Synthesis and Antiplasmodial Activity of Bicyclic Dioxanes as Simplified Dihydroplakortin Analogues

Transcription

1 SUPPORTING INFORMATION Synthesis and Antiplasmodial Activity of Bicyclic Dioxanes as Simplified Dihydroplakortin Analogues Sandra Gemma,,,& Sanil Kunjir,,,& Salvatore Sanna Coccone,,,& Margherita Brindisi,,,& Vittoria Moretti,,,& Simone Brogi,,,& Ettore Novellino,, Nicoletta Basilico,,,& Silvia Parapini,,,& Donatella Taramelli,,,& Giuseppe Campiani,,,&, and Stefania Butini,,& Corresponding author: Chemistry for intermediates 8b-g HPLC separation and NMR studies for compound rac-5g Chemistry for analogues rac-6a-h and NMR studies Experimental methods References and notes Table 1 SI. Elemental Analyses for Title Compounds S2 S2 S3 S3 S17 S18 Corresponding author. Tel.: ; fax: ; campiani@unisi.it S1

2 Chemistry for intermediates 8b-g The appropriate aldehydes 20b-g were submitted to the Wadsworth-Emmons olefination to obtain the corresponding α,β-unsaturated esters 21b-g. These latter compounds were subsequently converted into the desired intermediates 8b-g following a two-step procedure involving DIBALmediated reduction to 22b-g followed by treatment with iodide in the presence of imidazole and triphenylphosphine. 1 Aldehyde 20g was prepared starting from adamantanone 18 through the vinyl ether intermediate 19. Scheme 1 SI. Synthesis of allyl iodides 8b-g a a Reagents and conditions: (i) Methoxymethyltriphenylphosphonium chloride, NaHDMS, THF, 0 C; (ii) 6 N HCl, acetone, 25 C; (iii) triethyl 2-phosphonopropionate, NaH, from 0 C to 25 C, THF; (iv) DIBAL, DCM, -78 C; (v) PPh 3, imidazole, 1:3 MeCN/Et 2 O, 0 C. HPLC separation and NMR studies for compound rac-5g The most potent compound of the series rac-5g was resolved in its single enantiomers through semipreparative chiral HPLC. As reported in Figure 1 SI, the chromatogram presented four peaks corresponding to the four enantiomers of the mixture. However, although several attempts of optimization of the chromatographic conditions were performed, varying both mobile and stationary phases, it was possible to quantitatively separate and structurally characterize only two out of the four enantiomers. Compounds eluting at 10.6 and 11.4 min were diasteroisomers at C3 and the relative configuration was assigned by NMR studies through bidimensional COSY and NOESY experiments. Significant NOE correlations for the two compounds are shown in Figure 2 SI. Figure 1 SI. HPLC chromatogram of rac-5g showing the four peaks corresponding to the S2

3 enantiomers composing the mixture. Figure 2 SI. Key NOE correlations (double arrows) depicted on stable calculated conformations for two diasteroisomers of 5g eluted at 11.4 min (left) and 10.6 min (right). Absolute configuration has not been determined for diasteroisomers of 5g. Pictures were generated by Maestro. 2 Chemistry for analogues rac-6a-h and NMR studies. For the synthesis of C3-aryl-substituted analogues rac-6a-h (Scheme 2 of the Main Text) the key synthetic intermediates were the styrene derivatives 13a-e. Compound 13a was prepared in low yield starting from 2-methylbutyrolactone 7a by C-alkylation with phenethylbromide 11. The resulting compound 12 was brominated at the benzylic position and then dehydrobrominated with 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) to obtain 13a. Following a different strategy to 13b-e, benzylic aldehydes 15b-e, in turn prepared from compounds 14b-e, were reacted with the enolate of 7a to afford the condensation products 16b-e. The secondary alcohol group of the latter compounds was converted into the corresponding triflate, which in the presence of DBU underwent an 1,2- elimination to afford intermediates 13b-e. Finally, starting from 13a-e, the regioselective hydroperoxysilylation placed the hydroperoxide group on the benzylidene carbon, furnishing intermediates 17a-e which were cyclized without isolation as for alkyl derivatives rac-5a-m (see Scheme 1). The final diastereoisomers rac-6a-h were obtained as racemates. The relative configuration at C3 of compounds rac-6a and rac-6f was assigned by NOESY experiments. In particular, cross-peaks between the pair H3 and H5 for the first-eluting isomer and between H3 and the Me group at C4a for the second- eluting isomer led to the depicted (Figure 3 SI) relative configuration for rac-6a and rac-6f, respectively. Figure 3 SI. Key NOE correlations (double arrows) depicted on stable calculated conformations for compounds 6a (left), 6f (right). For the sake of clarity, only one enantiomer for racemic 6a and 6f is shown. Pictures were generated by Maestro. 2 Experimental methods. Chemistry 3-Methyl-3-(2-methylallyl)dihydrofuran-2(3H)-one (9a). To a stirred solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 3.4 ml, 3.4 mmol) and THF (10 ml), cooled to -78 o C, a solution of 7a (0.31 g, 3.1 mmol) in THF (5 ml) was added dropwise. The reaction mixture was stirred at -78 o C for 30 min, afterward a solution of 8a (0.67 g, 3.7 mmol) in THF (5 ml) was added dropwise and the resulting reaction mixture was stirred at the same temperature for 10 min and then allowed to warm to 25 o C and stirred for further 2 h. A saturated solution of ammonium chloride was S3

4 added to reaction mixture and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate, and the solvent was removed. The residue was purified by flash chromatography (1:10 ethyl acetate/n-hexane) to afford 9a as a colorless oil (90% yield); 1 H NMR (300 MHz, CDCl 3 ) δ 4.80 (s, 1H), 4.67 (s, 1H), (m, 2H), (m, 3H), (m, 1H), 1.63 (s, 3H), 1.14 (s, 3H); MS (ESI) m/z 177 (M+Na) +. (E/Z)-3-Methyl-3-(2-methylhex-2-enyl)dihydrofuran-2(3H)-one (9b). Starting from 7a and 8b, the title compound was prepared following the procedure described for the synthesis of 9a and was obtained as a 2:3 mixture of geometric isomers (colorless oil, 96% yield); 1 H NMR (300 MHz, CDCl 3 ) δ 5.30 (t, J = 7.2 Hz, 1H), 5.21 (t, J = 7.1 Hz, 1H), (m, 4H), 2.52 (d, J = 13.8 Hz, 1H), 2.36 (d, J = 14.4 Hz, 1H), (m, 4H), (m, 6H), 1.64 (s, 3H), 1.58 (s, 3H), (m, 4H), 1.20 (s, 3H), 1.18 (s, 3H), 0.85 (t, J = 7.3 Hz, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ 182.6, 182.5, 131.0, 130.9, 130.7, 130.6, 65.3, 47.7, 42.5, 42.3, 39.3, 34.3, 34.1, 30.6, 30.3, 24.9, 24.0, 23.9, 23.1, 22.9, 17.5, 14.0, 14.0; MS (ESI) m/z 197 (M+H) +, 219 (M+Na) +. (E/Z)-3-Methyl-3-(2-methylhept-2-enyl)dihydrofuran-2(3H)-one (9c). Starting from 7a and 8c, the