Fe-BPsalan Complex-Catalyzed Asymmetric 1,3-Dipolar [3 + 2] Cycloaddition of Nitrones with α,β-Unsaturated Acyl Imidazoles

Abstract

A highly efficient, iron­(III)-BPsalan complex-catalyzed asymmetric 1,3-dipolar cycloaddition of nitrones and α,β-unsaturated acyl imidazoles has been developed to afford isoxazolidine (31 examples) and isoxazoline derivatives (13 examples) in moderate to excellent yields (up to 99%) and excellent stereoselectivity (up to 99% ee and >20:1 dr). The reaction proceeds readily in acetone under air conditions, maintaining high efficiency and selectivity.

Introduction

Isoxazolidine and isoxazoline scaffolds are key structures in medicinal chemistry and chemical synthesis. Their distinct nitrogen- and oxygen-containing heterocyclic structures make them valuable building blocks with widespread applications in the synthesis of bioactive natural products and pharmaceuticals. For example (Figure ), they are key structures in cycloserine (antibiotic for drug-resistant TB), reglixane (antidiabetic), afoxolaner, and lotilaner. They also serve as useful synthetic precursors for the preparation of 1,3-aminoalcohols, alkaloids, β-amino acids, β-lactams, and azasugars. ,,, Therefore, due to their diverse biological activities, the preparation of isoxazolidine and isoxazolines has become an area of considerable interest.

1.

Examples of natural products and biologically active compounds bearing isoxazolidine and the isoxazoline scaffold.

The 1,3-dipolar cycloaddition of alkenes or alkynes is a simple and straightforward method for constructing five-membered heterocyclic compounds. Among these, the asymmetric 1,3-dipolar cycloaddition of nitrones with alkenes/alkynes has become the commonly used synthetic strategy for constructing enantiomerically enriched isoxazolidine and isoxazoline scaffolds, ,,,,, offering significant advantages in operational simplicity and superior atom economy. Consequently, efforts to develop efficient and selective catalytic asymmetric cycloadditions of nitrones with alkenes and/or alkynes are underway. Transition metal complexes of Cu, Ni, Zn, Co, etc., are commonly used as catalysts for these reactions. In 2006, Evans reported the Ce­(IV)-cis-bis-Ph-pybox-complex-catalyzed asymmetric cycloaddition of nitrone and α,β-unsaturated acyl imidazole to afford isoxazolidine derivatives with excellent enantioselectivity and diastereoselectivity under mild reaction conditions (Scheme a). In 2024, Li reported chiral-at-rhodium complex-catalyzed asymmetric 1,3-dipolar cycloaddititon of β-trifluoromethyl α,β-unsaturated 2-acyl imidazole with nitrones to afford chiral α-fluoroalkylated isoxazolidine derivatives with high efficiency and excellent enantioselectivity (Scheme b). It is worth noting that Huang reported an elegant iron-catalyzed asymmetric 1,3-dipolar cycloaddition of nonterminal alkynyl imides and α-aliphatic nitrones to afford chiral 4-isoxazoline derivatives with high efficiency and excellent enantioselectivity (Scheme c).

1. Asymmetric 1,3-Dipolar Cycloaddition of Nitrone.

Despite significant progress in the catalytic asymmetric [3 + 2] cycloadditions of nitrones with alkenes and/or alkynes, the growing demand for sustainable and green catalysis requires the development of stable, efficient, and selective base metal catalysts. Iron catalysis has attracted a considerable amount of interest due to iron’s earth abundance and biocompatibility, and interest in iron catalysis has intensified in recent years. , We are committed to developing asymmetric iron catalysis for practical organic transformations and report a series of readily prepared Lewis acidic Fe-BPsalan complexes that efficiently catalyze asymmetric fluorination, hydroxylation, chlorination, , cycloaddition, − and the Michael reaction, affording the corresponding products in high yields with high stereoselectivity. To further expand the applications of Fe-BPsalan catalysis in organic synthesis, we report the asymmetric 1,3-dipolar cycloaddition of nitrones with α,β-unsaturated acyl imidazoles catalyzed by Fe-BPsalan complexes (Scheme d). Under mild reaction conditions, the Fe-BPsalan complex (2 mol %) was used as a catalyst to efficiently synthesize isoxazolidine and isoxazoline derivatives in high yields with excellent enantioselectivity.

Results and Discussion

Initially, the iron-catalyzed asymmetric 1,3-dipolar cycloaddition was investigated using α,β-unsaturated acyl imidazole 1a and nitrone 2a as the starting materials. The reaction was carried out in dichloromethane (DCM) at 25 °C in the presence of 4 Å molecular sieves using Fe-BPsalan complex cat.1 (5 mol %) as the catalyst and AgOTf (5 mol %) as the additive. To our delight, the desired addition product 3a was successfully obtained in 88% yield, with a dr >20:1 and an ee of 91% (Table , entry 1). Subsequently, Fe-BPsalan complexes bearing various substituents on the phenyl ring were further tested, and all exhibited moderate to good reactivity (Table , entries 2–11). Among the screened iron catalysts, Fe-BPsalan complex cat.1 exhibited the best performance in terms of both yield and enantioselectivity (entry 1). The effect of silver salts was further investigated as it is known that when a weak coordination counteranion was introduced in asymmetric transition metal catalysis, the reaction efficiency and selectivity may be greatly enhanced (Table , entries 12–17). When no silver salt was added to the reaction mixture, complex cat.1 alone provided 3a, albeit with a significantly reduced product yield (12%) and ee (38%) (Table , entry 12). This significant change in catalyst activity and selectivity is consistent with our previous findings in asymmetric Fe-BPsalan-catalyzed reactions. A cationic iron complex was generated upon the addition of AgOTf, greatly enhanced the Lewis acidity of the catalyst, and provided a vacant extra binding position to coordinate with the α,β-unsaturated acyl imidazole. As expected, other sliver salts containing weak coordinating anions also significantly improved the reaction (Table , entries 13–17), with AgSbF₆ proving to be the optimal choice, affording 3a in 98% yield, >20:1 dr, and an ee of 96% (Table , entry 15).

1. Screening of Iron Catalysts .

entry	catalyst	Ag salt	yield (%)	dr	ee (%)
1	1	AgOTf	88	>20:1	91
2	2	AgOTf	29	>20:1	28
3	3	AgOTf	70	>20:1	37
4	4	AgOTf	60	>20:1	90
5	5	AgOTf	45	>20:1	58
6	6	AgOTf	21	>20:1	40
7	7	AgOTf	90	>20:1	90
8	8	AgOTf	97	>20:1	90
9	9	AgOTf	90	>20:1	84
10	10	AgOTf	67	>20:1	74
11	11	AgOTf	66	>20:1	76
12	1	–	12	>20:1	38
13	1	AgPF6	68	>20:1	94
14	1	AgBF4	66	>20:1	94
15	1	AgSbF6	98	>20:1	96
16	1	AgClO4	99	>20:1	92
17	1	AgOAc	20	>20:1	79

^aFor the reactions, 1a (0.10 mmol), 2a (0.12 mmol), an iron catalyst (5 mol %), a Ag salt (5 mol %), and 4 Å molecular sieves (30 mg) in DCM (1 mL) were stirred at 25 °C under an argon atmosphere.

^bIsolated yield.

^cDetermined by crude ¹H NMR.

^dDetermined by HPLC analysis.

The reaction conditions were further optimized, using “Fe-BPsalan complex cat.1 and AgSbF₆” as the catalyst (Table ). The reaction was compatible with common organic solvents, including THF, Et₂O, toluene, acetone, chloroform, DCE, and acetonitrile, affording 3a in moderate to good yields and good to excellent ee values (Table , entries 1–7, respectively). With MeOH or 1,2-dimethoxyethane (DME) as the solvent, 3a was obtained in lower yields due to their coordination with the Fe-BPsalan complex (Table , entry 8 or 9, respectively). Among the solvents examined, DCE provided the best result, affording 3a in 98% yield within 5 h with >20:1 dr and an ee value of 98% (Table , entry 6). The role of molecular sieves in the reaction was subsequently investigated (Table , entries 10–12). Notably, molecular sieves are not essential for the reaction, and 3a was obtained without the addition of molecular sieves in 99% yield, >20:1 dr, and an ee of 98% (Table , entry 12). The effect of temperature on the reaction was further investigated. When the reaction was carried out at 0 °C, the results were similar to those obtained at 25 °C (Table , entry 13 vs entry 6), while the ee was lower at 40 °C, at only 96% (Table , entry 14). We also investigated the effect of varying the loading of the iron catalyst (Table , entries 15 and 16). The results showed that 3a was obtained in excellent yields with excellent ee values in the presence of as little as 2 mol % cat.1 (Table , entry 16). To render the reaction more practical, we attempted to use water as the solvent (Table , entry 17), affording 3a in 45% yield, >20:1 dr, and an ee of 90%. Due to the low solubility of 1a in water, 50% of residue 1a was recovered. The reaction was further improved using a 1:1 mixture of water and acetone as the solvent (Table , entry 18). Interestingly, when the reaction was carried out in industry grade acetone under air, 3a was obtained in 96% yield with >20:1 dr and an ee of 96%, indicating its potential for large-scale application.

2. Optimization of the Reaction Conditions .

entry	solvent	x	t (h)	yield (%)	dr	ee (%)
1	THF	5	24	54	>20:1	91
2	Et2O	5	6	95	>20:1	90
3	toluene	5	24	83	>20:1	78
4	acetone	5	24	44	>20:1	92
5	CHCl3	5	24	97	>20:1	91
6	DCE	5	5	98	>20:1	98
7	MeCN	5	24	50	>20:1	94
8	MeOH	5	24	10	>20:1	91
9	DME	5	24	23	>20:1	91
10	DCE	5	6	99	>20:1	96
11	DCE	5	5	96	>20:1	97
12	DCE	5	5	99	>20:1	98
13,	DCE	5	5	99	>20:1	98
14,	DCE	5	2	99	>20:1	96
15	DCE	1	12	72	>20:1	98
16	DCE	2	5	99	>20:1	99
17	H2O	2	24	45	>20:1	90
18	1:1 H2O/acetone	2	12	76	>20:1	96
19,	acetone	2	6	96	>20:1	96

^aFor the reactions, 1a (0.1 mmol), 2a (0.12 mmol), complex cat.1 (x mol %), AgSbF₆ (x mol %), and 4 Å sieves (30 mg) in a solvent (1 mL) were stirred at 25 °C under an argon atmosphere.

^bIsolated yield.

^cDetermined by crude ¹H NMR.

^dDetermined by HPLC analysis.

^eWith 3 Å MS instead of 4 Å MS.

^fWith 5 Å MS instead of 4 Å MS.

^gWithout 4 Å MS.

^hRun at 0 °C.

ⁱRun at 40 °C.

^jUnder air.

^kPurchased from Shanghai experiment reagent Co., Ltd., and used directly as received.

