Approach to Merosesquiterpenes via Lewis Acid-Catalyzed Nazarov Type Cyclization: Total Synthesis of Akaol A

Supporting Information Approach to Merosesquiterpenes via Lewis Acid-Catalyzed Nazarov Type Cyclization: Total Synthesis of Akaol A Badrinath N. Kakde, Nivesh Kumar, Pradip kumar Mondal, and Alakesh Bisai* Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal Bypass Road, Bhopal, Madhya Pradesh - 462 066, India. E-mail: alakesh@iiserb.ac.in Table of Contents Materials and methods Synthesis of carbaldehyde 11 Synthesis of arylvinyl carbinols 6a-k from carbaldehyde 11 General procedure for metal triflate catalyzed cyclization Hydrogenation of carbotetracycle S2 S3-S6 S6-S25 S25-S35 S35-S36 Total synthesis of 9-epi-pelorol (epi-1c) S36-S3 9 Total synthesis of akaol A (1a) Comparison of 1 H, and 13 C NMR of akaol A (1a) with Literature Copies of 1 H, 13 C NMR and Scanned mass spectra S40-S44 S44-S46 S47-S141 S1

Materials and Methods Unless otherwise stated, reactions were performed in oven-dried glassware fitted with rubber septa under a nitrogen atmosphere and were stirred with Teflon-coated magnetic stirring bars. Liquid reagents and solvents were transferred via syringe using standard Schlenk techniques. Tetrahydrofuran (THF), diethyl ether (Et 2 O) was distilled over sodium/benzophenone ketyl. Dichloromethane (CH 2 Cl 2 ) and toluene were distilled over calcium hydride. All other solvents such as DMF, chloroform, dioxane, DMSO, DCE, acetonitrile, CCl 4, methanol and reagents such as (3aR)-(+)-sclareolide, ortho-vanillin, paravanillin, 2,5-dimethoxybenzaldehyde, 1,2,4-trimethoxy benzene, bromine, sodium dithionite, ceric(iv) ammonium nitrate, dimethyl sulphate, potassium carbonate, n-butyllithium, trifluroacetic acid, trifluromethanesulphonic acid, BF 3.OEt 2, different types of metal triflate etc. were used as received, unless otherwise noted. Thin layer chromatography was performed using Merck silicagel 60 F-254 precoated plates (0.25 mm) and visualized by UV irradiation, anisaldehyde, yellow dip stain and other stains. Silicagel from Merck (particle size 100-200 and 230-400 mesh) were used for flash chromatography. Melting points were recorded on a digital melting point apparatus from Jyoti Scientific (AN ISO 9001:2000) and are uncorrected. 1 H and 13 C NMR spectra were recorded on Bruker 400, 500 MHz spectrometers with 13 C operating frequencies of 100, 125 MHz, respectively. Chemical shifts (δ) are reported in ppm relative to the residual solvent signal (δ = 7.26 for 1 H NMR and δ = 77.0 for 13 C NMR). Data for 1 H NMR spectra are reported as follows: chemical shift (multiplicity, coupling constants and number of hydrogens). Abbreviations are as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad). IR spectra were recorded on a FT-IR system (Spectrum BX) from PerkinElmer spectrometer and are reported in frequency of absorption (cm -1 ). Only selected IR absorbencies are reported. High resolution mass spectra were obtained from the Central Instrumentation Facility (CIF) at the Indian Institute of Science Education and Research (IISER) Bhopal. S2

