Supporting Information for: Facile Synthesis of Spirocyclic lactams from β keto Carboxylic Acids

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1 Supporting Information for: Facile Synthesis of Spirocyclic lactams from β keto Carboxylic Acids Wei Yang, Xianyu Sun, Wenbo Yu, Rachita Rai, Jeffrey R. Deschamps, Lauren A. Mitchell, Chao Jiang, Alexander D. MacKerell, Jr., and Fengtian Xue., * Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, Maryland 21201, United States Naval Research Laboratory, Code 6930, 4555 Overlook Ave., Washington, DC 20375, United States Department of Pharmaceutical Engineering, School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu , China Table of Contents 1. General Information S2 2. General Procedure for the Synthesis of Compound 2a S2 3. General Procedure for the Synthesis of Compound 3 S3 4. General Procedure for the Synthesis of Starting Materials 5a-e S4 5. General Procedure for the Synthesis of Keto-Lactams 4 and 6 S4 6. Procedures for Ketone reduction, Phenylation and Cyclization S5 7. Characterization data of New Compounds S6 8. Computational Methods S H NMR and 13 C NMR Spectra of New Compounds S X-ray crystal data of compounds (please find detailed information in the other SI document) 11. References for SI S33 S1

2 1. General Information All experiments were conducted using anhydrous conditions under an atmosphere of nitrogen. Solvents (Toluene, CH 3 CN, DCM, THF and DMF) were taken from the Glass Contour Solvent Purification System. Other solvents and all reagents were used as received. Aqueous solutions of sodium chloride (brine) were saturated. Analytical thin layer chromatography (TLC) plates were visualized by ultraviolet irradiation or iodine staining. Flash column chromatography was carried out under a positive pressure of nitrogen. 1 H NMR spectra were recorded on 400 MHz or 500 MHz spectrometers. Data are presented as follows: chemical shift (in ppm on the δ scale relative to δ = 0.00 ppm for the protons in TMS), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad), coupling constant (J/Hz), which was taken directly from the spectra and are uncorrected, and integration. 13 C NMR spectra were recorded at 100 or 125 MHz, and all chemical shift values are reported in ppm on the δ scale, with an internal reference of δ 77.0 or 39.5 for CDCl 3 or DMSO-d 6, respectively. Low- resolution mass spectra were measured using liquid chromatography mass spectrometry (LC-MS). High-resolution mass spectra were measured using electrospray (EI). 2. General Procedure for the Synthesis of Compound 2a To a solution of 1a (1.0 mmol) in t-butanol (5 ml) was added DPPA (1.1 mmol) and Et 3 N (2.0 mmol) at room temperature. The mixture was stirred at 50 C for 16 h. The solvent was removed under reduced pressure, and the crude material was purified by silica gel column flash chromatography (Ethyl acetate/hexane, v/v = 1/2) to give compound 2a (97 mg, 65%) as an orange solid. mp o C. 1 H NMR (400 MHz, CDCl 3 ) δ (m, 1H), 2.37 (s, 3H), 2.55 (m, 1H), (m, 1H), (m, 1H), (m, 1H), 6.86 (s, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 22.4, 29.9, 40.5, 54.8, 173.8, ESI-MS m/z (M+Na + ) calcd for C 6 H 9 NNaO 2 150, found 150. S2

3 3. General Procedure for the Synthesis of Compound 3 Scheme S1. Synthetic route for compounds 3a-j Step 1. Synthesis of the intermediate II. To a suspension of NaH (22 mmol) in dimethyl carbonate (8.0 ml) or diethyl carbonate (8.0 ml) was added compound I (10 mmol) dropwise. The reaction was stirred at 80 o C overnight, and then cooled to room temperature. To the solution was added water, extracted with EaOAc, the combined organic phase was washed with brine, dried over anhydrous Na 2 SO 4, and concentrated. The resulting crude product was purified by flash chromatography (Ethyl acetate/hexane, v/v = 1/20) to give intermediate II as light yellow oil. Step 2. Synthesis of the intermediate III. To a solution of II (6.0 mmol) in MeOH (5 ml) was added ethyl acrylate (1.2 g, 12 mmol) and DMAP (366 mg, 3 mmol). The reaction mixture was stirred at room temperature for 5-16 h, and concentrated. The resulting crude product was purified by flash chromatography (Ethyl acetate/hexane, v/v = 1/10) to give intermediate III as yellow oil. Step 3. Synthesis of starting materials 3a-j. A solution of intermediate III (5 mmol) in HCl (6 N, 30 ml) was stirred at 90 o C overnight. Then the mixture was cooled in ice bath, and the precipitate was formed, filtered and washed to give compounds 3a-j as white solid. S3

