2025 Volume 73 Issue 7 Pages 616-620
Newly designed optically active cage type 2-azanorbornane-based amino amide organocatalysts were developed and employed in the asymmetric Michael addition of β-keto esters with nitroolefins to afford the chiral Michael adducts with good chemical yields (up to 99%) and stereoselectivities (up to diastereomeric ratio (dr) = 97 : 3, up to 96% enantiomeric excess (ee)).
Efficient organocatalysts have been successfully explored over the years toward a wide range of reactions.1–4) Excellent covalent and non-covalent organocatalysts have been developed and their catalytic activity was examined in a diverse range of reactions.5–8) Our research group also, have been continuously exploring a series of amino alcohols9–11) and its related organocatalysts in some asymmetric reactions.12–14) Most recently, we have reported the cage type 2-azanorbornane-based amino alcohols organocatalyst X (Chart 1) which showed satisfactory catalytic activity in the asymmetric Michael addition of β-keto esters with nitroolefins15) to afford the chiral Michael adducts which act as chiral key intermediates for the synthesis of various biologically active compounds and synthetic drug candidates.16–19) Based on these backgrounds, we designed an optically active 2-azanorbornane-based amino amides as an organocatalyst A which is derived from 2-azanorbornene Y and applied it to this reaction using β-keto esters B with nitroolefins C (Chart 1). Catalyst A has bulky 2-azanorbornane backbone and the cage structure contains nitrogen atom acting as Brønsted basic or an enamine formation site. Furthermore, A has the amide side chain at the 3-position on the 2-azanorbornane skeleton, which might show strong electronic and steric effects for controlling stereoselectivity in the course of reaction. Considering these structural properties, it is expected that A might show an efficient functionality as an organocatalyst for enantioselective reactions. However, to the best of our knowledge, the use of A has not been reported until now. Only a few successful studies have been reported by using our reported amino amide organocatalyst for this asymmetric Michael addition.11)
We herein describe a new 2-azanorbornane-based amino amide organocatalyst A with an efficient catalytic activity in the Michael addition of B with various C to obtain chiral Michael adducts D in satisfactory chemical yields and stereoselectivities (up to 99%, diastereomeric ratio (dr) = 97 : 3, 96% enantiomeric excess (ee)).
2-Azanorbornane-based amino amide organocatalysts 7a–f were derived from the Diels–Alder (DA) adduct 3 by a series of reactions as follows (Chart 2). Initially, 2-azanorbornenes 3 was prepared by the hetero DA reaction of cyclopentadiene with chiral imino dienophile which was obtained by the condensation of aldehydes 1 with chiral amines 2.20) The catalytic hydrogenation of 3 followed by the benzyloxycarbonyl (Cbz)-protection of nitrogen atom of 4 and the hydrolysis of ethoxycarbonyl group of obtained 5 afforded 6.21) The amidation of 6 with the corresponding amines followed by the hydrogenations of the obtained N-protected amino amides afforded the corresponding catalysts 7a–f in moderate to excellent yields.
