Next Article in Journal
Synthesis of Reusable Silica Nanosphere-Supported Pt(IV) Complex for Formation of Disulfide Bonds in Peptides
Next Article in Special Issue
Facial Regioselective Synthesis of Novel Bioactive Spiropyrrolidine/Pyrrolizine-Oxindole Derivatives via a Three Components Reaction as Potential Antimicrobial Agents
Previous Article in Journal
Recent Advances and Applications of Molecular Docking to G Protein-Coupled Receptors
Previous Article in Special Issue
Cytotoxicity and Antioxidant Potential of Novel 2-(2-((1H-indol-5yl)methylene)-hydrazinyl)-thiazole Derivatives
Article Menu
Issue 2 (February) cover image

Export Article

Molecules 2017, 22(2), 328; doi:10.3390/molecules22020328

Article
Diastereoselective Synthesis of Spirocyclopropanes under Mild Conditions via Formal [2 + 1] Cycloadditions Using 2,3-Dioxo-4-benzylidene-pyrrolidines
Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu 610052, China
*
Correspondence: Tel.: +86-139-8223-5594 (Q.-Z.L.); +86-28-8421-6087 (X.-J.G.); +86-183-8226-5469 (J.-L.L.)
Received: 16 January 2017 / Accepted: 16 February 2017 / Published: 22 February 2017

Abstract

:
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.
Keywords:
spirocyclopropanes; diastereoselective synthesis; catalyst free; sulfur ylide

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.
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.
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 3a3n 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).
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).
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.
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.
Enone substrates with electron-withdrawing or electron-donating groups on the phenyl ring were well tolerated, delivering the desired products 6a6g 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 6h6j 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).

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] D 20 = +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] D 20 = +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] D 20 = +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] D 20 = +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] D 20 = +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] D 20 = +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] D 20 = +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] D 20 = +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] D 20 = +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.

Supplementary Materials

Supplementary Files are available online.

Acknowledgments

Financial support from National Natural Science Foundation of China (no. 21502009), the Science & Technology Department of Sichuan Province (no. 2017JQ0032), Scientific Research Fund of Sichuan Provincial Education Department (no. 16ZB0430), “Thousand Talents Program” of Sichuan Province, and the Start-up Fund of Chengdu University (nos. 2081915026, 2080515047) is gratefully acknowledged.

Author Contributions

Jun-Long Li and Xiao-Jun Gou conceived and designed the experiments; Yi Li, Li Hang and Hong Liang performed the experiments; Hai-Jun Leng and Yue Liu analyzed the data; Yi Li, Kai-Chuan Yang and Xu-Dong Shen contributed reagents and materials; Jun-Long Li and Qing-Zhu Li wrote the paper.

Conflicts of Interest

The authors declare no conflict of interest.

