 58% (Scheme 4c,d). Figure S6 (SI) shows the X-ray structure of the borane complexes (S p )-12i of P-chirogenic AMPP* (S p )-13i, bearing an epimeric o-biphenyl-aminophosphine moiety in relation to (R P )-13f. The P-chirogenic AMPP* ligands bearing P-chirogenic aminophosphine 13 or A c c e p t e d phosphinite moieties 20 were studied in palladium-catalyzed allylic reactions of dimethyl
	malonate and benzylamine (vide infra). The palladium-catalyzed asymmetric allylic

Table 2 . Asymmetric Allylation of Dimethylmalonate and Benzylamine Catalyzed by Palladium Complexes of AMPP*13

 2

	Page 17 of 95

b

The reaction was performed to completion in 1 to 48 h.

c

Determined by HPLC on chiral column. d Reaction time 7 h.

e

Table 3 ,

 3 aminophosphine or -phosphinite moiety, led to catalyzed allylations with enantioselectivities up to 91% (R) or 95% (S) (Table2, entries 5, 8; Table3, entry 7).

	-Allylpalladium complexes 33-35 geometry was optimized considering the boat
	conformation of the seven-membered ring observed in the X-ray structure of PdCl 2 -
	complexes 30-32. This included changing the two chlorides by the -allyl ligand

entry 2: e.e. up to 44%). The origin of the observed enantioselectivity (i.e. R or S) has been addressed by DFT computations, notably for the -allylpalladium complexes 33-35 derived from the AMPP* ligands (R p )-13f, (S p )-13i and (R p )-20f, respectively (Schemes 5, 6; Table 4 and SI). These

A c c e p t e d M a n u s c r i p t ligands were derived from (+)-ephedrine and bearing a P-chirogenic o-biphenyl-(PhCCCPh). Both preferred M-or W-orientations of the -allyl moiety coordinated onto the palladium (II), were investigated (see Figures S22-S76, SI). The half-chair conformation in complexes 33-35 were also examined because the biphenyl substituent at the axial position to the Pd-square plane in complexes 34 and 35, could induce steric hindrance (R a

Table 4 . Data Selection of the Optimized Structures of Complexes 33-35 (DFT).

 4

	entr	complex	Relative total energy	Selected bond length	LUMO rel. atomic cont.
			(KJ mol -	Pd-C3		Pd-C1	C3 (%)	C1 (%)
	y 1 33M(boat) -65202.8789 (eV)	2.5	2.36703	(Å)	2.27063	13.79	10.71
	2 33W(boat) -65202.9047	1 ) 0	2.33082		2.28902	12.25	11.90
	3 34M(boat) -65202.6722	2.0	2.24787		2.35432	9.06	16.52
	4 34W(boat) -65202.6928	0	2.35003		2.26769	12.73	11.89
	5	34W(half-	-65202.6928	0	2.34958		2.26783	15.93	9.81
	chair) 6 35M(boat) -65202.7893	3.2	2.27871		2.37415	10.94	13.84
	7 35W(boat) -65202.8227	0	2.27178		2.32581	10.63	13.71
	8	35W(half-	-65202.8227	0	2.27193		2.32565	10.64	13.71
		chair)

  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

	for compounds (R p )-11e, (R p )-11h, (M,S p )-11v, R p )-12f, (R p )-12g, (S p )-12i, (S p )-15e, (S p )-21a, (S p )-21b, (R p )-21c, (R p )-21d, (S p )-21d, (R p )-21e, (R p )-21f, (R p )-Gaussian 16 and were detailed in the Supplementary Information (part C, SI). The DFT ground state calculations were carried out using the B3LYP/genecp method. A 6-31g (d, p) basis set was used for C, H, N and O atoms. VDZ (valence double ζ) with SBKJC effective core potentials was used for P and Pd atoms. 4.2. Synthesis of the oxazaphospholidine-2-borane complexes 10. 4.2.1. (2S,4R,5S)-3,4-Dimethyl-2,5-diphenyl-1,3,2-oxazaphospholidine-2-borane (-)-and 21g, (S Computational Details All density functional theory (DFT) calculations were performed with (+)-10a. These starting compounds were prepared from

p )-21h, 30, 31 and 32, respectively contain the supplementary crystallographic data

A c c e p t e d M a n u s c r i p t

bis(dimethylamino)phenylphosphine and (+)-and (-)-ephedrine 9, respectively, according to a methodology already described.

