Enantioselective Addition of Diethylzinc to Benzaldehyde Catalyzed by an Organometallic Ti ( IV ) Compound and a Xylose Derivative

Um derivado da D-xylose, 1,2-O-isopropilideno-α-D-xilofuranose (1), com Ti(OPr) 4 foi usado como catalisador chiral na alquilação assimétrica do benzaldeído com dietilzinco (Et 2 Zn) para produção de 1-fenil-1-propanol em alto rendimento (conversão de 90%) e enantiosseletividade moderada (45% ee (S)). As condições ótimas (conversão e enantiosseletividade) para o sistema catalítico formado por 1 e Ti(IV) foram 10.0 mol % de 1 e 1 equivalente de Ti(IV) com relação ao benzaldeído em CH 2 Cl 2 como solvente, a temperatura ambiente. Na alquilação assimétrica do benzaldeído com Et 2 Zn, o composto 1 em quantidade sub-estequiométrica com Ti(OPr) 4 forma um catalisador quiral do tipo Ti(IV)-açúcar, o que assegura uma conversão com bom rendimento e a enantiosseletividade da reação.


Introduction
1,2 enantioselective addition of organometallic compounds (asymmetric alkylation) to prochiral aldehydes or ketones is currently one of the most important synthetic procedures to obtain chiral alcohols, [1][2][3] which are natural biologically active compounds 4 and are also very useful synthetic precursors, as in the syntheses of some drugs and insecticides. 5,6,2 addition of dialkylzinc to aldehydes and ketones is extremely slow. 7However, it is accelerated by substoichiometric amounts of such chiral substances as aminoalcohols and diols, including some carbohydrate derivatives. 8,9In these conditions, a mixed catalyst is formed between Zn(II), the chiral ligand, and the carbonyl compound, which facilitates attack by the alkyl group (R-) on the prochiral carbonyl compound, preferentially on one of its faces.
After hydrolysis the alcohol is obtained, enriched in one configuration (R or S).
][9] The purpose of this paper was to study catalysis by the derivative of D-xylose 1 and Ti(O i Pr) 4 in the asymmetric alkylation of benzaldehyde with diethylzinc to obtain, after acid hydrolysis, 1-phenyl-1-propanol in high yield and with moderate enantioselectivity.

1,2 Enantioselective addition of diethylzinc to benzaldehyde catalyzed by an organometallic Ti(IV) compound and derivative 1
We found that the 1 and Ti(IV) catalytic system acts optimally in the mixture of 0.1 mL (1 mmol) of anhydrous benzaldehyde and 3 mL (3 mmol) of Et 2 Zn in 2.5 mL of anhydrous CH 2 Cl 2 in a Schlenk tube under nitrogen at room temperature with constant stirring.Under these conditions, a sufficient amount of 1-phenyl-1-propanol was obtained for its characterization and quantification by gas chromatography (GC).From the area under the chromatogram peaks we determined the yield (conversion% of benzaldehyde into 1-phenyl-1-propanol) and the enantioselectivity (ee%) of the reactions (Tables 1 and 2) and the products were identified by 1 H-NMR.The predominant configuration was determined for each catalytic system. 11,12o optimize the concentration conditions of the catalytic system of 1 and Ti(IV), several reactions were carried out by using mixtures of 1 in variable substoichiometric amounts (2.5, 5.0, 10.0, and 20.0 mol%) with respect to benzaldehyde with 1 mmol of Ti(O i Pr) 4 , because with concentrations of that order other authors 6,12 had achieved good results with other chiral catalysts and we had earlier obtained promising results with them. 14,15 high conversion of benzaldehyde into 1-phenyl-1propanol was obtained after a 6 h reaction, with Ti(IV) and 10.0 mol% of 1 with respect to benzaldehyde at room temperature (entry 8 in Table 1), indicating that the catalyst formed in situ in this reaction is effective with small amounts of 1 (Table 1).After an 18 h reaction, maximum conversion of benzaldehyde into 1-phenyl-1-propanol was obtained with 10.0 mol% of 1 (entry 12 in Table 1).After a 24 h reaction, there was decreased conversion of benzaldehyde into 1-phenyl-1-propanol (entries 14 and 15 in Table 1), because of decomposition of 1-phenyl-propanol after 18 hours. 11he optical rotation (αº) of all the asymmetric alkylation products with 1 had a negative sign, (−), indicating that the 1-phenyl-1-propanol preferably has the S configuration (Tables 1 and 2). 13nantioselectivity (45% ee) was achieved after a 6 h reaction with 10.0 mol% of 1 (entry 8 in Table 1).A larger amount of 1 (20%) did not increase enantioselectivity significantly (entry 9 in Table 1) probably because the sugar derivative 1 acts with Ti(IV) forming a chiral catalyst of the Ti(IV)-sugar type with an optimum amount of 1,  in this case 10.0 mol% of that derivative with respect to benzaldehyde.
Lowering the temperature from room temperature to 0 °C and -20 °C decreased conversion of benzaldehyde into 1-phenyl-1-propanol (Table 2), but the lower temperature did not significantly increase the enantioselectivity (ee%) of the reaction (Table 2).This is probably because the determining step in the asymmetric reaction is controlled by the structure of the metal-sugar type chiral catalyst, which should not depend very much on temperature. 7,8,11,12he use of other solvents such as toluene or THF rather than CH 2 Cl 2 produced no significant improvement in conversion or enantioselectivity (Table 2).Thus, most reactions were carried out in CH 2 Cl 2.

