New sulfur-phosphine ligands derived from sugars: synthesis and application in palladium-catalyzed allylic alkylation and in rhodium asymmetric hydrogenation

An efficient route to mixed phosphine / thioglycoside ligands type IV starting from glucose pentaacetate is reported. In only five steps the key epoxide 6 has been obtained in high yield and its structure determined by X-ray analysis. The ring opening of the tert-butyl 4,6-O -benzylidene- 2,3-anhydro-1-thio-β -D-allopyranoside 6 with diphenylphosphinyl lithium afforded the desired ligand as a single diastereoisomer. The prepared compounds act as a bidentate ligands as shown by X-ray analysis of the Rh(I)-complex 12 . Preliminary results on the behaviour of these ligands in Pd(0)-catalyzed allylic alkylation, and in Rh(I)-catalyzed enamide hydrogenation are also reported.


Introduction
The significance of optically pure compounds in important areas such as agriculture, fragance, and medicine is actually well recognized.As illustrative data, more than 50% of the drugs currently in the market are enantiopure compounds, and the main biologically significant molecules needed for basic biomedical studies, possess at least one chiral centre. 1 Consequently, the design of new and efficient processes allowing the synthesis of chiral compounds with high optical purities represent an important goal for academic and industrial synthetic chemists. 2mong all the different ways to ensure chiral transition state, enantioselective catalysis is the method of choice, as it combines both efficiency and versatility. 3Enantioselective catalysis is usually achieved by using a transition metal bound to a chiral organic ligand, responsible for the enantiodiscrimination.Surprisingly, an analysis of the massive literature on metal catalyzed asymmetric synthesis shows that most of the ligands developed so far, are based on discrete chiral framework. 4On the other hand, despite the enormous and continuous efforts devoted to this area in the last three decades, its impact in the arena of fine chemicals synthesis is still reduced. 5One of the main reasons for this situation is that the catalyst precursors are generally relatively expensive complex molecules obtained through multisteps synthesis.Carbohydrates, which are amongst the cheapest and abundant chiral starting materials, hold a range of structural characteristics making them very appealing for such venture. 6In a project directed toward the use of chiral sulfur compounds in asymmetric synthesis, 7 we have recently started a research program directed toward the use of sulfur based ligands derived from carbohydrates and their applications in enantioselective catalysis. 8Although, we have found that C 2 -symmetric bisthioglycosides I, 8a,c and C 1 -symmetric thioglycosides II, 8d (Figure 1), are good ligands for palladium catalyzed allylic alkylation, the catalyst derived from mixed S/P ligand III exhibited both improved reactivity and enantioselectivity.8b In order to evaluate the contribution of the phosphinite moiety, and the ring size in the metallacycle intermediate to the catalytic behavior of III, a related ligand with a phosphine directly linked to the C-2 carbon instead of a phosphinite was needed.In the present work, we report on the first synthesis of bidentated S/P ligand IV, derived from glucose, the characterization of its rhodium complex and the preliminary applications in Rh(I)-catalyzed enamide hydrogenation and palladium-(0)-catalyzed allylic substitution.One of the most salient features of thioether based ligands is that upon coordination to the metal, the sulfur atom becomes stereogenic. 8,9Consequently, high enantioselectivities are expected with these ligands, 10 as far as the low inversion barrier of the sulfur metal bond can be restricted. 11Thus any attempt to use sulfur based ligands must contemplate the stereocontrol of the sulfur metal bond, either through steric or stereoelectronic bias. 12In the case of S/P ligands reported in this work a tert-butyl group has been attached to the sulfur atom in order to favor one diastereomeric metal complex as a consequence of steric interactions between this group and the pyranose ring.8b While there is a large number of sugar based ligands with a phosphorus atom, the main type deals with a phosphorus atom attached to oxygen as a phosphinite and phosphite group. 13Ligands with phosphorus directly attached to a carbon atom of the pyranose ring are scarce, as a consequence of the synthetic difficulty for their preparation.Taking into account the large amount of elimination which takes place in the nucleophilic substitution with anions for the preparation of 2-deoxy-sugars, the best strategy followed so far, is the ring opening of epoxides. 14Nevertheless, in view of the absence of precedents on the synthesis of 2,3-anhydro-1deoxy-β-thioglycoside, a modular synthetic approximation was first developed (Scheme 1).The first step is a thioglycosylation using the sterically hindered tert-butanethiol as glycosyl acceptor, glucose pentaacetate 1 as glycosyl donor, and BF 3 Et 2 O as activator.We have recently found that this transformation is under thermodynamic control, being the α-thioglycoside the more stable isomer.8b In order to obtain the kinetic isomer, the reaction was conducted at 0 ºC affording the desired product 2 in 70% yield as a white solid.A Zemplen deacetylation followed by acid catalyzed benzylidene acetal formation in DMF afforded diol 4 in 90% yield.The double protection of 3,4-diol afforded the dimesylate 5 which, upon treatment with sodium methoxide, afforded the two possible allo-and manoepoxides 6 and 7 in a 3 : 2 ratio.Eventhough the two epoxides have a good separation factor, which allows their purification, the unequivocal determination of their structures could not be done by NMR analysis.Fortunately, we could obtain a single crystal of the major epoxide 6, suitable for X-ray crystallographic analysis, and its structure is given in Figure 2.  As it can be seen from Figure 2, the major compound 6 is the allo epoxide with a (2R, 3R) absolute configuration in the oxirane ring.The compound crystallizes in a O H 5 (D) half chair conformation with the bulky tert-butylsulfenyl group in a pseudo equatorial position.The NMR data of compound 6 are in complete agreement with the crystalline structure indicating that in solution the allo epoxide adopts also the O H 5 (D) half chair conformation.Once determined that the major and minor epoxides 6 and 7, correspond to the allo-and mano-epoxides respectively, the key opening oxirane step was studied.Addition of freshly prepared diphenylphosphinyl lithium (PPh 2 H + BuLi) on a solution of epoxide 6 disolved in a deoxygenated Et 2 O:DMF (1:1) mixture, afforded the desired phosphine 8 as a single diastereoisomer.Homo-and heteronuclear NMR analyses indicate that the opening of the epoxide takes place as predicted at the 2 position in accord with the Fürst-Plattner rule (1,2trans diaxial opening). 16Treatment of compound 8 with acetic anhydride in pyridine afforded the fully protected mixed S/P ligand 9.