Experimental Procedure: 1-((1R,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyldecahydronaphthalen-1-yl)propan-2- one (9a): A flame-dried round-bottom flask was charged with compound 9 (3.0 g, 11.98 mmol, 1.0 equiv) under nitrogen atmosphere in anhydrous Diethyl ether (90 ml) was added 3M solution of MeLi in Et 2 O (7.98 ml, 23.96 mmol) in portions via syringe for 10 min at room temprature and stirring was continued for 5 min. The reaction mixture was quenched with saturated aq. Solution of NH 4 Cl and then transferred to the funnel and shaken vigorously. The etheral layer was seperated and the aqueous layer was extracted with Et 2 O (40 ml). The combined Et 2 O extracts were dried over anhydrous Na 2 SO 4 and concentrated by rotatory evaporator under vaccum followed by column chromatography with EtOAc/hexane (2:8) to afford 2.48 g of pure compound 9a in 78% yield as colorless solid, R f = 0.45 (30% EtOAc in hexane); 1 H NMR (400 MHz, DMSO-D 6 ) δ: 4.00 (s, 1H), 3.36 (brs, 1H (OH)), 2.49 (dd, J = 16.9, 4.4 Hz, 1H), 2.29 (dd, J = 16.5, 5.9 Hz, 1H), 2.11 (s, 3H), 1.86 (t, J = 9.26, 1H), 1.73 (dt, J = 12.4, 2.9 Hz, 1H), 1.57-1.42 (m, 3H), 1.36-1.22 (m, 4H), 1.19-1.05 (m, 1H), 1.01 (s, 3H), 0.94(dd, J = 12.03, 1.58, 1H), 0.87 (s, 3H), 0.78 (s, 3H), 0.75 (s, 3H); 13 C NMR (100 MHz, DMSO-D 6 ) δ: 213.5, 76.3, 60.7, 60.5, 48.8, 46.7, 44.6, 44.2, 43.0, 38.4, 38.0, 34.9, 29.1, 26.5, 25.2, 23.2, 20.3; IR (film) υ max 3420, 2960, 1704, 1661, 1384, 1364, 1168, 1163, 1045, 1026, 1002, 940, 826, 764 cm -1 ; HRMS (ESI) m/z 289.2164 [(M + Na)] + ; calculated for [C 17 H 3 O 2 + Na] + : 289.2138; MP 89-90 ºC. ((1S,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyldecahydronaphthalen-1-yl)methyl acetate (9b): To a stirred, cooled (ice bath) solution of (CF 3 CO) 2 O (12.3 ml, 88.6 mmol) in CH 2 Cl 2 (80 ml) was added 30% aq. H 2 O 2 (3.8 ml, 43.1 mmol) and the mixture was allowed S3

to stand in an ice bath for 10 min. All subsequent operation was performed at room temperature. The solution was treated with solid NaHCO 3 (7.5 g. 89.8 mmol) for 2 min and after stirring mixture for 8 min. The solution of compound 9a (2.48 gm, 9.34 mmol, 1.0 equiv) in CH 2 Cl 2 (110 ml) was added. The resulting mixture was stirred for 30 min and then, after addition of H 2 O (10 ml) was treated with the solid NaHCO 3 in portions for 45 min until ph reached 7. Finally, reaction mixture was extracted with CH 2 Cl 2 (60 ml X 2), the combined organic extracts were dried over anhydrous Na 2 SO 4, filtered and concentrated using rotator evaporator followed by column chromatography with EtOAc/hexane (2:8) to give 2.0 g of pure compound 9b in 76% yield as colorless solid, R f = 0.55 (30% EtOAc in hexane); 1 H NMR (400 MHz, CDCl 3 ) δ: 4.33 (dd, J = 11.80,. 4.4 Hz, 1H), 4.21 (dd, J = 11.71, 5.5 Hz, 1H), 2.28 (brs, 1H (OH)), 2.02 (s, 3H), 1.86 (dt, J = 12.7, 3.3 Hz, 1H), 1.65-1.62 (m, 2H), 1.57 (dt, J = 13.7, 3.4 Hz, 1H), 1.49 (t, J = 4.9 Hz, 1H), 1.46-1.39 (m, 3H), 1.29-1.22 (m, 1H), 1.15 (s, 3H), 1.10-0.98 (m, 1H), 0.93 (dd, J = 12.2, 2.0, Hz, 1H), 0.85 (s, 3H), 0.83 (s, 3H), 0.78 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 171.3, 72.6, 62.5, 59.9, 55.7, 43.9, 41.7, 39.7, 38.1, 33.4, 33.2, 24.6, 21.5, 21.3, 20.3, 18.4, 15.8; IR (film) υ max 3444, 2924, 1738, 1448, 1462, 1385, 1368, 1243, 1128, 1067, 1029, 965, 940, 702cm -1 ; HRMS (ESI) m/z 305.2106 [(M + Na)] + ; calculated for [C 17 H 30 O 3 + Na] + : 305.2087; MP 108 110 ºC. (1S,2R,4aS,8aS)-1-(hydroxymethyl)-2,5,5,8a-tetramethyldecahydronaphthalen-2-ol (9c): Compound 9b (2.0 g, 7.1 mmol, 1.0 equiv) was dissolved in 10% solution of KOH in MeOH. (39 ml, 70.9 mmol) and resulting mixture was allowed to stand at room temperature for 10 min. after addition of H 2 O (10mL), the solution was extracted with Et 2 O (50 ml X 2). The extract was washed with the H 2 O (10 ml), dried over anhydrous Na 2 SO 4, filtered and concentrated using rotator evaporator under vaccum. The crude products were purified by flash chromatography (7:3 hexanes/etoac) to afford 1.56 g of compound 9c in 92% yield as colorless solid, R f = 0.5 (40% EtOAc in hexane); 1 H NMR (400 MHz, CDCl 3 ) δ: 3.90 (d, J = 6.3 Hz, 2H), 2.87 (s, 2H), 1.86 (dt, J = 12.4, 3.1 Hz, 1H), 1.74-1.57(m, 2H), 1.55-1.50 (m, 2H), 1.47-1.38 (m, 2H), 1.33 (s, 3H), 1.29-1.04 (m, 3H), 0.95 (dd, J = 12.1, 1.7 Hz, 1H), 0.86 S4

(s, 3H), 0.77 (s, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ: 74.9, 60.9, 60.2, 55.9, 44.1, 41.7, 40.0, 37.5, 33.5, 33.3, 24.2, 21.6., 20.1, 18.6., 16.0; IR (film) υ max 3321, 2893, 2842, 1446, 1382, 1365, 1284, 1235, 1162, 1126, 1049, 1022, 992, 934, 932 cm -1 ; HRMS (ESI) m/z 263.1997 [(M + Na)] + ; calculated for [C 15 H 28 O 2 + Na] + : 263.1982; MP 152-154 ºC. (1R,2R,4aS,8aS)-2-Hydroxy-2,5,5,8a-tetramethyldecahydronaphthalene-1-carbaldehyde (10): A long neck flame-dried round-bottom flask was charged with dry DMSO (1.46 ml, 18.72 mmol) under nitrogen atmosphere in dry CH 2 Cl 2 (25 ml) was added oxalyl chloride (0.71 ml, 8.32 mmol) diluted in dry CH 2 Cl 2 (5 ml) dropwise at 78 C and then after 20 min stirring compound 9c (1.0 g, 4.16 mmol, 1.0 equiv.) in dry CH 2 Cl 2 (10 ml) was added dropwise over period of 10 min. Mixture was kept on stirring for 45 min. at -78 C added Et 3 N (2.8 ml, 20.8 mmol). Reaction mixture was allowed to warm at room temperature followed by addition of H 2 O (20 ml) and organic layer was extracted using separating funnel. The extract was washed with the H 2 O (10 ml), dried over anhydrous Na 2 SO 4, filtered and concentrated using rotator evaporator under vaccum. The crude product was purified by flash chromatography (8:2 hexane/etoac) to afford 930 mg compound 10 in 94% yield as colorless solid, R f = 0.45 (20% EtOAc in hexane); 1 H NMR (400 MHz, CDCl 3 ) δ: 10.00 (d, J = 1.2 Hz, 1H), 3.19 (brs, 1H (OH)), 2.06 (s, 1H), 1.95-1.91 (m, 1H), 1.80 (dt, J =12.5, 3.1 Hz, 1H), 1.72-1.60 (m, 2H), 1.52-1.46 (m, 2H), 1.44-1.40 (m, 1H), 1.36 (s, 3H), 1.32-1.28 (m, 1H), 1.23-1.15 (m, 2H), 1.10 (s, 3H), 0.94 (dd, J = 12.1, 2.1 Hz, 1H), 0.87 (s, 3H), 0.81 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 208.2, 72.8, 71.3, 55.1, 42.7, 41.6, 39.8, 37.4, 33.3, 33.2, 25.2, 21.3, 19.8, 18.1, 17.5; IR (film) υ max 3432, 2931, 1702, 1698, 1445, 1372, 1266, 1200, 1061, 1007, 937, 746 cm -1 ; MP 120-123 ºC. S5

