Access to Spiropyrazolone-butenolides through NHC-Catalyzed [3 + 2]-Asymmetric Annulation of 3-Bromoenals and 1H-Pyrazol-4,5-diones

Abstract

The stereoselective synthesis of spirocyclic pyrazolin-5-ones by N-heterocyclic carbene (NHC) organocatalysis has been less studied so far. For this reason and considering the interest of this class of compounds, here, we present the NHC-catalyzed [3 + 2]-asymmetric annulation of β-bromoenals and 1H-pyrazol-4,5-diones that achieves to produce chiral spiropyrazolone-butenolides. The synthesis is general for aryl and heteroaryl β-bromo-α,β-unsaturated aldehydes and 1,3-disubstituted pyrazolones. The spirobutenolides have been obtained in good yields (up to 88%) and enantioselectivities (up to 97:3 er). This constitutes the first described example using pyrazoldiones as the starting materials for this class of spiro compounds.

Introduction

Since Sheehan and Hunneman¹ carried out the first enantioselective benzoin reaction more than fifty years ago, asymmetric organocatalysis enabled by N-heterocyclic carbenes (NHCs) has continued to evolve, especially during the last two decades. The progress in the knowledge of the intermediates formed when aldehydes and other carbonyls are activated with NHCs allows us to look at more specific fields such as catalysis via homoenolate,² via α,β-unsaturated acylazolium,³ via azolium enolate,⁴ or via azolium dienolate⁵ (Figure 1a). In general, these NHC-catalyzed transformations are operationally simple reactions that proceed at room temperature without the generation of reaction byproducts. If the precursor NHC/base combination is well selected, it is possible to prepare structurally complex molecules from easy the starting materials. In addition, high diastereo- and enantioselectivity levels are possible using chiral NHCs.

Figure 1.

(a) Typical reaction intermediates in NHC catalysis. (b) Some selected examples of chiral spirooxindoles and spiropyrazolones accessible via NHC-mediated pathways.

The synthesis of new chiral spiroheterocycles remains one of the most important goals for synthetic chemists because they are privileged scaffolds widely occurring in many natural products and drugs. Diverse examples can be found in the literature describing its preparation by NHC catalysis, mainly spirooxindole derivatives (Figure 1b, left). For example, in a pioneering work, Ye et al.⁶ reported the stereoselective synthesis of spirooxindole lactones by NHC-catalyzed homoenolate annulation of enals with isatins. Similar structures were obtained by the Scheidt group,⁷ who used a cooperative catalysis with lithium chloride as Lewis acid. Using in situ generated enolate species, an asymmetric Michael-intramolecular aldol-lactonization cascade reaction to propiolactone-fused spirocyclopentane-oxindoles⁸ was developed by Wang and coworkers. Nonetheless, other spirocyclic heterocycles, such as spiropyrazolones, have been much less studied despite their biologically and pharmacologically relevant properties.⁹ The challenging stereoselective generation of their C-4 quaternary stereocenter is highly desirable because it provides a three-dimensional structure crucial for the behavior of potential drug candidates.¹⁰ In particular, drawbacks such as the low spatial occupation or the limitation of their interactions with the three-dimensional structure of the target molecules that present the more traditional achiral planar (hetero)aromatic compounds can be minimized. Very few examples describe the NHC-catalyzed asymmetric synthesis of spirocyclic pyrazolones¹¹ (Figure 1b, right). The groups of Biju and Yang–Zhong have reported the preparation of pyrazolone spirocyclohexanones by addition of NHC-generated α,β-unsaturated acylazolium^11c or vinyl enolate^11a intermediates from enals and γ-chloro enals, respectively, to α-arylidene pyrazolinones. Very recently, we have described the first asymmetric synthesis of spirocyclic pyrazolone γ-butyrolactones by an NHC-catalyzed [3 + 2] annulation reaction.¹²

On the other hand, the γ-butenolide moiety is a motif present in a wide range of natural products and biologically active molecules. In the last few years, several reviews have documented the most recent enantioselective synthetic approaches for the construction of these frameworks,¹³ but the development of this field is still in its infancy. In fact, to our knowledge, no reports on the synthesis of chiral spiropyrazolone-butenolides have been disclosed so far.

Ma et al. disclosed that the use of 3-haloenals under NHC catalysis allows the selective generation of two types of α,β-unsaturated acylazolium intermediates I and II, depending on the presence or absence of an external oxidant (Scheme 1a).¹⁴ However, the use of NHC-bound homoenolates with a bromine atom in the β-position III has enabled an addition–dehalogenation–lactonization cascade process.¹⁵ Since we are interested in the preparation of enantiopure 4,4-disubstituted pyrazol-5-one derivatives, this possibility prompted us to carry out the reaction with pyrazolin-4,5-diones that have not yet been used as the starting materials for the synthesis of spiropyrazolones (Scheme 1b). As a result of this idea, we now present the enantioselective synthesis of novel chiral spiropyrazolone-butenolides via 3-halogen-substituted homoenolates promoted by NHC catalysis.

Scheme 1. Use of 3-Haloenals under NHC Catalysis.

Results and Discussion

We initiated our investigation by reacting pyrazolin-4,5-dione 1a with 3-bromo cinnamaldehyde 2a (1.5 equiv) in the presence of chiral triazolium precatalysts A–C (10 mol %), DBU (1.5 equiv) as base in THF. The reactions were maintained at room temperature for 16 h (Table 1). A screening of NHC precursors (entries 1, 2, and 4–6) indicated that pyroglutamic derivative A2 and C2, a modified Bode precatalyst, provided the highest enantiomeric ratio values for pyrazolone-butenolide 3a (entries 2 and 6), so we decided to test them under different reaction conditions. Performing the reaction at 50 °C in the presence of A2 (entry 3) resulted in less than 5% conversion and diminished er. Switching THF to chloroform, 1,4-dioxane or a THF/tBuOH (10:1) mixture was ineffective (entries 7–9), and in hexane, diethyl ether, or a THF/MeCN (1:1), the reaction did not proceed (entries 10–12). Other bases to generate the carbene catalyst did not improve the results. The yield rose to 71% when cesium carbonate was used instead of DBU, but the enantioselectivity decreased (entry 13). The presence of lithium chloride as additive was not beneficial (entry 14), and other bases such as TBD or a mixture of DBU and cesium carbonate provided product 3a with similar levels of enantioselectivity but inferior yield (entries 15 and 16). The same happened when using tBuOK or DMAP (entries 17 and 18). Changes in 1a/2a molar ratio provided very poor yields (entries 19 and 20). Treatment of the triazolium salt C2 with DBU in chloroform (entry 21) improved slightly the enantioselectivity compared to the reaction in THF. No significant improvement was achieved by performing the reaction at 0 °C (entry 22). Other solvents provided the pyrazolone-butenolide 3a in better yields, but the enantioselectivity decreased (entries 23–25). Again, a good yield for spiropyrazolone was obtained when the catalyst was formed from C2 using cesium carbonate (entry 26), but the enantioselectivity was worse. Finally, TBD and DMAP (entries 27 and 28) gave lower yields and enantiomeric ratios. Overall, the best balance between yield and enantiomeric ratio was achieved using a combination of C2/DBU/chloroform (entry 21).

