Lewis acid catalyzed cascade annulation of alkynols with α- ketoesters: A facile access to -spiroketal-γ-lactones

Transcript

1 Electronic Supplementary Material (ESI) for ChemComm. This journal is The Royal Society of Chemistry 2017 Lewis acid catalyzed cascade annulation of alkynols with α- ketoesters: A facile access to -spiroketal-γ-lactones Digambar A. Kambale, Sagar S. Thorat, Madhukar S. Pratapure, Rajesh G. Gonnade and Ravindar Kontham S1

2 Electronic Supplementary Information (ESI) S, No Contents Page No 1. General Information S3 2. General Procedure for the synthesis of unsaturated -spiroketal-γ-lactones from alkynols and -ketoesters s4 3. Synthesis of alkynols s4 4. Synthesis of α-ketoesters s10 5. Synthesis and Characterization of unsaturated -spiroketal-γ-lactones from alkynols possessing terminal alkyne functionality s12 6. Synthesis and Characterization of unsaturated -spiroketal-γ-lactones from alkynols possessing internal alkyne functionality s32 7. Supporting experiments for the postulated reaction mechanism s46 8. Synthetic utility of γ-spiroketal γ-lactones S H and 13 C NMR Spectra S50 S2

3 1. General Information: All reactions were performed under argon atmosphere with oven (80 ºC) or flamedried glassware with septum seal. Tetrahydrofuran (THF) was distilled from sodiumbenzophenone under argon atmosphere immediately prior to use. Dichloromethane and acetonitrile were freshly distilled over calcium hydride under argon atmosphere. 30 C corresponds to the room temperature (rt) of the laboratory when the experiments were carried out. Reaction temperatures are reported as the temperature of the bath surrounding the reaction vessel. Analytical thin layer chromatography (TLC) was performed on TLC Silica gel 60 F254. Visualization was accomplished with short wave UV light, anisaldehyde or KMn 4 staining solutions followed by heating. Chromatography was performed on silica gel ( mesh) by standard techniques eluting with solvents as indicated. 1 H and 13 C NMR spectra were recorded on Bruker AV 400 and 500 in solvents as indicated. Chemical shifts (δ) are given in ppm. The residual solvent signals were used as references and the chemical shifts converted to the TMS scale (CDCl 3 : δ H = 7.26 ppm, δ C = ppm), the following abbreviations were used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; AB q, AB quartet; dd, doublet of doublet; td, triplet doublet; and br, broad. HRMS data were recorded on a Thermo Scientific Q-Exactive, Accela 1250 pump. Experimental procedures for all new compounds and known compounds without published experimental procedures are described below. Compounds that are not presented in the main text (manuscript) are numbered starting from S1. S3

4 2. General Procedure for the synthesis of unsaturated -spiroketal-γlactones from alkynols and -ketoesters: Alkynol 1a (0.66 mmol)/or 4 (0.66 mmol) and -ketoester 2 (0.66 mmol) were taken in to a single neck round bottom flask, then dissolved in 5 ml of anhydrous CH 2 Cl 2. Bi(Tf) 3 (0.13 mmol) was added under argon atmosphere at room temperature (rt). The resulting reaction mixture was stirred at rt for respective reaction time. After completion of the reaction (typically after 12 h, monitored by TLC, visualized using UV, anisaldehyde, and KMn 4 staining solutions) the reaction was quenched with saturated aqueous-nahc 3 solution, then extracted with CH 2 Cl 2 (2x10 ml). The combined organic layers were dried over anhydrous Na 2 S 4, and filtered through sintered glass funnel. The filtrate was concentrated under reduced pressure and purified using silica-gel column chromatography ( mesh) to afford the corresponding unsaturated -spiroketal-γ-lactone 3 or Synthesis of alkynols: (see below experimental procedures) S4

5 (1-(Prop-2-yn-1-yl) cyclohexyl) methanol (1a): H 1a (1-(prop-2-yn-1-yl) cyclohexyl) methanol (1a) was prepared using known procedure. 11 H NMR (CDCl 3, 400 MHz): 3.55 (s, 2H), 2.26 (d, J = 2.45 Hz, 2H), 2.01 (t, J = 2.69 Hz, 1H), 1.84 (br s, 1H), (m, 10H); 13 C NMR (CDCl 3, 101 MHz): δ 82.0, 70.4, 68.5, 37.6, 31.8, 26.1, 25.1, 21.5, HRMS (ESI) m/z calcd for C 10 H 17 [M+H] , found ((1-(Prop-2-yn-1-yl) cyclohexyl) methoxy) tetrahydro-2h-pyran (S2): THP S2 To a cold (0 o C) mixture of (1-(prop-2-yn-1-yl)cyclohexyl) methanol (1a) (14 g, 100 mmol) and 3, 4-dihydro-2H-pyran (9.1 ml, 100 mmol) in 30 ml of anhydrous CH 2 Cl 2 was added camphor sulfonic acid (CSA, 2 g, 10 mmol). The reaction mixture was warmed slowly to rt and stirred for 3 h. Then the reaction was quenched with saturated aqueous NaHC 3 solution, extracted with CH 2 Cl 2 (2x50 ml). The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (Si 2, 2% EtAc/hexanes) to afford ((1-(prop-2-yn-1-yl) cyclohexyl) methoxy) tetrahydro-2h-pyran (S2), (18.5 g, 85%) as colourless liquid. TLC: R f = 0.40 (Si 2, 10% EtAc/hexanes); 1 H NMR (CDCl 3, 400 MHz) δ (m, 1H), (m, 1H), 3.65 (d, J = 9.8 Hz, 1H), 3.52 (d, J = 11.6 Hz, 1H), 3.21 (d, J = 9.2 Hz, 1H), (m, 2H), 1.80 (t, J = 2.4 Hz, 3H), (m, 1H), (m, 5H), (m, 10H); 13 C NMR (CDCl 3, 101 MHz) δ 98.8, 82.2, 72.1, 69.9, 61.7, 36.9, 32.3, 32.1, 30.6, 26.1, 25.6, 21.6, 19.2; HRMS (ESI) m/z calcd for C 15 H 25 2 [M+H] , found N. T. Patil, R. D. Kavthe, V. S. Raut, V. N. Reddy. J. rg. Chem. 2009, 74, S5

6 2-((1-(But-2-yn-1-yl) cyclohexyl) methoxy) tetrahydro-2h-pyran (S3): THP S3 To a solution of ((1-(prop-2-yn-1-yl) cyclohexyl) methoxy) tetrahydro-2h-pyran (S2) (1 g, 4.2 mmol) in anhydrous THF, nbuli (1.6 M in hexane, 8.1 ml, 5.1 mmol) was added at -78 o C and stirred this reaction mixture for 45 min at -78 o C under argon atmosphere. Then the solution of CH 3 I (1.8 ml, 12.7 mmol) in anhydrous HMPA (1 ml) was added at same temperature and resulting reaction mixture was slowly warmed to room temperature and further stirred for 6 h. Then the reaction mixture was quenched with saturated NH 4 Cl solution at 0 o C and extracted with ethyl acetate (3x25 ml). The combined extracts were dried over anhydrous Na 2 S 4, filtered and concentrated under reduced pressure. Crude product was purified by silica gel chromatography (Si 2, 2% EtAc/hexanes) to afford 2-((1-(but-2-yn-1- yl)cyclohexyl) methanol (S3) (1.23 g, 78%) as a colourless liquid. TLC: R f = 0.5 (Si 2, 10% EtAc/hexanes); 1 H NMR (CDCl 3, 400 MHz) δ 4.62 (t, J = 3.43 Hz, 1H), (m, 1H), 3.66 (d, J = 9.54 Hz, 1H), (m, 1H), 3.22 (d, J = 9.16 Hz, 1H), (m, 2H), 1.8 (t, J = 2.67 Hz, 3H), (m, 16H); 13 C NMR (CDCl 3, 101 MHz) δ 98.9, 72.3, 61.6, 37.1, 32.3, 32.1, 30.6, 26.2, 25.9, 25.6, 21.7, 19.2, 3.5; HRMS (ESI) m/z calcd for C 16 H 27 2 [M+H] , found (1-(But-2-yn-1-yl) cyclohexyl) methanol (4a): H 4a To a solution of 2-((1-(but-2-yn-1-yl) cyclohexyl) methoxy) tetrahydro-2h-pyran (S3) (1 g, 4 mmol) in methanol was added p-toluenesulfonic acid (PTSA, g, 0.4 mmol) at 0 C and then it was slowly warmed to rt. The resulting reaction mixture was stirred for 6 h at rt, then the methanol was evaporated under reduced pressure, diluted with ethyl acetate and quenched with saturated aqueous NaHC 3 solution and extracted with ethyl acetate (3x25 S6

