Supplementary Information

Transcription

1 Supplementary Information Copper(II)-Catalyzed Tandem Decarboxylative Michael/Aldol Reactions Leading to the Formation of Functionalized Cyclohexenones Jeonghyo Lee a, Sibin Wang a, Miranda Callahan b, and Pavel Nagorny* a a Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States. b Department of Chemistry, Sewanee: The University of the South, Sewanee, Tennessee 37383, United States. *nagorny@umich.edu Table of contents I. General Information.....page 2 II. Synthesis of Michael reaction substrates and catalyst optimization.. page 3 6 III. Decarboxylative Michael reactions leading to the formation of cyclohexenones with quaternary carbon....page 7 12 IV. Enantioselective Cu(II)-catalyzed decarboxylative Robinson annulation page V. HPLC traces for the racemic and chiral cyclohexenones 6a-6e...page VI. NMR spectra of cyclohexenone products 3a-3k and 6a-6e...page

2 I. General Information Methods and Reagents : Unless otherwise stated, all reagents were purchased from commercial suppliers and used without further purification. Tetrahyrofuran (THF), dichloromethane (DCM) and diethyl ether (Et 2 O) were filtered through a column (Innovative Technology PS-MD-5) of activated alumina under nitrogen atmosphere. All reactions were carried out under an atmosphere of nitrogen in flame- or oven-dried glassware with magnetic stirring. Reactions were cooled using Neslab Cryocool CB-80 immersion cooler (0 to -60 C) and Neslab Cryocool immersion cooler CC-100 II, or via external cooling baths: ice water (0 C), sodium chloride/ ice water (-10 C), or dry ice/acetone (- 78 C). Heating was achieved by use of a silicone bath with heating controlled by electronic contact thermometer. Deionized water was used in the preparation of all aqueous solutions and for all aqueous extractions. Solvents used for extraction and chromatography were ACS or HPLC grade. Purification of reactions mixtures was performed by flash chromatography using SiliCycle SiliaFlash P60 ( mesh). Diastereomeric ratios were determined by 1 H NMR analysis. Enantiomeric excess was determined by HPLC analysis using a Waters e2695 Separations Module with a Waters 2998 photodiode array detector. Instrumentation : All spectra were recorded on Varian vnmrs 700 (700 MHz), Varian vnmrs 500 (500 MHz), Varian MR400 (400 MHz), Varian Inova 500 (500 MHz) spectrometers and chemical shifts (δ) are reported in parts per million (ppm) and referenced to the 1 H signal of the internal tetramethylsilane according to IUPAC recommendations. Data are reported as (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, qn = quintet, sext = sextet, m = multiplet; coupling constant(s) in Hz; integration). High resolution mass spectra (HRMS) were recorded on MicromassAutoSpecUltima or VG (Micromass) S Magnetic sector mass spectrometers in the University of Michigan mass spectrometry laboratory. Infrared (IR) spectra were recorded as thin films on NaCl plates on a Perkin Elmer Spectrum BX FT-IR spectrometer. Absorption peaks were reported in wavenumbers (cm -1 ). 2

3 II. Synthesis of Michael reaction substrates and catalyst optimization 1. Synthesis of Michael Acceptors (β,β -disubstituted vinyl ketones) Method A. ((E)- selective HWE reaction 1, Weinreb amide synthesis 2, Grignard 2 ) General Procedure: 1) (E)- selective Horner Wadsworth Emmons reaction 1 Triethyl phosphonoacetate (1.0 eq), cesium carbonate (1.2 eq), and DBU (0.2 eq) were added and stirred in the flame dried reaction flask. After 10 minutes, a corresponding ketone (1.0 eq) was added to the reaction mixture. Then the reaction mixture was stirred in neat condition at 40 o C for 3 days under N 2. After reaction complete, the reaction was quenched with water and the crude product was extracted with EtOAc two times. The organic extract was washed with brine, and combined organic layer was dried over Na 2 SO 4 and concentrated in vacuo. The crude mixture was purified by a flash column chromatography (100% hexanes) to afford mixture of (E) and (Z) isomers of vinyl ester. ((E)- isomer is the major isomer) 2) Weinreb amide synthesis The (E) and (Z) mixtures of vinyl ester (1.0 eq), N,O-Dimethylhydroxylamine hydrochloride (2.0 eq), and THF (0.4 M) were added in a flame dried flask. Then a solution of iprmgcl (4.3 eq) in THF was slowly added at 0 o C. The reaction mixture was stirred for 30 minutes at 0 o C, and after that, the reaction was quenched with NH 4 Cl. The crude product was extracted with EtOAc three times, and combined organic layer was washed with brine, and dried over MgSO 4. After the crude mixture was concentrated in vacuo, it was purified by a column chromatography (6 : 1 / Hex : EtOAc). At this gradient, the (E)- and (Z)- isomers of Weinreb amides could be well separated, and (E) isomer was selectively moved forward. 3) Grignard reaction At -30 o C, a solution of corresponding Grignard (R 3 MgBr) (1.3 eq) in THF was slowly added to a solution of Weinreb amide (1.0 eq) in THF (0.35 M). The reaction mixture was stirred at -10 o C for 30 mins. After reaction completion, the reaction was quenched with the NH 4 Cl, and the crude mixture was extracted with EtOAc three times. The combined organic layer was washed with brined, dried over MgSO 4, and concentrated in vacuo. The crude mixture was purified by column chromatography (4 : 1 / Hex : EtOAc) to afford vinyl ketone. (Generally, the vinyl ketones were found to be volatile. Applying vacuum for long time (more than 20 mins) is not recommended.) 1 Green Chem, 2011, 13, Chem. Eur. J ,