References and Note

  1. Rajesh, S.M.; Perumal, S.; Menéndez, J.C.; Yogeeswari, P.; Sriram, D. Antimycobacterial activity of spirooxindolo-pyrrolidine, pyrrolizine and pyrrolothiazole hybrids obtained by a three-component regio- and stereoselective 1,3-dipolar cycloaddition. Med. Chem. Commun. 2011, 2, 626–630. [Google Scholar] [CrossRef]
  2. Saha, S.; Acharya, C.; Pal, U.; Chowdhury, S.R.; Sarkar, K.; Maiti, N.C.; Jaisankar, P.; Majumder, H.K. A Novel spirooxindole derivative inhibits the growth of leishmania donovani parasites both in vitro and in vivo by targeting type IB topoisomerase. Antimicrob. Agents Chemother. 2016, 60, 6281–6293. [Google Scholar] [CrossRef] [PubMed]
  3. Huang, C.-Y.; Chang, C.-W.; Tseng, Y.-J.; Lee, J.; Sung, P.-J.; Su, J.-H.; Hwang, T.-L.; Dai, C.-F.; Wang, H.-C.; Sheu, J.-H. Bioactive steroids from the formosan soft coral umbellulifera petasites. Mar. Drugs 2016, 14, 180. [Google Scholar] [CrossRef] [PubMed]
  4. Xie, J.; Xing, X.-Y.; Sha, F.; Wu, Z.-Y.; Wu, X.-Y. Enantioselective synthesis of spiro[indoline-3,4′-pyrano[2,3-c]pyrazole] derivatives via an organocatalytic asymmetric Michael/cyclization cascade reaction. Org. Biomol. Chem. 2016, 14, 8346–8355. [Google Scholar] [CrossRef] [PubMed]
  5. Zhang, J.-X.; Wang, H.-Y.; Jin, Q.-W.; Zheng, C.-W.; Zhao, G.; Shang, Y.-J. Thiourea-Quaternary Ammonium salt catalyzed asymmetric 1, 3-dipolar cycloaddition of imino esters to construct spiro[pyrrolidin-3,3′-oxindoles]. Org. Lett. 2016, 18, 4774–4777. [Google Scholar] [CrossRef] [PubMed]
  6. Qiu, Y.; Yang, B.; Zhu, C.; Bäckvall, J.E. Highly efficient cascade reaction for selective formation of spirocyclobutenes from dienallenes via palladium-catalyzed oxidative double carbocyclization-carbonylation-alkynylation. J. Am. Chem. Soc. 2016, 138, 13846–13849. [Google Scholar] [CrossRef] [PubMed]
  7. Schobert, R.; Knauer, S.; Seibt, S.; Biersack, B. Anticancer active illudins: Recent developments of a potent alkylating compound class. Curr. Med. Chem. 2011, 18, 790–807. [Google Scholar] [CrossRef] [PubMed]
  8. McMorris, T.C.; Cong, Q.; Kelner, M.J. Structure−activity relationship studies of illudins: Analogues possessing a spiro-cyclobutane ring. J. Org. Chem. 2003, 68, 9648–9653. [Google Scholar] [CrossRef] [PubMed]
  9. McMorris, T.C.; Kelner, M.J.; Wang, W.; Diaz, M.A.; Estes, L.A.; Taetle, R. Acylfulvenes, a new class of potent antitumor agents. Experientia 1996, 52, 75–80. [Google Scholar] [CrossRef] [PubMed]
  10. Tanasova, M.; Sturla, S.J. Chemistry and biology of acylfulvenes: Sesquiterpene-derived antitumor agents. Chem. Rev. 2012, 112, 3578–3610. [Google Scholar] [CrossRef] [PubMed]
  11. Santos, C.; Ferreirinha, P.; Sousa, H.; Ribeiro, J.; Bastos, M.M.; Neto, T.; Oliveira, P.A.; Medeiros, R.; Vilanova, M.; da Costa, R.M.G. Ptaquiloside from bracken (Pteridium spp.) inhibits tumour-infiltrating CD8+ T cells in HPV-16 transgenic mice. Food Chem. Toxicol. 2016, 97, 277–285. [Google Scholar] [CrossRef] [PubMed]