4 4. General Procedure for the Synthesis of Starting Materials 5a-e Scheme S2. Synthetic route for compounds 5a-e Step 1. Synthesis of diester V. To a solution of diethyl malonate (1.6 g, 10 mmol) in THF (20 ml) at 0 C was added NaOEt (680 mg, 10 mmol) followed by compound IV (10 mmol). The reaction mixture was allowed to stir at room temperature overnight. The solvent was removed by rotary evaporation. The resulting residue was dissolved in EtOAc (50 ml), washed with brine, dried over Na 2 SO 4, and concentrated. The crude product was purified by flash chromatography (Ethyl acetate/hexane, v/v = 1/20) to give compound V as colorless oil. Step 2. Synthesis of starting materials 5a-e. A solution of intermediate V (5.0 mmol) in HCl (6N, 30 ml) was stirred at 90 o C overnight. The mixture was cooled to room temperature, extracted with EtOAc. The combined organic layers were washed with brine, dried over Na 2 SO 4 and concentrated. The crude product was purified by chromatography to yield 5a-e as white solid. 5. General Procedure for the Synthesis of Keto-Lactams 4 and 6 Scheme S3. Synthetic route for keto-lactams 4a-j, 6a-e To a solution of 3 or 5 (1.0 mmol) in tert-butanol (5 ml) was added DPPA (1.1 mmol) and Et 3 N (2.0 mmol) at room temperature. The mixture was stirred at 50 C for 16 h. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (Ethyl acetate/hexane, v/v = 1/2 to 1/1) to give the title product as a white solid. S4

5 6. Procedures for Ketone reduction, Phenylation and Cyclization To a solution of lactam 4b (30 mg, 0.15 mmol) in MeOH (1 ml) at 0 o C was added NaBH 4 (7 mg, 0.18 mmol). The reaction mixture was allowed to stir at room temperature for an additional 2 h. The solvent was removed under vacuum and the resulting crude material was purified by column chromatography (Ethyl acetate/hexane, v/v = 1/2 to 1/1) to give alcohol 7 (26 mg, 88 %) as a white solid. mp o C. 1 H NMR (400 MHz, CDCl 3 ) δ (t, J = 4.8 Hz, 1H), (m, 3H), 6.70 (s, 1H), 5.02 (s, 1H), 3.90 (br, 1H), (d, J = 16 Hz, 1H), (m, 2H), (d, J = 16 Hz, 1H), (m, 1H), (m, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ , , , , , , , 82.18, 53.60, 40.18, 39.53, HRMS [M + H] + (ESI-TOF) calcd for C 12 H 14 NO , found To a solution of lactam 4b (30 mg, 0.15 mmol) and iodobenzene (62 mg, 0.3 mmol) in DMSO (0.5 ml) was added CuI (3 mg, mmol) followed by K 3 PO 4 (70 mg, 0.33 mmol). The reaction mixture was stirred at 120 o C for 12 h. The mixture was cooled to room temperature, and poured into water. The mixture was extracted with ethyl acetate for three times. The combined organic phase was washed with brine, dried over Na 2 SO 4, and concentrated. The resulting crude material was purified by column chromatography (Ethyl acetate/hexane, v/v = 1/4) to give compound 8 as a white solid (37 mg, 90%). mp o C. 1 H NMR (400 MHz, CDCl 3 ) δ (d, J = 8.0 Hz, 1H), (d, J = 8.0 Hz, 2H), (d, J = 8.0 Hz, 1H), (d, J = 8.0 Hz, 1H), (m, 3H), (t, J = 8.0 Hz, 1H), (m, 1H), (dt, J 1 = 2.4 Hz, J 2 = 5.2 Hz), (d, J = 17.2 Hz, 1H), (d, J = 17.2 Hz, 1H), (m, 1H), (m, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 204.3, 172.0, 153.6, 139.3, 135.4, 134.8, 128.8, 127.8, 126.4, 124.9, 124.6, 120.1, 60.2, 46.3, 37.9, HRMS [M + H] + (ESI-TOF) calcd for C 18 H 15 NO , found S5