Under the optimized reaction conditions (Table , entry 16), the applicable scope of nitrone in the reaction was examined, and the results are listed in Table . Benzaldehyde-derived nitrones, whether bearing either electron-withdrawing halogen atoms (3b–3e) and CN (3g) and CF₃ (3h) groups or electron-donating OMe (3f) and Me (3i) groups, were well tolerated; the corresponding cycloaddition products were obtained in excellent yields (90–97%), with excellent diastereoselectivity (>20:1 dr) and enantioselectivity (95–98% ee). Cycloaddition products (3j and 3k) with o- and m-methyl substitutions were also successfully obtained in high yields and selectivities. X-ray crystallographic analysis (CCDC 2470452) confirmed the absolute structure of product 3j as (3S,4R,5S), and the corresponding structures of the other products were assigned accordingly. Product 3l bearing an o-methoxy group was also obtained with high yield (97%), excellent diastereoselectivity (>20:1 dr), and enantioselectivity (92% ee). While when the reaction was performed using the nitrone prepared from 2,4,6-trimethoxy benzaldehyde, product 3m was obtained in high yield (95%) and diastereoselectivity (16:1 dr), albeit with a low ee value (44%). This is likely due to the steric hindrance of the nitrone substate. Nitrones prepared from alkyl aldehydes also exhibited good reactivity, with steric hindrance playing a critical role in selectivity. Nitrones prepared from less sterically hindered alkyl aldehydes such as acetaldehyde, propionaldehyde, and butyraldehyde all reacted well, affording 3n–3p, respectively, in excellent yields (90–99%), albeit with relatively low enantioselectivities (76–86%) and diastereoselectivities (2:1–8:1). Slightly increasing the steric hindrance of the alkyl aldehyde may improve the diastereoselectivity of the reaction (3q, >20:1 dr), and nitrones prepared from sterically hindered alkyl aldehydes exhibit increased selectivity in this reaction, affording 3r–3t in high yields (88–93%) and good to excellent stereoselectivity (84–96% ee, >20:1 dr). Notably, the reaction tolerates electron-withdrawing groups such as CF₃ and CO₂Et, and the electron-withdrawing properties of the substituents significantly influence the enantioselectivity of the products. The more electron-withdrawing CF₃ group results in a lower ee of 26% (3u), while the less electron-withdrawing CO₂Et results in a higher ee of 80% (3v). Furfural-derived nitrones are also amenable to this reaction, affording 3w in 59% yield, with >20:1 dr and an ee of 93%.

3. Investigation of Different Nitrones .

^aFor the reactions, 1a (0.1 mmol), 2 (0.12 mmol), complex cat.1 (2 mol %), and AgSbF₆ (2 mol %) in DCE (1 mL) were stirred at 25 °C under an argon atmosphere.

^bThe ee value of the minor diastereoisomer is in parentheses.

^cThermal ellipsoids are shown at the 50% probability level.

The substrate scope of α,β-unsaturated acyl imidazoles and other α,β-unsaturated acyl type substrates was further examined, and the results are shown in Table . α,β-Unsaturated acyl imidazole bearing electron-donating alkyl substituents successfully underwent the reaction, affording cycloaddition products 4a–4e in moderate to high yields (56–90%), excellent enantioselectivities (90–96% ee), and excellent diastereoselectivities (>20:1 dr). α,β-Unsaturated acyl imidazole bearing electron-withdrawing groups like CO₂Et and CF₃ were also suitable for the reaction, affording 4f and 4g, respectively, in high yields (73–86%) with excellent enantioselectivities (92–96% ee, >20:1 dr). However, α,β-unsaturated acyl imidazoles containing a phenyl substituent showed low activity in this reaction. In the presence of 10 mol % catalyst, the reaction time was extended to 4 days, and only 62% yield, 86% ee, and >20:1 dr of cycloaddition product 4h were obtained. The pyridine-substituted α,β-unsaturated acyl substrate reacted smoothly, affording cycloaddition product 5a in 75% yield, 70% ee, and 17:1 dr. Substitution of imidazole with furan, pyrazole, or pyrrolidone did not yield the desired cycloaddition product, and the substrate was completely recovered.

4. Investigation of Different α,β-Unsaturated Acyl Substrates .

^aFor the reactions, 1 (0.1 mmol), 2a (0.12 mmol), complex cat.1 (2 mol %), and AgSbF₆ (2 mol %) in DCE (1 mL) were stirred at 25 °C under an argon atmosphere.

^b cat.1 (10 mol %), AgSbF₆ (10 mol %), 4 days.

^cThe ee value of the minor diastereoisomer is in parentheses.

Because this reaction is insensitive to moisture and oxygen (Table , entry 19), we conducted cycloaddition reactions of various nitrones with α,β-unsaturated acyl imidazoles under “as simple as possible” conditions using industry grade acetone as the solvent and performing the reactions under air (Table ). The results showed that the reactions performed under these simplified conditions performed almost identically to those performed under inert conditions. In most cases, the yields and diastereoseletivities of the cycloaddition products were identical, while the ee values were slightly reduced by 0–4%, which is very attractive for practical applications.

5. Investigation of Different Nitrone and α,β-Unsaturated Acyl Imidazole under an Air Atmosphere .

^aFor the reactions, 1 (0.1 mmol), 2 (0.12 mmol), complex cat.1 (2 mol %), and AgSbF₆ (2 mol %) in acetone (1 mL) were stirred at 25 °C under an air atmosphere.

^bThe ee value of the minor diastereoisomer is in parentheses.

Given the importance of isoxazolines in organic synthesis, this study also investigated the conversion of 3a into isoxazoline 6a. We found that 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)-mediated debenzylation of 3a allowed the successful isolation of 6a in 94% yield, 98% ee, and >20:1 dr. Subsequently we further established a simple one-pot cycloaddition/debenzylation protocol, affording 6a in 93% yield, >20:1 dr, and an ee of 94%. This protocol was tested with various α,β-unsaturated acyl imidazole and nitrones, with the results listed in Table . Alkyl-substituted α,β-unsaturated acyl imidazoles reacted smoothly with nitrones bearing various aryl groups to afford isoxazolines 6a–6i in good to excellent yields (73–98%) with excellent selectivity (>20:1 dr, 90–94% ee), unaffected by the electronic and positional characteristics of the substituents. Nitrones bearing alkyl substituents were also amenable to this reaction, with the ee value of the product depending on the steric hindrance of the alkyl group, with greater steric hindrance resulting in higher ee values (6j–6l). A furan motif was also amenable to this reaction, affording 6m in 40% yield, >20:1 dr, and an ee of 88%.

6. One-Pot Synthesis of Isoxazolines .

^aFor the reactions, 1 (0.1 mmol), 2 (0.12 mmol), complex cat.1 (2 mol %), AgSbF₆ (2 mol %), and DDQ (0.25 mmol) in DCE (1 mL) were stirred at 25 °C under an argon atmosphere (see the Supporting Information for details).

^b 3a was reacted with DDQ after separating.

^cThe ee value of the minor diastereoisomer is in parentheses.

To demonstrate the synthetic utility of this protocol, a gram-scale reaction of 1a (1.06 g, 5.0 mmol) and nitrone 2a (1.28 g, 6.0 mmol) was carried out in DCE with 2 mol % cat.1 and 2 mol % AgSbF₆ (Scheme a). Gratifyingly, the reaction proceeded smoothly, affording 3a in 97% yield, >20:1 dr, and 99% ee. Furthermore, 3a could be easily reduced with sodium borohydride to afford chiral alcohol 7 in 87% yield with >20:1 dr. The isoxazolidine motif in 3a could be opened under palladium-catalyzed hydrogenation conditions, and the reaction products were further derivatized to afford synthetically useful β′-hydroxy-β-amino acid derivatives 8 and 9 in high yields (88–92%) and selectivities (99% ee, >20:1 dr) (Scheme b).

2. Gram-Scale Reaction and Derivatization.

Based on our previous work on iron­(III)-BPsalan complex-catalyzed asymmetric reactions, we propose two possible reaction intermediates, as depicted in Scheme . The cationic iron­(III)-BPsalan complex is generated in the presence of noncoordinating silver salts and activates 1a upon its coordination to iron to give six-coordinated intermediates I and II. The repulsion between the N-phenyl group of 1a and the tert-butyl group of the iron complex makes intermediate II less favorable. The si face of intermediate I is blocked by the hindered tert-butyl-substituted phenol ring of the iron complex, favoring the cycloaddition to occur from re face attack to give the desired addition product in high yield and enantioselectivity.

3. Plausible Intermediates for the Cycloaddition.

Conclusion

In summary, we have developed a highly efficient iron­(III)-BPsalan complex-catalyzed asymmetric 1,3-dipolar cycloaddition of nitrones with α,β-unsaturated acyl imidazoles. Using readily available Fe­(III)-BPsalan complex cat.1 as the catalyst in the presence of the AgSbF₆ additive, 31 examples of chiral isoxazolidine derivatives were efficiently prepared at room temperature with yields as high as 99% with good to excellent stereoselectivities (up to >20:1 dr and 99% ee). In addition, 13 examples of chiral isoxazoline products were efficiently obtained via a one-pot cycloaddition and debenzylation reaction with high yields and good to excellent stereoselectivities (up to 96% ee, >20:1 dr). We also demonstrated that this method can be carried out under more general conditions (air atmosphere and green solvents), affording the corresponding products in high yields and selectivities. This reaction is easily performed on a gram scale while maintaining excellent yield (97%) and stereoselectivity (99% ee, >20:1 dr), providing an appealing and practical route for the synthesis of chiral derivatives of isoxazolidine skeletons.

Experimental Section

General Procedure 1 for the Preparation of the Substrate of Isoxazolidines 3–5 under an Argon Atmosphere

To a 25 mL vacuum flame-dried Schlenk tube were added chiral catalyst cat.1 (2.0 mol %) and AgSbF₆ (2.0 mol %). Then the tube was purged with argon, and anhydrous DCE (1 mL) was added. The mixture was stirred at 25 °C for 30 min. α,β-Unsaturated 1-acylimidazole 1 (0.1 mmol, 1.0 equiv) was added, and the mixture was stirred for an additional 30 min at 25 °C. Finally, nitrone (0.12 mmol, 1.2 equiv) was added, and then the reaction mixture was stirred at 25 °C for 5–9 h (monitored by TLC) under an argon atmosphere. The mixture was purified by flash column chromatography on silica gel to give target compounds 3–5.

General Procedure 2 for the Preparation of the Substrate of Isoxazolidines 3 and 4 under an Air Atmosphere

To a 25 mL Schlenk tube were added chiral catalyst cat.1 (2.0 mol %), AgSbF₆ (2.0 mol %), and industry grade acetone (1 mL). The mixture was stirred at 25 °C for 30 min. α,β-Unsaturated 1-acylimidazole 1 (0.1 mmol, 1.0 equiv) was added, and the mixture was stirred for an additional 30 min at 25 °C. Finally, nitrone (0.12 mmol, 1.2 equiv) was added, and then the reaction mixture was stirred at 25 °C for 5–9 h (monitored by TLC) under an air atmosphere. The mixture was purified by flash column chromatography on silica gel to give target compounds 3 and 4.

((3S,4R,5S)-2-Benzyl-5-methyl-3-phenylisoxazolidin-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (3a)

Compound 3a was isolated as a white solid in 99% yield (41.8 mg) with >20:1 dr and 99% ee: R _f value = 0.47 (5:1 PE:EA); mp 77 – 79 °C; [α]_D ^27.6 = +80.8 (c 0.75, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC column, with 95:5 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (minor) = 9.40 min; t _R (major) = 12.18 min; ¹H NMR (400 MHz, CDCl₃) δ 7.56–7.46 (m, 5H), 7.39 (d, J = 7.6 Hz, 2H), 7.36–7.26 (m, 7H), 7.25–7.18 (m, 2H), 4.63–4.56 (m, 1H), 4.51–4.39 (m, 2H), 4.06 (d, J = 14.4 Hz, 1H), 3.90 (d, J = 14.4 Hz, 1H), 1.73 (d, J = 6.0 Hz, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 188.5, 143.0, 139.7, 138.3, 138.2, 130.2, 129.2, 129.1, 128.7, 128.4, 128.2, 128.0, 127.8, 127.7, 127.0, 126.0, 78.0, 72.5, 67.1, 59.8, 21.0; HRMS (ESI) for [C₂₇H₂₆N₃O₂]⁺ ([M + H]⁺) calcd 424.2020, found 424.2020.