9,[START_REF] Chaux | Enantiodivergent synthesis of P-chirogenic phosphines[END_REF]

3. Synthesis of aminophosphine-boranes 11.

	was successively extracted with ethyl acetate, dried over MgSO 4 and filtered. The solvent 4.3.2. Preparation of ferrocenyllithium reagent by ferrocene deprotonation. A 50 mL
	was removed under vacuum and the residue was purified by chromatography on silica gel three-necked flask equipped with a magnetic stirrer under an argon atmosphere was
	using a mixture of petroleum ether/dichloromethane (1:1) as eluent. The charged with ferrocene (0.74 g, 4 mmol) and THF (10 mL). At 0 °C, t-BuLi (2.75 mL, 1.6 M
	oxazaphospholidine-borane complex (-)-10b was recrystallized from a mixture of in hexane, 4.4 mmol) was added dropwise, and the reaction mixture was stirred at 0 °C for
	M a n u s c r i p t methanol/dichloromethane. 0.16 g, 43% yield; White crystals; Mp = 155 °C; R f = 0.53 (petroleum ether/dichloromethane 1/1); [α] D 20 = -12.8 (c 0.3, CHCl 3 ). 1 H NMR (300 MHz, CD 2 Cl 2 ): δ -0.18-1.24 (m, 3H), 0.50 (d, J = 6.5 Hz, 3H), 2.32 (d, J = 10.2 Hz, 3H), 3.21-3.33 (m, 1H), 4.56 (dd, J = 6.0, 2.3 Hz, 1H), 7.02-7.06 (m, 2H), 7.14-7.22 (m, 4H), 7.26 (br.s, M a n u s c r i p t 1 h, before use.
	1,3,2-oxazaphospholidine (1 mmol) previously prepared by reaction of PCl 3 with the (+)-ephedrine 9 and N-methylmorpholine, was added at -78 °C a solution of o-biphenyllithium A c c e p t e d 4.3.1. Preparation of aryllithium reagents by metal/halide exchange. To a solution of bromoaryl derivatives (2 M) in THF was added 1 equivalent of s-butyllithium at 0 °C or 2 equivalents of t-butyllithium at -78 °C. After the formation of a white precipitate, the mixture was stirred at 0 °C for 1 h (or at -78 °C in the second case). The organolithium reagent was A c c e p t e d
	in diethyl ether (0.7 mmol). After stirring overnight, borane-dimethylsulfide (1.1 mmol) was dissolved with a minimum of dry THF before use.
	added and the mixture was stirred under argon for 6 h. After hydrolysis, the organic phase

5H), 7.30-7.43 (m, 2H), 7.77 (ddd, J = 11.8, 7.4, 1.2 Hz, 1H).

[START_REF] Holz | P-Chirogenic Xantphos Ligands and related ether diphosphines: Synthesis and application in rhodium-catalyzed asymmetric hydrogenation[END_REF]

P{ 1 H} NMR (121.5 MHz, CD 2 Cl 2 ): δ 132.5 (br.s). Anal. calcd for C 22 H 25 BNOP: C 73.15, H 6.98, N 3.88; found C 73.02, H 7.03, N 3.98.

4.

  The o-anisyl-, 11b -naphtyl-, 11b,29 -naphtyl-, 11b,29b o-tolyl-,[START_REF] Colby | monodentate ferrocenyl phosphines, novel ligands for asymmetric catalysis[END_REF][START_REF] Holz | P-Chirogenic Xantphos Ligands and related ether diphosphines: Synthesis and application in rhodium-catalyzed asymmetric hydrogenation[END_REF] p-tolyl-,[START_REF] Holz | P-Chirogenic Xantphos Ligands and related ether diphosphines: Synthesis and application in rhodium-catalyzed asymmetric hydrogenation[END_REF] o-biphenyl-

