Synthesis of Novel 3-Deoxy-3-thio Derivatives of d-Glucosamine and Their Application as Ligands for the Enantioselective Addition of Diethylzinc to Benzaldehyde

A series of novel thio-derivatives of d-glucosamine has been synthesized using double inversion procedures at the C3 atom. New compounds were applied as ligands for the diethylzinc addition to benzaldehyde and the products of the addition were obtained with a low to good enantiomeric ratio. The direction and the level of the asymmetric induction were highly dependent on the type of protecting groups on the nitrogen and sulfur atoms.


Introduction
The asymmetric addition of dialkylzinc compounds to aldehydes is an important method for the synthesis of optically active secondary alcohols.Due to the low reactivity of dialkylzinc reagents toward the carbonyl group, the addition requires the presence of a catalyst, usually an amino alcohol, which increases the rate of reaction and often controls the stereochemical outcome of the alcohol product.Since the first efficient chiral catalyst, (-)-3-exo (dimethylamino)isoborneol (DAIB), was introduced by Noyori [1], syntheses and applications of several efficient chiral catalysts have been reported [2,3].
Derivatives of common, simple carbohydrates are not frequently reported among the many different forms of chiral ligands that are accessible.The benefit of sugar derivatives is their modular synthesis, which allows for easy ligand structure modification throughout synthesis, resulting in different ligands possessing the same chiral precursor.We previously reported the synthesis of hydroxy sulfonamides 2 derived from D-glucosamine 1, which were used as ligands in the titanium-promoted additions of diethyl- [4,5], and alkynylzincs [6] to aldehydes (Figure 1).
It has been observed that β-amino thiol can be viable alternative to β-amino alcohol as a catalyst for asymmetric organozinc addition because of certain crucial features, including the diminished tendency of metal thiolates to reduce the Lewis acidity of the metal in comparison to metal alcoholates, higher affinity of thiols to zinc and increased polarizability of sulfur in comparison to the oxygen atom [7].
Several amino thiol ligands were reported, and one of the most efficient was the L-valine-derived amino thiols 3 developed by Tseng and Yang [8].We have recently proved the efficacy of 3a in the highly enantioselective alkenylation of aldehydes [9].
Herein, we present our studies on the synthesis of D-glucosamine derivatives bearing thiol functionality at the C3 position (sugar nomenclature) and their application for the diethylzinc addition to aldehydes.
The enantioselective addition of organozinc compounds is usually catalyzed by two types of ligands, namely β-hydroxy amines, as described by Noyori, and β-hydroxy sulfonamides or diols in the presence of tetraisopropoxytitanium, according to the mechanism described by Gau [10] and Walsh [11].We decided to use our experience with the titaniumpromoted addition of organozinc compounds in the presence of β-hydroxy sulfonamides 2 and investigate the respective thio-analogs.Additionally, as we expected the incompatibility of the hard Ti(OiPr) 4 with the soft sulfur atom, we planned a synthesis of the thio-analogs of the classical β-hydroxy amines earlier described by Davis and co-workers [12].The enantioselective addition of organozinc compounds is usually catalyzed by two types of ligands, namely β-hydroxy amines, as described by Noyori, and β-hydroxy sulfonamides or diols in the presence of tetraisopropoxytitanium, according to the mechanism described by Gau [10] and Walsh [11].We decided to use our experience with the titanium-promoted addition of organozinc compounds in the presence of β-hydroxy sulfonamides 2 and investigate the respective thio-analogs.Additionally, as we expected the incompatibility of the hard Ti(OiPr)4 with the soft sulfur atom, we planned a synthesis of the thio-analogs of the classical β-hydroxy amines earlier described by Davis and coworkers [12].

Results
At first, we choose the known [4] amino alcohol 4 as a most versatile starting material for the synthesis of all the ligands.The synthesis of methyl 4,6-O-benzylidene-2,3dideoxy-3-thio-2-p-toluenesulfonamido-α-D-glucopyranoside 10 proceeded easily.The reaction at step (v) required some optimization, as the reaction in DMF gave a major product 9 contaminated with some side products; however, the same reaction performed in acetonitrile furnished 9 as a single compound (Scheme 1).

