Diastereoselective Synthesis of Spirocyclopropanes under Mild Conditions via Formal [2 + 1] Cycloadditions Using 2,3-Dioxo-4-benzylidene-pyrrolidines.

A highly diastereoselective cyclopropanation of cyclic enones with sulfur ylides was developed under catalyst-free conditions, producing multifunctional spirocyclopropanes in generally excellent yields (up to 99% yield and >99:1 d.r.). The asymmetric version of this method was realized by using an easily available chiral sulfur ylide, affording products with moderate to good stereoselectivity.

1. Introduction

Spirocycles are significant structures found in various natural products and many potent synthetic drug candidates [1,2,3]. Due to their important physiological functions, the synthesis of spirocycles has become an attractive target in organic chemistry, especially in recent years [4,5,6]. Among various spirocycles, spirocyclopropanes have shown high potential pharmaceutical activities (Figure 1). For example, the illudins [7,8], sesquiterpene secondary metabolites of basidiomycetes, have demonstrated activity against cancer; acylfulvene and irofulven [9,10], which are derived from illudin via a semisynthetic approach, also show anti-tumor bioactivity. Ptaquiloside [11], a toxic derivative from bracken, is recently reported to depress tumor-infiltration in HPV-16 transgenic mice. The natural products CC-1065, duocarmycin A and AS [12,13] were identified as strong anticancer drug candidates as well. Recently, many spirocyclopropanes possessing a pyrrolidin-2-one moiety have been developed into useful drug candidates. For instance, ledipasvir [14,15], a drug developed by Gilead Sciences, is an effective inhibitor of the hepatitis C virus. Other compounds reported by Berman et al. [16] also exhibited biological activities; for example, the OPH carboxylic acid can affect the function of disintegrin and metalloproteinase domain-containing proteins.

Figure 1

Selected products containing spirocyclopropanane possess biological activities.

Meanwhile, cyclopropanes can also be applied as versatile units for the construction of other frameworks due to their unique combination of reactivity and structural properties [17,18,19,20]. For instance, the ring-enlargement reactions of cyclopropanes with nucleophiles, such as amines, alcohols, and carboxylic acids, are efficient pathways to various heterocycles [21,22,23,24,25,26,27]. Consequently, numerous efforts have been devoted to the formation of three-membered carbocyclic rings during the last few decades [28,29,30,31,32,33,34,35,36]. The reactions of carbenoids with alkenes such as the Simmons–Smith cyclo-propanation involving organozinc carbenes [37,38,39,40], or the addition of carbenes, generated from diazo compounds in the presence of transition metals, to double bonds [41,42,43,44] are the most significant and useful classical methods for the construction of cyclopropanes. In addition, base-promoted cyclopropanations between α-halogenated compounds and electron-deficient olefins [45,46,47] are also reliable approaches to cyclopropanes. However, these methods often require the use of metals or harsh conditions.

The cyclopropanation of electron-deficient olefins and ylides, including sulfonium [48,49,50,51,52,53,54,55], telluronium [56,57], arsonium [58,59,60,61], and ammonium ylides [62,63,64,65], represents one of the most efficient and straightforward strategies to construct cyclopropane-containing frameworks. Among them, sulfonium ylides, as well-developed active units, can also react with cyclic electron-withdrawing alkenes to access synthetically challenging spirocyclopropanes [51,52,53,54,55]. A great number of studies have been directed to the cyclopropanation with sulfonium ylides; however, harsh conditions such as strong base were usually required, which has limited the structural diversity of cyclopropane scaffolds as well as restricted functional group tolerance. Therefore, the demand on exploring cyclopropanation chemistry under mild conditions and further expanding the structural generality is still highly desirable. Recently, we developed some convenient synthetic strategies directly toward heterocyclic compounds bearing the pyrrolidin-2-one moiety by using 2,3-dioxobenzylidenepyrrolidine, a highly reactive cyclic enone [66,67]. Considering the potential capacity of this enone to serve as an electron-deficient alkene, we report herein an efficient catalyst-free cyclopropanation with 2,3-dioxopyrrolidine and sulfur ylides which leads to the diastereoselective synthesis of spirocyclopropanes.

2. Results

In our initial research, the reaction of readily available cyclic enone 1a and sulfur ylide 2a was carried out in dichloromethane (DCM) at room temperature (Table 1). We were pleased to find that, under these conditions, 1a underwent the desired cyclopropanation with sulfur ylide 2a giving spirocyclopropane 3a in good yield (86%) and with promising diastereoselectivity (d.r. = 93:7, Entry 1). Encouraged by this result, we proceeded to optimize the reaction by evaluating the effect of solvents. As outlined in Table 1, a series of solvents were examined (Entries 2–9) and 1,4-dioxane provided the best yield and diastereoselectivity (Entry 5). Meanwhile, since the reactions worked quite well at room temperature, a screening study of temperature effects was avoided. Therefore, 1,4-dioxane as the solvent at room temperature were determined as the optimal reaction conditions.

Table 1

Screening studies of the cyclopropanation reaction a.

Entry	Solvent	d.r. b	Yield (%) c
1	DCM	93:7	86
2	CHCl3	96:4	94
3	DCE	94:6	90
4	THF	97:3	79
5	1,4-dioxane	98:2	92
6	MeOH	53:47	76
7	EtOH	68:32	74
8	MeCN	84:16	92
9	Toluene	87:13	88

a Reaction conditions: 1a (0.1 mmol), 2a (0.1 mmol), solvent (2 mL), r.t. DCE = 1,2-dichloroethane; Bn = benzyl; Bz = benzoyl; b Determined by 1H-NMR spectroscopy of the crude reaction mixture; c Isolated yields.

After the optimal conditions of the reaction were established, we then investigated the generality of this reaction with a variety of 2,3-dioxopyrrolidine derivatives 1 as substrates (Table 2). By using different cyclic enones 1 bearing various kinds of substituents on phenyl ring, the reactions can finished rapidly in 2 h to afford the corresponding spirocyclopropane 3a–3n in good to excellent yields with satisfactory diastereoselectivity (Entries 1–14). The reactions were also suitable for enone substrates with polycyclic or heteroaromatics, such as 1-naphthyl and thienyl rings (Entries 15 and 16) (For details, please see Supplementary File Part 2). Furthermore, the practicality of this methodology was illustrated by a scaled up reaction: 2.5 mmol of cyclic enone 1a was treated with 2.5 mmol of sulfur ylide 2a under the optimal conditions in 1,4-dioxane. The desired product 3a was obtained in excellent yield with outstanding diastereoselectivity (96% yield and 97:3 d.r., see Scheme 1).

Table 2

Substrates scope of cyclopropanation of cyclic enones 1 with sulfur ylides 2 a.

Entry	R1	R2	R3	Product	d.r. b	Yield (%) c
1	Ph	Bn	Ph	3a	98:2	92
2	3-MeC6H4	Bn	Ph	3b	92:8	83
3	4-MeC6H4	Bn	Ph	3c	98:2	93
4	2-MeOC6H4	Bn	Ph	3d	92:8	83
5	3-MeOC6H4	Bn	Ph	3e	97:3	91
6	4-MeOC6H4	Bn	Ph	3f	96:4	94
7	4-FC6H4	Bn	Ph	3g	96:4	88
8	2-ClC6H4	Bn	Ph	3h	97:3	98
9	3-ClC6H4	Bn	Ph	3i	97:3	94
10	4-ClC6H4	Bn	Ph	3j	96:4	59
11	3-BrC6H4	Bn	Ph	3k	94:6	84
12	4-BrC6H4	Bn	Ph	3l	96:4	57
13	3,4-(MeO)2C6H3	Bn	Ph	3m	98:2	81
14 d	2,4-Cl2C6H3	Bn	Ph	3n	>99:1	99
15	1-Naphthyl	Bn	Ph	3o	94:6	94
16	2-Thienyl	Bn	Ph	3p	98:2	86
17	Ph	PMB	Ph	3q	98:2	90
18 e	Ph	Bn	OEt	3r	92:8	99
19 e	Ph	Bn	Ot-Bu	3s	90:10	99

a Unless otherwise noted, reaction was carried out with 1 (0.1 mmol), 2 (0.1 mmol) in 2 mL of 1,4-dioxane at r.t. PMB = p-methoxybenzyl; b Determined by 1H-NMR spectroscopy of the crude reaction mixture; c Isolated yields; d The absolute configuration of 3n was determined by X-ray analysis. Other products were assigned by analogy; e Sulfonium bromide salts and 0.1 mmol extra TMG was used instead of 2.

Scheme 1

Scale-up experiment of the cyclopropanation reaction.