title compound was prepared following the procedure described for the synthesis of 9a and was obtained as a colorless oil (84% yield); 1 H NMR (300 MHz, CDCl 3 ) δ 5.28 (t, J = 7.2 Hz, 1H), 5.18 (t, J = 7.1 Hz, 1H), (m, 4H), 2.50 (d, J = 12.3 Hz, 1H), (m, 5H), (m, 6H), 1.62 (s, 3H), 1.56 (s, 3H), (m, 8H), 1.18 (s, 3H), 1.16 (s, 3H), (m, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ 182.6, 182.5, 130.9, 130.8, 130.7, 65.2, 47.6, 42.5, 42.3, 39.2, 34.3, 34.0, 32.9, 28.2, 27.9, 24.9, 23.9, 23.8, 22.5, 17.4, 14.1, 14.1; MS (ESI) m/z 233 (M+Na) +. (E/Z)-3-(4-Ethyl-2-methylhex-2-enyl)-3-methyldihydrofuran-2(3H)-one (9d). Starting from 7a and 8d, the title compound was prepared following the procedure described for the synthesis of 9a and was obtained as a colorless oil (74% yield); 1 H NMR (300 MHz, CDCl 3 ) δ 5.05 (d, J = 10.1 Hz, 1H), 4.94 (d, J = 9.6 Hz, 1H), (m, 4H), 2.59 (d, J = 14.1 Hz, 1H), 2.44 (d, J = 13.5 Hz, 1H), (m, 4H), (m, 2H), (m, 2H), 1.68 (d, J = 1.1 Hz, 3H), 1.62 (d, J = 1.2 Hz, 3H), (m, 4H), 1.25 (s, 3H), 1.24 (s, 3H), (m, 4H), (m, 12H); 13 C NMR (75 MHz, CDCl 3 ) δ 182.7, 136.1, 135.9, 130.9, 130.7, 65.3, 47.8, 42.6, 42.0, 41.8, 41.0, 39.6, 34.3, 34.2, 28.5, 28.4, 24.8, 24.1, 23.9, 18.1, 12.2, 12.1, 12.0, 11.8; MS (ESI) m/z 247 (M+Na) +. (E/Z)-3-(3-Cyclopentyl-2-methylallyl)-3-methyldihydrofuran-2(3H)-one (9e). Starting from 7a and 8e, the title compound was prepared following the procedure described for the synthesis of 9a and was obtained as a 3:2 mixture of geometric isomers (colorless oil, 95% yield); 1 H NMR (300 MHz, CDCl 3 ) δ 5.19 (d, J = 9.7 Hz, 1H), 5.12 (d, J = 8.7 Hz, 1H), (m, 4H), (m, 3H), (m, 7H), (m, 2H), (m, 16H), (m, 10H); 13 C NMR (75 MHz, CDCl 3 ) δ 182.6, 136.5, 136.2, 129.5, 129.0, 65.4, 47.7, 42.6, 42.0, 39.5, 39.3, 39.2, 34.4, 34.0, 33.9, 33.8, 33.7, 33.6, 25.6, 25.5, 25.4, 24.9, 24.1, 23.8, 17.7; MS (ESI) m/z 245 (M+Na) +. (E/Z)-3-(3-Cyclohexyl-2-methylallyl)-3-methyldihydrofuran-2(3H)-one (9f). Starting from 7a and 8f, the title compound was prepared following the procedure described for the synthesis of 9a and was obtained as a 1:1 mixture of geometric isomers (colorless oil, 76% yield); 1 H NMR (300 MHz, CDCl 3 ) δ 5.14 (d, J = 9.7 Hz, 1H), 5.06 (d, J = 9.0 Hz, 1H), (m, 4H), 2.55 (d, J = 13.9 Hz, 1H), 2.36 (d, J = 13.4 Hz, 1H), (m, 6H), (m, 2H), (m, 16H), (m, 12H), (m, 4H); 13 C NMR (75 MHz, CDCl 3 ) δ 182.7, 182.6, 137.1, 136.9, 129.1, 128.6, 65.3, 47.7, 42.5, 41.9, 39.5, 37.3, 34.4, 34.1, 33.5, 33.5, 33.3, 33.2, 26.3, 26.2, 26.1, 24.9, 24.2, 23.9, 17.6; MS (ESI) m/z 259 (M+Na) +. (E/Z)-3-(3-Adamantan-2-yl-2-methylallyl)-3-methyldihydrofuran-2(3H)-one (9g). Starting from 7a and 8g, the title compound was prepared following the procedure described for the synthesis of 9a and was obtained as a 3:2 mixture of geometric isomers (colorless oil, 77% yield); 1 H NMR (300 MHz, CDCl 3 ) δ 5.78 (d, J = 9.9 Hz, 1H), 5.62 (d, J = 8.7 Hz, 1H), (m, 4H), (m, 8H), (m, 36H), 1.24 (s, 3H), 1.23 (s, 3H); MS (ESI) m/z 311 (M+Na) +. 3-(2-Methylallyl)dihydrofuran-2(3H)-one (9h). Starting from 7b 3 and 8a, the title compound was prepared following the procedure described for the synthesis of 9a and was obtained as a colorless oil (99% yield); Physical and spectroscopic data are identical to those described in the literature. 4 S4

5 (E/Z)-3-(2-Methylhex-2-enyl)dihydrofuran-2(3H)-one (9i). Starting from 7b 3 and 8b, the title compound was prepared following the procedure described for the synthesis of 9a and was obtained as a 4:3 mixture of geometric isomers (colorless oil, 66% yield); 1 H NMR (300 MHz, CDCl 3 ) δ 5.25 (t, J = 7.1 Hz, 1H), 5.18 (t, J = 7.1 Hz, 1H), (m, 2H), (m, 2H), (m, 4H), (m, 3H), (m, 7H), 1.68 (s, 3H), 1.59 (s, 3H), (m, 4H), 0.86 (t, J = 7.3 Hz, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ 179.8, 179.7, 131.8, 131.6, 128.6, 127.9, 66.8, 66.7, 40.7, 38.2, 38.0, 32.2, 30.2, 28.5, 28.3, 23.3, 23.2, 23.0, 15.8, 14.0, 13.9; MS (ESI) m/z 205 (M+Na) +. (E/Z)-3-(2-Methylhept-2-enyl)dihydrofuran-2(3H)-one (9j). Starting from 7b 3 and 8c, the title compound was prepared following the procedure described for the synthesis of 9a and was obtained as a 5:3 mixture of geometric isomers (colorless oil, 64% yield); 1 H NMR (300 MHz, CDCl 3 ) δ 5.24 (t, J = 7.2 Hz, 1H), 5.17 (t, J = 7.2 Hz, 1H), (m, 2H), (m, 2H), (m, 4H), (m, 2H), (m, 8H), 1.67 (s, 3H), 1.58 (s, 3H), (m, 8H), (m, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ 179.8, 179.7, 131.5, 131.4, 128.8, 128.0, 66.8, 66.7, 40.7, 38.2, 38.0, 32.3, 32.2, 32.0, 28.5, 28.3, 27.9, 27.8, 23.2, 22.6, 22.5, 15.7, 14.2; MS (ESI) m/z 219 (M+Na) +. (E/Z)-3-(4-Ethyl-2-methylhex-2-enyl)dihydrofuran-2(3H)-one (9k). Starting from 7b 3 and 8d, the title compound was prepared following the procedure described for the synthesis of 9a and was obtained as a 2:1 mixture of geometric isomers (colorless oil, 64% yield); 1 H NMR (300 MHz, CDCl 3 ) δ 4.95 (d, J = 10.1 Hz, 1H), 4.86 (d, J = 9.8 Hz, 1H), 4.32 (td, J = 8.7, 3.2 Hz, 2H), (m, 2H), (m, 3H), 2.51 (dd, J = 14.0, 4.2 Hz, 1H), (m, 4H), (m, 4H), 1.70 (d, J = 1.2 Hz, 3H), 1.60 (d, J = 1.0 Hz, 3H), (m, 4H), (m, 4H), (m, 12H); 13 C NMR (75 MHz, CDCl 3 ) δ 179.8, 179.7, 133.8, 133.1, 131.8, 131.4, 66.7, 41.7, 41.2, 40.9, 38.2, 38.1, 32.6, 28.6, 28.5, 28.4, 23.2, 16.3, 12.2, 12.1, 11.9; MS (ESI) m/z 233 (M+Na) +. 3-Ethyl-3-(2-methylallyl)dihydrofuran-2(3H)-one (9l). To a stirred solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 2.5 ml, 2.5 mmol) and THF (10 ml), cooled to -78 o C, a solution of 9h (0.32 g, 2.28 mmol) in THF (5 ml) was added dropwise. The reaction mixture was stirred at -78 o C for 30 min, afterward a solution of ethyl iodide (0.43 g, 2.7 mmol) in THF (5 ml) was added dropwise and the resulting reaction mixture was stirred at the same temperature for 10 min. Subsequently, it was allowed to warm to 25 o C and further stirred for 2 h. A saturated solution of ammonium chloride was added to the reaction mixture and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate, and the solvent was removed. The residue was purified by flash chromatography (1:5 ethyl acetate/n-hexane) to afford 9l (0.29 g, 79%) as colorless oil. 1 H NMR (300 MHz, CDCl 3 ) δ 4.86 (s, 1H), 4.74 (s, 1H), 4.18 (t, J = 7.4 Hz, 2H), 2.40 (d, J = 13.8 Hz, 1H), (m, 2H), (m, 1H), 1.70 (s, 3H), (m, 2H), 0.92 (t, J = 7.5 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 181.7, 141.8, 115.8, 65.6, 46.38, 44.4, 30.8, 30.7, 23.7, 8.9; MS (ESI) m/z 191 (M+Na) +. 