We examined the catalytic activity of amino amides 7a–f in the Michael addition of β-keto ester 9a with nitrostyrene 10a (Fig. 1). The reactions were carried out using 10 mol% of catalysts 7a–f in i-Pr2O at 0°C (entries 1–7). All catalysts 7a–f showed catalytic activities in this reaction and afforded the Michael adduct [2S,3R]-11a. Especially, trityl-catalyst 7f afforded 11a (R = Me) in best enantioselectivity with good chemical yield and stereoselectivities (99%, dr = 95 : 5, 89% ee, entry 7). although adamantly-catalyst 7d also showed good catalytic activity (99%, dr = 96 : 4, 87% ee, entry 5). However, this reaction with bulky 9b and 10a using superior catalyst 7f and good catalyst 7d, respectively did not afford the corresponding 11b (entry 8). In addition, the catalytic activity of known proline-based catalyst 822) (Chart 1) was also examined in this reaction using 9a and 10a in comparison to cage type 7f. However, catalyst 8 did not show better catalytic activity than 7f in this reaction condition. Bulky 2-azanorbornane back bone in catalyst 7f may work effectively for the expression of highly enantioselectivity as stereocontrol factor. This result indicated the effectiveness of bulky cage structure in 7f toward the Michael reaction of 9a with 10a. The absolute configuration of the obtained product and diastereoselectivity of 11a were identified based on comparison with literature data.23–25)
To further improve the enantioselectivity of this reaction using superior trityl-catalyst 7f, we evaluated the effects of various solvents, mole ratios of catalyst, and reaction temperatures (Fig. 2). First, we examined the solvent effects in different non-polar aromatic, ethereal, chlorinated, and polar solvents in the superior trityl-catalyst 7f (10 mol%) at 0°C for 24 h (entries 1–4). As a result, i-Pr2O afforded the adduct 11a in satisfactory chemical yield and steleoselectivities (entry 2 in Fig. 2 and entry 7 in Fig. 1). When both CH2Cl2 and MeOH were used as a solvent, chemical yields and stereoselectivities decreased (entries 3,4). It might be because a better transition state (TS) is not formed by the electric influence of solvents for conducting enough chemical yield and stereoselectivities, although the reason is not clear. Based on these results, the reaction temperatures were screened in superior i-Pr2O solvent in the presence of superior catalyst 7f (10 mol%), respectively (entries 5–8). Good result was obtained at −30°C (99%, dr = 97 : 3, 91% ee) (entry 6). Furthermore, the effects of catalyst loading were examined in i-Pr2O solvent at −30°C for 24h (entry 9: 5 mol% and entry 10: 20 mol%). As a result, best enantioselectivity was observed when the reaction was carried out using 20 mol% (96% ee, entry 10). From these results, it was observed that 20 mol% of catalyst loading in i-Pr2O as a solvent at −30°C was the best reaction condition to afford the Michael adduct 11a in satisfactory result (entry 10).
After optimization of the reaction conditions, the Michael addition was extended to various β-keto esters 9a, c–e with nitroolefins 10a–g using catalyst 7f in the optimized condition (Chart 3). As summarized in Chart 3, the desired Michael adducts 11c–h were obtained in good chemical yields and stereoselectivities. The reactions of substrate 9a with nitrostyrenes (p-halogenated 10b, c, p-methylated 10d, and p-methoxylated 10e) afforded the corresponding chiral Michael adducts 11c–f, respectively, in excellent chemical yields and diastereoselectivities with moderate to excellent enantioselectivities. Furthermore, the reactions using heterocyclic nitroolefins 10f, g were also carried out and the corresponding adducts 11g, h were obtained in moderate to good chemical yield, good diastereoselectivities, and fairly good enantioselectivities. However, catalyst 7f did not show catalytic activity using substrate 9c with six-membered cyclohexanonyl skeleton to afford 11i. It might be because better TS is not formed by the steric influence of bulky cyclohexane ring in 9c for conducting satisfactory chemical yield and stereoselectivities, although the reason is not clear. On a just in case note, we tried the similar reaction with substrate 9c using sterically less bulky catalysts 7a and 7c than 7f, but these catalysts showed almost no catalytic activity, and the desired 11i was hardly confirmed to have been formed. Furthermore, the reaction of simple acyclic β-keto ester 9d with 10a afforded the corresponding 11j as with only low chemical yield and diastereoselectivity as racemate. Also, the use of acyclic substituted 9e did not afford the corresponding adduct 11k. The reason might be that substrates do not coordinate with catalyst 7f due to the steric interaction of bulky catalyst 7f and substrate 9e. The determinations of the absolute stereochemistries of 11c–h, j were confirmed on comparison with previous reports.23,25)
Considering both excellent 96% ee of the Michael adduct [2S,3R]-11a that was obtained in the reaction of 9a with 10a using catalyst 7f and its X-ray structure analysis, an enantioselective reaction course is proposed as follows (Chart 4). In addition, the formation of enamine species by catalyst 7f with β-keto ester 9a was not observed in the reaction under optimized reaction condition (Fig. 1). This result indicates that catalyst 7f may act as a basic catalyst in this reaction.