Results
At first, we choose the known [4] amino alcohol 4 as a most versatile starting material for the synthesis of all the ligands.The synthesis of methyl 4,6-O-benzylidene-2,3-dideoxy-3thio-2-p-toluenesulfonamido-α-D-glucopyranoside 10 proceeded easily.The reaction at step (v) required some optimization, as the reaction in DMF gave a major product 9 contaminated with some side products; however, the same reaction performed in acetonitrile furnished 9 as a single compound (Scheme 1).The enantioselective addition of organozinc compounds is usually catalyzed by two types of ligands, namely β-hydroxy amines, as described by Noyori, and β-hydroxy sulfonamides or diols in the presence of tetraisopropoxytitanium, according to the mechanism described by Gau [10] and Walsh [11].We decided to use our experience with the titanium-promoted addition of organozinc compounds in the presence of β-hydroxy sulfonamides 2 and investigate the respective thio-analogs.Additionally, as we expected the incompatibility of the hard Ti(OiPr)4 with the soft sulfur atom, we planned a synthesis of the thio-analogs of the classical β-hydroxy amines earlier described by Davis and coworkers [12].

Results
At first, we choose the known [4] amino alcohol 4 as a most versatile starting material for the synthesis of all the ligands.The synthesis of methyl 4,6-O-benzylidene-2,3dideoxy-3-thio-2-p-toluenesulfonamido-α-D-glucopyranoside 10 proceeded easily.The reaction at step (v) required some optimization, as the reaction in DMF gave a major product 9 contaminated with some side products; however, the same reaction performed in acetonitrile furnished 9 as a single compound (Scheme 1).Successful synthesis of the sulfonamide 10 prompted us to apply the same method to the morpholine ligand 16, belonging to the second series of ligands.The synthesis proceeded reasonably well; however, we encountered some problems.In particular, the inversion of C3 hydroxyl (step iii) was very slow and the product 13 was obtained with a moderate yield (Scheme 2).
Successful synthesis of the sulfonamide 10 prompted us to apply the same method to the morpholine ligand 16, belonging to the second series of ligands.The synthesis proceeded reasonably well; however, we encountered some problems.In particular, the inversion of C3 hydroxyl (step iii) was very slow and the product 13 was obtained with a moderate yield (Scheme 2).Next, we applied this approach for the synthesis of a piperidine derivative, namely methyl 4,6-O-benzylidene-2,3-dideoxy-2-(1-piperidynyl)-3-thio-α-D-glucopyranoside.Unfortunately, even after the long optimization of the conditions, we could not achieve the inversion of C3 hydroxyl from the equatorial to axial position with a yield higher than 20% and the prolonged reaction times did not increase the conversion over 50% with a simultaneous decomposition of the product.Therefore, we abandoned this path for the synthesis.
We reached the conclusion that the presence of cyclic amine at C2 could be responsible for the problems with the inversion of the configuration at C3. Therefore, we decided to synthesize an analog of the amino alcohol 4, the methyl 2-amino-4,6-Obenzylidene-2-deoxy-α-D-allopyranoside 20.
We decided to try a not very popular but often highly efficient method: Lattrell-Dax epimerization [13], which has been successfully used in carbohydrate chemistry [14].
We started from the carbamate 17, an easily available precursor of amino alcohol 4 [4].The synthesis of triflate 18 was straightforward and furnished the expected product with a high yield.The subsequent Lattrell-Dax epimerization proceeded smoothly, providing 19, which was converted to the expected allopyranoside 20 (Scheme 3).Next, we applied this approach for the synthesis of a piperidine derivative, namely methyl 4,6-O-benzylidene-2,3-dideoxy-2-(1-piperidynyl)-3-thio-α-D-glucopyranoside.Unfortunately, even after the long optimization of the conditions, we could not achieve the inversion of C3 hydroxyl from the equatorial to axial position with a yield higher than 20% and the prolonged reaction times did not increase the conversion over 50% with a simultaneous decomposition of the product.Therefore, we abandoned this path for the synthesis.
We reached the conclusion that the presence of cyclic amine at C2 could be responsible for the problems with the inversion of the configuration at C3. Therefore, we decided to synthesize an analog of the amino alcohol 4, the methyl 2-amino-4,6-O-benzylidene-2deoxy-α-D-allopyranoside 20.
We decided to try a not very popular but often highly efficient method: Lattrell-Dax epimerization [13], which has been successfully used in carbohydrate chemistry [14].
We started from the carbamate 17, an easily available precursor of amino alcohol 4 [4].The synthesis of triflate 18 was straightforward and furnished the expected product with a high yield.The subsequent Lattrell-Dax epimerization proceeded smoothly, providing 19, which was converted to the expected allopyranoside 20 (Scheme 3).