Scheme 3
The ability of the prepared phosphine thioglycosides 8 and 9 to act as chiral ligands in asymmetric catalysis was first assayed in the model reaction of palladium catalyzed allylic alkylation of 1,3-diphenylpropenyl acetate 10 with dimethyl malonate, 17 Scheme 3, and the results are given in Table 1.
As it can be seen from Table 1, in the particular case of ligand 8, beside the modest chemical yield, the enantioselectivity was also deceiving as the allylated product was obtained in racemic form (Table 1, entry 1).The acetyl group at the 3 position of the ligand has a beneficial effect on the palladium catalyzed allylic alkylation as the ligand 9 affordded the product 11 with better chemical yield.
Nevertheless, concerning the enantioselectivity the allylated product was obtained with a very low 20% ee in favor of the R isomer.The change of the solvent from acetonitrile to methylene chloride did not improve the enantioselectivity, while lowering the temperature allowed the synthesis of 11R in 30% enantiomeric excess and 55% chemical yield.It is worth mentioning that the enantioselectivity observed is far from the 96% ee obtained with the related phosphinite thioglycoside (Figure 1, ligand III, R = CMe 3 , R' = Ac) recently reported by us.8b These results may be rationalized by the different electronic effects of the phopshinite and phosphine moiety, together with a better ability of the six member palladacycle intermediate A, compared to the five member palladacycle B, to transfer the chiral information of the sugar to the π-allyl moiety, Figure 3. Next we evaluated the capacity of the prepared S/P ligands in the asymmetric synthesis of amino acids through the enantioselective hydrogenation of enamides. 18While there are a large number of effective chiral bis-phosphines for this transformation, 19 the few mixed ligands used, usually lead to low reactivity or selectivity or both.To start this study we first synthesized a well defined Rh(I) catalyst precursor.Treatment of 1 equiv. of 9 with 1 equiv. of [(COD) 2 Rh]SbF 6 , 20 in methylene chloride afforded the cationic complex 12 in quantitative yield as an orange solid, Scheme 4.