6 To a solution of lactam 4b (30 mg, 0.15 mmol) and 1-iodo-2-nitrobenzene (75 mg, 0.3 mmol) in dioxane (1 ml) was added CuI (12 mg, 0.06 mmol), followed by K 3 PO 4 (160 mg, 0.75 mmol) and glycine (9 mg, 0.12 mmol). The reaction mixture was stirred at 100 o C until the starting material was completely consumed. The mixture was extracted with ethyl acetate for three times, the combined organic phase was dried over Na 2 SO 4 and concentrated. The residue was purified by column chromatography to give the phenylation product as a solid. The solid was re-dissolved in acetic acid (1 ml). To the resulting solution was added Iron powder (80 mg). The reaction mixture was heated under reflux for an additional 2 h. The acid was removed under vacuum, and the residue was suspended in saturated NaHCO 3 and extracted with ethyl acetate. The combined crude product was purified by column chromatography (Ethyl acetate/hexane, v/v = 1/4) to give compound 9 as a solid (32 mg, 77% for two steps). mp o C. 1 H NMR (400 MHz, CDCl 3 ) δ (d, J = 7.6 Hz, 1H), (m, 2H), (d, J = 7.6 Hz, 1H), (t, J = 7.6 Hz, 1H), (d, J = 7.6 Hz, 1H), (m, 2H), (m, 1H), (dt, J 1 = 2.8 Hz, J 2 = 9.2 Hz, 1H), (d, J = 17.2 Hz, 1H), (d, J = 17.2 Hz, 1H), (m, 1H), (m, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 203.9, 160.8, 152.9, 148.1, 135.7, 134.3, 132.4, 128.1, 126.5, 125.1, 122.1, 122.0, 119.9, 109.8, 52.9, 42.0, 39.4, HRMS [M + H] + (ESI-TOF) calcd for C 18 H 15 N 2 O , found Characterization data of New Compounds Methyl 1-oxo-2,3-dihydro-1H-indene-2-carboxylate (IIb). Yellow oil. Yield: 83%, 1.58 g. 1 H NMR (400 MHz, CDCl 3 ) δ (d, J = 8.0 Hz, 1H), (m, 1.18H, keto+enol), (m, 1H), (m, 1.31H, keto+enol), 3.86 (s, 0.5H, enao), 3.80 (s, 3H), (dd, J = 4.0, 8.0 Hz, 1H), (dd, J = 4.0, 18.0 Hz, 1H), (dd, J = 8.0, 18.0 Hz, 1H), 2.35 (s, 0.33H, enol); 13 C NMR (100 MHz, CDCl 3 ) δ 199.4, 169.5, 153.6, 135.4, (enol), 129.4, 127.8, (enol), 126.5, 124.7, (enol), 53.1, 51.2 (enol), 52.7, 32.5 (enol), Methyl 2-(3-methoxy-3-oxopropyl)-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (IIIb). Yellow oil. Yield: 83%, 1.37 g. 1 H NMR (400 MHz, CDCl 3 ) δ (d, J = 8.0 Hz, 1H), (t, J = 7.2, 7.6 Hz, 1H), (d, J = 8.0 Hz, 1H), (t, J = 6.8, 8.0 Hz, 1H), (m, 4H), 3.55 (s, 3H), (d, J = 17.2 Hz, 1H), (m, 4H); 13 C NMR (100 MHz, CDCl 3 ) δ 201.8, 173.0, 171.1, 152.6, 135.5, 134.9, 127.9, 126.4, 124.7, 59.3, 52.7, 51.6, 37.1, 29.6, S6

