New Catalysts Derived from Natural Products as Highly Stereoselective Chiral Inductors for Diethylzinc Addition to Aromatic Aldehydes

Asymmetric addition of organozinc compounds to carbonyl groups is one of the most useful methods for the synthesis of alcohols with high enantioselectivity. There is a wide range of chiral catalysts, although their synthesis requires more than one step and not often readily available starting materials. In this work, chiral β-hydroxy oxazolines derived from (+)-camphor and (-)-fenchone were easily synthesized through a one-step method, with good yields. Both ligands were evaluated as catalysts for the stereoselective addition of diethylzinc to aromatic aldehydes. All ligands showed good catalytic activity, leading both to the preparation of the R enantiomer of chiral secondary alcohols. As ligand 2 provided slightly better enantioselectivities, it was used as chiral inductor for the addition of diethylzinc for a larger number of aldehydes, resulting in good to excellent yields (88-98%) and enantiomeric excess up to 96%.

Herein we describe the synthesis of β-hydroxy-2-oxazolines, easily prepared from (−)-fenchone and (+)-camphor and their application as chiral inductors in the enantioselective addition of diethylzinc to aldehydes.

General
All air-and moisture-sensitive reactions were carried out under dry argon atmosphere.Tetrahydrofuran (THF), hexane, toluene, and diethyl ether were dried by distillation from sodium using benzophenone as indicator.Diethylzinc and n-butyllithium solutions (in hexane) were purchased from Sigma-Aldrich (Saint Louis, USA) in 1 and 1.6 M, respectively.All other materials were commercially obtained with analytical purity.
The nuclear magnetic resonance (NMR) spectra were obtained on a Bruker (Billerica, USA) AC 200 spectrometer operating at 4.7 Tesla (200 MHz for 1 H) at 293 K, using CDCl 3 as solvent.The chemical shifts (d) are given in ppm, related to tetramethylsilane (TMS) signal at 0.00 ppm as internal reference, and the coupling constants (J) are given in hertz (Hz).
Chiral gas chromatography (GC) analyses were performed in a Varian (Palo Alto, USA) 3800 chromatograph equipped with a flame ionization detector, helium as carrier gas, and Chirasil-Dex CB-β-cyclodextrin (30 m × 0.25 mm × 0.25 µm) as stationary phase.The carrier gas was helium, used at a constant pressure of 59 kPa and a constant flow of 1 mL min -1 .The injector temperature was 280 °C, with the initial temperature set at 60 °C and a temperature ramp of 3 °C min -1 rising to a final temperature of 280 °C for 10 min.
High-resolution mass spectrometry (HRMS) data were obtained on a Waters (Mildford, USA) liquid chromatography time-of-flight (LC-TOF) mass spectrometer (LCT-XE Premier) with electrospray ionization (ESI) in the positive mode.

Synthesis of ligands
In a 25 mL round bottom flask equipped with a stir bar under argon atmosphere, anhydrous THF (4.0 mL) and (S)-(−)-2-methyl-4-isopropyloxazoline (0.254 g, 2.00 mmol) were added and the temperature reduced to −78 °C.After temperature stabilization, n-BuLi (2.10 mmol) in hexane was added at once.The reaction mixture was stirred for 15 min followed by addition, drop by drop, of a (−)-fenchone (0.308 g, 2.00 mmol) solution dissolved in anhydrous THF (4.0 mL).The mixture was stirred at −78 °C for 30 min and the cooling bath was removed.After reaching room temperature, the reactional mixture was washed with saturated NaHCO 3 aqueous solution (10 mL) and the aqueous layer was extracted with hexane/ethyl ether (1:1, 10 mL).The organic layers were combined, dried with anhydrous Na 2 SO 4 , filtrated, and evaporated.The crude product was purified by flash column chromatography using ethyl ether/ethyl acetate/hexane (0.25:0.25:9.5) to obtain the pure β-hydroxyoxazoline 1. 1  In a 25 mL round bottom flask equipped with a stir bar under argon atmosphere, anhydrous THF (4.0 mL) and (S)-(−)-2-methyl-4-isopropyloxazoline (0.254 g, 2.00 mmol) were added and the temperature reduced to −78 °C.After temperature stabilization, n-BuLi (2.10 mmol) in hexane was added at once.The reactional mixture was stirred for 15 min followed by addition, drop by drop, of a (+)-camphor (0.308 g, 2.00 mmol) solution dissolved in anhydrous THF (4.0 mL).The reaction mixture was kept under agitation at −78 ºC for 30 min and the cooling bath was removed.After reaching room temperature, the reactional mixture was washed with saturated NaHCO 3 aqueous solution (10 mL) and the aqueous layer was extracted with hexane/ethyl ether (1:1, 10 mL).The organic layers were combined, dried with anhydrous Na 2 SO 4 , filtrated, and evaporated.The crude product was purified with flash column chromatography using acetone/hexane (0.5:9.5), yielding 0.455 g (81%) of pure β-hydroxyoxazoline 2. 1  General procedure for addition of diethylzinc to aldehydes A 10 mL reaction vial with a stir bar was loaded with β-hydroxyoxazoline (0.05 mmol), anhydrous hexane (1.0 mL), and diethylzinc solution in hexane (2.50 mL, 2.50 mmol) under argon atmosphere.The solution was stirred at 20 °C for 20 min.After that, the temperature was reduced to 0 °C and aldehyde (2.00 mmol) in anhydrous hexane (4.0 mL) was added to the vial.After 2 h, the temperature was raised to room temperature and an NaHCO 3 saturated aqueous solution (4.0 mL) was added to the vial.The layers were separated, and the aqueous layer was extracted with hexane/ethyl ether (1:1, 5.0 mL) three times.All organic layers were combined, dried with anhydrous Na 2 SO 4 , filtrated, and concentrated in a rotatory evaporator.The crude product was purified using flash column chromatography.