Table 1. Optimization of Reaction Conditions^a.

entry	pre-NHC	base	solvent	yield (%)b	erc
1	A1	DBU	THF	n.r.	n.r.
2	A2	DBU	THF	27	96:4
3d	A2	DBU	THF	<5	88:12
4	B	DBU	THF	56	81:19
5	C1	DBU	THF	<5	32:68
6	C2	DBU	THF	57	92:8
7	A2	DBU	CHCl3	14	88:12
8	A2	DBU	dioxane	9	95:5
9	A2	DBU	THF/tBuOH (10:1)	33	88:12
10	A2	DBU	Et2O	n.r.	n.r.
11	A2	DBU	hexane	n.r.	n.r.
12	A2	DBU	THF/MeCN (1:1)	n.r.	n.r.
13	A2	Cs2CO3	THF	71	88:12
14e	A2	Cs2CO3	THF	<5	89:11
15	A2	TBD	THF	20	95:5
16	A2	DBU + Cs2CO3	THF	20	96:4
17	A2	tBuOK	THF	16	91:9
18	A2	DMAP	THF	47	86:14
19f	A2	DBU	THF	14	98:2
20g	A2	DBU	THF	27	96:4
21	C2	DBU	CHCl3	54	94:6
22h	C2	DBU	CHCl3	52	94:6
23	C2	DBU	DCE	74	83:17
24	C2	DBU	dioxane	74	79:21
25	C2	DBU	MeTHF	55	88:12
26	C2	Cs2CO3	CHCl3	70	90:10
27	C2	TBD	CHCl3	29	86:14
28	C2	DMAP	CHCl3	14	50:50

^aReaction conditions: 1a (0.06 mmol), 2a (0.09 mmol), pre-NHC (10 mol %), base (1.5 equiv), solvent (1 mL), at rt for 16 h.

^bYield of 3a after column chromatography.

^cEr values determined via chiral high-performance liquid chromatography (HPLC) analysis.

^dReaction temperature 50 °C.

^eLiCl (2 equiv) as additive.

^fMolar ratio 1a/2a 1:1.

^gMolar ratio 1a/2a 1.5:1.

^hReaction temperature 0 °C.

Once the optimal reaction conditions were established, we then explored the influence of the substituents of pyrazolin-4,5-dione. To do this, 3-bromo cinnamaldehyde 2a was reacted with pyrazolin-4,5-diones 1 with different substituents at C-3 and N-1 positions (Scheme 2). Regardless of whether an alkyl or an aryl group was present at C-3, the enantioselectivity was high. In all cases, the spirocycles 3a–f were obtained in moderate to good yields. NMR analysis of the reaction crude indicated a total conversion of the starting pyrazole-dione, so it is possible that the decrease in the yield is due to the formation of nonidentifiable byproducts. On the other hand, the influence of the N-substituent has also been considered and a slight drop of performance was detected when an N-methyl group was present in the butenolide (3g and 3h). Similar result was observed for compound 3i, with a p-chlorophenyl group at the N-1 position, that showed a good enantiomeric ratio, 90:10.¹⁶

Scheme 2. Scope of Reaction with Respect to Pyrazolin-4,5-dione^,b,c.

Reaction conditions: 1a−i (0.06 mmol), 2a (0.09 mmol), C2 (10 mol %), DBU (1.5 equiv), chloroform (1 mL), at rt for 16 h. ^bYield of 3 after column chromatography. ^cEr values determined via chiral HPLC analysis.

Next, the influence of the β-bromoenal on the annulation reaction was evaluated. For this purpose, aryl and heteroaryl β-bromo-α,β-unsaturated aldehydes 2b–l were used (Scheme 3). The process worked well when the pyrazolin-4,5-dione 1a was reacted with p-substituted cinnamyl aldehydes, and the corresponding spiropyrazolones were isolated (3ab–3ac and 3ae–3ah). The enantioselectivities were excellent when electron-withdrawing or donating groups were present on the enal, except for compound 3ac that gave a slightly lower enantiomeric ratio. However, a quasi-racemic mixture and poor yield were obtained when the enal had a methoxy group in the ortho-position of the phenyl ring (3ad). On the other hand, the meta-substitution of the aromatic ring did not lead to a significant change in either the yield or the enantioselectivity (3ah and 3ai). The reaction of 1a with 3-bromo-3-furanyl or 3-thienyl acrylaldehyde resulted in the corresponding spiropyrazolones 3aj and 3ak in good yield and er. Again, and regardless of the enal substitution, the enantiomeric ratios remained high when the pyrazolin-4,5-dione had an ethyl or isopropyl group at C-3 (3ce, 3db, and 3df). To further demonstrate the feasibility of our protocol, a scale-up reaction was conducted on a 1-mmol scale for the preparation of spirobutenolide 3ag, and good yield (367 mg, 80% yield) and similar enantioselectivity (er 91:9) were achieved in the presence of 10 mol % catalyst C2 (Scheme 3). Finally, the reaction using β-bromo benzylidene crotonaldehyde afforded the spirocyclic butenolide 3al in low yield and moderate enantioselectivity (18%, er 78:22).

Scheme 3. Substrate Scope Involving β-bromoenals^,b,c.

Reaction conditions: 1a,c,d (0.06 mmol), 2b-l (0.09 mmol), C2 (10 mol %), DBU (1.5 equiv), chloroform (1 mL), at rt for 16 h. ^b Yield of 3 after column chromatography. ^c Er values determined via chiral HPLC analysis.

The stereochemistry of the major enantiomer of 3a was established by chemical correlation with spirocyclic pyrazolone γ-butyrolactone 4,¹² obtained by catalytic hydrogenation of 3a (Scheme 4. See the Supporting Information for details and retention times for (4R,5S)-4 and racemic-4). The absolute configuration of the other products is expected to be the same by analogy.

Scheme 4. Selective Hydrogenation of SpiroButenolide 3a.

A plausible catalytic cycle for the NHC-catalyzed [3 + 2]-annulation reaction is depicted in Scheme 5. In the first stage, the NHC catalyst reacts with the aldehyde moiety of β-bromoenal 2, giving rise to the intermediate IM1 which evolves to the Breslow homoenolate IM2 after base-assisted 1,2-hydrogen migration.^12,17 In our previous electronic structure calculations, we proved that the Brønsted base used to generate the carbene catalyst assists the [1,2]-proton transfer for the generation of homoenolate. However, it is also worth mentioning that previous computational studies have found that it is the conjugated acid of the base that leads to the lowest energy barrier.¹⁸ Subsequently, the attack of the Re face of pyrazole-dione 1 on the Re face of homoenolate would be possible, giving rise to the formation of the intermediate IM3. Then, the cyclization and release of the bromide anion originate the butenolide unit in IM4. This C–O bond-forming event was found to be the stereoselectivity-determining step by the electronic structure calculations for a related reaction, the asymmetric annulation between pyrazolin-4,5-diones and enals.¹² In addition, the free energy barrier was lower for the stereoisomer with the (S) spiro center, which is the configuration obtained experimentally for 3a (Scheme 4). Finally, the catalytic cycle is completed with the formation of the butenolide product 3 and the regeneration of the NHC catalyst.

Scheme 5. Plausible Catalytic Cycle.

The synthetic utility of our method was demonstrated by the treatment of p-bromophenyl-substituted butenolide 3ag with phenylboronic acid under Suzuki conditions, and the cross-coupling product 5 was obtained with no erosion of the enantiomeric purity and excellent yield (Scheme 6).

Scheme 6. Transformation of Spiropyrazolone-butenolide 3ag.

Finally, although the aim of this work was the preparation of spiropyrazolone-butenolides, we extended our study to other ketones. The reaction of N-benzyl isatin 6 with 2a in the previously established conditions afforded the spirooxindole butenolide 7(15b) in 75% yield and good enantioselectivity (Scheme 7), thus providing evidence of the versatility of our synthetic methodology.

Scheme 7. Reaction of N-Benzyl Isatin with 3-Bromo Cinnamaldehyde.

Conclusions

In summary, we present an unprecedented strategy for the synthesis of novel chiral spiropyrazolone-butenolides. The key step consists of the use of 3-bromo homoenolates formed from β-bromoenals and a modified Bode catalyst with a nitro substituent on the indene ring. These intermediates trigger an addition–dehalogenation–lactonization cascade by reacting with the pyrazolin-4,5-diones. The process works under extremely mild conditions with a simple procedure and also tolerates a wide range of substituents on both substrates. The S-configuration of the quaternary center created at the C-4 position of the pyrazolone is consistent with our computational studies of the mechanism previously performed in the preparation of γ-butyrolactone derivatives.

