Catalytic Atroposelective Aerobic Oxidation Approaches to Axially Chiral Molecules

A copper and chiral nitroxide co-catalyzed aerobic enantioselective oxidation process has been developed that allows access to axially chiral molecules. Two complementary atroposelective approaches, oxidative kinetic resolution (OKR) and desymmetrization, were studied using ambient air as the stoichiometric terminal oxidant. OKR of rac-N-arylpyrrole alcohols and rac-biaryl alcohols affords the optically pure compounds with er up to 3.5:96.5 and 5.5:94.5, respectively. Desymmetrization of prochiral diols provides axially chiral biaryl compounds with er up to 99:1.


■ INTRODUCTION
Axially chiral molecules are prevalent structural motifs in a wide range of natural products, pharmaceuticals, and functional materials. 1 In addition, a plethora of chiral catalysts and privileged chiral ligands 1f have been developed based on axially chiral biaryl frameworks ( Figure 1). 2 Consequently, vast efforts have been made by the chemical community to prepare these atropisomers in an efficient and stereoselective manner. 3 One intriguing methodology is the use of enzymes for the atroposelective desymmetrization. 4 Clayden and Turner's groups successfully demonstrated the ability of a copper-containing enzyme, a variant of galactose oxidase (GOase M 3−5 ) for oxidative desymmetrization of prochiral substrates containing a pair of enantiotopic hydroxymethyl groups to access axially chiral compounds with up to 99% ee (Scheme 1a). 5 A complementary approach using man-made chiral catalysts would be of high interest.
Semmelhack pioneered the use of atmospheric air as an oxidant in copper-nitroxide-catalyzed aerobic oxidation of alcohols to the corresponding carbonyl compounds. 6 Based on this work, Stahl has developed several highly efficient nitroxide copper co-catalytic systems for efficient aerobic alcohol oxidation. 7 The Stahl group 8 and we 9 also extensively studied the mechanism of this reaction. Interestingly, enantioselective oxidations using atmospheric oxygen as a terminal oxidant are quite rare. 10,11 While nitroxides are outstanding catalysts and reagents for chemical synthesis 12 and even have seen use in enantioselective oxidation of alcohols, 13 their use in atroposelective oxidative kinetic resolution (OKR) and desymmetrization is still in infancy with the work by Blandin being the first example. 14 As part of our longstanding interest in nitroxides, 9,15 we recently reported our preliminary findings 16 on chiral nitroxide-copper co-catalyzed aerobic OKR of axially chiral N-aryl-pyrroles (Scheme 1b) using readily available (prepared in only five steps) 16 chiral α-hydrogen pre-catalyst 1 (97% ee, see Scheme 2 for the structure). In this full paper, we now report our complete findings on the OKR of biaryl systems and explore the use of this catalyst system in atroposelective desymmetrization reactions as well (Scheme 1b) ■ RESULTS AND DISCUSSION Our reaction protocol closely followed the conditions we had developed earlier 15e, 16 which in turn were based on Stahl's conditions. 7 Significantly, these exact conditions are compatible with various functional groups that are sensitive to oxidation including alkenes, alkynes, thiophenes, and electronrich aromatic systems, 15e see also ref 7. Thus, very little optimization work was needed apart from determining that 2 mol % of nitroxide and copper pre-catalyst were needed for efficient reactions. At lower catalyst loadings, the reaction was arrested, while at higher catalyst loadings, there was no change in stereoselectivity. Accordingly, as depicted in Scheme 2, the optimized OKR process requires only 2 mol % of the chiral hydroxyl amine precatalyst (1S,3S)-1. 2 mol % of inexpensive copper(I) bromide, 2 mol % of bipyridine, and 4 mol % of Nmethyl imidazole were used as additional catalytic components. Importantly, ambient air was used as the oxygen source in the acetonitrile solvent at room temperature. Under these catalytic conditions, the chiral hydroxylamine precatalyst (1S,3S)-1 oxidizes to generate chiral nitroxide radical, which participates in the catalytic process. Subjecting the Narylpyrrole rac-2a to the OKR conditions for 5 h afforded the recovered alcohol (R)-2a in 38% isolated yield with 3.5:96.5 er at 57% conversion (C), as determined by HPLC (see the Experimental Section and Supporting Information for details). The oxidized product aldehyde (S)-3a was obtained in 53% yield with 76.5:23.5 er. This corresponds to a selectivity factor (s) of 18.8 (Scheme 2). It should be noted that axially chiral N-phenylpyrroles are important structural components of pharmaceuticals and natural products. Also, axially chiral pyrroles can be employed as ligands and catalysts in asymmetric catalysis. 