((3S,4R,5S)-2-Benzyl-3-(4-fluorophenyl)-5-methylisoxazolidin-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (3b)

Compound 3b was isolated as a white semisolid in 95% yield (41.9 mg) with >20:1 dr and 98% ee: R _f value = 0.47 (5:1 PE:EA); [α]_D ^20.1 = +72.0 (c 1.29, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC column, with 95:5 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (minor) = 7.80 min; t _R (major) = 10.09 min; ¹H NMR (400 MHz, CDCl₃) δ 7.54–7.48 (m, 3H), 7.46–7.40 (m, 2H), 7.37–7.32 (m, 2H), 7.31–7.26 (m, 4H), 7.25–7.18 (m, 3H), 7.02–6.95 (m, 2H), 4.53 (d, J = 7.6, 5.6 Hz, 1H), 4.46–4.39 (m, 2H), 4.01 (d, J = 14.4 Hz, 1H), 3.89 (d, J = 14.4 Hz, 1H), 1.67 (d, J = 6.0 Hz, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 188.3, 162.3 (d, J = 244.0 Hz), 142.9, 138.2, 138.0, 135.6 (d, J = 3.0 Hz), 130.3, 129.5 (d, J = 8.0 Hz), 129.2, 129.1, 128.5, 128.3, 127.9, 127.1, 125.9, 115.5 (d, J = 21.0 Hz), 78.0, 71.8, 67.1, 59.8, 20.9; ¹⁹F NMR (376 MHz, CDCl₃) δ −114.85 to −114.97 (m); HRMS (ESI) for [C₂₇H₂₅N₃O₂F]⁺ ([M + H]⁺) calcd 442.1925, found 442.1929.

((3S,4R,5S)-2-Benzyl-3-(4-chlorophenyl)-5-methylisoxazolidin-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (3c)

Compound 3c was isolated as a white semisolid in 94% yield (43.0 mg) with >20:1 dr and 97% ee: R _f value = 0.50 (5:1 PE:EA); [α]_D ^21.6 = +93.7 (c 1.32, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC column, with 95:5 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (minor) = 7.65 min; t _R (major) = 9.92 min; ¹H NMR (400 MHz, CDCl₃) δ 7.54–7.49 (m, 3H), 7.42–7.38 (m, 2H), 7.36–7.32 (m, 2H), 7.31–7.26 (m, 5H), 7.26–7.16 (m, 4H), 4.52 (dd, J = 7.2, 5.6 Hz, 1H), 4.48–4.40 (m, 2H), 4.01 (d, J = 14.0 Hz, 1H), 3.91 (d, J = 14.4 Hz, 1H), 1.66 (d, J = 6.0 Hz, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 188.2, 142.9, 138.6, 138.2, 137.8, 133.4, 130.3, 129.2, 129.2, 129.1, 128.8, 128.5, 128.3, 128.0, 127.1, 126.0, 78.0, 71.8, 67.1, 59.9, 20.8; HRMS (ESI) for [C₂₇H₂₅N₃O₂Cl]⁺ ([M + H]⁺) calcd 458.1630, found 458.1628.

((3S,4R,5S)-2-Benzyl-3-(4-bromophenyl)-5-methylisoxazolidin-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (3d)

Compound 3d was isolated as a white semisolid in 96% yield (48.0 mg) with >20:1 dr and 97% ee: R _f value = 0.50 (5:1 PE:EA); [α]_D ^21.9 = +94.0 (c 1.71, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC column, with 95:5 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (minor) = 7.79 min; t _R (major) = 10.04 min; ¹H NMR (400 MHz, CDCl₃) δ 7.51 (7.53–7.49, 3H), 7.45–7.39 (m, 2H), 7.38–7.31 (m, 4H), 7.31–7.26 (m, 4H), 7.25–7.18 (m, 3H), 4.52 (dd, J = 7.6, 5.6 Hz, 1H), 4.49–4.38 (m, 2H), 4.01 (d, J = 14.0 Hz, 1H), 3.91 (d, J = 14.0 Hz, 1H), 1.66 (d, J = 6.0 Hz, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 188.2, 142.8, 139.2, 138.2, 137.8, 131.8, 130.3, 129.5, 129.2, 129.1, 128.5, 128.3, 128.0, 127.1, 125.9, 121.5, 78.0, 71.8, 67.1, 59.9, 20.7; HRMS (ESI) for [C₂₇H₂₅N₃O₂Br]⁺ ([M + H]⁺) calcd 502.1125, found 502.1119.

((3S,4R,5S)-2-Benzyl-3-(4-iodophenyl)-5-methylisoxazolidin-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (3e)

Compound 3e was isolated as a white semisolid in 97% yield (53.3 mg) with >20:1 dr and 97% ee: R _f value = 0.50 (5:1 PE:EA); [α]_D ^22.2 = +85.6 (c 2.03, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC column, with 95:5 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (minor) = 7.54 min; t _R (major) = 9.64 min; ¹H NMR (400 MHz, CDCl₃) δ 7.64–7.61 (m, 2H), 7.54–7.48 (m, 3H), 7.36–7.32 (m, 2H), 7.31–7.26 (m, 4H), 7.26–7.19 (m, 5H), 4.51 (dd, J = 7.2, 5.6 Hz, 1H), 4.47–4.38 (m, 2H), 4.01 (d, J = 14.0 Hz, 1H), 3.91 (d, J = 14.0 Hz, 1H), 1.65 (d, J = 6.0 Hz, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 188.2, 142.8, 139.9, 138.2, 137.8, 137.8, 130.3, 129.8, 129.2, 129.1, 128.5, 128.3, 128.0, 127.1, 125.9, 93.2, 78.1, 71.8, 67.1, 59.9, 20.7; HRMS (ESI) for [C₂₇H₂₅N₃O₂I]⁺ ([M + H]⁺) calcd 550.0986, found 550.0981.

((3S,4R,5S)-2-Benzyl-3-(4-methoxyphenyl)-5-methylisoxazolidin-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (3f)

Compound 3f was isolated as a white semisolid in 93% yield (42 mg) with >20:1 dr and 97% ee: R _f value = 0.42 (7:1 PE:EA); [α]_D ^22.4 = +89.5 (c 1.39, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC column, with 95:5 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (minor) = 12.70 min; t _R (major) = 19.00 min; ¹H NMR (400 MHz, CDCl₃) δ 7.52–7.48 (m, 3H), 7.42–7.34 (m, 4H), 7.31–7.26 (m, 3H), 7.26–7.16 (m, 4H), 6.88–6.81 (m, 2H), 4.56 (dd, J = 7.6, 5.6 Hz, 1H), 4.43–4.35 (m, 2H), 4.01 (d, J = 14.4 Hz, 1H), 3.83 (d, J = 14.4 Hz, 1H), 3.78 (s, 3H), 1.69 (d, J = 6.0 Hz, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 188.6, 159.2, 143.0, 138.3, 138.3, 131.4, 130.2, 129.2, 129.2, 129.0, 128.412, 128.2, 127.7, 126.9, 125.9, 114.1, 77.9, 72.2, 66.9, 59.6, 55.3, 21.0; HRMS (ESI) for [C₂₈H₂₈N₃O₃]⁺ ([M + H]⁺) calcd 454.2125, found 454.2127.

4-((3S,4R,5S)-2-Benzyl-5-methyl-4-(1-phenyl-1H-imidazole-2-carbonyl)­isoxazolidin-3-yl)­benzonitrile (3g)

Compound 3g was isolated as a white semisolid in 90% yield (40.3 mg) with >20:1 dr and 95% ee: R _f value = 0.41 (7:1 PE:EA); [α]_D ^22.5 = +122.1 (c 0.67, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC column, with 70:30 n-hexane/2-propanol, a 254 nm, with a flow rate of 0.8 mL/min: t _R (minor) = 11.84 min; t _R (major) = 13.56 min; ¹H NMR (400 MHz, CDCl₃) δ 7.62–7.49 (m, 7H), 7.37–7.27 (m, 7H), 7.25–7.18 (m, 2H), 4.58–4.47 (m, 3H), 4.10–3.99 (m, 2H), 1.63 (d, J = 5.2 Hz, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 187.8, 146.4, 142.7, 138.1, 137.3, 132.5, 130.4, 129.3, 129.2, 128.7, 128.3, 128.2, 127.3, 125.9, 118.9, 111.3, 78.2, 71.6, 67.3, 60.2, 20.3; HRMS (ESI) for [C₂₈H₂₅N₄O₂]⁺ ([M + H]⁺) calcd 449.1972, found 449.1971.

((3S,4R,5S)-2-Benzyl-5-methyl-3-(4-(trifluoromethyl)­phenyl)­isoxazolidin-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (3h)

Compound 3h was isolated as a white semisolid in 96% yield (46.9 mg) with >20:1 dr and 97% ee: R _f value = 0.53 (7:1 PE:EA); [α]_D ^29.5 = +75.1 (c 0.94, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC column, with 95:5 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (minor) = 6.07 min; t _R (major) = 7.28 min; ¹H NMR (400 MHz, CDCl₃) δ 7.61–7.50 (m, 7H), 7.37–7.33 (m, 2H), 7.32–7.26 (m, 4H), 7.26–7.19 (m, 3H), 4.56–4.45 (m, 3H), 4.07–3.93 (m, 2H), 1.66 (d, J = 6.0 Hz, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 188.1, 144.6, 142.8, 138.2, 137.6, 130.4, 129.8 (q, J = 32.3 Hz), 129.3, 129.2, 128.6, 128.3, 128.1, 127.2, 126.0, 125.6 (q, J = 3.8 Hz), 124.3 (q, J = 271.0 Hz), 78.2, 71.7, 67.3, 60.1, 20.6; ¹⁹F NMR (376 MHz, CDCl₃) δ −62.54; HRMS (ESI) for [C₂₈H₂₅N₃O₂F₃]⁺ ([M + H]⁺) calcd 492.1893, found 492.1894.

((3S,4R,5S)-2-Benzyl-5-methyl-3-(p-tolyl)­isoxazolidin-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (3i)

Compound 3i was isolated as a white semisolid in 94% yield (41.2 mg) with >20:1 dr and 96% ee: R _f value = 0.51 (7:1 PE:EA); [α]_D ^29.6 = +68.1 (c 0.77, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC column, with 95:5 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (minor) = 8.29 min; t _R (major) = 11.38 min; ¹H NMR (400 MHz, CDCl₃) δ 7.53–7.48 (m, 3H), 7.40–7.35 (m, 4H), 7.32–7.26 (m, 4H), 7.25–7.16 (m, 3H), 7.13 (d, J = 8.0 Hz, 2H), 4.57 (dd, J = 8.0, 5.6 Hz, 1H), 4.44–4.36 (m, 2H), 4.03 (d, J = 14.4 Hz, 1H), 3.85 (d, J = 14.4 Hz, 1H), 2.33 (s, 3H), 1.71 (d, J = 6.0 Hz, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 188.5, 143.0, 138.3, 138.3, 137.4, 136.5, 130.2, 129.4, 129.2, 129.0, 128.4, 128.2, 127.9, 127.7, 126.9, 125.9, 77.9, 72.4, 67.0, 59.6, 21.2, 21.0; HRMS (ESI) for [C₂₈H₂₈N₃O₂]⁺ ([M + H]⁺) calcd 438.2176, found 438.2171.

((3S,4R,5S)-2-Benzyl-5-methyl-3-(o-tolyl)­isoxazolidin-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (3j)

Compound 3j was isolated as a pale-yellow solid in 97% yield (42.6 mg) with >20:1 dr and 97% ee: R _f value = 0.52 (7:1 PE:EA); mp 125–127 °C; [α]_D ^29.3 = +59.3 (c 0.59, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC column, with 95:5 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (minor) = 9.29 min; t _R (major) = 12.20 min; ¹H NMR (400 MHz, CDCl₃) δ 7.86–7.79 (m, 1H), 7.54–7.48 (m, 3H), 7.40–7.35 (m, 2H), 7.32–7.25 (m, 4H), 7.26–7.17 (m, 4H), 7.14 (td, J = 7.6, 1.6 Hz, 1H), 7.06 (d, J = 7.2 Hz, 1H), 4.72 (d, J = 6.8 Hz, 1H), 4.58 (t, J = 6.0 Hz, 1H), 4.43 (p, J = 6.0 Hz, 1H), 4.07–3.93 (m, 2H), 2.18 (s, 3H), 1.68 (d, J = 6.0 Hz, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 188.9, 158.6, 143.0, 138.6, 138.3, 135.9, 130.3, 130.3, 129.2, 129.1, 128.5, 128.2, 127.9, 127.8, 127.2, 127.0, 126.5, 125.9, 78.6, 69.0, 66.7, 59.8, 20.7, 19.9; HRMS (ESI) for [C₂₈H₂₈N₃O₂]⁺ ([M + H]⁺) calcd 438.2176, found 438.2175.