The formation of the pyrrolidine 21 and piperidine 22 derivatives was achieved using the respective dibromides; however, the mesylation of these compounds at C3 was only possible using pyridine and not triethylamine as a base.We then tried to convert both mesylates 23 and 24 into thioacetate.Much to our disappointment, treating the mesylate derivatives with potassium thioacetate failed to produce any product (Scheme 4).
The problems we encountered prompted us to cease our efforts toward the synthesis of pyrrolidinyl and piperidinyl derivatives and to expand the pool of C2 sulfonamides.
First, the amino alcohol 20 was treated with an excess of methanesulfonyl chloride in the presence of pyridine.The resulting dimethanesulfonyl derivative 25 was subjected to the nucleophilic substitution reaction with potassium thioacetate in DMPU, which appeared to be the solvent of choice for this transformation.However, the expected product was accompanied by a by-product, presumably resulting from the elimination of the mesylate, and the mixture was inseparable at this stage.Fortunately, the reduction of thioacetate 26 furnished thiosulfonamide 27 in a good yield and the by-product could be removed at this final stage (Scheme 5).The formation of the pyrrolidine 21 and piperidine 22 derivatives was achieved using the respective dibromides; however, the mesylation of these compounds at C3 was only possible using pyridine and not triethylamine as a base.We then tried to convert both mesylates 23 and 24 into thioacetate.Much to our disappointment, treating the mesylate derivatives with potassium thioacetate failed to produce any product (Scheme 4).The problems we encountered prompted us to cease our efforts toward the synthesis of pyrrolidinyl and piperidinyl derivatives and to expand the pool of C2 sulfonamides.
First, the amino alcohol 20 was treated with an excess of methanesulfonyl chloride in the presence of pyridine.The resulting dimethanesulfonyl derivative 25 was subjected to the nucleophilic substitution reaction with potassium thioacetate in DMPU, which appeared to be the solvent of choice for this transformation.However, the expected product was accompanied by a by-product, presumably resulting from the elimination of the mesylate, and the mixture was inseparable at this stage.Fortunately, the reduction of thioacetate 26 furnished thiosulfonamide 27 in a good yield and the by-product could be removed at this final stage (Scheme 5).The formation of the pyrrolidine 21 and piperidine 22 derivatives was achieved using the respective dibromides; however, the mesylation of these compounds at C3 was only possible using pyridine and not triethylamine as a base.We then tried to convert both mesylates 23 and 24 into thioacetate.Much to our disappointment, treating the mesylate derivatives with potassium thioacetate failed to produce any product (Scheme 4).The problems we encountered prompted us to cease our efforts toward the synthesis of pyrrolidinyl and piperidinyl derivatives and to expand the pool of C2 sulfonamides.
First, the amino alcohol 20 was treated with an excess of methanesulfonyl chloride in the presence of pyridine.The resulting dimethanesulfonyl derivative 25 was subjected to the nucleophilic substitution reaction with potassium thioacetate in DMPU, which appeared to be the solvent of choice for this transformation.However, the expected product was accompanied by a by-product, presumably resulting from the elimination of the mesylate, and the mixture was inseparable at this stage.Fortunately, the reduction of thioacetate 26 furnished thiosulfonamide 27 in a good yield and the by-product could be removed at this final stage (Scheme 5).The same strategy could be applied for the synthesis of trifluoromethylsulfonamide derivative 31.The double protection of amino alcohol 20 could be achieved using an excess of triflic anhydride (3 equiv.) in DCM and pyridine (10 equiv.),resulting in a mixture of mono-and di-triflate products, approximately 40% to 60%.Fortunately, it was possible to separate these two compounds and the triflation of the remaining hydroxyl derivatives worked without any problems under similar conditions (Scheme 6).