(4aS,8aS)-2,5,5,8a-tetramethyl-3,4,4a,5,6,7,8,8a-octahydronaphthalene-1-carbaldehyde (11): In a clean and dry round-bottom flask was charged with compound 10 (900 mg, 3.78 mmol, 1.0 equiv) in CH 2 Cl 2 (25 ml) was added BF. 3 Et 2 O (0.523 ml, 4.1 mmol) dropwise over period of 10 min. Mixture was kept on stirring for 3 h at room temrature. Reaction mixture was treated with saturated aq. solution of NaHCO 3 for 15 min. transfered to funnel and shaken vigorously. Organic layer was extracted with CH 2 Cl 2 (20 ml X 2). The combined CH 2 Cl 2 extracts were dried over anhydrous Na 2 SO 4, filtered and concentrated using rotator evaporator under vaccum. The crude products were purified by flash chromatography (9:1 hexanes/etoac) to afford 698 mg of pure compound 11 in 84% yield as colorless gel, R f = 0.6 (10% EtOAc in hexane); 1 H NMR (400 MHz, CDCl 3 ) δ: 10.01 (s, 1H), 2.54 (m, 1H), 2.26-2.22 (m, 2H), 2.10-2.06 (m, 1H), 2.00 (s, 3H), 1.64-1.55 (m, 2H), 1.42-1.37 (m, 3H), 1.16 (s, 3H), 1.14-1.10 (m, 2H), 0.87 (s, 3H), 0.83 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 192.7, 153.8, 143.7, 51.6, 41.6, 36.6, 36.2, 33.4, 33.3, 33.2, 21.6, 20.1, 19.2, 18.9, 18.3; IR (film) υ max 2908, 2845, 1698, 1447, 1375, 1263, 1202, 1062, 1006, 744 cm -1 ; HRMS (ESI) m/z 221.1885 [(M + H)] + ; calculated for [C 15 H 24 O + H] + : 221.1900. General procedure for synthesis of arylvinylcarbinols 6a-b from carbaldehyde 11: Step 1: A flame-dried round-bottom flask was charged with compound 23a or 24a (1.0 equiv) under nitrogen atmosphere in dry THF (10 ml per 1.0 mmol) was added 1.6 M solution of n-buli in Hexane (1.1 equiv) in portions via syringe at 0 C and at the same S6

temperature TMEDA (1.22 equiv) was added dropwise via syringe. The reaction mixture was allowed to stand for continuous stirring for 30 min after that acetone (1.92 equiv) was added and reaction mixture was allowed to stand on stirring for additional 4 h. The mixture was treated with saturated aq. solution of NH 4 Cl solution. Organic layer was extracted with EtOAc and transferred to the separatory funnel and shaken vigorously. The organic layer was separated and dried over anhydrous Na 2 SO 4 and concentrated by rotatory evaporator under vacuum. The crude product was purified by column chromatography (2:8, hexane/etoac) to afford compound 23b or 24b. Step 2: Clean and dry round-bottom flask was charged with Compound 23b or 24b (1.0 equiv) dissolved in CH 2 Cl 2 was added Sn(OTf) 2 (0.001 equiv) at room temperature and kept on stirring for 10 min. The reaction mixture was allowed to stand on heating with reflux for 3 h. The mixture was treated with saturated aq. solution of NaHCO 3 and CH 2 Cl 2 for 5 min. It was transferred to the separatory funnel and shaken vigorously. The organic layer was extracted with CH 2 Cl 2 and dried over anhydrous Na 2 SO 4, concentrated using rotator evaporator under vacuum. The crude products were purified by flash chromatography (9:1 hexanes/etoac) to afford compound 23c or 24c. Step 3: A flame-dried round-bottom flask was charged with compound 23c or 24c (1.0 equiv) under nitrogen atmosphere in MeOH (20 ml) was added Palladium on activated charcoal (0.1 equiv) and then after 20 min of purging under by using nitrogen was replaced with hydrogen gas balloon for the period