7 ml). Combined organic layers were dried over anhydrous Na 2 S 4, filtered using sintered funnel, concentrated under reduced pressure to afford the crude product, which was purified by silica gel column chromatography (Si 2, 10% EtAc/hexanes) to afford (1-(but-2-yn-1- yl) cyclohexyl) methanol (4a), (0.59 g, 74%) as a colourless liquid. TLC: R f = 0.2 (Si 2, 20% EtAc/hexanes); 1 H NMR (CDCl 3, 400 MHz) δ 3.54 (s, 2 H), (m, 2 H), 1.82 (br. s., 1H), 1.8 (t, J = 2.44 Hz, 3H), (m, 10 H); 13 C NMR (CDCl 3, 101 MHz) δ 77.9, 76.4, 69.1, 37.7, 32.0, 26.2, 25.7, 21.6, 3.5; HRMS (ESI): m/z calcd for C 11 H 19 [M+H] , found ((1-(Pent-2-yn-1-yl) cyclohexyl) methoxy) tetrahydro-2h-pyran (S4): THP S4 To a solution of ((1-(prop-2-yn-1-yl) cyclohexyl) methoxy) tetrahydro-2h-pyran (S2) (1.5 g, 6.3 mmol) in anhydrous THF, nbuli (1.6 M in hexane, 5 ml, 7.6 mmol) was added, and stirred this reaction mixture for 45 min at -78 C under argon atmosphere. Then the solution of EtI (1.56 ml, 1.9 mmol) in anhydrous HMPA (1 ml) was added at -78 o C and resulting reaction mixture was stirred for 6 h at rt. The reaction mixture was quenched with saturated solution of NH 4 Cl and extracted with ethyl acetate (2x25 ml). Combined organic layers were dried over anhydrous Na 2 S 4 and concentrated under reduced pressure, crude product was purified by silica gel column chromatography (Si 2, 10% EtAc/hexanes) to give 2-((1-(pent-2-yn-1-yl) cyclohexyl) methoxy) tetrahydro-2h-pyran (S4) (1.1 g, 66%) as a colourless liquid. TLC: R f = 0.45 (Si 2, 10% EtAc/hexanes); 1 H NMR (CDCl 3, 400 MHz) δ 4.60 (m, 1H), (m, 1H), 3.64 (d, J = 9.8 Hz, 1H), (m, 1H), 3.2 (d, J = 9.8 Hz, 1H), (m, 2H), (m, 2 H), (m, 16H), 1.12 (t, J = 7.32 Hz, 3H); 13 C NMR (CDCl 3, 101 MHz) δ 98.8, 83.3, 76.9, 72.3, 61.5, 37.0, 32.3, 32.1, 30.6, 26.3, 25.9, 25.6, 21.7, 19.2, 14.5, 12.5; HRMS (ESI): m/z calcd for C 17 H 29 2 [M+H] , found S7

8 (1-(Pent-2-yn-1-yl) cyclohexyl) methanol (4b): H 4b To a solution of 2-((1-(pent-2-yn-1-yl) cyclohexyl) methoxy) tetrahydro-2h-pyran (S4) (1.1 g, 4.16 mmol) in methanol was added PTSA at 0 C and then it was warmed to room temperature, the resulting reaction mixture was stirred at rt for 6 h. Then methanol was evaporated under reduced pressure, diluted with ethyl acetate (25 ml) and washed with saturated solution of sodium bicarbonate and brine solution. The residue was dried over anhydrous sodium sulphate, filtered using sintered funnel, concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (Si 2, 10% EtAc/hexanes) to afford (1-(pent-2-yn-1-yl) cyclohexyl) methanol 4b (0.59 g, 78%) as a colourless liquid. TLC: R f = 0.5 (Si 2, 20% EtAc/hexanes); 1 H NMR (CDCl 3, 400 MHz) δ 3.53 (s, 2H), (m, 4H), 1.85 (br. s., 1H), (m, 10H), 1.12 (t, J = 7.32 Hz, 3H); 13 C NMR (CDCl 3, 101 MHz) δ 84.2, 76.6, 69.2, 37.6, 32.0, 26.2, 25.8, 21.6, 14.3, 12.4; HRMS (ESI): m/z calcd for C 12 H 20 Na [M+H] , found (1-(3-Phenylprop-2-yn-1-yl) cyclohexyl) methanol (4c): H Ph 4c (1-(3-phenylprop-2-yn-1-yl) cyclohexyl) methanol (4c) was prepared according to the literature. 2 Pd(PPh 3 ) 4 (0.023 g, mmol) and CuI (0.08 g, mmol) were added to the solution of iodobenzene (S1) (0.45 ml, 3.94 mmol) and (1-(prop-2-yn-1-yl) cyclohexyl) methanol (0.3 g, 1.97 mmol) (1a) in triethylamine (2.76 ml, 19.7 mmol) and THF (10 ml) under argon atmosphere. The reaction mixture was stirred at rt for 12 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. Purified by silica gel column chromatography (10% EtAc/hexanes) to afford the (1-(3-phenylprop-2-yn-1-yl) cyclohexyl) methanol (4c) as a brown oil (0.27 g, 60%). TLC: R f = 0.5 (Si 2, 20% EtAc/hexanes); 1 H NMR (CDCl 3, 400 MHz) δ (m, 2H), (m, 3H), 3.62 S8

9 (s, 2H), 2.49 (s, 2H), 1.92 (br s, 1H), (m, 10H); 13 C NMR (CDCl 3, 101 MHz) δ 131.6, 128.2, 127.6, 123.8, 87.6, 82.8, 68.7, 38.2, 32.0, 26.2, 26.1, 21.6; HRMS (ESI): m/z calcd for C 16 H 21 [M+H] , found (1-(Prop-2-yn-1-yl) cyclopentyl) methanol (1b): 1 (1-(prop-2-yn-1-yl) cyclopentyl) methanol (1b) was prepared using known procedure. 1 1 H NMR (CDCl 3, 400 MHz) δ 3.47 (s, 2H), 2.35 (s, 1H), 2.27 (d, J = 2.45 Hz, 2H), 1.94 (t, J = 2.45 Hz, 1H), (m, 4H), (m, 4H), 13 C NMR (CDCl 3, 101 MHz): δ 82.9, 69.3, 68.5, 46.9, 34.0, 26.5, 25.2; HRMS (ESI) m/z calcd for C 9 H 15 [M+H] , found (1-(3-Phenylprop-2-yn-1-yl) cyclopentyl) methanol (4d): (1-(3-phenylprop-2-yn-1- cyclopentyl) methanol (4d) was prepared according to the literature procedure. 1 Pd(PPh 3 ) 4 (0.042 g, mmol) and CuI (0.014 g, mmol) were added to the solution of iodobenzene (S1) (0.82 ml, 7.24 mmol) and (1-(prop-2-yn-1-yl) cyclopentyl) methanol (1b) (0.5 g, 3.62 mmol) in triethylamine (5 ml, 36.2 mmol) and THF (10 ml) under argon atmosphere. The reaction mixture was stirred at rt for 12 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. Purified by silica gel column chromatography (10% EtAc/hexanes) to afford (1-(3-phenylprop-2-yn-1- cyclopentyl) methanol (4d) (0.5 g, 64%) as brownish oil, TLC: R f = 0.5 (20% EtAc/hexanes); 1 H NMR (CDCl 3, 400 MHz): δ (m, 2H), (m, 3H), 3.57 (s, 2H), 2.50 (s, 2H), (m, 8H) ; 13 C NMR (CDCl 3, 101 MHz): δ 131.6, 128.2, 127.7, 123.8, 88.5, 81.7, 69.1, 47.6, 34.3, 27.7, 25.3; HRMS (ESI) m/z calcd for C 15 H 19 [M+H] , found S9

10 5-Phenylpent-4-yn-1-ol (4e): 5-phenylpent-4-yn-1-ol (4e) was prepared according to the literature procedure. 1 Pd(PPh 3 ) 4 (0.137 g, 0.12 mmol) and CuI (0.045 g, 0.24 mmol) were added to the solution of iodobenzene (S1) (2.7 ml, mmol) and pent-4-yn-1-ol (1c) (1 g, mmol) in triethylamine (16 ml, mmol) and anhydrous THF (15 ml) under argon atmosphere. The reaction mixture was stirred at rt for 6 h. Then the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purified by silica gel column chromatography (10% EtAc/hexanes) to afford 5-phenylpent-4-yn-1-ol (4e) (1.9 g, 98%) brown oil. TLC: R f = 0.4 (20% EtAc/hexanes); 1 H NMR (CDCl 3, 500 MHz) δ (m, 2H), (m, 3H), (m, 2H), (m, 2H), 2.1 (br. s., 1H), (m, 2H); 13 C NMR (CDCl 3, 126 MHz) δ 131.6, 128.3, 127.7, 123.8, 89.4, 81.1, 61.7, 61.6, 31.4, 16.0; HRMS (ESI): m/z calcd for C 11 H 13 [M+H] , found , 3,4,5 4. Synthesis of α-ketoesters: 2 2a and 2b were purchased from commercial sources. 3 S. Kawashima, K. Aikawa, K. Mikami. Eur. J. rg. Chem. 2016, H., M, S. Nakamura. Angew. Chem. Int. Ed., 2011, 50, see the next page for preparation. S10