4 Method B. (HWE reaction 2, Weinreb amide ketone synthesis 2, Grignard 2 ) 1) Horner Wadsworth Emmons reaction To a suspension of NaH (1.4 eq) in THF (1.3 M), a solution of ketone (1.0 eq) in THF was slowly added. The reaction mixture was stirred at room temp for 30 mins, and the corresponding ketone was added at 0 o C. Then the reaction mixture was stirred at room temp for 17 hours. After the reaction was completed, a solution of saturated NaHCO 3 was added to the mixture, then the crude product was extracted with EtOAc three times and combined organic layer was washed with brine. The resulting crude mixture was concentrated in vacuo, and purified by column chromatography (100% hexanes) to afford the mixture of isomeric (E) and (Z) vinyl esters. 2) Weinreb amide synthesis : exactly same as the method A, 2). The (E) and (Z) isomers of Weinreb amide could be separated by the column chromatography. 3) Grignard recation : exactly same as the method A, 3). Reaction was performed only with (E)- isomer. 2. Synthesis of Michael donor (β-keto acids) General Procedure: A corresponding β-keto ester (1.0 eq) was added to 1.5 M NaOH (1.2 eq) solution, and the reaction mixture was stirred at room temp for 24 h. The resultant mixture was diluted with ice water, and acidified with 3N HCl to ph = 2. Then solid KCl was added to the reaction mixture until saturation was achieved. The resultant mixture was extracted with EtOAc five times, and the combined organic layers were dried with Na 2 SO 4. The resulting crude mixture was filtered and concentrated in vacuo to afford β- keto acids without further separation. (Caution! β-keto acids could undergo decarboxylation. It is recommended to store them in a freezer) 4

5 3. Screening Catalysts (Initial study) Table S1. Catalyst screening with and without the p-tsa (p-toluensulfonic acid) 5

6 General Procedure: Condition 1: To a flame dried, N 2 flushed 1 dram vial, a stir bar and β-keto acids 1a (1.6 eq) was placed, and the reaction vial was taken to a glove box where the catalyst (20 mol %) was added. The closed vial was taken out of the glove box, and vinyl ketone 2a (1 eq) was added to the reaction mixture under N 2 flow. The reaction was left to stir at room temp for 12 hours and then quenched with water. The crude mixture was extracted with DCM three times and the combined organic layers were washed with brine, dried over Na 2 SO 4, filtered and concentrated in vacuo. Crude material was purified by flash chromatography to afford 3a. Condition 2: To a flame dried, N 2 flushed 1 dram vial, a stir bar and β-keto acids 1a (1.6 eq) was placed, and the reaction vial was taken to a glove box where catalyst (20 mol %) was added. The closed vial was taken out of the glove box, and vinyl ketone 2a (1 eq) was added to the reaction mixture under N 2 flow. The reaction was left to stir at room temp for 12 hours. After the reaction completed, p-tsa (0.5 eq) and THF (0.1 M) was added to the reaction mixture. The reaction was stirred at room temp for overnight, and the reaction was quenched with NaHCO 3. The crude mixture was extracted with DCM three times and the combined organic layer was washed with brine, dried over Na 2 SO 4, and concentrated in vacuo. Crude material was purified by a flash chromatography to afford 3a. With the experimental results, we confirmed that p-tsa promotes condensation of Michael adduct, which, in general, helps to increase the reaction yield. Interestingly the p-tsa itself could promote the whole process of Robinson annulation, but with low efficiency (15 % yield). From screening of catalysts, Cu(OTf) 2 is by far the best catalyst to promote Robinson annulation reaction. 6

7 III. Decarboxylative Michael reaction leading to the formation of cyclohexenones with quaternary carbon (Table 1 and 2). General Procedure: To a flame dried, N 2 flushed 1 dram vial, a stir bar and β-keto acids 1 (1.6 eq) was placed, and the reaction vial was taken to a glove box where Cu(OTf) 2 (20 mol %) was added. The closed vial was removed from the glove box, and vinyl ketone 2 (1 eq) was added to the reaction mixture under N 2 flow. The reaction was stirred at room temp for 12 hours (or 3 days). After the reaction was completed, p-tsa (0.5 eq) and THF (0.1 M) was added to the resultant mixture. The resultant solution was stirred at room temp overnight, and the reaction was quenched with NaHCO 3. The crude mixture was extracted with DCM three times and the combined organic layers were washed with brine, dried over Na 2 SO 4, filtered, and concentrated in vacuo. Crude material was purified by a flash chromatography to afford 3. (FYI: As the reactions are performed under the solvent-free conditions, it is essential to insure vigorous stirring of the viscous reaction mixture throughout the course of the decarboxylative Michael addition. All of the vinyl ketones were liquid; however, some of the β-keto acids were solid under normal conditions. In the instances when β- keto acid was solid, challenges with achieving effective stirring were initially observed. This problem gradually alleviates as these reactions proceed as the competitive decarboxylation of β-keto acids results in liquid ketone side-product, which reduces the viscosity of the reaction mixture and promotes better stirring.) 3,5,5-trimethylcyclohex-2-en-1-one (3a) (Followed by a general procedure): β-keto acids 1a (60 µl, mmol, 1.6 eq), Cu(OTf) 2 (31 mg, mmol, 20 mol %), vinyl ketone 2a (50 µl, mmol, 1 eq), p-tsa (37mg, mmol, 0.5 eq), THF (4.3 ml, 0.1 M). The crude product was purified by flash chromatography (9 : 1 / Hex : EtOAc) to afford 3a (49 mg, 83 %) as a colorless oil: IR (thin film, cm -1 ):2956, 2923, 2850, 1721, H NMR (700 MHz, CDCl 3 ) δ 5.85 (s, 1H), 2.16 (s, 2H), 2.14 (s, 2H), 1.91 (s, 3H), 1.00 (s, 6H). 13 C NMR (175 MHz, CDCl 3 ) δ 200.0, 160.5, 125.6, 50.8, 45.4, 33.6, 28.4, HRMS (ESI+) (m/z): [M+H] + calcd for C 9 H 14 O , found