7 3-(1-Oxo-2,3-dihydro-1H-inden-2-yl)propanoic acid (3b). White solid. Yield: 75%, 765 mg. 1 H NMR (400 MHz, CDCl 3 ) δ (m, 1H), (m, 1H), (m, 1H), (t, J = 7.6, 7.6 Hz, 2H), (m, 1H), (m, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 208.0, 178.8, 153.3, 136.5, 134.9, 127.6, 126.5, 124.0, 46.2, 32.8, 31.7, Methyl 6-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (IIc). Yellow oil. Yield: 65%, 1.32 g. 1 H NMR (400 MHz, CDCl 3 ) δ 7.57 (s, 1H), (m, 1H), (m, 1H), 3.79 (s, 3H), (dd, J = 4.0, 8.0 Hz, 1H), (dd, J = 4.0, 17.2 Hz, 1H), (dd, J = 8.0, 17.2 Hz, 1H), 2.40 (s, 3H), 13 C NMR (100 MHz, CDCl 3 ) δ 199.5, 169.7, 151.0, 137.8, 136.8, 135.4, 126.2, 124.6, 53.5, 52.7, Methyl 2-(3-ethoxy/methoxy-3-oxopropyl)-6-methyl-1-oxo-2,3-dihydro-1H-indene-2- carboxylate (IIIc). Yellow oil. Yield: 86% (a mixture of methyl and ethyl esters), 1.56 g. 1 H NMR (400 MHz, CDCl 3 ) δ 7.56 (s, 1H), (d, J = 8.0 Hz, 1H), (d, J = 8.0 Hz, 1H), (q, J = 6.8, 7.2 Hz, 1.19H), 3.68 (s, 3H), (m, 2.42H), (d, J = 17.2 Hz, 1H), 2.40 (s, 3H), (m, 4H), (t, J = 6.8, 7.2 Hz, 1.87H). 3-(6-Methyl-1-oxo-2,3-dihydro-1H-inden-2-yl)propanoic acid (3c). White solid. Yield: 82%, 893 mg. 1 H NMR (400 MHz, CDCl 3 ) δ 7.55 (s, 1H), (d, J = 8.0 Hz, 1H), (d, J = 7.6 Hz, 1H), (m, 1H), (m, 2H), (t, J = 7.2, 8.0 Hz, 2H), 2.40 (s, 3H), (m, 1H), (m, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 208.1, 178.4, 150.6, 137.5,136.2, 126.2, 123.9, 46.5, 32.4, 31.6, 26.4, Ethyl 5-methoxy-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (IId). Yellow oil. Yield: 77%, 1.80 g. 1 H NMR (400 MHz, CDCl 3 ) δ (d, J = 9.2 Hz, 1H); 6.92 (m, 2H), (q, J = 6.8, 7.2 Hz, 2H), 3.90 (s, 3H), (dd, J = 3.3, 7.6 Hz, 1H), (dd, J = 3.3, S7

8 17.6 Hz, 1H), (dd, J = 7.6, 17.6 Hz, 1H), (t, J = 6.8, 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 197.6, 165.8, 165.4, 156.7, 128.5, 126.3, 115.9, 109.5, 61.7, 55.7, 53.5, 30.3, Methyl/ethyl 2-(3-methoxy/ethoxy-3-oxopropyl)-5-methoxy-1-oxo-2,3-dihydro-1H-indene- 2-carboxylate (IIId). Yellow oil. Yield: 82% (a mixture of methyl and ethyl esters), 1.50 g. 1 H NMR (400 MHz, CDCl 3 ) δ (d, J = 8.4 Hz, 1H); (m, 2H), (m, 1.5H), 3.87 (s, 3H), (m, 5.47H), (m, 1H), (m, 4H), (m, 2.26H); 13 C NMR (100 MHz, CDCl 3 ) δ 199.9, 199.8, 173.2, 173.2, 171.4, 170.9, 166.0, 165.9, 155.7, 128.0, 126.5, 126.5, 116.1, 116.0, 109.4, 61.6, 59.7, 59.6, 55.7, 52.7, 51.7, 29.7, 29.6, (5-Methoxy-1-oxo-2,3-dihydro-1H-inden-2-yl)propanoic acid (3d). Light yellow solid. Yield: 86%, 1.01 g. 1 H NMR (400 MHz, CDCl 3 ) δ (m, 1H), (m, 1H), (t, J = 7.6, 8.0 Hz, 2H), (m, 2H), (m, 1H), 3.82 (s, 3H), (m, 2H), (d, J = 7.6 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 206.2, 178.1, 165.5, 156.3, 129.7, 125.7, 115.6, 109.6, 55.7, 46.2, 32.9, 31.6, Diethyl 2-(3-oxocyclopentyl)malonate (Va). Colorless oil. Yield: 65%, 1.57 g. 1 H NMR (400 MHz, CDCl 3 ) δ (m, 4H), (d, J = 9.2 Hz, 1H), (m, 1H), (dd, J = 7.2, 18.0 Hz, 1H), (m, 3H), (m, 1H), (m, 1H), (m, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 217.2, 168.1, 168.0, 61.6, 56.5, 42.9, 38.2, 36.3, 27.5, (3-oxocyclopentyl)acetic acid (5a). White solid. Yield: 82%, 582 mg. 1 H NMR (400 MHz, CDCl 3 ) δ (m, 4H), (m, 3H), (m, 1H), (m, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 218.4, 177.8, 44.5, 39.3, 38.3, 33.1, S8