On the other hand, the amide functional group commonly exists in many bioactive natural products and medicinal molecules [68,69]. With the intention of preparing amide-containing spirocyclopropanes, benzyl or PMB substituted amidic sulfonium salts 4a and 4b were prepared for further investigation. A simple attempt to cyclopropanate enone 1a with an amidic sulfur ylide of 4a was not successful. However, to our satisfaction, the reactions of cyclic enones 1 and amidic sulfonium salt 4 in the presence of 1,1,3,3-tetramethylguanidine (TMG) in 1,4-dioxone at room temperature proceeded efficiently to access the desired products within 4 h. As shown in Table 3, several cyclic enones bearing different substituents on the phenyl ring smoothly reacted with sulfonium salts 4a or 4b, to obtain an array of amide-containing spirocyclopropanes with good results (Entries 1–6). Moreover, the 1-naphthyl and 2-thienyl cyclic enones showed lower reactivity but also gave the corresponding products in good yields with excellent diastereoselectivity, albeit with longer reaction times (Entries 7–10) (For details, please see Supplementary File Part 3).

Table 3

Further studies of the cyclopropanation of cyclic enone 1 and sulfonium salts 4 a.

Entry	R1	R2	Product	d.r. b	Yield (%) c
1	Ph	Bn	5a	96:4	98
2	Ph	PMB	5b	>99:1	99
3	3-MeC6H4	Bn	5c	97:3	99
4	3-MeC6H4	PMB	5d	94:6	92
5	4-ClC6H4	Bn	5e	91:9	99
6	2-ClC6H4	PMB	5f	94:6	98
7 d	2-Naphthyl	Bn	5g	> 99:1	85
8 d	2-Naphthyl	PMB	5h	> 99:1	90
9 d	2-Thienyl	Bn	5i	> 99:1	83
10 d	2-Thienyl	PMB	5j	> 99:1	81

a Unless otherwise noted, reactions were carried out with 1 (0.1 mmol), 4 (0.1 mmol) and TMG (0.1 mmol) in 2 mL of 1,4-dioxane at rt for 4 h; b Determined by 1H-NMR spectroscopy of the crude reaction mixture; c Isolated yields; d Reaction time was 36 h.

Encouraged by the selective reaction outcomes of amide substrates 4a and 4b, further investigation of asymmetric synthesis of chiral spirocyclopropanes were evaluated by introducing a chirality-inducing group on the amidic sulfonium salt. As outlined in Table 4, the easily available chiral N-phenylethyl sulfur ylide precursor 4c was utilized to react with cyclic enone 1a in 1,4-dioxane at room temperature, which was promoted by a series of organic and inorganic bases. Chiral spirocyclopropane 6a was generally obtained in excellent yields with moderate diastereoselectivity (Entries 1–5), and TMG was demonstrated to be the optimal base. Notably, both the two diastereoisomers which are enantiopure products could be easily obtained by simple flash chromatography.

Table 4

Optimization of reaction condition for the synthesis of chiral spirocyclopropane 6a a.

Entry	Base	X (eq.)	Time	d.r. b	Yield (%) c
1	TMG	1.0	24 h	72:28	99
2	DBU	1.0	24 h	62:38	99
3	KOH	1.5	15 min	65:35	99
4	tBuOK	1.5	10 min	68:32	95
5	K2CO3	2.0	72 h	68:32	92

a Unless otherwise noted, reaction was carried out with 1 (0.1 mmol), 4c (0.1 mmol) and corresponding base in 2 mL of 1,4-dioxane at r.t.; b Determined by 1H-NMR spectroscopy of the crude reaction mixture; c Isolated yields of both diastereoisomers.

Having established the optimized conditions for the asymmetric cyclopropanation, we then investigated the performance of a variety of cyclic enone 1 in the reaction system promoted by TMG. The results are summarized in Table 5.

Table 5

Substrates scope of cyclopropanation of cyclic enones 1 with chiral sulfonium salt 4c a.

Entry	R1	Product	d.r. b	Yield(%) c
1	Ph	6a	72:28	99
2	4-MeC6H4	6b	70:30	97
3	4-MeOC6H4	6c	64:36	91
4	4-FC6H4	6d	81:19	92
5 d	2-ClC6H4	6e	70:30	90
6	4-BrC6H4	6f	62:38	81
7 e	1-Naphthyl	6g	72:28	97
8 e	2-Naphthyl	6h	77:23	99
9 e	2-Thienyl	6i	60:40	90

a Unless otherwise noted, reaction was carried out with 1 (0.1 mmol), 4 (0.1 mmol) and TMG (0.1 mmol) in 2 mL of 1,4-dioxane at r.t. for 24 h; b Determined by 1H-NMR spectroscopy of the crude reaction mixture; c Isolated yields of both diastereoisomers; d The absolute configuration of 6e was determined by X-ray analysis. Other products were assigned by analogy; e Reaction time was 36 h.

Enone substrates with electron-withdrawing or electron-donating groups on the phenyl ring were well tolerated, delivering the desired products 6a–6g in high yields with moderate to good diastereoselectivity (Entries 1–6). Furthermore, enones bearing diverse aryl or heteroaryl groups, such as 1-naphthyl, 2-naphthyl and 2-thienyl were also tolerated to produce 6h–6j with similar results (Entries 7–9) (For details, please see Supplementary File Part 4). Moreover, structural correctness and the absolute configuration of the spirocyclopropanes were confirmed by X-ray diffraction analysis of the representative products 3n and the enantiopure 6e (Figure 2) [70]. (For details, please see Supplementary File Parts 5 and 6).

Figure 2

Single crystal X-ray diffraction analysis of products 3n and 6e.

3. Materials and Methods

3.1. General Information

Commercial reagents and solvents were obtained from Adamas-beta (Shanghai, China), Aldrich Chemical Co. (Darmstadt, Germany), Alfa Aesar (Shanghai, China), Macklin (Shanghai, China) and Energy Chemical (Shanghai, China) and used as received with the following exceptions: THF, and toluene were purified by refluxing over Na-benzophenone under positive argon pressure followed by distillation [71,72,73]. The enone substrates were prepared according to literature procedure [74].

Proton nuclear magnetic resonance (1H-NMR, 400 MHz) and carbon-13 nuclear magnetic resonance (13C-NMR, 100 MHz) spectra were recorded in CDCl3 on an AV 400 MHz spectrometer (Bruker, Billerica, MA, USA). Proton chemical shifts are reported in parts per million (δ scale), and are referenced using residual protons in the NMR solvent (CHCl3 δ 7.26). Carbon chemical shifts are reported in parts per million (δ scale), and are referenced using the carbon resonances of the solvent (CDCl3: triplet centered at δ 77.01). High resolution mass spectra (HRMS) were recorded on a SYNAPT G2 system (Waters, Milford, CT, USA) using an electrospray (ESI) ionization source.

3.2. Synthesis

3.2.1. General Procedure for the Synthesis of Multi-Substituted Spirocyclopropane 3

A dried glass tube was charged with cyclic enone 1 (0.1 mmol) and sulfur ylide 2 (0.1 mmol) in 1,4-dioxane (0.5 M, 2 mL). The reaction vessel was sealed with a Teflon cap and stirred at room temperature for about 2 h. When the reaction was complete, the reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate) to afford the corresponding spirocyclopropane 3, which was dried under vacuum oven and further analyzed by 1H-NMR, 13C-HMR, HRMS, etc.

1-Benzoyl-5-benzyl-2-phenyl-5-azaspiro[2.4]heptane-6,7-dione (3a). Purification of the crude product via flash chromatography on silica gel (petroleum ether/ethyl acetate = 4:1) to afford the corresponding 3a as a white solid with 98:2 dr, 92% yield. 1H-NMR δ 8.05–7.99 (m, 2H), 7.69–7.60 (m, 1H), 7.52 (t, J = 7.7 Hz, 2H), 7.41–7.28 (m, 7H), 7.28–7.21 (m, 3H), 4.84–4.66 (dd, J = 14.4 Hz, 2H), 4.23 (d, J = 7.2 Hz, 1H), 3.88 (d, J = 12.2 Hz, 1H), 3.69 (d, J = 12.1 Hz, 1H), 3.59 (d, J = 7.2 Hz, 1H); 13C-NMR δ 194.9, 193.4, 159.2, 136.6, 134.5, 134.2, 131.7, 129.0, 129.0, 129.0, 128.6, 128.4, 128.4, 128.4, 128.1, 48.7, 47.3, 44.3, 41.1, 36.6; HRMS: m/z calculated for C21H17N3O2Na+: 366.1218, found: 366.1227.

