Iridium-catalyzed asymmetric hydrogenation of olefins using pyridine-phosphinites derived from the chiral pool

Cationic iridium complexes containing chiral pyridine-phosphinites, with their chirality derived from menthol or mandelic acid, were assessed in hydrogenations of trisubstituted non-functionalized olefins. Complexes with the new ligands showed high reactivity towards most of the olefins tested. The enantioselectivities varied with the structures of the substrate and the ligand. Best results were obtained in the hydrogenation of 3-hydroxy-2-methyl-1-phenylpropene using a ligand prepared from (-)-menthol, pyridyllithium and diphenylchlorophosphine (>99% conversion, 92% ee).


Introduction
Cationic iridium complexes with chiral P,N ligands have proved to be efficient catalysts for the hydrogenation of a wide range of functionalized and unfunctionalized olefins, 1 Unlike Rh-and Ru-diphosphine complexes they do not require the presence of a coordinating group near the C=C bond, so even purely alkyl-substituted olefins can be hydrogenated with high enantioselectivity.Chiral pyridine-phosphinites (1) belong to the most efficient ligands for the catalytic process, providing highly enantioenriched products from a variety of substrates. 2,3The enantioselectivity was found to be a function of the R 1 , R 2 , and R 3 substituents and was found to be particularly high when more rigid cyclic analogues were employed. 3The pyridinephosphinites were accessible from the appropriate chiral pyridyl alcohols, which were obtained from the racemates by preparative HPLC using a chiral column.Although this procedure gave access to the pure enantiomers, stereoselective synthesis is a more attractive option on a larger scale.Several methods are available for the synthesis of enantioenriched pyridyl alcohols, employing biological methods as well as synthetic reagents or catalysts.Use of hydrolases or esterases, for example, provides both enantiomers, one of them as an ester, with high enantiomeric excess. 4,5Obviously, the yield of each enantiomer is limited to a maximum of 50%, which is a disadvantage if only one enantiomer is needed.In addition, not all substrates are tolerated by the enzymes.A viable alternative is the reduction of ketones using chiral reducing agents 2a,6 or catalysts. 7However, enantioselectivities are not perfect, so in general, the ee of the product has to be increased by recrystallization or other methods.
An attractive alternative to these methods is based on compounds from the chiral pool.We have demonstrated that starting from cheap and easily accessible compounds such as menthol, mandelic acid, lactic acid or (R)-2,3-O-isopropylidene glyceraldehyde, the latter obtained by oxidative cleavage of protected mannitol, chiral stereochemically well-defined pyridyl alcohols can be obtained. 8,9We decided to evaluate pyridine-phosphinites derived from some of these pyridylalcohols in Ir-catalyzed hydrogenations of a number of unfunctionalized olefins and compare the results to those obtained using previously reported pyridine-phosphinites.

Preparation of ligands
Pyridylalcohols 2a and 2b were obtained in an 83:17 ratio (90% yield) as previously described by NaBH 4 reduction of the ketone obtained in 41% yield by reaction of 2-pyridyllithium with (1S,2S,5R)-1-cyano-2-isopropyl-5-methylcyclohexane, the latter obtained from (1R,2S,5R)menthyl tosylate in 99% yield (Scheme 1). 8,10The two diastereomers were easily separated by column chromatography.Since both enantiomers of menthol are available, this procedure also gives access to the enantiomers of 2a and 2b.Starting from methyl (S)-2-methoxy-2phenylacetate (methyl mandelate), an analogous procedure afforded 2c as a single isomer in 49% yield over two steps when the reduction was performed at low temperature (-78 °C). 11The corresponding reaction with 2-bromo-6-lithiopyridine gave a ketone which was reduced in situ to a single isomer (23% over two steps).Suzuki coupling with phenylboronic acid gave 2d (85%). 11RKAT USA, Inc.We have also demonstrated that the pyridylalcohols obtained in this way can be smoothly converted into pyridine-phosphinites. 11Thus, reactions of 2a-d with diphenylchlorophosphine followed by treatment with BH 3 -SMe 2 proceeded efficiently, providing protected ligands 1a-d (43%, 62%, 77% and 60%, respectively).Due to the modular nature of the synthetic procedure, ligand structures are easily varied not only by employing different natural products and differently substituted pyridine derivatives, but also by using different chlorophosphines.To demonstrate this, we decided to attach a stereochemically flexible phosphepine unit to alcohols 2a and 2b, hoping that the flexible unit would adopt the most suitable configuration in the catalytic reaction.Transformation of 2a and 2b to their lithium alcoholates followed by reaction of chlorophosphine 3 12 and BH 3 -protection gave access to 1e and 1f, respectively (Scheme 2).Tropoisomerization of the phosphepine unit is expected to be slow on the NMR time scale; ∆G # values for similar compounds have been determined to be around 19 kcal mol -1 at 298 K. 12 Since the phosphorus atom is not a stereogenic center, the presence of only two diastereoisomers is thus expected.Each compound was indeed obtained as a ca.1:1 mixture of the aR and aS diastereomers, as revealed for example by two sets of signals in their 1 H NMR spectra.