17 The methyl congener rac-2b was resolved with an s factor of 10.7 at 60% conversion with the unreacted alcohol (R)-2b isolated in 38% and 6.0:94.0 er. The aldehyde (S)-3b was isolated in 55% yield and like 3a in a lower er of 77:23. The chloro-analogue rac-2c of 2b was resolved with a s value of 6.4 at 51% conversion. However, this may be due to a solvent effect and not necessarily an electronic effect as the OKR of substrates 2c (and 2p see below) was carried out in a solvent mixture of acetonitrile and ethyl acetate (1:1) due to the poor solubility of the substrates. The acetal protected catechol-substituted N-arylpyrrole 2d was resolved with an s value of 8.7, affording the resolved alcohol (R)-2d in 45% yield and an er of 16:84 and the oxidized product (S)-3d with an er of 79.5:20.5 and 47% yield based on 52% conversion. The 3-bromophenyl-substituted rac-2e was resolved in acetonitrile with an s-value of 16.2 to give the recovered (R)-2e in 37% with an er of 4:96, and the corresponding aldehyde (S)-3e was isolated in 54% yield with an er of 76.5:23.5. The conversion was 58% after 5 h. The bromo-substituent is of course useful for further functionaliza-

Scheme 1. Oxidative Desymmetrization and Kinetic Resolution Approaches for the Synthesis of Atropisomers
The Journal of Organic Chemistry pubs.acs.org/joc Article tion. The resolution of 2e was scaled up to 1 mmol. At this scale, the reaction time required to reach 55% conversion increased to 27 h under air with an s-value of 13.4. This is not surprising for a heterogeneous reaction, in which oxygen solubility in the organic solvent is in fact the ratedetermining step. Indeed, 2e could be resolved at the same 1 mmol scale under a pure oxygen atmosphere with a reduced reaction time of 7 h at 46% conversion with an s-value of 13.2. The corresponding ethyl ester rac-2f was resolved with an svalue of 14.8 at 56% conversion after 5 h. The absolute configuration of resolved (R)-2e was determined by X-ray crystallography ( Figure 2) and the absolute configuration of all other products in Scheme 2 assigned accordingly.
We next examined the effect of the 2-substituent of the phenyl moiety of the N-aryl-pyrrole. As shown for compounds 2a−2f, alcohols with an isopropyl substituent generally gave high s-values. In comparison, the 2-ethyl substituted in rac-2g was resolved with an s-value of 9.2 at 56% conversion after 5 h compared to 14.8 for isopropyl-substituted 2f at the same conversion and reaction time. There was no significant difference between 2g and 2-methyl-substituted 2h which was resolved with an s-value of 9.7 at 55% conversion after 5 h. Adding a five-membered ring between the 2 and 3 positions on the phenyl moiety as in 2i also led to a drop in the s-value to 5.6 and slightly retarded the reaction rate, so after 5 h, 46% conversion was achieved. 2-Phenyl-substituted 2j was resolved with an s-value of 10.4 at 55% conversion after 24 h similar to what was achieved for 2-ethyl-substituted 2g. This indicates that steric rather than electronic effect plays a role in the atroposelective oxidation step in this part of the substrate.
For comparison with rac-2a, we also tested 2k with a sterically bulky 2-tert-butyl group. Resolution of rac-2k afforded the resolved alcohol (R)-2k with an er of 13.5:86.5 at 43% isolated yield with an s-value of 9.2 at 54% conversion although an additional hour was needed to reach that conversion. Compound 2l with a 2-bromo substituent was resolved at 53% conversion after 8 h with an s-value of 11.3. Interestingly, swapping the 2-substituent in the phenyl moiety to a phenyl group as in 2m afforded the (R)-alcohol 2m in 10.5:89.5 er at 49% conversion corresponding to an s-value of 24.
We then examined compounds for which the 2-phenyl substituent on the phenyl ring of the N-phenylpyrrole system was left as a constant, but the pyrrole phenyl ring substituted was varied. For formaldehyde acetal-protected catechol 2n, the reaction rate was very low taking 24 h to reach 41% conversion. As N-aryl-pyrroles may act as ligands for copper, it is possible that product inhibition caused this dropping reaction rate. The s-value for this OKR was 8.5. With a 3-nitro substituted phenyl group on the pyrrole in 2o, the reaction was also retarded, and the OKR took 36 h to reach 40% conversion with an s-value of 6.6. Similarly with a 2-naphthyl group on the pyrrole as in 2p, 48 h was required to reach 46% conversion with an s-value of 6.4.
