Separation of BINAPO enantiomers on brush-type chiral stationary phases

Brush-type chiral stationary phase CSP 12 was specifically designed for separation of BINAPO enantiomers, which can be useful as organocatalysts or as chiral ligands in organometallic catalysis. This chromatographic separation process can compete with other routes to enantiomerically pure BINAPO.


Introduction
Separation of enantiomers of axially chiral compounds is becoming an ever more important goal in chiral chromatography.2][3][4] Since chiral catalysis represents one of the most effective transfers of chirality in small and large-scale syntheses, 5,6 any route to chiral organic molecules in the enantiopure form that can act as the catalyst, or be part of a catalytic system, is a worthwhile goal from an academic and industrial point of view.
Prompted by continuous reporting on new applications of chiral bidentate ligands, and by our interest in developing new brush-type chiral stationary phases (CSPs) for specific applications, [7][8][9][10][11] we focused on the design and testing of a specific group of CSPs in order to perform chromatographic separation of BINAPO (1) enantiomers.So far in the literature the chromatographic enantioseparation of BINAPO 12 or its fluoro derivatives 13 is noted only for the purpose of the enantiomeric purity determination.1][22] We are using acronym BINAPO only for the latter compound.This axially chiral diphosphine-oxide was first developed as an intermediate in one of the synthetic routes to the enantiomerically pure BINAP (2). 23Catalytic applications of (+) and (-)-BINAP are numerous, beginning from enantioselective hydrogenation rearrangement of carbon skeletons.Nobel laureate Prof. R. Noyori has substantially contributed to the discovery and wide-scale application of BINAP.Chromatographic separation of BINAPO enantiomers and their one-step reduction using silane, 23 represent an effective route to the highly priced, optically pure BINAP enantiomers.S-BINAPO is acclaimed as starting material to prepare 5,5'-disubstituted S-BINAP congeners via bromination, cyanation and final hydrogenation of both cyano and phosphinoxide groups. 24A similar approach was reported where 5,5'-diamino S-BINAP is obtained starting from S-BINAPO. 25Soon after the first separation of BINAPO enantiomers, catalytic applications of this axially chiral bis-P-oxide were reported in production of chiral target compounds in the enantiomerically pure form.Thus S-BINAPO has been used as a chiral organocatalyst in enantioselective allylation of aldehydes with allyltrichlorosilane, 20,21 in allylation of benzoylhydrazones, 22 and in symmetric ring opening of meso-epoxides. 26The coordination chemistry of BINAPO has not been well explored. 15,27However catalytic activity of its organometallic complexes can be expected due to its high affinity for hard metal ions, as indicated by reductive coupling of ketones with α,β-unsaturated esters promoted by the complex of BINAPO with Sm(II)I 2 . 28ue to catalytic versatility of optically pure BINAPO and its intermediacy in the manufacture of BINAP, new effective methods for separation of racemic BINAPO are highly welcome.Based on our preliminary experience with chromatographic separation of BINAPO enantiomers, herein we report the synthesis and evaluation of novel CSPs for their large-scale separation.