Experimental Section

General Methods

¹H NMR (500 MHz), ¹³C NMR (126 MHz), and ¹⁹F NMR (376 MHz) spectra were recorded in CDCl₃ as solvent. Chemical shifts for protons are reported in ppm from TMS with the residual CHCl₃ resonance as an internal reference. Chemical shifts for carbons are reported in ppm from TMS and are referenced to the carbon resonance of the solvent. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and br = broad), coupling constants in hertz, and integration. Specific rotations were measured on a PerkinElmer 341 digital polarimeter using a 1 mL cell with a 1 dm path length, at 589 nm, and concentration is given in g per 100 mL. Infrared spectra were recorded on a PerkinElmer Spectrum One FT-IR spectrometer and are reported in the frequency of absorption (only the structurally most important peaks are given). Flash chromatography was carried out using a silica gel (230–240 mesh). Thin-layer chromatography (TLC) analysis was performed on glass-backed plates coated with a silica gel 60 and F254 indicator and visualized by either UV irradiation or by staining with phosphomolybdic acid solution. Chiral HPLC analysis was performed on a JASCO HPLC system (JASCO PU-2089 and UV-2075 UV/vis detector) with a quaternary pump and on Hewett-Packard 1090 Series II instrument equipped with a quaternary pump, using Phenomenex Lux-amylose-1, Lux-i-amylose-1, and Lux-i-cellulose-5; and Chiralpak OD, IA, and AD-H analytical columns (250 × 4.6 mm). Detection was monitored at 210, 220, 230, and 254 nm. ESI mass spectra were obtained on an Agilent 5973 inert GC/MS system.

Commercially available organic and inorganic compounds were used without further purification. Solvents were dried and stored over microwave-activated 4 Å molecular sieves. Pyrazolin-4,5-diones 1a–i,^12,19N-benzyl isatin 6,²⁰ β-bromoenals 2a–l,(21) and triazolium salts used as precatalysts A–C(22) were prepared according to the literature procedures. The racemic samples of spiropyrazolone-butenolides were prepared using an equimolar mixture of both enantiomers of precatalyst B.

General Procedure for Spiropyrazolone-butenolides

In a 5-mL heat gun-dried flask equipped with a magnetic stirring bar, the precatalyst C2 (6 μmol, 0.1 equiv) and the pyrazolin-4,5-dione 1a–i (0.06 mmol) were weighed. Then, β-bromoenal 2a–l (0.09 mmol, 1.5 equiv) was added under a N₂ atmosphere. Dry chloroform (1 mL) was added before the mixture was stirred. Several minutes later, the base (0.09 mmol, 1.5 equiv.) was introduced to the flask. After 16 h, the solvent was straight removed under the reduced pressure and the residue was subjected to column chromatography over a silica gel using a mixture of hexane and ethyl acetate as eluent to give the desired compound.

(S)-4,7,9-Triphenyl-1-oxa-7,8-diazaspiro[4.4]nona-3,8-diene-2,6-dione (3a)

Following the general procedure and after column chromatography using hexane/ethyl acetate 10:1 as eluent, 3a was isolated as white solid (12.1 mg, 54% yield). mp 137–139 °C (from hexane). [α]_D²⁵ = −94.5 (c 0.2, CHCl₃, er 94:6). ¹H NMR (500 MHz, CDCl₃): δ 7.97 (d, J = 9.8 Hz, 2H), 7.73 (d, J = 9.7 Hz, 2H), 7.50–7.42 (m, 4H), 7.41–7.38 (m, 4H), 7.37–7.33 (m, 2H), 7.30 (tt, J = 7.5, 1.1 Hz, 1H), 6.77 (s, 1H). ¹³C {¹H} NMR (126 MHz, CDCl₃): δ 170.3, 165.4, 162.3, 153.3, 137.2, 132.3, 131.7, 129.7, 129.2, 129.0, 128.1, 126.7, 124.4, 126.2, 119.2, 116.8, 87.3. IR v_max/cm^–1 3114, 3059, 2917, 1808, 1779, 1727, 1596, 1497, 1449, 1321, 1175, 1085. HRMS (ESI-TOF) m/z: calcd for C₂₄H₁₆N₂NaO₃ [M + Na]⁺, 403.1053; found, 403.1062. HPLC (Chiralcel OD, n-hexane/2-propanol 80:20, λ = 254 nm, 0.6 mL/min). t_R (major) = 16.2 min, t_R (minor) = 27.7 min (er 94:6).

(S)-9-Methyl-4,7-diphenyl-1-oxa-7,8-diazaspiro[4.4]nona-3,8-diene-2,6-dione (3b)

Following the general procedure and after column chromatography using hexane/ethyl acetate 10:1 as eluent, 3b was isolated as yellow oil (16.7 mg, 66% yield). [α]_D²⁵ = −78.1 (c 0.3, CHCl₃, er 92:8). ¹H NMR (500 MHz, CDCl₃): δ 7.88 (d, J = 9.8 Hz, 2H), 7.51–7.40 (m, 5H), 7.38–7.36 (m, 2H), 7.27 (tt, J = 7.4, 1.1 Hz, 1H), 6.67 (s, 1H), 2.08 (s, 3H). ¹³C {¹H} NMR (126 MHz, CDCl₃): δ 170.1, 165.2, 160.1, 156.2, 137.2, 132.4, 129.9, 129.2, 128.0, 126.5, 126.1, 118.9, 116.9, 87.5, 13.3. IR v_max/cm^–1 3109, 3062, 2961, 2921, 2849, 1806, 1770, 1727, 1597, 1481, 1366, 1294, 1182, 1121, 1063, 926, 901. HRMS (ESI-TOF) m/z: calcd for C₁₉H₁₅N₂O₃ [M + H]⁺, 319.1077; found, 319.1083. HPLC (Chiralcel OD, n-hexane/2-propanol 80:20, λ = 254 nm, 0.6 mL/min). t_R (major) = 17.7 min, t_R (minor) = 27.6 min (er 92:8).

(S)-9-Ethyl-4,7-diphenyl-1-oxa-7,8-diazaspiro[4.4]nona-3,8-diene-2,6-dione (3c)

Following the general procedure and after column chromatography using hexane/ethyl acetate 10:1 as eluent, 3c was isolated as yellow oil (14.6 mg, 60% yield). [α]_D²⁵ = −10.7 (c 0.4, CHCl₃, er 95:5). ¹H NMR (500 MHz, CDCl₃): δ 7.90 (d, J = 8.1 Hz, 2H), 7.50–7.35 (m, 7H), 7.27 (t, J = 8.0 Hz, 1H), 6.67 (s, 1H), 2.54–2.44 (m, 1H), 2.33–2.23 (m, 1H), 1.22 (t, J = 7.8 Hz, 3H). ¹³C {¹H} NMR (126 MHz, CDCl₃): δ 170.2, 165.4, 160.3, 160.2, 137.3, 132.4, 129.8, 129.1, 128.1, 126.5, 126.1, 118.9, 116.7, 87.6, 21.3, 9.3. IR v_max/cm^–1 3109, 3062, 2957, 1803, 1781, 1730, 1590, 1575, 1489, 1453, 1348, 1258, 1182, 1124, 1038, 753. HRMS (ESI-TOF) m/z: calcd for C₂₀H₁₆KN₂O₃ [M + K]⁺, 371.0793; found, 371.0799. HPLC (Chiralcel OD, n-hexane/2-propanol 85:15, λ = 210 nm, 1 mL/min). t_R (major) = 10.7 min, t_R (minor) = 18.6 min (er 95:5).