The major limitation found for this OKR process is the requirement to have an ester group at position 3 of the pyrrole ring for successful resolution. Although oxidation occurred, resolution of the substrate rac-2q with no ester group did not show any appreciable enantioselectivity. Although there is no concrete evidence, the presence of an ester group seems to be very specific for axially chiral pyrroles as it was also observed by the Tan's group during the development of asymmetric Paal−Knorr synthesis to access axially chiral pyrroles. 17a After the successful resolution of axially chiral pyrroles, we turned our attention to the resolution of racemic bis-benzenetype alcohols. Initially, the same catalytic conditions used for OKR of racemic N-phenylpyrrole alcohols 2 have been tested for biaryl alcohol 4a (Table 1, entry 1). In general, alcohols 4 reacted faster than N-arylpyrrole alcohols 2. Most substrates reached 50% conversion in 2.5−5 h of oxidation. Thus, after 2.5 h, racemic alcohol 4a was oxidized to the corresponding aldehyde 5a at 64% conversion, and the chiral R-alcohol was recovered in 5.5:94.5 er with a selectivity factor of 8.4. The product aldehyde 5a was obtained in 60:40 er. In order to check the influence of the solvent on stereoselectivity, the reaction was performed in different solvents while keeping the other parameters constant (Table 1, entries 2−5). Though the conversion in dichloromethane was similar to acetonitrile, the enantioselectivity diminished (Table 1, entry 2). In dimethylformamide, the reaction was slow resulting in the recovered 4a in 34.5:65.5 er and the aldehyde product 5a in 90:10 er with an s-value of 12.0 (Table 1, entry 4). The reaction was also quite slow in ethyl acetate and tetrahydrofuran producing only 4 and 2% conversion, respectively, after 20 h (Table 1, entries 3 and 5). The catalytic reactivity of other copper(I) salts was also investigated for 4a. However, the reactivity and stereoselectivity were lower for copper chloride and copper iodide in comparison to copper bromide (Table 1, entries 6−7). Hence, the use of 2 mol % of copper bromide in acetonitrile in the presence of 2 mol % of chiral hydroxyl amine precatalyst (1S,3S)-1 gave the best result for the OKR of 4a in terms of yield and er and was again chosen for further studying the scope of the reaction.
The absolute configuration of the known recovered alcohols 4b and 4j and product aldehydes 5b, 5f, and 5g was assigned by comparing the optical rotation of the obtained products to data that have been described previously 18−22 (see the Experimental Section and Supporting Information for details), and the configuration of the remaining compounds was assigned by analogy.
It was found that both substrates with electron-donating and electron-withdrawing groups on either part of the benzene rings are well tolerated. Bi-naphthyl alcohol rac-4b was resolved in 3 h at 56% conversion with an s value of 6.5. Other compounds with one substituted benzene ring and one naphthyl ring gave similar s-values. Thus, rac-4c was resolved with 60% conversion in 3.5 h to give the recovered alcohol (R)-4c in 35% isolated yield with an er of 19:81 (s-value 4.3). Differentially protected catechol 4d with one less oxygen on the benzene than 4c reacted even faster with an s-value of 2.9 and 64% conversion in 3 h. Compound 4e that has two identical methyl protecting groups on the catechol moiety underwent OKR with an s-value of 3.7.
