Fully Substituted Pyranones via Quasi-Heterogeneous Genuinely Ligand-Free Migita-Stille Coupling of Iodoacrylates

Transcription

1 Fully Substituted Pyranones via Quasi-Heterogeneous Genuinely Ligand-Free Migita-Stille Coupling of Iodoacrylates Jiří Kratochvíl, Zdeněk Novák, Mukund Ghavre, Lucie Nováková, Aleš Růžička, Jiří Kuneš and Milan Pour S1

2 Table of Contents: 1. General Information S3 2. Starting materials propargylic alcohols S3 3. Starting materials (E)-2-Stannyl-2-en-1-ols S7 4. Starting materials aryl halides S12 5. Starting materials methyl propiolates S12 6. Starting materials iodoacrylates S14 7. Final products S18 ONE-POT PROCEDURE S19 Solvent optimization S19 Catalyst reuse in Migita-Stille cross-coupling S19 The influence of the additives S30 8. Intramolecular Tsuji-Trost reaction S C labeled experiments S Catalysts S HPLC monitoring experiments and ICP-MS S NMR tube experiments and standard procedure set-up S Crystallographic details S References S NMR spectra for all new compounds S47 S2

3 1. General information: Unless noted otherwise, all chemicals were purchased from Sigma-Aldrich (St. Louis, MO, USA) and used without further purification. The reactions performed under argon atmosphere were done in flame-dried glass using Schlenk line techniques with magnetic stirring and dried solvent. Thin-layer chromatography analyses (TLC) were performed using Merck TLC Silica gel 60 F 254 TLC plates and visualized by UV in combination with permanganate or H 3Mo 12O 40P/Ce(SO 4) 2 staining. Column chromatography was carried out on Merck Silica gel 60 ( mm). 1 H and 13 C NMR spectra were recorded with Varian Mercury VxBB 300 or VNMR S500. The chemical shifts were reported relative to Me 4Si and referenced to the residual solvent peaks. IR spectra were recorded on NICOLET 6700 FT-IR equipped with an ATR device. Mass spectral data were recorded in cooperation with University of Pardubice and Department of Analytical Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University in Prague. Optical rotations were measured on Krüss P3000 using a 50 mm path-length cell at 589 nm. 2. Starting materials propargylic alcohols: 1-(3-hydroxyprop-1-yn-1-yl)cyclohexan-1-ol THP protected propargylic alcohol (7.0 mmol, 0.98 ml) was dissolved in anhdyrous THF (6 ml) under argon atmosphere and the mixture was cooled to -78 ⁰C. BuLi (7.35 mmol, 2.5 M sol. in hexanes, 2.94 ml) was then added dropwise and the mixture was left to warm to 0 ⁰C. Then cyclohexanone was added and the reaction mixture was warmed to ambient temperature. After 60 minutes sat. sol. of NH 4Cl (10 ml) was added and the slurry was mixed for another 10 minutes until it became clear two-phase mixture. Then the mixture was extracted three times with Et 2O (3 30 ml) and the organic layer dried over Na 2SO 4. The crude mixture was purified by column chromatography (gradient elution, hexanes hexanes:etoac (8:2)) to afford an yellow oil (1.569 g, R f = 0.18 in hexanes:etoac (8:2)). This oil was immediately used to the next reaction without further characterisation. The yellow oil from the previous reaction ( mmol, g) was dissolved in MeOH (10 ml) and ptsa.h 2O was added (0.658 mmol, 125 mg) and the solution was stirred at room temperature. After 90 minutes the solvent was evaporated and replaced with EtOAc (30 ml). This mixture was extracted with 5% sol. of Na 2CO 3 (25 ml). The inorganic phase was extracted with another portion of EtOAc (35 ml). Combined organic layers were then dried over Na 2SO 4 and purified by column chromatography (gradient elution, hexanes hexanes:etoac (1:1)) to afford desired product (0.971 g, overall yield 90 %, R f = 0.25 in hexanes:etoac (1:1)) as a yellowish viscous oil. 1 H NMR (500 MHz, CDCl 3) δ 4.30 (s, 2H), 2.99 (br, 2H), S3

4 (m, 2H), (m, 2H), (m, 5H), (m, 1H); 13 C NMR (126 MHz, CDCl 3) δ 89.33, 82.30, 68.60, 50.80, 39.66, 25.08, 23.14; IR (ATR) max 965, 1011, 1030, 1073, 1342, 1449, 2249, 2856, 2934, 3247 cm -1 ; LRMS (TOF-ESI + ): m/z (rel. intensity) [M+Na] + (100), [M+H] + (18), (18); HRMS (TOF-ESI + ) m/z calcd for C 9H 14O 2Na , found phenylbut-2-yn-1-ol 3-Phenylprop-1-yne (10.0 mmol, 1.24 ml) was dissolved in anhydrous THF (8 ml) under argon atmosphere and the mixture was cooled to -78 ⁰C. BuLi (10.5 mmol, 2.5 M sol. in hexanes, 4.2 ml) was then added dropwise and the mixture was left to warm to 0 ⁰C. Dry paraformaldehyde (25.0 mmol, g) was added in one portion and the mixture was left to warm to ambient temperature. Then the mixture was warmed to 40 ⁰C for 40 minutes until it became clear viscous solution. After that, sat. sol. of NH 4Cl (20 ml) was added and the slurry was mixed for another 10 minutes until it became clear twophase mixture. Then the mixture was extracted twice with Et 2O (2 40 ml) and the organic layer dried over Na 2SO 4. The crude mixture was purified by column chromatography (gradient elution, hexanes hexanes:etoac (9:1)) to afford desired product (0.846 g, yield 58 %, R f = 0.35 in hexanes:etoac (7:3)) as a yellow oil. 1 H NMR (500 MHz, CDCl 3) δ (m, 4H), (m, 1H), 4.32 (t, J = 2.2 Hz, 2H), 3.64 (t, J = 2.2 Hz, 2H), 1.71 (br, 1H); 13 C NMR (126 MHz, CDCl 3) δ , , , , 83.93, 80.40, 51.37, 25.08; IR (ATR) max 696, 730, 1010, 1131, 1454, 1495, 2227, 3031, 3063, 3382 cm -1 ; LRMS (TOF-CI - ): m/z (rel. intensity) [M-H] - (100), (71); HRMS (TOF-CI - ) m/z calcd for C 10H 9O , found chlorohex-2-yn-1-ol This alkynol was prepared according to the procedure described earlier in the literature by Belyk et al. 1 The NMR spectra were in agreement with the literature data. 4-methyl-4-[bis(tert-butoxycarbonyl)amino]pent-2-yn-1-ol S4