1-Benzoyl-5-benzyl-2-(m-tolyl)-5-azaspiro[2.4]heptane-6,7-dione (3b). Purification of the crude product via flash chromatography on silica gel (petroleum ether/ethyl acetate = 4:1) to afford the corresponding 3b as a white solid with 92:8 d.r., 83% yield. 1H-NMR δ (ppm) 8.06–7.99 (m, 2H), 7.68–7.61 (m, 1H), 7.52 (t, J = 7.8 Hz, 2H), 7.40–7.28 (m, 5H), 7.20 (t, J = 8.0 Hz, 1H), 7.06 (m, 3H), 4.74 (q, J = 14.4 Hz, 2H), 4.22 (d, J = 7.2 Hz, 1H), 3.87 (d, J = 12.4 Hz, 1H), 3.68 (d, J = 12.4 Hz, 1H), 3.55 (d, J = 7.2 Hz, 1H), 2.33 (s, 3H); 13C-NMR δ (ppm): 194.9, 193.4, 159.3, 138.1, 136.6, 134.5, 134.2, 131.6, 129.6, 129.0, 129.0, 128.9, 128.7, 128.6, 128.4, 128.3, 126.0, 48.7, 47.4, 44.4, 41.1, 36.6, 21.3; HRMS: m/z calculated for C27H23NO3Na+: 432.1576, found: 432.1573.

1-Benzoyl-5-benzyl-2-(p-tolyl)-5-azaspiro[2.4]heptane-6,7-dione (3c). Purification of the crude product via flash chromatography on silica gel (petroleum ether/ethyl acetate = 4:1) to afford the corresponding 3c as a white solid with 98:2 d.r., 93% yield; 1H-NMR δ (ppm) 8.10–7.86 (m, 2H), 7.68–7.60 (m, 1H), 7.52 (t, J = 7.8 Hz, 2H), 7.41–7.28 (m, 5H), 7.18–7.04 (m, 4H), 4.78 (d, J = 14.4 Hz, 1H), 4.69 (d, J = 14.4 Hz, 1H), 4.20 (d, J = 7.2 Hz, 1H), 3.87 (d, J = 12.0 Hz, 1H), 3.68 (d, J = 12.0 Hz, 1H), 3.55 (d, J = 7.2 Hz, 1H), 2.31 (s, 3H); 13C-NMR δ (ppm) 195.0, 193.4, 159.3, 137.9, 136.6, 134.5, 134.2, 129.1, 129.0, 129.0, 128.8, 128.7, 128.6, 128.6, 128.3, 48.7, 47.3, 44.3, 41.2, 36.6, 21.1; HRMS: m/z calculated for C27H23NO3Na+: 432.1576, found: 432.1579.

1-Benzoyl-5-benzyl-2-(2-methoxyphenyl)-5-azaspiro[2.4]heptane-6,7-dione (3d). Purification of the crude product via flash chromatography on silica gel (petroleum ether/ethyl acetate = 4:1) to afford the corresponding 3d as a white solid with 92:8 d.r., 83% yield; 1H-NMR δ (ppm) 8.11–7.99 (m, 2H), 7.70–7.61 (m, 1H), 7.57–7.48 (m, 2H), 7.43–7.31 (m, 5H), 7.30–7.21 (m, 2H), 6.96 (m, 1H), 6.78 (dd, J = 8.4, 0.8 Hz, 1H), 5.01 (d, J = 14.4 Hz, 1H), 4.54 (d, J = 14.4 Hz, 1H), 4.04 (d, J = 7.0 Hz, 1H), 3.95 (d, J = 11.8 Hz, 1H), 3.69 (d, J = 11.8 Hz, 1H), 3.62 (s, 3H); 13C-NMR δ (ppm): 195.2, 192.6, 159.8, 157.0, 136.8, 135.0, 134.1, 130.3, 130.1, 129.4, 129.0, 128.6, 128.4, 128.3, 121.2, 120.7, 110.3, 55.1, 48.5, 47.4, 39.8, 39.1, 36.7; HRMS: m/z calculated for C27H23NO4Na+: 448.1525, found: 448.1529.

1-Benzoyl-5-benzyl-2-(3-methoxyphenyl)-5-azaspiro[2.4]heptane-6,7-dione (3e). Purification of the crude product via flash chromatography on silica gel (petroleum ether/ethyl acetate = 4:1) to afford the corresponding 3e as a white solid with 97:3 d.r., 91% yield; 1H-NMR δ (ppm) 8.05–7.97 (m, 2H), 7.69–7.60 (m, 1H), 7.52 (t, J = 7.6 Hz, 2H), 7.41–7.27 (m, 5H), 7.22 (m, 1H), 6.87–6.75 (m, 3H), 4.79 (d, J = 14.4 Hz, 1H), 4.69 (d, J = 14.4 Hz, 1H), 4.21 (d, J = 7.2 Hz, 1H), 3.87 (d, J = 12.0 Hz, 1H), 3.79 (s, 3H), 3.68 (d, J = 12.0 Hz, 1H), 3.55 (d, J = 7.2 Hz, 1H); 13C-NMR δ (ppm): 194.8, 193.4, 159.5, 159.2, 136.6, 134.5, 134.2, 133.2, 129.4, 129.0, 129.0, 128.7, 128.5, 128.4, 121.3, 115.1, 113.2, 55.2, 48.7, 47.3, 44.2, 41.1, 36.6; HRMS: m/z calculated for C27H23NO4Na+: 448.1525, found: 448.1523.

1-Benzoyl-5-benzyl-2-(4-methoxyphenyl)-5-azaspiro[2.4]heptane-6,7-dione (3f). Purification of the crude product via flash chromatography on silica gel (petroleum ether/ethyl acetate = 4:1) to afford the corresponding 3f as a white solid with 96:4 d.r., 94% yield; 1H-NMR δ (ppm) 8.06–7.95 (m, 2H), 7.69–7.60 (m, 1H), 7.52 (t, J = 7.6 Hz, 2H), 7.40–7.28 (m, 5H), 7.22–7.13 (m, 2H), 6.89–6.78 (m, 2H), 4.78 (d, J = 14.4 Hz, 1H), 4.69 (d, J = 14.4 Hz, 1H), 4.19 (d, J = 7.2 Hz, 1H), 3.86 (d, J = 12.4 Hz, 1H), 3.78 (s, 3H), 3.68 (d, J = 12.0 Hz, 1H), 3.54 (d, J = 7.2 Hz, 1H); 13C-NMR δ (ppm) 195.0, 193.4, 159.4, 136.6, 134.5, 134.2, 130.1, 129.1, 129.0, 128.6, 128.4, 128.4, 128.0, 123.6, 113.9, 55.3, 48.7, 47.4, 44.2, 41.3, 36.8; HRMS: m/z calculated for C27H23NO4Na+: 448.1525, found: 448.1521.

1-Benzoyl-5-benzyl-2-(4-fluorophenyl)-5-azaspiro[2.4]heptane-6,7-dione (3g). Purification of the crude product via flash chromatography on silica gel (petroleum ether/ethyl acetate = 4:1) to afford the corresponding 3g as a white solid with 96:4 d.r., 88% yield; 1H-NMR δ (ppm) 8.05–7.96 (m, 2H), 7.66 (t, J = 7.6 Hz, 1H), 7.53 (t, J = 7.7 Hz, 2H), 7.35 (m, 3H), 7.30 (m, 2H), 7.27–7.17 (m, 2H), 7.00 (t, J = 8.6 Hz, 2H), 4.79 (d, J = 14.4 Hz, 1H), 4.68 (d, J = 14.4 Hz, 1H), 4.17 (d, J = 7.2 Hz, 1H), 3.86 (d, J = 12.0 Hz, 1H), 3.67 (d, J = 12.0 Hz, 1H), 3.55 (d, J = 7.2 Hz, 1H); 13C-NMR δ (ppm) 194.6, 193.5, 159.1, 136.5, 134.4, 134.3, 130.7, 130.6, 129.1, 129.0, 128.6, 128.4, 128.4, 115.5, 115.3, 48.7, 47.2, 43.3, 41.0, 36.8; HRMS: m/z calculated for C26H20FNO3Na+: 436.1325, found: 436.1322.

1-Benzoyl-5-benzyl-2-(2-chlorophenyl)-5-azaspiro[2.4]heptane-6,7-dione (3h). Purification of the crude product via flash chromatography on silica gel (petroleum ether/ethyl acetate = 4:1) to afford the corresponding 3h as a white solid with 97:3 d.r., 98% yield; 1H-NMR δ (ppm) 8.15–7.95 (m, 2H), 7.77–7.60 (m, 1H), 7.54 (t, J = 7.6 Hz, 2H), 7.41–7.29 (m, 7H), 7.27–7.20 (m, 2H), 5.06 (d, J = 14.4 Hz, 1H), 4.45 (d, J = 14.4 Hz, 1H), 4.16 (d, J = 6.8 Hz, 1H), 3.94 (d, J = 12.0 Hz, 1H), 3.67 (d, J = 12.0 Hz, 1H), 3.44 (d, J = 7.2 Hz, 1H); 13C-NMR δ (ppm) 194.4, 193.0, 159.2, 136.5, 135.2, 134.5, 134.4, 130.7, 130.6, 129.5, 129.4, 129.1, 129.0, 128.7, 128.4, 128.4, 126.8, 48.6, 46.5, 41.4, 39.9, 36.6; HRMS: m/z calculated for C26H20ClNO3Na+: 452.1029, found: 452.1028.