Catalytic reactions
Iridium complexes 4a-f were prepared by treatment of the appropriate ligand, after deprotection, with [Ir(COD)Cl] 2 followed by sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate. 13The complexes derived from 1e and 1f proved to be highly sensitive to oxygen.The complex from 1f was isolated in low yield after chromatography on silica-gel as an orange-red amorphous solid, whereas the analogous complex from 1e decomposed during work-up and chromatography and, therefore, was not further investigated.Catalytic hydrogenations were performed as previously described at room temperature and a hydrogen pressure of 50 bar in dichloromethane using 1 mol% of catalyst.
The results were compared to those previously obtained using ligands 1g-1l, which contain the same type of structural elements as the new ligands 1a-f.
Trisubstituted olefins 5-10 were selected as substrates.High conversions were observed in reactions of the sterically less demanding unfunctionalized olefins 6, 7, and 10 using all new ligands except 1d, which exhibited low reactivity, most likely as a result of steric hindrance.The α,β-unsaturated ester 8 gave low conversion with all catalysts, in line with previous results reported for ligands 1g-1l.In the hydrogenation of substrates 5 and 9 large differences in reactivity were observed between catalysts 1a-1d and 1f.The enantioselectivities varied considerably with the structure of the ligand and the substrate.Methylstilbene 5 was hydrogenated efficiently only when ligand 1f with a phosphepine group was used, but enantioselectivities were inferior to those previously observed using ligands 1g-1l.In the hydrogenation of E-and Z-methoxystyrenes 6 and 7 the new ligands also gave lower selectivities compared to ligands 1i-1l.The best results were obtained in the hydrogenation of allylic alcohol 9.Here the menthyl ligand 1a, which gave 92% ee and full conversion, clearly outperformed all other ligands, including 1j-1k.Finally, 1b and 1f showed results comparable to those previously observed for 1k and 1l in the hydrogenation of 10.
As expected, ligands 1a and 1b provided products with opposite absolute configuration, confirming that the stereocenter closest to phosphorus atom exerts the biggest influence on the stereoselectivity.For the same reason ligand 1c was expected to induce the same absolute configuration as 1a.This was indeed the case except for substrate 6.However, the enantioselectivities induced by ligands 1a and 1b in the hydrogenation of this substrate were very low, so these results should be interpretated with caution.Finally it may be concluded that no advantage was achieved by replacing the diphenylphosphine group by a phosphepine unit.
Pyridine-phosphinites are readily available in large quantities starting with easily accessible compounds from the chiral pool.The modular approach for the ligand synthesis allows extensive structural variations since different chiral natural products, pyridine derivatives, and phosphoruscontaining groups can be assembled.Cationic iridium complexes containing the new ligands and tetrakis [3,5-bis(trifluoromethyl)phenyl]borate as counter ion were found to be reactive and moderately enantioselective catalysts in hydrogenations of several trisubstituted unfunctionalized olefins.However, quite promising results were achieved in the hydrogenation of allylic alcohol 9 which gave 92% ee and full conversion with one of the catalysts.Considering the accessibility and the modular structure of these ligands, further optimization of the catalyst structure should be possible.

Experimental Section
General Procedures. 1 H NMR spectra were recorded at 400 or 500 MHz, 13 C NMR at 125 or 100 MHz and 31 P NMR at 202 MHz.The 1 H and 13 C chemical shifts are reported relative to remaining solvent peaks (CHCl 3 ), 31 P chemical shifts are reported relative to H 3 PO 4 (external).Optical rotations were recorded with a Perkin-Elmer 343 polarimeter at the sodium D line at ambient temperature.Air sensitive reactions were performed under nitrogen atmosphere in ovenor flame-dried glassware.CH 2 Cl 2 , PhMe and THF were taken from Meyer's Solvent Dispensing System.Flash chromatography was carried out using SDS silica gel 60 (40-63 µm).

Compound 1e-BH 3
n-BuLi (236 µL, 1.40 M, 0.33 mmol) was added to a degassed solution of alcohol 2a (80 mg, 0.32 mmol) in THF (2 mL) at -78 °C and the mixture was stirred at this temperature for 30 min.The temperature was increased to 0 °C and a degassed solution of phosphochloride 3 (86 mg, 0.35 mmol) in THF (0.7 mL) was added.The mixture was stirred at 0 °C for 3 h before BH 3 •Me 2 S (175 µL, 2M in THF, 0.35 mmol) was added and the resulting mixture was stirred at 0 °C for 14 h.H 2 O (5 mL) was added and the solvent was evaporated under vacuum.The crude product was purified by column chromatography on silica gel (CH 2 Cl 2 /EtOAc 98:2) to give 1e-    Complex 4f 1f-BH 3 (50 mg, 0.1 mmol) was deprotected using diethylamine (2 mL).Ligand 1f was dissolved in CH 2 Cl 2 (4 mL), and added to [Ir(COD)Cl] 2 (37 mg, 0.55mmol) in CH 2 Cl 2 (1 mL), to give an orange solution which was stirred at 50 °C for 2h.After cooling to room temperature, NaBAr F x3H 2 O (122 mg, 1.3 mmol) was added and the resulting red-orange mixture was stirred overnight.Then H 2 O (2 mL) was added and the mixture stirred for a further 30 min.The organic solvent was removed, the water phase extracted with CH 2 Cl 2 (2x3 mL) and the collected organic solution dried over MgSO 4 .The solvent was removed under vacuum at room temperature to give a brownish-red solid.The crude product was purified under N 2 by flash chromatography on silica