			The Journal of Organic Chemistry		Page 38 of 95
	4.3.4. , 11b,29,30	ferrocenyl-, 11b,14,30	t-butyl-, 11b,32	methyl-, 10,11b	cyclohexyl-, 11b	o-[(2-
	methoxyethoxy)methoxy]phenyl-, 9b o-isopropoxyphenyl-,
			M a n u s c r i p t
	A c c e p t e d
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  (d, J = 10.2 Hz), 130.6 (d, J = 2.3 Hz), 130.9 (d, J = 68.3 Hz), 132.0 (d, J = 10.5 Hz), 132.5 (d, J = 10.6 Hz), 141.5 (d, J = 2.3 Hz), 142.5. 31 P{ 1 H} NMR (121.5 MHz, CDCl 3 ): δ +69.8-70.2 (m). HRMS (ESI/Q-TOF) calcd for C 23 H 29 BNOPNa [M+Na] + : 400.19720; found:

	D 20 = -44.3 (c 0.5, CHCl 3 ). 1 H NMR (300 MHz, CDCl 3 ): δ 0.20-2.00 (m, 3H), 1.26 (d, J = 6.7 Hz, 3H), 1.89 (br.s, 1H), 2.41 (s, 3H), 2.49 (d, J = 7.8 Hz, 3H), 4.25-4.39 (m, 1H), 4.83 (d, J = 6.6 Hz, 1H), 7.14-7.20 (m, 2H), 7.25-7.44 (m, 8H), 7.47-7.53 (m, 4H). 13 C{ 1 H} NMR (75.5 The Journal of Organic Chemistry A c c e p t e d 400.19738. Anal. calcd for C 23 H 29 BNOP: C 73.22, H 7.75, N 3.71; found C 73.10, H 7.73, MHz, CDCl Page 39 of 95 M a n u s c r i p t N 3.62.
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Colorless crystals

(1.64 g, 87% yield). X-ray quality crystals were grown by slow evaporation of hexane. The structure and the data were reported in the SI; R f = 0.25 (toluene/ethyl acetate 9:1);

[α]

3 ): δ 13.5 (d, J = 1.2 Hz), 21.5, 30.4 (d, J = 3.7 Hz), 58.1 (d, J = 10.1 Hz), 78.7 (d, J = 6.1 Hz), 126.8, 127.6 (d, J = 61.7 Hz), 127.9, 128.3 (d, J = 10.7 Hz), 128.5, 129.2

  °C of t-butyllithium (1.9 M in hexane, 7.4 mL, 14 mmol) to a solution of (±)-2-bromo-1,1'binaphtyl 17 (2.3 g, 7 mmol) in Et 2 O (3.5 mL) and stirring at this temperature during one hour. The reaction mixture was stirred overnight until it reached room temperature, and 20 mL of water was added. The aqueous phase was extracted with CH 2 Cl 2 (3 x 20 mL). The organic extracts were dried over anhydrous MgSO 4 and the solvent was evaporated. The crude product was purified by chromatography on silica gel using CH 2 Cl 2 as eluent to give the aminophosphine-borane 11v as a mixture of diastereoisomers in 85:15 ratio. Recrystallization in ethyl acetate afforded the titled compound as only one diastereoisomer. (neat): ν max 3520, 3078, 2830, 2380, 2365, 1450, 1437, 1385, 1367, 1163, 1106, 1062, 1022, 998, 883, 822 cm -1 . HRMS (ESI/Q-TOF) calcd for C 36 H 35 BNOPNa [M+Na] + : 562.2448; found: 562.2446.