11 Ethyl 2-(4-nitrophenyl)-2-oxoacetate (2e) 6 : Bromine (3.51 ml, 68 mmol) was added drop wise over 20 min to anhydrous 1,4- dioxane (20 ml) at C under argon atmosphere and the mixture was kept under these conditions for 30 min. A solution of 1-(4-nitrophenyl)ethan-1-one (S5) (5 g, 34 mmol) in dioxane (20 ml) was added and the mixture was stirred for another 3 h. The reaction was then quenched with ice-cold water (400 ml, 10 volumes with respect to 1,4-dioxane) and the solid was filtered off and washed with chilled hexane to give 2,2-dibromo-1-(4- nitrophenyl)ethan-1-one (S6), which was used in the next step without further purification. The crude S6 was dissolved in anhydrous DMS (60 ml) under argon. The solution was then slowly heated to C and stirred at this temperature for 16 h. The mixture was then cooled to rt, then EtH (3.97 ml, 0.6 mol) was added, and the mixture was stirred for 2 h at rt. The mixture was then diluted with H 2 (100 ml) and extracted with EtAc (4 30 ml). The combined organic layers were washed successively with water (3 30 ml) and brine solution, dried over anhydrous Na 2 S 4, filtered and concentrated under reduced pressure. The pure product was isolated by silica gel column chromatography (12% EtAc/hexanes) to give 3.21 g (47%) of 2e as a yellow oil. TLC: R f = 0.35 (20% EtAc/hexanes). 1 H NMR (CDCl 3, 400 MHz) δ 8.32 (d, J = 8.55 Hz, 2H), 8.21 (d, J = 8.55 Hz, 2H), 4.47 (q, J = 7.32 Hz, 2H), 1.43 (t, J = 7.32 Hz, 3H); 13 C NMR (CDCl 3, 101 MHz ) δ 184.2, 162.3, 151.1, 137.0, 131.2, 123.9, 63.0, 14.0; HRMS (ESI): m/z calcd for C 10 H 10 5 N [M+H] , found A. Raghunadh, M. S. Babu, N. A. Kumar, G. S. Kumar, L. V. Rao, U. K. S. Kumar. Synthesis, 2012, 44, S11

12 5. Synthesis and Characterization of unsaturated -spiroketal-γ-lactones from alkynols possessing terminal alkyne functionality: 3-Methyl-1, 14-dioxadispiro [ ] tetradec-3-en-2-one (3aa): Following the General Procedure, to the mixture of (1-(prop-2-yn1 yl) cyclohexyl) methanol (1a) (0.100 g, 0.66 mmol) and ethyl pyruvate (2a) (0.104 g, 0.66 mmol) in anhydrous CH 2 Cl 2 (5 ml) was add Bi(Tf) 3 (0.090 g, 0.13 mmol) under argon atmosphere at room temperature and reaction mixture was stirred for 12 h at rt. Purification of the crude product by column chromatography (Si 2, 5% EtAc /hexanes) afforded 3-methyl-1, 14- dioxadispiro [ ] tetradec-3-en-2-one (3aa) (0.117 g, 80%). TLC: R f = 0.40 (Si 2, 20% EtAc/hexanes); 1 H NMR (CDCl 3, 400 MHz): δ (m, 1H), 3.95 (d, J = 8.8 Hz, 1H), 3.86 (d, J = 8.3 Hz, 1H), 2.12 (d, J = 13.7 Hz, 1H), 2.01 (d, J = 14.2 Hz, 1H), 1.91 (d, J = 0.98 Hz, 3H), (m, 2H), (m, 8H); 13 C NMR (CDCl 3, 101 MHz): δ 171.6, 145.1, 132.5, 113.2, 80.4, 47.1, 43.6, 37.4, 35.5, 25.5, 23.8, 23.7, 10.4; HRMS (ESI) m/z calcd for C 13 H 19 3 [M+H] , found Phenyl-1, 14-dioxadispiro [ ] tetradec-3-en-one (3ab): Following the General Procedure, to the mixture of (1-(prop-2-yn-1-yl) cyclohexyl) methanol (1a) (0.100 g, 0.66 mmol) and ethyl phenylglyoxylate (2b) (0.104 g, 0.66 mmol) in anhydrous CH 2 Cl 2 (5 ml) was added Bi(Tf) 3 (0.09 g, 0.13 mmol) under argon atmosphere at room temperature and reaction mixture was stirred for 12 h. Purification of the crude product by column chromatography (Si 2, 2% EtAc/hexanes) afforded 3-phenyl- S12

13 1,14-dioxadispiro[ ]tetradec-3-en-one( 3ab) as a crystalline solid (0.142 g, 76%). TLC: R f = 0.75 (Si 2, 20% EtAc/hexanes); 1 H NMR (CDCl 3, 400 MHz): δ (m, 2H), 7.42 (d, J = 3.7 Hz, 3H), 7.18 (s, 1H), 4.03 (d, J = 7.9 Hz, 1H), 3.94 (d, J = 8.5 Hz, 1H), 2.20 (dd, J = 36.01, 13.4 Hz, 2H), (m, 2H), (m, 8H); 13 C NMR (CDCl 3, 101 MHz): δ 169.3, 143.7, 133.6, 129.7, 129.0, 128.7, 127.5, 112.4, 80.5, 47.4, 43.8, 37.4, 35.5, 25.6, 23.9, 23.8; HRMS (ESI) m/z calcd for C 18 H 21 3 [M+H] , found (4-Methoxyphenyl)-1, 14-dioxadispiro [ ] tetradec-3-en-2-one (3ac): Following the General Procedure, to the mixture of (1-(prop- 2-yn-1-yl) cyclohexyl) methanol (1a) (0.05 g, 0.33 mmol) and ethyl anisylglyoxylate (2c) (0.054 g, 0.33 mmol) in anhydrous CH 2 Cl 2 (3 ml) was added Bi(Tf) 3 (0.045 g, mmol) under argon atmosphere at room temperature and stirred the reaction mixture for 12 h. Purification of the crude product by column chromatography (Si 2, 5% EtAc/hexanes) afforded 3-(4- methoxyphenyl)-1, 14-dioxadispiro [ ] tetradec-3-en-2-one (3ac) (0.06 g, 72%). TLC: R f = 0.75 (Si 2, 20% EtAc/hexanes); 1 H NMR (CDCl 3, 400 MHz): δ 7.81 (d, J = 8.8 Hz, 2H), 7.05 (s, 1H), 6.93 (d, J = 8.8 Hz, 2H), 4.01 (d, J = 8.3 Hz, 1H), 3.92 (d, J = 8.3 Hz, 1H), 3.84 (s, 3H), 2.16 (dd, J = 38.15, 13.7 Hz, 2H), (m, 2H), (m, 8H); 13 C NMR (CDCl 3, 101 MHz): δ 169.6, 160.7, 141.3, 132.9, 129.0, 121.5, 114.1, 112.4, 80.5, 55.3, 47.4, 43.8, 37.4, 35.5, 25.6, 23.9, 23.8; HRMS (ESI) m/z calcd for C 19 H 23 4 [M+H] , found S13

14 3-(p-Tolyl)-1, 14-dioxadispiro [ ] tetradec-3-en-2-one (3ad): 3ad X-ray, CCDC No: RTEP Diagram Following the General Procedure, to the reaction mixture of (1-(prop-2-yn-1-yl) cyclohexyl) methanol (1a) (0.05 g, 0.32 mmol) and ethyl p-tolylglyoxylate (2d) (0.063 g, 0.32 mmol) in anhydrous CH 2 Cl 2 (4 ml) was added Bi(Tf) 3 (0.042 g, mmol) under argon atmosphere at room temperature and stirred the reaction mixture for 12 h. Purification of the crude product by column chromatography (Si 2, 2% EtAc/hexanes) afforded 3-(ptolyl)-1, 14-dioxadispiro [ ] tetradec-3-en-2-one (3ad) (0.067 g, 70%) as a crystalline solid. TLC: R f = 0.60 (Si 2, 20% EtAc /hexanes); 1 H NMR (CDCl 3, 500 MHz): δ 7.75 (d, J = 8.01 Hz, 2H), 7.22 (d, J = 8.01 Hz, 2H), 7.12 (s, 1H), 4.02 (d, J = 8.4 Hz, 1H), 3.93 (d, J = 8.4 Hz, 1H), 2.38 (s, 3H), 2.23 (d, J = Hz, 1H), 2.13 (d, J = Hz, 1H), (m, 2H), (m, 8H); 13 C NMR (CDCl 3, 126 MHz): δ 169.4, 142.7, 139.9, 133.5, 129.4, 127.4, 126.1, 112.3, 80.5, 43.8, 37.4, 35.6, 25.6, 23.9, 23.8, 21.4; HRMS (ESI) m/z calcd for C 19 H 23 3 [M+H] found Methyl-1, 13-dioxadispiro [ ] tridec-3-en-2-one (3ba): Following the General Procedure, to the mixture of (1-(prop-2-yn-1- yl)cyclopentyl)methanol (1b) (0.1 g, 0.72 mmol) and ethylpyruvate (2a) (0.083 g, 0.72 mmol) in anhydrous CH 2 Cl 2 (5 ml) was added Bi(Tf) 3 (0.09 g, mmol) under argon atmosphere at room temperature and reaction mixture was stirred for 12 h at rt. Purification of the crude product by column chromatography (Si 2, 5% EtAc/hexanes) afforded 3- S14