8 (7R)-4,4,7-trimethyl-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one (3b) (Followed by a general procedure): β-keto acids 1a (60 µl, mmol, 1.6 eq), Cu(OTf) 2 (31 mg, mmol, 20 mol %), vinyl ketone 2b (70 µl, mmol, 1 eq), p-tsa (37mg, mmol, 0.5 eq), THF (4.3 ml, 0.1 M). The crude product was purified by flash chromatography (100% hexanes) to afford 3b (46 mg, 52 %) as a clear yellow oil: IR (thin film, cm -1 ): 2951, 2925, 2869, 1714, 1681, 1627, 1254, H NMR (500 MHz, CDCl 3 ) δ 5.78 (s, 1H), 2.42 (m, 1H), 2.19 (q, 2H), (m, 2H), (m, 2H), (m, 1H), 1.30 (dd, J = 13.3, 3.5 Hz, 1H), (m, 1H), 1.03 (s, 3H), 0.98 (d, J = 6.5 Hz, 3H), 0.93 (s, 3H). 13 C NMR (175 MHz, CDCl 3 ). δ 200.2, 166.1, 122.7, 50.3, 49.2, 45.2, 35.6, 34.8, 34.8, 28.8, 28.2, 24.8, HRMS (ESI+) (m/z): [M+H] + calcd for C 13 H 20 O , found ,4,5-trimethyl-1,6-dihydro-[1,1'-biphenyl]-3(2H)-one (3c) (Followed by a general procedure): β-keto acids 1b (46.4 mg, mmol, 1.6 eq), Cu(OTf) 2 (18 mg, 0.05 mmol, 20 mol %), vinyl ketone 2c (40 µl, 0.25 mmol, 1 eq), p-tsa (21.5mg, mmol, 0.5 eq), THF (2.5 ml, 0.1 M). The crude product was purified by flash chromatography (9 : 1 / Hex : EtOAc) to afford 3c (28 mg, 53 %) as a colorless oil: IR (thin film, cm -1 ): 2947, 2924, 2868, 1711, 1660, 1639, 1444, 1072,1029, 763, H NMR (700 MHz, CDCl 3 ) δ (m, 4H), 7.20 (tt, J = 5.4, 2.1 Hz, 1H), 2.86 (m, 2H), (m, 2H), 1.94 (s, 3H), 1.73 (s, 3H), 1.33 (s, 3H). 13 C NMR (175 MHz, CDCl 3 ) δ 198.6, 152.5, 147.4, 130.8, 128.6, 126.4, 125.3, 49.8, 46.2, 39.8, 29.5, 21.8, HRMS (ESI+) (m/z): [M+H] + calcd for C 15 H 18 O , found ethyl-1,5-dimethyl-1,6-dihydro-[1,1'-biphenyl]-3(2H)-one (3d) 8

9 (Followed by a general procedure): β-keto acids 1b (70 µl, mmol, 1.6 eq), Cu(OTf) 2 (31 mg, mmol, 20 mol %), vinyl ketone 2d (50 µl, mmol, 1 eq), p-tsa (37mg, mmol, 0.5 eq), THF (4.3 ml, 0.1 M). The crude product was purified by flash chromatography (9 : 1 / Hex : EtOAc) to afford 3d (42 mg, 43 %) as a colorless oil: IR (thin film, cm -1 ): 2965, 2927, 2873, 1713, 1659, 1638, 1496, 1444, 763, H NMR (700 MHz, CDCl 3 ) δ (m, 4H), (m, 1H), 2.90 (d, J = 15.9 Hz, 1H), 2.82 (d, J = 17.7 Hz, 1H), 2.61 (dd, J = 16.4, 13.3 Hz, 2H), (m, 2H), 1.74 (s, 3H), 1.33 (s, 3H), 1.02 (t, J = 7.6 Hz, 3H) 13 C NMR (175 MHz, CDCl 3 ) δ 199.2, 157.6, 147.5, 130.0, 128.6, 126.4, 125.3, 49.8, 44.0, 39.8, 29.2, 28.4, 11.4, HRMS (ESI+) (m/z): [M+H] + calcd for C 16 H 20 O , found ethyl-4,5-dimethyl-1,6-dihydro-[1,1'-biphenyl]-3(2H)-one (3e) (Followed by a general procedure): β-keto acids 1b (64 mg, mmol, 1.6 eq), Cu(OTf) 2 (25 mg, mmol, 20 mol %), vinyl ketone 2e (60 µl, mmol, 1 eq), p-tsa (30 mg, mmol, 0.5 eq), THF (3.4 ml, 0.1 M). The crude product was purified by flash chromatography (9 : 1 / Hex : EtOAc) to afford 3e (46.3 mg, 59 %) as a colorless oil: IR (thin film, cm -1 ): 2963, 2924, 2870, 1714, 1661, 1637, 1496, 1457, 759, H NMR (700 MHz, CDCl 3 ) δ (m, 2H), (m, 3H), 2.93 (dd, J = 15.9, 1.8 Hz, 1H), 2.79 (d, J = 17.6 Hz, 1H), (m, 2H), 1.93 (s, 3H), (m, 2H), 1.69 (s, 3H), 0.59 (t, J = 7.4 Hz, 3H). 13 C NMR (175 MHz, CDCl 3 ) δ 198.6, 152.4, 144.9, 131.2, 128.4, 126.2, 126.2, 47.7, 44.5, 43.5, 35.1, 21.9, 10.7, 8.3. HRMS (ESI+) (m/z): [M+H] + calcd for C 16 H 20 O , found '-chloro-1,4,5-trimethyl-1,6-dihydro-[1,1'-biphenyl]-3(2H)-one (3f) (Followed by a general procedure): β-keto acids 1b (48.5 mg, mmol, 1.6 eq), Cu(OTf) 2 (20 mg, mmol, 20 mol %), vinyl ketone 2f (50 µl, mmol, 1 eq), p-tsa (22.4 mg, 0.13 mmol, 0.5 eq), THF (2.6 ml, 0.1 M). The crude product was purified by flash chromatography (9 : 1 / Hex : EtOAc) to afford 3f (35 mg, 55 %) as a colorless oil: IR (thin film, cm -1 ): 2956, 2921, 2852, 1712, 1660, 1634, 1492, 1449, 1092, 1009, 821, 760, 711, 666, H NMR (700 MHz, CDCl 3 ) δ 7.27 (m, 2H), (m, 2H), 2.86 (dd, J = 15.9, 1.5 Hz, 1H), 2.77 (d, J = 17.9 Hz, 1H), (m, 2H), 1.93 (s, 3H), 1.72 (s, 3H), 1.31 (s, 3H). 13 C NMR (175 MHz, CDCl 3 ) δ 9

