Efficient asymmetric addition of diethylzinc to ketones using tartaric acid derivative as chiral ligand

A new chiral ligand derived from natural tartaric acid was synthesized and was applied to the asymmetric addition of diethylzinc to aldehyde and ketones. Moderate to good enantioselectivities were obtained in the asymmetric addition of diethylzinc to ketones with 10% mol catalyst loading at room temperature.


Introduction
Chiral alcohols are ubiquitous in the structure of natural products and drug compounds, and are also important precursors for many other functional organic molecules.One of the most useful methods for the asymmetric preparation of sec-alcohols and tert-alcohols is the enantioselective addition of dialkylzinc reagents to carbonyl compounds with chiral ligands 1 .Recent studies showed the ligands with C 2 -symmetrical axes could catalyze dialkylzinc to aldehydes 2 or ketones 3 .Taking the advantage of the chirality of L-tartaric acid, we 4 designed and synthesized a series of ligands with C 2 -symmetric axe, two of them were successfully applied to the asymmetric addition of diethylzinc to ketones.Recently, another new chiral ligands derived from L-tartaric acid were synthesized, as showed in Scheme 1. Furthermore, these ligands were employed as promoters in the addition of diethylzinc to aldehyde and ketones.

Synthesis of the chiral ligands
Initially, L-tartaric acid was easily transformed into its ester 1. Subsequently, 1 was reduced in the presence of sodium borohydride and closed ring with the aid of 4-methylbenzene sulfonic acid to obtain tetrahydrofuran 3, 4-diol 2. 5 Then, the hydroxyl group in compound 2 was converted into amino group through three steps, which generated tetrahydro-3,4-diamine 5 with high yields. 6Once the diamine was available, it reacted with 4-methylbenzene-1-sulfonyl chloride and D-(+)-camphor sulfonyl chloride respectively and the chiral ligand 6 7 and 7 2e were synthesized.The carbonyl in the camphor ring of compound 7 was reduced and the diasteromer 8 was separated as a major product.3a