Scheme 4
As stated in the introduction one of the most important characteristic of mixed S/P ligands is that upon coordination to the metal, the sulfur atom becomes stereogenic.Interestingly, 1 H, 31 P, and 13 C NMR analyses indicate that complex 12 is formed as a single diatereoisomer.
Furthermore, compound 12 is a crystalline compound, and we could get appropriate crystal for X-ray studies, Figure 4.As it can be seen from Figure 4, in the Rh(I) complex 12, compound 9 acts as a bidentate ligand, as the rhodium is coordinated to the phosphorus and the sulfur atoms, leading to a five member metalacycle.In complex 12, the sugar crystallizes under a 4 C 1 conformation, while the 5 member metalacycle has an envelope conformation.Unexpectedly, the absolute configuration at sulfur is R, and the bulky tert-butyl group, in a pseudo equatorial position, is in an unfavorable gauche relationship with the endocyclic oxygen. 22This result may be explained taking into account that under the envelope conformation, a pseudo axial disposition of the tert-butyl group undergoes a severe steric interaction with the cyclooctadiene coligand.The geometry around the rhodium atom is square planar, slightly distorted with S-Rh-P angle of 84.49 (8) Once determined the structure of the precatalyst, it was used in the model reaction of hydrogenation of methylacetamido cinnamate 13, leading to the protected phenylalanine 14, Scheme 5, and the results are given in Table 2.As it can be seen from Table 2, the Rh(I) catalyst 12 was not very active in the hydrogenation of methylacetamido cinnamate 13, as up to 40 atm.were necessary to afford only a 70% conversion to the phenylalanine derivative 14.With regard to the enantioselectivity, the product was obtained with a very low 10% ee in favor of the R isomer.These results which are in accord with those obtained in the Pd-catalyzed allylic alkylation, indicate that phosphine thioglycoside I are not suitable ligands for processes catalyzed by square planar d 8 metals.
In conclusion, we have reported a simple, modular and efficient synthetic approach for the synthesis of new mixed S/P ligands, using carbohydrates as cheap starting materials.The strategy is based on the diastereoselective opening of the tert-butyl 4,6-O-benzylidene-2,3anhydro-1-thio-β-D-allopyranoside with diphenylphosphinyl lithium.The obtained compounds act as a bidentate ligands as shown by the structural studies of the corresponding Rh(I)-complex 12. X-ray analysis, and dynamic NMR studies, demonstrated that there is an efficient stereochemical control of the sulfur configuration upon coordination to the rhodium, both in solution and in solid state.The prepared ligands were evaluated in two asymmetric reactions, namely the Pd(0)-catalyzed allylic alkylation, and the Rh(I)-catalyzed hydrogenation of enamides.In both cases the final products were obtained with low ees and moderate yields.Nevertheless, the synthetic simplicity of the synthetic route, associated with the high stereocontrol of the stereogenic sulfur atom, make us optimistic about the behavior of the new ligands in other metal catalyzed asymmetric transformations.

Experimental Section
General Methods.All reactions were run under an atmosphere of dry argon using oven-dried glassware and freshly distilled and dried solvents.THF and diethyl ether were distilled from sodium benzophenone ketyl.Dichloromethane was distilled from calcium hydride.TLC was performed on Silica Gel GF254 (Merck) with detection by charring with phosphomolybdic acid/EtOH.For flash chromatography, silica Gel (Merck 230-400 mesh) was used.Columns were eluted with positive air pressure.Chromatographic eluents are given as volume to volume ratios (v/v).NMR spectra were recorded with a Bruker AMX500 (1H, 500 MHz) and Bruker Avance DRX500 (1H, 500 MHz) spectrometers.Chemical shifts are reported in ppm, and coupling constants are reported in Hz.Routine spectra were referenced to the residual proton or carbon signals of the solvent.High-resolution mass spectra were recorded on a Kratos MS-80RFA 241-MC apparatus.Optical rotations were determined with a Perkin-Elmer 341 polarimeter.1,2,3,4,5-Penta-O-acetyl-β-D-glucopyranose 1, was purchased from Aldrich.

Table 1 .
Pd-Catalyzed allylic alkylation of 1,3-diphenylpropenyl acetate 10 with dimethyl malonate using S/P ligands 8 or 9aAll reactions were conducted using 4.3 mol% of the ligand and 1.5 mol% of [PdCl(C 3 H 5 )] 2 at r.t.b Isolated yields.c Determined by HPLC using chiral column Chiralpack-AD.d R or S configurations based on specific rotation.e Reaction conducted at -15 ºC.

Table 2 .
1ydrogenation of methyl acetamido cinnamate 13 using Rh(I)-complex 12aAll reactions were conducted using 1 mol% of the complex 12. b Determined by1H NMR analysis of the crude.c Determined by HPLC using chiral column Chiralcel OJ.