10 198.17, , , , , , , 49.81, 46.13, 39.71, 29.70, 21.83, HRMS (ESI+) (m/z): [M+H] + calcd for C 15 H 17 OCl , found '-methoxy-1,4,5-trimethyl-1,6-dihydro-[1,1'-biphenyl]-3(2H)-one (3g) (Followed by a general procedure): β-keto acids 1b (49 µl, mmol, 1.6 eq), Cu(OTf) 2 (19 mg, mmol, 20 mol %), vinyl ketone 2g (50 µl, mmol, 1 eq), p-tsa (22.6 mg, mmol, 0.5 eq), THF (2.6 ml, 0.1 M). The crude product was purified by flash chromatography (9 : 1 / Hex : EtOAc) to afford 3g (33 mg, 51 %) as a colorless oil: IR (thin film, cm -1 ): 2959, 2926, 2833, 1708, 1661, 1601, 1582, 1429, 1376, 1285, 1243, 1214, 1174, 1070, 868, H NMR (700 MHz, CDCl 3 ) δ 7.23 (t, J = 8.0 Hz, 1H), (m, 1H), 6.82 (t, J = 2.2 Hz, 1H), (m, 1H), 3.79 (s, 3H), 2.88 (d, J = 15.8 Hz, 1H), 2.81 (d, J = 17.9 Hz, 1H), (m, 2H), 1.94 (s, 3H), 1.74 (s, 3H), 1.32 (s, 3H). 13 C NMR (175 MHz, CDCl 3 ) δ 198.5, 159.8, 152.4, 149.3, 130.8, 129.6, 117.8, 112.0, 111.0, 55.3, 49.9, 46.2, 39.9, 29.3, 21.8, HRMS (ESI+) (m/z): [M+H] + calcd for C 16 H 20 O , found ,4,4',5-tetramethyl-1,6-dihydro-[1,1'-biphenyl]-3(2H)-one (3h) (Followed by a general procedure): β-keto acids 1b (75 mg, mmol, 1.6 eq), Cu(OTf) 2 (30 mg, mmol, 20 mol %), vinyl ketone 2h (70 µl, mmol, 1 eq), p-tsa (34mg, mmol, 0.5 eq), THF (4.3 ml, 0.1 M). The crude product was purified by flash chromatography (9 : 1 / Hex : EtOAc) to afford 3h (35 mg, 60 %) as a colorless oil: IR (thin film, cm -1 ): ): 2948, 2923, 2865, 1731, 1662, 1514, 1453, 1376, 954, 840, H NMR (700 MHz, CDCl 3 ) δ (m, 2H), 7.11 (d, J = 8.1 Hz, 2H), 2.88 (d, J = 15.9 Hz, 1H), 2.80 (d, J = 17.9 Hz, 1H), 2.59 (m, 2H), 2.31 (s, 3H), 1.93 (s, 3H), 1.73 (s, 3H), 1.31 (s, 3H). 13 C NMR (175 MHz, CDCl 3 ). δ 198.7, 152.5, 144.4, 135.9, 130.8, 129.3, 125.2, 49.9, 46.3, 39.5, 29.6, 21.9, 21.0, HRMS (ESI+) (m/z): [M+H] + calcd for C 16 H 20 O , found