((3S,4R,5S)-2-Benzyl-5-methyl-3-(m-tolyl)­isoxazolidin-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (3k)

Compound 3k was isolated as a white solid in 93% yield (40.8 mg) with >20:1 dr and 99% ee: R _f value = 0.52 (7:1 PE:EA); mp 85–87 °C; [α]_D ^22.4 = +84.0 (c 1.09, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC column, with 95:5 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (minor) = 8.89 min; t _R (major) = 11.48 min; ¹H NMR (400 MHz, CDCl₃) δ 7.54–7.48 (m, 3H), 7.40–7.35 (m, 2H), 7.32–7.26 (m, 6H), 7.25–7.17 (m, 4H), 7.06 (d, J = 7.6 Hz, 1H), 4.57 (dd, J = 7.6, 5.6 Hz, 1H), 4.45–4.37 (m, 2H), 4.04 (d, J = 14.4 Hz, 1H), 3.87 (d, J = 14.4 Hz, 1H), 2.34 (s, 3H), 1.72 (d, J = 6.4 Hz, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 188.5, 143.0, 139.5, 138.3, 138.3, 138.3, 130.2, 129.2, 129.0, 128.6, 128.5, 128.5, 128.4, 128.2, 127.7, 126.9, 125.9, 125.0, 78.0, 72.5, 67.0, 59.7, 21.6, 21.0; HRMS (ESI) for [C₂₈H₂₈N₃O₂]⁺ ([M + H]⁺) calcd 438.2176, found 438.2176.

((3S,4R,5S)-2-Benzyl-3-(2-methoxyphenyl)-5-methylisoxazolidin-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (3l)

Compound 3l was isolated as a white semisolid in 97% yield (44.0 mg) with >20:1 dr and 92% ee: R _f value = 0.50 (6:1:6 PE:EA:DCM); [α]_D ^22.3 = +1.0 (c 1.10, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC column, with 70:30 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (minor) = 6.40 min; t _R (major) = 7.91 min; ¹H NMR (400 MHz, CDCl₃) δ 7.88 (d, J = 7.6 Hz, 1H), 7.58–7.50 (m, 3H), 7.45 (d, J = 7.6 Hz, 2H), 7.40–7.33 (m, 2H), 7.32–7.26 (m, 2H), 7.25–7.16 (m, 4H), 6.99 (t, J = 7.6 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 4.74–4.66 (m, 1H), 4.56–4.47 (m, 2H), 4.27 (d, J = 13.6 Hz, 1H), 4.17 (d, J = 13.6 Hz, 1H), 3.46 (s, 3H), 1.48 (d, J = 4.4 Hz, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 190.0, 156.3, 143.4, 138.5, 138.4, 130.7, 130.1, 129.3, 129.0, 128.8, 128.2, 127.9, 127.6, 127.0, 125.8, 120.8, 110.0, 78.5, 68.4, 66.6, 60.3, 55.0, 19.3; HRMS (ESI) for [C₂₈H₂₈N₃O₃]⁺ ([M + H]⁺) calcd 454.2125, found 454.2129.

((3S,4R,5S)-2-Benzyl-5-methyl-3-(2,4,6-trimethoxyphenyl)­isoxazolidin-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (3m)

Compound 3m was isolated as a white semisolid in 95% yield (48.5 mg) with 16:1 dr and 44% ee (59% ee): R _f value = 0.22 (7:1 PE:EA); [α]_D ^26.2 = −9.5 (c 0.76, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC column, with 70:30 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: minor, t _R (major) = 7.29 min, t _R (minor) = 7.82 min; major, t _R (major) = 10.03 min, t _R (minor) = 20.29 min; ¹H NMR (400 MHz, CDCl₃) δ 7.47–7.42 (m, 3H), 7.32 (d, J = 7.2 Hz, 2H), 7.24–7.18 (m, 4H), 7.17–7.09 (m, 3H), 6.06 (s, 2H), 5.23 (dd, J = 8.4, 5.2 Hz, 1H), 4.91 (d, J = 8.4 Hz, 1H), 4.51 (p, J = 6.0 Hz, 1H), 4.01–3.85 (m, 2H), 3.78 (s, 6H), 3.77 (s, 3H), 1.65 (d, J = 6.0 Hz, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 190.4, 160.9, 160.4, 143.5, 139.1, 138.5, 129.9, 129.1, 128.7, 128.4, 127.9, 127.1, 126.5, 125.7, 106.7, 91.4, 77.7, 64.2, 60.8, 60.5, 56.2, 55.3, 20.4; HRMS (ESI) for [C₃₀H₃₂N₃O₅]⁺ ([M + H]⁺) calcd 514.2337, found 514.2329.

((3R,4R,5S)-2-Benzyl-3,5-dimethylisoxazolidin-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (3n)

Compound 3n was isolated as a white semisolid in 90% yield (32.5 mg) with 8:1 dr and 86% ee (74% ee): R _f value = 0.49 (7:1 PE:EA); [α]_D ^28.5 = +2.0 (c 1.17, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC column, with 95:5 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: minor, t _R (minor) = 17.02 min, t _R (major) = 23.28 min; major, t _R (minor) = 21.12 min, t _R (major) = 42.57 min; ¹H NMR (400 MHz, CDCl₃) δ 7.51–7.44 (m, 3H), 7.44–7.39 (m, 2H), 7.38–7.26 (m, 4H), 7.26–7.21 (m, 2H), 7.20 (s, 1H), 4.60–4.42 (m, 2H), 4.17 (t, J = 6.4 Hz, 0.1H) (minor), 4.11–3.98 (m, 2H), 3.83–3.64 (m, 0.9H) (major), 3.47–3.35 (m, 0.1H) (minor), 1.46 (d, J = 6.0 Hz, 0.3H) (minor), 1.31 (d, J = 6.0 Hz, 3H), 0.97 (d, J = 6.4 Hz, 2.7H) (major); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 188.4, 143.5, 143.3, 138.4, 138.3, 137.9, 137.7, 130.3, 130.0, 129.2, 129.1, 129.1, 129.0, 128.3, 128.3, 128.0, 127.6, 127.3, 127.1, 126.0, 125.9, 75.0, 65.6, 64.3, 61.9, 59.9, 29.8, 19.9, 19.6, 16.1; HRMS (ESI) for [C₂₂H₂₄N₃O₂]⁺ ([M + H]⁺) calcd 362.1863, found 362.1857.

((3R,4R,5S)-2-Benzyl-3-ethyl-5-methylisoxazolidin-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (3o)

Compound 3o was isolated as a white semisolid in 99% yield (37.2 mg) with 2:1 dr and 76% ee (80% ee): R _f value = 0.55 (7:1 PE:EA); [α]_D ^26.2 = −3.7 (c 0.26, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak AD-H column, with 95:5 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: minor, t _R (major) = 11.16 min, t _R (minor) = 12.90 min; major, t _R (major) = 15.79 min, t _R (minor) = 18.63 min; ¹H NMR (400 MHz, CDCl₃) δ 7.55–7.41 (m, 4H), 7.38–7.32 (m, 2H), 7.32–7.26 (m, 4H), 7.26–7.15 (m, 2H), 4.64–4.55 (m, 1H), 4.55–4.48 (m, 0.3H) (minor), 4.26 (dd, J = 7.6, 5.2 Hz, 0.7H) (major), 4.22–3.93 (m, 2H), 3.72–3.60 (m, 0.3H) (minor), 3.31–3.19 (m, 0.7H) (major), 1.75–1.62 (m, 1.7H) (major), 1.53–1.46 (m, 0.3H) (minor), 1.44 (d, J = 6.0 Hz, 2H) (major), 1.34 (d, J = 5.6 Hz, 1H) (minor), 1.15 (s, 0.3H) (minor), 0.86–0.74 (m, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 190.1, 188.0, 143.4, 143.3, 138.4, 138.3, 137.9, 130.3, 130.1, 129.4, 129.4, 129.2, 129.2, 129.1, 129.1, 128.3, 128.3, 128.1, 127.6, 127.3, 127.2, 126.0, 125.9, 77.4, 76.0, 71.7, 70.1, 64.5, 60.7, 59.7, 29.8, 28.9, 23.6, 20.5, 19.0, 11.5, 11.3; HRMS (ESI) for [C₂₃H₂₆N₃O₂]⁺ ([M + H]⁺) calcd 376.2020, found 376.2019.

((3R,4R,5S)-2-Benzyl-5-methyl-3-propylisoxazolidin-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (3p)

Compound 3p was isolated as a white semisolid in 95% yield (36.8 mg) with 2:1 dr and 79% ee (63% ee): R _f value = 0.56 (7:1 PE:EA); [α]_D ^26.2 = +2.9 (c 0.30, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak AD-H column, with 95:5 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: major, t _R (major) = 10.66 min, t _R (minor) = 12.47 min; minor, t _R (major) = 13.31 min, t _R (minor) = 17.71 min; ¹H NMR (400 MHz, CDCl₃) δ 7.56–7.42 (m, 4H), 7.37–7.26 (m, 6H), 7.26–7.18 (m, 2H), 4.65–4.57 (m, 1H), 4.57–4.50 (m, 0.3H) (minor), 4.25 (dd, J = 7.6, 4.8 Hz, 0.7H) (major), 4.21–3.93 (m, 2H), 3.84–3.73 (m, 0.3H) (minor), 3.38–3.29 (m, 0.7H) (major), 1.76–1.47 (m, 2H), 1.47–1.31 (m, 4H), 1.21–0.99 (m, 1H), 0.80–0.66 (m, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 190.1, 143.4, 143.3, 138.4, 138.3, 137.9, 130.3, 130.1, 129.4, 129.4, 129.2, 129.2, 129.1, 129.1, 128.4, 128.3, 128.1, 127.6, 127.3, 127.2, 126.0, 125.9, 77.4, 76.1, 69.9, 68.3, 64.8, 60.7, 59.7, 38.2, 32.7, 29.8, 20.6, 20.3, 19.8, 19.1, 13.9, 13.9; HRMS (ESI) for [C₂₄H₂₈N₃O₂]⁺ ([M + H]⁺) calcd 390.2176, found 390.2177.

((3R,4R,5S)-2-Benzyl-5-methyl-3-neopentylisoxazolidin-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (3q)

Compound 3q was isolated as a white semisolid in 97% yield (39.5 mg) with >20:1 dr and 66% ee: R _f value = 0.65 (7:1 PE:EA); [α]_D ^28.0 = −23.9 (c 0.72, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC column, with 95:5 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (minor) = 6.50 min; t _R (major) = 9.76 min; ¹H NMR (400 MHz, CDCl₃) δ 7.55–7.48 (m, 3H), 7.40–7.26 (m, 7H), 7.25–7.18 (m, 2H), 4.57–4.47 (m, 1H), 4.26–4.17 (m, 1H), 4.11 (d, J = 13.6 Hz, 1H), 3.90 (d, J = 13.6 Hz, 1H), 3.58–3.51 (m, 1H), 1.86 (dd, J = 14.0, 8.0 Hz, 1H), 1.63 (dd, J = 14.0, 4.4 Hz, 1H), 1.46 (d, J = 6.0 Hz, 3H), 0.84 (s, 9H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 190.4, 143.3, 138.4, 138.3, 130.3, 129.3, 129.1, 129.1, 128.3, 128.0, 127.0, 125.9, 76.8, 67.5, 67.0, 59.8, 50.3, 30.9, 30.0, 19.3; HRMS (ESI) for [C₂₆H₃₂N₃O₂]⁺ ([M + H]⁺) calcd 418.2489, found 418.2486.