	4.22 (m, 1H), 4.52-4.53 (m, 1H), 7.02-7.07 (m, 1H), 7.13-7.17 (m, 3H), 7.23-7.30 (m, 4H), 7.33-7.45 (m, 8H), 7.48-7.54 (m, 3H). J = 9.8 Hz), 128.3, 128.4 (d, J = 65.6 Hz), 130.1, 130.3 (d, J = 2.1 Hz), 130.3 (d, J = 2.1 Hz), 130.6 (d, J = 2.2 Hz), 131.3 (d, J = 52.9 Hz), 132.3 (d, J = 9.8 Hz), 132.6 (d, J = 8.8 Hz), 133.7 (d, J = 9.8 Hz), 141.3 (d, J = 2.7 Hz), 143.0, 146.7 (d, J = 9.6 Hz). 31 P{ 1 H} NMR The Journal of Organic Chemistry A c c e p t e d A c c e p t e d 3H), 0.46 (d, J = 7.1 Hz, 3H), 2.56 (d, J = 7.7 Hz, 3H), 3.71-3.74 (m, 1H), 4.86-4.87 (m, 1H), 7.02 (d, J = 8.4 Hz, 1H), 7.12-7.27 (m, 10H), 7.35-7.43 (m, 4H), 7.52 (t, J = 7.5 Hz, 1H), 7.57-7.62 (m, 3H), 7.82-7.85 (m, 2H), 7.91-7.92 (m, 2H). 13 C{1H} NMR (125.8 MHz), CDCl 3 ): δ 9.7 (d, J = 5.5 Hz), 32.6 (d, J = 3.5 Hz), 57.9 (d, J = 9.4 Hz), 78.9, 125.1, 125.5, 125.6, 125.7, 126.7, 126.9, 127.1, 127.5 (d, J = 9.8 Hz), 127.6, 127.8, 127.9, 128.1, 128.2, 128.5, 129.3 (d, J = 10.7 Hz), 129.8, 130.3 (d, J = 2.0 Hz), 131.9 (d, J = 9.8 Hz), 133.2, A c c e p t e d (121.5 MHz, CD Page 40 of 95 M a n u s c r i p t M a n u s c r i p t 38 (m, M a n u s c r i p t
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1

H NMR (300 MHz, CD 2 Cl 2 ): δ 0.52-1.82 (m, 3H), 0.85 (d, J = 6.9 Hz, 3H), 2.43 (d, J = 8.0 Hz, 3H), 4.17-13 C{ 1 H} NMR (125.8 MHz, CD 2 Cl 2 ): δ 11.4, 30.8 (d, J = 5.0 Hz), 57.8 (d, J = 10.0 Hz), 78.1 (d, J = 7.7 Hz), 126.4, 126.9, 127.0, 127.5, 127.7 (d, 2 Cl 2 ): δ +70.7 (br.s). FTIR (neat): ν max 3448, 2961, 2897, 2388, 1643, 1604, The X-ray structure and the data were reported in the SI. White solid (0.72 g, 38% yield). R f = 0.41 (CH 2 Cl 2 ); [α] D 20 = +18.0 (c 0.3, CHCl 3 ). 1 H NMR (500 MHz, CDCl 3 ): δ 0.40-1.133.4, 133.7, 134.0 (d, J = 9.7 Hz), 134.1, 134.2 (d, J = 7.2 Hz), 134.8 (d, J = 4.0 Hz), 142.6, 144.2 (d, J = 9.9 Hz). 31 P{ 1 H} NMR (202.5 MHz), CDCl 3 ): δ +71.7 (br.s). FTIR

  1587, 1572, 1471, 1456, 1437, 1383, 1372, 1275, 1244, 1222, 1164, 1132, 1113, 1061, 1013, 983, 952, 890, 865, 768, 752, 735, 714, 694 cm -1 . HRMS (ESI/Q-TOF) calcd for C 37 H 44 B 2 NO 2 P 2 [M-H] + : 618.3033; found 618.3043. Anal. calcd for C 37 H 45 B 2 NO 2 P 2 :

	C 71.75, H 7.32, N 2.26; found C 72.02, H 7.56, N 2.32.

  J = 13.0, 7.2, 1.0 Hz, 1H).[START_REF]C{ 1 H} NMR (100.6 MHz[END_REF] C{ 1 H} NMR (125.8 MHz, CDCl 3 ): δ 15.8 (d, J = 1.6 Hz),