1-Benzoyl-5-benzyl-2-(3-chlorophenyl)-5-azaspiro[2.4]heptane-6,7-dione (3i). Purification of the crude product via flash chromatography on silica gel (petroleum ether/ethyl acetate = 4:1) to afford the corresponding 3i as a white solid with 97:3 d.r., 94% yield; 1H-NMR δ (ppm) 8.05–7.97 (m, 2H), 7.70–7.62 (m, 1H), 7.53 (t, J = 7.8 Hz, 2H), 7.41–7.28 (m, 5H), 7.25 (m, 3H), 7.13 (m, 1H), 4.78 (d, J = 14.4 Hz, 1H), 4.69 (d, J = 14.4 Hz, 1H), 4.18 (d, J = 7.2 Hz, 1H), 3.86 (d, J = 12.0 Hz, 1H), 3.65 (d, J = 12.0 Hz, 1H), 3.54 (d, J = 7.2 Hz, 1H); 13C-NMR δ (ppm) 194.4, 193.4, 159.0, 136.4, 134.4, 134.4, 134.3, 133.7, 129.6, 129.1, 129.1, 129.1, 128.6, 128.4, 128.4, 128.3, 127.2, 48.8, 47.1, 43.0, 40.8, 36.5 HRMS: m/z calculated for C26H20ClNO3Na+: 452.1029, found: 452.1028.

1-Benzoyl-5-benzyl-2-(4-chlorophenyl)-5-azaspiro[2.4]heptane-6,7-dione (3j). Purification of the crude product via flash chromatography on silica gel (petroleum ether/ethyl acetate = 4:1) to afford the corresponding 3j as a white solid with 96:4 d.r., 59% yield; 1H-NMR δ (ppm) 8.04–7.97 (m, 2H), 7.70–7.61 (m, 1H), 7.53 (t, J = 7.6 Hz, 2H), 7.35 (m, 2H), 7.32–7.24 (m, 5H), 7.22–7.15 (m, 2H), 4.79 (d, J = 14.4 Hz, 1H), 4.68 (d, J = 14.4 Hz, 1H), 4.17 (d, J = 7.2 Hz, 1H), 3.86 (d, J = 12.0 Hz, 1H), 3.66 (d, J = 12.0 Hz, 1H), 3.54 (d, J = 7.2 Hz, 1H); 13C-NMR δ (ppm) 194.6, 193.5, 159.1, 136.5, 134.5, 134.4, 134.1, 130.4, 130.3, 129.1, 129.1, 128.7, 128.6, 128.5, 128.4, 48.8, 47.2, 43.2, 41.0, 36.7; HRMS: m/z calculated for C26H20ClNO3Na+: 452.1029, found: 452.1028.

1-Benzoyl-5-benzyl-2-(3-bromophenyl)-5-azaspiro[2.4]heptane-6,7-dione (3k). Purification of the crude product via flash chromatography on silica gel (petroleum ether/ethyl acetate = 3:1) to afford the corresponding 3k as a white solid with 94:6 d.r., 84% yield; 1H-NMR δ (ppm) 8.05–7.96 (m, 2H), 7.70–7.61 (m, 1H), 7.53 (t, J = 7.6 Hz, 2H), 7.45–7.38 (m, 2H), 7.35 (m, 3H), 7.30 (m, 2H), 7.21–7.15 (m, 2H), 4.78 (d, J = 14.4 Hz, 1H), 4.69 (d, J = 14.4 Hz, 1H), 4.18 (d, J = 7.2 Hz, 1H), 3.86 (d, J = 12.0 Hz, 1H), 3.65 (d, J = 12.0 Hz, 1H), 3.54 (d, J = 7.2 Hz, 1H); 13C-NMR δ (ppm) 194.4, 193.4, 159.0, 136.4, 134.4, 134.4, 134.0, 132.0, 131.3, 129.9, 129.1, 129.0, 128.6, 128.4, 128.4, 127.6, 122.4, 48.8, 47.1, 42.9, 40.8, 36.5; HRMS: m/z calculated for C26H20BrNO3Na+: 496.0524, found: 496.0526.

1-Benzoyl-5-benzyl-2-(4-bromophenyl)-5-azaspiro[2.4]heptane-6,7-dione (3l). Purification of the crude product via flash chromatography on silica gel (petroleum ether/ethyl acetate = 3:1) to afford the corresponding 3l as a white solid with 96:4 d.r., 57% yield; 1H-NMR δ (ppm) 8.05–7.95 (m, 2H), 7.66 (t, J = 7.4 Hz, 1H), 7.53 (t, J = 7.6 Hz, 2H), 7.47–7.41 (m, 2H), 7.35 (m, 3H), 7.30 (m, 2H), 7.13 (d, J = 8.4 Hz, 2H), 4.79 (d, J = 14.4 Hz, 1H), 4.68 (d, J = 14.4 Hz, 1H), 4.17 (d, J = 7.2 Hz, 1H), 3.86 (d, J = 12.0 Hz, 1H), 3.66 (d, J = 12.0 Hz, 1H), 3.52 (d, J = 7.2 Hz, 1H); 13C-NMR δ (ppm) 194.5, 193.5, 159.0, 136.5, 134.4, 134.4, 131.6, 130.8, 130.6, 129.1, 129.1, 128.6, 128.4, 128.4, 122.2, 48.8, 47.3, 43.2, 40.9, 36.6; HRMS: m/z calculated for C26H20BrNO3Na+: 496.0524, found: 496.0522.

1-Benzoyl-5-benzyl-2-(3,4-dimethoxyphenyl)-5-azaspiro[2.4]heptane-6,7-dione (3m). Purification of the crude product via flash chromatography on silica gel (petroleum ether/ethyl acetate = 2:1) to afford the corresponding 3m as a white solid with 98:2 d.r., 81% yield; 1H-NMR δ (ppm): 8.01 (m, 2H), 7.69–7.61 (m, 1H), 7.52 (t, J = 7.8 Hz, 2H), 7.40–7.28 (m, 5H), 6.87–6.76 (m, 3H), 4.79 (d, J = 14.4 Hz, 1H), 4.69 (d, J = 14.4 Hz, 1H), 4.19 (d, J = 7.6 Hz, 1H), 3.88 (s, 3H), 3.85 (s, 4H), 3.68 (d, J = 12.0Hz, 1H), 3.54 (d, J = 7.2 Hz, 1H); 13C-NMR δ (ppm): 194.8, 193.5, 159.3, 148.9, 148.7, 136.6, 134.5, 134.2, 129.0, 129.0, 128.5, 128.3, 128.3, 124.2, 121.5, 112.0, 110.9, 56.0, 55.9, 48.7, 47.3, 44.4, 41.4, 37.0; HR-MS (ESI): m/z calculated for C28H25NO5Na+: 478.1630, found: 478.1628.

1-Benzoyl-5-benzyl-2-(2,4-dichlorophenyl)-5-azaspiro[2.4]heptane-6,7-dione (3n). Purification of the crude product via flash chromatography on silica gel (petroleum ether/ethyl acetate = 4:1) to afford the corresponding 3n as a white solid with >99:1 d.r., 99% yield; 1H-NMR δ (ppm) 8.07–7.98 (m, 2H), 7.72–7.62 (m, 1H), 7.54 (t, J = 7.6 Hz, 2H), 7.42–7.20 (m, 8H), 5.05 (d, J = 14.4 Hz, 1H), 4.42 (d, J = 14.4 Hz, 1H), 4.11 (d, J = 7.2 Hz, 1H), 3.91 (d, J = 12.0 Hz, 1H), 3.65 (d, J = 12.0 Hz, 1H), 3.38 (d, J = 7.2 Hz, 1H); 13C-NMR δ (ppm) 194.0, 193.0, 159.0, 136.3, 135.8, 134.7, 134.4, 131.4, 129.4, 129.2, 129.1, 128.9, 128.9, 128.7, 128.6, 128.4, 127.2, 48.6, 46.4, 40.4, 39.7, 36.4; HRMS: m/z calculated for C26H19Cl2NO3Na+: 486.0640, found: 486.0641.