((3R,4R,5S)-2-Benzyl-3-isopropyl-5-methylisoxazolidin-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (3r)

Compound 3r was isolated as a white semisolid in 93% yield (36.0 mg) with >20:1 dr and 84% ee: R _f value = 0.57 (7:1 PE:EA); [α]_D ^29.5 = −29.7 (c 0.23, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC column, with 95:5 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (minor) = 9.43 min; t _R (major) = 26.22 min; ¹H NMR (400 MHz, CDCl₃) δ 7.57–7.49 (m, 3H), 7.39 (d, J = 7.2 Hz, 2H), 7.34 (s, 1H), 7.32–7.27 (m, 4H), 7.26–7.19 (m, 2H), 4.56–4.44 (m, 2H), 4.19 (d, J = 13.2 Hz, 1H), 3.97 (d, J = 12.8 Hz, 1H), 3.18 (dd, J = 7.6, 4.8 Hz, 1H), 1.91–1.78 (m, 1H), 1.43 (d, J = 5.2 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H), 0.85 (d, J = 6.8 Hz, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 190.4, 143.3, 138.5, 138.2, 130.4, 129.5, 129.3, 129.1, 128.3, 128.2, 127.2, 126.0, 78.6, 76.7, 62.5, 61.5, 33.2, 20.0, 19.4, 18.2; HRMS (ESI) for [C₂₄H₂₈N₃O₂]⁺ ([M + H]⁺) calcd 390.2176, found 390.2179.

((3R,4R,5S)-2-Benzyl-3-cyclohexyl-5-methylisoxazolidin-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (3s)

Compound 3s was isolated as a white semisolid in 91% yield (39.0 mg) with >20:1 dr and 88% ee: R _f value = 0.61 (7:1 PE:EA); [α]_D ^26.2 = −17.8 (c 0.46, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC column, with 95:5 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (minor) = 8.33 min; t _R (major) = 27.60 min; ¹H NMR (400 MHz, CDCl₃) δ 7.57–7.48 (m, 3H), 7.42–7.36 (m, 2H), 7.35–7.33 (m, 1H), 7.32–7.26 (m, 4H), 7.26–7.19 (m, 2H), 4.53–4.40 (m, 2H), 4.19 (d, J = 13.2 Hz, 1H), 3.94 (d, J = 13.2 Hz, 1H), 3.18 (dd, J = 8.4, 5.2 Hz, 1H), 1.95 (d, J = 11.2 Hz, 1H), 1.70–1.56 (m, 4H), 1.57–1.44 (m, 1H), 1.43 (d, J = 5.2 Hz, 3H), 1.29–1.14 (m, 2H), 1.13–1.00 (m, 1H), 0.91–0.66 (m, 2H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 190.3, 143.2, 138.5, 138.2, 130.4, 129.4, 129.3, 129.1, 128.2, 128.2, 127.1, 125.9, 78.5, 75.8, 62.6, 61.5, 42.9, 30.7, 29.9, 26.5, 26.3, 26.1, 18.2; HRMS (ESI) for [C₂₇H₃₂N₃O₂]⁺ ([M + H]⁺) calcd 430.2489, found 430.2494.

((3S,4R,5S)-2-Benzyl-3-(tert-butyl)-5-methylisoxazolidin-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (3t)

Compound 3t was isolated as a white semisolid in 88% yield (35.5 mg) with >20:1 dr and 96% ee: R _f value = 0.61 (7:1 PE:EA); [α]_D ^20.9 = −71.9 (c 1.02, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC column, with 95:5 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (minor) = 6.68 min; t _R (major) = 30.53 min; ¹H NMR (400 MHz, CDCl₃) δ 7.55–7.50 (m, 3H), 7.43–7.38 (m, 2H), 7.37–7.34 (m, 1H), 7.33–7.26 (m, 4H), 7.26–7.17 (m, 2H), 4.64 (dd, J = 8.8, 5.6 Hz, 1H), 4.49–4.41 (m, 1H), 4.28 (d, J = 13.2 Hz, 1H), 3.93 (d, J = 13.2 Hz, 1H), 3.25 (d, J = 5.6 Hz, 1H), 1.41 (d, J = 6.0 Hz, 3H), 0.87 (s, 9H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 190.8, 143.2, 138.5, 138.4, 130.5, 129.5, 129.3, 129.1, 128.3, 128.2, 127.1, 125.9, 80.2, 79.2, 61.7, 60.4, 34.9, 26.6, 17.4; HRMS (ESI) for [C₂₅H₃₀N₃O₂]⁺ ([M + H]⁺) calcd 404.2333, found 404.2332.

((3S,4R,5S)-2-Benzyl-5-methyl-3-(trifluoromethyl)­isoxazolidin-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (3u)

Compound 3u was isolated as a white semisolid in 42% yield (17.4 mg) with >20:1 dr and 26% ee: R _f value = 0.59 (7:1 PE:EA); [α]_D ^29.0 = −13.7 (c 0.15, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC column, with 95:5 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (minor) = 6.96 min; t _R (major) = 7.96 min; ¹H NMR (400 MHz, CDCl₃) δ 7.55–7.49 (m, 3H), 7.41–7.34 (m, 3H), 7.34–7.26 (m, 5H), 7.26–7.20 (m, 1H), 4.78 (dd, J = 7.6, 4.4 Hz, 1H), 4.51–4.40 (m, 1H), 4.21 (d, J = 12.8 Hz, 1H), 4.09–3.97 (m, 2H), 1.55 (d, J = 6.0 Hz, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 187.0, 142.4, 138.1, 136.3, 131.0, 129.4, 129.3, 129.3, 128.8, 128.5, 127.7, 126.0, 79.3, 68.5 (q, J = 30.0 Hz), 61.0, 59.4, 18.0; ¹⁹F NMR (376 MHz, CDCl₃) δ −74.23 (d, J = 7.9 Hz); HRMS (ESI) for [C₂₂H₂₁N₃O₂F₃]⁺ ([M + H]⁺) calcd 416.1580, found 416.1576.

Ethyl (3S,4R,5S)-2-Benzyl-5-methyl-4-(1-phenyl-1H-imidazole-2-carbonyl)­isoxazolidine-3-carboxylate (3v)

Compound 3v was isolated as a white semisolid in 65% yield (27.0 mg) with >20:1 dr and 80% ee: R _f value = 0.25 (7:1 PE:EA); [α]_D ^28.6 = −6.7 (c 0.33, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak AD-H column, with 95:5 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (minor) = 29.86 min; t _R (major) = 36.77 min; ¹H NMR (400 MHz, CDCl₃) δ 7.53–7.47 (m, 3H), 7.39 (d, J = 6.8 Hz, 2H), 7.32–7.26 (m, 5H), 7.23 (s, 2H), 4.81 (dd, J = 6.8, 5.6 Hz, 1H), 4.54 (p, J = 6.0 Hz, 1H), 4.21–4.05 (m, 5H), 1.54 (d, J = 6.0 Hz, 3H), 1.22 (t, J = 6.8 Hz, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 187.8, 170.7, 142.6, 138.2, 137.0, 130.6, 129.2, 129.2, 129.1, 128.3, 128.0, 127.4, 126.0, 77.5, 70.0, 61.5, 61.5, 61.2, 18.8, 14.2; HRMS (ESI) for [C₂₄H₂₆N₃O₄]⁺ ([M + H]⁺) calcd 420.1918, found 420.1921.

((3S,4R,5S)-2-Benzyl-3-(furan-2-yl)-5-methylisoxazolidin-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (3w)

Compound 3w was isolated as a white semisolid in 59% yield (24.2 mg) with >20:1 dr and 93% ee: R _f value = 0.50 (7:1 PE:EA); [α]_D ^29.2 = +34.6 (c 0.26, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC column, with 95:5 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (minor) = 12.84 min; t _R (major) = 37.11 min; ¹H NMR (400 MHz, CDCl₃) δ 7.52–7.47 (m, 3H), 7.39–7.34 (m, 3H), 7.32–7.26 (m, 5H), 7.24–7.18 (m, 2H), 6.31–6.27 (m, 2H), 4.81 (t, J = 6.4 Hz, 1H), 4.57 (d, J = 6.8 Hz, 1H), 4.44 (p, J = 6.0 Hz, 1H), 4.11 (d, J = 14.0 Hz, 1H), 3.97 (d, J = 13.6 Hz, 1H), 1.66 (d, J = 6.0 Hz, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 188.2, 152.4, 142.9, 142.7, 138.3, 137.8, 130.4, 129.2, 129.1, 128.7, 128.3, 128.0, 127.1, 126.0, 110.3, 108.2, 78.2, 65.5, 63.0, 60.2, 20.1; HRMS (ESI) for [C₂₅H₂₄N₃O₃]⁺ ([M + H]⁺) calcd 414.1812, found 414.1810.

((3S,4R,5S)-2-Benzyl-5-ethyl-3-phenylisoxazolidin-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (4a)

Compound 4a was isolated as a white semisolid in 80% yield (35.0 mg) with >20:1 dr and 96% ee: R _f value = 0.65 (7:1 PE:EA); [α]_D ^29.4 = +57.9 (c 0.32, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC column, with 95:5 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (minor) = 6.79 min; t _R (major) = 8.89 min; ¹H NMR (400 MHz, CDCl₃) δ 7.53–7.48 (m, 3H), 7.48–7.43 (m, 2H), 7.39–7.34 (m, 2H), 7.33–7.26 (m, 5H), 7.25–7.23 (m, 1H), 7.23–7.14 (m, 4H), 4.62 (dd, J = 8.0, 5.6 Hz, 1H), 4.39 (d, J = 7.6 Hz, 1H), 4.21–4.13 (m, 1H), 4.02 (d, J = 14.4 Hz, 1H), 3.87 (d, J = 14.0 Hz, 1H), 2.24–2.09 (m, 1H), 2.09–1.97 (m, 1H), 0.97 (t, J = 7.6 Hz, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 188.8, 143.0, 139.6, 138.3, 130.2, 129.2, 129.1, 128.7, 128.5, 128.2, 128.0, 127.8, 127.7, 126.9, 126.0, 83.3, 72.7, 65.6, 59.7, 28.1, 10.9; HRMS (ESI) for [C₂₈H₂₈N₃O₂]⁺ ([M + H]⁺) calcd 438.2176, found 438.2175.

((3S,4R,5S)-2-Benzyl-3-phenyl-5-propylisoxazolidin-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (4b)

Compound 4b was isolated as a white semisolid in 75% yield (33.8 mg) with >20:1 dr and 94% ee: R _f value = 0.66 (7:1 PE:EA); [α]_D ^26.3 = +32.1 (c 0.38, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC column, with 95:5 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (minor) = 6.58 min; t _R (major) = 7.99 min; ¹H NMR (400 MHz, CDCl₃) δ 7.54–7.48 (m, 3H), 7.48–7.43 (m, 2H), 7.38–7.33 (m, 2H), 7.33–7.26 (m, 5H), 7.26–7.16 (m, 5H), 4.62 (dd, J = 7.6, 5.2 Hz, 1H), 4.38 (d, J = 8.0 Hz, 1H), 4.30–4.21 (m, 1H), 4.02 (d, J = 14.4 Hz, 1H), 3.88 (d, J = 14.4 Hz, 1H), 2.21–2.07 (m, 1H), 2.02–1.87 (m, 1H), 1.56–1.42 (m, 1H), 1.41–1.29 (m, 1H), 0.92 (t, J = 7.2 Hz, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 188.9, 143.0, 139.7, 138.4, 138.3, 130.2, 129.2, 129.0, 128.7, 128.5, 128.1, 127.9, 127.8, 126.9, 126.0, 81.8, 72.8, 65.8, 59.7, 37.1, 19.7, 14.1; HRMS (ESI) for [C₂₉H₃₀N₃O₂]⁺ ([M + H]⁺) calcd 452.2333, found 452.2338.