Asymmetric addition of diethylzinc to aldehyde and ketones
Our initial experiments in the asymmetric addition of diethylzinc to p-chlorobenzaldehyde involved the use of ligand 6, 7 and 8 (Scheme 2).Under the conditions the reaction was carried out smoothly, giving the desired secondary alcohol with high yields (entries 1-3 in Table 1).Among them ligand 6 gave the best enantioselectivity, which being up to 56%ee (entry 1 in Table 1).So, we choosed the ligand 6 as the model catalyst for further trial.The modulation of the catalyst loading, the reaction solvent and the temperature were of no much improvement on the enantioselectivity (entries 4-8 in Table 1 Afterwards, the chiral ligands were applied to the asymmetric addition of diethylzinc to pchloro acetophenone (Scheme 3).The results were listed in Table 2.As indicated the chiral ligand 8 gave the best enantioselectivity in high yields in toluene (entry 3 vs entries 1 or 2 in Table 2).Therefore, chiral ligand 8 was selected as the model catalyst for further optimization of the conditions.Using hexane as reaction solvent, the reaction only gave 52% yields with less than 50% ee (entry 4 in Table 2).It was ascribed to the weak solubility of 8 in hexane.The ARKAT USA, Inc. cooperation time of chiral ligand and titanium tetraisopropoxide was slightly propitious to the enantioselectivity.As illustrated in entry 5, the ee value was improved to 78% when the time was prolonged to 1 hour from 10 min (entry 5 vs entry 3 in Table 2).The further optimization in catalyst loading (entries 6-8 in Table 2), the temperature (entry 9 in Table 2) and the amount of Et 2 Zn (entry 10 in Table 2) established that the reaction condition in entry 6 were the optimal conditions for this type of asymmetric addition.a isolated yields.Unless other indicated, the chiral ligand and Ti (O i Pr) 4 were mixed in the vessel and stirred for 10 min before other substrate was added into the system.b The ee values were determined by chiral HPLC using OJ-H column.c No desired product was detected.d The cooperation time was prolonged to 1 hour before other reagents were added to the vessel.The succedent experiment was performed according to this cooperation time.e 3 equiv.Et 2 Zn was used in the reaction.
Having established the optimal conditions, different ketones were submitted to the addition in the presence of ligand 8 (Scheme 4).All the experimental results are illustrated in Table 3.As shown in Table 3, in all cases tested, acetophenone gave the best enantioselectivity, being up to 99% with a good yield (entry 1 in Table 3).Electron-withdrawing substituents at the paraposition of acetophenone favored both enantioselectivity and reaction yield, with the enantiomeric excess ranged from 77% to 80% (entries 2-4 in Table 3), while electron-donating ARKAT USA, Inc.
substituents at the para-position of acetophenone disfavored either reaction yield or enantioselectivity (entries 6-8 in Table 3).The substituents at the ortho-position or meta-position of acetophenone were negative to the reaction.No desired products were detected when these substrates were introduced in the addition reaction (entries 5, 9 and 10).These phenomena was ascribed to the steric repulsion of the substituent (Cl, Me) and the ethyl group.As a result, the ethyl nucleophile can hardly approach the carbon atom of carbonyl.In addition, we also investigated ketones containing heteroaromatic groups in the asymmetric addition, such as 2acetyl furan and 2-acetyl thiophene, which generated the corresponding products with low eanatioselectivities and moderate yields under the condition (entries 11 and 12 in Table 3).This result may stem from the binding of the heteroatom (O, S) in the substrate with the Ti center.Therefore, the reactivity and enantioselectivity of the chiral ligand were weakened to a certain extend.The same phenomenon was investigated in the addition of diethylzinc to 4-methoxy benzophenone (entry 6 in Table 3).It was noted that 2-acetyl naphthalene, which has more steic hindrance than other ketones, gave excellent enantioselectivity in this addition reaction (entry 13 in Table 3).General procedure for enantioselective addition of diethylzinc to p-chlorobenzaldehyde (6) (10 mg, 0.025 mmol, 0.05 equiv.)and Ti(O i Pr) 4 (175 mg, 0.6 mmol, 1.2 equiv.)were dissolved in toluene (2 ml) or other solvents under nitrogen.The resulting mixture was stirred for 10 min.Diethylzinc solution 0.6 ml (1.8 equiv., 1.5 M in hexane) was added to above vessel.2 minutes later, p-chlorobenzaldehyde 70 mg (0.5 mmol, 1.0 equiv., dissolved in 0.5 ml toluene or other solvents) were added at this temperature.The reaction was stirred for the appointed time in Table 1 until it was quenched with diluted hydrochloric acid.The resulting mixture was filtered through silica gel, extracted with ethyl acetate (3 × 10 ml) and the organic layer dried over anhydrous Na 2 SO 4 .The solvent was removed under reduced pressure and the residue was purified by flash chromatography column to afford the expected sec-alcohol.The enantiomeric excess was determined by chiral HPLC.General procedure for enantioselective addition of diethylzinc to ketones Ligand 8 (27 mg, 0.05 mmol, 0.1 equiv.)and Ti(O i Pr) 4 (175 mg, 0.6 mmol, 1.2 equiv.)were dissolved in toluene (2.5 ml) under nitrogen.The resulting mixture was stirred for 1 hour at room temperature (20˚C).Diethylzinc solution (0.6 ml, 0.9 mmol, 1.5 M in hexane) was added to above flask and the color of solution became orange-green.After 2 min, the corresponding ketone (0.5 mmol, 1.0 equiv., dissolved in 0.5 ml toluene or diluted with 0.5 ml toluene) was added at this temperature.The reaction was stirred for the appointed time in the Table 3 until it was quenched with diluted hydrochloric acid.The following work up was the same with above procedure.
All the spectral data of tert-alcohol and 1-(p-chlorophenyl)-1-propanol were listed in the previous paper 4a .

Table 1 .
). Optimization of the reaction conditions a isolated yields.bTheee values were determined by chiral HPLC using Daicel OD-H column.

Table 2 .
Enantioselective addition of diethylzinc to ketone under different conditions

Table 3 .
Asymmetric addition of ethyl groups to ketones *Scheme 4a isolated yields.bTheeevalueswere determined by chiral HPLC using OD-H or OJ-H column.cNodesired products were detected.d 2.5 equiv.Et 2 Zn was used in the reaction.