Compound 4f with a methyl substituent in the 2-position of the bottom naphthyl and no substituents on the upper phenyl ring apart from the methyl alcohol was resolved with an er of 30:70 (44% isolated yield) corresponding to an s-value of 4.8. Racemic alcohol 4g with an electron-donating methyl group on the phenyl ring and a methyl substituent on the naphthyl in the 4-position was resolved with an s-factor 4.1 in 3.5 h at 66% conversion with an er of 19:81. Substrates 4h and 4i with 2- CF 3 groups in the lower phenyl ring were resolved with higher selectivity factors of 6.3 and 7.3, respectively. In contrast, Racalcohols 4j and 4k, with the upper ring being of the naphthyl type, were found to be poor substrates for OKR and yielded low er for the recovered alcohols. However, a rac-alcohol with an upper naphthyl group and a lower 2-phenyl-phenyl group 4l was resolved with high er (8:92, 20% isolated yield at 65% conversion in 5 h) and a selectivity factor of 6.6. Racemic alcohols 4m−4q containing alkoxy group at meta-position with respect to the hydroxymethyl group were resolved successfully. While compound 4m substituted with a trifluoromethyl group in the lower phenyl group was resolved with an s-value of 4.6 in 3 h at 63% conversion, a similar compound with methyl substitution 4q was resolved with a higher s-value 6.1 in 3 h, indicating that a methyl group is better than the trifluoromethyl group in the atropo-differentiating step. Racemic alcohol 4n with a lower naphthyl ring and a methoxy substitution on the phenyl ring was resolved in 3 h at 70% conversion with a s-factor 6.1. Replacing methoxy group in 4n with the ethoxy group as in compound 4o did not have great impact except slightly reducing the rate of oxidation. Compound 4o was resolved in 3 h with an s-value of 6.1 at 64% conversion. Compound 4p substituted with a benzyloxy group was resolved successfully with an s-value of 6.3. Replacing the lower naphthyl group of 4n with a 2-methyl-phenyl group, i.e., compound 4q, allowed resolution with an s-value of 6.1.
Finally, compound 4r with an iodo-substituent on the lower phenyl group was resolved on a 1 mmol scale in only 3.5 h with an s-value of 4.3, allowing the isolation of recovered (R)-4r in 22% isolated yield based on 76% conversion. The corresponding aldehyde oxidation product was isolated in 73% yield and a 62.5:37.5 er.
These axially chiral iodine-substituted compounds can be elaborated to further transformations using iodine as a handle or could potentially be used as chiral oxidants for enantioselective processes α-tosylation of carbonyl compounds. 23 It is noteworthy to mention that unlike the OKR of rac-Naryl pyrroles (Scheme 2), there is no requirement to have an ester group ortho to the hydroxy methyl group for the successful resolution of rac-biaryls (Scheme 3). However, the OKR of rac-aryl pyrroles exhibited higher orders of enantioselectivities compared to the resolution of rac-biaryls.
We next addressed the possibility of applying this copperchiral nitroxide oxidation process to the desymmetrization of prochiral diols to synthesize atropisomers (Scheme 4). To this end, we synthesized prochiral diols 6a−6c from the commercially available starting materials (see the Supporting Information). Achiral diol 6a was subjected to desymmetrization using the same set of reaction conditions established for resolution. Remarkably, after 3 h of oxidation, optically pure mono aldehyde 7a was obtained in 58% of isolated yield with 8:92 er. Along with chiral monoaldehyde 7a, achiral dialdehyde 8a was also formed in 18% yield. Formation of dialdehyde is due to the over oxidation of monoaldehyde 7a. Similarly, achiral diols 6b and 6c were also subjected to the desymmetrization. In the case of substrate 6b, after 6 h of oxidation, desired product 7b was isolated in 68% yield with 4.5:95.5 er along with 28% of dialdehyde 8b. Substrate substituted with phenyl group 6c also underwent desymmetrization and afforded the desired chiral monoaldehyde 7c in 73% yield with an exceptional er 99:1 in 7 h of oxidation.
The examined axially chiral compounds in this study were found to be configurationally stable on storage and even when standing in solution for several days. Thus, the few percent stereo-erosion observed must have occurred during the oxidation step.