5 3-amino-3-methylbut-1-yne (6.0 mmol, 0.67 ml) was dissolved in anhydrous dichloromethane (20 ml) under argon atmosphere. Di-tert-butyl dicarbonate (7.20 mmol, g) was added in one portion and the mixture was stirred at room temperature for 24 hours. Then the solvent was evaporated and the slurry was diluted with Et 2O (40 ml). The organic phase was then extracted with H 2O (40 ml) and dried over Na 2SO 4. The resulting solution was dried (1.085 g) and immediately used to the next reaction. The crude mixture from the previous reaction ( mmol, g) was dissolved in anhydrous THF (15 ml) under argon atmosphere and the solution was cooled to -78 ⁰C. LDA (6.22 mmol, 1.5 M LDA-THF complex in cyclohexane, 4.15 ml) was then added dropwise and after 60 minutes a solution of (Boc) 2O (11.8 mmol, 2.59 g) in anhydrous THF (5 ml) was cannulated to the solution. The reaction mixture was then left to warm to ambient temperature. After 24 hours another portion of anhydrous THF (10 ml) was added to dilute the thick slurry. After another 2 hours, the reaction mixture was diluted with Et 2O (50 ml) and extracted with 5% sol. of NaCl (50 ml). The organic phase was dried over Na 2SO 4 and purified by column chromatography (gradient elution, hexanes hexanes:etoac (9:1)) to afford desired product (1.324 g, overall yield 78 %, R f = 0.35 in hexanes:etoac (9:1)) as a yellow oil. 1 H NMR (500 MHz, CDCl 3) δ 2.38 (s, 1H), 1.72 (s, 6H), 1.49 (s, 18H); 13 C NMR (126 MHz, CDCl 3) δ , 86.46, 82.52, 70.34, 52.40, 28.41, 27.86; IR (ATR) max 852, 1109, 1140, 1164, 1281, 1332, 1369, 1720, 1751, 2935, 2980, 3279 cm -1 ; HRMS (TOF-ESI + ) m/z calcd for C 15H 25NO 4Na , found The diboc-protected alkyne (4.020 mmol, g) was dissolved in anhydrous THF (5 ml) under argon atmosphere and the solution was cooled to -78 ⁰C. LDA (4.42 mmol, 1.5 M LDA-THF complex in cyclohexane, 2.95 ml) was then added dropwise and the mixture was left to warm to 0 ⁰C. Dried paraformaldehyde (12.1 mmol, g) was added in one portion and the mixture was left to warm to ambient temperature. After 90 minutes, sat. sol. of NH 4Cl (10 ml) was added and the slurry was mixed for another 10 minutes until it became clear two-phase mixture. Then it was extracted twice with Et 2O (2 40 ml) and the organic layer dried over Na 2SO 4. The crude mixture was purified by column chromatography (gradient elution, hexanes hexanes:etoac (7:3)) to afford desired product (0.696 g, yield 55 %, R f = 0.35 in hexanes:etoac (7:3)) as a yellow oil while considerable amount of starting material was re-isolated (0.431 g, yield 38 %) from the reaction, which was then re-utilized. 1 H NMR (500 MHz, CDCl 3) δ 4.26 (s, 2H), 1.70 (s, 6H), 1.49 (s, 18H); 13 C NMR (126 MHz, CDCl 3) δ , 88.38, 82.48, 80.48, 52.70, 51.14, 28.34, 27.86; IR (ATR) max 849, 1084, 1110, 1142, 1164, 1288, 1335, 1712, 1748, 2872, 2935, 2981, 3429 cm -1 ; HRMS (TOF-ESI + ) m/z calcd for C 16H 27NO 5Na , found S5

6 6-(tert-butoxycarbonyl)aminohex-2-yn-1-ol This compound was synthesized according to the protocols reported in the literature. The process comprised hydroxymethylation 1, azide substitution 2 and the sequence of OH protection, Staudinger reduction and -NH 2 protection 3. Last step was the silyl deprotection. In this step the protected alkynol (2.31 mmol, mg) was dissolved in MeOH (12 ml) and KF.2H 2O (6.92 mmol, g) was added. The mixture was heated to 60 ⁰C for 220 minutes and then the solvent was evaporated. The residue was diluted with Et 2O (25 ml) and washed with water (25 ml). The inorganic phase was then extracted three times with E 2O (3 25 ml) and combined organic layers were washed with 5 % sol. of NaCl (25 ml) and dried over Na 2SO 4. The crude mixture was purified by column chromatography (gradient elution, hexanes:etoac (8:2) hexanes:etoac (7:3)) to afford desired product (0.473 g, yield 96 %, R f = 0.43 in hexanes:etoac (1:1)) as a yellowish oil. 1 H NMR (500 MHz, CDCl 3) δ 4.69 (br, 1H), 4.22 (t, J = 2.3 Hz, 2H), (m, 2H), 2.26 (tt, J = 6.9, 2.2 Hz, 2H), 2.17 (br, 1H), (m, 2H), 1.43 (s, 9H); 13 C NMR (126 MHz, CDCl 3) δ , 85.10, 79.41, 79.33, 51.12, 39.53, 28.57, 28.37, 16.15; IR (ATR) max 1012, 1169, 1252, 1275, 1366, 1522, 1686, 2226, 2875, 2934, 2977, 3337 cm -1 ; LRMS (TOF-ESI + ): m/z (rel. intensity) [M+Na] + (100), (17); HRMS (TOF-ESI + ) m/z calcd for C 11H 19NO 3Na , found [(2-bromothiophene-3-yl)methoxy]but-2-yn-1-ol S6

7 First reaction of this sequence was previously reported by Blond et al. 4 Our NMR spectra were in good agreement with this report. Then NaH (9.25 mmol, 60% dispersion in mineral oil, 0.37 g) was dispersed in anhydrous DMF (12 ml) under argon atmosphere and cooled to 0 ⁰C. The solution of partially protected butynediol from the previous reaction (8.41 mmol, 1.43 g) in anhydrous DMF (5 ml) was added dropwise. Evolution of H 2 was observed. After 10 minutes, the mixture was removed from the ice-bath and left for another 50 minutes to stir at room temperature until there was no visible gas evolution. Then the slurry was cooled to 0 ⁰C again. After that, 2-bromo-3-(bromomethyl)thiophene was added slowly and the mixture was once again removed from the ice-bath. After 60 minutes of stirring at room temperature, the reaction was carefully quenched with sat. sol. of NH 4Cl (20 ml) and extracted with EtOAc (50 ml). The organic phase was then washed with 5% sol. of NaCl (30 ml) and dried over Na 2SO 4. The crude mixture was purified by column chromatography (gradient elution, hexanes hexanes:etoac (9:1)) to afford desired product (1.564 g, yield 86 %, R f = 0.38 in hexanes:etoac (9:1)) as a yellowish oil. 1 H NMR (500 MHz, CDCl 3) δ 7.25 (d, J = 5.6 Hz, 1H), 6.99 (d, J = 5.6 Hz, 1H), 4.83 (t, J = 3.5 Hz, 1H), 4.54 (s, 2H), (m, 2H), 4.21 (t, J = 1.8 Hz, 2H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 4H); 13 C NMR (126 MHz, CDCl 3) δ , , , , 96.81, 82.78, 81.59, 65.44, 61.99, 57.61, 54.24, 30.22, 25.32, 19.03; IR (ATR) max 692, 736, 903, 1024, 1097, 1118, 1343, 1440, 1540, 2867, 2943, 3105 cm -1 ; HRMS (TOF-ESI + ) m/z calcd for C 14H 17BrO 3SNa , found The resulting protected alkynediol from the previous reaction (4.339 mmol, g) was dissolved in MeOH (10 ml) and ptsa.h 2O (0.43 mmol, g) was added. The reaction mixture was stirred at room temperature for 60 minutes. Then the solvent was evaporated and the residue diluted with EtOAc (30 ml) and extracted with 5 % sol. of Na 2CO 3 (25 ml). The inorganic phase was extracted with EtOAc (35 ml) and combined organic phases were dried over Na 2SO 4. The crude mixture was purified by column chromatography (gradient elution, hexanes hexanes:etoac (7:3)) to afford desired product (1.105 g, yield 98 %, R f = 0.35 in hexanes:etoac (7:3)) as a white cloudy oil. 1 H NMR (500 MHz, CDCl 3) δ 7.25 (d, J = 5.6 Hz, 1H), 6.99 (d, J = 5.6 Hz, 1H), 4.55 (s, 2H), (m, 2H), 4.20 (t, J = 1.8 Hz, 2H), 1.65 (br, 1H); 13 C NMR (126 MHz, CDCl 3) δ , , , , 84.93, 81.55, 65.58, 57.54, 51.14; IR (ATR) max 691, 735, 827, 997, 1013, 1073, 1125, 1349, 1415, 2863, 2940, 3107, 3379 cm Starting materials (E)-2-Stannyl-2-en-1-ols: General procedure for hydrostannation: Appropriate alk-2-yn-1-ol (1 mmol) along with Pd(PPh 3) 4 ( mmol, g) were dissolved in anhydrous THF (1 ml) under argon atmosphere. Then Bu 3SnH (1.1 mmol, 0.28 ml) was added dropwise. The reaction was exothermic and therefore cold-water bath was used during the addition of Bu 3SnH. After that, the cold-water bath was removed and the mixture was stirred at room temperature for 20 minutes. Finally, the solvent was evaporated and the slurry was purified by column chromatography. S7