11
In order to test the catalytic capacity of 1 with other metal ions, alkylation of benzaldehyde with ZnEt 2 was studied by using Co(II) or Cu(II).The reaction was carried out with Co(II) or Cu(II) acetylacetonate (Co(acac) 2 or Cu(acac) 2 ) (Table 2) instead of Ti(O i Pr) 4 .Conditions for the reactions with these ions were the same as used with the Ti(IV) and 1 system.The catalytic system of Co(II) and 1 gave lower conversion and enantioselectivity of 1-phenyl-1-propanol than those achieved with Ti(IV) and 1 (Table 2).The Cu(II) and 1 system did not catalyze the reaction.These results indicate that the metal-sugar type catalyst in the asymmetric alkylation must be an octahedral complex   as obtained with Ti(IV) and Co(II), and not a square planar one formed mainly by Cu(II).Therefore, optimum catalytic conditions in asymmetric alkylation are with 10 mol% of 1 with respect to benzaldehyde, and Ti(IV) as the metal reaction center in CH 2 Cl 2 (entry 8 in Table 1). 11he conversion and enantioselectivity of the reaction in the presence of 1 and Ti(O i Pr) 4 probably involve formation of a complex of the "Ti(IV)-sugar" type, allowing ethyl group (Et-) transfer preferentially to one of the faces of benzaldehyde, and favoring formation of the enantiomer with the S configuration of the product.
The possible mechanism for asymmetric alkyl addition is given in Scheme 1.The reaction of the xylose derivative 1 with 1 molar equiv. of Ti(O i Pr) 4 involves the dimeric complex 2, because Ti(O i Pr) 4 reacts with 1 (C 36.26 (36.80);H 5.48 (5.37); %found (%calculated)).Complex 2 further reacts with 1 molar equiv. of Ti(O i Pr) 4 , giving another dimeric complex, 3.18][19][20][21][22]25 Complex 3 reacts with Et 2 Zn or with EtTi(O i Pr) 3 , giving complex 4. EtTi(O i Pr) 3 can be generated from reaction of excess Ti(O i Pr) 4 with Et 2 Zn, as described for similar catalytic systems. 7,25Complex 4 further reacts with 1 mol of benzaldehyde, giving complex 5. To achieve the S configuration of the chiral alcohol, the attached Et-moves to the carbonyl carbon and the benzaldehyde oxygen probably moves simultaneously toward the second titanium center with the attached alkyl group, giving complex 6.Complex 6 gives complex 2. Regeneration of the starting complex 2 completes the catalytic cycle.