The inversion procedure (KSAc, DMPU) developed for mesylate 25 did not work for the triflate 28.The expected product 30 was obtained with a very low yield (15%), probably due to competitive elimination.The optimization of this reaction showed that acetonitrile is the solvent of choice for this transformation and 30 was obtained with 40% yield; however, the elimination was still a major problem.In the final conversion to free thiol 31 using standard approach, the reduction of thioacetate with LiAlH 4 was unsuccessful and it could not be obtained by this method.We decided to hydrolyze the acetate under the Zemplen conditions [15].The expected ligand 31 was obtained in a 76% yield.The same strategy could be applied for the synthesis of trifluoromethylsulfonamide derivative 31.The double protection of amino alcohol 20 could be achieved using an excess of triflic anhydride (3 equiv.) in DCM and pyridine (10 equiv.),resulting in a mixture of mono-and di-triflate products, approximately 40% to 60%.Fortunately, it was possible to separate these two compounds and the triflation of the remaining hydroxyl derivatives worked without any problems under similar conditions (Scheme 6).The inversion procedure (KSAc, DMPU) developed for mesylate 25 did not work for the triflate 28.The expected product 30 was obtained with a very low yield (15%), probably due to competitive elimination.The optimization of this reaction showed that acetonitrile is the solvent of choice for this transformation and 30 was obtained with 40% yield; however, the elimination was still a major problem.In the final conversion to free thiol 31 using standard approach, the reduction of thioacetate with LiAlH4 was unsuccessful and it could not be obtained by this method.We decided to hydrolyze the The same strategy could be applied for the synthesis of trifluoromethylsulfonamide derivative 31.The double protection of amino alcohol 20 could be achieved using an excess of triflic anhydride (3 equiv.) in DCM and pyridine (10 equiv.),resulting in a mixture of mono-and di-triflate products, approximately 40% to 60%.Fortunately, it was possible to separate these two compounds and the triflation of the remaining hydroxyl derivatives worked without any problems under similar conditions (Scheme 6).The inversion procedure (KSAc, DMPU) developed for mesylate 25 did not work for the triflate 28.The expected product 30 was obtained with a very low yield (15%), probably due to competitive elimination.The optimization of this reaction showed that acetonitrile is the solvent of choice for this transformation and 30 was obtained with 40% yield; however, the elimination was still a major problem.In the final conversion to free thiol 31 using standard approach, the reduction of thioacetate with LiAlH4 was unsuccessful and it could not be obtained by this method.We decided to hydrolyze the Having to hand all the available ligands, we began studies on the enantioselective additions of diethylzinc to benzaldehyde.We started with the p-toluenesulfonamide ligand 10 using the titanium tetraisopropoxide-based method.Not very surprisingly, the enantioselectivity in the toluene was very poor (e.r.57:43, S/R), and it was even lower when using methylene chloride as a solvent (e.r.54.5:45.5).Supposedly, the required titanium-sulfur complex was not formed as expected; however, the ligands exhibited very good catalytic properties-the chemical yields of 1-phenylpropanol were high at -95% and 85%, respectively (Table 1, entries 1 and 2).Then, we tried the morpholine ligand 16 in the absence of Ti(OiPr) 4 and we obtained the expected product with a very good chemical yield of 83%, but again with a surprisingly low enantioselectivity, where the enantiomeric ratio was only 55:45, R/S, much lower than that for the respective amino alcohol reported by Davis and co-workers (Table 1, entry 3) [12].It became obvious that the 3-thio-glucosamine ligands did not follow the expected modes of action; therefore, we decided to check the inductive properties of the sulfonamide ligands in the absence of Ti(OiPr) 4 Lewis acid.First, we tried the ligand 10 and noticed a substantial improvement of the enantiodiscrimination to 74.5:25.5, again with a good yield and the S enantiomer prevailing (Table 1, entry 4).The bulky trifluoromethanesulfonamide ligand 31 was less efficient and the observed e.r. was only 64:36 (Table 1, entry 5).Unexpectedly, the highest enantiomer ratio 80.5:19.5 was obtained for the methanesulfonamide derivative 27 (Table 1, entry 6).enantiomeric ratio was only 55:45, R/S, much lower than that for the respective a alcohol reported by Davis and co-workers (Table 1, entry 3) [12].It became obviou the 3-thio-glucosamine ligands did not follow the expected modes of action; therefo decided to check the inductive properties of the sulfonamide ligands in the abse Ti(OiPr)4 Lewis acid.First, we tried the ligand 10 and noticed a substantial improv of the enantiodiscrimination to 74.5:25.5, again with a good yield and the S enant prevailing (Table 1, entry 4).The bulky trifluoromethanesulfonamide ligand 31 wa efficient and the observed e.r. was only 64:36 (Table 1, entry 5).Unexpectedly, the h enantiomer ratio 80.5:19.5 was obtained for the methanesulfonamide derivative 27 1, entry 6).
The literature reports indicate that thioacetate derivative may also be an eff chiral ligand [16,17].
Therefore, we decided to check four intermediate compounds, 9, 15, 26, and ligands.They appeared to be much less efficient ligands than the respective thio results are presented in Table 1, entries 7-10.