9 Diethyl 2-(2,2-dimethyl-5-oxocyclohexyl)malonate (Vb). Yellow solid. Yield: 68%, 1.93 g. 1 H NMR (400 MHz, CDCl 3 ) δ (m, 4H), (d, J = 4.4 Hz, 1H), (m, 1H), (m, 4H), (m, 2H), (m, 6H), 1.05 (s, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ 210.1, 168.8, 168.6, 61.8, 61.4, 52.2, 45.1, 40.4, 40.0, 37.8, 33.2, 28.69, 20.1, (2,2-Dimethyl-5-oxocyclohexyl)acetic acid (5e). White solid. Yield: 80%, 736 mg. 1 H NMR (400 MHz, CDCl 3 ) δ (d, J = 14.0 Hz, 1H), (m, 3H), (m, 3H), (m, 2H), 1.07 (s, 3H), 1.02 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 207.8, 177.6, 43.1, 42.9, 39.7, 38.0, 35.8, 32.4, 28.5, Acetylpyrrolidin-2-one (2a). Orange solid. Yield: 65%, 83 mg. mp o C. 1 H NMR (400 MHz, CDCl 3 ) δ 6.86 (s, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), 2.37 (s, 3H), (m, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 203.5, 173.8, 54.8, 40.5, 29.9, Azaspiro[4.4]nonane-1,6-dione (4a). Colorless oil. Yield: 61%, 93 mg. 1 H NMR (400 MHz, CDCl 3 ) δ 5.81 (s, 1H), (m, 2H), (m, 2H), (m, 2H), (m, 2H), (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 221.3, 156.5, 47.2, 39.5, 37.9, 29.9, 29.3, HRMS [M + H] + (ESI-TOF) calcd for C 8 H 12 NO , found Spiro[indene-2,3'-pyrrolidine]-1,2'(3H)-dione (4b). White solid. Yield: 61%, 122 mg. 1 H NMR (400 MHz, CDCl 3 ) δ (d, J = 7.6 Hz, 1H), (t, J = 6.8, 8.0 Hz, 1H), S9

10 (d, J = 7.2 Hz, 1H), (t, J = 6.8, 8.0 Hz, 1H), 7.15 (s, 1H), (m, 2H), (m, 1H), (d, J = 17.2 Hz, 1H), (m, 1H), (m, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 204.7, 176.8, 153.7, 135.4, 135.0, 127.8, 126.4, 58.0, 40.0, 37.7, HRMS [M + H] + (ESI-TOF) calcd for C 12 H 12 NO , found Methylspiro[indene-2,3'-pyrrolidine]-1,2'(3H)-dione (4c). Colorless solid. Yield: 71%, 152 mg. 1 H NMR (400 MHz, CDCl 3 ) δ 7.55 (s, 1H), (d, J = 7.6 Hz, 1H), (d, J = 8.0 Hz, 1H), 6.78 (s, 1H), (m, 1H), (d, J = 17.2 Hz, 1H), (m, 1H), (d, J = 17.6 Hz, 1H), (m, 1H), 2.39 (s, 3H), (m, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 204.6, 176.7, 151.0, 137.8, 136.7, 135.2, 126.0, 124.5, 58.2, 39.9, 37.3, 32.4, HRMS [M + H] + (ESI-TOF) calcd for C 13 H 14 NO , found Methoxyspiro[indene-2,3'-pyrrolidine]-1,2'(3H)-dione (4d). White solid. Yield: 68%, 157 mg. 1 H NMR (400 MHz, CDCl 3 ) δ (d, J = 8.8 Hz, 1H), (m, 2H), 6.16 (s, 1H), 3.89 (s, 3H), (m, 1H), (d, J = 17.2 Hz, 1H), (m, 1H), (d, J = 16.4 Hz, 1H), (m, 1H), (m, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 203.2, 176.6, 165.9, 156.7, 128.1, 126.3, 116.0, 109.4, 57.9, 55.7, 39.9, 37.5, HRMS [M + H] + (ESI-TOF) calcd for C 13 H 14 NO , found Bromospiro[indene-2,3'-pyrrolidine]-1,2'(3H)-dione (4e). White powder. Yield: 73%, 203 mg. 1 H NMR (400 MHz, CDCl 3 ) δ 7.66 (s, 1H), (d, J = 8.0 Hz, 1H), (d, J = 8.8 Hz, 1H), 6.18 (s, 1H), (m, 1H), (d, J = 17.2 Hz, 1H), (m, 1H), (d, J = 17.2 Hz, 1H), (m, 1H), (m, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 203.3, 175.7, 155.1, 133.8, 131.5, 131.0, 129.7, 125.7, 57.9, 39.8, 37.1, HRMS [M + H] + (ESI-TOF) calcd for C 12 H 11 BrNO , found S10

