Stereoselective Addition of Diethylzinc to Aldehydes Using Chiral β-Hydroxy-2-oxazolines as Catalysts

The enantioselective addition of organometallic reagents to carbonyl compounds is one of the fundamental reactions to form a new carbon-carbon bond in asymmetric synthesis. The asymmetric addition of organolithium and Grignard reagents to carbonyl substrates usually occurs with low stereoselectivity, due to their high reactivities. On the other hand, the catalytic asymmetric addition of diorganozinc compounds to aldehydes is by far one of the most studied asymmetric transformations, and consists of a very useful method for the enantioselective preparation of secondary alcohols. Chiral alcohols are widely found in nature and are also important building blocks in organic synthesis. Recently, the catalytic asymmetric addition of diethylzinc to aldehydes was applied to obtain optically active lactones, cyclopropyl alcohols, and also in the synthesis of the natural product (+)-(R)-gossonorol, which shows antifungal, anticancer and antioxidant activities. The chiral catalysts developed so far can induce good to excellent selectivities; they include primary amino alcohols, diamines, disulfonamides, diols and others. The synthesis of these catalysts usually involves more than one step, so the development of new catalysts, readily available and versatile, remains an important challenge in this field. Natural ketones such as camphor, fenchone and menthone have been widely used in the synthesis of chiral ligands employed in the asymmetric addition of organozinc reagents to carbonyl compounds, furnishing good to excellent results. They represent an inexpensive and readily available source of chirality, which makes their use in the synthesis of the catalysts very advantageous. Oxazolines have been extensively used in asymmetric catalysis, especially 2-oxazolines. There are a few examples of oxazoline-based catalysts used in the addition of organozinc reagents to carbonyl compounds, most of them employing α-hydroxy-2-oxazolines. Herein we describe the synthesis of some β-hydroxy2-oxazolines derived from (−)-menthone, and their application as chiral ligands in the enantioselective addition of diethylzinc to aldehydes.


Introduction
The enantioselective addition of organometallic reagents to carbonyl compounds is one of the fundamental reactions to form a new carbon-carbon bond in asymmetric synthesis. 1The asymmetric addition of organolithium and Grignard reagents to carbonyl substrates usually occurs with low stereoselectivity, due to their high reactivities. 24][5][6] Chiral alcohols are widely found in nature and are also important building blocks in organic synthesis. 6ecently, the catalytic asymmetric addition of diethylzinc to aldehydes was applied to obtain optically active lactones, 7 cyclopropyl alcohols, 8 and also in the synthesis of the natural product (+)-(R)-gossonorol, which shows antifungal, anticancer and antioxidant activities. 96][27][28][29][30][31][32][33][34][35][36] The synthesis of these catalysts usually involves more than one step, so the development of new catalysts, readily available and versatile, remains an important challenge in this field.

Results and Discussion
To obtain the oxazolines derived from 2-amino-2methylpropan-1-ol we used the method proposed by Meyers, in which a carboxylic acid, in this case acetic acid, is reacted with an amino alcohol under heating. 63he 2-oxazoline derivatives from (+) or (−)-valinol were obtained by another method, also developed by Meyers, in which an amino alcohol reacts with an orthoester, in this case triethyl orthoacetate, under reflux. 64ith the 2-oxazolines in hand, we performed the addition of their anions, generated by reaction with n-butyllithium, 65 to (−)-menthone, affording the chiral β-hydroxy-2-oxazolines outlined below (Figure 1).
Ligand 1 was obtained as a mixture of diastereomers in a 75:25 ratio (Figure 2a), the same stereoselectivity observed in the synthesis of the other two ligands.
Using ligand 1 as a model, we determined the stereoselectivity of the major addition product obtained by nuclear Overhauser effect (NOE) experiment.The CH 2 (2.74 ppm) alpha to the hydroxyl group was strongly correlated with Ha and Hb (2.09 and 2.19 ppm), as shown in Figure 3.This confirmed that the oxazoline anion attacked the carbonyl moiety mainly via an equatorial approach, in accordance with previous reports. 38,44n order to evaluate the effect of the stereochemistry of the generated stereocenters of the new ligands on the stereoselective course of the addition of diethylzinc to aldehydes, the diastereomeric mixture was enriched in the   major diastereomer by column chromatography, reaching a 95:5 diastereomeric ratio (Figure 2b).The addition of diethylzinc to p-chlorobenzaldehyde was performed with both diastereomeric mixtures in the same conditions (entry 1a, using the 75:25 and entry 1b, using the 95:5 diastereomeric ratio, Table 1).The results showed that the products were obtained with the same enantiomeric excess.][68][69] Ligand 1, in a 75:25 diastereomeric ratio, was chosen in order to evaluate the influence of the solvent, temperature and amount of the catalyst in the stereoselective addition of diethylzinc to aromatic aldehydes, using p-chlorobenzaldehyde as a model (Table 1).
After the reaction conditions were optimized, all β-hydroxy-2-oxazolines prepared were tested, without diastereomeric purification, as chiral ligands to perform the stereoselective addition of diethylzinc to p-chlorobenzaldehyde (Table 2).
Interestingly, the ligand with the fewest stereogenic centers showed the best result.We assumed that the stereogenic center present in the oxazoline portion could improve the stereoselectivity, if acting in synergism with the steric hindrance provided by the menthane portion; however, both ligands 2 and 3 led to lower stereoselectivities.
Since ligand 1 showed the best results, it was used in the addition to other aromatic aldehydes (Table 3).
The best enantiomeric excess (e.e.) (78%) was achieved using 3-methoxybenzaldehyde.This result is probably related to the lower steric hindrance caused by the methoxy group when located at the 3-position, compared to the starting material with the methoxy group at the 2-position.
The e.e. achieved employing the other aldehydes were compared to those obtained using benzaldehyde.0][61][62] Although some e.e. obtained when using α-hydroxy-2-oxazolines are better than those reported herein, β-hydroxy-2-oxazolines are much easier to prepare, using less-expensive, commercially available materials.The results obtained in this study are being used by our group in order to synthesize other chiral β-hydroxy-2-oxazolines, aiming to improve the stereoselectivity of this process.