Discussion
The data presented in the introduction, indicating that amino thiols can be eq good, and often better, ligands in the addition of organozinc reagents to car The literature reports indicate that thioacetate derivative may also be an effective chiral ligand [16,17].
Therefore, we decided to check four intermediate compounds, 9, 15, 26, and 30, as ligands.They appeared to be much less efficient ligands than the respective thiols; the results are presented in Table 1, entries 7-10.

Discussion
The data presented in the introduction, indicating that amino thiols can be equally good, and often better, ligands in the addition of organozinc reagents to carbonyl compounds, are not confirmed in the case presented here of 3-thio-glucosamine derivatives.
The low asymmetric induction of the reaction catalyzed by the sulfonamides in the presence of Ti(OiPr) 4 was not very surprising in the context of hard and soft acids and bases theory (Table 1, entries 1 and 2).However, the very low e.r. in the reaction catalyzed by the ligand 16 was unexpected (Table 1, entry 3).The earlier-reported hydroxy analogue [12] was quite efficient and we expected at least comparable enantioselectivity.Supposedly, the geometry of the transition state can be adversely influenced by the length of the zinc-sulfur bond, 2.2-2.4Å vs. 1.9-2.2Å for the zinc-oxygen bond.We performed MM2 energy minimalization in order to analyze the geometry of the most probable transition state based on the Noyori's model (Figure 2).
The left image shows the model for the addition of Davis' ligand [12], which exhibited good enantioselectivity (e.r.82.5:17.5).As indicated in Noyori's model, the ethyl group attached to the same zinc atom as the benzaldehyde efficiently hinders the rotation of the aldehyde, securing high enantiodiscrimination.A quite different situation is observed in the case of the thiol ligand 16.That ethyl group is directed backwards relative to the aldehyde, which creates much less steric hindrance and does not prevent rotation of the aldehyde molecule.As a result, an attack on both faces of the carbonyl group is almost equally probable, what results in poor selectivity.compounds, are not confirmed in the case presented here of 3-thio-glucosamine derivatives.
The low asymmetric induction of the reaction catalyzed by the sulfonamides in the presence of Ti(OiPr)4 was not very surprising in the context of hard and soft acids and bases theory (Table 1, entries 1 and 2).However, the very low e.r. in the reaction catalyzed by the ligand 16 was unexpected (Table 1, entry 3).The earlier-reported hydroxy analogue [12] was quite efficient and we expected at least comparable enantioselectivity.Supposedly, the geometry of the transition state can be adversely influenced by the length of the zinc-sulfur bond, 2.2-2.4Å vs. 1.9-2.2Å for the zinc-oxygen bond.We performed MM2 energy minimalization in order to analyze the geometry of the most probable transition state based on the Noyori's model (Figure 2).The left image shows the model for the addition of Davis' ligand [12], which exhibited good enantioselectivity (e.r.82.5:17.5).As indicated in Noyori's model, the ethyl group attached to the same zinc atom as the benzaldehyde efficiently hinders the rotation of the aldehyde, securing high enantiodiscrimination.A quite different situation is observed in the case of the thiol ligand 16.That ethyl group is directed backwards relative to the aldehyde, which creates much less steric hindrance and does not prevent rotation of the aldehyde molecule.As a result, an attack on both faces of the carbonyl group is almost equally probable, what results in poor selectivity.
The reaction proceeded quite well for the sulfonamide ligands in the absence of the Lewis acid.The best results were obtained for the least sterically demanding mesyl derivative 27 and not for the highly hindered trifluorosulfonamide 31 (Table 1, entry 6 and 5), which, on the basis of our previous studies and the very high selectivity observed in the presence of the 3-hydroxy analog of 31, should be the most efficient ligand.
In the case of sulfonamides, the main factor influencing enantiodiscrimination is probably the interaction of the anomeric methoxyl group with the methyl-and trifluoromethylsulfonamide groups in 27 and 31, respectively (Figure 3A,B).The bigger CF3 substituent has to be placed farther from the anomeric OCH3 (Figure 3A) and that allows for the easier rotation of the aldehyde, leading to diminished enantioselectivity.The smaller methanesulfonyl group locates itself in close proximity of the anomeric methoxy (Figure 3B) and hinders the rotation of the carbonyl group, securing higher enantiodiscrimination.The reaction proceeded quite well for the sulfonamide ligands in the absence of the Lewis acid.The best results were obtained for the least sterically demanding mesyl derivative 27 and not for the highly hindered trifluorosulfonamide 31 (Table 1, entry 6 and 5), which, on the basis of our previous studies and the very high selectivity observed in the presence of the 3-hydroxy analog of 31, should be the most efficient ligand.
In the case of sulfonamides, the main factor influencing enantiodiscrimination is probably the interaction of the anomeric methoxyl group with the methyl-and trifluoromethylsulfonamide groups in 27 and 31, respectively (Figure 3A,B).The bigger CF 3 substituent has to be placed farther from the anomeric OCH 3 (Figure 3A) and that allows for the easier rotation of the aldehyde, leading to diminished enantioselectivity.The smaller methanesulfonyl group locates itself in close proximity of the anomeric methoxy (Figure 3B) and hinders the rotation of the carbonyl group, securing higher enantiodiscrimination.Also, the results for the acetate derivatives tested suggest that various coordination modes are possible for the ligand-diethylzinc system, thus highly altering the transition state geometry and, as a consequence, the observed asymmetric induction.
In conclusion, we have synthesized a series of novel 3-thio-derivatives of D- Also, the results for the acetate derivatives tested suggest that various coordination modes are possible for the ligand-diethylzinc system, thus highly altering the transition state geometry and, as a consequence, the observed asymmetric induction.
In conclusion, we have synthesized a series of novel 3-thio-derivatives of D-glucosamine.New compounds were applied as ligands for the diethylzinc addition to benzaldehyde and the products of the addition were obtained with a low to good enantiomeric ratio.