3-Isobutyl-3-(2-methylallyl)dihydrofuran-2(3H)-one (9m). Starting from 9h and isobutyl iodide, the title compound was prepared following the procedure described for the synthesis of 9l and was obtained as a colorless oil (64% yield); 1 H NMR (300 MHz, CDCl 3 ) δ 4.84 (d, J = 1.4 Hz, 1H), 4.72 (s, 1H), (m, 2H), 2.35 (d, J = 13.6 Hz, 1H), (m, 3H), (m, 1H), 1.67 (s, 3H), (m, 2H), (m, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ 182.1, , 116.0, 65.5, 46.3, 45.8, 45.6, 31.1, 25.0, 24.9, 23.8, 23.5; MS (ESI) m/z 197 (M+Na) +. 3-Methyl-3-(2-methyl-2-(triethylsilylperoxy)propyl)dihydrofuran-2(3H)-one (10a). To a solution of 9a (0.42 g, 2.72 mmol) and Co(thd) 2 (0.34 g, 0.81 mmol) in 1,2-dichloroethane (20 ml), stirred under an oxygen atmosphere, was added triethylsilane (0.86 ml) together with a drop of tertbutylhydroperoxide (5.5 M in nonane, catalytic amount). The resulting green mixture was stirred at 25 o C for 4 h, until consumption of the starting material. Thereafter the solvent was evaporated and the resulting residue was purified by flash chromatography (1:20 ethyl acetate/n-hexane) to afford 10a (0.72 g, 88% yield) as a greenish oil; 1 H NMR (300 MHz, CDCl 3 ) δ (m, 1H), (m, 1H), (m, 1H), 2.10 (d, J = 15.3 Hz, 1H), (m, 1H), 1.85 (d, J = 15.2 Hz, 1H), 1.26 (s, 6H), 1.19 (s, 3H), 0.96 (t, J = 7.8 Hz, 9H), 0.66 (q, J = 7.8 Hz, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ 182.9, 83.0, 65.5, 43.9, 41.4, 33.8, 27.4, 25.4, 24.6, 6.9, 4.0; MS (ESI) m/z 325 S5

6 (M+Na) +. 3-Methyl-3-(2-methyl-2-(triethylsilylperoxy)hexyl)dihydrofuran-2(3H)-one (10b). Starting from 9b, the title compound was prepared following the procedure described for the synthesis of 10a and was obtained as a greenish oil (79% yield); 1 H NMR (300 MHz, CDCl 3 ) δ (m, 2H), (m, 2H), (m, 2H), (m, 4H), 1.82 (d, J = 15.2 Hz, 2H), (m, 4H), (m, 20H), (m, 24H), (m, 12H); 13 C NMR (75 MHz, CDCl 3 ) δ 182.7, 85.2, 65.5, 65.4, 42.3, 41.9, 41.3, 39.5, 37.9, 34.1, 33.8, 26.4, 26.3, 25.4, 25.2, 23.9, 23.5, 23.4, 21.6, 14.3, 14.2, 6.9, 4.0; MS (ESI) m/z 367 (M+Na) +. 3-Methyl-3-(2-methyl-2-(triethylsilylperoxy)heptyl)dihydrofuran-2(3H)-one (10c). Starting from 9c, the title compound was prepared following the procedure described for the synthesis of 10a and was obtained as a greenish oil (86% yield); 1 H NMR (300 MHz, CDCl 3 ) δ (m, 2H), (m, 2H), (m, 2H), (m, 4H), 1.83 (d, J = 15.3 Hz, 2H), (m, 4H), (m, 24H), 0.95 (t, J = 7.9 Hz, 18H), (m, 6H), 0.64 (q, J = 7.9 Hz, 12H); 13 C NMR (75 MHz, CDCl 3 ) δ 182.7, 85.2, 65.5, 65.4, 42.3, 41.9, 41.3, 41.2, 39.8, 38.1, 34.1, 33.8, 32.6, 32.5, 25.4, 25.2, 23.9, 23.8, 22.8, 22.7, 21.6, 14.2, 6.9, 4.0; MS (ESI) m/z 359 (M+H) +, 381 (M+Na) +. 3-(4-Ethyl-2-methyl-2-(triethylsilylperoxy)hexyl)-3-methyldihydrofuran-2(3H)-one (10d). Starting from 9d, the title compound was prepared following the procedure described for the synthesis of 10a and was obtained as a greenish oil (69% yield); 1 H NMR (300 MHz, CDCl 3 ) δ (m, 2H), (m, 2H), (m, 2H), 2.30 (d, J = 15.2 Hz, 1H), (m, 3H), 1.78 (d, J = 15.2 Hz, 1H), (m, 4H), (m, 20H), 1.18 (s, 3H), 0.97 (t, J = 7.9 Hz, 18H), (m, 12H), 0.66 (q, J = 7.9 Hz, 12H); 13 C NMR (75 MHz, CDCl 3 ) δ 183.1, 182.9, 86.1, 86.0, 65.5, 43.4, 43.3, 42.6, 41.5, 41.3, 41.2, 36.2, 35.9, 33.9, 33.7, 27.2, 27.1, 26.9, 25.7, 25.6, 24.1, 22.2, 11.3, 10.9, 10.85, 10.82, 7.0, 6.9, 4.1, 4.0; MS (ESI) m/z 395 (M+Na) +. 3-(3-Cyclopentyl-2-methyl-2-(triethylsilylperoxy)propyl)-3-methyldihydrofuran-2(3H)-one (10e). Starting from 9e, the title compound was prepared following the procedure described for the synthesis of 10a and was obtained as a greenish oil (72% yield); 1 H NMR (300 MHz, CDCl 3 ) δ (m, 2H), (m, 2H), (m, 2H), 2.19 (d, J = 15.2 Hz, 1H), 2.03 (d, J = 15.1 Hz, 1H), (m, 2H), (m, 6H), (m, 12H), (m, 10H), (m, 8H), 0.95 (t, J = 7.8 Hz, 18H), (m, 12H); 13 C NMR (75 MHz, CDCl 3 ) δ 182.9, 85.7, 85.6, 65.5, 65.4, 45.9, 44.3, 42.9, 42.4, 41.3, 36.1, 36.0, 34.9, 34.8, 34.7, 34.0, 33.8, 25.6, 25.5, 25.4, 25.2, 25.1, 24.5, 22.3, 7.0, 6.9, 4.0; MS (ESI) m/z 393 (M+Na) +. 3-(3-Cyclohexyl-2-methyl-2-(triethylsilylperoxy)propyl)-3-methyldihydrofuran-2(3H)-one (10f). Starting from 9f, the title compound was prepared following the procedure described for the synthesis of 10a and was obtained as a greenish oil (53% yield); 1 H NMR (300 MHz, CDCl 3 ) δ (m, 2H), (m, 2H), (m, 2H), 2.20 (d, J = 15.2 Hz, 2H), (m, 4H), (m, 12H), (m, 6H), (m, 20H), 0.96 (t, J = 7.8 Hz, 18H), (m, 12H); 13 C NMR (75 MHz, CDCl 3 ) δ 182.9, 85.9, 85.8, 65.5, 65.4, 47.2, 45.7, 43.1, 42.5, 41.3, 35.6, 35.5, 35.4, 33.9, 33.8, 33.6, 33.4, 28.8, 26.7, 26.5, 26.4, 25.6, 25.4, 24.2, 22.1, 6.98, 4.1; MS (ESI) m/z 407 (M+Na) +. 3-(3-(Adamantan-2-yl)-2-methyl-2-(triethylsilylperoxy)propyl)-3-methyldihydrofuran-2(3H)- one (10g). Starting from 9g, the title compound was prepared following the procedure described for the synthesis of 10a and was obtained as a greenish oil (71% yield); 1 H NMR (300 MHz, CDCl 3 ) δ (m, 2H), (m, 2H), 8.83 (bs, 2H), (m, 38H), (m, 16H), (m, 16H), (m, 12H); MS (ESI) m/z 459 (M+Na) +. 3-(2-Methyl-2-(triethylsilylperoxy)propyl)dihydrofuran-2(3H)-one (10h). Starting from 9h, the title compound was prepared following the procedure described for the synthesis of 10a and was obtained as a greenish oil (63% yield); 1 H NMR (300 MHz, CDCl 3 ) δ 4.33 (dt, J = 8.8, 1.8 Hz, 1H), (m, 1H), (m, 2H), (m, 2H), 1.82 (dd, J = 14.6, 10.0 Hz, 1H), 1.26 (s, 3H), 1.20 (s, 3H), 0.97 (t, J = 7.9 Hz, 9H), 0.65 (q, J = 7.9 Hz, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ 180.4, 81.8, 66.9, 39.3, 36.1, 30.8, 26.1, 23.7, 6.97, 4.1; MS (ESI) m/z 311 (M+Na) +. 3-(2-Methyl-2-(triethylsilylperoxy)hexyl)dihydrofuran-2(3H)-one (10i). Starting from 9i, the title compound was prepared following the procedure described for the synthesis of 10a and was obtained as a greenish oil (75% yield); 1 H NMR (300 MHz, CDCl 3 ) δ 4.31 (t, J = 8.5 Hz, 2H), S6