11 2,3,5-trimethyl-5-phenethylcyclohex-2-en-1-one (3i) (Followed by a general procedure): β-keto acids 1b (50 mg, mmol, 1.6 eq), Cu(OTf) 2 (20 mg, mmol, 20 mol %), vinyl ketone 2i (50 µl, mmol, 1 eq), p-tsa (23.2 mg, mmol, 0.5 eq), THF (2.7 ml, 0.1 M). The crude product was purified by flash chromatography (9 : 1 / Hex : EtOAc) to afford 3i (40 mg, 62 %) as a colorless oil: IR (thin film, cm -1 ): 2952, 2926, 2871, 1737, 1662, 1636, 1454, 721, H NMR (700 MHz, CDCl 3 ) δ 7.28 (d, J = 7.6 Hz, 2H), 7.17 (dd, J = 20.1, 7.2 Hz, 3H), (m, 2H), (m, 2H), 2.30 (d, J = 15.2 Hz, 1H) 2.21 (d, J = 18.0 Hz, 1H), 1.90 (s, 3H), 1.78 (s, 3H), (m, 2H), 1.06 (s, 3H). 13 C NMR (175 MHz, CDCl 3 ). δ , , , , , , , 49.62, 45.50, 43.77, 35.65, 30.41, 24.99, 21.79, HRMS (ESI+) (m/z): [M+H] + calcd for C 17 H 22 O , found butyl-2,3,5-trimethylcyclohex-2-en-1-one (3j) Large scale reaction. (Followed by a general procedure): β-keto acids 1b (1.06 g, 9.13 mmol, 1.6 eq), Cu(OTf) 2 (412 mg, mmol, 20 mol %), vinyl ketone 2j (0.8 ml, 5.71 mmol, 1 eq), p-tsa (491.6 mg, mmol, 0.5 eq), THF (10 ml, 0.57 M). The crude product was purified by flash chromatography (9 : 1 / Hex : EtOAc) to afford 3j (770 mg, 70 %) as a colorless oil: IR (thin film, cm -1 ): 2955, 2928, 2860, 1710, 1638, 1376, 1081, H NMR (700 MHz, CDCl 3 ) δ (m, 2H), 2.21 (dd, J = 15.7, 1.3 Hz, 1H), 2.12 (d, J = 18.0 Hz, 1H), 1.90 (s, 3H), 1.76 (s, 3H), (m, 6H), 0.94 (s, 3H), 0.89 (t, J = 7.1 Hz, 3H). 13 C NMR (175 MHz, CDCl 3 ) δ 199.7, 152.5, 130.1, 49.8, 45.5, 41.5, 35.4, 26.1, 25.1, 23.5, 21.8, 14.2, HRMS (ESI+) (m/z): [M+H] + calcd for C 13 H 22 O , found

12 5,5-dimethyl-5,6-dihydro-[1,1'-biphenyl]-3(4H)-one (3k) (Followed by a general procedure): β-keto acids 1c (115 mg, mmol, 1.6 eq), Cu(OTf) 2 (31 mg, mmol, 20 mol %), vinyl ketone 2a (50 µl, mmol, 1 eq), p-tsa (0.37 mg, mmol, 0.5 eq), THF (4.3 ml, 0.1 M). The reaction was heated at 60 o C for 1d for the cyclization. The crude product was purified by flash chromatography (9 : 1 / Hex : EtOAc) to afford 3k (70 mg, 82 %) as a colorless oil: IR (thin film, cm -1 ): 2956, 2868, 1657, 1606, 1467, 1361, 902, 754, H NMR (700 MHz, CDCl 3 ) δ (m, 2H), 7.41 (m, 3H), 6.42 (s, 1H), 2.65 (s, 2H), 2.35 (s, 2H), 1.13 (s, 6H). 13 C NMR (175 MHz, CDCl 3 ) 200.3, 157.7, 139.2, 130.1, 128.9, 126.3, 124.5, 51.1, 42.5, 33.9, MS (ESI+) (m/z): [M+H] + calcd for C 14 H 16 O , found IV. Enantioselective Cu(II)-catalyzed decarboxylative Robinson annulation (scheme 2) General Procedure: Racemic reaction: To a flame dried, N 2 flushed 1 dram vial, a stir bar and β-keto acids 4 (1.6 eq) was placed, and the reaction vial was taken to a glove box where Cu(OTf) 2 (20 mol %) was added. The closed vial was removed from the glove box, and vinyl ketones 5 (1 eq) and DCM (0.2M) were added to the reaction mixture under N 2 flow. The reaction was left to stir at rt for 5 hours. After the reaction completed, p-tsa (0.5 eq) and THF (0.1 M) was added to the reaction mixture. The reaction was stirred at rt for overnight, and then quenched with NaHCO 3. The crude mixture was extracted with DCM three times and the combined organic layer was washed with brine, dried over Na 2 SO 4, filtered and concentrated in vacuo. Crude material was purified by a flash chromatography to afford 6. Enantioselective reaction: To a flame dried, N 2 flushed 1 dram vial, a stir bar and β-keto acids 4 (1.6 eq) was placed, and the reaction vial was taken to a glove box where Cu(II)-(R,R)-Box catalyst (10 mol %) was added. The closed vial was taken out from the glove box, and vinyl ketone 5 (1 eq) and DCM (0.2M) were added to the reaction mixture at -10 o C under N 2 flow. The reaction was placed in the cryocool, which was set to -10 o C, and stirred at -10 o C for 1 (or 3) days. After the reaction was completed, p-tsa (0.5 eq) and THF (0.1 M) were added to the reaction mixture. The reaction was stirred at rt overnight, and then quenched with NaHCO 3. The crude mixture was extracted with DCM three times and the combined organic layer was washed with brine, dried over Na 2 SO 4, filtered and concentrated in vacuo. Crude material was purified by a flash chromatography to afford 6. 12

