Alkaloid-catalyzed enantioselective [3 + 2] cycloaddition of ketenes and azomethine imines.

Transcription

1 Alkaloid-catalyzed enantioselective [3 + 2] cycloaddition of ketenes and azomethine imines. Mukulesh Mondal a, Kraig A. Wheeler b and essan J. Kerrigan a, * a Department of Chemistry, akland University, Squirrel Road, Rochester, MI , USA. b Department of Chemistry, Eastern Illinois University, 600 Lincoln Avenue, Charleston, IL , USA Experimental Procedures & Characterization Data General Information Table of Contents: S2 Preparation of,-cyclic azomethine imine General procedure for alkaloid-catalyzed [3 + 2] cycloaddition Experimental procedure and tabulated data of 1a Experimental procedure and tabulated data of 1b & 1c Experimental procedure and tabulated data of 1d, 1e & 1f X-Ray structure of 1f Separation of diatereomers by recrystallization Experimental procedure and tabulated data of 1g & 1h Experimental procedure and tabulated data of 1i & 1j Experimental procedure and tabulated data of 1k & 1l Experimental procedure and tabulated data of 1m & 1n Experimental procedure and tabulated data of 1o & 1p X-Ray structure of 1p Experimental procedure and tabulated data of 1q chanistic experiments ptimization of Reaction Conditions (Table 1) S3 S3 S3 S4 S5 S6 S6 S7 S8 S9 S10 S11 S12 S12 S13 S14 S1

2 General Information THF was freshly distilled from benzophenone ketyl radical under nitrogen prior to use, while Hünig's base (diisopropylethylamine) was distilled from calcium hydride. 1 Most anhydrous solvents (dichloromethane and diethyl ether) were obtained by passing through activated alumina columns on a solvent purification system. Hydrazine monohydrate, methyl acrylate, benzaldehyde, p-anisaldehyde, o-tolualdehyde, p-tolualdehyde, 4-fluorobenzaldehyde, lithium perchlorate, copper(ii) triflate, erbium(iii) triflate, ytterbium(iii) triflate, copper(i) iodide, quinine, quinidine and zinc dust (<10 m), were purchased from Aldrich Chemical Co. (DHQ)2PHAL and (DHQD)2PHAL were purchased from AK Scientific, Inc. Propionyl chloride, butyryl chloride, valeroyl chloride, acetoxyacetyl chloride and octanoyl chloride were purchased from Aldrich Chemical Co. and distilled prior to use. 1 TLC plates (Sorbent Technologies, UV254, 250μM) and silica gel (Silicycle, μm particle size) were used as received. TMS-quinine, -quinidine and epi-quinine thiourea were synthesized according to literature procedure. 2 MR spectra were recorded on a Bruker DPX Avance 200 spectrometer (200 MHz for 1 H and 50 MHz for 13 C) and on a Bruker Biospin AG 400 spectrometer (400 MHz for 1 H and 100 MHz for 13 C). MR chemical shifts were reported relative to TMS (0 ppm) for 1 H and to CDCl3 (77.23 ppm) for 13 C spectra. High resolution mass spectra were recorded on Agilent Technologies 6520 Accurate Mass Q-TF LC-MS instrument at akland University. Low resolution mass spectra were recorded on a GC-MS Hewlett Packard HP 6890 GC instrument with a 5973 mass selective detector. IR spectra were recorded on a Bio Rad FTS-175C spectrometer. ptical rotations were measured on a Rudolph DigiPol 781 TDV automatic polarimeter. Chiral high performance liquid chromatography analysis (HPLC) was performed using Daicel Chiralpak AD, Chiralpak ADH, Chiralpak D and Chiralpak DH ( cm) (Daicel chemical Ind., Ltd.) on a Perkin Elmer Flexar instrument attached with diode array detector (deuterium lamp, nm) with HPLC-grade isopropanol and hexanes as the eluting solvents. Enantiomeric excesses were determined at = 254 or 225 nm (details given for each compound). S2