((3S,4R,5R)-2-Benzyl-5-(tert-butyl)-3-phenylisoxazolidin-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (4c)

Compound 4c was isolated as a white semisolid in 90% yield (41.8 mg) with >20:1 dr and 90% ee: R _f value = 0.65 (7:1 PE:EA); [α]_D ^28.2 = +61.7 (c 0.93, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak AD-H column, with 95:5 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (major) = 10.53 min; t _R (minor) = 13.60 min; ¹H NMR (400 MHz, CDCl₃) δ 7.54–7.45 (m, 5H), 7.37–7.33 (m, 2H), 7.32–7.26 (m, 3H), 7.26–7.18 (m, 5H), 7.17 (s, 1H), 7.14 (s, 1H), 5.06 (t, J = 7.6 Hz, 1H), 4.36 (d, J = 8.0 Hz, 1H), 4.17 (d, J = 7.2 Hz, 1H), 4.10 (d, J = 13.6 Hz, 1H), 3.99 (d, J = 14.0 Hz, 1H), 0.94 (s, 9H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 190.6, 143.2, 139.8, 138.4, 138.0, 130.3, 129.2, 129.0, 128.9, 128.5, 128.2, 127.9, 127.7, 127.6, 127.0, 125.9, 89.6, 75.9, 60.3, 59.9, 34.5, 26.3; HRMS (ESI) for [C₃₀H₃₂N₃O₂]⁺ ([M + H]⁺) calcd 466.2489, found 466.2484.

((3S,4R,5S)-2-Benzyl-5-neopentyl-3-phenylisoxazolidin-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (4d)

Compound 4d was isolated as a white semisolid in 62% yield (30.0 mg) with >20:1 dr and 92% ee: R _f value = 0.66 (7:1 PE:EA); [α]_D ^28.2 = +14.5 (c 0.70, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak AD-H column, with 95:5 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (major) = 6.11 min; t _R (minor) = 9.06 min; ¹H NMR (400 MHz, CDCl₃) δ 7.53–7.46 (m, 3H), 7.48–7.42 (m, 2H), 7.35–7.27 (m, 4H), 7.27–7.20 (m, 5H), 7.23–7.12 (m, 3H), 4.53 (dd, J = 8.0, 5.6 Hz, 1H), 4.42–4.28 (m, 2H), 3.98 (d, J = 13.6 Hz, 1H), 3.83 (d, J = 13.6 Hz, 1H), 2.13 (dd, J = 14.4, 10.0 Hz, 1H), 1.88 (dd, J = 14.4, 1.6 Hz, 1H), 0.82 (s, 9H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 188.9, 143.0, 139.8, 138.3, 138.1, 130.2, 129.2, 129.1, 128.7, 128.0, 127.7, 126.9, 126.0, 79.6, 72.3, 67.1, 60.0, 47.8, 30.6, 29.9; HRMS (ESI) for [C₃₁H₃₄N₃O₂]⁺ ([M + H]⁺) calcd 480.2646, found 480.2638.

((3S,4R,5S)-2-Benzyl-5-cyclohexyl-3-phenylisoxazolidin-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (4e)

Compound 4e was isolated as a white semisolid in 56% yield (27.8 mg) with >20:1 dr and 90% ee: R _f value = 0.64 (7:1 PE:EA); [α]_D ^28.0 = +35.9 (c 0.62, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC column, with 95:5 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (minor) = 6.67 min; t _R (major) = 8.38 min; ¹H NMR (400 MHz, CDCl₃) δ 7.56–7.50 (m, 3H), 7.48–7.43 (m, 2H), 7.37–7.33 (m, 2H), 7.33–7.29 (m, 2H), 7.29–7.26 (m, 4H), 7.26–7.20 (m, 2H), 7.19 (d, J = 4.4 Hz, 2H), 4.93 (t, J = 7.2 Hz, 1H), 4.26–4.17 (m, 2H), 4.07 (d, J = 14.0 Hz, 1H), 3.97 (d, J = 13.6 Hz, 1H), 2.01–1.90 (m, 1H), 1.90–1.79 (m, 1H), 1.77–1.62 (m, 4H), 1.31–1.22 (m, 2H), 1.20–1.08 (m, 1H), 1.07–0.90 (m, 2H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 190.0, 143.0, 139.8, 138.4, 138.0, 130.2, 129.2, 129.0, 128.9, 128.6, 128.1, 127.9, 127.7, 127.0, 125.9, 86.2, 75.0, 62.9, 59.7, 42.1, 29.6, 29.3, 26.5, 26.2, 25.9; HRMS (ESI) for [C₃₂H₃₄N₃O₂]⁺ ([M + H]⁺) calcd 492.2646, found 492.2639.

Ethyl (3S,4R,5R)-2-Benzyl-3-phenyl-4-(1-phenyl-1H-imidazole-2-carbonyl)­isoxazolidine-5-carboxylate (4f)

Compound 4f was isolated as a white semisolid in 73% yield (35.1 mg) with >20:1 dr and 92% ee: R _f value = 0.47 (7:1 PE:EA); [α]_D ^26.4 = +15.0 (c 0.60, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC column, with 70:30 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (minor) = 12.75 min; t _R (major) = 83.60 min; ¹H NMR (400 MHz, CDCl₃) δ 7.54–7.46 (m, 5H), 7.39–7.31 (m, 3H), 7.31–7.27 (m, 5H), 7.26–7.24 (m, 1H), 7.23–7.13 (m, 3H), 5.28 (dd, J = 8.0, 4.4 Hz, 1H), 4.85 (d, J = 4.4 Hz, 1H), 4.44–4.23 (m, 3H), 4.01 (d, J = 15.2 Hz, 1H), 3.80 (d, J = 14.8 Hz, 1H), 1.31 (t, J = 7.2 Hz, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 187.3, 171.0, 142.3, 138.1, 137.7, 137.6, 130.5, 129.2, 129.1, 128.7, 128.6, 128.3, 128.2, 128.1, 127.7, 127.0, 126.0, 79.0, 72.4, 62.3, 61.6, 58.9, 14.3; HRMS (ESI) for [C₂₉H₂₈N₃O₄]⁺ ([M + H]⁺) calcd 482.2074, found 482.2069.

((3S,4R,5R)-2-Benzyl-3-phenyl-5-(trifluoromethyl)­isoxazolidin-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (4g)

Compound 4g was isolated as a white semisolid in 86% yield (41.0 mg) with >20:1 dr and 96% ee: R _f value = 0.61 (7:1 PE:EA); [α]_D ^28.5 = +86.5 (c 1.08, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak AD-H column, with 95:5 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (major) = 14.18 min; t _R (minor) = 16.66 min; ¹H NMR (400 MHz, CDCl₃) δ 7.54–7.49 (m, 3H), 7.45–7.41 (m, 2H), 7.36–7.26 (m, 8H), 7.25–7.20 (m, 2H), 7.16 (s, 1H), 7.11 (s, 1H), 5.34 (dd, J = 9.2, 5.6 Hz, 1H), 4.77–4.67 (m, 1H), 4.11–3.98 (m, 2H), 3.80 (d, J = 15.2 Hz, 1H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 186.5, 142.3, 138.0, 137.1, 135.9, 130.8, 129.3, 129.2, 128.9, 128.8, 128.4, 128.3, 128.2, 127.1, 125.9, 123.0, 75.7, 59.0; ¹⁹F NMR (376 MHz, CDCl₃) δ −75.52 (d, J = 7.1 Hz); HRMS (ESI) for [C₂₇H₂₃N₃O₂F₃]⁺ ([M + H]⁺) calcd 478.1737, found 478.1731.

((3S,4R,5R)-2-Benzyl-3,5-diphenylisoxazolidin-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (4h)

Compound 4h was isolated as a pale-yellow solid in 62% yield (30.1 mg) with >20:1 dr and 86% ee: R _f value = 0.61 (7:1 PE:EA); mp 134–136 °C; [α]_D ^28.5 = −25.9 (c 0.57, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak AD-H column, with 95:5 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (major) = 18.75 min; t _R (minor) = 71.72 min; ¹H NMR (400 MHz, CDCl₃) δ 7.57–7.46 (m, 5H), 7.45–7.35 (m, 4H), 7.35–7.26 (m, 9H), 7.26–7.20 (m, 2H), 7.15 (d, J = 7.6 Hz, 2H), 5.45 (d, J = 5.6 Hz, 1H), 5.19–5.10 (m, 1H), 4.48 (d, J = 7.6 Hz, 1H), 4.12 (d, J = 14.0 Hz, 1H), 4.02 (d, J = 14.0 Hz, 1H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 188.7, 141.4, 139.1, 138.3, 137.9, 130.3, 129.3, 129.1, 129.0, 128.7, 128.3, 128.2, 128.1, 127.9, 127.5, 127.2, 126.7, 126.0, 82.3, 74.3, 67.4, 60.2; HRMS (ESI) for [C₃₂H₂₈N₃O₂]⁺ ([M + H]⁺) calcd 486.2176, found 486.2171.

((3S,4R,5R)-2-Benzyl-3,5-diphenylisoxazolidin-4-yl)­(pyridin-2-yl)­methanone (5a)

Compound 5a was isolated as a white semisolid in 75% yield (31.6 mg) with 17:1 dr and 70% ee (18% ee): R _f value = 0.50 (7:1 PE:EA); [α]_D ^25.7 = −44.1 (c 0.25, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak AD-H column, with 95:5 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: major, t _R (major) = 21.54 min, t _R (minor) = 44.15 min; minor, t _R (minor) = 27.52 min, t _R (major) = 39.85 min; ¹H NMR (400 MHz, CDCl₃) δ 8.40–8.29 (m, 1H), 8.08 (d, J = 7.6 Hz, 1H), 7.82–7.76 (m, 1H), 7.52–7.45 (m, 2H), 7.46–7.33 (m, 5H), 7.37–7.24 (m, 5H), 7.27–7.18 (m, 4H), 5.48 (d, J = 5.6 Hz, 1H), 5.27 (dd, J = 7.6, 6.0 Hz, 1H), 4.55 (d, J = 7.2 Hz, 1H), 4.17 (d, J = 14.0 Hz, 1H), 4.07 (d, J = 14.0 Hz, 1H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 199.6, 152.6, 148.9, 141.8, 139.4, 137.9, 136.9, 129.0, 128.6, 128.3, 128.2, 128.1, 127.8, 127.4, 127.4, 127.2, 126.8, 122.8, 82.1, 74.1, 65.9, 60.3; HRMS (ESI) for [C₂₈H₂₅N₂O₂]⁺ ([M + H]⁺) calcd 421.1911, found 421.1906.

General Procedure 3 for the Preparation of the Substrate of Isoxazoline 6

To a 25 mL vacuum flame-dried Schlenk tube were added chiral catalyst cat.1 (2.0 mol %) and AgSbF₆ (2.0 mol %). Then the tube was purged with argon, and anhydrous DCE (1 mL) was added. The mixture was stirred at 25 °C for 30 min. α,β-Unsaturated 1-acylimidazole 1 (0.1 mmol, 1.0 equiv) was added, and the mixture was stirred for an additional 30 min at 25 °C. Finally, nitrone (0.12 mmol, 1.2 equiv) was added, and then the reaction mixture was stirred at 25 °C for 5–9 h (monitored by TLC) under an argon atmosphere. The DDQ (0.25 mmol, 2.5 equiv) was added to the mixture for 3–5 h after 1 was consumed completely. The reaction was quenched with a saturated Na₂S₂O₃ solution (10 mL). The aqueous phase was extracted with DCM (3 × 5 mL), and the organic phase was combined, dried over anhydrous sodium sulfate, and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (3:1 to 2:1 petroleum ether/EtOAc) to give target compound 6.