8 2a - (E)-2-(tributylstannyl)hex-2-en-1-ol The crude mixture was purified by column chromatography (gradient elution, hexanes hexanes:etoac (98:2)) to afford desired product (0.203 g, yield 52 %, R f = 0.48 in hexanes:etoac (9:1)) as a colorless oil. 1 H NMR (300 MHz, CDCl 3) δ 5.55 (tt, J = 7.0, 2.0 Hz, 1H), 4.36 (s, 2H), 2.05 (q, J = 7.1 Hz, 2H), (m, 14H), (m, 18H); 13 C NMR (75 MHz, CDCl 3) δ , , 63.65, 31.45, (J Sn = 19.1 Hz), 27.38, 22.71, 13.72, 13.70, (J 119Sn = Hz, J 117Sn = Hz); IR (ATR) max 1012, 1043, 1376, 1463, 1614, 2854, 2871, 2925, 2956, 3341 cm -1 ; LRMS (TOF-ESI - ): m/z (rel. intensity) [M - H] - (100), (25); HRMS (TOF-ESI - ) m/z calcd for C 18H 37OSn , found b - (E)-2-(tributylstannyl)oct-2-en-1-ol The crude mixture was purified by column chromatography (gradient elution, hexanes hexanes:etoac (98:2)) to afford desired product (0.337 g, yield 81 %, R f = 0.58 in hexanes:etoac (9:1)) as a colorless oil. 1 H NMR (500 MHz, CDCl 3) δ 5.55 (tt, J = 7.0, 2.0 Hz, 1H), (m, 2H), 2.07 (q, J = 7.1 Hz, 2H), (m, 6H), (m, 12H), (m, 18H); 13 C NMR (126 MHz, CDCl 3) δ , , 63.64, 31.47, 29.40, 29.24, (J = 19.5 Hz), (J 119Sn = 57.8 Hz, J 117Sn = 55.4 Hz), 22.53, 14.04, 13.72, (J 119Sn = Hz, J 117Sn = Hz); IR (ATR) max 1019, 1376, 1463, 1611, 2854, 2871, 2925, 2955, 3391 cm -1 ; LRMS (TOF-ESI + ): m/z (rel. intensity) [M + Na] + (100), (96), (19); HRMS (TOF- ESI + ) m/z calcd for C 20H 42OSnNa , found c (E)-2-(tributylstannyl)but-2-en-1,4-diol The crude mixture was purified by column chromatography (gradient elution, hexanes hexanes:etoac (7:3)) to afford desired product (0.357 g, yield 95 %, R f = 0.60 in hexanes:etoac (1:1)) as a dark green oil. S8

9 1 H NMR (300 MHz, CDCl 3) δ (m, 1H), (m, 2H), 4.20 (t, J = 5.5 Hz, 2H), 1.80 (t, J = 5.1 Hz, 1H), 1.72 (t, J = 5.6 Hz, 1H), (m, 6H), (m, 6H), (m, 15H); 13 C NMR (126 MHz, CDCl 3) δ , , 63.53, 59.78, (J Sn = 19.6 Hz), (J Sn119 = 59.1 Hz, J Sn117 = 56.6 Hz), 13.68, (J Sn119 = Hz, J Sn117 = Hz); IR (ATR) max 1028, 1376, 1463, 2852, 2871, 2923, 2955, 3288 cm -1 ; LRMS (APCI - ): m/z (rel. intensity) [M-H] - (100), (94), (21); HRMS (TOF- ESI + ) m/z calcd for C 16H 34O 2SnNa , found d (E)-1-[3-hydroxy-2-(tributylstannyl)prop-1-en-1-yl]cyclohexan-1-ol The crude mixture was purified by column chromatography (gradient elution, hexanes hexanes:etoac (8:2)) to afford desired product (0.389 g, yield 87 %, R f = 0.38 in hexanes:etoac (8:2)) as a greenish oil. We found this compound labile, even when stored in the freezer under argon atmosphere and was therefore characterized only by NMR and used immediately to the coupling reaction. 1 H NMR (500 MHz, CDCl 3) δ 5.61 (t, J = 1.9 Hz, 1H), (m, 2H), 2.91 (br, 1H), 2.26 (br, 1H), (m, 4H), (m, 10H), (m, 8H), (m, 15H). 2e - (E)-4-phenyl-2-(tributylstannyl)but-2-en-1-ol The crude mixture was purified by column chromatography (gradient elution, hexanes hexanes:etoac (96:4)) to afford desired product (0.146 g, yield 33 %, R f = 0.35 in hexanes:etoac (9:1)) as an yellow oil. We found this compound labile, even when stored in the freezer under argon atmosphere and was therefore characterized only by NMR and used immediately to the coupling reaction. 1 H NMR (500 MHz,CDCl 3) δ (m, 2H), (m, 3H), 5.75 (tt, J = 7.0, 2.0 Hz, 1H), 4.48 (s, 2H), (m, 2H), (m, 1H), (m, 6H), (m, 6H), (m, 15H). S9

10 2f (E)-6-chloro-2-(tributylstannyl)hex-2-en-1-ol The crude mixture was purified by column chromatography (gradient elution, hexanes hexanes:etoac (98:2)) to afford desired product (0.201 g, yield 47 %, R f = 0.30 in hexanes:etoac (9:1)) as a colorless oil. 1 H NMR (500 MHz, CDCl 3) δ 5.49 (tt, J = 7.1, 2.0 Hz, 1H), (m, 2H), 3.53 (t, J = 6.5 Hz, 2H), 2.25 (q, J = 7.1 Hz, 2H), (m, 2H), (m, 6H), 1.38 (t, J = 5.3 Hz, 1H), (m, 6H), (m, 15H); 13 C NMR (126 MHz, CDCl 3) δ , , 63.54, 44.42, 32.15, (J Sn = 19.4 Hz), (J 119Sn = 58.2 Hz, J 117Sn = 55.9 Hz), 26.54, 13.71, (J 119Sn = Hz, J 117Sn = Hz); IR (ATR) max 666, 1004, 1021, 1376, 1463, 1612, 2847, 2870, 2918, 2955 cm -1 ; LRMS (TOF-ESI + ): m/z (rel. intensity) [M+Na] + (100), (23), (32); HRMS (TOF-ESI + ) m/z calcd for C 18H 37ClOSnNa , found g (E)-4-methyl-4-[bis(tert-butoxycarbonyl)amino]-2-(tributylstannyl)pent-2-en-1-ol mmol of Pd(PPh 3) 4 (0.023 g) and 2.1 mmol of Bu 3SnH (0.57 ml) were used in this reaction. The crude mixture was purified by column chromatography (gradient elution, hexanes hexanes:etoac (93:7)) to afford desired product (0.492 g, yield 81 %, R f = 0.25 in hexanes:etoac (9:1)) as a yellowish oil. 1 H NMR (500 MHz, CDCl 3) δ 5.52 (s, 1H), (m, 2H), 1.74 (t, J = 5.3 Hz, 1H), (m, 30H), (m, 6H), (m, 15H); 13 C NMR (126 MHz, CDCl 3) δ , , , 82.01, 62.94, 59.06, (J Sn = 19.1 Hz), 27.90, 27.64, 27.37, 13.70, (J 119Sn = Hz, J 117Sn = Hz); IR (ATR) max 852, 1080, 1144, 1278, 1331, 1368, 1457, 1718, 1748, 2871, 2931, 2955, 2978, 3527 cm -1 ; LRMS (TOF-ESI + ): m/z (rel. intensity) [M+Na] + (100), (40), (31), (19); HRMS (TOF- ESI + ) m/z calcd for C 28H 55NO 5SnNa , found S10