of 30 min. Reaction mixture was filtered through celite filtere and concentrated using rotator evaporator under vacuum. The crude products were purified by flash chromatography (9:1 hexanes/etoac) to afford compound 23d or 24d. Step 4: In a clean and dry round-bottom flask was charged with compound 23d or 24d (1.0 equiv) under nitrogen atmosphere in CH 2 Cl 2 was added N-bromosuccinamide (1.2 equiv). The reaction mixture was allowed to stand on continuous stirring for 10 min - 1 h at room temperature. Reaction mixture was treated with saturated aq. solution of sodium thiosulphate for 5 min. It was transferred to separatory funnel and shaken vigorously. Organic layer was extracted with CH 2 Cl 2. The combined CH 2 Cl 2 extracts were dried over anhydrous Na 2 SO 4, filtered and concentrated using rotator evaporator under vacuum. The crude products were purified by flash chromatography (9:1 hexanes/etoac) to afford compound 23e or 24e. S7

Step 5: A flame-dried round-bottom flask was charged with bromoarenes 23e or 24e [1.2 equiv.] under nitrogen atmosphere in dry THF (7 ml for per mmol) and cooled to -78 ºC. The n-butyl lithium solution [1.3 equiv. (1.6 M in cyclohexane)] was added drop wise to the reaction mixture by a syringe and allowed to stirred for 10 min followed by dropwise addition of compound 11 [1.0 equiv.(generally 300 mg)]. The stirring was continued till TLC showed complete consumption of starting materials. The reaction mixture was quenched by saturated NH 4 Cl solution and then diluted with 20 ml of EtOAc. The whole reaction mixture was taken in a separatory funnel and extracted with 20 ml of water. The organic filtrate was separated and the aqueous part was again washed with 10 ml EtOAc, the combined organic filtrate dried over anhydrous Na 2 SO 4 and concentrated in a rotary evaporator under vacuum. The crude products were purified by flash chromatography (8:2 hexanes/etoac) to afford 6a or 6b. MeO HO Me OMe Me OMe (23b) 2-(2,3,6-Trimethoxyphenyl)propan-2-ol (23b): 62% yield as colorless gel (8.3 g, 59.5 mmol), R f = 0.5 (20% EtOAc in hexane); 1 H NMR (400 MHz, CDCl 3 ) δ: 6.79 (d, J = 9.0 Hz, 1H), 6.61 (d, J = 9.0 Hz, 1H), 5.88 (brs, 1H, (OH)), 3.83 (s, 3H), 3.80 (s, 6H), 1.64 (s, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ: 151.5, 148.1, 147.4, 130.0, 110.6, 107.3, 74.2, 61.3, 56.24, 56.20, 31.2; IR (film) υ max 3499, 2966, 2839, 1712, 1587, 1454, 1388, 1254, 1083, 956, 801 cm -1 ; HRMS (ESI) m/z 249.1120 [(M + Na)] + ; calculated for [C 12 H 18 O 4 + Na] + : 249.1097. 1,2,4-Trimethoxy-3-(prop-1-en-2-yl)benzene (23c): 71% yield as colorless gel (5.27 g, 35.4 mmol), R f = 0.6 (10% EtOAc in hexane); 1 H NMR (400 MHz, CDCl 3 ) δ: 6.75 (d, J = 9.0 Hz, 1H), 6.56 (d, J = 8. Hz, 1H), 5.30 (t, J = 1.5 Hz, 1H), 4.88 (d, J = 1.0 Hz, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 3.75 (s, 3H), 2.03 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 151.1, 147.3, 147.0, 139.2, 128.0, 115.7, 110.1, 105.9, 61.3, 56.3, 56.27, 23.8; IR (film) υ max 3081, 2940, 2835, S8