7 (m, 2H), (m, 4H), (m, 4H), (m, 2H), (m, 4H), (m, 8H), (m, 30H), 0.61 (q, J = 7.9 Hz, 12H); 13 C NMR (75 MHz, CDCl 3 ) δ 180.5, 84.0, 66.9, 66.8, 38.3, 37.6, 37.3, 36.1, 35.9, 35.8, 31.0, 30.8, 27.6, 26.3, 26.2, 23.5, 23.1, 21.3, 14.2, 6.9, 6.8, 6.0, 4.1; MS (ESI) m/z 353 (M+Na) +. 3-(2-Methyl-2-(triethylsilylperoxy)heptyl)dihydrofuran-2(3H)-one (10j). Starting from 9j, the title compound was prepared following the procedure described for the synthesis of 10a and was obtained as a greenish oil (75% yield); 1 H NMR (300 MHz, CDCl 3 ) δ 4.32 (t, J = 8.2 Hz, 2H), (m, 2H), (m, 4H), (m, 4H), (m, 4H), (m, 2H), (m, 12H), (m, 24H), 0.88 (t, J = 6.6 Hz, 6H), (m, 12H); MS (ESI) m/z 367 (M+Na) +. 3-(4-Ethyl-2-methyl-2-(triethylsilylperoxy)hexyl)-3-methyldihydrofuran-2(3H)-one (10k). Starting from 9k, the title compound was prepared following the procedure described for the synthesis of 10a and was obtained as a greenish oil (70% yield); 1 H NMR (300 MHz, CDCl 3 ) δ (m, 2H), (m, 2H), (m, 2H), (m, 2H), 2.25 (dd, J = 14.6, 2.5 Hz, 2H), (m, 2H), 1.69 (dd, J = 14.5, 9.7 Hz, 2H), (m, 4H), (m, 6H), (m, 4H), (m, 20H), 0.81 (t, J = 6.8 Hz, 12H), (m, 12H); 13 C NMR (75 MHz, CDCl 3 ) δ 180.4, 84.7, 66.7, 42.2, 38.7, 35.9, 31.4, 27.0, 26.9, 22.0, 10.9, 10.8, 6.9, 6.8, 6.0, 4.1; MS (ESI) m/z 395 (M+Na) +. 3-Ethyl-3-(2-methyl-2-(triethylsilylperoxy)propyl)dihydrofuran-2(3H)-one (10l). Starting from 9l, the title compound was prepared following the procedure described for the synthesis of 10a and was obtained as a greenish oil (83% yield); 1 H NMR (300 MHz, CDCl 3 ) δ 4.30 (dt, J = 9.1, 4.8 Hz, 1H), 4.18 (dd, J = 16.5, 8.3 Hz, 1H), 2.85 (ddd, J = 13.3, 9.1, 7.8 Hz, 1H), 2.13 (d, J = 15.3 Hz, 1H), 1.98 (ddd, J = 12.8, 8.7, 4.6 Hz, 1H), 1.77 (d, J = 15.3 Hz, 1H), 1.59 (q, J = 7.6 Hz, 2H), 1.23 (s, 3H), 1.15 (s, 3H), (m, 12H), 0.63 (q, J = 7.9 Hz, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ 182.3, 83.0, 65.7, 45.2, 42.3, 32.3, 30.0, 27.8, 24.0, 8.8, 6.9, 4.0; MS (ESI) m/z 339 (M+Na) +. 3-Isobutyl-3-(2-methyl-2-(triethylsilylperoxy)propyl)dihydrofuran-2(3H)-one (10m). Starting from 9m, the title compound was prepared following the procedure described for the synthesis of 10a and was obtained as a greenish oil (90% yield); 1 H NMR (300 MHz, CDCl 3 ) δ 4.34 (td, J = 8.8, 5.5 Hz, 1H), 4.22 (dd, J = 15.6, 8.5 Hz, 1H), (m, 1H), 2.17 (d, J = 15.2 Hz, 1H), (m, 1H), (m, 1H), 1.57 (dd, J = 14.2, 4.8 Hz, 1H), (m, 2H), 1.24 (s, 3H), 1.16 (s, 3H), (m, 15H), 0.65 (q, J = 7.9 Hz, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ 182.9, 83.0, 65.7, 48.0, 44.7, 42.9, 30.2, 27.9, 25.1, 24.9, 23.8, 23.7, 6.9, 4.0; MS (ESI) m/z 367 (M+Na) +. (4aS*,7aR*)-3,3,4a-Trimethyltetrahydrofuro[2,3-c][1,2]dioxane (5a). To a solution of 10a (0.24 g, 0.8 mmol) in dry dichloromethane (15 ml), cooled to -78 o C, was added dropwise a 1 M solution of diisobutylaluminium hydride (0.8 ml, 0.8 mmol) and the resulting reaction mixture was stirred at -78 o C for 1.5 h. Subsequently, water was added and the resulting mixture was allowed to warm to 25 o C and stirred for further min. The white precipitate was filtered off, and the aqueous phase was extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate and the solvent was removed. The crude residue was purified by flash chromatography (1:10 ethyl acetate/n-hexane) to give the lactol intermediate as a colorless oil (0.14 g, 58% yield); MS (ESI) m/z 327 (M+Na) +. To a stirred solution of the above lactol (0.29 g, 0.96 mmol) in dry dichloromethane (15 ml), trimethylsilyl triflate (0.34 ml, 1.9 mmol) was added dropwise at -78 o C and the resulting reaction mixture was stirred for 5 min at same temperature. The reaction mixture was quenched with a saturated solution of sodium bicarbonate, and the aqueous phase was extracted with dichloromethane. The organic extracts were dried over sodium sulfate, and solvent was evaporated. The crude product was purified by flash chromatography (1:10 ethyl acetate/n-hexane) to give 5a as a colorless oil (83% yield); 1 H NMR (300 MHz, CDCl 3 ) δ 4.98 (s, 1H, H-7a), 4.18 (dt, J = 8.6, 4.4 Hz, 1H, H-6), (m, 1H, H-6), (m, 1H, H-5), 1.89 (d, J = 14.1 Hz, 1H, H-4), (m, 2H, H-5/H-4), 1.28 (s, 6H, 3-diMe), 1.09 (s, 3H, 4a- Me); 13 C NMR (75 MHz, CDCl 3 ) δ 110.0, 78.0, 68.5, 42.7, 40.6, 36.4, 28.8, 27.6, 27.0; MS (ESI) m/z 173 (M+H) +, 195 (M+Na) +. Anal. (C 9 H 16 O 3 ) C, H, N. (3R*,4aS*,7aR*)-3-Butyl-3,4a-dimethyltetrahydrofuro[2,3-c][1,2]dioxane and (3S*,4aS*,7aR*)-3-Butyl-3,4a-dimethyltetrahydrofuro[2,3-c][1,2]dioxane (5b). Compound 10b was reduced to the corresponding lactol (colorless oil, 58% yield, MS (ESI) m/z 367 (M+Na) + ) and S7

8 this latter intermediate was converted to the title compound (colorless oil, 82% yield) following the procedure described for the synthesis of 5a; 1 H NMR (300 MHz, CDCl 3 ) δ 5.00 (d, J = 7.0 Hz, 1H), 4.97 (s, 1H), (m, 2H), 3.96 (q, J = 7.8 Hz, 2H), (m, 2H), (m, 1H), 1.87 (d, J = 14.1 Hz, 1H), (m, 10H), (m, 6H), 1.25 (s, 3H), 1.24 (s, 3H), 1.12 (s, 3H), 1.11 (s, 3H), 0.88 (t, J = 6.6 Hz, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ 110.1, 110.0, 80.2, 80.1, 68.5, 68.3, 42.20, 41.4, 41.1, 40.5, 40.3, 39.8, 37.0, 36.4, 27.3, 27.2, 26.0, 25.4, 24.6, 23.4, 23.3, 14.3, 14.2; MS (ESI) m/z 237 (M+Na) +, 451 (2M+Na) +. Anal. (C 12 H 22 O 3 ) C, H, N. (3R*,4aS*,7aR*)-3-Pentyl-3,4a-dimethyltetrahydrofuro[2,3-c][1,2]dioxane and (3S*,4aS*,7aR*)-3-Pentyl-3,4a-dimethyltetrahydrofuro[2,3-c][1,2]dioxane (5c). Compound 10c was reduced to the corresponding lactol (colorless oil, 68% yield, MS (ESI) m/z 383 (M+Na) + ) and this latter intermediate was converted to the title compound (colorless oil, 84% yield) following the procedure described for the synthesis of 5a; 1 H NMR (300 MHz, CDCl 3 ) δ 4.97 (s, 1H), 4.94 (s, 1H), 4.16 (ddd, J = 18.4, 8.6, 4.5 Hz, 2H), (m, 2H), (m, 2H), 1.90 (d, J = 14.2 Hz, 1H), 1.84 (d, J = 14.1 Hz, 1H), (m, 8H), (m, 18H), 1.09 (s, 3H), 1.08 (s, 3H), 0.83 (t, J = 6.6 Hz, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ 110.1, 110.0, 80.2, 80.0, 68.5, 68.3, 42.2, 41.4, 41.3, 40.5, 40.3, 40.1, 37.0, 36.4, 32.5, 32.4, 27.3, 27.1, 25.3, 24.6, 23.5, 23.4, 22.8, 22.7, 14.2, 14.1; MS (ESI) m/z 251 (M+Na) +, 479 (2M+Na) +. Anal. (C 13 H 24 O 3 ) C, H, N. (3R*,4aS*,7aR*)-3-(2-Ethylbutyl)-3,4a-dimethyltetrahydrofuro[2,3-c][1,2]dioxane and (3S*,4aS*,7aR*)-3-(2-Ethylbutyl)-3,4a-dimethyltetrahydrofuro[2,3-c][1,2]dioxane (5d). Compound 10d was reduced to the corresponding lactol (colorless oil, 80% yield, MS (ESI) m/z 397 (M+Na) + ) and this latter intermediate was converted to the title compound (colorless oil, 92% yield) following the procedure described for the synthesis of 5a; 1 H NMR (300 MHz, CDCl 3 ) δ 4.99 (s, 1H), 4.96 (s, 1H), (m, 2H), (m, 2H), (m, 2H), 1.89 (d, J = 14.1 Hz, 2H), 1.70 (dd, J = 14.2, 5.7 Hz, 1H), (m, 17H), 1.29 (s, 3H), 1.25 (s, 3H), 1.11 (s, 3H), 1.09 (s, 3H), (m, 12H); 13 C NMR (75 MHz, CDCl 3 ) δ 110.3, 110.2, 80.9, 80.7, 68.6, 68.4, 44.3, 44.3, 43.3, 42.9, 40.6, 40.4, 37.1, 36.3, 