11 2h (E)-6-[(tert-butoxycarbonyl)amino]-2-(tributylstannyl)hex-2-en-1-ol 1.1 eq. of Bu 3SnH was used in this reaction. The crude mixture was purified by column chromatography (gradient elution, hexanes hexanes:etoac (85:15)) to afford desired product (0.279 g, yield 55 %, R f = 0.43 in hexanes:etoac (8:2)) as a yellowish oil. 1 H NMR (500 MHz, CDCl 3) δ (m, 1H), 4.55 (br, 1H), 4.31 (d, J = 4.9 Hz, 2H), (m, 2H), 2.12 (q, J = 7.0 Hz, 2H), 1.78 (br, 1H), (m, 17H), (m, 6H), (m, 15H); 13 C NMR (126 MHz, CDCl 3) δ , , , 79.22, 63.21, 39.73, 29.88, (J Sn = 19.5 Hz), 28.41, (J Sn119 = 57.8 Hz, J Sn117 = 55.8 Hz), 26.27, 13.71, 9.99 (J Sn119 = Hz, J Sn117 = Hz); IR (ATR) max 1171, 1251, 1366, 1456, 1509, 1616, 1693, 2853, 2870, 2924, 2955, 3367 cm -1 ; LRMS (TOF-ESI + ): m/z (rel. intensity) [M+Na] + (100), (9), (9), (8); HRMS (TOF-ESI + ) m/z calcd for C 23H 47NO 3SnNa , found i (E)-4-[(2-bromothiophen-3-yl)methoxy]-2-(tributylstannyl)but-2-en-1-ol The crude mixture was purified by column chromatography (gradient elution, hexanes hexanes:etoac (95:5)) to afford desired product (0.196 g, yield 35 %, R f = 0.25 in hexanes:etoac (9:1)) as a colorless oil. 1 H NMR (500 MHz, CDCl 3) δ 7.25 (d, J = 5.7 Hz, 1H), 6.99 (d, J = 5.6 Hz, 1H), (m, 1H), 4.46 (s, 2H), (m, 2H), (m, 2H), 1.66 (t, J = 5.4 Hz, 1H), (m, 6H), (m, 6H), (m, 15H); 13 C NMR (126 MHz, CDCl 3) δ , , , , , , 66.88, 66.04, 63.75, (J Sn = 19.6 Hz), (J 119Sn = 59.3 Hz, J 117Sn = 56.9 Hz), 13.71, (J 119Sn = Hz, J 117Sn = Hz); IR (ATR) max 688, 994, 1033, 1072, 1376, 1416, 1463, 1618, 2852, 2869, 2922, 2954, 3107, 3438 cm -1 ; LRMS (APCI - ): m/z (rel. intensity) [M-H] - (100), (64), (58); HRMS (TOF-ESI + ) m/z calcd for C 21H 37BrO 2SSnNa , found S11

12 4. Starting materials aryl halides: 4-iodoacetanilide Acetic anhydride (16.0 mmol, 1.51 ml) and triethylamine (16.0 mmol, 2.23 ml) were dissolved in anhydrous dichloromethane (20 ml) under argon atmosphere. 4-Iodoaniline (10.0 mmol, 2.19 g) was then added in one portion and the mixture was stirred at room temperature overnight. The solvent was then evaporated and the residue was diluted with Et 2O (30 ml) and extracted with 1.5 M sol. of HCl (30 ml). The inorganic phase was then extracted three times with Et 2O (3 30 ml). Combined organic layers were washed with sat. sol. of NaHCO 3 (90 ml) and sat. sol. of Na 2S 2O 3 (50 ml) and dried over Na 2SO 4. The crude mixture was purified by column chromatography (gradient elution, hexanes:etoac (8:2) hexanes:etoac (1:1)) to afford desired product (2.16 g, yield 83 %, R f = 0.25 in hexanes:etoac (1:1)) as a light violet solid. The characterization was in good agreement with the published data. 5 1 H NMR (500 MHz, CDCl 3) δ (m, 2H), (m, 3H), 2.16 (s, 3H); 13 C NMR (126 MHz, CDCl 3) δ , , , , 87.42, 24.64; IR (ATR) max 739, 816, 1003, 1308, 1390, 1483, 1529, 1580, 1598, 1665, 3045, 3288 cm -1 ; LRMS (TOF-CI + ): m/z (rel. intensity) [M+H] + (100), (61); HRMS (TOF- CI + ) m/z calcd for C 8H 9INO , found Starting materials methyl propiolates: Methyl 4-hydroxybut-2-ynoate THP-protected butynoate was prepared according to the procedure published by Leonard et al. 6 The resulting yellow oil (4.59 mmol, g) was dissolved in MeOH (7 ml) and ptsa.h 2O (0.46 mmol, g) was added. After 70 minutes of stirring at room temperature the solvent was evaporated. Next, the residue was diluted with EtOAc (30 ml) and extracted with 5 % sol. of Na 2CO 3 (25 ml). The inorganic phase was extracted with EtOAc (35 ml) and combined organic phases were dried over Na 2SO 4. The crude mixture was purified by column chromatography (gradient elution, hexanes hexanes:etoac (7:3)) to afford desired product (0.422 g, yield 81 %, R f = 0.28 in hexanes:etoac (7:3)) as a pale yellow oil. 1 H NMR (500 MHz, CDCl 3) δ 4.40 (d, J = 6.1 Hz, 2H), 3.79 (s, 3H), 2.14 (t, J = 6.4 Hz, 1H); 13 C NMR (126 MHz, CDCl 3) δ , 85.56, 77.03, 52.85, 50.63; IR (ATR) max 752, 1022, 1271, 1437, 1718, 2241, 2956, 3395 cm -1 ; LRMS (TOF-ESI + ): m/z (rel. intensity) [M+Na] + (100); HRMS (TOF-ESI + ) m/z calcd for C 5H 6O 3Na , found S12

13 General procedure for Sonogashira coupling: (TFP) 2PdCl 2 (0.032 g, mmol) was suspended in anhydrous THF (1 ml) under argon atmosphere and cooled to -78 ⁰C. Then BuLi (40 μl, 2.5 M sol. in hexanes, 0.1 mmol) was added and the mixture was allowed to warm to -30 ⁰C (the mixture turned dark brown or black). Next, pre-dried aryl iodide (1 mmol) was added in one portion. After 10 minutes ZnBr 2 solution (see below) was canulated a then methyl propiolate (0.32 ml, 4.0 mmol) was added in one portion. The mixture was allowed to warm to room temperature and stirred overnight. ZnBr 2 solution: ZnBr 2 (0.45 g, 2.0 mmol) was dried with heating gun under vacuum and allowed to cool to room temperature. The flask was flushed with argon and anhydrous THF (3 ml) was added. When ZnBr 2 dissolved, triethylamine (1.25 ml, 9.0 mmol) was added in one portion. Finally, the mixture was poured to the separating funnel containing EtOAc (30 ml) and sat. sol of NH 4Cl (25 ml) and extracted. Organic phase was washed again with sat. sol. of NH 4Cl and water (volume ratio 1:1) and dried over Na 2SO 4. Methyl 3-(4-nitrophenyl)propiolate The crude mixture was purified by column chromatography (gradient elution, hexanes hexanes:etoac (9:1)) to afford desired product (0.179 g, yield 87 %, R f = 0.25 in hexanes:etoac (9:1)) as a pale yellow crystalline solid. Melting point: ⁰C (recrystallized from hot hexanes); 1 H NMR (500 MHz, CDCl 3) δ (m, 2H), (m, 2H), 3.87 (s, 3H); 13 C NMR (126 MHz, CDCl 3) δ , , , , , 83.81, 83.09, 53.11; IR (ATR) max 749, 859, 1174, 1206, 1284, 1293, 1373, 1518, 1706, 2206, 3110 cm -1 ; LRMS (TOF-ESI + ): m/z (rel. intensity) [M+H] + (100), (12); HRMS (TOF-ESI + ) m/z calcd for C 10H 8NO , found Methyl 3-(4-methoxycarbonylphenyl)propiolate The crude mixture was purified by column chromatography (gradient elution, hexanes hexanes:etoac (9:1)) to afford desired product (0.191 g, yield 87 %, R f = 0.43 in hexanes:etoac (8:2)) as a white crystalline solid. Melting point: ⁰C (recrystallized from hot hexanes); 1 H NMR (300 MHz, S13