11 5-Chlorospiro[indene-2,3'-pyrrolidine]-1,2'(3H)-dione (4f). White solid. Yield: 65%, 152 mg. 1 H NMR (400 MHz, CDCl 3 ) δ (d, J = 8.8 Hz, 1H), 7.49 (s, 1H), (d, J = 8.8 Hz, 1H), 6.79 (s, 1H), (m, 2H), (m, 1H), (d, J = 17.2 Hz, 1H), (m, 1H), (m, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 203.1, 176.1, 155.0, 142.0, 133.4, 128.6, 126.6, 125.6, 58.1, 39.8, 37.2, HRMS [M + H] + (ESI-TOF) calcd for C 12 H 11 ClNO , found Fluorospiro[indene-2,3'-pyrrolidine]-1,2'(3H)-dione (4g). White solid. Yield: 64%, 140 mg. 1 H NMR (400 MHz, CDCl 3 ) δ (m, 1H), (m, 2H), 6.67 (s, 1H), (m, 2H), (m, 1H), (d, J = 17.2 Hz, 1H), (m, 1H), (m, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 202.6, 176.2, 168.8, 166.3, 156.6, 156.5, 131.4, 127.0, 126.9, 116.4, 116.1, 113.2, 113.0, 58.2, 39.9, 37.4, HRMS [M + H] + (ESI-TOF) calcd for C 12 H 11 FNO , found Methoxyspiro[indene-2,3'-pyrrolidine]-1,2'(3H)-dione (4h). White solid. Yield: 57%, 132 mg. 1 H NMR (400 MHz, CDCl 3 ) δ (m, 2H), (d, J = 8.0 Hz, 1H), 6.70 (s, 1H), 3.90 (s, 3H), (m, 1H), (d, J = 18.0 Hz, 1H), (m, 1H), (d, J = 18.0 Hz, 1H), (m, 1H), (m, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 204.8, 176.6, 156.7, 142.6, 136.4, 129.4, 116.1, 115.5, 57.7, 55.4, 39.9, 34.5, HRMS [M + H] + (ESI-TOF) calcd for C 13 H 14 NO , found ,4-Dihydro-1H-spiro[naphthalene-2,3'-pyrrolidine]-1,2'-dione (4j). White solid. Yield: 55%, 118 mg. 1 H NMR (400 MHz, CDCl 3 ) δ (d, J = 8.0 Hz, 1H), (t, J = 7.2, 7.6 Hz, 1H), (t, J = 7.2, 8.0 Hz, 1H), (d, J = 7.2 Hz, 1H), 6.24 (s, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 2H), (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 196.4, 176.9, 143.9, 133.8, 130.9, 128.7, 128.1, 126.8, 54.9, 39.3, 31.9, 31.3, HRMS [M + H] + (ESI-TOF) calcd for C 13 H 14 NO , found S11

12 Tetrahydrocyclopenta[c]pyrrole-1, 6(2H,6aH)-dione (6a). Colorless oil. Yield: 58%, 124 mg. 1 H NMR (400 MHz, CDCl 3 ) δ 5.43 (s, 1H), (m, 2H), (m, 3H), (m, 1H), (m, 1H), (m, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 217.8, 156.8, 45.0, 425.5, 37.9, 37.1, HRMS [M + H] + (ESI-TOF) calcd for C 13 H 14 NO , found ,3a-Dihydroindeno[1,2-c]pyrrole-1,8(2H,8aH)-dione (6b). Brown solid. Yield: 70%, 130 mg. 1 H NMR (400 MHz, CDCl 3 ) δ (d, J = 7.6 Hz, 1H), (t, J = 7.2, 7.6 Hz, 1H), (d, J = 8.0 Hz, 1H), (t, J = 6.8, 8.0 Hz, 1H), 6.74 (s, 1H), (t, J = 7.6, 8.0 Hz, 1H), (t, J = 8.4, 10.4 Hz, 1H), (d, J = 7.2 Hz, 1H), (d, J = 10.4 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 197.5, 171.0, 155.6, 138.0, 135.7, 128.9, 125.7, 124.5, 55.3, 47.0, HRMS [M + H] + (ESI-TOF) calcd for C 11 H 10 NO , found Methoxy-3,3a-dihydroindeno[1,2-c]pyrrole-1,8(2H,8aH)-dione (6c). Brown solid. Yield: 72%, 156 mg. 1 H NMR (400 MHz, DMSO-d6) δ 7.78 (s, 1H), (d, J = 8.4 Hz, 1H), 7.28 (s, 1H), (d, J = 8.8 Hz, 1H), (m, 1H), 3.90 (s, 3H), (m, 1H), (d, J = 7.6 Hz, 1H), (d, J = 10.4 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 196.8, 170.4, 165.9, 159.9, 128.8, 125.2, 116.9, 110.3, 56.3, 56.2, 46.3, HRMS [M + H] + (ESI-TOF) calcd for C 12 H 12 NO , found Hexahydro-1H-isoindole-1,7(7aH)-dione (6d). Colorless oil. Yield: 70%, 107 mg. 1 H NMR (400 MHz, CDCl 3 ) δ 5.69 (s, 1H), (m, 2H), (t, J = 12.8, 18.8 Hz, 2H), (m, 1H), (m, 2H), (m, 1H), (m, 2H), (m, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 210.6, 156.8, 46.0, 45.3, 41.2, 39.3, 28.6, HRMS [M + H] + (ESI-TOF) calcd for C 8 H 12 NO , found S12