Material and Methods
Benzaldehyde was distilled under reduced pressure and stored under argon.Diethylzinc solution (1.1 M in toluene) was purchased from Sigma-Aldrich (St. Louis, MO, USA).All the reactions were performed under an argon atmosphere in oven-dried glassware using the Schlenk technique when necessary.The 1 H and 13 C NMR spectra were recorded in CDCl 3 using a Bruker AVANCE 300 MHz spectrometer (Bruker, Billerica, MA, USA).All the chemical shifts are quoted in parts per million relatives to tetramethylsilane (δ, 0.00 ppm) as the internal standard.The 1 H-NMR splitting patterns are abbreviated as follows: singlet (s), doublet (d), triplet (t), quartet (q), dd (doublet of doublets), and m (multiplets).The high-resolution mass spectra were recorded on a Quattro LC Micromass, LCT Micromass TOF HiRes, and Shimadzu LCMS-9030 apparatus.Flash column chromatography was performed on silica gel (Kieselgel-60, Merck, 230-400 mesh).TLC analyses were performed on 250 µm Silica Gel 60 F254 plates (Merck, Rahway, NJ, USA) and visualized by the quenching of the UV fluorescence at 254 nm or by staining with molybdic acid-cerium (II) sulphate solution.High-performance liquid chromatography was conducted on a Knauer chromatograph (Berlin, Germany) equipped with a diode array detector using a Diacel Chiralcel OD-H column (Osaka, Japan).Compounds 4, 5 and 17 were synthesized according to published procedures [4].
The Supplementary Material (Figures S1-S27) contains the 1 H and 13 C NMR spectra as PDF copies.