(S)-9-Isopropyl-4,7-diphenyl-1-oxa-7,8-diazaspiro[4.4]nona-3,8-diene-2,6-dione (3d)

Following the general procedure and after column chromatography using hexane/ethyl acetate 10:1 as eluent, 3d was isolated as yellow oil (17.1 mg, 81% yield). [α]_D²⁵ = −74.8 (c 0.3, CHCl₃, er 95:5). ¹H NMR (500 MHz, CDCl₃): δ 7.91 (d, J = 8.8 Hz, 2H), 7.49–7.35 (m, 7H), 7.27 (t, J = 8.0 Hz, 1H), 6.69 (s, 1H), 2.70–2.60 (m, 1H), 1.26 (d, J = 6.9 Hz, 3H), 1.10 (d, J = 7.0 Hz, 3H). ¹³C {¹H} NMR (126 MHz, CDCl₃): δ 170.3, 165.5, 163.3, 160.1, 137.3, 132.4, 129.8, 129.1, 128.3, 126.5, 126.1, 119.0, 116.5, 87.8, 29.2, 20.2. IR v_max/cm^–1 3058, 2964, 2928, 1808, 1774, 1730, 1597, 1500, 1377, 1344, 1328, 1240, 1186, 1124, 1045. HRMS (ESI-TOF) m/z: calcd for C₂₁H₁₈N₂NaO₃ [M + Na]⁺, 369.1210; found, 369.1216. HPLC (Chiralcel OD, n-hexane/2-propanol 90:10, 0.8 mL/min, λ = 210 nm). t_R (major) = 13.3 min, t_R (minor) = 29.9 min (er 95:5).

(S)-9-(tert-Butyl)-4,7-diphenyl-1-oxa-7,8-diazaspiro[4.4]nona-3,8-diene-2,6-dione (3e)

Following the general procedure and after column chromatography using hexane/ethyl acetate 10:1 as eluent, 3e was isolated as yellow oil (17.8 mg, 76% yield). [α]_D²⁵ = −103.7 (c 0.4, CHCl₃, er 89:11). ¹H NMR (500 MHz, CDCl₃): δ 7.88 (d, J = 8.6 Hz, 2H), 7.49–7.35 (m, 7H), 7.27 (t, J = 8.7 Hz, 1H), 6.69 (s, 1H), 1.20 (s, 9H). ¹³C {¹H} NMR (126 MHz, CDCl₃): δ 170.3, 165.6, 164.6, 162.0, 137.3, 132.3, 129.7, 129.1, 128.6, 126.5, 126.1, 118.9, 116.2, 88.1, 36.9, 28.6. IR v_max/cm^–1 3098, 2972, 2932, 1817, 1770, 1723, 1601, 1500, 1362, 1294, 1207, 1175, 1067, 1023, 955. HRMS (ESI-TOF) m/z: calcd for C₂₂H₂₀N₂NaO₃ [M + Na]⁺, 383.1366; found, 383.1372. HPLC (Chiralcel OD, n-hexane/2-propanol 80:20, λ = 254 nm, 0.6 mL/min). t_R (major) = 11.6 min, t_R (minor) = 22.9 min (er 89:11).

(S)-9-(Naphthalen-2-yl)-4,7-diphenyl-1-oxa-7,8-diazaspiro[4.4]nona-3,8-diene-2,6-dione (3f)

Following the general procedure and after column chromatography using hexane/ethyl acetate 10:1 as eluent, 3f was isolated as pale yellow oil (11.2 mg, 52% yield). [α]_D²⁵ = −70.1 (c 0.2, CHCl₃, er 96:4). ¹H NMR (500 MHz, CDCl₃): δ 8.01–7.98 (m, 4H), 7.87 (d, J = 8.6 Hz, 1H), 7.81 (t, J = 8.5 Hz, 2H), 7.56–7.48 (m, 4H), 7.42–7.38 (m, 3H), 7.35–7.30 (m, 3H), 6.8 (s, 1H). ¹³C {¹H} NMR (126 MHz, CDCl₃): δ 170.3, 165.4, 162.6, 153.1, 137.2, 134.6, 132.8, 132.3, 129.7, 129.2, 129.2, 129.0, 128.2, 128.1, 127.8, 127.0, 126.8, 126.7, 126.5, 126.4, 122.5, 119.2, 116.8, 87.4. IR v_max/cm^–1 3066, 2954, 2925, 2860, 1803, 1770, 1730, 1597, 1453, 1308, 1175, 1128, 1059, 966. HRMS (ESI-TOF) m/z: calcd forC₂₈H₁₈N₂NaO₃ [M + Na]⁺, 453.1210; found, 453.1222. HPLC (Chiralcel OD, n-hexane/2-propanol 80:20, λ = 254 nm, 0.6 mL/min). t_R (major) = 18.3 min, t_R (minor) = 32.3 min (er 96:4).

(S)-7-Methyl-4,9-diphenyl-1-oxa-7,8-diazaspiro[4.4]nona-3,8-diene-2,6-dione (3g)

Following the general procedure and after column chromatography using hexane/ethyl acetate 10:1 as eluent, 3g was isolated as yellow oil (11.6 mg, 46% yield). [α]_D²⁵ = −72.0 (c 0.2, CHCl₃, er 90:10). ¹H NMR (500 MHz, CDCl₃): δ 7.60 (d, J = 9.8 Hz, 2H), 7.45–7.33 (m, 8H), 6.70 (s, 1H), 3.51 (s, 3H). ¹³C {¹H} NMR (126 MHz, CDCl₃): δ 170.4, 167.3, 162.4, 151.6, 132.2, 131.3, 129.6, 129.1, 128.2, 126.7, 125.9, 116.7, 86.2, 32.5. IR v_max/cm^–1 3109, 3069, 2925, 2853, 1808, 1770, 1727, 1604, 1445, 1391, 1341, 1229, 1095, 1063, 864. HRMS (ESI-TOF) m/z: calcd for C₁₉H₁₄N₂NaO₃ 1579, [M + Na]⁺, 341.0897; found, 341.0907. HPLC (Lux Amylose-1, n-hexane/2-propanol 80:20, λ = 254 nm, 0.6 mL/min). t_R (minor) = 25.1 min, t_R (major) = 39.0 min (er 90:10).

(S)-9-(tert-Butyl)-7-methyl-4-phenyl-1-oxa-7,8-diazaspiro[4.4]nona-3,8-diene-2,6-dione (3h)

Following the general procedure and after column chromatography using hexane/ethyl acetate 10:1 as eluent, 3h was isolated as pale yellow oil (13.3 mg, 50% yield). [α]_D²⁵ = −14.3 (c 0.3, CHCl₃, er 88:12). ¹H NMR (500 MHz, CDCl₃): δ 7.50–7.40 (m, 3H), 7.33 (d, J = 9.7 Hz, 2H), 6.63 (s, 1H), 3.43 (s, 3H), 1.12 (s, 9H). ¹³C {¹H} NMR (126 MHz, CDCl₃): δ 170.5, 167.7, 163.9, 162.0, 132.2, 129.6, 128.7, 126.5, 116.0, 87.0, 36.6, 32.2, 28.6. IR v_max/cm^–1 3120, 2972, 2936, 2878, 1803, 1777, 1727, 1611, 1500, 1449, 1399, 1283, 1204, 1164, 1121, 1045. HRMS (ESI-TOF) m/z: calcd for C₁₇H₁₈N₂NaO₃ [M + Na]⁺, 321.1210; found, 321.1216. HPLC (Chiralpak AD-H, n-hexane/2-propanol 90:10, λ = 254 nm, 0.7 mL/min). t_R (minor) = 17.2 min, t_R (major) = 20.3 min (er 88:12).