((4R,5S)-5-Methyl-3-phenyl-4,5-dihydroisoxazol-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (6a)

Compound 6a was isolated as a white semisolid in 94% yield (31.1 mg) with >20:1 dr and 98% ee: R _f value = 0.22 (5:1 PE:EA); [α]_D ^28.4 = −54.4 (c 0.29, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC column, with 70:30 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (minor) = 26.70 min; t _R (major) = 36.66 min; ¹H NMR (400 MHz, CDCl₃) δ 7.68–7.61 (m, 2H), 7.43–7.35 (m, 4H), 7.35–7.27 (m, 4H), 7.18–7.13 (m, 2H), 5.68 (d, J = 6.0 Hz, 1H), 4.96 (p, J = 6.4 Hz, 1H), 1.59 (d, J = 6.4 Hz, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 186.2, 155.2, 142.2, 137.7, 130.7, 130.0, 129.3, 129.2, 129.1, 128.8, 128.6, 127.1, 125.7, 83.3, 62.7, 21.1; HRMS (ESI) for [C₂₀H₁₈N₃O₂]⁺ ([M + H]⁺) calcd 332.1394, found 332.1388.

((4R,5S)-3-(4-Methoxyphenyl)-5-methyl-4,5-dihydroisoxazol-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (6b)

Compound 6b was isolated as a white semisolid in 95% yield (34.1 mg) with >20:1 dr and 92% ee: R _f value = 0.17 (5:1 PE:EA); [α]_D ^27.5 = −40.0 (c 0.90, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC column, with 70:30 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (major) = 49.02 min; t _R (minor) = 68.34 min; ¹H NMR (400 MHz, CDCl₃) δ 7.62–7.56 (m, 2H), 7.42–7.35 (m, 4H), 7.30–7.27 (m, 1H), 7.19–7.13 (m, 2H), 6.86–6.80 (m, 2H), 5.65 (d, J = 6.0 Hz, 1H), 4.93 (p, J = 6.4 Hz, 1H), 3.79 (s, 3H), 1.57 (d, J = 6.4 Hz, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 186.4, 161.0, 154.7, 142.2, 137.7, 130.7, 129.2, 129.1, 128.6, 128.6, 125.7, 121.9, 114.2, 83.0, 62.7, 55.4, 21.1; HRMS (ESI) for [C₂₁H₂₀N₃O₃]⁺ ([M + H]⁺) calcd 362.1499, found 362.1495.

((4R,5S)-5-Methyl-3-(p-tolyl)-4,5-dihydroisoxazol-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (6c)

Compound 6c was isolated as a white semisolid in 96% yield (33.1 mg) with >20:1 dr and 93% ee: R _f value = 0.23 (5:1 PE:EA); [α]_D ^26.9 = −57.2 (c 0.88, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC column, with 70:30 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (major) = 29.38 min; t _R (minor) = 36.20 min; ¹H NMR (400 MHz, CDCl₃) δ 7.55–7.51 (m, 2H), 7.42–7.35 (m, 4H), 7.30–7.28 (m, 1H), 7.18–7.10 (m, 4H), 5.66 (d, J = 6.0 Hz, 1H), 4.94 (p, J = 6.0 Hz, 1H), 2.32 (s, 3H), 1.58 (d, J = 6.4 Hz, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 186.3, 155.1, 142.2, 140.2, 137.7, 130.7, 129.5, 129.2, 129.1, 128.6, 127.0, 126.5, 125.7, 83.1, 62.6, 21.5, 21.1; HRMS (ESI) for [C₂₁H₂₀N₃O₂]⁺ ([M + H]⁺) calcd 346.1550, found 346.1546.

((4R,5S)-5-Methyl-3-(o-tolyl)-4,5-dihydroisoxazol-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (6d)

Compound 6d was isolated as a white semisolid in 98% yield (33.8 mg) with >20:1 dr and 92% ee: R _f value = 0.25 (5:1 PE:EA); [α]_D ^28.5 = −77.2 (c 0.81, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC column, with 70:30 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (major) = 19.07 min; t _R (minor) = 23.62 min; ¹H NMR (400 MHz, CDCl₃) δ 7.45–7.33 (m, 3H), 7.35–7.30 (m, 1H), 7.32–7.25 (m, 1H), 7.25–7.18 (m, 3H), 7.18–7.07 (m, 1H), 7.08–7.00 (m, 2H), 5.79 (d, J = 7.2 Hz, 1H), 4.97 (p, J = 6.4 Hz, 1H), 2.54 (s, 3H), 1.62 (d, J = 6.4 Hz, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 186.2, 156.0, 142.4, 138.4, 137.7, 131.4, 130.6, 129.3, 129.2, 129.1, 129.0, 128.4, 128.3, 125.7, 125.6, 82.1, 64.8, 22.3, 20.6; HRMS (ESI) for [C₂₁H₂₀N₃O₂]⁺ ([M + H]⁺) calcd 346.1550, found 346.1545.

((4R,5S)-5-Methyl-3-(m-tolyl)-4,5-dihydroisoxazol-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (6e)

Compound 6e was isolated as a white solid in 98% yield (33.7 mg) with >20:1 dr and 92% ee: R _f value = 0.25 (5:1 PE:EA); mp 120–122 °C; [α]_D ^25.9 = −69.4 (c 0.91, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC column, with 70:30 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (minor) = 31.96 min; t _R (major) = 45.53 min; ¹H NMR (400 MHz, CDCl₃) δ 7.56–7.50 (m, 1H), 7.44–7.33 (m, 5H), 7.30–7.28 (m, 1H), 7.24–7.10 (m, 4H), 5.67 (d, J = 6.0 Hz, 1H), 4.96 (p, J = 6.4 Hz, 1H), 2.30 (s, 3H), 1.59 (d, J = 6.4 Hz, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 186.3, 155.3, 142.3, 138.5, 137.7, 130.8, 130.7, 129.2, 129.2, 129.1, 128.6, 128.5, 127.7, 125.7, 124.3, 83.2, 62.6, 21.4, 21.0; HRMS (ESI) for [C₂₁H₂₀N₃O₂]⁺ ([M + H]⁺) calcd 346.1550, found 346.1546.

((4R,5S)-3-(4-Iodophenyl)-5-methyl-4,5-dihydroisoxazol-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (6f)

Compound 6f was isolated as a pale-yellow solid in 93% yield (42.5 mg) with >20:1 dr and 94% ee: R _f value = 0.25 (5:1 PE:EA); mp 156–158 °C; [α]_D ^28.5 = +6.0 (c 1.08, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC column, with 70:30 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (major) = 15.98 min; t _R (minor) = 27.37 min; ¹H NMR (400 MHz, CDCl₃) δ 7.69–7.61 (m, 2H), 7.44–7.35 (m, 6H), 7.31–7.28 (m, 1H), 7.21–7.14 (m, 2H), 5.63 (d, J = 6.0 Hz, 1H), 4.96 (p, J = 6.0 Hz, 1H), 1.58 (d, J = 6.4 Hz, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 186.0, 154.5, 142.0, 137.9, 137.6, 130.8, 129.3, 129.2, 128.9, 128.8, 128.6, 125.7, 96.1, 83.6, 62.2, 21.1; HRMS (ESI) for [C₂₀H₁₇N₃O₂I]⁺ ([M + H]⁺) calcd 458.0360, found 458.0354.

((4R,5S)-5-Methyl-3-(4-(trifluoromethyl)­phenyl)-4,5-dihydroisoxazol-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (6g)

Compound 6g was isolated as a pale-yellow solid in 95% yield (37.9 mg) with >20:1 dr and 94% ee: R _f value = 0.35 (5:1 PE:EA); mp 92–94 °C; [α]_D ^27.7 = −47.0 (c 0.80, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC column, with 70:30 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (major) = 8.11 min; t _R (minor) = 12.09 min; ¹H NMR (400 MHz, CDCl₃) δ 7.80–7.71 (m, 2H), 7.57 (d, J = 8.0 Hz, 2H), 7.45–7.35 (m, 4H), 7.32 (s, 1H), 7.23–7.14 (m, 2H), 5.68 (d, J = 6.0 Hz, 1H), 5.01 (p, J = 6.4 Hz, 1H), 1.61 (d, J = 6.3 Hz, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 185.9, 154.2, 142.0, 137.6, 132.9 (d, J = 1.0 Hz), 131.6 (q, J = 32.0 Hz), 130.9, 129.3, 128.9, 127.3, 125.8 (q, J = 4.0 Hz), 125.7, 123.9 (q, J = 270.0 Hz), 84.0, 62.2, 21.1; ¹⁹F NMR (376 MHz, CDCl₃) δ −62.60 to −63.10 (m); HRMS (ESI) for [C₂₁H₁₇N₃O₂F₃]⁺ ([M + H]⁺) calcd 400.1267, found 400.1263.

((4R,5S)-5-Ethyl-3-phenyl-4,5-dihydroisoxazol-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (6h)

Compound 6h was isolated as a white semisolid in 74% yield (25.5 mg) with >20:1 dr and 90% ee: R _f value = 0.36 (5:1 PE:EA); [α]_D ^27.2 = −77.2 (c 0.70, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak AD-H column, with 70:30 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (major) = 8.54 min; t _R (minor) = 9.64 min; ¹H NMR (400 MHz, CDCl₃) δ 7.70–7.61 (m, 2H), 7.42–7.34 (m, 4H), 7.34–7.27 (m, 4H), 7.17–7.11 (m, 2H), 5.77 (d, J = 6.0 Hz, 1H), 4.79 (q, J = 6.0 Hz, 1H), 1.99–1.84 (m, 2H), 1.08 (t, J = 7.6 Hz, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 186.6, 155.3, 142.2, 137.7, 130.7, 130.0, 129.3, 129.2, 129.1, 128.8, 128.6, 127.1, 125.7, 88.3, 60.6, 28.3, 9.5; HRMS (ESI) for [C₂₁H₂₀N₃O₂]⁺ ([M + H]⁺) calcd 346.1550, found 346.1546.

((4R,5R)-5-(tert-Butyl)-3-phenyl-4,5-dihydroisoxazol-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (6i)

Compound 6i was isolated as a white semisolid in 73% yield (27.2 mg) with >20:1 dr and 91% ee: R _f value = 0.58 (5:1 PE:EA); [α]_D ^27.9 = −158.1 (c 0.80, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak AD-H column, with 70:30 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (major) = 6.64 min; t _R (minor) = 10.31 min; ¹H NMR (400 MHz, CDCl₃) δ 7.73–7.66 (m, 2H), 7.41–7.34 (m, 4H), 7.32–7.26 (m, 4H), 7.10–7.03 (m, 2H), 6.01 (d, J = 7.2 Hz, 1H), 4.58 (d, J = 7.2 Hz, 1H), 1.03 (s, 9H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 187.7, 155.2, 142.2, 137.8, 130.7, 129.9, 129.2, 129.2, 129.1, 128.7, 128.6, 127.1, 125.7, 95.8, 56.8, 35.2, 25.3; HRMS (ESI) for [C₂₃H₂₄N₃O₂]⁺ ([M + H]⁺) calcd 374.1863, found 374.1859.