36.0, 27.4, 27.1, 27.0, 26.7, 26.3, 25.6, 24.9, 11.2, 11.1, 10.7, 10.6; MS (ESI) m/z 265 (M+Na) +. Anal. (C 14 H 26 O 3 ) C, H, N. (3R*,4aS*,7aR*)-3-(Cyclopentylmethyl)-3,4a-dimethyltetrahydrofuro[2,3-c][1,2]dioxane and (3S*,4aS*,7aR*)-3-(Cyclopentylmethyl)-3,4a-dimethyltetrahydrofuro[2,3-c][1,2]dioxane (5e). Compound 10e was reduced to the corresponding lactol (colorless oil, 78% yield, MS (ESI) m/z 395 (M+Na) + ) and this latter intermediate was converted to the title compound (colorless oil, 75% yield) following the procedure described for the synthesis of 5a; 1 H NMR (300 MHz, CDCl 3 ) δ 4.98 (s, 1H), 4.95 (s, 1H), (m, 2H), (m, 2H), (m, 2H), 1.91 (d, J = 13.9 Hz, 2H), (m, 9H), (m, 13H), 1.27 (s, 3H), 1.25 (s, 3H), (m, 10H); 13 C NMR (75 MHz, CDCl 3 ) δ 110.2, 110.1, 80.6, 80.5, 68.5, 68.4, 46.9, 46.4, 42.8, 42.4, 40.5, 40.3, 37.1, 36.3, 36.2, 35.9, 34.8, 34.7, 34.4, 33.9, 27.3, 27.2, 25.8, 25.4, 25.2, 25.0, 24.9; MS (ESI) m/z 263 (M+Na) +, 503 (2M+Na) +. Anal. (C 14 H 24 O 3 ) C, H, N. (3R*,4aS*,7aR*)-3-(Cyclohexylmethyl)-3,4a-dimethyltetrahydrofuro[2,3-c][1,2]dioxane and (3S*,4aS*,7aR*)-3-(Cyclohexylmethyl)-3,4a-dimethyltetrahydrofuro[2,3-c][1,2]dioxane (5f). Compound 10f was reduced to the corresponding lactol (colorless oil, 57% yield, MS (ESI) m/z 409 (M+K) + ) and this latter intermediate was converted to the title compound (colorless oil, 86% yield) following the procedure described for the synthesis of 5a; 1 H NMR (300 MHz, CDCl 3 ) δ 4.96 (s, 1H), 4.94 (s, 1H), (m, 2H), (m, 2H), (m, 2H), 1.87 (d, J = 14.1 Hz, 4H), (m, 12H), (m, 6H), (m, 12H), 1.09 (s, 3H), 1.07 (s, 3H), (m, 4H); 13 C NMR (75 MHz, CDCl 3 ) δ 110.2, 110.1, 80.7, 80.5, 68.5, 68.4, 48.4, 48.2, 43.3, 42.8, 40.6, 40.3, 37.0, 36.4, 35.5, 34.9, 34.5, 33.9, 33.6, 27.3, 26.7, 26.5, 26.4, 25.6, 24.9; MS (ESI) m/z 277 (M+Na) +, 531 (2M+Na) +. Anal. (C 15 H 26 O 3 ) C, H, N. (4aS*,7aR*)-3,3-Dimethyltetrahydrofuro[2,3-c][1,2]dioxane (5h). Compound 10h was reduced to the corresponding lactol (colorless oil, 71% yield, MS (ESI) m/z 313 (M+Na) + ) and this latter intermediate was converted to the title compound (colorless oil, 53% yield) following the procedure described for the synthesis of 5a; 1 H NMR (300 MHz, CDCl 3 ) δ 5.43 (d, J = 5.9 Hz, 1H), 4.17 (dd, J = 14.7, 7.7 Hz, 1H), (m, 1H), (m, 1H), (m, 2H), (m, 2H), 1.28 (s, 3H), 1.26 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 104.6, 77.6, 68.1, 34.7, 33.9, 29.9, 27.9, 26.9; MS (ESI) m/z 181 (M+Na) +. Anal. (C 8 H 14 O 3 ) C, H, N. S8

9 (3R*,4aS*,7aR*)-3-Butyl-3-methyltetrahydrofuro[2,3-c][1,2]dioxane (3S*,4aS*,7aR*)-3- Butyl-3-methyltetrahydrofuro[2,3-c][1,2]dioxane (5i). Compound 10i was reduced to the corresponding lactol (colorless oil, 57% yield, MS (ESI) m/z 355 (M+Na) + ) and this latter intermediate was converted to the title compound (colorless oil, 79% yield) following the procedure described for the synthesis of 5a; 1 H NMR (300 MHz, CDCl 3 ) δ 5.47 (d, J = 5.7 Hz, 1H), 5.43 (d, J = 6.1 Hz, 1H), 4.17 (dt, J = 14.8, 7.6 Hz, 3H), (m, 2H), (m, 2H), (m, 4H), (m, 6H), (m, 3H), (m, 6H), 1.24 (s, 3H), 1.21 (s, 3H), 0.89 (t, J = 6.9 Hz, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ 104.8, 104.7, 79.7, 68.2, 67.9, 40.4, 39.4, 33.9, 33.8, 33.5, 30.5, 30.0, 26.1, 25.8, 25.1, 23.4, 23.3, 14.3, 14.2; MS (ESI) m/z 223 (M+Na) +. Anal. (C 11 H 20 O 3 ) C, H, N. (3R*,4aS*,7aR*)-3-Pentyl-3-methyltetrahydrofuro[2,3-c][1,2]dioxane (3S*,4aS*,7aR*)-3- Pentyl-3-methyltetrahydrofuro[2,3-c][1,2]dioxane (5j). Compound 10j was reduced to the corresponding lactol (colorless oil, 62% yield, MS (ESI) m/z 369 (M+Na) + ) and this latter intermediate was converted to the title compound (colorless oil, 85% yield) following the procedure described for the synthesis of 5a; 1 H NMR (300 MHz, CDCl 3 ) δ 5.46 (d, J = 5.7 Hz, 1H), 5.42 (d, J = 6.1 Hz, 1H), (m, 2H), (m, 2H), (m, 2H), (m, 5H), (m, 6H), (m, 3H), (m, 16H), 0.86 (t, J = 6.7 Hz, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ 104.8, 104.7, 79.7, 68.2, 67.8, 40.7, 39.7, 33.9, 33.8, 33.5, 32.5, 32.4, 30.4, 30.0, 25.0, 23.5, 23.3, 23.2, 22.8, 22.7, 14.2; MS (ESI) m/z 237 (M+Na) +, 451 (2M+Na) +. Anal. (C 12 H 22 O 3 ) C, H, N. (3R*,4aS*,7aR*)-3-(2-Ethylbutyl)-3-methyltetrahydrofuro[2,3-c][1,2]dioxane and (3R*,4aS*,7aR*)-3-(2-Ethylbutyl)-3-methyltetrahydrofuro[2,3-c][1,2]dioxane (5k). Compound 10k was reduced to the corresponding lactol (colorless oil, 62% yield, MS (ESI) m/z 383 (M+Na) + ) and this latter intermediate was converted to the title compound (colorless oil, 57% yield) following the procedure described for the synthesis of 5a; 1 H NMR (300 MHz, CDCl 3 ) δ 5.48 (d, J = 5.9 Hz, 1H), 5.45 (d, J = 6.3 Hz, 1H), (m, 2H), (m, 2H), (m, 2H), (m, 5H), 1.82 (dd, J = 14.1, 4.3 Hz, 1H), (m, 6H), (m, 16H), (m, 12H); 13 C NMR (75 MHz, CDCl 3 ) δ 104.8, 80.4, 68.4, 67.86, 44.6, 43.0, 36.2, 36.1, 35.1, 34.9, 34.3, 33.5, 30.4, 29.9, 27.1, 26.8, 26.4, 25.5, 23.5, 11.2, 11.1, 10.7, 10.6; MS (ESI) m/z 251 (M+Na) +. Anal. (C 13 H 24 O 3 ) C, H, N. (4aS*,7aR*)-4a-Ethyl-3,3-dimethyltetrahydrofuro[2,3-c][1,2]dioxane (5l). Compound 10l was reduced to the corresponding lactol (colorless oil, 71% yield, MS (ESI) m/z 341 (M+Na) + ) and this latter intermediate was converted to the title compound (colorless oil, 85% yield) following the procedure described for the synthesis of 5a; 1 H NMR (300 MHz, CDCl 3 ) δ 4.99 (s, 1H), 4.19 (dt, J = 8.5, 5.4 Hz, 1H), 3.92 (dd, J = 15.0, 8.0 Hz, 1H), 2.12 (ddd, J = 12.4, 8.8, 6.9 Hz, 1H), 1.84 (d, J = 14.0 Hz, 1H), (m, 1H), 1.51 (d, J = 14.1 Hz, 1H), 1.43 (q, J = 7.5 Hz, 2H), 1.28 (s, 3H), 1.27 (s, 3H), 0.87 (t, J = 7.5 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 109.5, 78.0, 68.8, 44.5, 40.0, 33.3, 32.6, 28.9, 27.8, 8.5; MS (ESI) m/z 187 (M+H) +, 209 (M+Na) +. Anal. (C 10 H 18 O 3 ) C, H, N. (4aS*,7aR*)-4a-Isobutyl-3,3-dimethylhexahydrofuro[2,3-c][1,2]dioxane (5m). Compound 10m was reduced to the corresponding lactol (colorless oil, 57% yield, MS (ESI) m/z 369 (M+Na) + ) and this latter intermediate was converted to the title compound (colorless oil, 82% yield) following the procedure described for the synthesis of 5a; 1 H NMR (300 MHz, CDCl 3 ) δ 5.01 (s, 1H), 4.20 (dt, J = 8.4, 5.7 Hz, 1H), 3.95 (dt, J = 8.1, 6.6 Hz, 1H), 2.16 (ddd, J = 12.4, 8.5, 6.6 Hz, 1H), 1.87 (d, J = 14.1 Hz, 1H), (m, 2H), 1.61 (d, J = 14.0 Hz, 1H), (m, 2H), 1.30 (s, 3H), 1.28 (s, 3H), 0.94 (s, 3H), 0.92 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 109.8, 77.8, 68.6, 48.7, 44.4, 40.5, 34.9, 28.7, 27.9, 25.2, 24.9; MS (ESI) m/z 237 (M+Na) +, 253 (M+K) +. Anal. (C 12 H 22 O 3 ) C, H, N. 3-Methyl-3-phenethyldihydrofuran-2(3H)-one (12). To a mixture of lithium bis(trimethylsilyl)amide (1.0 M in THF, 10 ml, 10 mmol) and THF (10 ml), cooled to -78 o C, was added dropwise a solution of 7a (1.0 g, 10 mmol) in THF (5 ml). The reaction mixture was stirred at -78 o C for 30 min, afterward a solution of 11 (2.2 g, 12 mmol) in THF (5 ml) was added dropwise. The resulting reaction mixture was stirred at the same temperature for 10 min and then allowed to warm to 25 o C and stirred overnight. The reaction was quenched with saturated solution of ammonium and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate, and the solvent was removed. The residue was purified by S9