(S)-7,9-Diphenyl-4-(p-tolyl)-1-oxa-7,8-diazaspiro[4.4]nona-3,8-diene-2,6-dione (3ab)

Following the general procedure and after column chromatography using hexane/ethyl acetate 10:1 as eluent, 3ab was isolated as pale yellow oil (11.9 mg, 51% yield). [α]_D²⁵ = −134.9 (c 0.2, CHCl₃, er 96:4). ¹H NMR (500 MHz, CDCl₃): δ 7.97 (d, J = 7.1 Hz, 2H), 7.72 (d, J = 8.1 Hz, 2H), 7.50–7.43 (m, 4H), 7.40–7.36 (m, 2H), 7.32–7.29 (m, 2H), 7.15 (d, J = 7.8 Hz, 2H), 6.73 (s, 1H), 2.30 (s, 3H). ¹³C {¹H} NMR (126 MHz, CDCl₃): δ 170.5, 165.5, 162.2, 153.5, 143.3, 137.3, 131.7, 130.5, 129.2, 129.1, 129.0, 126.6, 126.3, 126.2, 125.3, 119.1, 115.6, 87.2, 21.5. IR v_max/cm^–1 3065, 2953, 2921, 2856, 1803, 1774, 1737, 1593, 1492, 1384, 1319, 1182, 1142, 1063. HRMS (ESI-TOF) m/z: calcd forC₂₅H₁₈N₂NaO₃ [M + Na]⁺, 417.1210; found, 417.1224. HPLC (Chiralcel OD, n-hexane/2-propanol 95:5, λ = 254 nm, 0.8 mL/min). t_R (major) = 25.7 min, t_R (minor) = 30.5 min (er 96:4).

(S)-4-(4-Methoxyphenyl)-7,9-diphenyl-1-oxa-7,8-diazaspiro[4.4]nona-3,8-diene-2,6-dione (3ac)

Following the general procedure and after column chromatography using hexane/ethyl acetate 10:1 as eluent, 3ac was isolated as pale pink solid (8.1 mg, 33% yield). mp 67–69 °C (from hexane). [α]_D²⁵ = −120.9 (c 0.2, CHCl₃, er 86:14). ¹H NMR (500 MHz, CDCl₃): δ 7.98 (d, J = 8.8 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.51–7.43 (m, 3H), 7.40–7.36 (m, 4H), 7.30 (t, J = 7.5 Hz, 1H), 6.84 (d, J = 8.0 Hz, 2H), 6.65 (s, 1H), 3.76 (s, 3H). ¹³C {¹H} NMR (126 MHz, CDCl₃): δ 170.6, 165.6, 162.8, 161.6, 153.8, 137.3, 131.7, 129.2, 129.0, 128.6, 126.1, 120.6, 119.1, 115.2, 114.0, 87.0, 55.5. IR v_max/cm^–1 3105, 3062, 2961, 2918, 2853, 1803, 1781, 1727, 1597, 1496, 1316, 1240, 1063, 901. HRMS (ESI-TOF) m/z: calcd forC₂₅H₁₈N₂NaO₃ [M + Na]⁺, 433.1159; found, 433.1169. HPLC (Lux i-Cellulose-5, n-hexane/2-propanol 70:30, λ = 254 nm, 0.6 mL/min). t_R (minor) = 47.9 min, t_R (major) = 81.0 min (er 86:14).

(S)-4-(2-Methoxyphenyl)-7,9-diphenyl-1-oxa-7,8-diazaspiro[4.4]nona-3,8-diene-2,6-dione (3ad)

Following the general procedure and after column chromatography using hexane/ethyl acetate 10:1 as eluent, 3ad was isolated as white solid (5.6 mg, 23% yield). mp 38–40 °C (from hexane). ¹H NMR (500 MHz, CDCl₃): δ 8.01 (d, J = 7.7 Hz, 2H), 7.68 (d, J = 9.7 Hz, 2H), 7.48 (t, J = 7.6 Hz, 1H), 7.42–7.32 (m, 5H), 7.28 (t, J = 8.5 Hz, 1H), 7.03 (s, 1H), 6.89 (d, J = 8.1 Hz, 2H), 3.71 (s, 3H). ¹³C {¹H} NMR (126 MHz, CDCl₃): δ 170.8, 165.8, 158.3, 157.9, 153.2, 137.6, 133.5, 131.3, 129.2, 129.0, 128.5, 126.2, 125.9, 121.4, 119.7, 118.8, 117.6, 111.8, 83.0, 55.1. IR v_max/cm^–1 3077, 2956, 2923, 1861, 1806, 1780, 1725, 1600, 1491, 1465, 1384, 1263, 1139, 1025, 941, 754. HRMS (ESI-TOF) m/z: calcd forC₂₅H₁₈N₂NaO₃ [M + Na]⁺, 433.1159; found, 433.1163. HPLC (Lux i-Cellulose-5, n-hexane/2-propanol 70:30, λ = 254 nm, 0.6 mL/min). t_R = 57.8 min, 63.9 min (er 53:47).

(S)-4-(4-Fluorophenyl)-7,9-diphenyl-1-oxa-7,8-diazaspiro[4.4]nona-3,8-diene-2,6-dione (3ae)

Following the general procedure and after column chromatography using hexane/ethyl acetate 10:1 as eluent, 3ae was isolated as yellow oil (11.9 mg, 51% yield). [α]_D²⁵ = −13.8 (c 0.1, CHCl₃, er 96:4). ¹H NMR (500 MHz, CDCl₃): δ 7.95 (d, J = 9.8 Hz, 2H), 7.71 (d, J = 7.2 Hz, 2H), 7.50–7.45 (m, 3H), 7.45–7.38 (m, 4H), 7.31 (t, J = 7.4 Hz, 1H), 7.05 (t, J = 8.4 Hz, 2H), 6.71 (s, 1H). ¹³C {¹H} NMR (126 MHz, CDCl₃): δ 170.0, 165.5 (d, J = 177.2 Hz), 165.2, 163.8, 153.2, 137.1, 131.8, 129.3, 129.2, 129.0, 128.9, 128.8, 126.5, 126.2, 124.4, 119.1, 117.2, 117.1, 116.7, 87.2. ¹⁹F NMR (470 MHz, CDCl₃): δ −106.3. IR v_max/cm^–1 3069, 2957, 2925, 2853, 1777, 1734, 1604, 1492, 1445, 1387, 1319, 1294, 1233, 1164, 1142. HRMS (ESI-TOF) m/z: calcd forC₂₄H₁₆FN₂O₃ [M + H]⁺, 399.1139; found, 399.1147. HPLC (Lux i-Cellulose-5, n-hexane/2-propanol 80:20, λ = 230 nm, 0.6 mL/min). t_R (minor) = 36.7 min, t_R (major) = 56.2 min (er 96:4).

(S)-4-(4-Chlorophenyl)-7,9-diphenyl-1-oxa-7,8-diazaspiro[4.4]nona-3,8-diene-2,6-dione (3af)

Following the general procedure and after column chromatography using hexane/ethyl acetate 10:1 as eluent, 3af was isolated as white solid (17 mg, 69% yield). mp 52–54 °C (from hexane). [α]_D²⁵ = −157.7 (c 0.1, CHCl₃, er 93:7). ¹H NMR (500 MHz, CDCl₃): δ 7.95 (d, J = 9.6 Hz, 2H), 7.70 (d, J = 9.7 Hz, 2H), 7.50–7.45 (m, 3H), 7.40 (t, J = 6.6 Hz, 1H), 7.35–7.29 (m, 5H), 6.75 (s, 1H). ¹³C {¹H} NMR (126 MHz, CDCl₃): δ 169.9, 165.1, 161.0, 153.1, 138.7, 137.1, 131.9, 130.1, 129.3, 129.2, 128.8, 127.9, 126.6, 126.5, 126.2, 119.1, 117.3, 87.1. IR v_max/cm^–1 2968, 2925, 2860, 1806, 1774, 1734, 1591, 1489, 1388, 1323, 1301, 1178, 1142. HRMS (ESI-TOF) m/z: calcd for C₂₄H₁₅ClN₂NaO₃ [M + Na]⁺, 437.0663; found, 437.0674. HPLC (Chiralcel OD, n-hexane/2-propanol 95:5, λ = 254 nm, 0.8 mL/min). t_R (minor) = 26.0 min, t_R (major) = 32.9 min (er 93:7).