3 ,-Cyclic azomethine imine Azomethine imines 4a-e were prepared according to procedures known in the literature. 3 1) Armarego, W. L. F.; Perrin, D. D. Purification of Laboratory Chemicals, 4th Ed. Butterworth Heinemann, ) (a) Papageorgiou, C. D.; Ley, S. V.; Gaunt, M. J. Angew. Chem., Int. Ed. 2003, 42, 828. (b) Calter, M. A. J. rg. Chem. 1996, 61, (c) Vakulya, B.; Varga, S.; Csámpai, A.; Soós, T. rg. Lett. 2005, 7, (d) Hammar, P.; Marcelli, T.; Hiemstra, H.; Himo, F. Adv. Synth. Catal. 2007, 349, ) (a) Shintani, R.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, (b) Suárez, A.; Downey, C. W.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, (c) Shintani, R.; Hayashi, T. J. Am. Chem. Soc. 2006, 128, (d) Zhao, H. -W.; Li, B.; Pang, H. -L.; Tian, T.; Chen, X. -Q.; Song, X. -Q.; ng, W.; Yang, Z.; Zhao, Y. -D. and Liu, Y. - Y. rg. Lett. 2016, 18, 848. (e) Li, S. -M.; Yu, B.; Liu, J.; Li, H. -L.; a, R. Synlett 2016; 27, 282. General procedure for alkaloid-catalyzed [3 + 2] cycloaddition of ketene and azomethine imine To a stirring solution of azomethine imine (0.30 mmol) and catalyst (0.03 mmol) in dichloromethane (2.0 ml) at 25 C, Hünig's base (0.10 ml, 0.60 mmol) was added. To this stirring reaction mixture, a solution of acid chloride (0.60 mmol) in dichloromethane (1.0 ml) was added over a period of 10 h via syringe pump. The reaction was stirred at this temperature for another 6 h and then poured into cold water (15 ml), extracted with dichloromethane (20 ml x 3). The combined organic layers were washed with water (50 ml), and brine (50 ml), and dried over sodium sulfate. The solvent was removed under reduced pressure. The residue was then dissolved in dichloromethane and passed through a plug of regular silica gel (10g, 2 x 2 cm) using 10% EtAc/dichloromethane as elutant to afford crude product (free from catalyst) for diastereomeric ratio and enantiomeric excess measurement (see SI spectra for dr determination in each case). Pure product was isolated after further regular silica gel column chromatographic purification using EtAc/dichloromethane as eluent (mentioned details below). (2R,3S)-Tetrahydro-2-methyl-3-phenylpyrazolo[1,2-a]pyrazole-1,7-dione (1a): Following general procedure, propionyl chloride (0.064 ml, 0.69 mmol) in dichloromethane (1.2 ml) was added over 10 h to a solution of 4a (60 mg, 0.34 mmol), Hünig's base (0.12 ml, 0.69 mmol) and (DHQ)2PHAL (27 mg, 0.03 mmol) in dichloromethane (2.3 ml) at 25 C. Elution with 3% EtAc/dichloromethane through 1a S3

4 silica gel column afforded 1a as a light yellowish solid (71 mg, 90%), dr = 3.5:1 (by 1 H MR); HPLC analysis: 99% ee [Daicel Chiralcel AD-H column; 1.2 ml/min; solvent system: 2% isopropanol in hexane; retention times: 45.6 min (major), 54.1 min (minor)]; Mp: o C; IR (thin film) 2985, 2921, 2885, 1770, 1701, 1455, 1320, 1294, 1275, 699 cm -1 ; 1 H MR (400 MHz, CDCl3, TMS, Major isomer): δ (m, 5H), (m, 2H), (m, 2H), (m, 2H), 1.19 (d, J = 7.1 Hz, 3H); 13 C MR (100 MHz, CDCl3, Major isomer): δ 166.8, 165.0, 135.6, 129.2, 129.0, 127.6, 78.9, 52.4, 50.8, 36.6, 11.0; (M + H) + HRMS m/z calcd for (C13H1522) + : ; found: (2R,3S)-Tetrahydro-2-methyl-3-p-tolylpyrazolo[1,2-a]pyrazole-1,7-dione (1b): Following general procedure, propionyl chloride (0.059 ml, 0.64 mmol) in dichloromethane (1.0 ml) was added over 10 h to a solution of 4b (60 mg, 0.32 mmol), Hünig's base (0.11 ml, 0.64 mmol) and (DHQ)2PHAL (25 mg, 0.03 mmol) in dichloromethane (2.2 ml) at 25 C. Elution with 2.5% EtAc/dichloromethane through a silica gel column afforded 1b as a white solid (73 mg, 94%), dr = 5:1 (by 1 H MR and HPLC); HPLC analysis: 98% ee [Daicel Chiralcel AD-H column; 1 1b ml/min; solvent system: 3% isopropanol in hexane; retention times: 34.2 min (major), 39.9 min (minor)]; Mp: o C; IR (thin film) 2974, 2918, 2884, 1771, 1699, 1520, 1327, 1294, 1275, 830 cm -1 ; 1 H MR (400 MHz, CDCl3, TMS, Major isomer): δ (m, 2H), (m, 2H), (m, 2H), (m, 2H), (m, 2H), 2.38 (s, 3H), 1.18 (d, J = 7.0 Hz, 3H); 13 C MR (100 MHz, CDCl3, Major isomer): δ 166.9, 165.0, 139.2, 132.6, 129.9, 127.6, 78.9, 52.4, 50.8, 36.6, 21.4, 11.0; (M + H) + HRMS m/z calcd for (C14H1722) + : ; found: (2R,3S)-Tetrahydro-2-methyl-3-o-tolylpyrazolo[1,2-a]pyrazole-1,7-dione (1c): Following general procedure, propionyl chloride (0.049 ml, 0.53 mmol) in dichloromethane (0.9 ml) was added over 10 h to a solution of 4c (50 mg, 0.27 mmol), Hünig's base (0.09 ml, 0.53 mmol) and (DHQ)2PHAL (21 mg, mmol) in dichloromethane (1.8 ml) at 25 C. Elution with 2% EtAc/dichloromethane through a silica gel column afforded 1c as a white solid (55 mg, 85%), dr = 5:1 (by 1 H MR and HPLC); HPLC analysis: 99% ee [Daicel Chiralcel AD-H column; 0.5 ml/min; solvent 1c system: 5% isopropanol in hexane; retention times: 44.0 min (major), 52.9 min (minor)]; Mp: o C; IR (thin film) 2979, 2932, 2865, 1777, 1695, 1295, 1273, 731 cm -1 ; 1 H MR (400 MHz, CDCl3, TMS, Major isomer): δ (m, 1H), (m, 3H), 3.95 (d, J = 12.2 Hz, 1H), 3.48 (t, J = 8.5 Hz, 1H), (m, 2H), (m, 2H), 2.40 (s, 3H), 1.19 (d, J = 7.1 Hz, 3H); 13 C MR (100 MHz, CDCl3, Major isomer): δ 166.8, 165.1, 136.7, 133.8, 131.1, 128.7, 127.6, 127.0, 74.7, 52.5, 51.6, 36.7, 19.9, 11.3; (M + H) + HRMS m/z calcd for (C14H1722) + : ; found: S4