10 flash chromatography (1:5 ethyl acetate/n-hexane) to afford 12 (1.2 g, 60% yield) as a colorless oil; MS (ESI) m/z 227 (M+Na) +. (E)-3-Methyl-3-styryldihydrofuran-2(3H)-one (13a). To a solution of 12 (0.4 g, 1.96 mmol), in carbon tetrachloride (15 ml), NBS (0.35 g, 1.96 mmol) and azobisisobutyronitirile (33 mg, 0.2 mmol) were added and the resulting suspension was heated under reflux for 4 h. After cooling to 25 C, the white precipitate was filtered off and the solvent was evaporated. The residue was purified by means of flash chromatography (1:5 ethyl acetate/n-hexane) to afford the corresponding bromoderivative (0.49 g, 90% yield) as a colorless oil; MS (ESI) m/z 306 (M+Na) +. A mixture of this latter compound (50 mg, 0.18 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (35 µl, 0.23 mmol) was placed in a sealed tube and heated to 70 C for 20 min. The crude reaction mixture was purified by flash-chromatography (1:5 ethyl acetate/n-hexane) to afford 13a (13 mg, 35% yield) as a colorless oil; 1 H NMR (300 MHz, CDCl 3 ) δ (m, 5H), 6.52 (d, J = 16.2 Hz, 1H), 6.24 (d, J = 16.2 Hz, 1H), (m, 2H), (m, 1H), (m, 1H), 1.46 (s, 3H); MS (ESI) m/z 225 (M+Na) +. 2-Isobutylbenzaldehyde (14e). PdCl 2 (dppf) (0.29 g, 0.39 mmol) was added to a stirred mixture of isobutylboronic acid (1.63 g, 15.9 mmol), 2-bromobenzaldeyde (1.48 g, 8.0 mmol), and K 2 CO 3 (2.37 g, 23.9 mmol) in dry toluene (25 ml). The resulting reaction mixture was heated under reflux for 2 h. The reaction mixture was then cooled to 25 C and the solvent was removed and diluted with dichloromethane and water. The combined organic extracts were washed with brine, dried over sodium sulfate and the solvent was evaporated. The crude residue was purified by flash chromatography (1:60 ethyl acetate/n-hexane) to afford aldehyde 14e as brownish oil (1.25 g, 97% yield) which was immediately used in the next step; MS (ESI) m/z 185 (M+Na) +. 2-o-Tolylacetaldehyde (15b). To a suspension of methoxymethyltriphenylphosphonium chloride (14.2 g, 41.6 mmol) in dry THF (20 ml) cooled to 0 o C, NaHMDS (1 M solution in THF, 41.6 ml, 41.6 mmol) was added, and resulting orange solution was stirred at 0 o C for 30 min. The reaction was cooled to -78 o C and a solution of 2-methylbenzaldehyde 14b 5 (5.0 g, 41.6 mmol) in THF (20 ml) was added dropwise, and the resulting mixture was warmed to 25 o C and stirred at the same temperature for 1.30 h. Thereafter the reaction was quenched with water and the aqueous phase was extracted with dichloromethane and the collected organic layer dried over Na 2 SO 4. The solvent was evaporated and the residue was purified by flash chromatography (1:50 ethyl acetate/n-hexane) to give the corresponding enolether (5.6 g, 91% yield) as a brownish oil; 1 H NMR (300 MHz, CDCl 3 ) δ 7.92 (d, J = 7.0 Hz, 2H), (m, 2H), (m, 4H), 6.90 (d, J = 12.6 Hz, 1H), 6.21(d, J = 7.1 Hz, 1H), 5.96 (d, J = 12.9 Hz, 1H), 5.36 (d, J = 7.3 Hz, 1H), 3.81 (s, J = 0.8 Hz, 3H), 3.78 (s, 3H), 2.37 (s, 6H); MS (ESI) m/z 171 (M+Na) +. 6 N hydrochloric acid (13.4 ml) was added dropwise to a solution of the above compound (2.0 g, 13.4 mmol) in acetone (20 ml), and the resulting mixture was stirred at 25 o C until consumption of the starting material. Thereafter water was added and the aqueous phase was extracted with dichloromethane, the collected organic layers were dried over Na 2 SO 4, and the solvent evaporated to give the crude aldehyde 15b (1.4 g, 78% yield) as a yellowish oil which was immediately used for the next reaction; MS (ESI) m/z 157 (M+Na) +. 2-(2-Ethylphenyl)acetaldehyde (15c). Aldehyde 14c was converted into the corresponding vinyl ether as previously described and was obtained in 85% yield as a brownish oil composed by a 2:1 mixture of geometric isomers; 1 H NMR (300 MHz, CDCl 3 ) δ 8.03 (d, J = 7.6 Hz, 2H), (m, 2H), (m, 4H), 6.98 (d, J = 12.7 Hz, 1H), 6.26 (d, J = 7.2 Hz, 1H), 6.12 (d, J = 12.7 Hz, 1H), 5.50 (d, J = 7.2 Hz, 1H), 3.81 (s, J = 0.8 Hz, 3H), 3.78 (s, 3H), 2.78 (q, J = 7.5 Hz, 4H), 1.33 (t, J = 7.6 Hz, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ 149.7, 148, 141.2, 141.1, 134.7, 129.6, 128.8, 128.6, 126.5, 126.4, 126.3,125.9, 125.5, 103.1,102.7, 60.7, 56.9, 27.0, 26.8, 15.4, 15.1; MS (ESI) m/z 185 (M+Na) +. This latter intermediate was converted to the title compound (pale yellow oil, 83% yield) following the procedure described for the synthesis of 15b and immediately used for the next reaction; MS (ESI) m/z 171 (M+Na) +. 2-(2-Isopropylphenyl)acetaldehyde (15d). Aldehyde 14d was converted into the corresponding vinyl ether as previously described and was obtained in 85% yield as a brownish oil composed by a 2:1 mixture of geometric isomers; 1 H NMR (300 MHz, CDCl 3 ) δ (m, 2H), 7.45 (d, J = 3.1 Hz, 2H), (m, 4H), 6.94 (d, J = 12.7 Hz, 1H), 6.28 (d, J = 7.2 Hz, 1H), 6.22 (d, J = 12.7 Hz, 1H), 5.59 (d, J = 7.2 Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), (m, 2H), 1.39 (d, J = 2.5 Hz, 3H), 1.37 (d, J = 2.5 Hz, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 149.9, 147.9, 145.7, 145.6, S10