15 methyl-1,13-dioxadispiro[ ]tridec-3-en-2-one (3ba) (0.117 g, 78%) as a white solid. TLC: R f = 0.3 (Si 2, 20% EtAc/hexanes); 1 H NMR (CDCl 3, 500 MHz): δ (m, 1H), 4.01 (d, J = 8.4 Hz, 1H), 3.85 (d, J = 8.4 Hz, 1H), 2.18 (s, 2H), 1.92 (d, J = 1.14 Hz, 3H), (m, 2H), (m, 6H); 13 C NMR (CDCl 3, 126 MHz): δ 171.6, 145.2, 132.5, 113.3, 81.1, 50.3, 47.4, 38.0, 37.2, 24.6, 24.4, 10.4; HRMS (ESI): calcd for C 12 H 17 3 [M+H] , found Phenyl-1, 13-dioxadispiro [ ] tridec-3-en-one (3bb): Following the General Procedure, to the mixture of (1-(prop-2-yn-1- yl) cyclopentyl) methanol (1b) (0.1 g, 0.72 mmol) ethyl phenylglyoxylate (2b) (0.128 g, 0.72 mmol) in anhydrous CH 2 Cl 2 (6 ml) was added Bi(Tf) 3 (0.09 g, mmol) under argon atmosphere at room temperature and reaction mixture was stirred for 12 h at rt. Purification of the crude product by column chromatography (Si 2, 5% EtAc /hexanes) afforded 3- phenyl-1,13-dioxadispiro[ ]tridec-3-en-one (3bb) (0.136 g, 70%). TLC: R f = 0.5 (Si 2, 20% EtAc /hexanes); 1 H NMR (CDCl 3, 500 MHz): δ (m, 2H), (m, 3H), 7.19 (s, 1H), 4.08 (d, J = 8.0 Hz, 1H), 3.92 (d, J = 8.0 Hz, 1H), 2.31 (dd, J = 17.55, Hz, 2H), (m, 2H), (m, 6H); 13 C NMR (CDCl 3, 126 MHz): δ 169.3, 143.7, 133.6, 129.7, 129.0, 128.7, 127.5, 112.4, 81.2, 50.5, 47.7, 38.0, 37.2, 24.7, 24.4; HRMS (ESI): calcd for C 17 H 19 3 [M+H] , found S15

16 3-(4-Methoxyphenyl)-1, 13-dioxadispiro [ ] tridec-3-en-2-one (3bc): Following the General Procedure, to the reaction mixture of (1-(prop-2-yn-1-yl) cyclopentyl) methanol (1b) (0.1 g, 0.72 mmol) and ethyl anisylglyoxylate (2c) (0.15 g, 0.72 mmol) in anhydrous CH 2 Cl 2 (2 ml) was added Bi(Tf) 3 (0.094 g, 0.14 mmol) under argon atmosphere at room temperature and the reaction mixture was stirred for 12 h at rt. Purification of crude product by column chromatography (Si 2, 8% EtAc /hexanes) afforded 3-(4-methoxyphenyl)-1,13-dioxadispiro[ ]tridec-3-en-2-one (3bc) crystalline solid (0.151 g, 70%). TLC: R f = 0.60 (Si 2, 20% EtAc /hexanes); 1 H NMR (CDCl 3, 500 MHz): δ (m, 2H), 7.06 (s, 1H), (m, 2H), 4.07 (d, J = 8.01 Hz, 1H), 3.91 (d, J = 8.01 Hz, 1H), 3.84 (s, 3H), 2.29 (dd, J = 13.35, 3.43 Hz, 2H), (m, 2H), (m, 6H); 13 C NMR (126MHz, CDCl 3 ): δ 169.6, 160.7, 141.3, 132.9, 129.0, 121.6, 114.1, 112.4, 81.2, 55.3, 50.5, 47.7, 38.1, 37.2, 29.7, 24.7, 24.4; HRMS (ESI) m/z calcd for C 18 H 21 4 [M+H] found (p-Tolyl)-1, 13-dioxadispiro [ ] tridec-3-en-2-one (3bd): Following the General Procedure, to the reaction mixture of (1-(prop-2-yn-1-yl) cyclopentyl) methanol (1b) (0.05 g, 0.36 mmol) and ethyl p-tolylglyoxylate (2d) (0.069 g, 0.36 mmol) in anhydrous CH 2 Cl 2 (3 ml) was added Bi(Tf) 3 (0.042 g, mmol) under argon atmosphere at room temperature and stirred for 12 h at rt. Purification of the crude S16

17 product by column chromatography (Si 2, 2% EtAc /hexanes) afforded 3-(p-tolyl)-1,13- dioxadispiro[ ]tridec-3-en-2-one (3bd) (0.073 g, 72%) as a white solid. TLC: R f = 0.60 (Si 2, 20% EtAc /hexanes); 1 H NMR (CDCl 3, 400 MHz): δ 7.75 (d, J = 8.5 Hz, 2H), 7.22 (d, J = 7.9 Hz, 2H), 7.13 (s, 1H), 4.07 (d, J = 8.5 Hz, 1H), 3.91 (d, J = 7.9 Hz, 1H), 2.39 (s, 3H), 2.29 (dd, J = , 1.22 Hz, 2H), (m, 2H), (m, 6H); 13 C NMR (CDCl 3, 101 MHz): δ 169.4, 142.7, 139.9, 133.4, 129.4, 127.4, 126.1, 112.4, 81.2, 50.5, 47.7, 38.0, 37.2, 24.7, 24.4, 21.4; HRMS (ESI) m/z calcd for C 18 H 21 3 [M+H] found (4-Nitrophenyl)-1, 13-dioxadispiro [ ] tridec-3-en-2 one (3be): 3be N 2 Following the General Procedure, to the mixture of (1-(prop-2-yn-1-yl) cyclopentyl) methanol (1b) (0.112 g, mmol) and ethyl 2-(4-nitrophenyl)-2-oxoacetate (2e) (0.181 g, mmol) in anhydrous CH 2 Cl 2 (5 ml) was added Bi(Tf) 3 (0.106 g, mmol) at room temperature under argon atmosphere and the mixture was stirred for 12 h at rt. Quenched with aqueous NaHC 3 solution (5 ml), stirred for 5 min then extracted with CH 2 Cl 2 (2x5 ml), dried over anhydrous Na 2 S 4, filtered and concentrated. Resulting solid was dissolved in hexanes (5 ml) and slowly added the minimum amount of CH 2 Cl 2, then resulting solution was stand at room temperature until all solvents were evaporated to form crystalline product 3-(4-nitrophenyl)-1,13-dioxadispiro[ ]tridec-3-en-2-one (3be) (0.144 g, 78%). TLC: R f = 0.75 (Si 2, 20% EtAc /hexanes); 1 H NMR (CDCl 3, 400 MHz): δ 8.28 (d, J = 8.5 Hz, 2H), 8.05 (d, J = 9.2 Hz, 2H), 7.38 (s, 1H), 4.10 (d, J = 8.5 Hz, 1H), 3.94 (d, J = 7.9 Hz, 1H), (m, 2H), (m, 2H), (m, 6H); 13 C NMR (CDCl 3, 101 MHz): δ 168.3, 148.3, 147.0, 135.0, 131.7, 128.5, 123.9, 112.6, 81.5, 50.6, 47.6, 37.9, 37.1, 24.7, 24.4; HRMS (ESI) m/z calcd for C 17 H 18 5 N [M+H] , found S17

18 3-Methyl-1, 6-dioxaspiro [4.4] non-3-en-2-one (3ca): Following the General Procedure, to the reaction mixture of pent-4-yn-1-ol (1c) (0.1 g, 1.1 mmol) and ethyl pyruvate (2a) (0.137 g, 1.1 mmol) in anhydrous CH 2 Cl 2 (5 ml) was added Bi(Tf) 3 (0.154 g, 0.22 mmol) under argon atmosphere at room temperature and the reaction mixture was stirred for 48 h at rt. Purification of crude product by column chromatography (Si 2, 5% EtAc /hexanes) afforded 3-methyl-1,6-dioxaspiro[4.4]non-3-en- 2-one (3ca) (0.106 g, 58%) as a yellow oily liquid. TLC: R f = 0.60 (Si 2, 20% EtAc /hexanes); 1 H NMR (CDCl 3, 500 MHz): δ (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 3H), 1.93 (d, J = 1.91 Hz, 3H); 13 C NMR (CDCl 3, 126 MHz): δ 171.4, 144.4, 133.3, 112.7, 70.3, 35.3, 24.2, 10.5; HRMS (ESI) m/z calcd for C 8 H 11 3 [M+H] found Phenyl-1, 6-dioxaspiro [4, 4] non-3-en-2-one (3cb): Following the General Procedure, to the mixture of 4-pentyne-1-ol (1c) (0.1 g, 1.19 mmol) and ethyl phenylglyoxylate (2b) (0.21 g, 1.19 mmol) in anhydrous CH 2 Cl 2 (5 ml) was added Bi(Tf) 3 (0.249 g, mmol) under argon atmosphere at room temperature and the resulting mixture was stirred for 48 h at rt. Purification of the crude product by column chromatography (Si 2, 5% EtAc/hexane) afforded 3-phenyl-1, 6-dioxaspiro [4, 4] non-3- en-2-one (3cb) (0.138 g, 54%). TLC: R f = 0.45 (Si 2, 20% EtAc /hexanes); 1 H NMR (CDCl 3, 400 MHz): δ (m, 2H), (m, 3H), 7.21 (s, 1H), 4.28 (td, J = 8.2, 3.7 Hz, 1H), 4.11 (q, J = 7.5 Hz, 1H), (m, 4H); 13 C NMR (CDCl 3, 101 MHz): δ 169.2, 143.1, 134.3, 129.8, 129.0, 128.7, 128.2, 128.1, 127.7, 127.5, 127.3, 111.9, 70.5, 35.7, 24.3; HRMS (ESI) m/z calcd for C 13 H 13 3 [M+H] , found S18