1-Benzoyl-5-benzyl-2-(naphthalen-1-yl)-5-azaspiro[2.4]heptane-6,7-dione (3o). Purification of the crude product via flash chromatography on silica gel (petroleum ether/ethyl acetate = 3:1) to afford the corresponding 3o as a white solid with 94:6 d.r., 94% yield; 1H-NMR δ (ppm) 8.15–8.08 (m, 2H), 7.84 (d, J = 8.2 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.71–7.65 (m, 1H), 7.61–7.51 (m, 3H), 7.51–7.44 (m, 5H), 7.40 (m, 4H), 5.20 (d, J = 14.4 Hz, 1H), 4.39 (d, J =6.8 Hz, 2H), 4.35 (d, J = 14.4 Hz, 2H), 4.14 (d, J = 12.4 Hz, 1H), 3.85 (s, 1H), 3.82 (d, J = 4.8Hz, 1H); 13C-NMR δ (ppm) 194.9, 192.6, 159.1, 136.6, 134.8, 134.3, 133.6, 132.5, 129.2, 129.1, 129.1, 129.0, 128.6, 128.5, 128.5, 128.0, 127.0, 126.9, 126.0, 125.0, 122.2, 48.6, 47.0, 42.0, 40.4, 36.1; HRMS: m/z calculated for C28H25NO5Na+: 468.1576, found: 468.1573.

Ethyl-5-benzyl-6,7-dioxo-2-phenyl-5-azaspiro[2.4]heptane-1-carboxylate (3p). Purification of the crude product via flash chromatography on silica gel (petroleum ether/ethyl acetate = 3:1) to afford the corresponding 3p as a white solid with 98:2 d.r., 86% yield; 1H-NMR δ (ppm) 8.04–7.95 (m, 2H), 7.68–7.60 (m, 1H), 7.55–7.47 (m, 2H), 7.39–7.27 (m, 5H), 7.20 (dd, J = 5.2, 1.2 Hz, 1H), 7.04 (m, 1H), 6.95 (m, 1H), 4.76 (d, J = 14.4 Hz, 1H), 4.71 (d, J = 14.4 Hz, 1H), 4.18 (d, J = 7.0 Hz, 1H), 3.85 (d, J = 12.0 Hz, 1H), 3.66 (d, J = 12.0 Hz, 1H), 3.62 (dd, J = 7.0, 0.8Hz, 1H); 13C-NMR (100 MHz, CDCl3) δ (ppm) 194.2, 192.6, 159.1, 136.4, 134.4, 134.4, 134.2, 129.0, 128.9, 128.5, 128.3, 128.3, 127.5, 126.9, 125.6, 48.6, 47.0, 41.4, 38.5, 37.9; HRMS: m/z calculated for C24H19NO3SNa+: 424.0983, found: 424.0981.

1-Benzoyl-5-(4-methoxybenzyl)-2-phenyl-5-azaspiro[2.4]heptane-6,7-dione (3q). Purification of the crude product via flash chromatography on silica gel (petroleum ether/ethyl acetate = 4:1) to afford the corresponding 3q as a white solid with 98:2 d.r., 90% yield; 1H-NMR δ (ppm) 8.04–7.98 (m, 2H), 7.69–7.60 (m, 1H), 7.52 (t, J = 8.0 Hz, 2H), 7.35–7.27 (m, 3H), 7.27–7.19 (m, 5H), 6.92–6.84 (m, 2H), 4.72 (d, J = 14.4 Hz, 1H), 4.64 (d, J = 14.4 Hz, 1H), 4.22 (d, J = 7.2 Hz, 1H), 3.86 (d, J = 12.0 Hz, 1H), 3.80 (s, 3H), 3.66 (d, J = 12.0 Hz, 1H), 3.58 (d, J = 7.2 Hz, 1H); 13C-NMR (100 MHz, CDCl3) δ (ppm) 194.9, 193.6, 159.6, 159.1, 136.6, 134.2, 131.7, 130.0, 129.0, 128.4, 128.4, 128.1, 126.5, 114.4, 55.3, 48.1, 47.1, 44.2, 41.1, 36.6; HRMS: m/z calculated for C27H23NO4Na+: 448.1525, found: 448.1528.

Ethyl-5-benzyl-6,7-dioxo-2-phenyl-5-azaspiro[2.4]heptane-1-carboxylate (3r). Purification of the crude product via flash chromatography on silica gel (petroleum ether/ethyl acetate = 4:1) to afford the corresponding 3r as a white solid with 92:8 d.r., 99% yield; 1H-NMR δ (ppm) 7.42–7.34 (m, 3H), 7.34–7.30 (m, 2H), 7.29 (d, J = 1.8 Hz, 1H), 7.28–7.25 (m, 2H), 7.22–7.17 (m, 2H), 4.75 (s, 2H), 4.19 (qd, J = 7.2, 2.8 Hz, 2H), 3.77 (q, J = 12.0 Hz, 2H), 3.33 (d, J = 7.2 Hz, 1H), 3.21 (d, J = 7.2 Hz, 1H), 1.28 (t, J = 7.2 Hz, 3H); 13C-NMR δ (ppm) 192.9, 169.3, 159.1, 134.5, 131.1, 129.0, 128.9, 128.5, 128.3, 128.3, 128.0, 61.8, 48.6, 47.4, 42.9, 38.1, 33.5, 14.0; HRMS: m/z calculated for C22H21NO4Na+: 386.1386, found: 386.1385.

Tert-butyl-5-benzyl-6,7-dioxo-2-phenyl-5-azaspiro[2.4]heptane-1-carboxylate (3s). Purification of the crude product via flash chromatography on silica gel (petroleum ether/ethyl acetate = 4:1) to afford the corresponding 3s as a white solid with 90:10 d.r., 99% yield; 1H-NMR δ (ppm) 7.30 (m, 3H), 7.28–7.24 (m, 2H), 7.22 (dd, J = 7.1, 1.8 Hz, 2H), 7.20–7.18 (m, 1H), 7.15–7.11 (m, 2H), 4.67 (s, 2H), 3.68 (d, J = 12.0 Hz, 1H), 3.62 (d, J = 12.0 Hz, 1H), 3.21 (d, J = 7.2 Hz, 1H), 3.05 (d, J = 7.2 Hz, 1H), 1.36 (s, 9H); 13C-NMR δ (ppm) 192.1, 167.3, 158.2, 133.5, 130.3, 128.0, 127.9, 127.5, 127.3, 127.2, 126.9, 81.8, 47.5, 46.3, 41.6, 37.0, 33.9, 27.0; HRMS: m/z calculated for C24H25NO4Na+: 414.1681, found: 414.1680.

3.2.2. General Procedure for the Synthesis of Multi-Substituted Spirocyclopropane 5

A dried glass tube was charged with cyclic enones 1 (0.1 mmol) and amidic sulfonium salt 4 (0.1 mmol) at the presence of TMG (13 μL, 0.1 mmol, 1.0 equiv.) in 1,4-dioxane (0.5 M, 2 mL). The reaction was sealed with a Teflon cap and stirred at room temperature overnight. When the reaction was complete, the reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate) to afford the corresponding spirocyclopropane 5, which was dried under vacuum oven and further analyzed by 1H-NMR, 13C-HMR, HRMS, etc.

N,5-Dibenzyl-6,7-dioxo-2-phenyl-5-azaspiro[2.4]heptane-1-carboxamide (5a). Purification of the crude product via flash chromatography on silicagel (petroleum ether/ethyl acetate = 2:1) to afford the corresponding 5a as a white solid with 96:4 d.r., 98% yield; 1H-NMR δ (ppm) 8.27 (s, 1H), 7.36–7.30 (m, 3H), 7.26 (m, 5H), 7.21 (m, 2H), 7.14 (m, 4H), 4.73 (d, J = 4.4 Hz, 2H), 4.48 (dd, J = 15.2, 6.4 Hz, 1H), 4.36 (dd, J = 15.2, 5.6 Hz, 1H), 3.68 (d, J = 5.2 Hz, 2H), 3.53 (d, J = 7.6 Hz, 1H), 3.15 (d, J = 7.2 Hz, 1H); 13C-NMR δ (ppm) 195.1, 167.0, 160.3, 138.1, 134.2, 132.3, 129.2, 129.1, 128.9, 128.4, 128.2, 128.2, 127.6, 127.3, 126.9, 48.7, 47.7, 43.6, 41.4, 38.1, 36.9; HRMS: m/z calculated for C27H24N2O3Na+: 447.1685, found: 447.1684.

5-Benzyl-N-(4-methoxybenzyl)-6,7-dioxo-2-phenyl-5-azaspiro[2.4]heptane-1-carboxamide (5b). Purification of the crude product via flash chromatography on silica gel (petroleum ether/ethyl acetate = 2:1) to afford the corresponding 5b as a white solid with >99:1 d.r., 99% yield; 1H-NMR δ (ppm) 7.91 (t, J = 5.6 Hz, 1H), 7.27–7.24 (m, 3H), 7.24–7.16 (m, 5H), 7.10–7.03 (m, 4H), 6.69–6.60 (m, 2H), 4.67 (s, 2H), 4.32 (dd, J = 15.0, 6.2 Hz, 1H), 4.24 (dd, J = 14.8, 5.4 Hz, 1H), 3.70 (s, 3H), 3.62 (d, J = 8.8 Hz, 2H), 3.45 (d, J = 7.2 Hz, 1H), 3.03 (d, J = 7.6 Hz, 1H); 13C-NMR δ (ppm) 195.0, 166.9, 160.3, 158.6, 134.2, 132.3, 130.2, 129.2, 129.1, 128.7, 128.2, 128.2, 128.2, 127.6, 113.8, 55.2, 48.7, 47.7, 43.2, 41.4, 38.1, 37.0; HRMS: m/z calculated for C28H26N2O4Na+: 477.1790, found: 477.1785.