11 134.3, 134.2, 133.9, 133.2,129, 128.8, 126.8, 126.7, 126.3, 126.1, 125.6, 125.2, 124.9, 103.3, 102.9, 60.6, 56.9, 29.7, 23.7, 23.5; MS (ESI) m/z 199 (M+Na) +. This latter intermediate was converted to the title compound (pale yellow oil, 95% yield) following the procedure described for the synthesis of 15b and immediately used for the next reaction; MS (ESI) m/z 185 (M+Na) +. 2-(2-Isobutylphenyl)acetaldehyde (15e). Aldehyde 14e was converted into the corresponding vinyl ether as previously described and was obtained in 75% yield as a brownish oil; 1 H NMR (300 MHz, CDCl 3 ) δ 7.96 (d, J = 8.0 Hz, 2H), (m, 2H), (m, 4H), 6.88 (d, J = 12.7 Hz, 1H), 6.19 (d, J = 7.3 Hz, 1H), 6.04 (d, J = 12.7 Hz, 1H), 5.41 (d, J = 7.2 Hz, 1H), 3.77 (s, J = 0.8 Hz, 3H), 3.73 (s, 3H), 2.55 (d, J = 7.1 Hz, 4H), (m, 2H), 0.97 (d, J = 3.5 Hz, 6H), 0.95 (d, J = 3.5 Hz, 6H); MS (ESI) m/z 213 (M+Na) +. This latter intermediate was converted to the title compound (colorless oil, 90% yield) following the procedure described for the synthesis of 15b and immediately used for the next reaction; MS (ESI) m/z 199 (M+Na) +. 3-(1-Hydroxy-2-o-tolylethyl)-3-methyldihydrofuran-2(3H)-one (16b). To a stirred solution of lithium bis(trimethylsilyl) amide (1.0 M in THF, 32.1 ml, 32.1 mmol) and THF (20 ml), cooled to - 78 o C, was added dropwise a solution of 7a (2.95 g, 29.5 mmol) in THF (10 ml). The reaction mixture was stirred at -78 o C for 30 min, afterward a solution of 15b (3.95 g, 29.5 mmol) in THF (15 ml) was added dropwise. The resulting reaction mixture was stirred at the same temperature for 10 min and then allowed to warm to 25 o C and was stirred for 2 h. A saturated solution of ammonium chloride was added to the reaction mixture and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate, and the solvent was removed. The residue was purified by flash chromatography (1:10 ethyl acetate/n-hexane) to afford 16b (5.9 g, 85% yield) as brownish oil; 1 H NMR (300 MHz, CDCl 3 ) δ (m, 4H), 4.39 (td, J = 8.9, 4.3 Hz, 1H), (m, 1H), 4.03 (dd, J = 11.0, 2.2 Hz, 1H), 3.00 (dd, J = 13.7, 2.2 Hz, 1H), 2.74 (dt, J = 12.6, 8.5 Hz, 1H), 2.51 (dd, J = 13.7, 11.0 Hz, 1H), 2.35 (s, 3H), (m, 1H), 1.35 (s, 3H); MS (ESI) m/z 257 (M+Na) +. 3-(2-(2-Ethylphenyl)-1-hydroxyethyl)-3-methyldihydrofuran-2(3H)-one (16c). The title compound was prepared from 15c in 77% yield as described for synthesis of 16b and was obtained as a yellowish oil; 1 H NMR (300 MHz, CDCl 3 ) δ (m, 4H), (m, 2H), (m, 1H), (m, 2H), (m, 2H), (m, 1H), (m, 1H), 1.42 (s, 3H), (m, 3H); MS (ESI) m/z 271 (M+Na) +. 3-(1-Hydroxy-2-(2-isopropylphenyl)ethyl)-3-methyldihydrofuran-2(3H)-one (16d). The title compound was prepared from 15d in 80% yield as described for synthesis of 16b and was obtained as a yellowish oil; 1 H NMR (300 MHz, CDCl 3 ) δ (m, 4H), (m, 2H), (m, 1H), (m, 1H), (m, 2H), (m, 1H), (m, 1H), 1.42 (s, 3H), (m, 6H); MS (ESI) m/z 285 (M+Na) +. 3-(1-Hydroxy-2-(2-isobutylphenyl)ethyl)-3-methyldihydrofuran-2(3H)-one (16e). The title compound was prepared from 15e in 44% yield as described for synthesis of 16b and was obtained as a yellowish oil; 1 H NMR (400 MHz, CDCl 3 ) δ (m, 8H), (m, 2H), (m, 2H), (m, 2H), (m, 2H), (m, 6H), (m, 6H), 1.39 (s, 3H), 1.32 (s, 3H), (m, 12H). MS (ESI) m/z 299 (M+Na) +. (E)-3-Methyl-3-(2-methylstyryl)dihydrofuran-2(3H)-one (13b). To a stirred solution of 16b (2.5 g, 10.6 mmol) and pyridine (2.5 ml, 32 mmol) in dichloromethane (25 ml), cooled to 78 o C, trifluromethanesulfonic anhydride (2.1 ml, 12.8 mmol) was added. The resulting reaction mixture was stirred at 0 o C for 1 h. Thereafter 1,8-diazabicyclo[5.4.0]undec-7-ene (4.7 ml, 32 mmol) was added and resulting reaction mixture was stirred at 25 o C for 1 h. Afterward a saturated solution of sodium bicarbonate was added and the aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate, and the solvent was removed. The residue was purified by flash chromatography (1:20 ethyl acetate/n-hexane) to afford 13b (0.96 g, 42% yield) as yellowish oil; 1 H NMR (300 MHz, CDCl 3 ) δ (m, 1H), (m, 3H), 6.73 (d, J = 16.1 Hz, 1H), 6.10 (d, J = 16.1 Hz, 1H), (m, 2H), 2.45 (ddd, J = 12.6, 6.7, 4.7 Hz, 1H), 2.33 (s, 3H), 2.26 (dt, J = 12.7, 7.9 Hz, 1H), 1.47 (s, 3H); MS (ESI) m/z 239 (M+Na) +. (E)-3-(2-Ethylstyryl)-3-methyldihydrofuran-2(3H)-one (13c). The title compound was prepared from 16c in 82% yield as described for synthesis of 13b and was obtained as a yellowish oil; 1 H NMR (300 MHz, CDCl 3 ) δ 7.41 (d, J = 7.9 Hz, 1H), (m, 3H), 6.80 (d, J = 16.1 Hz, 1H), S11

12 6.10 (d, J = 16.1 Hz, 1H), (m, 2H), 2.69 (q, J = 7.5 Hz, 2H), (m, 1H), (m, 1H), 1.48 (s, 3H), (m, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 179.9, 141.9, 135.1, 131.8, 128.9, 128.3, 128.2, 126.4, 126.2, 65.3, 45.7, 36.5, 26.6, 23.7, 15.4; MS (ESI) m/z 253 (M+Na) +. (E)-3-(2-Isopropylstyryl)-3-methyldihydrofuran-2(3H)-one (13d). The title compound was prepared from 16d in 53% yield as described for synthesis of 13b and was obtained as a yellowish oil; 1 H NMR (300 MHz, CDCl 3 ) δ 7.37 (d, J = 7.4 Hz, 1H), (m, 2H), (m, 1H), 6.88 (d, J = 16.0 Hz, 1H), 6.05 (d, J = 16.0 Hz, 1H), (m, 2H), (m, 1H), 2.45 (ddd, J = 12.7, 6.7, 4.5 Hz, 1H), 2.27 (dt, J = 12.7, 8.0 Hz, 1H), 1.48 (s, 3H), (m, 6H); MS (ESI) m/z 267 (M+Na) +. (E)-3-(2-Isobutylstyryl)-3-methyldihydrofuran-2(3H)-one (13e). The title compound was prepared from 16e in 57% yield as described for synthesis of 13b and was obtained as a yellowish oil; 1 H NMR (300 MHz, CDCl 3 ) δ (m, 1H), (m, 3H), 6.75 (d, J = 15.7 Hz, 1H), 6.05 (d, J = 15.7 Hz, 1H), (m, 2H), (m, 4H), (m, 1H), 1.45 (s, 3H), 0.88 (d, J = 8.3 Hz, 6H); MS (ESI) m/z 281 (M+Na) +. 3-Methyl-3-(2-phenyl-2-(triethylsilylperoxy)ethyl)dihydrofuran-2(3H)-one (17a). To a solution of 13a (0.21 g, 1.04 mmol) and Co(acac) 2 (0.013 g, 0.05 mmol) in 1,2-dichloroethane (15 ml), stirred under an oxygen atmosphere, was added triethylsilane (0.33 ml, 2.04 mmol), together with a drop of tert-butylhydroperoxide (catalytic, 5.5 M in nonane). The resulting green mixture was stirred at 25 o C until consumption of the starting material (3 h). Thereafter the solvent was evaporated and resulting residue was purified by flash chromatography (1:6 ethyl acetate/n-hexane) to afford 17a (0.26 g, 72% yield) as yellowish oil; 1 H NMR (300 MHz, CDCl 3 ) δ (m, 8H), 5.06 (dd, J = 10.1, 3.8 Hz, 1H), 4.95 (dd, J = 8.1, 4.7 Hz, 1H), (m, 4H), (m, 1H), (m, 2H), (m, 2H), (m, 3H), 1.30 (s, 3H), 1.28 (s, 3H), (m, 18H), (m, 12H); 13 C NMR (75 MHz, CDCl 3 ) δ 178.2, 177.9, 137.6, 124.8, 124.7, 124.6, 124.5, 123.7, 123.6, 81.6, 80.5, 61.7, 61.6, 38.6, 38.2, 38.0, 37.5, 31.1, 19.9, 19.2, 3.1, 3.0; MS (ESI) m/z 373 (M+Na) +. 3-Methyl-3-(2-o-tolyl-2-(triethylsilylperoxy)ethyl)dihydrofuran-2(3H)-one (17b). Starting from 13b, the title compound was prepared in 80% yield following the procedure described for 17a and was obtained as a yellowish oil; 1 H NMR (300 MHz, CDCl 3 ) δ (m, 2H), (m, 6H), 5.39 (dd, J = 10.1, 3.5 Hz, 1H), 5.25 (dd, J = 8.9, 3.6 Hz, 1H), (m, 4H), (m, 2H), 2.37 (s, 6H), (m, 3H), (m, 3H), 1.33 (s, 3H), 1.28 (s, 3H), 0.97 (t, J = 7.9 Hz, 3H), 0.87 (t, J = 7.9 Hz, 15H), (m, 12H); 13 C NMR (75 MHz, CDCl 3 ) δ 181.9, 181.6, 139.8, 139.6, 135.6, 135.2, 130.6, 130.5, 127.8, 127.7, 126.7, 126.6, 126.2, 126.1, 81.8, 80.6, 65.4, 65.3, 42.1, 41.8, 41.7, 41.3, 35.1, 34.7, 24.1, 22.7, 19.4, 19.3, 6.7, 6.0, 3.8, 3.7; MS (ESI) m/z 387 (M+Na) +. 