19 3-(4-Methoxyphenyl)-1, 6-dioxaspiro [4, 4] non-3-en-2-one (3cc): Following the General Procedure, to the mixture of 4-pentyne-1-ol (1c) (0.3 g, 3.57 mmol) and ethyl anisylglyoxylate (2c) (0.743 g, 3.57 mmol) in anhydrous CH 2 Cl 2 (6 ml) was added Bi(Tf) 3 (0.465 g, mmol) under argon atmosphere at room temperature and the reaction mixture was stirred for 48 h at rt. Purification of the crude product by column chromatography (Si 2, 5% EtAc /hexanes) afforded 3-(4-methoxyphenyl)-1,6- dioxaspiro[4,4]non-3-en-2-one (3cc) (0.46 g, 52%). TLC: R f = 0.40 (Si 2, 20% EtAc /hexanes); 1 H NMR (CDCl 3, 500 MHz): δ 7.82 (d, J = 8.8 Hz, 2H), 7.07 (s, 1H), 6.92 (d, J = 8.8 Hz, 2H), (m, 1H), (m, 1H), 3.83 (s, 3H), (m, 4H); 13 C NMR (CDCl 3, 126 MHz): δ 169.5, 160.8, 140.5, 133.7, 129.0, 121.6, 114.1, 111.9, 70.4, 55.3, 35.7, 24.3; HRMS (ESI): calcd for C 14 H 15 4 [M+H] , found (p-Tolyl)-1,6-dioxaspiro[4.4]non-3-en-2-one (3cd): Following the General Procedure, to the reaction mixture of pent-4-yn-1-ol (1c) (0.1 g, 1.1 mmol) and ethyl p-tolylglyoxylate (2d) (0.228 g, 1.1 mmol) in anhydrous CH 2 Cl 2 (5 ml) was added Bi(Tf) 3 (0.154 g, 0.22 mmol) under argon atmosphere at room temperature and the reaction mixture was stirred for 48 h at rt. Purification of crude product by column chromatography (Si 2, 8% EtAc /hexanes) afforded 3-(p-tolyl)-1, 6-dioxaspiro [4.4] non-3- en-2-one (3cd) crystalline solid (0.084 g, 62%). TLC: R f = 0.60 (Si 2, 20% EtAc /hexanes); 1 H NMR (CDCl 3, 400 MHz): δ 7.76 (d, J = 7.9 Hz, 2H), 7.23 (d, J = 7.9 Hz, 2H), 7.15 (s, 1H), (m, 1H), (m, 1H), 2.38 (s, 3H), (m, 4H); 13 C NMR (CDCl 3, 101 MHz): δ 169.3, 141.9, 140.0, 134.2, 129.4, 127.4, 126.2, 111.8, 70.4, 35.7, 24.3, 21.4; HRMS (ESI) m/z calcd for C 14 H 15 3 [M+H] found S19

20 2, 2-diphenylpent-4-yn-1-ol (1d): Compound (1d) was prepared using known procedure. 71 H NMR (CDCl 3, 500MHz) δ (m, 4H), (m, 6H), 4.30 (s, 2H), 3.08 (d, J = 2.29 Hz, 2H), 1.93 (t, J = 2.7 Hz, 1H); 13 C NMR (CDCl 3, 126 MHz) δ , 128.9, , 126.7, 81.4, 71.5, 68.3, 51.5, 27.4; HRMS (ESI) m/z calcd for C 17 H 17 [M+H] , found methyl-8, 8-diphenyl-1, 6-dioxaspiro [4.4] non-3-en-2-one (3da): Following the General Procedure, to the mixture of 2, 2-diphenylpent-4-yn-1-ol (1d) (0.1 g, 0.42 mmol) and ethyl pyruvate (2a) (0.049 g, 0.42mmol) in anhydrous CH 2 Cl 2 (5 ml) was added Bi(Tf) 3 (0.055 g, 0.08 mmol) under argon atmosphere at room temperature and the reaction mixture was stirred for 12 h at rt. Purification of the crude product by column chromatography (Si 2, 5% EtAc /hexanes) afforded3-methyl-8, 8-diphenyl-1, 6-dioxaspiro [4.4] non-3-en-2-one (3da) (0.80 g, 62%). TLC: R f = 0.5 (Si 2, 20% EtAc/hexanes); 1 H NMR (CDCl 3, 500 MHz) δ (m, 6H), (m, 2H), (m, 2H), 6.35 (d, J =1.53 Hz 1H), 4.86 (d, J =8.7 Hz, 1H), 4.49 (d, J = 9.1 Hz, 1H), 3.27 (d, J = 14.1Hz, 1H), 2.95 (d, J = 13.7 Hz, 1H), 1.86 (s, 3H); 13 C NMR (CDCl 3, 126 MHz) δ 171.4, 145.6, 145.2, 143.6, 131.7, 128.7, 128.3, 127.1, 127.0, 126.8, 112.9, 77.9, 56.3, 47.5, 10.3; HRMS (ESI) m/z calcd for C 20 H 19 3 [M+H] , found Nakamura, I.; Chan, C. S.; Araki, T.; Terada, M, Yamamoto, Y. Adv. Synth. Catal. 2009, 351, S20

21 3, 8, 8-triphenyl-1, 6-dioxaspiro [4.4] non-3-en-2-one (3db): Following the General Procedure, to the mixture of 2, 2-diphenylpent-4-yn-1-ol (1d) (0.1 g, 0.42 mmol) and ethyl phenylglyoxylate (2b) (0.075 g, 0.42 mmol) in anhydrous CH 2 Cl 2 (5 ml) was add Bi(Tf) 3 (0.055 g, 0.08 mmol) under argon atmosphere at room temperature and the reaction mixture was stirred for 12 h at rt. Purification of the crude product by column chromatography (Si 2, 5% EtAc /hexanes) afforded3,8,8-triphenyl-1,6- dioxaspiro[4.4]non-3-en-2-one (3db) (0.109 g, 70%). TLC: R f = 0.40 (Si 2, 20% EtAc/hexanes); 1 H NMR(CDCl 3, 400 MHz) δ (m, 2H), (m, 9H), (m, 4H), 6.79 (s, 1H), 4.91(d, J = 9.1 Hz, 1H), 4.55 (d, J = 9.1 Hz, 1H), 3.36 (d, J = 14 Hz, 1H), 3.07 (d, J = 14 Hz, 1H); 13 C NMR (CDCl 3, 101 MHz) δ 169, 145.5, 143.5, 132.7, 128.8, 129.8, 128.7, 128.6, 127.5, 127.1, 126.9, 126.8, 112.1, 78.1, 56.4, 47.8; HRMS (ESI) m/z calcd for C 25 H 21 3 [M+H] , found phenylpent-4-yn-1-ol (1e): Compound 1e was prepared using known procedure. 8 PhMgBr (1.0 M in THF, 18 ml, 1.82 mmol) was added drop wise to a solution of pent-4-ynal (S7) (0.5 g, mmol) in THF (20 ml) at room temperature, the reaction mixture was stirred at rt for 2 h. Reaction was quenched by adding ice cold water (10 ml), then neutralized with 2N HCl (20 ml), extracted with EtAc (20 ml), which was washed once with 2N HCl (20 ml) and brine solution (20 ml). rganic layer was dried over anhydrous MgS 4. Filtration and evaporation of the solvent under reduced pressure afforded the desired product 1-phenylpent-4-yn-1-ol (1e) (0.72 g, 70 %). 1 H NMR (CDCl 3, 200 MHz) δ (m, 5H), (m, 1H), 2.96 (d, 8 Ravindar, K.; Reddy, M. S.; Deslongchamps, P. rg. Lett. 2011, 13, S21

22 J = 3.66 Hz, 1H), (m, 2H), (m, 3H); HRMS (ESI) m/z calcd for C 11 H 13 [M+H] , found methyl-7-phenyl-1,6-dioxaspiro[4.4]non-3-en-2-one (3ea): Following the General Procedure, to the mixture of 1-phenylpent-4-yn-1-ol (1e) (0.1 g, mmol) and ethyl pyruvate (2a) (0.072 g, mmol) in anhydrous CH 2 Cl 2 (2 ml) was added Bi(Tf) 3 (0.081 g, mmol), then reaction mixture was stirred under reflux conditions (40 o C) for 12 h. The reaction mixture was cooled to room temperature and quenched using aqueous NaHC 3 solution. Extracted with dichloromethane (2x10 ml), dried over anhydrous Na 2 S 4, filtered and concentrated. Purification of the crude product by silica gel column chromatography (Si 2, 6% EtAc/hexanes) afforded two separable diastereomers of 3-methyl-7-phenyl-1,6-dioxaspiro[4.4]non-3-en-2-one (3ea-Isomer-1, 27% yield (0.038 g), 3ea-Isomer-2, 29% yield (0.041 mg), in dr approx 1:1) as a yellow oil. 3ea-Isomer-1: TLC: R f = 0.3 (Si 2, 20% EtAc/hexanes); 1 H NMR (CDCl 3, 500 MHz) δ (m, 5H), 6.89 (s, 1H), 5.45 (t, J = 5.72 Hz, 1H), (m, 1H), (m, 2H), (m, 1H), 1.97 (s, 3H); 13 C NMR (CDCl 3, 126 MHz) δ 171.4, 144.3, 141.3, 133.3, 128.5, 127.8, 125.5, 112.8, 82.4, 34.4, 32.5, ea-Isomer-2: TLC: R f = 0.28 (Si 2, 20% EtAc/hexanes); 1 H NMR (CDCl 3, 400 MHz) δ (m, 5H), 6.79 (s, 1H), 5.21 (t, J = 4.88 Hz, 1H), (m, 1H), (m, 3H), 1.97 (s, 3H); 13 C NMR (CDCl 3, 101 MHz) δ 171.4, 144.5, 141.0, 133.5, 128.6, 128.4, 128.1, 126.3, 112.7, 85.0, 37.2, 34.1, 10.6; HRMS (ESI) m/z calcd for C 14 H 15 3 [M+H] , found S22