  12. Boger, D.L.; Hughes, T.V.; Hedrick, M.P. Synthesis, chemical properties, and biological evaluation of CC-1065 and duocarmycin analogues incorporating the 5-methoxycarbonyl-1,2,9,9a-tetrahydrocyclopropa. J. Org. Chem. 2001, 66, 2207–2216. [Google Scholar] [CrossRef] [PubMed]
  13. Boger, D.L.; Boyce, C.W.; Garbaccio, R.M.; Goldberg, J.A. CC-1065 and the duocarmycins: Synthetic studies. Chem. Rev. 1997, 97, 787–828. [Google Scholar] [CrossRef] [PubMed]
  14. Kumari, R.; Nguyen, M.H. Fixed-dose combination of sofosbuvir and ledipasvir for the treatment of chronic hepatitis C genotype 1. Expert. Opin. Pharmacother. 2015, 16, 739–748. [Google Scholar] [CrossRef] [PubMed]
  15. Younossi, Z.M.; Stepanova, M.; Marcellin, P.; Afdhal, N.; Kowdley, K.V.; Zeuzem, S.; Hunt, S.L. Treatment with ledipasvir and sofosbuvir improves patient-reported outcomes: Results from the ION-1, -2, and -3 clinical trials. Hepatology 2015, 61, 1798–1808. [Google Scholar] [CrossRef] [PubMed]
  16. Berman, H.M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T.N.; Weissig, H.; Shindyalov, I.N.; Bourne, P.E. The protein data bank. Nucleic Acids Res. 2000, 28, 235–242. [Google Scholar] [CrossRef] [PubMed]
  17. René, O.; Stepek, I.A.; Gobbi, A.; Fauber, B.P.; Gaines, S. Palladium-catalyzed ring expansion of spirocyclopropanes to form caprolactams and azepanes. J. Org. Chem. 2015, 80, 10218–10225. [Google Scholar]
  18. Gopalakrishnan, B.; Mohan, S.; Parella, R.; Babu, S.A. Diastereoselective Pd(II)-catalyzed sp3 C-H arylation followed by ring opening of cyclopropanecarboxamides: Construction of anti β-Acyloxy carboxamide derivatives. J. Org. Chem. 2016, 81, 8988–9005. [Google Scholar] [CrossRef] [PubMed]
  19. Chen, H.-Y.; Zhang, J.; Wang, D.Z. Gold-catalyzed rearrangement of alkynyl donor-acceptor cyclopropanes to construct highly functionalized alkylidenecyclopentenes. Org. Lett. 2015, 17, 2098–2101. [Google Scholar] [CrossRef] [PubMed]
  20. Fu, X.; Lin, L.-L.; Xia, Y.; Zhou, P.-F.; Liu, X.-H.; Feng, X.-M. Catalytic asymmetric [3 + 3] annulation of cyclopropanes with mercaptoacetaldehyde. Org. Biomol. Chem. 2016, 14, 5914–5917. [Google Scholar] [CrossRef] [PubMed]
  21. Zhang, R.; Liang, Y.-J.; Zhou, G.-Y.; Wang, K.-W.; Dong, D.-W. Ring-enlargement of dimethylaminopropenoyl cyclopropanes: An efficient route to substituted 2,3-dihydrofurans. J. Org. Chem. 2008, 73, 8089–8092. [Google Scholar] [CrossRef] [PubMed]
  22. Zhang, Z.-G.; Zhang, W.; Li, J.-L.; Liu, Q.-F.; Liu, T.-X.; Zhang, G.-S. Synthesis of multisubstituted pyrroles from doubly activated cyclopropanes using an iron-mediated oxidation domino reaction. J. Org. Chem. 2014, 79, 11226–11233. [Google Scholar] [CrossRef] [PubMed]
  23. Rösner, C.; Hennecke, U. Homohalocyclization: Electrophilic bromine-induced cyclizations of cyclopropanes. Org. Lett. 2015, 17, 3226–3229. [Google Scholar] [CrossRef] [PubMed]
  24. Tsunoi, S.; Maruoka, Y.; Suzuki, I.; Shibata, I. Catalytic [3 + 2] cycloaddition through ring cleavage of simple cyclopropanes with isocyanates. Org. Lett. 2015, 17, 4010–4013. [Google Scholar] [CrossRef] [PubMed]