3-(2-(2-Ethylphenyl)-2-(triethylsilylperoxy)ethyl)-3-methyldihydrofuran-2(3H)-one (17c). Starting from 13c, the title compound was prepared in 89% yield following the procedure described for 17a and was obtained as a yellowish oil; 1 H NMR (300 MHz, CDCl 3 ) δ (m, 2H), (m, 6H), 5.45 (dd, J = 10.4, 3.3 Hz, 1H), 5.31 (dd, J = 9.3, 3.2 Hz, 1H), (m, 4H), (m, 4H), (m, 2H), (m, 3H), (m, 1H), (m, 2H), 1.34 (s, 3H), 1.30 (s, 3H), 1.25 (t, J = 5.7 Hz, 6H), 0.86 (dd, J = 11.8, 4.1 Hz, 18H), (m, 12H); 13 C NMR (75 MHz, CDCl 3 ) δ 181.9, 181.6, 141.8, 141.4, 139.3, 139.1, 128.7, 128.6, 128.0, 126.9, 126.8, 126.2, 126.1, 81.1, 79.8, 65.5, 65.3, 42.5, 42.4, 42.2, 41.4, 35.1, 34.8, 25.6, 25.5, 24.3, 22.8, 15.9, 6.7, 3.9, 3.8; MS (ESI) m/z 401 (M+Na) +. 3-(2-(2-Isopropylphenyl)-2-(triethylsilylperoxy)ethyl)-3-methyldihydrofuran-2(3H)-one (17d). Starting from 13d, the title compound was prepared in 68% yield following the procedure described for 17a and was obtained as a yellowish oil; 1 H NMR (300 MHz, CDCl 3 ) δ 7.38 (d, J = 7.5 Hz, 1H), (m, 3H), 5.53 (dd, J = 10.3, 3.4 Hz, 1H), (m, 2H), (m, 1H), (m, 1H), (m, 2H), 1.90 (dd, J = 15.2, 3.5 Hz, 1H), 1.33 (s, 3H), 1.27 (dd, J = 12.2, 5.1 Hz, 6H), 0.97 (t, J = 7.8 Hz, 9H), (m, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ 181.9, 145.9, 138.3, 128.1, 126.9, 125.9, 125.1, 79.5, 65.3, 42.8, 41.4, 35.0, 28.4, 24.4, 23.9, 22.8, S12

13 6.0, 3.8; MS (ESI) m/z 415 (M+Na) +. 3-(2-(2-Isobutylphenyl)-2-(triethylsilylperoxy)ethyl)-3-methyldihydrofuran-2(3H)-one (17e). Starting from 13e, the title compound was prepared in 72% yield following the procedure described for 17a and was obtained as a yellowish oil; 1 H NMR (400 MHz, CDCl 3 ) δ (m, 2H), (m, 4H), 7.00 (d, J = 7.0 Hz, 2H), 5.39 (dd, J = 10.7, 3.0 Hz, 1H), 5.25 (dd, J = 9.6, 3.0 Hz, 1H), (m, 4H), (m, 6H), (m, 3H), (m, 1H), (m, 4H), 1.28 (s, 3H), 1.24 (s, 3H), (m, 12H), 0.78 (t, J = 7.9 Hz, 9H), 0.77 (t, J = 7.9 Hz, 9H), (m, 12H); 13 C NMR (75 MHz, CDCl 3 ) δ 181.9, 181.5, 140.0, 139.7, 139.2, 138.9, 130.5, 130.4, 127.4, 126.9, , 126.9, 126.2, 81.0, 79.6, 65.4, 65.3, 42.6, 42.1, 41.9, 41.4, 35.1, 34.8, 30.2, 30.0, 29.9, 24.4, 22.9, 22.8, 22.7, 22.6, 6.7, 6.6, 3.9, 3.8; MS (ESI) m/z 429 (M+Na) +. (3R*,4aS*,7aR*)-4a-Methyl-3-phenyltetrahydrofuro[2,3-c][1,2]dioxane (6a) and (3S*,4aS*,7aR*)-4a-Methyl-3-phenyltetrahydrofuro[2,3-c][1,2]dioxane (6f). To a solution of 17a (0.26 g, 0.74 mmol) in dry dichloromethane (15 ml), cooled to -78 o C, a 1 M solution of diisobutylaluminium hydride in dichloromethane (0.74 ml, 0.74 mmol) was added dropwise and the resulting reaction mixture was stirred at -78 o C for 1.30 h. After completion of reaction, water was added and the reaction mixture was allowed to warm to 25 o C and stirred for min. The white precipitate was filtered off, and the aqueous phase was extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate and the solvent was removed. The crude residue was purified by flash chromatography (1:4 ethyl acetate/n-hexane) to give the corresponding lactol (0.23 g, 88% yield) as yellowish oil. The above compound (0.23 g, 0.65 mmol) was dissolved in dry dichloromethane (10 ml) and cooled to -78 C. Subsequently, trimethylsilyl trifluoromethanesulfonate (0.24 ml, 1.3 mmol) was added dropwise at -78 o C and the resulting reaction mixture was stirred for 5 min at same temperature. The reaction mixture was quenched with a saturated solution of sodium bicarbonate, and the aqueous phase was extracted with dichloromethane. The organic extracts were dried over sodium sulfate, and solvent was evaporated. The crude product was purified by flash chromatography (1:15 ethyl acetate/n-hexane) to give 6a (55 mg, 38% yield) and 6f (22 mg, 14% yield). 6a: pale yellow low melting solid; 1 H NMR (300 MHz, CDCl 3 ) δ (m, 5H), 5.23 (dd, J = 11.4, 3.8 Hz, 1H), 5.20 (s, 1H), (m, 1H), (m, 1H), 2.42 (dd, J = 21.6, 9.7 Hz, 1H), 2.23 (dd, J = 14.1, 3.8 Hz, 1H), 2.05 (dd, J = 14.1, 11.4 Hz, 1H), 1.66 (ddd, J = 12.0, 7.5, 2.5 Hz, 1H), 1.17 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 138.7, 128.8, 128.7, 126.8, 108.6, 79.6, 69.1, 41.7, 40.1, 32.6, 24.9; MS (ESI) m/z 243 (M+Na) +, 463 (2M+Na) +. Anal. (C 13 H 16 O 3 ) C, H, N. 6f: pale yellow low melting solid; 1 H NMR (300 MHz, CDCl 3 ) δ (m, 5H), (m, 2H), 4.20 (dd, J = 16.2, 8.4 Hz, 1H), (m, 1H), 2.12 (dd, J = 13.8, 10.0 Hz, 1H), (m, 3H), 1.32 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 139.3, 128.7, 128.6, 126.8, 109.6, 78.4, 66.6, 39.0, 38.1, 37.3, 23.6; MS (ESI) m/z 243 (M+Na) +, 463 (2M+Na) +. Anal. (C 13 H 16 O 3 ) C, H, N. (3R*,4aS*,7aR*)-4a-Methyl-3-o-tolyltetrahydrofuro[2,3-c][1,2]dioxane (6b) and (3S*,4aS*,7aR*)-4a-Methyl-3-o-tolyltetrahydrofuro[2,3-c][1,2]dioxane (6g). Starting from 17b, the title compounds were prepared following the procedure described for the synthesis of 6a and 6f. 6b: white solid, 34% yield; Mp (hexane) C; 1 H NMR (300 MHz, CDCl 3 ) δ (m, 1H), (m, 3H), 5.42 (dd, J = 11.2, 3.4 Hz, 1H), 5.22 (s, 1H), (m, 1H), 4.13 (dd, J = 16.9, 8.3 Hz, 1H), (m, 4H), (m, 1H), 2.05 (dd, J = 14.2, 11.2 Hz, 1H), (m, 1H), 1.17 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 136.6, 136.0, 130.7, 128.5, 126.4, 125.8, 108.5, 76.7, 69.1, 41.8, 39.4, 32.6, 24.9, 19.4; MS (ESI) m/z 257 (M+Na) +, 491 (2M+Na) +. Anal. (C 14 H 18 O 3 ) C, H, N. 6g: white low melting solid, 4% yield; 1 H NMR (400 MHz, CDCl 3 ) δ (m, 1H), (m, 3H), 5.27 (dd, J = 10.3, 3.6 Hz, 1H), 5.07 (s, 1H), 4.18 (td, J = 8.8, 7.0 Hz, 1H), 4.00 (td, J = 8.1, 3.4 Hz, 1H), 2.32 (s, 3H), 2.02 (dd, J = 13.8, 10.4 Hz, 1H), (m, 2H), 1.75 (dd, J = 13.8, 3.6 Hz, 1H), 1.27 (s, 3H); MS (ESI) m/z 257 (M+Na) +, 491 (2M+Na) +. Anal. (C 14 H 18 O 3 ) C, H, N. (3R*,4aS*,7aR*)-4a-Methyl-3-(2-ethylphenyl)tetrahydrofuro[2,3-c][1,2]dioxane (6c) and (3S*,4aS*,7aR*)-4a-Methyl-3-(2-ethylphenyl)tetrahydrofuro[2,3-c][1,2]dioxane (6h). Starting from 17c, the title compounds were prepared following the procedure described for the synthesis of 6a and 6f. 6c: white low melting solid, 53% yield; 1 H NMR (300 MHz, CDCl 3 ) δ 7.37 (d, J = 7.1 Hz, 1H), (m, 3H), 5.49 (dd, J = 9.5, 5.2 Hz, 1H), 5.24 (s, 1H), (m, 1H), 4.14 (dd, S13