13 4,4-Dimethylhexahydro-1H-isoindole-1,7(7aH)-dione (6e). White solid. Yield 66%, 117 mg. 1 H NMR (400 MHz, CDCl 3 ) δ 5.10 (s, 1H), (m, 1H), (m, 1H), (m, 2H), (m, 1H), (m, 3H), 1.12 (s, 3H), 1.07 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 210.6, 156.7, 46.8, 42.3, 41.3, 40.3, 38.1, 32.2, 28.6, HRMS [M + H] + (ESI-TOF) calcd for C 10 H 16 NO , found Hydroxy-1,3-dihydrospiro[indene-2,3'-pyrrolidin]-2'-one (7). White solid. Yield: 88%, 26 mg. mp o C. 1 H NMR (400 MHz, CDCl 3 ) δ (t, J = 4.8 Hz, 1H), (m, 3H), 6.70 (s, 1H), 5.02 (s, 1H), 3.90 (br, 1H), (d, J = 16 Hz, 1H), (m, 2H), (d, J = 16 Hz, 1H), (m, 1H), (m, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ , , , , , , , 82.18, 53.60, 40.18, 39.53, HRMS [M + H] + (ESI-TOF) calcd for C 12 H 14 NO , found '-Phenylspiro[indene-2,3'-pyrrolidine]-1,2'(3H)-dione (8). White solid. Yield: 90%, 37 mg. mp o C. 1 H NMR (400 MHz, CDCl 3 ) δ (d, J = 8.0 Hz, 1H), (d, J = 8.0 Hz, 2H), (d, J = 8.0 Hz, 1H), (d, J = 8.0 Hz, 1H), (m, 3H), (t, J = 8.0 Hz, 1H), (m, 1H), (dt, J 1 = 2.4 Hz, J 2 = 5.2 Hz), (d, J = 17.2 Hz, 1H), (d, J = 17.2 Hz, 1H), (m, 1H), (m, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 204.3, 172.0, 153.6, 139.3, 135.4, 134.8, 128.8, 127.8, 126.4, 124.9, 124.6, 120.1, 60.2, 46.3, 37.9, HRMS [M + H] + (ESI-TOF) calcd for C 18 H 15 NO , found ,2-Dihydrospiro[benzo[d]pyrrolo[1,2-a]imidazole-3,2'-inden]-1'(3'H)-one (9). Off-white solid. Yield: 77% for two steps, 32 mg. mp o C. 1 H NMR (400 MHz, CDCl 3 ) δ (d, J = 7.6 Hz, 1H), (m, 2H), (d, J = 7.6 Hz, 1H), (t, J = 7.6 Hz, 1H), (d, J = 7.6 Hz, 1H), (m, 2H), (m, 1H), (dt, J 1 = S13