5 (2S,3R)-Tetrahydro-2-methyl-3-o-tolylpyrazolo[1,2-a]pyrazole-1,7-dione (1d): Following general procedure, propionyl chloride (0.049 ml, 0.53 mmol) in dichloromethane (0.9 ml) was added over 10 h to a solution of 4c (50 mg, 0.27 mmol), Hünig's base (0.09 ml, 0.53 mmol) and (DHQD)2PHAL (21 mg, mmol) in dichloromethane (1.8 ml) at 25 C. Elution with 2% EtAc/dichloromethane through silica gel column afforded 1d as a light yellow oil (52 mg, 80%), dr = 4:1 (by 1 H MR); HPLC analysis: 99% ee [Daicel Chiralcel AD-H column; 0.5 ml/min; solvent system: 1d 5% isopropanol in hexane; retention times: 44.5 min (minor), 52.4 min (major)]; Mp: o C; IR (thin film) 2977, 2932, 2862, 1777, 1695, 1300, 1277, 731 cm -1 ; 1 H MR (400 MHz, CDCl3, TMS, Major isomer): δ (m, 1H), (m, 3H), 3.94 (d, J = 12.2 Hz, 1H), 3.48 (t, J = 8.4 Hz, 1H), (m, 2H), (m, 2H), 2.40 (s, 3H), 1.19 (d, J = 7.1 Hz, 3H); 13 C MR (100 MHz, CDCl3, Major isomer): δ 166.8, 165.1, 136.7, 133.8, 131.1, 128.7, 127.6, 127.0, 74.7, 52.5, 51.6, 36.7, 20.0, 11.3; (M + H) + HRMS m/z calcd for (C14H1722) + : ; found: e (2R,3S)-Tetrahydro-3-(4-methoxyphenyl)-2-methylpyrazolo[1,2-a]pyrazole-1,7- dione (1e): Following general procedure, propionyl chloride (0.052 ml, 0.59 mmol) in dichloromethane (1.0 ml) was added over 10 h to a solution of 4d (60 mg, 0.29 mmol), Hünig's base (0.10 ml, 0.59 mmol) and (DHQ)2PHAL (23 mg, mmol) in dichloromethane (2.0 ml) at 25 C. Elution with 2.5% EtAc/dichloromethane through silica gel column afforded 1e as a light yellow solid (76 mg, 99%), dr = 6.5:1 (by 1 H MR and HPLC); HPLC analysis: 99% ee [Daicel Chiralcel AD-H column; 1.0 ml/min; solvent system: 7% isopropanol in hexane; retention times: 27.5 min (major), 32.5 min (minor)]; Mp: o C; IR (thin film) 2951, 2887, 2837, 1768, 1697, 1514, 1287, 1245, 831 cm -1 ; 1 H MR (400 MHz, CDCl3, TMS, Major isomer): δ (m, 2H), (m, 2H), 3.83 (s, 3H), (m, 2H), (m, 2H), (m, 2H), 1.17 (d, J = 7.0 Hz, 3H); 13 C MR (100 MHz, CDCl3, Major isomer): δ 167.0, 165.1, 160.5, 128.9, 127.5, 114.7, 78.7, 55.6, 52.4, 50.8, 36.7, 11.0; (M + H) + HRMS m/z calcd for (C14H1723) + : ; found: (2S,3R)-Tetrahydro-3-(4-methoxyphenyl)-2-methylpyrazolo[1,2-a]pyrazole-1,7- dione (1f): Following general procedure, propionyl chloride (0.052 ml, 0.59 mmol) in dichloromethane (1.0 ml) was added over 10 h to a solution of 4d (60 mg, 0.29 mmol), Hünig's base (0.10 ml, 0.59 mmol) and (DHQD)2PHAL (23 mg, mmol) in dichloromethane (2.0 ml) at 25 C. Elution with 2.5% EtAc/dichloromethane through silica gel column afforded 1f as a yellowish solid 1f S5