13 N1-((1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-N3-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)- 2,2-dimethylmalonamide L1 and (4S,4'S)-2,2'-(propane-2,2-diyl)bis(4-phenyl-4,5-dihydrooxazole) L3 were synthesized based on the known procedure. 3 Bis((R)-4-phenyl-4,5-dihydrooxazol-2-yl)methane L2 and (4R,4'R)-2,2'-(cyclopropane-1,1-diyl)bis(4-phenyl-4,5-dihydrooxazole) L4 were produced according to literature procedure. 4,5 (R)-5-butyl-3-ethylcyclohex-2-en-1-one (6a) Racemic reaction (entry 1) (followed by a general procedure): β-keto acids 4a (88.3 mg, mmol, 1.6 eq), Cu(OTf) 2 (35 mg, mmol, 20 mol %), vinyl ketone 5a (60 µl, mmol, 1 eq), DCM (2.3 ml, 0.2M), p-tsa (41mg, mmol, 0.5 eq), THF (4.7 ml, 0.1 M). Purified by a flash chromatography (9 : 1 / Hex : EtOAc to 5 : 1 / Hex : EtOAc) to afford 6a (49 mg, 58 %) as a colorless oil: Enantioselective reaction (entry 2) (followed by a general procedure): β-keto acids 4a (88.3 mg, mmol, 1.6 eq), (R,R) cyclopropane-substituted diphenyl bis-(oxazoline)-copper(ii) catalyst (41.2 mg, mmol, 10 mol %), vinyl ketone 5a (60 µl, mmol, 1 eq), DCM (2.3 ml, 0.2M), reaction for 1 3 Adv. Synth. Catal., 2016, 358, Tetrahedron: Asymmetry, 2004, 15, J. Am. Chem. Soc. 2015, 137,

14 day, p-tsa (41 mg, mmol, 0.5 eq), THF (4.7 ml, 0.1 M), Purified by a flash chromatography (9 : 1 / Hex : EtOAc to 5 : 1 / Hex : EtOAc) to afford 6a (55 mg, 65 %) as a colorless oil: IR (thin film, cm -1 ): 2955, 2922, 2857, 1664, 1636, 1429, 1378, 1131, 1083, H NMR (700 MHz, CDCl 3 ) δ 5.86 (s, 1H), 2.47 (d, J = 12.1 Hz, 1H), (m, 1H), 2.23 (q, J = 7.5 Hz, 2H), (m, 3H), (m, 2H), (m, J = 5.6, 4.6 Hz, 4H), 1.10 (t, J = 7.4 Hz, 3H), 0.90 (t, 3H). 13 C NMR (175 MHz, CDCl 3 ) δ 200.6, 167.3, 124.5, 44.0, 36.6, 35.6, 35.2, 31.0, 28.9, 22.9, 14.2, HRMS (ESI+) (m/z): [M+H] + calcd for C 12 H 20 O , found [α] D = (c 0.9, CHCl 3 ) Enantiopurity was determined to be 92% ee by chiral HPLC (DAICEL CHIRALPAK IA, 4.6 X 250 mm, hexanes/2-proponal = 99.5/0.5, flow rate = 1 ml/min, λ = nm, RT(minor) = 30.3 min, RT(major) = 32.6 min). (R)-5-butyl-2-ethyl-3-methylcyclohex-2-en-1-one (6b) Racemic reaction (entry 1) (followed by a general procedure): β-keto acids 4b (66 mg, mmol, 1.6 eq), Cu(OTf) 2 (23 mg, mmol, 20 mol %), vinyl ketone 5a (40 µl, mmol, 1 eq), DCM (1.6 ml, 0.2M), p-tsa (27mg, mmol, 0.5 eq), THF (3.1 ml, 0.1 M). Purified by a flash chromatography (10 : 1 / Hex : EtOAc to 5 : 1 / Hex : EtOAc) to afford 6b (38 mg, 63 %) as a colorless oil. Enantioselective reaction (entry 2) (followed by a general procedure): β-keto acids 4b (66 mg, mmol, 1.6 eq), (R,R) cyclopropane- substituted diphenyl bis-(oxazoline)-copper(ii) catalyst (27.5 mg, mmol, 10 mol %), vinyl ketone 5a (40 µl, mmol, 1 eq), DCM (1.6 ml, 0.2M), reaction for 1 day, p-tsa (27 mg, mmol, 0.5 eq), THF (3.1 ml, 0.1 M), Purified by a flash chromatography (10 : 1 / Hex : EtOAc to 5 : 1 / Hex : EtOAc) to afford 6b (41 mg, 67 %) as a colorless oil: IR (thin film, cm -1 ): 2957, 2926, 2871, 2854, 1687, 1630, 1460, 1380, 980, 728, H NMR (700 MHz, CDCl 3 ) δ (m, 1H), (m, 3H), (m, 3H), 1.93 (s, 3H), 1.30 (m, 6H), 0.90 (m, 6H).. 13 C NMR (175 MHz, CDCl 3 ) δ 199.3, 154.2, 137.0, 44.4, 39.7, 35.7, 34.5, 28.8, 22.9, 21.1, 18.5, 14.2, 14