1483, 1420, 1254, 1097, 1065, 795 cm -1 ; HRMS (ESI) m/z 231.1014 [(M + Na)] + ; calculated for [C 12 H 16 O 3 + Na] + : 231.0992. 2-Isopropyl-1,3,4-trimethoxybenzene (23d): 98% yield as colorless solid (7.96 g, 38.5 mmol), R f = 0.4 (5% EtOAc in hexane); 1 H NMR (400 MHz, CDCl 3 ) δ: 6.67 (d, J = 8.9 Hz, 1H), 6.54 (d, J = 8.9 Hz, 1H), 3.79 (s, 3H), 3.78 (s, 3H), 3.74 (s, 3H), 3.52 (heptate, J = 7.1 Hz, 1H), 1.29 (d, J = 7.1 Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ: 152.9, 147.9, 147.4, 130.9, 109.5, 106.3, 61.0, 56.1, 55.1, 25.2, 21.2; IR (film) υ max 2958, 2923, 2852, 1598, 1419, 1256, 1121, 1079 cm -1 ; HRMS (ESI) m/z 233.1161 [(M + Na)] + ; calculated for [C 12 H 18 O 3 + Na] + : 233.1148. 1-Bromo-3-isopropyl-2,4,5-trimethoxybenzene (23e): 99% yield as colorless liquid (9.53 g, 33.3 mmol), R f = 0.6 (5% EtOAc in hexane); 1 H NMR (400 MHz, CDCl 3 ) δ: 6.91 (s, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.75 (s, 3H), 3.43 (heptate, J = 7.1 Hz, 1H), 1.31 (d, J = 7.1 Hz, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ: 150.1, 149.0, 148.0, 136.7, 114.1, 110.8, 61.6, 60.8, 56.0, 26.7, 21.7; IR (film) υ max 2959, 2840, 1586, 1566, 1470, 1425, 1254, 1229, 1120, 1043, 830, 765 cm -1 ; HRMS (ESI) m/z 311.0273 [(M + Na)] + ; calculated for [C 12 H 17 BrO 3 + Na] + : 311.0253. 2-(5-Methoxybenzo[d][1,3]dioxol-4-yl)propan-2-ol (24b): 78% yield as colorless liquid (5.38 g, 32.9 mmol), R f = 0.7 (10% EtOAc in hexane); 1 H NMR (400 MHz, CDCl 3 ) δ: 6.61 (d, J = 8.6 Hz, 1H), 6.33 (d, J = 8.6 Hz, 1H), 5.85 (s, 2H), 4.82 (brs, 1H), 3.83 (s, 3H), 1.62 S9

(s, 6H); 13 C NMR (100 MHz, CDCl 3 ) δ: 152.6, 144.3, 142.3, 119.7, 105.7, 103.7, 100.5, 72.7, 56.4, 30.3; IR (film) υ max 3487, 3088, 2940, 1405, 1230, 1190, 1046, 975, 910, 853 cm - 1 ; HRMS (ESI) m/z 233.0814 [(M + Na)] + ; calculated for [C 11 H 14 O 4 + Na] + : 233.0784. 5-Methoxy-4-(prop-1-en-2-yl)benzo[d][1,3]dioxole (24c): 81% yield as colorless gel (5.7 g, 23.8 mmol), R f = 0.5 (5% EtOAc in hexane); 1 H NMR (400 MHz, CDCl 3 ) δ: 6.62 (d, J = 8.5 Hz, 1H), 6.29 (d, J = 8.5 Hz, 1H), 5.90 (s, 2H), 5.33-5.32 (m, 1H), 5.10-5.09 (m, 1H), 3.75 (s, 3H), 2.1 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 152.4, 145.3, 141.5, 137.3, 117.3, 116.1, 105.9, 102.8, 101.0, 56.5, 22.9; IR (film) υ max 3087, 2925, 1454, 1242, 1135, 1085, 788 cm -1. 4-Isopropyl-5-methoxybenzo[d][1,3]dioxole (24d): 99% yield as colorless solid (5.5 g, 28.6 mmol), R f = 0.6 (5% EtOAc in hexane); 1 H NMR (400 MHz, CDCl 3 ) δ: 6.56 (d, J = 8.5 Hz, 1H), 6.26 (d, J = 8.4 Hz, 1H), 5.87 (s, 2H), 3.73 (s, 3H), 3.39-3.28 (m, 1H), 1.27 (s, 3H), 1.25 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 152.7, 146.0, 141.7, 120.3, 104.6, 102.9, 100.6, 56.5, 24.8, 21.0; IR (film) υ max 2968, 2928, 1458, 1364, 1167, 1012, 955, 790, 760 cm -1. 6-Bromo-4-isopropyl-5-methoxybenzo[d][1,3]dioxole (24e): 99% yield as colorless liquid (6.96 g, 25.7 mmol), R f = 0.6 (5% EtOAc in hexane); 1 H NMR (400 MHz, CDCl 3 ) δ: 6.83 (s, 1H), 5.92 (s, 2H), 3.73 (s, 3H), 3.33-3.26 (m, 1H), 1.29 (s, 3H), 1.27 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 149.1, 145.7, 144.5, 126.1, 109.8, 107.7, 101.4, 61.7, 26.1, 21.1; IR (film) υ max 2965, 1454, 1404, 1120, 1046, 987 cm -1 ; HRMS (ESI) m/z 294.9959 [(M + Na)] + ; calculated for [C 11 H 13 BrO 3 + Na] + : 294.9940. S10