6 (74 mg, 97%), dr = 3:1 (by 1 H MR and HPLC); HPLC analysis: 99% ee [Daicel Chiralcel AD-H column; 1.0 ml/min; solvent system: 7% isopropanol in hexane; retention times: 27.2 min (minor), 31.8 min (major)]; Mp: o C (after recrystallization); IR (thin film) 2951, 2886, 2837, 1768, 1697, 1513, 1285, 1244, 831 cm -1 ; 1 H MR (400 MHz, CDCl3, TMS, Major isomer): δ (m, 2H), (m, 2H), 3.83 (s, 3H), (m, 2H), (m, 2H), (m, 2H), 1.17 (d, J = 7.0 Hz, 3H); 13 C MR (100 MHz, CDCl3, Major isomer): δ 167.0, 165.1, 160.4, 128.8, 127.4, 114.6, 78.6, 55.6, 52.3, 50.7, 36.6, 10.9; (M + H) + HRMS m/z calcd for (C14H1723) + : ; found: X-Ray structure of 1f Separation of diastereomers by recrystallization: Following general procedure, propionyl chloride (0.17 ml, 1.96 mmol) in dichloromethane (3.3 ml) was added over 10 h to a solution of 4d (200 mg, 0.98 mmol), Hünig's base (0.34 ml, 1.96 mmol) and S6

7 (DHQD)2PHAL (76 mg, mmol) in dichloromethane (6.6 ml) at 25 C. Elution with 2.5% EtAc/dichloromethane through silica gel column afforded 1f as a light yellow solid (247 mg, 97%), dr = 3:1 (by 1 H MR and HPLC); HPLC analysis: 99% ee [Daicel Chiralcel AD-H column; 1.0 ml/min; solvent system: 7% isopropanol in hexane; retention times: 28.9 min (minor), 34.3 min (major)]. Recrystallization: 1f (247 mg) was dissolved in dichloromethane (5 ml) at room temperature and diluted with n-pentane (40 ml). The clear solution on standing was allowed to undergo crystallization slowly and was kept overnight undisturbed at room temperature. Filtration followed by washing with n-pentane afforded 1f as a light yellow crystalline solid (170 mg, 67%), dr = 37:1 (by 1 H MR); HPLC analysis: >99% ee [Daicel Chiralcel AD-H column; 1.0 ml/min; solvent system: 7% isopropanol in hexane; retention times: 34.3 min (major)]; Mp: o 24 C; [ ] D = (c = 1.45, CH2Cl2); IR (thin film) 2951, 2886, 2837, 1768, 1697, 1513, 1285, 1244, 831 cm -1 ; 1 H MR (400 MHz, CDCl3, TMS, Major isomer): δ (m, 2H), (m, 2H), 3.83 (s, 3H), (m, 2H), (m, 2H), (m, 2H), 1.17 (d, J = 7.0 Hz, 3H); 13 C MR (100 MHz, CDCl3, Major isomer): δ 166.9, 165.0, 160.4, 128.8, 127.4, 114.7, 78.7, 55.6, 52.4, 50.8, 36.7, 11.0; (M + H) + HRMS m/z calcd for (C14H1723) + : ; found: F 1g (2R,3S)-3-(4-Fluorophenyl)-tetrahydro-2-methylpyrazolo[1,2-a]pyrazole-1,7-dione (1g): Following general procedure, propionyl chloride (0.055 ml, 0.63 mmol) in dichloromethane (1.0 ml) was added over 10 h to a solution of 4e (60 mg, 0.31 mmol), Hünig's base (0.11 ml, 0.63 mmol) and (DHQ)2PHAL (24 mg, 0.03 mmol) in dichloromethane (2.1 ml) at 25 C. Elution with 2.5% EtAc/dichloromethane through silica gel column afforded 1g as a white solid (74 mg, 95%), dr = 4:1 (by 1 H MR and HPLC); HPLC analysis: 98% ee [Daicel Chiralcel AD-H column; 0.5 ml/min; solvent system: 10% isopropanol in hexane; retention times: 35.2 min (major), 46.5 min (minor)]; Mp: o C; IR (thin film) 3065, 2981, 2941, 2878, 1771, 1699, 1510, 1312, 1277, 1219, 843 cm -1 ; 1 H MR (400 MHz, CDCl3, TMS, Major isomer): δ (m, 2H), (m, 2H), (m, 2H), (m, 4H), 1.18 (d, J = 7.0 Hz, 3H); 13 C MR (100 MHz, CDCl3, Major isomer): δ 166.5, 165.0, (d, J = Hz, 1C), (d, J = 3.2 Hz, 1C), (d, J = 8.3 Hz, 2C), (d, J = 21.9 Hz, 2C), 78.1, 52.3, 50.9, 36.6, 10.9; (M + H) + HRMS m/z calcd for (C13H14F22) + : ; found: F 1h (2S,3R)-3-(4-Fluorophenyl)-tetrahydro-2-methylpyrazolo[1,2-a]pyrazole-1,7-dione (1h): Following general procedure, propionyl chloride (0.055 ml, 0.63 mmol) in dichloromethane (1.0 ml) was added over 10 h to a solution of 4e (60 mg, 0.31 mmol), Hünig's base (0.11 ml, 0.63 mmol) and (DHQD)2PHAL (24 mg, 0.03 mmol) in dichloromethane (2.1 ml) at 25 C. Elution with 2.5% EtAc/dichloromethane through silica gel column afforded 1h as a white solid (72 mg, 93%), dr = 3:1 (by 1 H MR); HPLC analysis: 99% ee [Daicel Chiralcel AD-H column; 0.5 ml/min; solvent system: 10% isopropanol in hexane; retention times: 33.9 min (minor), 44.6 min S7