General Procedure for Diethylzinc Addition to Benzaldehyde
In the Schlenk tube equipped with a stirring element, a ligand was placed (0.1 equiv.), and the tube was flushed three times with argon.Then, the solvent was added (1.25 mL).After 10 min, 1.1 M ZnEt 2 in toluene (2 equiv., 0.945 mL) was added.After 30 min of stirring at room temperature, freshly distilled benzaldehyde (0.5 mmol, 51 µL) was added, and then the reaction was stirred at the indicated time until TLC showed the disappearance of the aldehyde.The reaction was diluted with diethyl ether and quenched with 1 M HCl.The organic layer was separated, and the aqueous layer was extracted twice with ether.The combined organic layers were then concentrated and purified by column chromatography (hexane-EtOAc 7:3) to give 1-phenyl-1-propanol as a colorless oil.The 1 H-NMR (300 MHz, CDCl 3 ) δ 7.43-7.23(m, 5H, C 6 H 5 ), 4.62 (t, J 6.6 Hz, 1H, PhCH(OH)Et), 1.90-1.70(m, 2H, CH 2 ), and 0.95 (t, J 7.4 Hz, 3H, CH 3 ).

General Procedure for Diethylzinc Addition to Benzaldehyde in the Presence of Ti(OiPr 4 )
In the Schlenk tube equipped with a stirring element, a ligand was placed (0.1 equiv.), and the tube was flushed three times with argon.Then, methylene chloride was added (3 mL), followed by Ti(OiPr) 4 (1.4 equiv., 0.24 mL).After 1.5 h, the reaction mixture was cooled to 0 • C and 1.1 M ZnEt 2 (3 equiv., 1.35 mL) was added.After 45 min, an aldehyde (0.5 mmol) was added and stirred at 0 • C for an additional 30 min, then allowed to warm up to room temperature.The reaction was stirred at this temperature until TLC showed the disappearance of the aldehyde.The reaction was diluted with diethyl ether and quenched with 1 M HCl.The organic layer was separated, and the aqueous layer was extracted twice with ether.The combined organic layers were then concentrated and purified by column chromatography (hexane-EtOAc 7:3) to give 1-phenyl-1-propanol as a colorless oil.The 1 H-NMR (300 MHz, CDCl 3 ) δ 7.43-7.23(m, 5H, C 6 H 5 ), 4.62 (t, J 6.6 Hz, 1H, PhCH(OH)Et), 1.90-1.70(m, 2H, CH 2 ), and 0.95 (t, J 7.4 Hz, 3H, CH 3 ).

Figure 1 .
Figure 1.Ligands for the enantioselective additions of organozinc compounds.

Figure 1 .
Figure 1.Ligands for the enantioselective additions of organozinc compounds.

a
All reactions performed at r.t.; b In the presence of Ti(OiPr) 4 (1.4 equiv.).

Table 1 .
Results of the diethylzinc additions to benzaldehyde.

Table 1 .
Results of the diethylzinc additions to benzaldehyde.