(3-isopropyl-2,4,5-trimethoxyphenyl)((4aS,8aS)-2,5,5,8a-tetramethyl-3,4,4a,5,6,7,8,8aoctahydronaphthalen-1-yl)methanol (6a): 84% yield as colorless gel (490 mg), R f = 0.5 (10% EtOAc in hexane); 1 H NMR (400 MHz, DMSO-D 6 ) δ: 6.83 (s, 1H), 5.54 (d, J = 4.5 Hz, 1H), 4.70 (d, J = 4.6 Hz, 1H), 3.71 (s, 3H), 3.65 (s, 3H), 3.60 (s, 3H), 3.38 (brs, (H 2 O)), 3.28-3.21 (m, 1H), 2.47 (m, DMSO), 2.02 (m, 2H), 1.62-1.53 (m, 2H), 1.49 (s, 3H), 1.43-1.40 (m, 2H), 1.38-1.36 (m, 2H), 1.32 (m, 1H), 1.24 (s, 3H), 1.22 (s, 3H), 1.12-1.08 (m, 2H), 0.85 (d, J = 3.3 Hz, 6H), 0.77 (s, 3H); 13 C NMR (100 MHz, DMSO-D 6 ) δ: 149.6, 148.6, 147.7, 141.5, 134.0, 133.2, 130.4, 111.4, 66.3, 62.3, 60.6, 56.0, 52.1, 41.8, 39.3, 37.3, 35.1, 33.8, 33.6, 25.8, 22.33, 22.32, 22.26, 22.0, 21.0, 19.21, 19.20; IR (film) υ max 3500, 2922, 1589, 1450, 1340, 1223, 1118, 1041, 855, 744 cm -1 ; HRMS (ESI) m/z 453.2975 [(M + Na)] + ; calculated for [C 27 H 42 O 4 + Na] + 20.6 ºC : 453.2975, [α] 589 = 16.802 (c = 0.333, CH 2 Cl 2 ). (7-isopropyl-6-methoxybenzo[d][1,3]dioxol-5-yl)((4aS,8aS)-2,5,5,8a-tetramethyl- 3,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)methanol (6b): 91% yield as colorless gel (510 mg), R f = 0.5 (10% EtOAc in hexane); 1 H NMR (400 MHz, DMSO-D 6 ) δ: 6.65 (s, 1H), 5.89 (d, J = 7.0 Hz, 2H), 5.53 (s, 1H), 4.68 (s, 1H), 3.60 (s, 3H), 3.16-3.13 (m, 1H), 2.01-1.99 (m, 2H), 1.50 (s, 3H), 1.34 (m, 2H), 1.24 (s, 3H), 1.22 (s, 3H), 1.10 (m, 4H), 0.85 (s, 3H), 0.84 (brs, 3H), 0.81 (s, 2H), 0.77 (s, 3H); 13 C NMR (100 MHz, DMSO-D 6 ) δ: 154.9, 149.6, 148.0, 146.4, 136.2, 134.9, 129.0, 110.9, 105.9, 71.0, 67.4, 56.8, 50.9, 46.5, 44.0, 42.1, 39.8, 38.6, 38.3, 29.9, 27.0, 26.8, 26.4, 25.8, 23.9, 16.9; IR (film) υ max 3495, 2919, 1450, 1342, 1322, 1261, 1221, 1108, 1041, 1007, 852, 746 cm -1 ; HRMS (ESI) m/z 437.2668 [(M + Na)] + ; calculated for [C 26 H 38 O 4 + Na] + 21.7 ºC : 437.2662, [α] 589 = 3.00 (c = 0.600, CH 2 Cl 2 ) Procedure for synthesis of arylvinylcarbinol 6c from carbaldehyde 11: S11

Step 1: A oven-dried round-bottom flask was charged with compound 25a (1.265 g, 7.49 mmol, 1.0 equiv.) in MeOH (20 ml) was added NaBH 4 (342 mg, 9.0 mmol ) in portions at 0 C. The reaction mixture was allowed to stand for continuous stirring for 30 min. The mixture was treated with saturated aq. solution of NH 4 Cl solution. Organic layer was extracted with CH 2 Cl 2 (30 ml X 2) and transferred to the separatory funnel and shaken vigorously. The organic layer was separated and dried over anhydrous Na 2 SO 4 and concentrated by rotatory evaporator under vacuum. The crude product was purified by column chromatography (7:3, hexane/ EtOAc) to afford compound benzyl alcohol. Step 2: Clean and dry round-bottom flask was charged with benzyl alcohol (1269 mg, 7.48 mmol, 1.0 equiv.) under nitrogen atmosphere dissolved in diethylether (25 ml) was added phosphorous tribromide ( 284 µl, 2.99 mmol) at 0 C and kept on stirring for 10 min. The mixture was treated with saturated aq. Solution of NaHCO 3. It was transferred to the separatory funnel and shaken vigorously. The organic layer was extracted with EtOAc (20 ml X 2) and dried over anhydrous Na 2 SO 4, concentrated using