8 (major)]; Mp: o C; IR (thin film) 3055, 2981, 2883, 1772, 1699, 1512, 1277, 1221, 840 cm -1 ; 1 H MR (400 MHz, CDCl3, TMS, Major isomer): δ (m, 2H), (m, 2H), (m, 2H), (m, 4H), 1.18 (d, J = 7.0 Hz, 3H); 13 C MR (100 MHz, CDCl3, Major isomer): δ 166.5, 165.0, (d, J = Hz, 1C), (d, J = 3.1 Hz, 1C), (d, J = 8.3 Hz, 2C), (d, J = 21.8 Hz, 2C), 78.2, 52.3, 51.0, 36.6, 10.9; (M + H) + HRMS m/z calcd for (C13H14F22) + : ; found: i (2R,3S)-2-Ethyl-tetrahydro-3-(4-methoxyphenyl)pyrazolo[1,2-a]pyrazole-1,7- dione (1i): Following general procedure, butyryl chloride (0.063 ml, 0.59 mmol) in dichloromethane (1.0 ml) was added over 10 h to a solution of 4d (60 mg, 0.29 mmol), Hünig's base (0.10 ml, 0.59 mmol) and (DHQ)2PHAL (23 mg, mmol) in dichloromethane (2.0 ml) at 25 C. Elution with 2.0% EtAc/dichloromethane through silica gel column afforded 1i as a yellowish oil (60 mg, 74%), dr = 4:1 (by 1 H MR and HPLC); HPLC analysis: 98% ee [Daicel Chiralcel AD-H column; 1.0 ml/min; solvent system: 3% isopropanol in hexane; retention times: 52.3 min (major), 65.3 min (minor)]; IR (thin film) 2966, 2934, 2876, 2838, 1775, 1703, 1514, 1280, 1245, 838 cm -1 ; 1 H MR (400 MHz, CDCl3, TMS, Major isomer): δ (m, 2H), (m, 2H), 3.83 (s, 3H), 3.61 (d, J = 12.3 Hz, 1H), 3.45 (t, J = 8.6 Hz, 1H), (m, 2H), (m, 2H), (m, 2H), 0.91 (t, J = 7.5 Hz, 3H); 13 C MR (100 MHz, CDCl3, Major isomer): δ 166.4, 164.9, 160.5, 129.1, 127.8, 114.7, 76.1, 56.3, 55.6, 52.2, 36.6, 19.6, 11.1; (M + H) + HRMS m/z calcd for (C15H1923) + : ; found: j ((2R,3S)-Tetrahydro-3-(4-methoxyphenyl)-2-propylpyrazolo[1,2-a]pyrazole- 1,7-dione (1j): Following general procedure, valeroyl chloride (0.07 ml, 0.59 mmol) in dichloromethane (1.0 ml) was added over 10 h to a solution of 4d (60 mg, 0.29 mmol), Hünig's base (0.10 ml, 0.59 mmol) and (DHQ)2PHAL (23 mg, mmol) in dichloromethane (2.0 ml) at 25 C. Elution with 2.0% EtAc/dichloromethane through silica gel column afforded 1j as a yellowish oil (69 mg, 81%), dr = 5:1 (by 1 H MR and HPLC); HPLC analysis: 99% ee [Daicel Chiralcel AD-H column; 0.5 ml/min; solvent system: 7% isopropanol in hexane; retention times: 49.3 min (major), 65.8 min (minor)]; IR (thin film) 2959, 2933, 2871, 2839, 1776, 1704, 1514, 1280, 1246, 836 cm -1 ; 1 H MR (400 MHz, CDCl3, TMS, Major isomer): δ (m, 2H), (m, 2H), 3.83 (s, 3H), 3.57 (d, J = 12.3 Hz, 1H), 3.43 (t, J = 8.5 Hz, 1H), (m, 2H), (m, 2H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), 0.80 (t, J = 7.3 Hz, 3H); 13 C MR (100 MHz, CDCl3, Major isomer): δ 166.6, 164.9, 160.5, 129.2, 127.8, 114.6, 76.9, 55.6, 54.9, 52.2, 36.6, 29.0, 20.0, 14.2; (M + H) + HRMS m/z calcd for (C16H2123) + : ; found: S8