	1 H NMR (500 MHz, CDCl 3 ): δ 0.50-1.82 (m, 6H), 1.37 (d, J = 6.9 Hz, 3H), 2.45 (d,
	J = 6.9 Hz, 3H), 4.55-4.58 (m, 1H), 5.47 (t, J = 8.2 Hz, 1H), 6.39 (t, J = 7.7 Hz, 2H), 6.53 (t,
	J = 7.4 Hz, 1H), 6.83-6.87 (m, 6H), 6.98-7.08 (m, 7H), 7.16-7.27 (m, 4H), 7.35-7.38 (m,
	2H), 7.41-7.44 (m, 2H), 7.57 (d, J = 8.3 Hz), 7.65-7.75 (m, 3H), 7.80 (d, J = 8.3 Hz, 1H),
	7.94 (d, J = 8.3 Hz, 1H), 8.01 (d, J = 7.8 Hz, 1H), 8.11 (dd, J = 15.6, 6.4 Hz, 1H), 8.38
	(ddd,

  J = 11.9, 7.0, 1.7 Hz, 1H).[START_REF]C{ 1 H} NMR (100.6 MHz[END_REF] C{ 1 H} NMR: (125.8 MHz, CDCl 3 ): δ 16.0, 29.4 (d, J = 4.5 Hz), 55.5, 57.6 (dd, J = 11.1, 8.6 Hz), 82.4 (dd, J =

	(+)-N-[(1S,2R)-2-hydroxy-1-methyl-2-phenylethyl], phosphine-borane 11a previously prepared from (-)-ephedrine 9. 11b X-ray quality crystals N-methylamino(o-anisyl)phenyl were grown by slow evaporation of CH 2 Cl 2 ; The structure and the data were reported in the SI. White crystalline needles (0.38 g, 65% yield); R f = 0.60 (toluene); Mp = 155 °C. [α] D 20 = +68.8 (c 0.6, CHCl 3 ). Page 61 of 95 The Journal of Organic Chemistry A c c e p t e d M a n u s c r i p t 6.58 (m, 2H), 6.77 (dd, J = 8.2, 4.6 Hz, 1H), 6.95-7.09 (m, 8H), 7.10-7.15 (m, 1H), 7.16-7.34 (m, 7H), 7.35-7.50 (m, 4H), 7.80 (ddd, 8.9, 2.5 Hz), 111.8 (d, J = 5.2 Hz), 120.2 (d, J = 70.2 Hz), 120.8 (d, J = 10.5 Hz), 127.4 (d, J = 10.9 Hz), 128.0 (d, J = 10.9 Hz), 128.1, 128.3 (d, J = 8.4 Hz), 128.4, 128.7, 129.7 (d, J = 71.7 Hz), 130.3 (d, J = 2.4 Hz), 130.6 (d, J = 2.2 Hz), 130.7 (d, J = 57.3 Hz), 131.0, 131.7 (d, J = 10.5 Hz), 132.5 (d, J = 10.2 Hz), 132.6 (d, J = 62.4 Hz), 133.3 (d, J = 9.3 Hz), 133.9 (d, J = 2.0 Hz), 138.4, 160.9 (d, J = 4.4 Hz). 31 P{ 1 H} NMR (202.5 MHz, CDCl 3 ): δ +71.1 (br.s), +105.3 (br.s). HRMS (ESI/Q-TOF) calcd for C 35 H 41 B 2 NO 2 P 2 Na [M+Na] + : 614.27026; found 614.26804. Anal. calcd for C 35 H 41 B 2 NO 2 P 2 : C 71.10, H 6.99, N 2.37; found: C 70.76, H 7.02, N 2.46. 4.7.3. (R p )-(+)-N-[(1R,2S)-2-(o-Anisylphenylphosphinito-borane)-1-methyl-2-phenylethyl], N-methylaminodiphenylphosphine-borane 21a. This enantiomer was synthesized from (R p )-(+)-N-[(1R,2S)-2-hydroxy-1-methyl-2-phenylethyl], N-methylamino(o-anisyl)phenyl phosphine-borane 11a previously prepared from (+)-ephedrine 9. 11b (0.40 g, 68% yield). 31 P{ 1 H} NMR (202.5 MHz, CDCl 3 ): δ +71.3 (br.s), +105.1 (br.s). 4.7.4. The Journal of Organic Chemistry A c c e p t e d synthesized from (S p )-(+)-N-[(1S,2R)-2-hydroxy-1-methyl-2-phenylethyl], N-methylamino(-naphtyl)phenylphosphine-borane 11c previously prepared from (-)-ephedrine 9. 11b,29 X-ray quality crystals were grown by slow evaporation of CH 2 Cl 2 . The structure and the data were reported in the SI. Colorless crystals (0.37 g, 61% yield); R f = 0.60 (toluene); Mp = (S Page 62 of 95 M 198 °C. [α] D 20 = +48.9 (c 0.5, CHCl 3 ). 1 H NMR (500 MHz, CDCl 3 ): δ 0.38-1.61 (m, 6H), 1.02 (d, J = 6.6 Hz, 3H), 2.19 (d, J = 7.6 Hz, 3H), 4.42-4.54 (m, 1H), 5.51 (t, J = 9.7 Hz, 1H), 6.56 (dd, J = 11.3, 7.8 Hz, 2H), 6.93-7.02 (m, 4H), 7.03-7.21 (m, 8H), 7.22-7.45 (m, 8H), 7.49-7.54 (m, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 8.5 Hz, 2H), 8.31 (ddd, J = 14.8, a n u s c r i p t 7.1, 0.7 Hz, 1H). 13
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1