14 2.8 Hz, J 2 = 9.2 Hz, 1H), (d, J = 17.2 Hz, 1H), (d, J = 17.2 Hz, 1H), (m, 1H), (m, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 203.9, 160.8, 152.9, 148.1, 135.7, 134.3, 132.4, 128.1, 126.5, 125.1, 122.1, 122.0, 119.9, 109.8, 52.9, 42.0, 39.4, HRMS [M + H] + (ESI-TOF) calcd for C 18 H 15 N 2 O , found Computational Methods To explore the different behavior of the 5- and 6-membered ring spiro compounds, conformational preferences of the reaction intermediates were studied using molecular dynamics (MD) simulations. The CHARMM General Force Field (CGenFF) 1,2 was used to describe the molecules. As the isocyanate functional group was not present in the current version of CGenFF, full parametrization was performed for this functional group using methyl-isocyanate and ethylisocyanate as model compounds following the standard protocol. 1,2 The quality of the optimized parameters for the isocyanate group was also validated by liquid phase simulations. The difference between calculated and experimental densities for methyl-isocyanate and ethylisocyanate are within 2% of the experimental values and the difference between calculated and experimental heat of vaporization for methyl-isocyanate is less than 0.8 kcal/mol (experimental value is kcal/mol at 280K). The resulting parameters in conjunction with the additional missing parameters linking the isosyanate to the alkyl chain were derived by analogy using the CGenFF program. 3 The gas-phase MD runs for the four intermediates were performed using the CHARMM program. 4 The initial structures of the four molecules were set in fully extended conformations to avoid conformational bias. These structures were first minimized through 200 steps of adopted-basis Newton Raphson (ABNR) minimization. MD simulations were then conducted for 20 ns with a 2 fs time step using Langevin dynamics 5 with a friction coefficient of 50 ps -1 and SHAKE of all covalent bonds involving hydrogens 6 was turned on. Non-bond interactions were calculated using a constant dielectric of 1 with an infinite cutoff. A high simulation temperature of 450 K, versus that used in the experiments was used to accelerate the sampling of all possible conformations. The coordinates accumulated in the MD simulation were analyzed to get the final histograms of the interested geometric parameters. S14

15 9. 1 H NMR and 13 C NMR Spectra of New Compounds Figure S1. 1 H NMR of compound 2a Figure S2. 13 C NMR of compound 2a S15

16 Figure S3. 1 H NMR of compound 4a Figure S4. 13 C NMR of compound 4a S16

17 Figure S5. 1 H NMR of compound 4b Figure S6. 13 C NMR of compound 4b S17

18 Figure S7. 1 H NMR of compound 4c Figure S8. 13 C NMR of compound 4c S18

19 Figure S9. 1 H NMR of compound 4d Figure S C NMR of compound 4d S19

20 Figure S11. 1 H NMR of compound 4e Figure S C NMR of compound 4e S20

21 Figure S13. 1 H NMR of compound 4f Figure S C NMR of compound 4f S21

22 Figure S15. 1 H NMR of compound 4g Figure S C NMR of compound 4g S22

23 Figure S17. 1 H NMR of compound 4h Figure S C NMR of compound 4h S23

24 Figure S19. 1 H NMR of compound 4j Figure S C NMR of compound 4j S24

25 Figure S21. 1 H NMR of compound 6a Figure S C NMR of compound 6a S25

26 Figure S23. 1 H NMR of compound 6b Figure S C NMR of compound 6b S26

27 Figure S25. 1 H NMR of compound 6c Figure S C NMR of compound 6c S27

28 Figure S27. 1 H NMR of compound 6d Figure S C NMR of compound 6d S28

29 Figure S29. 1 H NMR of compound 6e Figure S C NMR of compound 6e S29

30 Figure S31. 1 H NMR of compound 7 Figure S C NMR of compound 7 S30

31 Figure S33. 1 H NMR of compound 8 Figure S C NMR of compound 8 S31

32 Figure S35. 1 H NMR of compound 9 Figure S C NMR of compound 9 S32

33 11. References 1. Vanommeslaeghe, K., Hatcher, E., Acharya, C., Kundu, S., Zhong, S., Shim, J., Darian, E., Guvench, O., Lopes, P., Vorobyov, I., Mackerell, A. D. J. Comput. Chem., , Yu, W., He, X., Vanommeslaeghe, K., MacKerell, A. D. J. Comput. Chem., , Vanommeslaeghe, K., MacKerell, A. D. J. Chem. Inf. Model , Brooks, B. R., Brooks, C. L., Mackerell, A. D., Nilsson, L., Petrella, R. J., Roux, B., Won, Y., Archontis, G., Bartels, C., Boresch, S., Caflisch, A., Caves, L., Cui, Q., Dinner, A. R., Feig, M., Fischer, S., Gao, J., Hodoscek, M., Im, W., Kuczera, K., Lazaridis, T., Ma, J., Ovchinnikov, V., Paci, E., Pastor, R. W., Post, C. B., Pu, J. Z., Schaefer, M., Tidor, B., Venable, R. M., Woodcock, H. L., Wu, X., Yang, W., York, D. M. and Karplus, M. J. Comput. Chem. 2009, 30, Allen, M. P.; Tildesley, D. J. Computer Simulation of Liquids; Oxford University Press: New York, Ryckaert, J. P.; Ciccotti, G.; Berendsen, H. J. C. J. Comput. Phys. 1977, 23, 327. S33