9 1k (2R,3S)-2-Hexyl-tetrahydro-3-(4-methoxyphenyl)pyrazolo[1,2- a]pyrazole-1,7-dione (1k): Following general procedure, octanoyl chloride (0.10 ml, 0.59 mmol) in dichloromethane (1.0 ml) was added over 10 h to a solution of 4d (60 mg, 0.29 mmol), Hünig's base (0.10 ml, 0.59 mmol) and (DHQ)2PHAL (23 mg, mmol) in dichloromethane (2.0 ml) at 25 C. Elution with 1.5% EtAc/dichloromethane through silica gel column afforded 1k as a yellowish oil (82 mg, 84%), dr = 6:1 (by 1 H MR); HPLC analysis: 99% ee [Daicel Chiralcel AD-H column; 1.0 ml/min; solvent system: 5% isopropanol in hexane; retention times: 23.5 min (major), 28.6 min (minor)]; IR (thin film) 2953, 2927, 2856, 1777, 1706, 1514, 1304, 1280, 1246, 837 cm -1 ; 1 H MR (400 MHz, CDCl3, TMS, Major isomer): δ (m, 2H), (m, 2H), 3.83 (s, 3H), 3.58 (d, J = 12.3 Hz, 1H), 3.44 (t, J = 8.4 Hz, 1H), (m, 2H), (m, 2H), (m, 2H), (m, 8H), 0.82 (t, J = 7.0 Hz, 3H); 13 C MR (100 MHz, CDCl3, Major isomer): δ 166.6, 164.9, 160.5, 129.1, 127.8, 114.6, 76.8, 55.5, 55.0, 52.2, 36.6, 31.6, 29.3, 26.7, 26.5, 22.7, 14.1; (M + H) + HRMS m/z calcd for (C19H2723) + : ; found: [ ] D 1l (2R,3R)-2-Acetoxy-tetrahydro-3-(4-methoxyphenyl)pyrazolo[1,2- a]pyrazole-1,7-dione (1l): Following general procedure, acetoxyacetyl chloride (0.053 ml, 0.49 mmol) in dichloromethane (0.8 ml) was added over 10 h to a solution of 4d (50 mg, 0.25 mmol), Hünig's base (0.09 ml, 0.49 mmol) and (DHQ)2PHAL (19 mg, mmol) in dichloromethane (1.7 ml) at 25 C. Elution with 3.0% EtAc/dichloromethane through silica gel column afforded 1l as a colorless gum (43 mg, 58%), dr = 27:1 (by 1 H MR); HPLC analysis: 99% ee [Daicel Chiralcel AD-H column; 1.0 ml/min; solvent system: 12% isopropanol in hexane; retention times: 34.1 min (major), 41.4 min (minor)]; = (c = 2.3, CH2Cl2); IR (thin film) 2928, 2844, 1788, 1751, 1713, 1514, 1249, 1211, 1172, 836 cm -1 ; 1 H MR (400 MHz, CDCl3, TMS, Major isomer): δ (m, 2H), (m, 2H), 5.75 (d, J = 11.2 Hz, 1H), 3.94 (d, J = 11.2 Hz, 1H), 3.82 (s, 3H), 3.57 (t, J = 8.1 Hz, 1H), (m, 1H), (m, 1H), (m, 1H), 2.11 (s, 3H); 13 C MR (100 MHz, CDCl3, Major isomer): δ 168.9, 165.2, 160.8, 160.7, 129.0, 125.0, 114.8, 77.3, 75.4, 55.5, 52.6, 35.4, 20.6; (M + H) + HRMS m/z calcd for (C15H1725) + : ; found: S9