H NMR (500 MHz, CDCl 3 ): δ 0.34-1.45 (m, 6H), 1.26 (d, J = 6.6 Hz, 3H), 2.21 (d, J = 7.6 Hz, 3H), 3.47 (s, 3H), 4.47-4.57 (m, 1H), 5.33 (t, J = 9.4 Hz, 1H), 6.

51-p )-(+)-N-[(1S,2R)-2-(-Naphtylphenylphosphinito-borane)-1-methyl-2-

phenylethyl], N-methylaminodiphenylphosphine-borane 21b. This compound was

  1 (br.s), +125.5 (br.s). HRMS (ESI/Q-TOF) calcd for C 32 H 43 B 2 NOP 2 Na [M+Na] + : 564.28982; found: 664.28944. Anal. calcd for C 32 H 43 B 2 NOP 2 : C 71.01, H 8.01, N 2.59; found: C 70.92, H 8.39, N 2.65.

ACKNOWLEDGMENTS

The authors are grateful for A.J. fellowship and financial support provided by the "Ministère de l'éducation nationale de l'enseignement supérieur et de la recherche", the "Conseil régional de Bourgogne" (research programs 3MIM, PARI santé, CD2A), the Satt-SAYENS, the CNRS (Centre National de la Recherche Scientifique) and the FEDER (Fond Européen de Développement Régional). The authors would like also to thank Ms. M. J. Penouilh, F. Chaux, Mrs M. Picquet, Q. Bonin and E. Closier at the Satt-Sayens for spectroscopy analyses and valuation, Ms E. Pousson and M. M. Soustelle for the elemental analyses, M P. Richard for X-ray structures, Ms N. Khiri-Meribout, M. J. Eymin and M. M. Lagrelette, D. Moulin, P. Rasque and J. Rey for synthesis. PDH acknowledges the Natural Science and Engineering Research Council of Canada for funding. Ms L. Qin at the University of New South Wales, Australia, is warmly thanked for his help to the preparation of this manuscript.

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ASSOCIATED CONTENT

Supporting Information

1 H, [START_REF]C{ 1 H} NMR (100.6 MHz[END_REF] C{ 1 H}, [START_REF] Holz | P-Chirogenic Xantphos Ligands and related ether diphosphines: Synthesis and application in rhodium-catalyzed asymmetric hydrogenation[END_REF] P{ 1 H} NMR spectra, X-ray structures with crystallographic data, HPLC chromatograms on chiral column, catalysis complementary results and computational calculations are reported in part A, B and C, respectively. This material is available free of charge via the internet at http://pubs.acs.org.

AUTHOR INFORMATION

Corresponding Authors

* E-mail: Sylvain.Juge@u-bourgogne.fr Present Address § Oril Industrie, 76210-Bolbec-France  RTP France, ZI Beaune-Vignolles 21207-Beaune Cedex-France Note: This work is the subject in part of the patent C-bulky P-chirogenic organophosphorus compounds WO 2019/180084 (2019 sept. 26 th ).

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