23 2-(prop-2-yn-1-yl)cyclohexan-1-ol (1f): H 1f Compound 1f was prepared using analogous literature procedure: 9 1f: 1 H NMR (CDCl 3, 500 MHz): δ 3.38 (td, J = 9.9, 4.4 Hz, 1H), (m, 1H), 2.32 (ddd, J = 16.8, 6.9, 2.7 Hz, 1H), (m, 3H), (m, 1H), (m, 2H), (m, 1H), (m, 4H); 13 C NMR (CDCl 3, 126 MHz): δ 83.0, 73.5, 69.7, 43.9, 35.5, 30.3, 25.4, 24.9, 21.8; HRMS (ESI) m/z calcd for C 9 H 15 [M+H] , found '-methyl-3a,4,5,6,7,7a-hexahydro-3H,5'H-spiro[benzofuran-2,2'-furan]-5'-one (3fa and 3fa 1 ): Following the General Procedure, to the mixture of 2-(prop-2-yn-1-yl)cyclohexan-1- ol (1f) (0.15 g, 1.09 mmol) and ethyl pyruvate (2a) (0.12 g, 1.09 mmol) in anhydrous CH 2 Cl 2 (5 ml) was added Bi(Tf) 3 (0.073g, 0.22 mmol) under argon atmosphere at room temperature and the reaction mixture was stirred for 24 h at rt. Purification of the crude product by silica gel column chromatography (Si 2, 8% EtAc/hexanes) afforded two separable diastereomers of 4'-methyl-3a,4,5,6,7,7a-hexahydro-3H,5'H-spiro[benzofuran-2,2'- furan]-5'-one (0.095 g of 3fa (42%) and g of 3fa 1 (21%); : = 7:3) as a white solid. 3fa: TLC: R f = 0.6 (Si 2, 20% EtAc/hexanes); Relative stereochemistry was assigned based on NE analysis (see below). 1 H NMR (CDCl 3, 400 MHz): δ 6.72 (s, 1H), (m, 1H), 2.35 (dd, J = 13.4, 7.9 Hz, 1H), (m, 2H), (m, 1H), 1.91 (s, 3H), 1.88 (d, J = 11.6 Hz, 1H), 1.78 (d, J = 7.3 Hz, 1H), (m, 1H), Man, Z.; Dai, H.; Shi,Y.; Yang, D.; Li, C.Y. rg. Lett., 2016, 18, S23

24 (m, 2H), (m, 2H); 13 C NMR (CDCl 3, 101 MHz): δ 171.9, 145.7, 131.2, 111.8, 84.7, 46.3, 39.8, 30.5, 28.5, 25.5, 24.0, 10.3; HRMS (ESI) m/z calcd for C 12 H 17 3 [M+H] , found Figure 1. Key NE interactions in compound 3fa. 3fa 1 : R f = 0.58 (Si 2, 20% EtAc/hexanes), Relative stereochemistry was assigned based on analogy to 3fa; 1 H NMR (CDCl 3, 500 MHz): δ 6.72 (d, J = 1.5 Hz, 1H), 3.39 (td, J = 10.7, 3.8 Hz, 1H), (m, 2H), 2.0 (d, J = 14.1 Hz, 1H), (m, 1H), 1.91 (d, J = 1.5 Hz, 3H), (m, 1H), (m, 1H), 1.50 (qd, J = 11.7, 3.8 Hz, 1H), (m, 3H), 1.17 (td, J = 12.2, 3.4 Hz, 1H); 13 C NMR (CDCl 3, 126 MHz): δ 171.3, 145.9, 132.4, 111.4, 86.7, 43.7, 41.5, 31.3, 28.5, 25.5, 24.2, 10.4; HRMS (ESI) m/z calcd for C 12 H 17 3 [M+H] , found ,2-di(prop-2-yn-1-yl)-2,3-dihydro-1H-inden-1-one (S9) and 2-(prop-2-yn-1-yl)-2,3- dihydro-1h-inden-1-one (S10) To a flame dried (100 ml) two neck round bottom flask, anhydrous THF (20 ml) was added under argon atmosphere and cooled it to 0 C, to this diisopropylamine (0.42 ml, 4.16 mmol) followed by n-butyllithium (1.6 M in hexanes, ml,) was added drop wise at 0 S24

25 C and stirred for 45 min at 0 C to generate LDA solution. To this LDA solution was added 1-indanone (S8) (0.5 g, 3.78 mmol) in THF (20 ml) and stirred the reaction mixture at -78 C for 30 min, then warmed to 0 C and stirred for another 30 min. Reaction mixture was cooled back to -78 C and propargyl bromide (80% in toluene, 0.2 ml, 3.78 mmol) was added drop wise. The resulting mixture was stirred at -78 C for 1 h and warmed to 25 C and stirred for overnight. The reaction was quenched with saturated aqueous NH 4 Cl solution and extracted with EtAc (3x25 ml), combined organic layers were dried over anhydrous Na 2 S 4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford 2,2-di(prop-2-yn-1-yl)-2,3-dihydro-1H-inden-1- one (S9) (0.2 g, 25%) and (S10) 2-(prop-2-yn-1-yl)-2,3-dihydro-1H-inden-1-one (0.64 g, 42% ) TLC: R f = 0.6 and 0.59 (Si 2, 20% EtAc/hexanes); S9: 1 H NMR (CDCl 3, 200 MHz): δ 7.78 (d, J = 7.6 Hz, 1H), (m, 1H), (m, 1H), (m, 1H), 3.32 (s, 2H), (m, 4H), 1.88 (t, J = 2.7 Hz, 2H); HRMS (ESI) m/z calcd for C 15 H 12 Na [M+Na] , found S10: 1 H NMR (CDCl 3, 500 MHz): δ 7.76 (d, J = 7.3 Hz, 1H), 7.60 (t, J = 7.3 Hz, 1H), 7.49 (d, J = 7.3 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 3.40 (dd, J = 17.7, 8.54 Hz, 1H), 3.10 (dd, J = 17.1, 4.3 Hz, 1H), (m, 1H), (m, 1H), 2.54 (ddd, J = 16.4, 7.9, 2.4 Hz, 1H), 1.90 (t, J = 2.7 Hz, 1H); HRMS (ESI) m/z calcd for C 12 H 11 [M+H] , found ,2-di(prop-2-yn-1-yl)-2,3-dihydro-1H-inden-1-ol (1g): To a solution of 2,2-di(prop-2-yn-1-yl)-2,3-dihydro-1H-inden-1-one (S9) (0.13 g 0.66 mmol) in methanol (3 ml), sodium borohydride (0.015 g, 0.4 mmol) was slowly added at 0 C. The reaction mixture was stirred at 0 C for 30 min and then for 2.5 h at room temperature, after which the solvent was evaporated under reduced pressure. Aqueous NH 4 Cl solution (5 ml) was added to the resulting suspension, and then extracted with EtAc (3 5 ml). rganic phases were combined and dried over anhydrous Na 2 S 4, filtered and the S25