10 24 [ ] D 1m (2S,3S)-2-Acetoxy-tetrahydro-3-(4-methoxyphenyl)pyrazolo[1,2-a]pyrazole- 1,7-dione (1m): Following general procedure, acetoxyacetyl chloride (0.053 ml, 0.49 mmol) in dichloromethane (0.8 ml) was added over 10 h to a solution of 4d (50 mg, 0.25 mmol), Hünig's base (0.09 ml, 0.49 mmol) and (DHQD)2PHAL (19 mg, mmol) in dichloromethane (1.7 ml) at 25 C. Elution with 3.0% EtAc/dichloromethane through silica gel column afforded 1m as a colorless gum (41 mg, 55%), dr = 18:1 (by 1 H MR); HPLC analysis: 96% ee [Daicel Chiralcel AD-H column; 1.0 ml/min; solvent system: 12% isopropanol in hexane; retention times: 34.5 min (minor), 40.7 min (major)]; = (c = 2.1, CH2Cl2); IR (thin film) 2930, 2842, 1788, 1751, 1713, 1514, 1249, 1211, 1171, 836 cm -1 ; 1 H MR (400 MHz, CDCl3, TMS, Major isomer): δ (m, 2H), (m, 2H), 5.75 (d, J = 11.2 Hz, 1H), 3.94 (d, J = 11.2 Hz, 1H), 3.82 (s, 3H), 3.57 (t, J = 8.1 Hz, 1H), (m, 1H), (m, 1H), (m, 1H), 2.11 (s, 3H); 13 C MR (100 MHz, CDCl3, Major isomer): δ 168.9, 165.2, 160.8, 160.7, 129.0, 125.0, 114.8, 77.3, 75.4, 55.5, 52.6, 35.4, 20.6; (M + H) + HRMS m/z calcd for (C15H1725) + : ; found: n (2R,3R)-2-Acetoxy-tetrahydro-3-p-tolylpyrazolo[1,2-a]pyrazole-1,7-dione (1n): Following general procedure, acetoxyacetyl chloride (0.057 ml, 0.53 mmol) in dichloromethane (0.9 ml) was added over 10 h to a solution of 4b (50 mg, 0.27 mmol), Hünig's base (0.093 ml, 0.53 mmol) and (DHQ)2PHAL (21 mg, mmol) in dichloromethane (1.8 ml) at 25 C. Elution with 3.0% EtAc/dichloromethane through silica gel column afforded 1n as a white solid (49 mg, 64%), dr = 22:1 (by 1 H MR and HPLC); HPLC analysis: 99% ee [Daicel Chiralcel AD-H column; 1.0 ml/min; solvent system: 8% isopropanol in hexane; retention times: 30.9 min (major), 38.1 min (minor)]; 24 [ ] D = (c = 1.65, CH2Cl2); Mp: o C; IR (thin film) 2928, 2850, 1787, 1753, 1715, 1514, 1315, 1212, 1103, 836 cm -1 ; 1 H MR (400 MHz, CDCl3, TMS, Major isomer): δ (m, 2H), (m, 2H), 5.76 (d, J = 11.3 Hz, 1H), 3.97 (d, J = 11.3 Hz, 1H), 3.58 (t, J = 8.0 Hz, 1H), (m, 2H), (m, 1H), 2.37 (s, 3H), 2.10 (s, 3H); 13 C MR (100 MHz, CDCl3, Major isomer): δ 168.8, 165.2, 160.6, 139.7, 130.2, 130.0, 127.6, 77.3, 75.5, 52.6, 35.4, 21.4, 20.5; (M + H) + HRMS m/z calcd for (C15H1724) + : ; found: S10

11 1o (2S,3S)-2-Acetoxy-tetrahydro-3-p-tolylpyrazolo[1,2-a]pyrazole-1,7-dione (1o): Following general procedure, acetoxyacetyl chloride (0.057 ml, 0.53 mmol) in dichloromethane (0.9 ml) was added over 10 h to a solution of 4b (50 mg, 0.27 mmol), Hünig's base (0.093 ml, 0.53 mmol) and (DHQD)2PHAL (21 mg, mmol) in dichloromethane (1.8 ml) at 25 C. Elution with 3.0% EtAc/dichloromethane through silica gel column afforded 1o as a white solid (40 mg, 52%), dr = 19:1 (by 1 H MR and HPLC); HPLC analysis: 99% ee [Daicel Chiralcel AD-H column; 1.0 ml/min; solvent system: 8% isopropanol in hexane; retention times: 29.9 min (minor), 38.0 min (major)]; 24 [ ] D = (c = 1.8, CH2Cl2); Mp: o C; IR (thin film) 3015, 2927, 2857, 1787, 1754, 1716, 1514, 1300, 1213, 1104, 822 cm -1 ; 1 H MR (400 MHz, CDCl3, TMS, Major isomer): δ (m, 2H), (m, 2H), 5.76 (d, J = 11.3 Hz, 1H), 3.96 (d, J = 11.3 Hz, 1H), 3.58 (t, J = 8.0 Hz, 1H), (m, 1H), (m, 1H), (m, 1H), 2.37 (s, 3H), 2.10 (s, 3H); 13 C MR (100 MHz, CDCl3, Major isomer): δ 168.8, 165.2, 160.6, 139.8, 130.3, 130.1, 127.6, 77.4, 75.6, 52.7, 35.4, 21.4, 20.6; (M + H) + HRMS m/z calcd for (C15H1724) + : ; found: p (2R,3R)-2-Acetoxy-tetrahydro-3-phenylpyrazolo[1,2-a]pyrazole-1,7-dione (1p): Following general procedure, acetoxyacetyl chloride (0.074 ml, 0.79 mmol) in dichloromethane (1.2 ml) was added over 10 h to a solution of 4a (60 mg, 0.35 mmol), Hünig's base (0.14 ml, 0.79 mmol) and (DHQ)2PHAL (27 mg, mmol) in dichloromethane (2.3 ml) at 25 C. Elution with 3.0% EtAc/dichloromethane through silica gel column afforded 1p as a colorless crystalline solid (65 mg, 69%), dr = 16:1 (by 1 H MR); HPLC analysis: 99% ee [Daicel Chiralcel AD-H column; 1.0 ml/min; solvent system: 5% isopropanol in hexane; retention times: 68.7 min (major), 75.2 min (minor)]; 24 [ ] D = 9.79 (c = 3.3, CH2Cl2); Mp: o C; IR (thin film) 2931, 2851, 1789, 1751, 1714, 1297, 1208, 1169, 1118, 911, 832 cm -1 ; 1 H MR (400 MHz, CDCl3, TMS, Major isomer): δ (m, 5H), 5.76 (d, J = 11.2 Hz, 1H), 4.02 (d, J = 11.2 Hz, 1H), 3.60 (t, J = 7.7 Hz, 1H), (m, 2H), (m, 1H), 2.11 (s, 3H); 13 C MR (100 MHz, CDCl3, Major isomer): δ 168.8, 165.2, 160.5, 133.4, 129.7, 129.3, 127.6, 77.4, 75.6, 52.7, 35.4, 20.5; (M + H) + HRMS m/z calcd for (C14H1524) + : ; found: S11