  25. Kaicharla, T.; Roy, T.; Thangaraj, M.; Gonnade, R.G.; Biju, A.T. Lewis acid catalyzed selective reactions of donor-acceptor cyclopropanes with 2-naphthols. Angew. Chem. Int. Ed. 2016, 55, 10061–10064. [Google Scholar] [CrossRef] [PubMed]
  26. Nambu, H.; Ono, N.; Yakura, T. Acid-catalyzed ring-opening cyclization of spirocyclopropanes for the construction of a 2-arylbenzofuran skeleton: Total synthesis of cuspidan B. Synthesis 2016, 48, 1892–1901. [Google Scholar] [CrossRef]
  27. Nambu, H.; Fukumoto, M.; Hirota, W.; Yakura, T. Ring-opening cyclization of cyclohexane-1,3-dione-2-spirocyclopropanes with amines: Rapid access to 2-substituted 4-hydroxyindole. Org. Lett. 2014, 16, 4012–4015. [Google Scholar] [CrossRef] [PubMed]
  28. Chanthamath, S.; Iwasa, S. Enantioselective cyclopropanation of a wide variety of olefins catalyzed by Ru(II)-Pheox complexes. Acc. Chem. Res. 2016, 49, 2080–2090. [Google Scholar] [CrossRef] [PubMed]
  29. Schröder, F. Present and future of cyclopropanations in fragrance chemistry. Chem. Biodivers. 2014, 11, 1734–1751. [Google Scholar] [CrossRef] [PubMed]
  30. Lebel, H.; Marcoux, J.F.; Molinaro, C.; Charette, A.B. Stereoselective cyclopropanation reactions. Chem. Rev. 2003, 103, 977–1050. [Google Scholar] [CrossRef] [PubMed]
  31. Donaldson, W.A. Synthesis of cyclopropane containing natural products. Tetrahedron 2001, 57, 8589–8627. [Google Scholar] [CrossRef]
  32. Shchepin, V.V.; Stepanyan, Y.G.; Silaichev, P.S.; Ezhikova, M.A.; Kodess, M.I. Reactions of bromine-containing organozinc compounds derived from α,α-dibromo ketones with 2-arylmethylideneindan-1,3-diones and 5-arylmethylidene-2,2-dimethyl-1,3-dioxane-4,6-diones. Russ. J. Org. Chem. 2010, 46, 499–502. [Google Scholar] [CrossRef]
  33. Russo, A.; Meninno, S.; Tedesco, C.; Lattanzi, A. Synthesis of Activated Cyclopropanes by an MIRC Strategy: An enantioselective organocatalytic approach to spirocyclopropanes. Eur. J. Org. Chem. 2011, 2011, 5096–5103. [Google Scholar] [CrossRef]
  34. Wang, G.-W.; Gao, J. Selective formation of spiro dihydrofurans and cyclopropanes through unexpected reaction of aldehydes with 1,3-dicarbonyl compounds. Org. Lett. 2009, 11, 2385–2388. [Google Scholar] [CrossRef] [PubMed]
  35. Yoshida, J.-I.; Yamamoto, M.; Kawabata, N. Electrochemical reduction of dibromodiketones facile [3 + 2] cycloaddition with olefins. Tetrahedron Lett. 1985, 26, 6217–6220. [Google Scholar] [CrossRef]
  36. Qian, P.; Du, B.-N.; Song, R.-C.; Wu, X.-D.; Mei, H.-B.; Han, J.-L.; Pan, Y. N-Iodosuccinimide-initiated spirocyclopropanation of styrenes with 1,3-dicarbonyl compound for the synthesis of spirocyclopropanes. J. Org. Chem. 2016, 81, 6546–6553. [Google Scholar] [CrossRef] [PubMed]
  37. Lautens, M.; Klute, W.; Tam, W. Transition metal-mediated cycloaddition reactions. Chem. Rev. 1996, 96, 49–92. [Google Scholar] [CrossRef] [PubMed]