N,5-Dibenzyl-6,7-dioxo-2-(p-tolyl)-5-azaspiro[2.4]heptane-1-carboxamide (5c). Purification of the crude product via flash chromatography on silica gel (petroleum ether/ethyl acetate = 2:1) to afford the corresponding 5c as a white solid with 97:3 d.r., 99% yield; 1H-NMR δ (ppm) 7.92 (s, 1H), 7.27–7.23 (m, 3H), 7.21–7.20 (m, 3H), 7.16–7.13 (m, 2H) , 7.12–7.09 (m, 2H), 7.02–6.92 (m, 4H), 4.67 (s, 2H), 4.41 (dd, J = 15.2, 6.0 Hz, 1H), 4.31 (dd, J = 15.2, 5.6 Hz, 1H), 3.62 (q, J = 16.8, 12.4 Hz, 2H), 3.43 (d, J = 7.4 Hz, 1H), 3.02 (d, J = 7.6 Hz, 1H), 2.26 (s, 3H); 13C-NMR δ (ppm) 194.9, 167.1, 160.3, 138.0, 137.3, 134.3, 129.2, 129.1, 129.0, 128.9, 128.4, 128.3, 128.2, 127.4, 127.0, 48.7, 47.8, 43.7, 41.5, 38.3, 36.9, 21.1; HRMS: m/z calculated for C28H26N2O3Na+: 461.1841, found: 461.1838.

5-Benzyl-N-(4-methoxybenzyl)-6,7-dioxo-2-(p-tolyl)-5-azaspiro[2.4]heptane-1-carboxamide (5d). Purification of the crude product via flash chromatography on silica gel (petroleum ether/ethyl acetate = 2:1) to afford the corresponding 5d as a white solid with 94:6 d.r., 92% yield; 1H-NMR δ (ppm) 7.97 (t, J = 5.8 Hz, 1H), 7.27–7.16 (m, 5H), 7.10–7.03 (m, 2H), 7.01–6.92 (m, 4H), 6.67–6.60 (m, 2H), 4.66 (s, 2H), 4.27 (qd, J = 15.0, 5.8 Hz, 2H), 3.69 (s, 3H), 3.67–3.55 (m, 2H), 3.41 (d, J = 7.2 Hz, 1H), 3.01 (d, J = 7.6 Hz, 1H); 13C-NMR δ (ppm) 195.0, 167.0, 160.3, 158.6, 137.3, 134.3, 130.2, 129.2, 129.1, 129.0, 128.9, 128.7, 128.2, 128.2, 113.8, 55.2, 48.6, 47.7, 43.1, 41.3, 38.2, 37.1, 21.1; HRMS: m/z calculated for C29H28N2O4Na+: 491.1947, found: 491.1958.

N,5-Dibenzyl-2-(4-chlorophenyl)-6,7-dioxo-5-azaspiro[2.4]heptane-1-carboxamide (5e). Purification of the crude product via flash chromatography on silica gel (petroleum ether/ethyl acetate = 2:1) to afford the corresponding 5e as a white solid with 91:9 d.r., 99% yield; 1H-NMR δ (ppm) 8.24 (t, J = 6.0 Hz, 1H), 7.40–7.29 (m, 3H), 7.29–7.24 (m, 3H), 7.24–7.13 (m, 6H), 7.11–7.01 (m, 2H), 4.80 (d, J = 14.4 Hz, 1H), 4.68 (d, J = 14.4 Hz, 1H), 4.52 (dd, J = 15.2, 6.4 Hz, 1H), 4.35 (dd, J = 15.2, 5.6 Hz, 1H), 3.68 (q, J = 15.6, 12.4 Hz, 2H), 3.50 (d, J = 7.4 Hz, 1H), 3.10 (d, J = 7.6 Hz, 1H); 13C-NMR δ (ppm) 195.2, 166.7, 160.2, 137.9, 134.0, 133.5, 130.8, 130.5, 129.2, 128.4, 128.4, 128.4, 128.1, 127.3, 127.1, 48.7, 47.6, 43.7, 40.4, 37.9, 37.1; HRMS: m/z calculated for C27H23ClN2O3Na+: 481.1295, found: 481.1296.

5-Benzyl-2-(2-chlorophenyl)-N-(4-methoxybenzyl)-6,7-dioxo-5-azaspiro[2.4]heptane-1-carboxamide (5f). Purification of the crude product via flash chromatography on silica gel (petroleum ether/ethyl acetate = 2:1) to afford the corresponding 5f as a white solid with 94:6 d.r., 98% yield; 1H-NMR δ (ppm) 8.25–8.08 (m, 1H), 7.27–7.20 (m, 4H), 7.20–7.11 (m, 5H), 7.10–7.03 (m, 2H), 6.71–6.63 (m, 2H), 4.88 (d, J = 14.4 Hz, 1H), 4.40 (d, J = 14.4 Hz, 1H), 4.28 (qd, J = 14.8, 5.6 Hz, 2H), 3.72 (s, 3H), 3.68 (d, J = 12.2 Hz, 1H), 3.54 (d, J = 12.2 Hz, 1H), 3.22 (d, J = 7.4 Hz, 1H), 3.00–2.87 (m, 1H); 13C-NMR δ (ppm) 194.6, 166.6, 160.2, 158.7, 135.2, 134.3, 131.4, 130.9, 130.2, 129.2, 129.0, 129.0, 129.0, 128.8, 128.6, 128.2, 126.7, 113.8, 55.2, 48.5, 47.0, 43.3, 38.9, 37.0; HRMS: m/z calculated for C28H25ClN2O4Na+: 511.1401, found: 511.1401.

N,5-Dibenzyl-2-(naphthalen-2-yl)-6,7-dioxo-5-azaspiro[2.4]heptane-1-carboxamide (5g). Purification of the crude product via flash chromatography on silica gel (petroleum ether/ethyl acetate = 2:1) to afford the corresponding 5g as a white solid with >99:1 d.r., 85% yield; 1H-NMR δ (ppm) 7.92 (t, J = 6.0 Hz, 1H), 7.82–7.80 (m, 1H), 7.76–7.68 (m, 1H), 7.63 (d, J = 1.6 Hz, 1H), 7.54–7.40 (m, 2H), 7.31–7.15 (m, 9H), 7.14–7.06 (m, 1H), 7.06–6.98 (m, 2H), 4.76 (s, 2H), 4.49 (dd, J = 15.2, 6.4 Hz, 1H), 4.35 (dd, J = 15.2, 5.2 Hz, 1H), 3.76 (d, J = 12.4 Hz, 1H), 3.72–3.62 (m, 2H), 3.22 (d, J = 7.6 Hz, 1H); 13C-NMR δ (ppm) 194.9, 167.0, 160.2, 137.9, 134.2, 133.0, 132.8, 129.8, 129.1, 128.4, 128.3, 128.3, 128.2, 128.0, 127.9, 127.6, 127.3, 127.1, 127.0, 126.3, 126.2, 48.7, 47.7, 43.7, 41.5, 38.1, 37.0; HRMS: m/z calculated for C31H26N2O3Na+: 497.1841, found: 497.1841.

5-Benzyl-N-(4-methoxybenzyl)-2-(naphthalen-2-yl)-6,7-dioxo-5-azaspiro[2.4]heptane-1-carboxamide (5h). Purification of the crude product via flash chromatography on silica gel (petroleum ether/ethyl acetate = 2:1) to afford the corresponding 5h as a white solid with >99:1 d.r., 90% yield; 1H-NMR δ (ppm) 7.76–7.61 (m, 3H), 7.58 (s, 1H), 7.43–7.33 (m, 2H), 7.20 (d, J = 9.1 Hz, 7H), 7.14–7.12 (m, 1H), 7.09–7.02 (m, 2H), 6.63 (d, J = 8.4 Hz, 2H), 4.68 (dq, J = 12.6, 14.4 Hz, 2H), 4.29 (dd, J = 5.7, 3.3 Hz, 2H), 4.33–4.26 (m, 2H), 3.77–3.70 (m, 2H), 3.66 (s, 3H), 3.63–3.56 (m, 1H), 3.08 (d, J = 7.4 Hz, 1H); 13C-NMR δ (ppm) 195.0, 166.8, 160.2, 158.7, 134.2, 133.0, 132.7, 130.0, 129.8, 129.1, 128.8, 128.3, 128.2, 128.2, 127.9, 127.8, 127.6, 127.0, 126.3, 126.1, 113.8, 55.2, 48.7, 47.7, 43.3, 41.5, 38.1, 37.2; HRMS: m/z calculated for C32H28N2O4Na+: 527.1947, found: 527.1943.