12 X-Ray structure of 1p 1q (2S,3S)-2-Acetoxy-tetrahydro-3-phenylpyrazolo[1,2-a]pyrazole-1,7-dione (1q): Following general procedure, acetoxyacetyl chloride (0.062 ml, 0.57 mmol) in dichloromethane (1.0 ml) was added over 10 h to a solution of 4a (50 mg, 0.29 mmol), Hünig's base (0.10 ml, 0.57 mmol) and (DHQD)2PHAL (22 mg, mmol) in dichloromethane (1.9 ml) at 25 C. Elution with 3.0% EtAc/dichloromethane through silica gel column afforded 1q as a colorless gum (50 mg, 64%), dr = 12:1 (by 1 H MR); HPLC analysis: 96% ee [Daicel Chiralcel AD-H column; 1.0 ml/min; solvent system: 5% isopropanol in hexane; retention times: 65.1 min (minor), 71.8 min (major)]; 24 [ ] D = 6.44 (c = 0.9, CH2Cl2); IR (thin film) 2932, 2851, 1789, 1750, 1713, 1297, 1208, 1118, 912, 832 cm -1 ; 1 H MR (400 MHz, CDCl3, TMS, Major isomer): δ (m, 5H), 5.77 (d, J = 11.2 Hz, 1H), 4.00 (d, J = 11.2 Hz, 1H), 3.61 (t, J = 8.0 Hz, 1H), (m, 1H), (m, 1H), (m, 1H), 2.12 (s, 3H); 13 C MR (100 MHz, CDCl3, Major isomer): δ 168.8, 165.1, 160.5, 133.4, 129.8, 129.4, 127.7, 77.4, 75.7, 52.8, 35.5, 20.6; (M + H) + HRMS m/z calcd for (C14H1524) + : ; found: S12

13 chanistic experiments: To a suspension of Zn-dust (80 mg, 1.22 mmol) in THF (2.0 ml) under sonication at room temperature and under reduced pressure (100 torr), a solution of 2-bromopropionyl bromide (0.05 ml, 0.49 mmol) in THF (1.0 ml) was added dropwise over 5 min. This reaction was carried out in a small distillation set-up where the collection flask was completely immersed in liquid nitrogen. After the addition was complete, vacuum was replaced with nitrogen and the collection flask was warmed up to 78 o C to afford a light lime colored methylketene solution. This ketene solution was added dropwise via syringe to a stirring solution of 4d (50 mg, 0.25 mmol) and (DHQ)2PHAL (19 mg, mmol) in dichloromethane (2.5 ml) at 25 o C. The reaction was stirred at this temperature for another 6 h. Removal of the solvent under reduced pressure followed by passing through a plug of regular silica gel, using 10% EtAc/dichloromethane as elutant, afforded crude product (free from catalyst) for diasteriomeric ratio and enantiomeric excess measurement. Further regular silica gel column chromatographic purification, eluting with 2.5% EtAc/dichloromethane, afforded 1e as a light yellow solid (10 mg, 16%), dr = 7:1 (by GC-MS); HPLC analysis: 98% ee [Daicel Chiralcel AD-H column; 1.0 ml/min; solvent system: 7% isopropanol in hexane; retention times: 28.9 min (major), 34.2 min (minor)]; Mp: o C; IR (thin film) 2951, 2887, 2837, 1768, 1697, 1514, 1287, 1245, 831 cm -1 ; 1 H MR (400 MHz, CDCl3, TMS, Major isomer): δ (m, 2H), (m, 2H), 3.83 (s, 3H), (m, 2H), (m, 2H), (m, 2H), 1.17 (d, J = 7.0 Hz, 3H); 13 C MR (100 MHz, CDCl3, Major isomer): δ 167.0, 165.1, 160.5, 128.9, 127.5, 114.7, 78.7, 55.6, 52.4, 50.8, 36.7, 11.0; (M + H) + HRMS m/z calcd for (C14H1723) + : ; found: S13

14 Table 1. ptimization of Alkaloid-Catalyzed [3 + 2] cycloaddition of Ketenes with Azomethine Imines. entry cat. temp ( C) additive % yield a drb % eec none 80 1: none : none (70) 1: LiCl Cu(Tf)2 (80) 1: Er(Tf) 3 (75) 1: Yb(Tf) 3 (70) 1: none (40) 1.5: none (25) 2: none 90 3: none 61 3: CuI 89 2: d 9 25 none 85 3:1 99 a Isolated yield for both diastereomers. Conversion as determined by GC-MS in parentheses. b dr determined by 1 H MR or HPLC analysis of crudes. (R,S)-isomer = major in most cases. c ee determined by chiral HPLC or chiral GC analysis for major diastereomer. d 2.5 mol % of catalyst used. S14