  38. Young, I.S.; Qiu, Y.-P.; Smith, M.J.; Hay, M.B.; Doubleday, W.W. Preparation of a tricyclopropylamino acid derivative via Simmons–Smith cyclopropanation with downstream intramolecular aminoacetoxylation for impurity control. Org. Process Res. Dev. 2016, 20, 2108–2115. [Google Scholar] [CrossRef]
  39. Lévesque, E.; Goudreauand, S.R.; Charette, A.B. Improved zinc-catalyzed Simmons-Smith reaction: Access to various 1,2,3-trisubstituted cyclopropanes. Org. Lett. 2014, 16, 1490–1493. [Google Scholar] [CrossRef] [PubMed]
  40. Lu, T.; Hayashi, R.; Hsung, R.P.; DeKorver, K.A.; Lohse, A.G.; Song, Z.; Tang, Y. Synthesis of amido-spiro[2.2]pentanes via Simmons-Smith cyclopropanation of allenamides. Org. Biomol. Chem. 2009, 7, 3331–3337. [Google Scholar] [CrossRef] [PubMed]
  41. Davies, S.G.; Ling, K.B.; Roberts, P.M.; Russell, A.J.; Thomson, J.E. Diastereoselective Simmons-Smith cyclopropanations of allylic amines and carbamates. Chem. Commun. 2007, 39, 4029–4031. [Google Scholar] [CrossRef] [PubMed]
  42. Pellissier, H. Recent developments in asymmetric cyclopropanation. Tetrahedron 2008, 64, 7041–7095. [Google Scholar] [CrossRef]
  43. Su, Y.; Li, Q.-F.; Zhao, Y.-M.; Gu, P.-M. Preparation of optically active cis-cyclopropane carboxylates: Cyclopropanation of α-silyl stryenes with aryldiazoacetates and desilylation of the resulting silyl cyclopropanes. Org. Lett. 2016, 18, 4356–4359. [Google Scholar] [CrossRef] [PubMed]
  44. Rosenfeld, M.J.; Shankar, B.K.R.; Shechter, H. Rhodium(II) acetate-catalyzed reactions of 2-diazo-1,3-indandione and 2-diazo-1-indanone with various substrates. J. Org. Chem. 1988, 53, 2699–2705. [Google Scholar] [CrossRef]
  45. Su, Y.; Bai, M.; Qiao, J.-B.; Li, X.-J.; Li, R.; Tu, Y.-Q.; Gu, P.-M. Diastereo- and enantioselective cyclopropanation of alkyenyl fluorides with benzyl diazoarylacetates. Tetrahedron Lett. 2015, 56, 1805–1807. [Google Scholar] [CrossRef]
  46. Arai, S.; Nakayama, K.; Hatano, K.; Shioiri, T. Stereoselective synthesis of cyclopropane rings under phase-transfer-catalyzed conditions. J. Org. Chem. 1998, 63, 9572–9575. [Google Scholar] [CrossRef]
  47. Miyagawa, T.; Tatenuma, T.; Tadokoro, M.; Satoh, T. A short and stereoselective synthesis of highly substituted cyclopropanes from α,β-unsaturated carbonyl compounds with dichloromethyl p-tolyl sulfoxide. Tetrahedron 2008, 64, 5279–5284. [Google Scholar] [CrossRef]
  48. Elinson, M.N.; Feducovich, S.K.; Vereshchagin, A.N.; Gorbunov, S.V.; Belyakov, P.A.; Nikishin, G.I.; Wang, Q.-F.; Song, X.-K.; Chen, J.; Yan, C.-G. Pyridinium ylide-assisted one-pot two-step tandem synthesis of polysubstituted cyclopropanes. J. Comb. Chem. 2009, 11, 1007–1010. [Google Scholar]
  49. Li, A.-H.; Dai, L.-X.; Aggarwal, V.K. Asymmetric ylide reactions: Epoxidation, cyclopropanation, aziridination, olefination, and rearrangement. Chem. Rev. 1997, 97, 2341–2372. [Google Scholar] [CrossRef] [PubMed]
  50. McGarrigle, E.M.; Myers, E.L.; Illa, O.; Shaw, M.A.; Riches, S.L.; Aggarwal, V.K. Chalcogenides as organocatalysts. Chem. Rev. 2007, 107, 5841–5883. [Google Scholar] [CrossRef] [PubMed]