Results and Discussion
We previously identified the CSP 1 as a promising separator of BINAPO enantiomers, 7,8 as illustrated in Figure 1, for a MeOH -MTBE mixture as eluent.In spite of large difference in R t values of enantiomers, significant peak-broadening and the need for binary solvent mixture leave the space for improved separation capacity of new CSPs.Prompted by this result we decided to get more knowledge about structural segments of brush-type CSPs required for effective molecular recognition of BINAPO enantiomers, in order to prepare highly effective CSP for the large-scale, including SMB separation of BINAPO.BINAPO possess two oxygen atoms in the P-O bonds as good hydrogen-bond acceptors, while highly polarized resonance structures of BINAPO can be involved in the strong electrostatic interactions with the chiral selector.These properties qualify BINAPO as a good candidate for enantioseparation on the brush-type CSPs that can accommodate such a large C 2 symmetric molecule and match both types of interactions.Indeed, inspection of the models of 1 in its skewed conformation and of the chiral separator unit within CSP 1 has revealed many possible mutual orientations that allow hydrogen bonding between some of the three amide N-H bonds, one vinylogous amide N-H in CSP 1, and one or both P-O oxygen atoms in BINAPO, as well as electrostatic interactions between P-O and π-deficient aromatic DNB unit.It was intuitively concluded that not all interactions of BINAPO are contemporaneously possible along the CSP 1 backbone, and that properly designed new chiral selectors should contain less complex and more effective assembly of selected subunits.
Preparation of CSPs designed following this rationale is presented in Scheme 1.The synthesis started from commercial aminopropyl silica gel which was acylated to the stationary phase SP 1 according to the published procedure. 7In the next steps insertion of the spacer to obtain intermediate SP 2 to SP 4, followed by introduction of chiral unit (separator) afforded CSP 1 to CSP 12. Reagents and conditions are listed in Scheme 1 for the different steps, while detailed protocols are given in the Experimental.
The testing of CSP 1 to CSP 4 in separation of BINAPO enantiomers has revealed crucial role of π-basic phenyl unit at stereogenic center in CSP 1 in enantiorecognition of BINAPO, since CSP 2 to CSP 4, derived from L-Ala, L-Leu and L-Phe, exhibit very low separation, Table 1.Second set of CSPs (CSP 5 to CSP 8) was designed to examine the impact of the terminal group.These CSPs instead of strong π-acceptor 3,5-dinitrobenzoyl (DNB) group contain π-donor aromatic, phenyl or naphthyl, group (CSP 7 and CSP 8) or aliphatic, methyl or tert-butyl, group (CSP 5 and CSP 6).All four CSPs exhibit good separation of BINAPO enantiomers, suggesting that terminal π-acid group is not included in the interactions with BINAPO and can be safely eliminated from the structure of chiral selector.
To test the effect of the flexibility of the aliphatic spacer, stationary phases CSP 9 and CSP 10 were prepared via SP 3 and SP 4. CSP 9 with longer n-butane spacer effects the enantioseparation of BINAPO with similar efficacy as CSP 1, revealing limited influence of that the length of spacer.To the contrary, CSP 10 that contain the more rigid, cyclic piperazine unit exhibit very low separation efficacy.Lost of efficacy of CSP 9 could be ascribed to the bulkiness of piperazine ring, and more probably to the absence of the terminal sec.amide group H-N(CO)-R to enter hydrogen bonding with BINAPO.
Assuming that not all four N-H amide protons in CSP 1 to CSP 8 and in CSP 10 can be engaged in hydrogen bonding, CSP 11 and CSP 12 are prepared.Both CSPs lack one amide unit as compared to CSP 1-4, and mutually differ in the orientation of the terminal amide group.Somewhat surprisingly, CSP 11 exhibited low separation capacity, but to our satisfaction CSP 12 proved most effective of all tested new CSPs, Table 1.0][31] Huge difference in enantiorecognition capacity between CSP 11 and CSP 12 is demonstrated on the Figs. 2 and 3 for the selected binary solvent mixture.In the final attempts to improve separation efficacy of CSP 12 π-acidic unit bound to γaminopropyl silica was varied.Two novel π-acidic aromatic units were build in the CSP 13 and CSP 14, Scheme 2, one of them with linear the other with angular position of the two alkylamino chains.The routes to CSP 13 and CSP 14 start from SP 5 and SP 7, via SP 6 and SP 8, respectively, applying similar reaction conditions as for CSPs in the Scheme 1.It deserves mentioning that in the CSP 14 an element of planar chirality is introduced, angularly alkylamino substituted aromatic ring, which corresponds to irregular triangle, simplex of the twodimensional space imaginable on the silica surface.1, revealing that high degree of optimization of distance and orientation of interacting units with BINAPO, H-bond acceptors and donors and π−aromatic units is achieved with CSP 12.
During this study the elution order of enantiomers was simultaneously checked by CD detector.On all CSPs that contain chiral unit derived from amino acids with S-absolute configuration, the elution order of BINAPO enantiomers was the same; (+)-enantiomer with R absolute configuration 33 was eluted first and (-)-S-enantiomer was the second.Only on CSP 9, derived from L-phenylglycine with piperazine as a spacer, and on CSP 12, derived from Snaproxene, the elution order was reversed.
In conclusion, optimization of chiral stationary phases suitable for preparative separation of BINAPO enantiomers was performed.The exceptional enantioseparation (α = 2.51, R S = 7.06) was achieved on CSP 12 derived from S-naproxen what affirmed this CSP as the chiral phase of choice for scale-up separation of BINAPO enantiomers.From the results obtained with this short series of CSPs it can be assumed that mechanism of chiral recognition of BINAPO include hydrogen bonding between one amide proton and one oxygen of BINAPO, and electrostatic interactions of π-deficient aromatic unit close to silica surface with second oxygen of BINAPO.