(S)-4-(4-Bromophenyl)-7,9-diphenyl-1-oxa-7,8-diazaspiro[4.4]nona-3,8-diene-2,6-dione (3ag)

Following the general procedure and after column chromatography using hexane/ethyl acetate 10:1 as eluent, 3ag was isolated as yellow oil (23.9 mg, 88% yield). [α]_D²⁵ = −52.7 (c 0.5, CHCl₃, er 92:8). ¹H NMR (500 MHz, CDCl₃): δ 7.95 (d, J = 7.9 Hz, 2H), 7.70 (d, J = 9.0 Hz, 2H), 7.51–7.42 (m, 5H), 7.40–7.38 (m, 2H), 7.31 (t, J = 7.5 Hz, 1H), 7.24–7.23 (m, 1H), 6.76 (s, 1H). ¹³C {¹H} NMR (126 MHz, CDCl₃): δ 169.9, 165.1, 161.1, 153.0, 137.1, 133.1, 131.9, 129.3, 129.2, 128.8, 128.0, 127.2, 127.0, 126.5, 126.1, 119.1, 117.3, 87.1. IR v_max/cm^–1 3063, 2960, 2923, 2857, 1806, 1777, 1733, 1593, 1494, 1387, 1299, 1178, 1141, 1071, 1009. HRMS (ESI-TOF) m/z: calcd forC₂₄H₁₅BrN₂NaO₃ [M + Na]⁺, 481.0158; found, 481.0169. HPLC (Chiralcel OD, n-hexane/2-propanol 85:15, λ = 254 nm, 0.8 mL/min). t_R (minor) = 23.8 min, t_R (major) = 32.4 min (er 92:8).

(S)-4-(4-Nitrophenyl)-7,9-diphenyl-1-oxa-7,8-diazaspiro[4.4]nona-3,8-diene-2,6-dione (3ah)

Following the general procedure and after column chromatography using hexane/ethyl acetate 10:1 as eluent, 3ah was isolated as white solid (10.6 mg, 42% yield). mp 48–50 °C (from hexane). [α]_D²⁵ = −30.7 (c 0.2, CHCl₃, er 92:8). ¹H NMR (500 MHz, CDCl₃): δ 8.02 (d, J = 8.8 Hz, 2H), 7.94 (d, J = 9.7 Hz, 2H), 7.71 (d, J = 9.5 Hz, 2H), 7.53 (d, J = 8.3 Hz, 2H), 7.49 (t, J = 7.3 Hz, 3H), 7.42 (t, J = 7.7 Hz, 2H), 7.32 (d, J = 7.4 Hz, 1H), 6.89 (s, 1H). ¹³C {¹H} NMR (126 MHz, CDCl₃): δ 169.1, 164.7, 159.8, 152.4, 149.5, 136.9, 133.8, 132.1, 129.4, 129.3, 128.6, 127.8, 126.7, 126.1, 124.8, 120.4, 119.0, 87.3. IR v_max/cm^–1 3109, 1815, 1779, 1717, 1598, 1525, 1489, 1348, 1323, 1178, 1138, 1058, 909. HRMS (ESI-TOF) m/z: calcd for C₂₄H₁₅N₃NaO₅ [M + Na]⁺, 448.0904; found, 448.0915. HPLC (Chiralcel OD, n-hexane/2-propanol 80:20, λ = 254 nm, 0.6 mL/min). t_R (minor) = 33.6 min, t_R (major) = 50.4 min (er 92:8).

(S)-4-(3-Nitrophenyl)-7,9-diphenyl-1-oxa-7,8-diazaspiro[4.4]nona-3,8-diene-2,6-dione (3ai)

Following the general procedure and after column chromatography using hexane/ethyl acetate 10:1 as eluent, 3ai was isolated as white solid (13.4 mg, 43% yield). mp 184–186 °C (from hexane/acetate). [α]_D²⁵ = – 35.8 (c 0.2, CHCl₃, er 95:5). ¹H NMR (500 MHz, CDCl₃): δ 8.29–8.27 (m, 2H), 7.75–7.73 (m, 2H), 7.70–7.67 (m, 1H), 7.61–7.58 (m, 1H), 7.58–7.52 (m, 4H), 7.45–7.42 (m, 3H), 7.31 (tt, J = 7.1, 1.2 Hz, 1H), 6.90 (s, 1H). ¹³C {¹H} NMR (126 MHz, CDCl₃): δ 169.2, 164.8, 159.6, 152.6, 148.8, 136.9, 132.1, 131.0, 130.6, 129.6, 129.4, 129.1, 128.7, 128.7, 126.8, 126.5, 121.7, 119.5, 119.4, 119.2, 87.2. IR v_max/cm^–1 2971, 2923, 2846, 1776, 1732, 1597, 1538, 1487, 1381, 1381, 1351, 1326, 1139, 1069, 956. HRMS (ESI-TOF) m/z: calcd for C₂₄H₁₅N₃NaO₅ [M + Na]⁺, 448.0904; found, 448.0899. HPLC (Chiralcel OD, n-hexane/2-propanol 75:25, λ = 254 nm, 1 mL/min). t_R (major) = 17.0 min, t_R (minor) = 20.3 min (er 95:5).

(S)-4-(Furan-2-yl)-7,9-diphenyl-1-oxa-7,8-diazaspiro[4.4]nona-3,8-diene-2,6-dione (3aj)

Following the general procedure and after column chromatography using hexane/ethyl acetate 10:1 as eluent, 3aj was isolated as white solid (14.8 mg, 68% yield). mp 155–157 °C (from hexane). [α]_D²⁵ = −84.5 (c 0.2, CHCl₃, er 97:3). ¹H NMR (500 MHz, CDCl₃): δ 7.98 (d, J = 8.5 Hz, 2H), 7.71 (d, J = 7.9 Hz, 2H), 7.53–7.44 (m, 4H), 7.42–7.38 (m, 2H), 7.31 (t, J = 6.5 Hz, 1H), 6.70 (s, 1H), 6.60 (s, 1H), 6.43 (s, 1H). ¹³C {¹H} NMR (126 MHz, CDCl₃): δ 170.5, 165.4, 153.4, 150.2, 147.1, 143.6, 131.7, 131.2, 129.2, 129.1, 128.8, 126.3, 126.2, 119.1, 115.1, 113.3, 112.0, 85.6. IR v_max/cm^–1 3148, 3115, 3075, 2957, 2932, 2862, 1797, 1775, 1735, 1628, 1592, 1500, 1383, 1316, 1170, 1070, 1026, 905. HRMS (ESI-TOF) m/z: calcd for C₂₂H₁₅N₂O₄ [M + Na]⁺, 371.1026; found, 371.1030. HPLC (Chiralcel IA, n-hexane/2-propanol 90:10, λ = 254 nm, 0.5 mL/min). t_R (major) = 42.9 min, t_R (minor) = 147.7 min (er 97:3).