Conclusions
The presence of derivatives of D-xylose (1) in a substoichiometric amount with Ti(O i Pr) 4 in the asymmetric alkylation of benzaldehyde with Et 2 Zn forms a chiral catalyst of dimeric complexes 6 ensuring the conversion and enantioselectivity of the reaction.The best catalytic condition (conversion and enantioselectivity) was achieved with 10.0 mol% of 1 with respect to benzaldehyde.The conversion and enantioselectivity achieved in the synthesis of the alcohol with 1 is due to the formation within the reaction system of dimeric complexes Ti(IV)sugar (Scheme 1), facilitating transfer of the ethyl group to one face of benzaldehyde.The intrinsic chiral properties of carbohydrate 1 are transmitted through the dimeric Ti(IV)-sugar type complexes formed during the synthesis of 1-phenyl-1-propanol, yielding preferably its S enantiomer.The catalytic efficiency of the dimeric  1. Conditions in which the chromatogram was performed: Injector temperature, 250 ºC; detector temperature, 250 ºC; pressure, 10 psi; initial temperature, 100 ºC; initial time, 10 min; rate, 1 ºC min -1 ; final temperature, 140 ºC; final time, 4 min (top).Retention times (min) and peak areas of benzaldehyde and S-and R-1-phenyl-1-propanol present in the chromatogram are tabulated.Calculation of ee% from these areas is shown at the bottom.Ti(IV)-sugar complexes in the asymmetric alkylation of benzaldehyde with diethylzinc is determined by their stability and rigidity.

Experimental
All reagents and solvents were analytical grade.
Enantioselective 1,2-addition of diethylzinc to benzaldehyde catalyzed by a Ti(IV) organometallic compound and a xylose derivative Compound 1 (19 mg, 10.0 mol% with respect to benzaldehyde) was placed in a dry 50 mL Schlenk tube, closed with a silicone stopper, and air was removed by purging three times with nitrogen and vacuum.The following were then added successively: 0.1 mL (1 mmol) benzaldehyde, 2.5 mL dichoromethane, 0.3 mL (1 mmol) 97% titanium(IV) isopropoxide, and finally 3 mL (3 mmol) of a 1 mol L -1 solution of Et 2 Zn in hexane.
The reaction proceeded with stirring for 3 hours at room temperature, and was stopped by adding a saturated solution of ammonium chloride (releasing ethane and forming a white precipitate of zinc oxide).The mixture was transferred to a separatory funnel, 10 mL of 2 mol L -1 HCl were added, and the product was extracted with three 10 mL portions of ethyl ether, dried with anhydrous MgSO 4 and the ether was evaporated, yielding crude 1-phenyl-1propanol.
This general procedure was applied to all the catalytic reactions with different concentrations, solvents and reaction temperatures as shown in Tables 1 and 2 under Results and Discussion.

Product analysis
To analyze the products and determine percentage conversion, the sample, 0.4 μL, was injected into an HP 5890 series II gas chromatograph equipped with an Allchrom plus program and a methylsilicone-gum-type 5 m × 0.53 mm × 2.65 μm column.Working conditions were: Initial temperature, 100 °C; initial time, 5 min; rate, 20 °C min -1 ; final time, 18 min; pressure, 10 psi.
Conversion percentages were confirmed by 1 H-NMR spectroscopy.The products were dissolved in CDCl 3 and run on a Bruker DRX-300 spectrometer at 300 MHz.Calculation of conversion% was made from the areas of the Ph-CH(Et)-OH proton signal of 1-phenyl-1-propanol located at 4.5 ppm and that of the CHO of benzaldehyde located at 10.0 ppm with respect to TMS.
Cu(II) b CH 2 Cl 2 20 Reaction with a 5.0 and b 10.0 mol% of 1 with respect to 1 mmol de benzaldehyde and 3 mmol Et 2 Zn in the presence of 1 mmol of metal ion c determined by GC. d Determined by GC with β-DEX 120 column.e Determined from optical rotation.

Table 1 .
Asymmetric alkylation of benzaldehyde with Et 2 Zn catalyzed by carbohydrate derivative 1 and Ti(O i Pr) 4 a Reaction with 1 mmol of benzaldehyde and 3 mmol of Et 2 Zn in the presence of 1 mmol of Ti(OiPr) 4 .b Mol percentages referred to benzaldehyde.c Determined by GC. d Determined by GC with β-DEX 120 column.e Determined from optical rotation.

Table 2 .
Results of the asymmetric alkylation of benzaldehyde with Et 2 Zn catalyzed by carbohydrate derivative 1 and a metal ion after 6 h of reaction a,b