In conclusion, we have developed efficient copper and chiral nitroxide-catalyzed enantioselective oxidation protocols to synthesize axially chiral N-arylpyrroles and axially chiral biaryl compounds in high enantioselectivities. Importantly, ambient air was used as a stoichiometric terminal oxidant. A diverse range of racemic substrates were resolved with moderate to good selectivity factors. Additionally, desymmetrization of prochiral diols may be achieved with high enantioselectivities. Further enantioselective oxidation processes using this elegant copper-chiral nitroxide protocol is underway in our laboratory. ■ EXPERIMENTAL SECTION General Information. Unless indicated otherwise, all nonaqueous reactions were carried out using oven-dried (120°C) glassware under a positive pressure of argon. Commercially available reagents were used without further purification. Except if specified otherwise, reactions were magnetically stirred and monitored by thinlayer chromatography (TLC) using Merck Silica Gel 60 F254 plates and visualized under UV light. In addition, TLC plates were stained using potassium permanganate and 2,4-dinitrophenylhydrazine stains. Chromatographic purification of products (flash chromatography) was performed on silica gel (230−400 mesh). Concentration under reduced pressure was performed by rotary evaporation at 40°C at the appropriate pressure. Yields refer to chromatographically purified compounds. NMR spectroscopy: NMR spectra were recorded on a Bruker spectrometer operating at 400 MHz and 101 MHz for 1 H and 13 C acquisitions, respectively. Chemical shifts (δ) for 1 H NMR are reported in parts per million (ppm) relative to tetramethylsilane in CDCl 3 (δ 0.00 ppm) or residual chloroform in CDCl 3 (δ 7.26 ppm). All the 13 C chemical shifts were reported in ppm with reference to CDCl 3 (δ 77.16 ppm). All 13 C spectra were measured with complete proton decoupling. Data are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and br = broad signal; coupling constants in Hz. IR spectroscopy: IR spectra were recorded on a JASCO FT-IR spectrometer (as neat) in the 600−3600 cm −1 region. Absorptions are given in wavenumbers (cm −1 ). Chiral HPLC: enantiomeric excess was determined by Thermo Scientific HPLC and Shimadzu HPLC instruments, using a Lux 5 μm Cellulose-1 (250 × 4.60 mm) column, a Lux 5 μm Amylose-2 (250 × 4.60 mm) column, Chiralpak AD-H (250 × 4.60 mm), Chiralpak AD-H (150 × 4.60 mm), and Cellulose-1 OD-H (250 × 4.60 mm) column with hexane and isopropanol (IPA) as solvents. Mass spectra: high-resolution mass spectra were obtained using a Xevo G2-XS-QToF device. Data were acquired using the resolution mode under positive/negative electrospray ionization. The acquisition range was 50−1200 m/z. The capillary voltage was 2.0 kV, and the cone voltage was 40 V. Scan time was 0.5 s. In all cases, samples were injected direct to MS using methanol as the eluent. Optical activity: optical activity of the compounds was measured by a Bellingham Stanley polarimeter ADP 450. Absolute stereochemistry: absolute stereochemistry of products was determined by comparing the optical rotation of known compounds. The absolute stereochemistry of remaining compounds was assigned by analogy. Selectivity factor (s): the selectivity factor of these kinetic resolution process was calculated by Kagan's equation. 24 X-ray structure: X-ray crystallographic data were measured on a Bruker Apex-II instrument.
Procedure for 1 mmol Scale OKR of Racemic N-Aryl Pyrrole Alcohol Using Pure Oxygen (2e). 16 In a 100 mL single-neck roundbottom flask, racemic 2e (429 mg, 1 mmol, 1 equiv) was dissolved in 10 mL (0.1 M) of analytical grade acetonitrile. Copper(I) bromide (2.87 mg, 0.02 mmol, 0.02 equiv), bipyridine (3.12 mg, 0.02 mmol, 0.02 equiv), hydroxylamine precatalyst (1S,3S)-1 (15.32 mg, 0.02 mmol, 0.02 equiv), and N-methyl imidazole [3.28 mg, 0.04 mmol, 0.04 equiv (0.4 mL of 0.1 M acetonitrile solution)] were added to the reaction flask. The reaction flask was attached to oxygen balloon and stirred at room temperature (23−25°C) under an oxygen atmosphere. The reaction progress was monitored by 1 H NMR analysis of the crude reaction mixture. After 7 h of oxidation, at 46% conversion, the reaction was stopped. The acetonitrile was removed from the reaction mixture under reduced pressure at room temperature on a Rotavapor. The crude reaction mixture was subjected to flash column chromatography using hexane and ethyl acetate as the eluent to obtain recovered alcohol 2e and the product aldehyde 3e.
General Procedure for the OKR of Racemic Biaryl Alcohols (4a− r). In a 20 mL glass vial, 100 mg of racemic 4 (1 equiv) was dissolved in analytical grade acetonitrile (0.05−0.1 M). CuBr (2 mol %), bipyridine (2 mol %), chiral hydroxylamine (1S,3S)-1 (2 mol %), and N-methylimidazole (4 mol %, 0.1 M acetonitrile solution) were added to the reaction mixture. The resulting red/brown colored reaction mixture was stirred at RT (23−25°C) open to air for specified time. The reaction progress was monitored by 1 H NMR analysis. After the specified conversion, the solvent from the reaction mixture was removed under the reduced pressure. The crude reaction mixture was subjected to flash column chromatography using hexane and ethyl acetate as the eluent to afford aldehyde 5 and recovered alcohol 4.