  51. Luo, J.; Wu, B.; Chen, M.-W.; Jiang, G.-F.; Zhou, Y.-G. The concise synthesis of spiro-cyclopropane compounds via the dearomatization of indole derivatives. Org. Lett. 2014, 16, 2578–2581. [Google Scholar] [CrossRef] [PubMed]
  52. Yuan, Z.-B.; Fang, X.-X.; Li, X.-Y.; Wu, J.; Yao, H.-Q.; Lin, A.-J. 1,6-Conjugated addition-mediated [2 + 1] annulation: Approach to spiro[2.5]octa-4,7-dien-6-one. J. Org. Chem. 2015, 80, 11123–11130. [Google Scholar] [CrossRef] [PubMed]
  53. Zhang, S.; Hu, X.-Q.; Wang, Z.-Y.; Xu, P.-F. Reactions of sulfonium salts with 2,3-dioxopyrrolidine derivatives: A concise synthesis of spirocyclopropane. Synthesis 2015, 47, 2529–2537. [Google Scholar]
  54. Nambu, H.; Ono, N.; Hirota, W.; Fukumoto, M.; Yakura, T. An efficient method for the synthesis of 2′,3′-nonsubstituted cycloalkane-1,3-dione-2-spirocyclopropanes using (2-bromoethyl)diphenylsulfonium trifluoromethanesulfonate. Chem. Pharm. Bull. (Tokyo) 2016, 64, 1763–1768. [Google Scholar] [CrossRef] [PubMed]
  55. Nambu, H.; Fukumoto, M.; Hirota, W.; Ono, N.; Yakura, T. An efficient synthesis of cycloalkane-1,3-dione-2-spirocyclopropanes from 1,3-cycloalkanediones using (1-aryl-2-bromoethyl)-dimethylsulfonium bromides: Application to a one-pot synthesis of tetrahydroindol-4(5H)-one. Tetrahedron Lett. 2015, 56, 4312–4315. [Google Scholar] [CrossRef]
  56. Liao, W.-W.; Li, K.; Tang, Y. Controllable diastereoselective cyclopropanation. Enantioselective synthesis of vinylcyclopropanes via chiral telluronium ylides. J. Am. Chem. Soc. 2003, 125, 13030–13031. [Google Scholar] [CrossRef] [PubMed]
  57. Zheng, J.-C.; Liao, W.-W.; Tang, Y.; Sun, X.-L.; Dai, L.-X. The michael addition-elimination of ylides to α,β-unsaturated imines. Highly stereoselective synthesis of vinylcyclopropanecarbaldehydes and vinylcyclopropylaziridines. J. Am. Chem. Soc. 2005, 127, 12222–12223. [Google Scholar] [CrossRef] [PubMed]
  58. Cao, W.-G.; Zhang, H.; Chen, J.; Zhou, X.-H.; Shao, M.; McMills, M.C. Stereoselective synthesis of highly substituted trans-2,3-dihydrofuran and trans-1,2-cyclopropane derivatives containing sulfonyl groups. Tetrahedron 2008, 64, 163–167. [Google Scholar] [CrossRef]
  59. Wu, X.-Y.; Cao, W.-G.; Zhang, H.; Chen, J.; Jiang, H.-Y.; Deng, H.-M.; Shao, S.; Zhang, J.-P.; Chen, H.-Y. Highly stereoselective synthesis of β,γ-disubstituted and α,β,γ-trisubstituted butyrolactones. Tetrahedron 2008, 64, 10331–10338. [Google Scholar] [CrossRef]
  60. Zhao, Y.-H.; Zheng, C.-W.; Zhao, G.; Cao, W.-G. Highly enantioselective tandem cyclopropanation/Wittig reaction of α,β-unsaturated aldehydes with arsonium ylides catalyzed by recyclable dendritic catalyst. Tetrahedron Asymmetry 2008, 19, 701–708. [Google Scholar] [CrossRef]
  61. Cao, W.-G.; Zhang, H.; Chen, J.; Deng, H.-M.; Shao, M.; Lei, L.; Qian, J.-X.; Zhu, Y. A facile preparation of trans-1,2-cyclopropanes containing p-trifluoromethylphenyl group and its application to the construction of pyrazole and cyclopropane ring fused pyridazinone derivatives. Tetrahedron 2008, 64, 6670–6674. [Google Scholar] [CrossRef]