N,5-Dibenzyl-6,7-dioxo-2-(thiophen-2-yl)-5-azaspiro[2.4]heptane-1-carboxamide (5i). Purification of the crude product via flash chromatography on silica gel (petroleum ether/ethyl acetate = 2:1) to afford the corresponding 5i as a white solid with >99:1 d.r., 83% yield; 1H-NMR δ (ppm) 8.44–8.21 (m, 1H), 7.32–7.25 (m, 3H), 7.23–7.20 (m, 2H), 7.18–7.13 (m, 2H), 7.13–7.09 (m, 4H), 6.86–6.76 (m, 2H), 4.74 (d, J = 14.6 Hz, 1H), 4.61 (d, J = 14.6 Hz, 1H), 4.43 (dd, J = 15.2, 6.4 Hz, 1H), 4.28 (dd, J = 15.2, 5.4 Hz, 1H), 3.61 (s, 2H), 3.51 (d, J = 6.8 Hz, 1H), 3.11–2.97 (m, 1H); 13C-NMR δ (ppm) 194.3, 166.5, 160.3, 138.0, 135.2, 134.2, 129.1, 128.4, 128.3, 127.4, 127.3, 127.0, 126.7, 125.3, 48.7, 47.5, 43.7, 38.6, 38.3, 35.9; HRMS: m/z calculated for C25H22N2O3SNa+: 453.1249, found: 453.1250.

5-Benzyl-N-(4-methoxybenzyl)-6,7-dioxo-2-(thiophen-2-yl)-5-azaspiro[2.4]heptane-1-carboxamide (5j). Purification of the crude product via flash chromatography on silica gel (petroleum ether/ethyl acetate = 2:1) to afford the corresponding 5j as a white solid with >99:1 d.r., 81% yield; 1H-NMR δ (ppm) 8.20–8.01 (m, 1H), 7.39–7.32 (m, 3H), 7.32–7.28 (m, 2H), 7.21–7.11 (m, 3H), 6.92–6.89 (m, 1H), 6.89–6.82 (m, 1H), 6.77–6.69 (m, 2H), 4.80 (d, J = 14.6 Hz, 1H), 4.70 (d, J = 14.6 Hz, 1H), 4.42 (dd, J = 14.9, 6.2 Hz, 1H), 4.30 (dd, J = 14.8, 6.0 Hz, 1H), 3.77 (s, 3H), 3.69 (d, J = 1.8 Hz, 2H), 3.58 (d, J = 7.2, 1H), 3.07 (d, J = 7.2 Hz, 1H); 13C-NMR δ (ppm) 194.2, 166.3, 160.2, 158.7, 135.2, 134.2, 130.1, 129.1, 128.7, 128.3, 127.4, 126.7, 125.3, 113.9, 55.2, 48.7, 47.5, 43.3, 38.6, 38.3, 35.9; HRMS: m/z calculated for C26H24N2O4Na+: 483.1354, found: 483.1356.

3.2.3. General Procedure for the Synthesis of Multi-substituted Chiral Spirocyclopropane 6

A dried glass tube was charged with cyclic enone 1 (0.1 mmol) and (S)-dimethyl(2-oxo-2-((1-phenylethyl)amino)ethyl)sulfonium bromide 4c (0.1 mmol) at the presence of TMG (13 μL, 0.1 mmol, 1.0 equiv.) in 1,4-dioxane (0.5 M, 2 mL). The reaction was sealed with a Teflon cap and stirred at room temperature overnight. When the reaction was complete, the reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel (methanol/dichloromethane) to afford the corresponding chiral spirocyclopropane 6, which was dried under vacuum oven and further analyzed by 1H-NMR, 13C-HMR, HRMS, etc.

(1S,2R,3S)-5-Benzyl-6,7-dioxo-2-phenyl-N-((S)-1-phenylethyl)-5-azaspiro[2.4]heptane-1-carboxamide (6a). Purification of the crude product via flash chromatography on silica gel (methanol/dichloromethane = 1:300) to afford the corresponding 6a as a white solid with 72:28 d.r., 99% yield, [α] = +94.6 (c = 0.84 in CHCl3); 1H-NMR δ (ppm) 7.31–7.23 (m, 3H), 7.23–7.14 (m, 10H), 7.14–7.08 (m, 2H), 7.01 (d, J = 7.6 Hz, 1H), 5.03–4.86 (m, 1H), 4.73 (d, J = 14.4 Hz, 1H), 4.34 (d, J = 14.4 Hz, 1H), 3.57 (d, J = 12.2 Hz, 1H), 3.46–3.32 (m, 2H), 2.99 (d, J = 7.2 Hz, 1H), 1.38 (d, J = 7.0 Hz, 3H); 13C-NMR δ (ppm) 194.9, 166.1, 159.5, 143.3, 134.5, 132.1, 129.2, 129.0, 128.6, 128.5, 128.2, 128.2, 127.7, 127.2, 126.2, 49.8, 48.6, 47.5, 41.4, 38.1, 36.6, 21.8; HRMS: m/z calculated for C28H26N2O3Na+: 461.1841, found: 461.1832.

(1S,2R,3S)-5-Benzyl-6,7-dioxo-N-((S)-1-phenylethyl)-2-(p-tolyl)-5-azaspiro[2.4]heptane-1-carboxamide (6b). Purification of the crude product via flash chromatography on silica gel (methanol/dichloromethane = 1:300) to afford the corresponding 6b as a white solid with 70:30 d.r., 97% yield, [α] = +96.6 (c = 0.54 in CHCl3); 1H-NMR δ (ppm) 7.35–7.30 (m, 3H), 7.28–7.19 (m, 7H), 7.07 (s, 4H), 7.04–7.01 (m, 1H), 5.07–4.97 (m, 1H), 4.79 (d, J = 14.4 Hz, 1H), 4.47 (d, J = 14.4 Hz, 1H), 3.64 (d, J = 12.2 Hz, 1H), 3.50–3.41 (m, 2H), 3.03 (d, J = 7.2 Hz, 1H), 2.31 (s, 3H), 1.46 (d, J = 7.0 Hz, 3H); 13C-NMR δ (ppm) 194.8, 166.2, 159.6, 143.3, 137.4, 134.6, 129.1, 129.0, 129.0, 128.9, 128.6, 128.5, 128.2, 127.2, 126.1, 49.7, 48.6, 47.5, 41.5, 38.3, 36.6, 21.9, 21.1; HRMS: m/z calculated for C29H28N2O3Na+: 475.1998, found: 475.1995.

(1S,2R,3S)-5-Benzyl-2-(4-methoxyphenyl)-6,7-dioxo-N-((S)-1-phenylethyl)-5-azaspiro[2.4]heptane-1-carboxamide (6c). Purification of the crude product via flash chromatography on silica gel (methanol/dichloromethane = 1:300) to afford the corresponding 6c as a white solid with 64:36 d.r., 91% yield, [α] = +94.6 (c = 0.84 in CHCl3); 1H-NMR δ (ppm) 7.35–7.27 (m, 6H), 7.25–7.18 (m, 5H), 7.11 (d, J = 8.0 Hz, 2H), 6.82–6.75 (m, 2H), 5.06–4.97 (m, 1H), 4.79 (d, J = 14.4 Hz, 1H), 4.39 (d, J = 14.4 Hz, 1H), 3.76 (s, 3H), 3.62 (d, J = 12.2 Hz, 1H), 3.49–3.39 (m, 2H), 3.09 (d, J = 7.2 Hz, 1H), 1.44 (d, J = 7.0 Hz, 3H); 13C-NMR δ (ppm) 194.9, 166.2, 159.6, 159.0, 143.4, 134.6, 130.3, 128.9, 128.5, 128.4, 128.2, 127.1, 126.2, 124.0, 113.5, 55.2, 49.7, 48.6, 47.5, 41.2, 38.4, 36.8, 21.8; HRMS: m/z calculated for C29H28N2O4Na+: 491.1947, found: 491.1947.

(1S,2R,3S)-5-Benzyl-2-(4-fluorophenyl)-6,7-dioxo-N-((S)-1-phenylethyl)-5-azaspiro[2.4]heptane-1-carboxamide (6d). Purification of the crude product via flash chromatography on silica gel (methanol/dichloromethane = 1:300) to afford the corresponding 6d as a white solid with 81:19 d.r., 92% yield, [α] = +112.0 (c = 0.97 in CHCl3); 1H-NMR δ (ppm) 7.36–7.27 (m, 6H), 7.26–7.20 (m, 5H), 7.17–7.12 (m, 2H), 6.96–6.89 (m, 2H), 5.07–4.98 (m, 1H), 4.79 (d, J = 14.4 Hz, 1H), 4.41 (d, J = 14.4 Hz, 1H), 3.63 (d, J = 12.2 Hz, 1H), 3.47–3.39 (m, 2H), 3.06 (d, J = 7.2 Hz, 1H), 1.47 (d, J = 7.0 Hz, 3H); 13C-NMR δ (ppm) 195.0, 165.9, 159.5, 143.3, 134.4, 130.9, 130.8, 129.0, 128.5, 128.5, 128.3, 127.2, 126.2, 115.2, 115.0, 49.8, 48.7, 47.4, 40.5, 38.0, 36.8, 21.8; HRMS: m/z calculated for C28H25FN2O3Na+: 479.1747, found: 479.1749.