((4R,5S)-3,5-Dimethyl-4,5-dihydroisoxazol-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (6j)

Compound 6j was isolated as a white solid in 34% yield (9.9 mg) with 7:1 dr and 83% ee (68% ee): R _f value = 0.30 (5:1 PE:EA); mp 104–106 °C; [α]_D ^25.6 = −208.0 (c 0.28, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC column, with 70:30 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: minor, t _R (major) = 26.14 min, t _R (minor) = 46.21 min; major, t _R (major) = 48.29 min, t _R (minor) = 90.90 min; ¹H NMR (400 MHz, CDCl₃) δ 7.52–7.45 (m, 3H), 7.37–7.30 (m, 1H), 7.30–7.26 (m, 3H), 5.14 (d, J = 8.0 Hz, 1H), 4.93–4.82 (m, 1H), 1.94 (s, 3H), 1.49 (d, J = 6.4 Hz, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 185.5, 153.2, 142.4, 137.8, 130.7, 130.5 (minor), 129.3, 129.3, 128.5, 125.9 (minor), 125.9, 80.9, 79.5 (minor), 65.6, 61.5 (minor), 20.4, 16.3 (minor), 13.1, 13.1 (minor); HRMS (ESI) for [C₁₅H₁₅N₃O₂Na]⁺ ([M + Na]⁺) calcd 292.1056, found 292.1051.

((4R,5S)-3-Cyclohexyl-5-methyl-4,5-dihydroisoxazol-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (6k)

Compound 6k was isolated as a white semisolid in 90% yield (30.3 mg) with >20:1 dr and 80% ee: R _f value = 0.36 (5:1 PE:EA); [α]_D ^28.5 = −47.9 (c 0.56, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC column, with 70:30 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (minor) = 28.22 min; t _R (major) = 32.33 min; ¹H NMR (400 MHz, CDCl₃) δ 7.51–7.46 (m, 3H), 7.37–7.34 (m, 1H), 7.31–7.27 (m, 3H), 5.22 (dd, J = 6.8, 0.8 Hz, 1H), 4.77 (p, J = 6.4 Hz, 1H), 2.33–2.21 (m, 1H), 1.98–1.91 (m, 1H), 1.90–1.82 (m, 1H), 1.79–1.70 (m, 2H), 1.66–1.59 (m, 1H), 1.56–1.48 (m, 1H), 1.46 (d, J = 6.0 Hz, 3H), 1.24–1.17 (m, 4H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 186.3, 160.7, 142.4, 137.9, 130.6, 129.3, 129.3, 128.5, 125.9, 81.2, 63.4, 37.1, 31.0, 30.0, 26.1, 26.0, 25.8, 20.5; HRMS (ESI) for [C₂₀H₂₄N₃O₂]⁺ ([M + H]⁺) calcd 338.1863, found 338.1858.

((4R,5S)-3-(tert-Butyl)-5-methyl-4,5-dihydroisoxazol-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (6l)

Compound 6l was isolated as a pale-yellow solid in 85% yield (26.4 mg) with >20:1 dr and 96% ee: R _f value = 0.35 (5:1 PE:EA); mp 85–87 °C; [α]_D ^28.4 = −123.8 (c 0.64, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak AD-H column, with 70:30 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (major) = 5.64 min; t _R (minor) = 6.18 min; ¹H NMR (400 MHz, CDCl₃) δ 7.50–7.44 (m, 3H), 7.36–7.34 (m, 1H), 7.30–7.26 (m, 2H), 7.26–7.23 (m, 1H), 5.27 (d, J = 4.4 Hz, 1H), 4.79–4.69 (m, 1H), 1.41 (d, J = 6.0 Hz, 3H), 1.18 (s, 9H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 186.5, 163.8, 142.3, 137.9, 130.5, 129.3, 129.2, 128.6, 125.9, 82.5, 62.0, 33.7, 28.8, 20.9; HRMS (ESI) for [C₁₈H₂₂N₃O₂]⁺ ([M + H]⁺) calcd 312.1707, found 312.1703.

((4R,5S)-3-(Furan-2-yl)-5-methyl-4,5-dihydroisoxazol-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanone (6m)

Compound 6m was isolated as a pale-yellow solid in 40% yield (12.8 mg) with >20:1 dr and 88% ee: R _f value = 0.30 (5:1 PE:EA); mp 118–120 °C; [α]_D ^26.5 = −49.0 (c 0.33, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak AD-H column, with 70:30 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (major) = 8.20 min; t _R (minor) = 9.89 min; ¹H NMR (400 MHz, CDCl₃) δ 7.45–7.39 (m, 4H), 7.38–7.36 (m, 1H), 7.32–7.28 (m, 1H), 7.26–7.20 (m, 2H), 6.67 (d, J = 3.6 Hz, 1H), 6.43–6.37 (m, 1H), 5.56 (d, J = 6.4 Hz, 1H), 4.99–4.88 (m, 1H), 1.57 (d, J = 6.4 Hz, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 185.7, 147.3, 144.7, 144.2, 142.2, 137.7, 130.7, 129.3, 129.2, 128.6, 125.8, 111.9, 83.1, 62.5, 20.7; HRMS (ESI) for [C₁₈H₁₆N₃O₃]⁺ ([M + H]⁺) calcd 322.1186, found 322.1182.

General Procedure 4 for the Preparation of the Substrate of 7

To a stirred solution of 3a (0.5 mmol, 1 equiv) in MeOH (5 mL) was added NaBH₄ (1.25 mmol, 2.5 equiv) at 0 °C. The reaction mixture was stirred at 25 °C for 1 h and monitored by TLC. The reaction was quenched with H₂O. The resulting solution was diluted with EtOAc (10 mL) and H₂O (10 mL). The aqueous phase was extracted with EtOAc (3 × 10 mL). The organic portion was combined, dried over anhydrous Na₂SO₄, and then concentrated under reduced pressure. The residue was further purified by flash column chromatography on silica gel (4:1 petroleum ether/EtOAc) to give target compound 7 as a white solid (184.9 mg, 87% yield, >20:1 dr).

(S)-((3S,4S,5S)-2-Benzyl-5-methyl-3-phenylisoxazolidin-4-yl)­(1-phenyl-1H-imidazol-2-yl)­methanol (7)

Compound 7 was isolated as a white solid in 87% yield (184.9 mg) with >20:1 dr: R _f value = 0.30 (3:1 PE:EA); mp 119–120 °C; [α]_D ^28.1 = −86.4 (c 0.46, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ 7.45–7.36 (m, 3H), 7.31–7.26 (m, 3H), 7.25–7.15 (m, 5H), 7.11–7.04 (m, 3H), 6.91–6.84 (m, 3H), 4.90 (d, J = 6.0 Hz, 1H), 4.08 (p, J = 6.0 Hz, 1H), 3.99–3.83 (m, 3H), 3.70 (bs, 1H), 2.42 (q, J = 6.4 Hz, 1H), 1.18 (d, J = 6.0 Hz, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 148.0, 141.4, 138.3, 136.7, 129.7, 128.9, 128.4, 128.4, 128.2, 128.1, 127.4, 127.2, 126.9, 125.6, 122.1, 75.3, 72.3, 66.2, 64.7, 59.7, 19.8; HRMS (ESI) for [C₂₇H₂₈N₃O₂]⁺ ([M + H]⁺) calcd 426.2176, found 426.2171.

General Procedure 5 for the Preparation of the Substrate of 8

To a stirred solution of 3a (1 mmol, 1 equiv) in MeOH (20 mL) were added Pd­(OH)₂/C (0.5 mmol, 0.5 equiv, 20 wt %) and Boc₂O (2 mmol, 2 equiv) at 25 °C. After being purged several times with H₂, the reaction mixture was stirred for 12 h at room temperature under a H₂ atmosphere. As monitored by TLC, the reaction mixture was filtered and evaporated after 3a was consumed completely. The residue was further purified by flash column chromatography on silica gel (3:1 petroleum ether/EtOAc) to give target compound 8 as a white solid (385.7 mg, 88% yield, 99% ee, >20:1 dr).

tert-Butyl ((1S,2R,3S)-3-Hydroxy-1-phenyl-2-(1-phenyl-1H-imidazole-2-carbonyl)­butyl)­carbamate (8)

Compound 8 was isolated as a white solid in 88% yield (385.7 mg) with >20:1 dr and 99% ee: R _f value = 0.15 (2:1 PE:EA); mp 75–77 °C; [α]_D ^25.2 = −78.9 (c 0.79, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC column, with 70:30 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (minor) = 11.42 min; t _R (major) = 12.42 min; ¹H NMR (400 MHz, CDCl₃) δ 7.40–7.26 (m, 7H), 7.26–7.19 (m, 2H), 7.11 (s, 1H), 6.77–6.63 (m, 2H), 5.62 (d, J = 9.6 Hz, 1H), 5.29 (s, 1H), 4.51–4.27 (m, 3H), 1.40 (s, 9H), 1.19 (d, J = 6.0 Hz, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 190.4, 155.2, 143.8, 141.8, 137.6, 129.6, 129.1, 128.7, 128.6, 127.5, 127.3, 127.0, 125.3, 79.8, 67.4, 59.7, 54.0, 28.5, 20.6; HRMS (ESI) for [C₂₅H₃₀N₃O₄]⁺ ([M + H]⁺) calcd 436.2231, found 436.2225.

General Procedure 6 for the Preparation of the Substrate of 9

To a stirred solution of 8 (0.1 mmol, 1 equiv) in DMF (1 mL) were added imidazole (0.5 mmol, 5 equiv) and TBSCl (0.25 mmol, 2.5 equiv) at 0 °C. After being stirred overnight at 25 °C, the reaction mixture was diluted with ether and washed with water and brine. The aqueous phase was extracted with ether. The combined organic phase was dried over anhydrous Na₂SO₄, filtered, and evaporated. The residue was further purified by flash column chromatography on silica gel (5:1 petroleum ether/EA) to give target compound 9 as a white semisolid (48.1 mg, 92% yield, 99% ee, >20:1 dr).

tert-Butyl ((1S,2R,3S)-3-((tert-Butyldimethylsilyl)­oxy)-1-phenyl-2-(1-phenyl-1H-imidazole-2-carbonyl)­butyl)­carbamate (9)

Compound 9 was isolated as a white semisolid in 92% yield (48.1 mg) with >20:1 dr and 99% ee: R _f value = 0.33 (5:1 PE:EA); [α]_D ^28.3 = −3.9 (c 1.59, CHCl₃). The enantiomeric ratio was determined by chiral HPLC using a Daicel Chiralpak IC column, with 95:5 n-hexane/2-propanol, at 254 nm, with a flow rate of 0.8 mL/min: t _R (major) = 8.44 min; t _R (minor) = 11.18 min; ¹H NMR (400 MHz, CDCl₃) δ 7.40–7.26 (m, 5H), 7.24–7.17 (m, 3H), 7.17–7.10 (m, 1H), 7.03 (s, 1H), 7.00–6.92 (m, 2H), 5.78 (d, J = 8.0 Hz, 1H), 5.14 (s, 1H), 4.65–4.55 (m, 1H), 4.48–4.37 (m, 1H), 1.37 (s, 9H), 1.19 (d, J = 6.0 Hz, 3H), 0.83 (s, 9H), 0.09 (d, J = 9.6 Hz, 6H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 190.8, 155.1, 144.2, 141.4, 138.2, 129.5, 128.9, 128.5, 128.2, 127.5, 127.1, 126.7, 125.6, 69.7, 57.9, 55.0, 28.4, 25.9, 21.3, 18.1, −4.3, −4.7; HRMS (ESI) for [C₃₁H₄₄N₃O₄Si]⁺ ([M + H]⁺) calcd 550.3101, found 550.3094.

The data underlying this study are available in the published article and its .

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.5c02152.

• FAIR data, including the primary NMR FID files, for compounds 1d, 1e, 3a–3w, 4a–4h, 5a, 6a–6m, and 7–9 (ZIP)

• Additional information (ZIP)

• Experimental details, characterization data for all new compounds, and X-ray crystal structure and structural data of compound 3j (PDF)

The authors declare no competing financial interest.