Experimental Section
General Procedures.Thin layer chromatography was performed on DC-Alufolien Kieselgel 60 F 254 (Merck, Darmstadt, Germany) and the compounds were detected using Spectroline UV lamp at 254 nm.Column chromatography was performed by using silica gel, particle size 0.063-0.200mm (J.T. Baker, Deventer, Netherlands).Silica gel Separon SGX NH2 (Tessek, Prague, Czech Republic), particle size 5 µm and pore size 100 Å, was used for the binding of chiral selectors.HPLC was performed with Knauer HPLC Pump 64 (Knauer, Berlin, Germany) equipped with 4-Port Knauer Degasser, CD detector Jasco CD-2095 Plus permitting simultaneous UV and CD detection (Jasco, Tokyo, Japan), Interface Knauer, Solvent Saver VICI Jour Research Model 2909 (VICI Jour Research, Onsala, Sweden) and UV detector Knauer Variable Wavelength Monitor.The detection was achieved at 270 nm on both detectors.Integration of the chromatograms was made with Chromatography Software Management System EUROCHROM 2000 for Windows, Version 1.65, software package (Knauer, Berlin, Germany).The packing of HPLC columns, purchased from Max Stevenson (Berlin, Germany), dimensions 150 mm x 4.6 mm I.D., was performed by slurry technique using Knauer pneumatic HPLCpump.n-Hexane, propan-2-ol, methanol and MTBE used for the chromatography and the packing of columns were of analytical grade (J.T. Baker) and redistilled before use.The HPLC column dead volume (t 0 ) was estimated by using 1,3,5-tri-tert-butylbenzene.Analyte samples were prepared by dissolving 2 mg of the racemic BINAPO in 1 ml of mobile phase.For analytical purposes 20 µl of freshly prepared solution was used.On the basis of retention times of the enantiomers (t R1 and t R2 ), the following chromatographic parameters were calculated: ARKAT USA, Inc.

Preparation of stationary phases
Synthesis of SP 1 and SP 2 was published previously. 7,34

SP 3
The mixture of SP 1 (3.0 g), piperazine (10 ml) and dichloromethane (10 ml) was homogenized by sonification for 5 min.The obtained suspension was stirred for 2 h at room temperature.Product was isolated by vacuum filtration on G-4 filter, washed with methanol (100 ml) and dried at 70 ºC for 5 h.It was obtained 2.99 g of SP 3. Anal.found: C 5.49, H 1.16, N 2.24 %.As calculated on C %, 1.0 g of CSP contains 0.23 mmol of bound organic material.

SP 4
The mixture of SP 1 (3.0 g), 1,4-diaminobutane (10 ml) and dichloromethane (10 ml) was homogenized by sonification for 5 min.The obtained suspension was stirred for 2 h at room temperature.Product was isolated by vacuum filtration on G-4 filter, washed with methanol (100 ml) and dried at 70 ºC for 5 h.It was obtained 3.01 g of SP 4. Anal.found: C 5.89, H 1.25, N 2.41 %.As calculated on C %, 1.0 g of CSP contains 0.26 mmol of bound organic material.

SP 6
The mixture of SP 5 (3.0 g), 1,2-diaminoethane (10 ml) and dichloromethane (10 ml) was homogenized by sonification for 5 min.The obtained suspension was stirred for 2 h at room temperature.Product was isolated by vacuum filtration on G-4 filter, washed with methanol (100 ml) and dried at 70 ºC for 5 h.It was obtained 2.99 g of SP 6. Anal.found: C 7.16, H 1.38, N 3.70 %.As calculated on C %, 1.0 g of CSP contains 0.49 mmol of bound organic material.

SP 8
The mixture of SP 7 (3.0 g), 1,2-diaminoethane (10 ml) and dichloromethane (10 ml) was homogenized by sonification for 5 min.The obtained suspension was stirred for 2 h at room temperature.Product was isolated by vacuum filtration on G-4 filter, washed with methanol (100 ml) and dried at 70 ºC for 5 h.It was obtained 3.04 g of SP 8. Anal.found: C 5.63, H 1.16, N 1.88 %.As calculated on C %, 1.0 g of CSP contains 0.33 mmol of bound organic material.

Preparation of chiral stationary phases CSP 1 -CSP 14 General procedure for preparation of chiral stationary phases
The mixture of starting substances was homogenized by treatment in ultrasonic bath for 5 min.After that the suspension was stirred at room temperature overnight and product, obtained in the form of yellow powder, isolated by vacuum filtration on G-4 filter, washed with methanol (100 ml) and dried at 70 ºC for 5 h.Synthesis of CSP 1 -CSP 3 and CSP 7 was published previously. 7,34P 4 Prepared from SP 2 (2.00 g), N-(3,5-dinitrobenzoyl)-L-phenylalanine (0.71 g. 2.0 mmol) and EEDQ (0.49 g, 2.0 mmol) in anhydrous THF (10 ml).It was obtained 2.25 g of CSP 4. Anal.found: C 8.76, H 1.33, N 3.01 %.As calculated on C %, 1.0 g of CSP contains 0.22 mmol of bound selector.