Conclusions
We describe herein the synthesis of new chiral β-hydroxy-2-oxazolines, and their application in the asymmetric addition of diethylzinc to aromatic aldehydes.The best ligand 1, which was readily synthesized from inexpensive and commercially available materials, showed good catalytic activity (up to 93% yield and 78% e.e.).Other chiral β-hydroxy-2-oxazolines are being synthesized in our laboratory, aiming at applications beyond the organozinc additions to aldehydes, such as in the asymmetric addition of alkynes to carbonyl compounds, 71 and in the asymmetric addition of boronic acids to carbonyl compounds. 72

Oxazolines
All three oxazolines (2,4,4-trimethyl-2-oxazoline and (S) and (R)-4-isopropyl-2-methyl-2-oxazoline) were synthesized, and afforded spectral data according with the literature. 63,64neral procedure for the preparation of β-hydroxy-2oxazolines 1-3 In a 25 mL flask equipped with magnetic stirring, a solution of n-butyllithium (1.31 mL, 2.1 mmol) in hexane was added at −78 °C to a solution of the corresponding 2-oxazoline (2 mmol) in tetrahydrofuran (THF) (4 mL).The reaction mixture was stirred for 30 min and then a solution of menthone (308 mg, 2 mmol) in THF (4 mL) was added dropwise.After the addition, the cooling bath was removed and the mixture was stirred for 2 h at 25 o C. The reaction mixture was quenched with aqueous saturated NH 4 Cl solution (10 mL), and extracted with diethyl ether (3 × 30 mL).The combined organic layer was dried over anhydrous Na 2 SO 4 .After filtration and evaporation of the solvent under reduced pressure, the crude product was purified by flash chromatography using a mixture of hexane/ethyl acetate (9:0.5) as eluent to give the corresponding chiral β-hydroxy-2-oxazolines.

General procedure for the addition of diethylzinc to aldehydes
The chiral β-hydroxy-2-oxazoline (0.05 mmol) was dissolved in the desired solvent (1 mL) then a solution of diethylzinc was added (2.5 mL, 2.5 mmol, 1 mol L −1 in hexane) at 25 °C.The mixture was stirred for 20 min and then cooled to 0 °C.A solution of the aldehyde (2 mmol Vol. 26, No. 1, 2015 in 3 mL of solvent) was added dropwise.After 2 h, the cooling bath was removed and the reaction was quenched with an aqueous saturated solution of NH 4 Cl (5 mL), extracted with a mixture of hexane (2 mL) and diethyl ether (2 mL).The organic layer was dried over anhydrous Na 2 SO 4 , and after filtration, the solvent was eliminated under reduced pressure.The product was purified by flash chromatography using hexane/ethyl acetate 9:1 as eluent leading to the corresponding secondary alcohol.The enantiomeric excess was determined by chiral gas chromatography.

Figure 3 .
Figure 3. Determination of the stereochemistry of the major diastereomer of ligand 1 by NOE.

a
Yield of isolated product; b determined by chiral GC (column: CB-cyclodextrin-β); c absolute configuration determined by comparison of the optical rotation with published data.70

Table 3 .
Addition of diethylzinc to benzaldehydes using ligand 1 as catalyst