14 CDCl 3) δ (m, 2H), (m, 2H), 3.93 (s, 3H), 3.85 (s, 3H); 13 C NMR (75 MHz, CDCl 3) δ , , , , , , 84.91, 82.25, 52.94, 52.42; IR (ATR) max 692, 766, 855, 1104, 1182, 1211, 1276, 1293, 1434, 1708, 1729, 2230, 2963, 3013 cm -1 ; LRMS (APCI + ): m/z (rel. intensity) [M+H] + (100), (7); HRMS (TOF-ESI + ) m/z calcd for C 12H 10O 4Na , found Methyl 3-(3,4-dichlorophenyl)propiolate The crude mixture was purified by column chromatography (gradient elution, hexanes hexanes:etoac (98:2)) to afford desired product (0.210 g, yield 92 %, R f = 0.40 in hexanes:etoac (9:1)) as a white crystalline solid. Melting point: ⁰C (recrystallized from hot hexanes); 1 H NMR (500 MHz, CDCl 3) δ 7.66 (d, J = 1.9 Hz, 1H), 7.46 (d, J = 8.3 Hz, 1H), 7.40 (dd, J = 8.3, 1.9 Hz, 1H), 3.84 (s, 3H); 13 C NMR (126 MHz, CDCl 3) δ , , , , , , , 83.47, 81.69, 52.96; IR (ATR) max 696, 743, 816, 883, 904, 1175, 1199, 1300, 1716, 2227, 2968 cm -1 ; LRMS (TOF-CI + ): m/z (rel. intensity) [M+H] + (75), [M+H] + (100); HRMS (TOF-CI + ) m/z calcd for C 10H 7Cl 2O , found Starting materials iodoacrylates: Compounds 3b and 3h were synthesized smoothly according the procedure of Piers et al. 7 The following isomerization of 3b to 3i was also previously reported 8 and our data were in agreement with the published ones. S14

15 General procedure for hydroiodination of substituted methyl propiolates: Our procedure was very much inspired by Piers et al. 7 Substituted methyl propiolate (1.0 mmol) was mixed with glacial acetic acid and sodium iodide (number of equivalents specified for each compound) under argon atmosphere. The mixture was then heated to 110 ⁰C until TLC indicated starting material consumption. Then the mixture was cooled down to room temperature and poured to the separating funnel containing Et 2O (30 ml) and water (25 ml). After the extraction, the inorganic layer was re-extracted with Et 2O (20 ml). Combined organic layers were washed with 5% sol. of Na 2CO 3 (25 ml) and sat. sol. of Na 2S 2O 3 (10 ml) and eventually dried over Na 2SO 4. 3a methyl (Z)-3-iodo-3-phenylacrylate 12.8 eq. of AcOH and 3.2 eq. of NaI were used. The reaction took 4 hours. The crude mixture was purified by column chromatography (gradient elution, hexanes hexanes:etoac (98:2)) to afford desired product (0.225 g, yield 78 %, R f = 0.35 in hexanes:etoac (9:1)) as an yellow opalescent oil. 1 H NMR (500 MHz, CDCl 3) δ (m, 2H), (m, 3H), 6.65 (s, 1H), 3.82 (s, 3H).; 13 C NMR (126 MHz, CDCl 3) δ , , , , , , , 51.80; IR (ATR) max 692, 765, 1164, 1191, 1307, 1603, 1728, 2948, 3028 cm -1 ; LRMS (APCI): m/z (rel. intensity) [M+H] + (100), (24). S15

16 3c methyl (Z)-3-iodo-3-(4-nitrophenyl)acrylate 12.8 eq. of AcOH and 3.2 eq. of NaI were used. The reaction took 4 hours. The crude mixture was purified by column chromatography (gradient elution, hexanes hexanes:etoac (9:1)) to afford desired product (0.299 g, yield 90 %, R f = 0.40 in hexanes:etoac (8:2)) as an yellow crystalline solid. Melting point: ⁰C (recrystallized from hot hexanes); 1 H NMR (500 MHz, CDCl 3) δ (m, 2H), (m, 2H), 6.72 (s, 1H), 3.85 (s, 3H); 13 C NMR (126 MHz, CDCl 3) δ , , , , , , , 52.10; IR (ATR) max 850, 1162, 1305, 1347, 1507, 1589, 1597, 1610, 1726, 3041, 3099 cm -1 ; LRMS (TOF-ESI + ): m/z (rel. intensity) [M+H] + (100), (56), (17), (11); HRMS (TOF-ESI + ) m/z calcd for C 10H 9INO , found d methyl (Z)-3-iodohex-2-enoate 6.4 eq. of AcOH and 1.6 eq. of NaI were used. The reaction took 4 hours. The crude mixture was purified by column chromatography (gradient elution, hexanes hexanes:etoac (98:2)) to afford desired product (0.216 g, yield 85 %, R f = 0.50 in hexanes:etoac (9:1)) as a pale yellow oil. 1 H NMR (300 MHz, CDCl 3) δ (m, 1H), 3.74 (s, 3H), 2.67 (td, J = 7.3, 1.1 Hz, 2H), (m, 2H), 0.92 (t, J = 7.4 Hz, 3H); 13 C NMR (126 MHz, CDCl 3) δ , , , 51.53, 49.76, 22.47, 12.66; IR (ATR) max 1170, 1191, 1381, 1433, 1621, 1731, 2873, 2946, 2961 cm -1 ; LRMS (TOF-ESI + ): m/z (rel. intensity) [M+Na] + (100), [M+H] + (15); HRMS (TOF-ESI + ) m/z calcd for C 7H 12IO , found S16

17 3e methyl (Z)-3-iodo-3-(4-methoxycarbonylphenyl)acrylate 12.8 eq. of AcOH and 3.2 eq. of NaI were used. The reaction took 4 hours. The crude mixture was purified by column chromatography (gradient elution, hexanes hexanes:etoac (9:1)) to afford desired product (0.292 g, yield 84 %, R f = 0.30 in hexanes:etoac (9:1)) as a yellow crystalline solid. Melting point: ⁰C (recrystallized from hot mixture of hexanes and EtOAc (98:2)); 1 H NMR (300 MHz, CDCl 3) δ (m, 2H), (m, 2H), 6.69 (s, 1H), 3.93 (s, 3H), 3.83 (s, 3H); 13 C NMR (126 MHz, CDCl 3) δ , , , , , , , , 52.32, 51.93; IR (ATR) max 696, 730, 768, 845, 948, 1105, 1191, 1274, 1434, 1608, 1716, 1731, 3013, 3028, 3046 cm -1 ; LRMS (TOF-ESI + ): m/z (rel. intensity) [M+Na] + (100), [M+H] + (7); HRMS (TOF-ESI + ) m/z calcd for C 12H 12IO , found f methyl (Z)-3-iodo-3-(3,4-dichlorophenyl)acrylate 12.8 eq. of AcOH and 3.2 eq. of NaI were used. The reaction took 4 hours. The crude mixture was purified by column chromatography (gradient elution, hexanes hexanes:etoac (95:5)) to afford desired product (0.283 g, yield 79 %, R f = 0.33 in hexanes:etoac (9:1)) as a pale yellow crystalline solid. Melting point: ⁰C (recrystallized from hot hexanes); 1 H NMR (500 MHz, CDCl 3) δ 7.61 (d, J = 2.2 Hz, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.36 (dd, J = 8.4, 2.3 Hz, 1H), 6.64 (s, 1H), 3.83 (s, 3H); 13 C NMR (126 MHz, CDCl 3) δ , , , , , , , , , 51.99; IR (ATR) max 823, 861, 1169, 1199, 1305, 1431, 1468, 1604, 1714, 2938, 3030 cm -1 ; LRMS (TOF-CI + ): m/z (rel. intensity) [M+H] + (65), [M+H] + (100), (17), (25), (44), (54); HRMS (TOF-CI + ) m/z calcd for C 10H 8Cl 2IO , found S17