(S)-7,9-Diphenyl-4-(thiophen-2-yl)-1-oxa-7,8-diazaspiro[4.4]nona-3,8-diene-2,6-dione (3ak)

Following the general procedure and after column chromatography using hexane/ethyl acetate 10:1 as eluent, 3ak was isolated as white solid (15.0 mg, 66% yield). mp 130–132 °C (from hexane). [α]_D²⁵ = −150.7 (c 0.3, CHCl₃, er 92:8). ¹H NMR (500 MHz, CDCl₃): δ 7.98 (d, J = 9.3 Hz, 2H), 7.74 (d, J = 8.8 Hz, 2H), 7.52–7.45 (m, 4H), 7.24–7.38 (m, 2H), 7.31 (t, J = 7.3 Hz, 1H), 7.23 (d, J = 3.8 Hz, 1H), 7.01 (dd, J = 4.7, 3.9 Hz, 1H), 6.57 (s, 1H). ¹³C {¹H} NMR (126 MHz, CDCl₃): δ 170.2, 165.3, 155.2, 153.6, 137.2, 132.0, 131.8, 130.6, 129.4, 129.3, 129.2, 129.1, 128.8, 126.4, 126.2, 119.1, 113.6, 86.7. IR v_max/cm^–1 3115, 2965, 2921, 2851, 1801, 1768, 1742, 1592, 1482, 1386, 1173, 1148, 1085, 1067, 946. HRMS (ESI-TOF) m/z: calcd for C₂₂H₁₄N₂NaO₃S [M + Na]⁺, 409.0617; found, 409.0624. HPLC (Chiralcel OD, n-hexane/2-propanol 95:5, λ = 254 nm, 0.5 mL/min). t_R (major) = 56.3 min, t_R (minor) = 63.2 min (er 92:8).

(S)-7,9-Diphenyl-4-styryl-1-oxa-7,8-diazaspiro[4.4]nona-3,8-diene-2,6-dione (3al)

Following the general procedure and after column chromatography using hexane/ethyl acetate 10:1 as eluent, 3al was isolated as pale yellow oil (8.5 mg, 18% yield). [α]_D²⁵ = −75.7 (c 0.2, CHCl₃, er 78:22). ¹H NMR (500 MHz, CDCl₃): δ 8.00 (d, J = 9.8 Hz, 2H), 7.73 (d, J = 9.7 Hz, 2H), 7.52–7.46 (m, 3H), 7.42 (t, J = 8.3 Hz, 2H), 7.33–7.30 (m, 6H), 6.94 (d, J = 16.5 Hz, 1H), 6.77 (dd, J = 16.5, 0.7 Hz, 1H), 6.48 (s, 1H). ¹³C {¹H} NMR (126 MHz, CDCl₃): δ 170.7, 165.5, 159.5, 153.6, 140.0, 137.2, 134.3, 131.8, 130.6, 129.3, 129.2, 129.0, 128.8, 127.8, 126.4, 126.2, 119.2, 116.3, 115.8, 87.0. IR v_max/cm^–1 2924, 2854, 1804, 1774, 1727, 1621, 1588, 1494, 1315, 1293, 1169, 1143, 1070, 899. HRMS (ESI-TOF) m/z: calcd for C₂₆H₁₈N₂NaO₃ [M + H]⁺, 429.1210; found, 429.1219. HPLC (Chiralcel OD, n-hexane/2-propanol 90:10, λ = 220 nm, 0.5 mL/min). t_R (major) = 36.3 min, t_R (minor) = 28.7 min (er 78:22).

(S)-9-Ethyl-4-(4-fluorophenyl)-7-phenyl-1-oxa-7,8-diazaspiro[4.4]nona-3,8-diene-2,6-dione (3ce)

Following the general procedure and after column chromatography using hexane/ethyl acetate 10:1 as eluent, 3ce was isolated as yellow oil (9.2 mg, 35% yield). [α]_D²⁵ = −45.7 (c 0.2, CHCl₃, er 92:8). ¹H NMR (500 MHz, CDCl₃): δ 7.90 (d, J = 8.8 Hz, 2H), 7.46 (t, J = 7.7 Hz, 2H), 7.39–7.36 (m, 2H), 7.28 (t, J = 7.3 Hz, 1H), 7.11 (t, J = 8.2 Hz, 2H), 6.61 (s, 1H), 2.54–2.44 (m, 1H), 2.31–2.23 (m, 1H), 1.22 (t, J = 7.5 Hz, 3H). ¹³C {¹H} NMR (126 MHz, CDCl₃): δ 170.0, 166.2, 164.5 (d, J = 177.2 Hz), 160.2, 159.1, 137.2, 129.2, 128.9, 128.8, 126.2, 124.4, 118.9, 117.4, 117.1, 116.5, 87.5, 21.3, 9.3. ¹⁹F NMR (470 MHz, CDCl₃): δ −106.4. IR v_max/cm^–1 2986, 2913, 2855, 1808, 1783, 1728, 1598, 1500, 1457, 1391, 1348, 1239, 1181, 1163, 1120, 1051. HRMS (ESI-TOF) m/z: calcd for C₂₀H₁₅FN₂NaO₃ [M + Na]⁺, 373.0959; found, 373.0961. HPLC (Chiralcel OD, n-hexane/2-propanol 95:5, λ = 254 nm, 1 mL/min). t_R (minor) = 21.3 min, t_R (major) = 24.6 min (er 92:8).

(S)-9-Isopropyl-7-phenyl-4-(p-tolyl)-1-oxa-7,8-diazaspiro[4.4]nona-3,8-diene-2,6-dione (3db)

Following the general procedure and after column chromatography using hexane/ethyl acetate 10:1 as eluent, 3db was isolated as yellow oil (18.8 mg, 86% yield). [α]_D²⁵ = −93.0 (c 0.4, CHCl₃, er 93:7). ¹H NMR (500 MHz, CDCl₃): δ 7.90 (d, J = 9.8 Hz, 2H), 7.46 (t, J = 7.4 Hz, 2H), 7.29–7.25 (m, 3H), 7.21–7.19 (m, 2H), 6.63 (s, 1H), 2.70–2.61 (m, 1H), 2.35 (s, 3H), 1.26 (d, J = 6.9 Hz, 3H), 1.10 (d, J = 7.0 Hz, 3H). ¹³C {¹H} NMR (126 MHz, CDCl₃): δ 170.5, 165.3, 163.5, 160.8, 143.3, 137.4, 130.5, 129.1, 126.5, 126.0, 125.5, 118.9, 115.3, 87.7, 29.1, 21.5, 20.2. IR v_max/cm^–1 2975, 2874, 1803, 1774, 1727, 1597, 1500, 1380, 1326, 1182, 1128, 1049, 904. HRMS (ESI-TOF) m/z: calcd for C₂₂H₂₀N₂NaO₃ [M + Na]⁺, 383.1366; found, 383.1378. HPLC (Lux i-Cellulose-5, n-hexane/2-propanol 80:20, λ = 210 nm, 0.8 mL/min). t_R (minor) = 28.1 min, t_R (major) = 38.9 min (er 93:7).

(S)-4-(4-chlorophenyl)-9-isopropyl-7-phenyl-1-oxa-7,8-diazaspiro[4.4]nona-3,8-diene-2,6-dione (3df)

Following the general procedure and after column chromatography using hexane/ethyl acetate 10:1 as eluent, 3df was isolated as yellow oil (16.6 mg, 71% yield). [α]_D²⁵ = −65.1 (c 0.3, CHCl₃, er 91:9). ¹H NMR (500 MHz, CDCl₃): δ 7.89 (d, J = 9.5 Hz, 2H), 7.46 (t, J = 7.6 Hz, 2H), 7.40–7.38 (m, 2H), 7.30–7.28 (m, 3H), 6.67 (s, 1H), 2.70–2.60 (m, 1H), 1.26 (d, J = 6.9 Hz, 3H), 1.11 (d, J = 6.9 Hz, 3H). ¹³C {¹H} NMR (126 MHz, CDCl₃): δ 170.0, 165.3, 163.1, 159.4, 138.8, 137.2, 130.2, 129.2, 127.8, 126.7, 126.2, 118.9, 116.9, 87.7, 29.2, 20.2. IR v_max/cm^–1 3108, 2979, 2939, 2880, 1808, 1772, 1731, 1588, 1489, 1375, 1342, 1181, 1093, 927. HRMS (ESI-TOF) m/z: calcd for C₂₁H₁₇ClN₂NaO₃ [M + Na]⁺, 403.0820; found, 403.0821. HPLC (Lux i-Cellulose-5, n-hexane/2-propanol 80:20, λ = 210 nm, 0.6 mL/min). t_R (minor) = 31.9 min, t_R (major) = 47.8 min (er 91:9).