(1S,2S,3S)-5-Benzyl-2-(2-chlorophenyl)-6,7-dioxo-N-((S)-1-phenylethyl)-5-azaspiro[2.4]heptane-1-carboxamide (6e). Purification of the crude product via flash chromatography on silica gel (methanol/dichloromethane = 1:300) to afford the corresponding 6e as a white solid with 70:30 d.r., 90% yield, [α] = +104.3 (c = 1.01 in CHCl3); 1H-NMR δ (ppm) 7.38–7.28 (m, 7H), 7.27–7.20 (m, 7H), 7.19–7.13 (m, 1H), 5.09–4.93 (m, 2H), 4.22 (d, J = 14.4 Hz, 1H), 3.71 (d, J = 12.2 Hz, 1H), 3.44 (d, J = 12.2 Hz, 1H), 3.28 (d, J = 7.2 Hz, 1H), 2.96 (d, J = 7.2 Hz, 1H), 1.48 (d, J = 7.0 Hz, 3H); 13C-NMR δ (ppm) 194.5, 165.7, 159.4, 143.4, 135.3, 134.5, 131.2, 130.9, 129.1, 129.1, 128.9, 128.6, 128.5, 128.2, 127.2, 126.5, 126.2, 49.8, 48.5, 48.5, 46.7, 39.0, 37.0, 36.5, 21.8; HRMS: m/z calculated for C28H25ClN2O3Na+: 495.1451, found: 495.1449.

(1S,2R,3S)-5-Benzyl-2-(4-bromophenyl)-6,7-dioxo-N-((S)-1-phenylethyl)-5-azaspiro[2.4]heptane-1-carboxamide (6f). Purification of the crude product via flash chromatography on silica gel (methanol/dichloromethane = 1:300) to afford the corresponding 6f as a white solid with 62:38 d.r., 81% yield, [α] = +106.8 (c = 0.44 in CHCl3); 1H-NMR δ (ppm) 7.40–7.32 (m, 5H), 7.31–7.27 (m, 2H), 7.27–7.21 (m, 5H), 7.06–6.98 (m, 3H), 5.09–4.99 (m, 1H), 4.79 (d, J = 14.4 Hz, 1H), 4.42 (d, J = 14.4 Hz, 1H), 3.64 (d, J = 12.2 Hz, 1H), 3.46 (d, J = 12.2 Hz, 1H), 3.40 (d, J = 7.2 Hz, 1H), 2.99 (d, J = 7.2 Hz, 1H), 1.49 (d, J = 7.0 Hz, 3H); 13C-NMR δ (ppm) 194.8, 165.7, 159.3, 143.1, 134.4, 131.3, 131.1, 130.9, 129.0, 128.6, 128.5, 128.3, 127.3, 126.2, 121.7, 49.8, 48.7, 47.4, 40.5, 37.9, 36.6, 21.7; HRMS: m/z calculated for C28H25BrN2O3Na+: 539.0946, found: 539.0935.

(1S,2R,3S)-5-Benzyl-2-(naphthalen-1-yl)-6,7-dioxo-N-((S)-1-phenylethyl)-5-azaspiro[2.4]heptane-1-carboxamide (6g). Purification of the crude product via flash chromatography on silica gel (methanol/dichloromethane = 1:300) to afford the corresponding 6g as a white solid with 77:28 d.r., 97% yield, [α] = +116.9 (c = 0.12 in CHCl3); 1H-NMR δ (ppm) 7.78–7.70 (m, 2H), 7.41–7.31 (m, 6H), 7.29–7.23 (m, 4H), 7.22–7.15 (m, 5H), 6.85 (d, J = 7.8 Hz, 1H), 5.07 (d, J = 14.4 Hz, 1H), 4.99–4.90 (m, 1H), 4.09 (d, J = 14.4 Hz, 1H), 3.82 (d, J = 12.2 Hz, 1H), 3.63 (d, J = 7.2 Hz, 1H), 3.51 (d, J = 12.2 Hz, 1H), 3.08 (d, J = 7.2 Hz, 1H), 1.32 (d, J = 7.0 Hz, 3H); 13C-NMR δ (ppm) 194.0, 166.1, 159.3, 143.3, 134.8, 133.5, 132.6, 129.0, 129.0, 128.7, 128.6, 128.5, 128.4, 128.4, 127.3, 127.1, 126.8, 126.2, 125.9, 124.9, 122.4, 49.9, 48.5, 47.1, 39.4, 37.6, 36.0, 21.8; HRMS: m/z calculated for C32H28N2O3Na+: 511.1998, found: 511.2004.

(1S,2R,3S)-5-Benzyl-2-(naphthalen-2-yl)-6,7-dioxo-N-((S)-1-phenylethyl)-5-azaspiro[2.4]heptane-1-carboxamide (6h). Purification of the crude product via flash chromatography on silica gel (methanol/dichloromethane = 1:300) to afford the corresponding 6h as a white solid with 77:23 d.r., 99% yield, [α] = +120.0 (c = 0.40 in CHCl3); 1H-NMR δ (ppm) 7.83–7.76 (m, 2H), 7.73–7.66 (m, 2H), 7.51–7.45 (m, 2H), 7.34 (q, J = 3.8 Hz, 3H), 7.30–7.22 (m, 8H), 6.53 (d, J = 7.6 Hz, 1H), 5.11–5.00 (m, 1H), 4.79 (d, J = 14.4 Hz, 1H), 4.53 (d, J = 14.4 Hz, 1H), 3.74 (d, J = 12.2 Hz, 1H), 3.61 (d, J = 7.4 Hz, 1H), 3.56 (d, J = 12.2 Hz, 1H), 3.07 (d, J = 7.4 Hz, 1H), 1.47 (d, J = 7.0 Hz, 3H); 13C-NMR δ (ppm) 194.5, 166.1, 159.4, 144.1, 135.5, 132.5, 132.2, 130.8, 128.8, 128.3, 128.0, 127.8, 127.7, 127.5, 127.5, 127.4, 126.7, 126.3, 126.0, 125.8, 48.4, 47.5, 47.4, 40.6, 38.1, 34.7, 22.5; HRMS: m/z calculated for C32H28N2O3Na+: 511.1998, found: 511.1997.

(1S,2S,3R)-5-Benzyl-6,7-dioxo-N-((S)-1-phenylethyl)-2-(thiophen-2-yl)-5-azaspiro[2.4]heptane-1-carboxamide (6i). Purification of the crude product via flash chromatography on silica gel (methanol/dichloromethane = 1:300) to afford the corresponding 6i as a white solid with 60:40 d.r., 90% yield, [α] = +97.6 (c = 0.54 in CHCl3); 1H-NMR δ (ppm) 7.38–7.32 (m, 3H), 7.31–7.22 (m, 7H), 7.20–7.17 (m, 1H), 7.00–6.96 (m, 1H), 6.95–6.90 (m, 1H), 6.83 (d, J = 7.6 Hz, 1H), 5.11–4.97 (m, 1H), 4.76 (d, J = 14.4 Hz, 1H), 4.52 (d, J = 14.4 Hz, 1H), 3.65 (d, J = 12.2 Hz, 1H), 3.56–3.43 (m, 2H), 3.04 (d, J = 7.0 Hz, 1H), 1.49 (d, J = 7.0 Hz, 3H); 13C-NMR δ (ppm) 193.8, 165.5, 159.4, 143.0, 134.8, 134.5, 129.0, 128.7, 128.5, 128.3, 127.6, 127.4, 126.8, 126.1, 125.5, 49.9, 48.7, 47.2, 38.7, 37.7, 36.1, 21.8; HR-MS (ESI): m/z calculated for C26H24N2O3SNa+: 467.1405, found: 467.1406.

4. Conclusions

In conclusion, we have developed a highly diastereoselective cyclopropanation reaction of readily available cyclic enones with sulfur ylides. An array of ketone or amide substituted spirocyclopanane derivatives with high molecular complexity were efficiently produced in a concise procedure. A series of chiral spirocyclopananes were also successfully accessed by using a chiral amidic sulfur ylide in excellent yields with moderate to good stereoselectivity. Currently the development of a catalytic asymmetric version of this cyclopropanation is under investigation in our laboratory.