The reaction might proceed through TS-1–4 in which an enolate of 9a fixes with the ammonium hydrogen atom on the ammonium catalyst species and 10a fixes with the hydrogen atom at the amide group on the ammonium catalyst species. In the proposed TS-1–4, the reaction might be proceed through TS-2 that has a smaller steric interactions both between substrates 9a and 10a and between 9a and the ammonium catalyst species than those of TS-1,3,4 that have a larger steric interactions between substrates 9a, 10a and the ammonium catalyst species.
In conclusion, a newly designed optically cage type active 2-azanorbornane-based amino amide organocatalysts 7 showed efficient catalytic activities in the asymmetric Michael addition of β-keto esters with nitroolefins. Especially, trityl-catalyst 7f showed best catalytic activity and afforded the corresponding chiral Michael adducts 11 with good to excellent chemical yields, and stereoselectivities (up to 99%, up to dr = 97 : 3, up to 96% ee). The modification of 2-azanorbornane-based amino amide organocatalysts, the applications to further substrates, and the detailed mechanistic study are in progress.
All commercial reagents were purchased and used without further purification. All reactions were carried out under argon atmosphere in flame-dried glassware with magnetic stirring. TLC was performed on silica gel 60 F254 and analytes were detected using UV light (254 nm) and iodine vapor. Column chromatography was carried out on silica gel 60N (40–100 µm) and Preparative TLC was carried out on silica gel 60 F254. Melting points were measured using a micro-melting point apparatus. IR spectra were measured with a JASCO (Tokyo, Japan) FT/IR-4100 spectrophotometer. 1H-NMR spectra were measured on a JNM-ECA500 (500 MHz) spectrometer. Data were reported as follows: chemical shifts in ppm from tetramethylsilane or the residual solvent as an internal standard, integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, dd = double-doublet, m = multiplet, and br = broad), coupling constants (Hz), and assignment. 13C-NMR spectra were measured on a JEOL (Tokyo, Japan) JNM-ECA500 (125 MHz) spectrometer with complete proton decoupling. Chemical shifts were reported in ppm from the residual solvent as an internal standard. HPLC was performed using Daicel Chiralcel OD-H 4.6 mm × 25 cm column. Optical rotations were measured with a JASCO-DIP-370 digital polarimeter. MS were taken on JEOL-JMS-700 V spectrometers. Circular dichroism (CD) spectra were measured using a JASCO J-500A spectropolarimeter.
General Procedure for the Preparation of Catalysts 7a–fTo a stirred solution of carboxylic acid 6 (0.140 g, 1.0 mmol) in CH2Cl2 (10 mL) at 0°C was added corresponding amine (1.2 mmol), 1-Hydroxybenzotriazole (HOBt) (207 mg, 1.2 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.27 mL, 1.2 mmol). The reaction mixture was gradually allowed to come to room temperature and stirred for 20 h. After the completion of reaction indicated by TLC, the reaction mixture was washed with 0.1 M HCl aq. The organic layer was washed with saturated NaHCO3 aq, and finally water. After drying the organic layer over Na2SO4, the solvent was removed under reduced pressure. To the obtained crude product in EtOH was added 10%Pd-C (10 mg) and stirred under H2 atmosphere at rt for 48 h. After 48h, the reaction mixture was filtered and the obtained filtrate was concentrated in vacuo to afford the crude residue. The residue was purified by flash chromatography on silica gel (n-hexanes/EtOAc = 3/1-5/1) to give 7a–f as a solid. Compounds 3–5, 6 were prepared according to the previously reported method.15,20)
(1S,3R,4R)-2-Azabicyclo[2.2.1]heptane-3-exo-phenylamide (7a)White solid (mp: 119°C);
White solid (mp: 134°C);
White solid (mp: 220°C);
White solid (mp: 159°C);
Orange solid (mp: 112°C);
White solid (mp: 189°C);
The authors declare no conflict of interest.
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