Results and Discussion
The β-hydroxy-2-oxazolines were easily obtained by the addition of 2-oxazoline anions to the respective ketones, as previously described. 32The β-hydroxy-2-oxazoline 1 was obtained through an exo approach of the oxazoline anion to the carbonyl group of (−)-fenchone, as reported in the literature, 71,72 generating the endo-alcohol derivative with diastereomeric excess (d.e.) greater than 97%.
On the other hand, since (+)-camphor has a high steric hindrance caused by the methyl groups at the exo side of the bicyclic system, the addition of the oxazoline anion to the carbonyl group of (+)-camphor occurred via endo approximation (Figure 2) resulting in the exo-alcohol 2, which was obtained with d.e. higher than 97%.
The stereochemistry and structure of both β-hydroxy-2oxazolines 1 and 2 were determined using NMR analysis, such as coupling constants, heteronuclear single quantum coherence spectroscopy (HSQC), heteronuclear multiple bond correlation (HMBC) and nuclear Overhauser effect (NOE).For detailed information, see Supplementary Information (SI) section.
With the chiral inductors obtained, all stereoselective diethylzinc additions to aldehydes were carried out in hexane following reported procedures, 33,36 and the results are presented in Table 1.
As ligand 2 provided slightly better enantioselectivities in the previous study (up to 93%, e.e.), it was used as the chiral inductor for the addition of diethylzinc to some more aldehydes.The results are displayed in Table 2. Acceptable to good asymmetric inductions of 82-96% and good to excellent yields (88-98%) were reached.
The proposed mechanism for the addition of diethylzinc to aldehydes using the endo-β-hydroxy-2-oxazoline 2 as the chiral catalyst is shown in Figure 3.2][73][74][75][76][77][78][79] We believe that the mechanism consists of two steps.In the preceding step, diethylzinc reacts with the oxazoline 2 to generate the catalytically active species 3A and 3B, of which 3A is energetically favored since it avoids steric repulsion of the ethyl zinc part with the isopropyl group of the oxazoline and the methyl group of camphor moiety, as it occurs in 3B.Coordination of diethyl zinc and the aldehyde to 3A leads to the favored transition state 4A, which gives, in good agreement with the experimental results, highly enantioselectively the corresponding chiral alcohol with S configuration.

Conclusions
In summary, we report the easy synthesis of new chiral inductors 1 and 2, prepared from natural ketones through a one-step method, and their application as a catalyst in stereoselective addition of diethylzinc to aldehydes, which allowed the preparation of chiral secondary alcohols in good to excellent yields and enantiomeric excess up to 96%.We envisioned that this approach will enable further ligand  designs, that shall pave the way to new easily accessible chiral pre-catalysts.

Figure 3 .
Figure 3. Proposed mechanism for the stereoselective addition of diethylzinc to aldehydes in the presence of the chiral inductor 2.

Table 1 .
Yield and products in the addition reaction of diethylzinc to aldehydes

Table 2 .
Yield and products in the addition reaction of diethylzinc to aldehydes using ligand 2