26 solvent was evaporated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (Si 2, 6% EtAc/hexanes) to afford 2,2-di(prop-2-yn- 1-yl)-2,3-dihydro-1H-inden-1-ol (1g) (0.12 g, 87%) as a colourless liquid. TLC: R f = 0.4 (Si 2, 20% EtAc/hexanes); 1 H NMR (CDCl 3, 500 MHz): δ (m, 1H), (m, 3H), 5.13 (s, 1H), 3.09 (d, J = 15.9 Hz, 1H), 2.92 (d, J = 15.9 Hz, 1H), 2.66 (dd, J = 17.1, 2.4 Hz, 1H), (m, 2H), 2.44 (dd, J = 17.1, 2.4 Hz, 1H), 2.28 (br s, 1H), 2.12 (t, J = 2.4 Hz, 1H), 2.05 (t, J = 2.7 Hz, 1H); 13 C NMR (CDCl 3, 126 MHz): δ 142.8, 140.5, 128.6, 127.1, 125.2, 124.7, 81.9, 81.6, 80.7, 71.4, 70.6, 50.0, 40.1, 26.0, 22.1; HRMS (ESI) m/z calcd for C 15 H 15 [M+H] , found methyl-3a'-(prop-2-yn-1-yl)-3',3a',4',8b'-tetrahydro-5H-spiro[furan-2,2'-indeno[1,2- b]furan]-5-one (3ga, 3ga 1 ) Following the General Procedure, to the mixture of 2,2-di(prop-2-yn-1-yl)-2,3- dihydro-1h-inden-1-ol (1g) (0.05 g, 0.24 mmol) and ethyl pyruvate (2a) (0.027 g, 0.24 mmol) in anhydrous CH 2 Cl 2 (5 ml) was added Bi(Tf) 3 (0.032g, 0.05 mmol) under argon atmosphere at room temperature and the reaction mixture was stirred for 12 h at rt. Purification of the crude product by silica gel column chromatography (Si 2, 5% EtAc/hexanes) afforded 4-methyl-3a'-(prop-2-yn-1-yl)-3',3a',4',8b'-tetrahydro-5Hspiro[furan-2,2'-indeno[1,2-b]furan]-5-one and its diastereomer (77% yield,: 0.04 g of 3ga (60%) and g of 3ga 1 (17%) isolated yield dr: 8:2). 3ga: TLC: R f = 0.4 (Si 2, 20% EtAc/hexanes); Relative stereochemistry was assigned based on NE analysis (see below); 1 H NMR (CDCl 3, 500 MHz): δ (m, 4H), 6.56 (s, 1H), 5.59 (s, 1H), 3.30 (d, J = 16.5 Hz, 1H), 3.10 (d, J = 17.1 Hz, 1H), 2.88 (AB q, J = 17.0, 3.0 Hz, 2H), 2.50 (d, J = 13.4 Hz, 1H), 2.21 (d, J = 14.0 Hz, 1H), 1.99 (t, J = 2.7 Hz, 1H), 1.93 (d, J = 1.2 Hz, 3H); 13 C NMR (CDCl 3, 126 MHz): δ 171.2, 144.5, 141.2, 140.8, S26

27 133.3, 129.4, 127.5, 125.7, 125.4, 113.2, 93.7, 81.4, 70.0, 52.6, 46.8, 43.0, 27.4, 10.5; HRMS (ESI) m/z calcd for C 18 H 17 3 [M+H] , found Figure 2. Key NE interactions in compound 3ga. 3ga 1 : TLC: R f = 0.38 (Si 2, 20% EtAc/hexanes); Relative stereochemistry was assigned based on analogy to 3ga; 1 H NMR (CDCl 3, 400 MHz): δ 7.40 (d, J = 7.3 Hz, 1H), (m, 1H), (m, 2H), 6.77 (s, 1H), 5.47 (s, 1H), 3.61 (d, J = 16.5 Hz, 1H), 3.04 (d, J = 16.5 Hz, 1H), (m, 2H), (m, 1H), 2.38 (d, J = 13.4 Hz, 1H), 2.06 (br s., 1H), 1.91 (s, 3H); 13 C NMR (CDCl 3, 101 MHz): δ 171.4, 144.6, 142.7, 139.6, 133.3, 129.6, 127.4, 126.1, 125.3, 113.9, 94.4, 80.8, 70.6, 52.6, 46.5, 43.7, 28.4, 10.4; HRMS (ESI) m/z calcd for C 18 H 17 3 [M+H] , found phenyl-3a'-(prop-2-yn-1-yl)-3',3a',4',8b'-tetrahydro-5H-spiro[furan-2,2'-indeno[1,2- b]furan]-5-one (3gb) H Ph 3gb, 64% Following the General Procedure, to the mixture of 2,2-di(prop-2-yn-1-yl)-2,3- dihydro-1h-inden-1-ol (1h) (0.1 g, 0.48 mmol) and ethyl phenyl glyoxylate (2b)(0.08 g, 0.48 mmol) in anhydrous CH 2 Cl 2 (5 ml) was added Bi(Tf) 3 (0.06 g, 0.1 mmol) under argon atmosphere at room temperature and the reaction mixture was stirred for 12 h at rt. S27

28 Purification of the crude product by silica gel column chromatography (Si 2, 3% EtAc/hexanes) afforded inseparable diastereomeric mixture of 4-phenyl-3a'-(prop-2-yn-1- yl)-3',3a',4',8b'-tetrahydro-5h-spiro[furan-2,2'-indeno[1,2-b]furan]-5-one (3gb) in g (64% yield, dr: 1:1)) as a solid. TLC: R f = 0.5 (Si 2, 20% EtAc/hexanes); (3gb; mixture of two diastereomers): Relative stereochemistry was assigned based on analogy to 3ga 1 ; 1 H NMR (CDCl 3, 400 MHz): δ (m, 2H), (m, 9H), 7.02 (s, 1H), 5.63 (s, 1H), (m, 1H), (m, 1H), (m, 2H), (m, 1H), (m, 3H), (m, 4H), (m, 2H), (m, 2H); 13 C NMR (CDCl 3, 101 MHz): δ 168.9, 143.1, 141.1, 140.8, 134.3, 129.9, 129.5, 128.8, 128.7, 127.6, 127.5, 127.4, 127.2, 125.8, 125.4, 125.3, 124.7, 112.4, 93.8, 81.4, 71.1, 70.2, 52.8, 50.6, 50.2, 48.8, 47.1, 43.7, 43.4, 42.9, 28.5, 27.4; HRMS (ESI) m/z calcd for C 23 H 19 3 [M+H] , found ,2-di(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalen-1-ol (1h) To a flame dried (100 ml) two neck round bottom flask, anhydrous THF (50 ml) was added under argon atmosphere and cooled it to 0 C, to this diisopropylamine (3.16 ml, 22.2 mmol) followed by n-butyllithium (1.6 M in hexanes, ml,) was added drop wise at 0 C and stirred for 45 min at 0 C to generate LDA solution. To this LDA solution was added 1-tetralone (S11) (2.5 g, 17.1 mmol) in THF (10 ml) and stirred the reaction mixture at -78 C for 30 min, then warmed to 0 C and stirred for another 30 min. Reaction mixture was cooled back to -78 C and propargyl bromide (80% in toluene, 1.2 ml, 17.1 mmol) was added drop wise. The resulting mixture was stirred at -78 C for 1 h and warmed to 25 C and stirred for overnight. The reaction was quenched with saturated aqueous NH 4 Cl solution and extracted with EtAc (4x50 ml), combined organic layers were dried over anhydrous Na 2 S 4, concentrated under reduced pressure to give the crude product S12 in (1 g, 26% yield), which was subjected to next reaction without further purification. To a solution of S12 (0.3 g, 1.35 mmol) in methanol (10 ml), sodium borohydride (0.05 g, 1.35 mmol) was slowly S28

29 added at 0 C. The reaction mixture was stirred at 0 C for 30 min and then for 2.5 h at room temperature, after which the solvent was evaporated under reduced pressure. Aqueous NH 4 Cl solution (5 ml) was added to the resulting suspension, and then extracted with EtAc (3 10 ml). rganic phases were combined and dried over anhydrous Na 2 S 4, filtered and the solvent was evaporated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (Si 2, 8% EtAc/hexanes) to afford 2,2- di(prop-2-yn-1-yl)-1,2,3,4-tetrahydronaphthalen-1-ol (1h) (0.28 g, 92%) as a solid as a colourless liquid. TLC: R f = 0.35 (Si 2, 20% EtAc/hexanes); 1 H NMR (CDCl 3, 200 MHz) δ (m, 1H), (m, 2H), (m, 1H), 4.68 (d, J = 5.3 Hz, 1H), (m, 2H), 2.44 (AB q, J = 2.2 Hz, 16.7 Hz, 2H), 2.43 (AB q, J = 17.1, 2.2 Hz, 2H), 2.15 (d, J = 5.7 Hz, 1H), 2.09 (t, J = 2.7 Hz, 1H), 2.06 (t, J = 2.7 Hz, 1H), (m, 1H), (m, 1H); 13 C NMR (CDCl 3, 126 MHz): δ 136.7, 135.7, 129.4, 128.9, 127.9, 126.5, 81.1, 80.8, 72.6, 71.0, 70.9, 39.9, 26.6, 25.4, 23.8, 23.2; HRMS (ESI) m/z calcd for C 16 H 17 [M+H] , found methyl-3a'-(prop-2-yn-1-yl)-3a',4',5',9b'-tetrahydro-3'H,5H-spiro[furan-2,2'- naphtho[1,2-b]furan]-5-one (3ha, 3ha 1 ) Following the General Procedure, to the mixture of 2,2-di(prop-2-yn-1-yl)-1,2,3,4- tetrahydronaphthalen-1-ol (1h) (0.1 g, 0.45 mmol) and ethyl pyruvate (2a) (0.05 g, 0.45 mmol) in anhydrous CH 2 Cl 2 (5 ml) was added Bi(Tf) 3 (0.05 g, 0.09 mmol) under argon atmosphere at room temperature and the reaction mixture was stirred for 12 h at rt. Purification of the crude product by silica gel column chromatography (Si 2, 5% EtAc/hexanes) afforded 4-methyl-3a'-(prop-2-yn-1-yl)-3a',4',5',9b'-tetrahydro-3'H,5Hspiro[furan-2,2'-naphtho[1,2-b]furan]-5-one along with their partially separable diastereomer (70% yield,: g (52%) and g (18%) isolated yield (3ha:3ha 1 ; dr: : : 8.57:1.43)) as a solid. S29