18 3g methyl (Z)-4-hydroxy-3-iodobut-2-enoate 6.4 eq. of AcOH and 2.4 eq. of NaI were used. The reaction took 80 minutes. The crude mixture was purified by column chromatography (gradient elution, hexanes hexanes:etoac (85:15)) to afford desired product (0.185 g, yield 76 %, R f = 0.38 in hexanes:etoac (7:3)) as a white amorphous solid. 1 H NMR (500 MHz, CDCl 3) δ 6.82 (t, J = 1.8 Hz, 1H), 4.37 (d, J = 4.5 Hz, 2H), 3.78 (s, 3H), 2.35 (t, J = 6.2 Hz, 1H); 13 C NMR (126 MHz, CDCl 3) δ , , , 72.63, 51.78; IR (ATR) max 849, 1086, 1178, 1203, 1293, 1627, 1687, 2887, 2916, 2958, 3022, 3039, 3450 cm -1 ; LRMS (APCI + ): m/z (rel. intensity) [M+H] + (100), (6), 89.0 (8); HRMS (TOF-ESI + ) m/z calcd for C 5H 8IO , found Final products: General Procedure for Stille cross-coupling: To a solution of halide (1.0 mmol) and corresponding organotin compound (1.2 mmol unless stated otherwise) in DMF (3 ml) a portion of Pd black powder ( mmol, g) was suspended. The mixture was heated to 70 ⁰C (unless stated otherwise) and stirred until TLC analysis indicated consumption of the halide. The suspension was then filtered to separating funnel containing EtOAc (25 ml) and saturated solution of NH 4Cl (15 ml) and extracted. The organic layer was then extracted twice with 4 % sol. of NaF (2 20 ml) and the precipitate (when formed) was filtered. The resulting solution was dried over Na 2SO 4. 4a After 90 minutes of heating and work-up the crude mixture was purified by column chromatography (gradient elution, hexanes hexanes:etoac (9:1)) to afford desired lactone (0.211 g, yield 92 %, R f = 0.35 in hexanes:etoac (9:1)) as a white amorphous solid. 1 H NMR (500 MHz, CDCl 3) δ (m, 3H), (m, 2H), 5.91 (s, 1H), 5.88 (t, J = 7.8 Hz, 1H), 5.10 (s, 2H), 2.21 (q, J = 7.5 Hz, 2H), (m, 2H), 0.92 (t, J = 7.4 Hz, 3H); 13 C NMR (126 MHz, CDCl 3) δ , , , , , , , , , 66.36, 30.33, 22.24, 13.72; IR (ATR) max 703, 713, 770, 890, 1036, 1224, S18

19 1398, 1448, 1643, 1704, 2870, 2930, 2956, 3066 cm -1 ; LRMS (APCI + ): m/z (rel. intensity) [M+H] + (100), (35); HRMS (TOF-ESI + ) m/z calcd for C 15H 17O , found ONE-POT PROCEDURE DEVELOPED: Hex-2-yn-1-ol (8.0 mmol, 0.88 ml) and Pd(PPh 3) 4 ( mmol, g) were dissolved in anhydrous THF (8 ml) under argon atmosphere. Bu 3SnH (8.40 mmol, 2.26 ml) was then slowly added, while the reaction mixture was cooled with cold water bath. When the addition was complete, cold water bath was removed and after 30 minutes (when TLC indicated consumption of the starting material), the flask was opened and the mixture was bubbled with oxygen for 20 minutes (it slowly turned black). Then the solvent was evaporated and the mixture dried. After that the mixture was diluted with DMF (10 ml) and iodoacrylate 3a (5 mmol, 1.44 g) was added. The mixture was heated to 70 ⁰C for 70 minutes. Then it was filtered to a separating funnel containing EtOAc (100 ml) and sat. sol. of NH 4Cl (50 ml). After the extraction, the organic phase was washed twice with 4% sol. of NaF (2 80 ml) and the precipitate filtered. The crude mixture was dried over Na 2SO 4 and purified by column chromatography (gradient elution, hexanes hexanes:etoac (95:5)) to afford desired lactone (0.728 g, yield 64 %) as a white amorphous solid. Solvent optimization: This reaction was used as a probe for solvent optimization experiments. The results are summarized in the text (see Scheme 2). Identical conditions for these experiments were used, except that the solvent was different, while its volume remained the same. The reaction was heated to 70 ⁰C in case of DMF and NMP and to reflux in case of THF. Catalyst reuse in Migita-Stille cross-coupling: This reaction was also used as a probe for investigating catalyst reusability. To a solution of iodoacrylate 3a (1.0 mmol) and stannane 2a (1.2 mmol) in DMF (3 ml) a portion of Pd black powder ( mmol, g) was added. The mixture was then heated to 70 ⁰C and stirred until TLC analysis indicated complete consumption of the halide 3a. The suspension was cooled to room temperature and allowed to stand in refrigerator for 2 h. The supernatant solution was pipetted out by means of pasteur pipette. The Pd black powder (settled at the bottom) was washed with 2 2 ml EtOAc in aforementioned way and the flask containing Pd black was warmed to 70 ⁰C for 10 min. The supernatant solution and EtOAc washings were combined and transferred to a separating funnel containing EtOAc (25 ml) and saturated solution of NH 4Cl (15 ml) and extracted. The organic layer was then separated, washed twice with 4 % sol. of NaF (2 25 ml) and the precipitate (when formed) was filtered. The resulting solution was dried over Na 2SO 4. Crude mixture was purified by column chromatography (gradient elution, hexanes hexanes:etoac (9:1)) to afford desired lactone (R f = 0.35 in hexanes:etoac (9:1)) as a white amorphous solid. The flask containing Pd black powder was cooled to room temperature and a new batch of 2a and 3a was charged to it for the next cycle. Then, same procedure was followed. S19

20 cycle time (h) isolated yield (%) b 1.5 eq. of organotin compound was used. After 24 minutes of heating and work-up the crude mixture was purified by column chromatography (gradient elution, hexanes hexanes:etoac (87:13)) to afford desired lactone (0.132 g, yield 87 %, R f = 0.40 in hexanes:etoac (7:3)) as a colorless oil. 1 H NMR (500 MHz, CDCl 3) δ 6.94 (d, J = 9.7 Hz, 1H), (m, 2H), 5.06 (s, 2H), 2.10 (q, J = 7.5 Hz, 2H), (m, 2H), 0.94 (t, J = 7.4 Hz, 3H); 13 C NMR (126 MHz, CDCl 3) δ , , , , , 66.52, 30.18, 22.03, 13.69; IR (ATR) max 1044, 1222, 1409, 1458, 1638, 1718, 2875, 2932, 2961 cm -1 ; LRMS (APCI + ): m/z (rel. intensity) [M+H] + (100), (36); HRMS (TOF-ESI + ) m/z calcd for C 9H 13O , found c 1.3 eq. of organotin compound was used. After 140 minutes of heating and work-up the crude mixture was purified by column chromatography (gradient elution, hexanes hexanes:etoac (7:3)) to afford desired lactone (0.257 g, yield 85 %, R f = 0.38 in hexanes:etoac (7:3)) as a yellow crystalline solid. Melting point: ⁰C (recrystallized from hot hexanes:etoac (95:5)); 1 H NMR (500 MHz, CDCl 3) δ (m, 2H), (m, 2H), 5.95 (s, 1H), 5.76 (t, J = 7.8 Hz, 1H), 5.13 (d, J = 1.5 Hz, 2H), 2.23 (q, J = 7.6 Hz, 2H), (m, 2H), (m, 4H), 0.88 (t, J = 6.9 Hz, 3H); 13 C NMR (126 MHz, CDCl 3) δ , , , , , , , , , 66.38, 31.40, 28.58, 28.50, 22.33, 13.89; IR (ATR) max 861, 1015, 1223, 1345, 1467, 1522, 1651, 1708, 2858, 2929, 3082, 3111 S20