Procedure for Scale-Up Synthesis of Spiropyrazolone-butenolide 3ag

In a-50 mL heat gun-dried flask equipped with a magnetic stirring bar, the precatalyst C2 (42 mg, 0.1 mmol, 0.1 equiv) and the pyrazolin-4,5-dione 1a (254 mg, 1 mmol) were weighed. Then, β-bromoenal 2g (435 mg, 1.5 mmol, 1.5 equiv) was added under a N₂ atmosphere. Dry chloroform (15 mL) was added before the mixture was stirred. Several minutes later, the base (0.24 mL, 1.5 mmol, 1.5 equiv) was introduced to the flask. After 16 h, the solvent was straight removed under the reduced pressure and the residue was subjected to column chromatography over a silica gel using hexane/ethyl acetate 10:1 as eluent to give 3ag, as a yellow oil (367 mg, 80% yield).

Catalytic Hydrogenation of Spiropyrazolone-butenolide 3a

To a solution of spirocyclic butenolide 3a (34.8 mg, 0.091 mmol) in ethyl acetate (2 mL), Pd/C (10 wt %) was added. The mixture was stirred under hydrogen atmospheric pressure for 20 h. After the removal of the palladium on carbon, the solvent was removed and the crude product was purified by a column chromatography (hexane/ethyl acetate 10:1) affording compound 4 as a single diastereomer (15.7 mg, 45% yield).

(4R,5S)-4,7,9-Triphenyl-1-oxa-7,8-diazaspiro[4.4]non-8-ene-2,6-dione (4)

Analytical data were consistent with the reported data.¹²¹H NMR (500 MHz, CDCl₃): δ 7.98–8.00 (m, 2H), 7.54–7.59 (m, 3H), 7.43–7.45 (m, 2H), 7.22–7.31 (m, 5H), 7.14–7.18 (m, 1H), 7.11–7.13 (m, 2H), 4.15 (dd, J = 13.8, 8.2 Hz, 1H), 3.82 (dd, J = 14.0, 13.8 Hz, 1H), 2.93 (dd, J = 17.1, 8.2 Hz, 1H). ¹³C {¹H} NMR (126 MHz, CDCl₃): δ 173.5, 168.7, 153.2, 136.5, 131.5, 130.5, 129.4, 129.1, 128.8, 128.7, 128.6, 127.6, 126.8, 126.1, 119.5, 87.8, 49.0, 30.3. HPLC (Lux Amylose-1, n-hexane/2-propanol 70:30, λ = 254 nm, 0.8 mL/min): t_R (minor) = 6.4 min, t_R (major) = 7.8 min (er 94:6).

Transformation of Spiropyrazolone-butenolide 3ag

To a solution of spirocyclic butenolide 3ag (38.3 mg, 0.083 mmol), phenylboronic acid (15.3 mg, 0.125 mmol), and K₃PO₄ (35.3 mg, 0.166 mmol) in THF/H₂O 5:1 (1.2 mL) under a N₂ atmosphere, PdCl₂(PPh₃)₂ (10 mol %) was added. After refluxing for 8 h, the solvent was removed under the reduced pressure. The crude mixture was purified by a column chromatography (hexane/ethyl acetate 10:1) affording 5 as a white solid (36.8 mg, 96% yield).

(S)-4-([1,1′-Biphenyl]-4-yl)-7,9-diphenyl-1-oxa-7,8-diazaspiro[4.4]nona-3,8-diene-2,6-dione (5)

mp 66–68 °C (from hexane/acetate). [α]_D²⁵ = −116.0 (c 0.4, CHCl₃, er 95:5). ¹H NMR (500 MHz, CDCl₃): δ 7.99 (d, J = 8.8 Hz, 2H), 7.75 (d, J = 8.1 Hz, 2H), 7.58 (d, J = 8.3 Hz, 2H), 7.52–7.48 (m, 5H), 7.47–7.46 (m, 2H), 7.44–7.37 (m, 5H), 7.31 (t, J = 8.0 Hz, 1H), 6.80 (s, 1H). ¹³C {¹H} NMR (126 MHz, CDCl₃): δ 170.3, 165.4, 161.7, 153.5, 145.2, 139.1, 137.3, 133.1, 131.8, 129.2, 129.0, 128.4, 128.3, 127.0, 126.8, 126.4, 126.3, 119.2, 116.3, 81.2. IR v_max/cm^–1 3073, 3030, 2927, 2851, 1804, 1774, 1723, 1599, 1559, 1442, 1384, 1180, 1143, 1070, 1005. HRMS (ESI-TOF) m/z: calcd for C₃₀H₂₁N₂O₃ [M + H]⁺, 457.1547; found, 457.1528. HPLC (Lux i-Cellulose 5, n-hexane/2-propanol 85:15, λ = 254 nm, 0.8 mL/min). t_R (minor) = 56.4 min, t_R (major) = 85.4 min (er 95:5).

Procedure for Spirooxindole-butenolide 7

In a 5-mL heat gun-dried flask equipped with a magnetic stirring bar, the precatalyst C2 (6 μmol, 0.1 equiv) and N-benzyl isatin 6 (0.06 mmol) were weighed. Then, β-bromoenal 2a (0.09 mmol, 1.5 equiv) was added under a N₂ atmosphere. Dry chloroform (1 mL) was added before the mixture was stirred. Several minutes later, DBU (0.09 mmol, 1.5 equiv) was introduced to the flask. After 16 h, the solvent was straight removed under the reduced pressure and the residue was purified by a column chromatography (hexane/ethyl acetate, 10:1) affording compound 7 as a white solid (16.6 mg, 75%).^15b

(S)-1′-Benzyl-3-phenyl-5H-spiro[furan-2,3′-indoline]-2′,5-dione (7)

[α]_D²⁵ = +15.0 (c 0.4, CHCl₃, er 93:7). ¹H NMR (500 MHz, CDCl₃): δ 7.37–7.33 (m, 2H), 7.30–7.28 (m, 3H), 7.24–7.22 (m, 2H), 7.20–7.17 (m, 3H), 7-09-7.04 (m, 3H), 6.88 (d, J = 7.9 Hz, 1H), 6.67 (s, 1H), 5.13 (d, J = 15.4 Hz, 1H), 4.76 (d, J = 15.5 Hz, 1H). ¹³C {¹H} NMR (126 MHz, CDCl₃): δ 171.3, 170.0, 163.0, 143.5, 134.7, 131.8, 131.4, 129.1, 129.0, 128.8, 128.1, 127.6, 127.2, 125.1, 124.0, 123.8, 117.0, 110.4, 86.5, 44.6. HPLC (Chiralcel OD, n-hexane/2-propanol 85:15, λ = 254 nm, 0.4 mL/min). t_R (major) = 77.7 min, t_R (minor) = 87.8 min (er 93:7).

Data Availability Statement

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

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.3c00188.

• Copies of ¹H, ¹³C, ¹⁹F NMR spectra, and HPLC profiles of all new compounds free of charge are available (PDF)

The authors declare no competing financial interest.