15 13.6. HRMS (ESI+) (m/z): [M+H] + calcd for C 13 H 22 O , found [α] D = 50.1 (c 0.7, CHCl 3 ) Enantiopurity was determined to be 91% ee by chiral HPLC (DAICEL CHIRALPAK IA, 4.6 X 250 mm, hexanes/2-proponal = 99.5/0.5, flow rate = 1 ml/min, λ = nm, RT(major) = 7.7 min, RT(minor) = 8.4 min). 3-(tert-butyl)-5-butylcyclohex-2-en-1-one (6c) Racemic reaction (entry 1) (followed by a general procedure): β-keto acids 4c (110 mg, mmol, 1.6 eq), Cu(OTf) 2 (35 mg, mmol, 20 mol %), vinyl ketone 5a (60 µl, mmol, 1 eq), DCM (2.3 ml, 0.2M), p-tsa (41mg, mmol, 0.5 eq), THF (4.7 ml, 0.1 M). The reaction was heated at 60 o C for 1d for the cyclization. Purified by a flash chromatography (10 : 1 / Hex : EtOAc to 5 : 1 / Hex : EtOAc) to afford 6c (62 mg, 69 %) as a colorless oil. Enantioselective reaction (entry 2) (followed by a general procedure): β-keto acids 4c (110 mg, mmol, 1.6 eq), (R,R) cyclopropane- substituted diphenyl bis- (oxazoline)- copper(ii) catalyst (41.2 mg, mmol, 10 mol %), vinyl ketone 5a (60 µl, mmol, 1 eq), DCM (2.3 ml, 0.2M), reaction for 1 day, p-tsa (41 mg, mmol, 0.5 eq), THF (4.7 ml, 0.1 M). The reaction was heated at 60 o C for 1d for the cyclization. Purified by a flash chromatography (10 : 1 / Hex : EtOAc to 5 : 1 / Hex : EtOAc) to afford 6c (66 mg, 73 %) as a colorless oil: IR (thin film, cm -1 ): 2956, 2928, 2871, 1706, 1666, 1614, 1466, 1364, 890, H NMR (700 MHz, CDCl 3 ) δ 5.94 (s, 1H), (m, 2H), (m, 3H), (m, 6H), 1.12 (s, 9H), 0.91 (t, J = 6.4 Hz, 3H). 13 C NMR (175 MHz, CDCl 3 ) δ , 173.1, 123.0, 44.0, 36.9, 35.7, 35.6, 32.8, 29.0, 28.4, 22.9, HRMS (ESI+) (m/z): [M+H] + calcd for C 14 H 24 O , found [α] D = (c 0.7, CHCl 3 ) Enantiopurity was determined to be 84% ee by chiral HPLC (DAICEL CHIRALPAK IA, 4.6 X 250 mm, 15

16 hexanes/2-proponal = 99/1, flow rate = 1 ml/min, λ = nm, RT(major) = 8.2 min, RT(minor) = 8.7 min). 4-butyl-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one (6d) Racemic reaction (entry 1) (followed by a general procedure): β-keto acids 4d (65 mg, mmol, 1.6 eq), Cu(OTf) 2 (21 mg, mmol, 20 mol %), vinyl ketone 5a (37 µl, mmol, 1 eq), DCM (1.45 ml, 0.2M), p-tsa (24.8mg, mmol, 0.5 eq), THF (2.9 ml, 0.1 M). Purified by a flash chromatography (8 : 1 to 3 : 1 / Hex : EtOAc) to afford 6d (50 mg, 85 %) as a colorless oil. The most enantioselective reaction (entry 5) (followed by a general procedure): β-keto acids 4d (65 mg, mmol, 1.6 eq), (R,R) cyclopropane-substituted diphenyl bis-(oxazoline)-copper(ii) catalyst (24 mg, mmol, 10 mol %), vinyl ketone 5a (37 µl, mmol, 1 eq), DCM (1.45 ml, 0.2M), reaction for 1 day, p-tsa (24.8mg, mmol, 0.5 eq), THF (2.9 ml, 0.1 M). Purified by a flash chromatography (8 : 1 to 3 : 1 / Hex : EtOAc) to afford 6d (44 mg, 75 %) as a colorless oil: IR (thin film, cm -1 ): 2951, 2924, 2868, 1768, 1715, 1673, 1453, 943, 861, 736 HRMS (ESI+) (m/z): [M+H] + calcd for C 14 H 22 O , found Major diastereomer (Trans stereochemistry was assigned based on 3 J (H 4 -H 5 ) = 12 Hz) 1 H NMR (700 MHz, CDCl 3 ) δ 5.80 (s, 1H), (m, 2H), (m, 2H), 2.09 (dd, J = 15.8, 11.6 Hz, 1H), 2.02 (dt, J = 12.4, 6.4 Hz, 1H), 1.91 (ddt, J = 12.6, 4.9, 2.4 Hz, 1H), (m, 1H), (ddp, J = 12.0, 8.2, 4.1 Hz, 1H), 1.47 (dt, J = 13.1, 3.4 Hz, 1H), (m, 3H), (m, 3H), 16

17 (m, 1H), 1.13 (qd, J = 12.9, 3.6 Hz, 1H), 0.89 (t, J = 7.2 Hz, 3H). 13 C NMR (175 MHz, CDCl 3 ) δ , , , 43.63, 41.83, 39.82, 36.33, 32.98, 32.86, 28.73, 27.39, 26.00, 22.96, Enantiopurity was determined to be 94% ee by chiral HPLC (DAICEL CHIRALPAK IA, 4.6 X 250 mm, hexanes/2-proponal = 99/1, flow rate = 1 ml/min, λ = nm, RT(minor) = 18.3 min, RT(major) = 12.4 min). (Separation of minor diastereomer from major isomer was not completely possible due to similar R f ) 14-hydroxy-13-methyl-1,3,4,8,9,10,11,12,13,14,15,16-dodecahydro-7H-cyclopenta[a]phenanthrene- 7,17(2H)-dione (6e) Racemic reaction (entry 1): To a flame dried, N 2 flushed 1 dram vial, a stir bar, β-keto acids 4d (65.5 mg, mmol, 1.6 eq), and vinyl ketone 5b 6 (60 mg, mmol, 1 eq) were placed, and the reaction vial was taken to a glove box to add Cu(OTf) 2 (21 mg, mmol, 20 mol %). The closed vial was taken out from the glove box, and DCM (1.45 ml, 0.2M) were added to the reaction mixture at room temp under 6 Cichowicz, N. R.; Kaplan, W.; Khomutnyk, Y.; Bhattarai, B.; Sun, Z.; Nagorny, P. J. Am. Chem. Soc. 2015, 137,