30 3ha: TLC: R f = 0.3 (Si 2, 20% EtAc/hexanes); Relative stereochemistry was assigned based on NE analysis (see below); 1 H NMR (CDCl 3, 400 MHz): δ 7.38 (d, 7.3 Hz, 1H), (m, 2H), (m, 1H), 6.67 (s, 1H), 5.0 (s, 1H), (m, 2H), (m, 3H), 2.34 (d, J = 14.0 Hz, 1H), (m, 2H), (m, 4H); 13 C NMR (CDCl 3, 101 MHz): δ 171.5, 144.7, 137.2, 132.8, 132.3, 130.9, 128.7, 128.5, 126.7, 111.2, 83.9, 80.5, 70.8, 46.4, 43.9, 31.1, 26.6, 25.8, 10.4; HRMS (ESI) m/z calcd for C 19 H 19 3 [M+H] , found Figure 3. Key NE interactions in compound 3ha. 3ha 1 impure with 3ha (3ha+3ha 1 ; dr: : : 1 : 1.25): TLC: R f = (Si 2, 20% EtAc/hexanes); Relative stereochemistry was assigned based on analogy to 3ha; 1 H NMR (CDCl 3, 500 MHz): δ (m, 2H), (m, 9H), 6.81 (d, J = 1.1 Hz, 1H), 6.67 (d, J = 1.5 Hz, 1H), 5.01 (s, 1H), 4.93 (s, 1H), (m, 13H), (m, 10H); 13 C NMR (CDCl 3, 126 MHz): δ 171.5, 171.2, 145.7, 144.7, 137.2, 136.2, 132.9, 132.6, 132.3, 132.2, 130.9, 130.7, 128.7, 128.7, 128.5, 128.5, 126.7, 126.6, 111.9, 111.2, 83.9, 83.8, 80.5, 80.3, 71.5, 70.8, 46.6, 46.4, 43.9, 43.2, 31.2, 29.7, 28.3, 26.6, 25.8, 25.5, 10.4, 10.4; HRMS (ESI) m/z calcd for C 19 H 19 3 [M+H] , found S30

31 4-phenyl-3a'-(prop-2-yn-1-yl)-3a',4',5',9b'-tetrahydro-3'H,5H-spiro[furan-2,2'- naphtho[1,2-b]furan]-5-one (3hb) Following the General Procedure, to the mixture of 2,2-di(prop-2-yn-1-yl)-1,2,3,4- tetrahydronaphthalen-1-ol (1h) (0.1 g, 0.45 mmol) and ethyl phenylglyoxylate (2b) (0.08 g, 0.45 mmol) in anhydrous CH 2 Cl 2 (5 ml) was added Bi(Tf) 3 (0.05 g, 0.09 mmol) under argon atmosphere at room temperature and the reaction mixture was stirred for 12 h at rt. Purification of the crude product by silica gel column chromatography (Si 2, 5% EtAc/hexanes) afforded g of inseparable diastereomeric mixture of 4-phenyl-3a'- (prop-2-yn-1-yl)-3a',4',5',9b'-tetrahydro-3'h,5h-spiro[furan-2,2'-naphtho[1,2-b]furan]-5-one 3hb (61% yield, (dr: 8:2)) as a solid. TLC: R f = 0.5 (Si 2, 20% EtAc/hexanes); 1 H NMR (CDCl 3, 400 MHz): δ (m, 2H), (m, 12H), 5.08 (s, 1H), (m, 12H), (m, 5H); 13 C NMR (CDCl 3, 101 MHz): δ 169.2, 144.2, 143.2, 137.2, 133.8, 132.2, 131.0, 130.8, 130.1, 129.8, 129.4, 128.8, 128.7, 128.6, 127.5, 126.8, 126.6, 126.5, 126.4, 110.4, 84.0, 83.9, 80.5, 71.4, 70.9, 51.1, 46.8, 46.7, 44.1, 42.8, 40.2, 31.2, 28.2, 26.6, 26.5, 25.8, 25.3; HRMS (ESI) m/z calcd for C 24 H 21 3 [M+H] , found (E)-3-styryl-1,13-dioxadispiro[ ]tridec-3-en-2-one (3bf) Following the General Procedure, to the mixture of (1-(pent-2-yn-1-yl) cyclopentyl) methanol (1b) (0.1 g, 0.14 mmol) and ethyl (E)-2-oxo-4-phenylbut-3-enoate (2f) 10 (0.294 g, 0.14 mmol) in anhydrous CH 2 Cl 2 (5 ml) was added Bi(Tf) 3 (0.189 g, mmol) under 10 Dujardin, G.; Leconte, S.; Benard, A.; Brown, E. Synlett, 2001, 1, S31

32 argon atmosphere at room temperature and the reaction mixture was stirred for 12 h at rt. Purification of the crude product by silica gel column chromatography (Si 2, 5% EtAc/hexanes) afforded (E)-3-styryl-1,13-dioxadispiro[ ]tridec-3-en-2-one (3bf) (0.135 g, 63%) as a solid. TLC: R f = 0.6 (Si 2, 20% EtAc/hexanes); 1 H NMR (CDCl 3, 500 MHz) δ 7.71 (d, J = Hz, 1H), 7.51 (d, J = 7.3 Hz, 2H), (m, 3H), 6.90 (s, 1H), 6.81 (d, J = Hz, 1H), 4.06 (d, J = 8.54 Hz, 1H), 3.9 (d, J = 8.54 Hz, 1H) 2.27 (s, 2H), (m, 2H), (m, 6H); 13 C NMR (CDCl 3, 126 MHz) δ 169.4, 143.0, 136.6, 136.2, 131.4, 128.7, 127.1, 116.1, 113.1, 81.2, 50.5, 47.8, 38.0, 37.2, 24.6, 24.4; HRMS (ESI) m/z calcd for C 19 H 21 3 [M+H] , found Synthesis and Characterization of unsaturated -spiroketal-γ-lactones from alkynols possessing internal alkyne functionality: 3, 4-Dimethyl-1, 14-dioxadispiro [ ] tetradec-3-en-2-one (6aa): Following the General Procedure, to the mixture of (1-(but-2-yn-1-yl) cyclohexyl) methanol (4a) (0.05 g, 0.3 mmol) and ethyl pyruvate 2a (0.05 g, 0.3 mmol) in anhydrous CH 2 Cl 2 (3 ml) was added Bi(Tf) 3 (0.04 g, 0.06 mmol) under argon atmosphere at room temperature and the reaction mixture was stirred for 12 h at rt. Purification of the crude product by silica gel column chromatography (Si 2, 5% EtAc/hexanes) gave 3, 4-dimethyl- 1, 14-dioxadispiro [ ] tetradec-3-en-2-one (6aa) (0.046 g, 65%) as a yellow oil. TLC: R f = 0.7 (Si 2, 20% EtAc/hexanes); 1 H NMR (CDCl 3, 500 MHz): δ 3.95 (d, J = 8.8 Hz, 1H), 3.85 (d, J = 8.8 Hz, 1H), (m, 2H), 1.90 (s, 3H), 1.80 (s, 3H), (m, 2H), (m, 8H); 13 C NMR (CDCl 3, 126 MHz): δ 171.7, 154.9, 126.0, 114.5, 80.6, 45.7, 43.4, 37.4, 35.6, 25.5, 23.8, 23.7, 10.5, 8.6; HRMS (ESI) m/z calcd for C 14 H 21 3 [M+H] , found S32

33 4-Methyl-3-phenyl-1, 14-dioxadispiro [ ] tetradec-3-en-2-one (6ab): Following the General Procedure, to the mixture of (1-(but-2-yn-1-yl) cyclohexyl) methanol (4a) (0.05 g, 0.3 mmol) and ethyl phenylglyoxylate (2b) (0.054 g, 0.3 mmol) in dry CH 2 Cl 2 (3 ml) was added Bi(Tf) 3 (0.04 g, mmol) under argon atmosphere at room temperature and the reaction mixture was stirred for 12 h at rt. Purification of the crude product by column chromatography (Si 2, 3% EtAc/hexanes) afforded 4-methyl-3-phenyl- 1, 14-dioxadispiro[ ] tetradec-3-en-2-one (6ab) (0.062 g, 68%) as a crystalline solid. TLC: R f = 0.5 (Si 2, 20% EtAc/hexanes). 1 H NMR (CDCl 3, 400 MHz): δ (m, 5H), 4.06 (d, J = 8.5 Hz, 1H), 3.95 (d, J = 7.9 Hz, 1H), (m, 2H), 2.13 (s, 3H), (m, 2H), (m, 8H); 13 C NMR (CDCl 3, 101 MHz); δ 169.9, 156.0, 129.6, 129.0, , 128.7, 128.5, 113.9, 80.9, 46.1, 43.7, 37.4, 35.6, 25.5, 23.9, 23.8, 11.5; HRMS (ESI) m/z calcd for C 19 H 23 3 [M+H] , found (4-Methoxyphenyl)-4-methyl-1, 14-dioxadispiro [ ] tetradec-3-en-2-one (6ac): Following the General Procedure, to the mixture of (1-(but-2-yn-1-yl) cyclohexyl) methanol (4a) (0.050 g, 0.3 mmol) and ethyl anisylglyoxylate (2c) (0.063 g, 0.3 mmol) in anhydrous CH 2 Cl 2 (3 ml) was added Bi(Tf) 3 (0.04 g, mmol) under argon atmosphere at room temperature and the reaction mixture was stirred for 12 h at rt. Purification of the crude product by column chromatography (Si 2, 5% EtAc/hexanes) afforded 3-(4- S33