21 cm -1 ; LRMS (APCI + ): m/z (rel. intensity) [M+H] + (100), (7), (4); HRMS (TOF-ESI + ) m/z calcd for C 17H 20NO , found d 1.5 eq. of organotin compound was used. After 180 minutes of heating and work-up the crude mixture was purified by column chromatography (gradient elution, hexanes:etoac (7:3) hexanes:etoac (1:1)) to afford desired lactone (0.121 g, yield 66 %, R f = 0.40 in hexanes:etoac (3:7)) as a yellow oil. 1 H NMR (300 MHz, CDCl 3) δ (m, 1H), 5.79 (s, 1H), 4.97 (m, 2H), 4.34 (d, J = 6.2 Hz, 2H), (m, 3H), (m, 2H), 0.96 (t, J = 7.3 Hz, 3H); 13 C NMR (75 MHz, CDCl 3) δ , , , , , 66.07, 58.49, 33.49, 20.94, 13.83; IR (ATR) max 854, 1057, 1255, 1415, 1461, 1678, 2875, 2930, 2962, 3449 cm -1 ; LRMS (APCI + ): m/z (rel. intensity) [M+H] + (100), (31), (14), (22); HRMS (TOF-ESI + ) m/z calcd for C 10H 15O , found e To a solution of halide (8.940 mmol, g) and corresponding organotin compound (9.830 mmol, g) in DMF (27 ml) a portion of Pd black powder (0.18 mmol, g) was suspended. After 110 minutes of heating the reaction was worked-up. The suspension was filtered to separating funnel containing EtOAc (200 ml) and saturated solution of NH 4Cl (100 ml) and extracted. The organic layer was then extracted twice with 4% sol. of NaF (2 150 ml) and the precipitate was filtered. The resulting solution was dried over Na 2SO 4. The crude mixture was purified by column chromatography (gradient elution, hexanes:etoac (8:2) hexanes:etoac (6:4)). The resulting solid was dissolved in the smallest possible amount of hot EtOAc, then approx. four times larger volume of hexanes was added and the solution was left in the freezer overnight. Resulting white crystalline solid was collected and dried to afford desired lactone (1.605 g, yield 83 %, R f = 0.35 in hexanes:etoac (3:7)). Melting point: ⁰C; 1 H NMR (500 MHz, CDCl 3) δ (m, 3H), (m, 2H), 6.02 (t, J = 6.2 Hz, 1H), 5.94 (s, 1H), 5.14 (s, 2H), 4.38 (d, J = 6.2 Hz, 2H), 2.40 (br, 1H); 13 C NMR (126 MHz, CDCl 3) δ , , , , , , , , , 66.30, 58.70; IR (ATR) max 716, 768, 860, 1050, S21

22 1073, 1245, 1413, 1448, 1678, 2929, 3411 cm -1 ; LRMS (APCI + ): m/z (rel. intensity) [M+H] + (100), (68), (28); HRMS (TOF-ESI + ) m/z calcd for C 13H 13O , found f After 210 minutes of heating and work-up the crude mixture was purified by column chromatography (gradient elution, hexanes:etoac (6:4) EtOAc) to afford desired lactone (0.188 g, yield 72 %, R f = 0.30 in hexanes:etoac (3:7)) as a yellow crystalline solid. Melting point: ⁰C (recrystallized from hot hexanes:etoac (7:3)); 1 H NMR (500 MHz, CDCl 3) δ (m, 2H), (m, 2H), 6.03 (s, 1H), 5.88 (t, J = 6.1 Hz, 1H), 5.20 (s, 2H), 4.42 (d, J = 6.1 Hz, 2H), 1.69 (br, 1H); 13 C NMR (126 MHz, CDCl 3) δ , , , , , , , , , 66.32, 58.83; IR (ATR) max 856, 1013, 1054, 1228, 1255, 1348, 1516, 1600, 1693, 3068, 3107, 3474 cm 1 ; LRMS (APCI + ): m/z (rel. intensity) [M+H] + (100), (21), (17); HRMS (TOF-ESI + ) m/z calcd for C 13H 12NO , found LiCl addition: Identical conditions were applied, except that 3 eq. of LiCl were added to the mixture before it was heated (see Table 3 in the text). The yield was comparable (75 %), the reaction time dropped down to 110 minutes. 4g After 200 minutes of heating and work-up the crude mixture was purified by column chromatography (gradient elution, hexanes:etoac (6:4) hexanes:etoac (3:7)). The resulting crystals were washed three times with cold hexanes (3 2 ml) to afford desired lactone (0.217 g, yield 79 %, R f = 0.35 in hexanes:etoac (3:7)) as a white crystalline solid. Melting point: ⁰C (recrystallized from hot hexanes:etoac (7:3)); 1 H NMR (300 MHz, CDCl 3) δ (m, 2H), (m, 2H), 6.00 (s, 1H), (m, 1H), 5.16 (s, 2H), 4.40 (d, J = 6.5 Hz, 2H), 3.94 (s, 3H), 1.91 (br, 1H); 13 C NMR (75 MHz, CDCl 3) δ , , , , , , , , , , 66.30, 58.81, S22

23 52.40; IR (ATR) max 771, 856, 1032, 1047, 1111, 1236, 1256, 1287, 1638, 1674, 1720, 2929, 3049, 3432 cm -1 ; LRMS (APCI + ): m/z (rel. intensity) [M+H] + (100), (16), (11); HRMS (TOF-ESI + ) m/z calcd for C 15H 15O , found h 1.5 eq. of organotin compound was used. After 100 minutes of heating and work-up the crude mixture was purified by column chromatography (gradient elution, hexanes:etoac (65:35) hexanes:etoac (4:6)). The resulting crystals were washed three times with cold hexanes (3 2 ml) to afford desired lactone (0.228 g, yield 80 %, R f = 0.40 in hexanes:etoac (3:7)) as a white crystalline solid. Melting point: ⁰C (recrystallized from hot hexanes:etoac (95:5)); 1 H NMR (500 MHz, CDCl 3) δ 7.52 (d, J = 8.3 Hz, 1H), 7.46 (d, J = 1.9 Hz, 1H), 7.21 (dd, J = 8.3, 2.0 Hz, 1H), 5.96 (m, 2H), 5.14 (s, 2H), 4.41 (d, J = 6.1 Hz, 2H), 1.86 (br, 1H); 13 C NMR (126 MHz, CDCl 3) δ , , , , , , , , , , , 66.25, 58.84; IR (ATR) max 848, 1032, 1048, 1243, 1253, 1644, 1697, 2927, 3092, 3434 cm -1 ; LRMS (APCI + ): m/z (rel. intensity) [M+H] + (14), [M+H] + (66), [M+H] + (100), (14); HRMS (TOF-ESI + ) m/z calcd for C 13H 11Cl 2O , found i After 120 minutes of heating and work-up the crude mixture was purified by column chromatography (gradient elution, hexanes hexanes:etoac (75:25)) to afford desired lactone (0.251 g, yield 88 %, R f = 0.18 in hexanes:etoac (7:3)) as a white crystalline solid. Melting point: ⁰C (the solid was dissolved in the smallest possible amount of hot EtOAc, then approx. three times larger volume of hexanes was added and the solution was left in the freezer overnight; resulting white crystalline solid was collected and dried); 1 H NMR (500 MHz, CDCl 3) δ (m, 3H), (m, 2H), 5.95 (s, 1H), 5.88 (s, 1H), 5.53 (d, J = 1.1 Hz, 2H), 1.74 (br, 1H), (m, 7H), (m, 2H), 1.33 S23