18 N 2 flow. The reaction was left to stir at rt for 5 hours. After the reaction completed, p-tsa (24.8mg, mmol, 0.5 eq) and THF (2.9 ml, 0.1 M) was added to the reaction mixture. The reaction was stirred at 40 o C for overnight, and the reaction was quenched with NaHCO 3. The crude mixture was extracted with DCM three times and the combined organic layer was washed with brine, dried over Na 2 SO 4, filtered and concentrated in vacuo. Crude material was purified by a flash chromatography (5 : 1 to 3 : 1 / Hex : EtOAc) to afford 6e (66 mg, 80 %) as a white solid. The most optimized enantioselective reaction (entry 8) To a flame dried, N 2 flushed 1 dram vial, a stir bar, β-keto acids 4d (956 mg, mmol, 1.6 eq), and vinyl ketone 5b (1 g, mmol, 1 eq) were placed, and the reaction vial was taken to a glove box to add (R,R) cyclopropane- substituted diphenyl bis- (oxazoline)- copper(ii) catalyst (416 mg, mmol, 10 mol %). The closed vial was taken out from the glove box, and DCM (24 ml, 0.2M) were added to the reaction mixture at -10 o C under N 2 flow. The reaction was placed in the cryocool, which was set to -10 o C, and stirred at -10 o C for 3 days. After the reaction completed, p-tsa (413mg, mmol, 0.5 eq) and THF (24 ml, 0.2 M) was added to the reaction mixture. The reaction was stirred at 40 o C for overnight, and the reaction was quenched with NaHCO 3. The crude mixture was extracted with DCM three times and the combined organic layer was washed with brine, dried over Na 2 SO 4, filtered and concentrated in vacuo. Crude material was purified by a flash chromatography (5 : 1 to 3 : 1 / Hex : EtOAc) to afford 6e (1.1 g, 85 %) as a white solid. IR (thin film, cm -1 ): 3455, 2938, 2858, 1739, 1669, 1640, 1447, 1141, 1047, 984, 959, 856, 635 HRMS (ESI+) (m/z): [M+H] + calcd for C 18 H 24 O , found Major diastereomer: 1 H NMR (700 MHz, CDCl 3 ) δ 5.85 (s, 1H), 4.46 (s, 1H), (m, 2H), (m, 2H), 2.25 (ddd, J = 12.1, 5.6, 2.5 Hz, 1H), (m, 2H), (m, 2H), (m, 1H), (m, 2H), (m, 1H), (m, 6H), 1.09 (s, 3H), 1.04 (qd, J = 12.9, 3.5 Hz, 1H). 13 C NMR (175 MHz, CDCl 3 ) δ , , , , 80.2, 53.19, 52.22, 43.64, 41.94, 35.61, 32.94, 32.11, 31.23, 27.91, 26.38, 25.41, 25.38, [α] D = (c 0.34, MeOH) Minor diastereomer: 1 H NMR (700 MHz, CDCl 3 ) δ 5.85 (s, 1H), 4.55 (s, 1H), 2.52 (dt, J = 19.6, 9.9 Hz, 1H), (m, 1H), (m, 2H), (m, 1H), (m, 2H), 2.13 (dd, J = 9.7, 2.4 Hz, 2H), (m, 2H), (m, 1H), (m, 1H), (m, 2H), (m, 2H), (m, 2H), 1.09 (s, 3H). 13 C NMR (175 MHz, CDCl 3 ) δ , , , , 47.87, 43.79, 38.03, 37.66, 33.00, 31.21, 30.59, 29.01, 27.92, 26.33, 24.29, [α] D = (c 0.16, MeOH) Enantiopurity was determined to be 93% ee by chiral HPLC (DAICEL CHIRALPAK IA, 4.6 X 250 mm, hexanes/2-proponal = 80/20, flow rate = 1 ml/min, λ = nm, RT(major) = 10.3 min, RT(minor) = 35.2 min). 18

19 V. HPLC traces for the racemic and chiral cyclohexenones 6a-6e racemic (IA column 99.5% hexanes / 0.5% iso-propanol) 19

20 enantioselective (IA column 99.5% hexanes / 0.5% iso-propanol) 20

21 racemic (IA column 99.5% hexanes / 0.5% iso-propanol) 21

22 enantioselective (IA column 99.5% hexanes / 0.5% iso-propanol) 22

23 racemic (IA column 99% hexanes / 1% iso-propanol) 23

24 enantioselective (IA column 99% hexanes / 1% iso-propanol) 24

25 racemic (IA column 99% hexanes / 1% iso-propanol) rt and (min) are the peaks for major diastereomer, and the other two peaks are minor one. Separation of two diastereomer was not possible. 25

26 enantioselective (major) (IA column 99% hexanes / 1% iso-propanol) rt and (min) are the peaks for major diastereomer, and the other two peaks are minor one. Separation of two diastereomer was not possible. 26

27 enantioselective (minor) (IA column 99% hexanes / 1% iso-propanol) * ee was the same for major and minor diastereomer (both 94%) 27

28 racemic (IA column 80% hexanes / 20% iso-propanol) 28

29 enantioselective (IA column 80% hexanes / 20% iso-propanol) 29

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