  62. Papageorgiou, C.D.; Cubillo de Dios, M.A.; Ley, S.V.; Gaunt, M.J. Enantioselective organocatalytic cyclopropanation via ammonium ylides. Angew. Chem. Int. Ed. 2004, 43, 4641–4644. [Google Scholar] [CrossRef] [PubMed]
  63. Vanecko, J.A.; Wan, H.; West, F.G. Recent advances in the Stevens rearrangement of ammonium ylides. Application to the synthesis of alkaloid natural products. Tetrahedron 2006, 62, 1043–1062. [Google Scholar] [CrossRef]
  64. Jończyk, A.; Konarska, A. Generation and reactions of ammonium ylides in basic two-phase systems: Convenient synthesis of cyclopropanes, oxiranes and alkenes substituted with electron-withdrawing groups. Synlett 1999, 7, 1085–1087. [Google Scholar] [CrossRef]
  65. Kowalkowska, A.; Sucholbiak, D.; Jończyk, A. Generation and reaction of ammonium ylides in basic two-phase systems. Eur. J. Org. Chem. 2005, 925–933. [Google Scholar]
  66. Li, J.-L.; Yang, K.-C.; Li, Y.; Li, Q.; Zhu, H.-P.; Han, B.; Peng, C.; Zhi, Y.-G.; Gou, X.-J. Asymmetric synthesis of bicyclic dihydropyrans via organocatalytic inverse-electron-demand oxo-Diels-Alder reactions of enolizable aliphatic aldehydes. Chem. Commun. 2016, 52, 10617–10620. [Google Scholar] [CrossRef] [PubMed]
  67. Li, J.-L.; Li, Q.; Yang, K.-C.; Li, Y.; Zhou, L.; Han, B.; Peng, C.; Gou, X.-J. A practical green chemistry approach to synthesize fused bicyclic 4H-pyranes via an amine catalysed 1,4-addition and cyclization cascade. RSC Adv. 2016, 6, 38875–38879. [Google Scholar] [CrossRef]
  68. Kaufmann, D.; West, P.J.; Smith, M.D.; Yagen, B.; Bialer, M.; Devor, M.; White, H.S.; Brennan, K.C. sec-Butylpropylacetamide (SPD), a new amide derivative of valproic acid for the treatment of neuropathic and inflammatory pain. Pharmacol. Res. 2016, 117, 129–139. [Google Scholar] [CrossRef] [PubMed]
  69. Mathieson, S.R.; Livingstone, V.; Low, E.; Pressler, R.; Rennie, J.M.; Boylan, G.B. Phenobarbital reduces EEG amplitude and propagation of neonatal seizures but does not alter performance of automated seizure detection. Clin. Neurophysiol. 2016, 127, 3343–3350. [Google Scholar] [CrossRef] [PubMed]
  70. CCDC 1478324 (3n) and CCDC 1524538 (6e) Contain the Supplementary Crystallographic Data for This Paper. These Data can Be Obtained Free of Charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
  71. Krell, E. Handbook of Laboratory Distillation; Elsevier Publishing Company: Amsterdam, The Netherlands, 1963. [Google Scholar]
  72. Rosengart, M.J. The Technique of Distillation and Rectification in the Laboratory; VEB Verlag Technik: Berlin, Germany, 1954. [Google Scholar]
  73. Stage, H. Columns for laboratory distillation. Angew. Chem. 1947, B19, 175. [Google Scholar] [CrossRef]
  74. Southwick, P.L.; Barnas, E.F. 4-Benzylidine-2,3-dioxopyrrolidines and 4-benzyl-2,3-dioxopyrrolidines. synthesis and experiments on reduction and alkylation. J. Org. Chem. 1962, 27, 98–106. [Google Scholar] [CrossRef]
  • Sample Availability: All samples 3, 5 and 6 are available from the authors.