24 1.22 (m, 1H); 13 C NMR (126 MHz, CDCl 3) δ , , , , , , , , , 72.72, 66.71, 38.74, 24.92, 21.81; IR (ATR) max 711, 769, 987, 1036, 1234, 1254, 1343, 1447, 1643, 1673, 2848, 2886, 2945, 3058, 3479 cm -1 ; LRMS (APCI - ): m/z (rel. intensity) [M-H] - (100), (13); HRMS (TOF-ESI + ) m/z calcd for C 18H 20O 3Na , found j After 120 minutes of heating and work-up the crude mixture was purified by column chromatography (gradient elution, hexanes:etoac (6:4) hexanes:etoac (3:7)) to afford desired lactone (0.157 g, yield 66 %, R f = 0.28 in hexanes:etoac (3:7)) as a white amorphous solid. 1 H NMR (500 MHz, DMSO-d 6) δ 5.97 (s, 1H), 5.90 (s, 1H), 5.32 (d, J = 1.7 Hz, 2H), 5.30 (t, J = 5.6 Hz, 1H), 4.83 (s, 1H), 4.29 (dd, J = 5.7, 1.7 Hz, 2H), (m, 6H), (m, 3H), (m, 1H); 13 C NMR (126 MHz, DMSO-d 6) δ , , , , , 71.04, 66.20, 59.19, 38.12, 25.08, 21.58; IR (ATR) max 867, 1048, 1056, 1108, 1144, 1165, 1263, 1322, 1368, 1458, 1676, 2851, 2870, 2927, 2956, 3335 cm -1 ; LRMS (APCI + ): m/z (rel. intensity) [M+H] + (11), (100), (68); HRMS (TOF-ESI + ) m/z calcd for C 13H 18O 4Na , found k After 120 minutes of heating and work-up the crude mixture was purified by column chromatography (gradient elution, hexanes:etoac (85:15) hexanes:etoac (65:35)) to afford desired lactone (0.198 g, yield 95 %, R f = 0.30 in hexanes:etoac (6:4)) as a white crystalline solid. Melting point: ⁰C (recrystallized from hot hexanes:etoac (9:1)); 1 H NMR (500 MHz, CDCl 3) δ 6.89 (d, J = 9.7 Hz, 1H), 5.86 (d, J = 9.7 Hz, 1H), 5.81 (s, 1H), 5.47 (d, J = 2.0 Hz, 2H), 1.75 (br, 1H), (m, 6H), (m, 3H), (m, 1H); 13 C NMR (126 MHz, CDCl 3) δ , , , , , 72.55, 67.09, S24

25 38.19, 24.98, 21.78; IR (ATR) max 822, 1049, 1237, 1251, 1370, 1409, 1452, 1646, 1682, 2855, 2929, 3043, 3365 cm -1 ; LRMS (APCI - ): m/z (rel. intensity) [M-H] - (100); HRMS (TOF-ESI + ) m/z calcd for C 12H 17O , found l After 270 minutes of heating and work-up the crude mixture was purified by column chromatography (gradient elution, hexanes hexanes:etoac (8:2)) to afford desired lactone (0.284 g, yield 85 %, R f = 0.53 in hexanes:etoac (6:4)) as a white crystalline solid. Melting point: ⁰C (recrystallized from hot hexanes:etoac (8:2)); 1 H NMR (500 MHz, CDCl 3) δ 8.06 (d, J = 8.1 Hz, 2H), 7.42 (d, J = 8.1 Hz, 2H), (m, 3H), 7.11 (d, J = 7.9 Hz, 2H), (m, 2H), 5.23 (s, 2H), 3.93 (s, 3H), 3.58 (d, J = 7.9 Hz, 2H); 13 C NMR (126 MHz, CDCl 3) δ , , , , , , , , , , , , , , 66.36, 52.34, 34.49; IR (ATR) max 733, 862, 1021, 1037, 1251, 1278, 1651, 1702, 1723, 3003, 3054 cm -1 ; LRMS (APCI + ): m/z (rel. intensity) [M+H] + (100), (16), (14); HRMS (TOF-ESI + ) m/z calcd for C 21H 19O , found m After 160 minutes of heating and work-up the crude mixture was purified by column chromatography (gradient elution, hexanes hexanes:etoac (75:25)) to afford desired lactone (0.166 g, yield 83 %, R f = 0.25 in hexanes:etoac (7:3)) as a yellow oil. 1 H NMR (500 MHz, CDCl 3) δ (m, 1H), 5.79 (s, 1H), (m, 2H), 3.56 (t, J = 6.2 Hz, 2H), 2.36 (q, J = 7.5 Hz, 2H), (m, 3H), (m, 2H); 13 C NMR (126 MHz, CDCl 3) δ , , , , , 66.18, 43.96, 31.53, 25.11, 18.56; IR (ATR) max 721, 878, 1033, 1273, 1417, 1458, 1642, 1702, 2855, 2927, 2968 cm -1 ; LRMS (APCI + ): m/z (rel. intensity) [M+H] + (29), [M+H] + (100), (33), (43); HRMS (TOF-ESI + ) m/z calcd for C 10H 14ClO , found S25

26 4n After 360 minutes of heating and work-up the crude mixture was purified by column chromatography (gradient elution, hexanes hexanes:etoac (87:13)) to afford viscous yellow oil (R f = 0.30 in hexanes:etoac (8:2)). This oil was re-dissolved in anhydrous dichloromethane (2 ml) and trifluoroacetic acid (0.5 ml) was added dropwise. After 30 minutes the liquids were evaporated and the residual oil was diluted with EtOAc (5 ml) and extracted with mixture consisting of 5 % solution of Na 2CO 3 and sat. sol. of NaCl (volume ratio 2:1 respectively; 5 ml). The organic layer was dried over Na 2SO 4 and the solvents were evaporated. Resulting white solid was dissolved in the smallest possible amount of hot EtOAc, then approx. four times larger volume of hexanes was added and the solution was left in the freezer overnight. Resulting white crystalline solid was dried and collected (0.112 g, overall yield 46 %, R f = 0.13 in EtOAc:MeOH (96:4)). Melting point: not determined (decomposition over 105 ⁰C observed); 1 H NMR (500 MHz, DMSO-d 6) δ (m, 3H), (m, 2H), 5.86 (s, 1H), 5.80 (s, 1H), 5.59 (d, J = 1.2 Hz, 2H), 1.94 (br, 2H), 1.20 (s, 6H); 13 C NMR (126 MHz, DMSO-d 6) δ , , , , , , , , , 65.98, 51.58, 32.48; IR (ATR) max 712, 770, 896, 1041, 1230, 1254, 1284, 1643, 1686, 2206, 2930, 2961, 3056, 3349 cm -1 ; LRMS (APCI + ): m/z (rel. intensity) [M+Na] + (42); [M+H] + (100); (6); HRMS (TOF-ESI + ) m/z calcd for C 15H 18NO , found o After 160 minutes of heating and work-up the crude mixture was purified by column chromatography (gradient elution, hexanes:etoac (85:15) hexanes:etoac (65:35)) to afford desired lactone (0.354 g, yield 86 %, R f = 0.28 in hexanes:etoac (7:3)) as a viscous yellow oil. 1 H NMR (500 MHz, CDCl 3) δ 7.51 (d, J = 8.3 Hz, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.20 (dd, J = 8.3, 2.1 Hz, 1H), 5.90 (s, 1H), 5.80 (t, J = 7.7 Hz, 1H), (m, 2H), 4.55 (br, 1H), (m, 2H), 2.28 (q, J = 7.6 Hz, 2H), (m, 2H), 1.43 (s, 9H); 13 C NMR (126 MHz, CDCl 3) δ , , , , , , , , , , , , 79.48, 66.23, 39.89, 29.53, 28.36, 25.73; IR (ATR) max 756, 868, 1031, 1168, S26