Figure 1. Selected products containing spirocyclopropanane possess biological activities.
Figure 1. Selected products containing spirocyclopropanane possess biological activities.
Molecules 22 00328 g001
Scheme 1. Scale-up experiment of the cyclopropanation reaction.
Scheme 1. Scale-up experiment of the cyclopropanation reaction.
Molecules 22 00328 sch001
Figure 2. Single crystal X-ray diffraction analysis of products 3n and 6e.
Figure 2. Single crystal X-ray diffraction analysis of products 3n and 6e.
Molecules 22 00328 g002
Table 1. Screening studies of the cyclopropanation reaction a.
Table 1. Screening studies of the cyclopropanation reaction a.
Molecules 22 00328 i001
EntrySolventd.r. bYield (%) c
1DCM93:786
2CHCl396:494
3DCE94:690
4THF97:379
51,4-dioxane98:292
6MeOH53:4776
7EtOH68:3274
8MeCN84:1692
9Toluene87:1388
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.
Table 2. Substrates scope of cyclopropanation of cyclic enones 1 with sulfur ylides 2 a.
Table 2. Substrates scope of cyclopropanation of cyclic enones 1 with sulfur ylides 2 a.
Molecules 22 00328 i002
EntryR1R2R3Productd.r. bYield (%) c
1PhBnPh3a98:292
23-MeC6H4BnPh3b92:883
34-MeC6H4BnPh3c98:293
42-MeOC6H4BnPh3d92:883
53-MeOC6H4BnPh3e97:391
64-MeOC6H4BnPh3f96:494
74-FC6H4BnPh3g96:488
82-ClC6H4BnPh3h97:398
93-ClC6H4BnPh3i97:394
104-ClC6H4BnPh3j96:459
113-BrC6H4BnPh3k94:684
124-BrC6H4BnPh3l96:457
133,4-(MeO)2C6H3BnPh3m98:281
14 d2,4-Cl2C6H3BnPh3n>99:199
151-NaphthylBnPh3o94:694
162-ThienylBnPh3p98:286
17PhPMBPh3q98:290
18 ePhBnOEt3r92:899
19 ePhBnOt-Bu3s90:1099
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.
Table 3. Further studies of the cyclopropanation of cyclic enone 1 and sulfonium salts 4 a.
Table 3. Further studies of the cyclopropanation of cyclic enone 1 and sulfonium salts 4 a.
Molecules 22 00328 i003
EntryR1R2Productd.r. bYield (%) c
1PhBn5a96:498
2PhPMB5b>99:199
33-MeC6H4Bn5c97:399
43-MeC6H4PMB5d94:692
54-ClC6H4Bn5e91:999
62-ClC6H4PMB5f94:698
7 d2-NaphthylBn5g> 99:185
8 d2-NaphthylPMB5h> 99:190
9 d2-ThienylBn5i> 99:183
10 d2-ThienylPMB5j> 99:181
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.
Table 4. Optimization of reaction condition for the synthesis of chiral spirocyclopropane 6a a.
Table 4. Optimization of reaction condition for the synthesis of chiral spirocyclopropane 6a a.
Molecules 22 00328 i004
EntryBaseX (eq.)Timed.r. bYield (%) c
1TMG1.024 h72:2899
2DBU1.024 h62:3899
3KOH1.515 min65:3599
4tBuOK1.510 min68:3295
5K2CO32.072 h68:3292
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.
Table 5. Substrates scope of cyclopropanation of cyclic enones 1 with chiral sulfonium salt 4c a.
Table 5. Substrates scope of cyclopropanation of cyclic enones 1 with chiral sulfonium salt 4c a.
Molecules 22 00328 i005
EntryR1Productd.r. bYield(%) c
1Ph6a72:2899
24-MeC6H46b70:3097
34-MeOC6H46c64:3691
44-FC6H46d81:1992
5 d2-ClC6H46e70:3090
64-BrC6H46f62:3881
7 e1-Naphthyl6g72:2897
8 e2-Naphthyl6h77:2399
9 e2-Thienyl6i60:4090
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.
Molecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top