rotator evaporator under vacuum. Step 3: A flame-dried round-bottom flask was charged with crude benzyl bromide (1260 mg, 5.18 mmol, 1.0 equiv.) in THF (25 ml) was added LiAlH 4 (236 mg, 6.22 mmol) at room temperature for 20 min. The mixture was treated with 2.0M aq. solution of NaOH and compound was extracted by using EtOAc and dried over anhydrous Na 2 SO 4, concentrated using rotator evaporator under vacuum. The crude products were purified by flash chromatography (15:1 hexanes/etoac) to afford compound arene. Step 4: In a clean and dry round-bottom flask was charged with arene (650 mg, 4.28 mmol) under nitrogen atmosphere in CH 2 Cl 2 (10 ml) was added N-bromosuccinamide (798 mg, 4.48 mmol). The reaction mixture was allowed to stand on continuous stirring for 12 h at room temperature. Reaction mixture was treated with saturated aq. Solution of sodium S12

thiosulphate for 5 min. It was transferred to separatory funnel and shaken vigorously. Organic layer was extracted with CH 2 Cl 2 (20mL X 2). The combined CH 2 Cl 2 extracts were dried over anhydrous Na 2 SO 4, filtered and concentrated using rotator evaporator under vacuum. The crude products were purified by flash chromatography (9:1 hexanes/etoac) to afford compound 25b in 59% yield over 4 steps. Step 5: Same as discussed for the synthesis of 6a-b step 5. 1-Bromo-2,5-dimethoxy-4-methylbenzene (250b): 59% yield (over 4 steps) as colorless liquid, R f = 0.55 (5% EtOAc in hexane); 1 H NMR (400 MHz, CDCl 3 ) δ: 6.97 (s, 1H), 6.72 (s, 1H), 3.82 (s, 3H), 3.76 (s, 3H), 2.16 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 152.2, 149.7, 126.8, 115.4, 115.2, 108.0, 56.96, 56.08, 16.30; IR (film) υ max 3021, 2839, 1474, 1369, 1263, 1215, 1081, 1048, 862, 783, 744cm -1 ; HRMS (ESI) m/z 228.9869 [(M - H)] + ; calculated for [C 9 H 11 BrO 2 - H] + : 228.9859. (2,5-dimethoxy-4-methylphenyl)((4aS,8aS)-2,5,5,8a-tetramethyl-3,4,4a,5,6,7,8,8aoctahydronaphthalen-1-yl)methanol (6c): 75% yield as colorless solid (380 mg), R f = 0.6 (10% EtOAc in hexane); 1 H NMR (400 MHz, DMSO-D 6 ) δ: 6.91 (s, 1H), 6.71 (s, 1H), 5.43 (d, J = 4.5 Hz, 1H), 4.53 (d, J = 4.7 Hz, 1H), 3.64 (s, 3H), 3.62 (s, 3H), 3.36 (s, (H 2 O)), 2.47 (m, DMSO), 2.90 (s, 3H), 1.97-1.95 (m, 3H), 1.61-1.48 (m, 3H), 1.43-1.40 (m, 2H), 1.35 (s, 3H), 1.33 (s, 1H), 1.11-1.07 (m, 2H), 0.93 (s, 3H), 0.85 (s, 3H), 0.80 (s, 3H); 13 C NMR (100 MHz, DMSO-D 6 ) δ: 151.0, 150.8, 141.0, 132.1, 130.1, 124.6, 114.5, 111.7, 66.3, 56.2, 56.0, 52.2, 41.8, 39.4, 37.1, 35.1, 33.8, 33.5, 22.1, 22.0, 20.8, 19.2, 19.1, 16.2; IR (film) υ max 3542, 2913, 1462, 1450, 1387, 1368, 1207, 1046, 960, 857, 746 cm -1 ; HRMS (ESI) m/z 395.2570 [(M + Na)] + ; calculated for [C 24 H 36 O 3 + Na] + 18.7 ºC : 395.2557, [α] 589 = 31.00 (c = 0.20, CH 2 Cl 2 ). S13

Procedure for synthesis of arylvinylcarbinol 6d from carbaldehyde 11: Step- 1: In a clean and dry round-bottom flask was charged with 1,2,4-trimethoxy benzene (5 g, 33.5 mmol, 1.0 equiv.) in CH 2 Cl 2 (60 ml) was added N-bromosuccinamide (6.3 g, 35.14 mmol). The reaction mixture was allowed to stand on continuous stirring for 1 h at room temperature. Reaction mixture was treated with saturated aq. solution of sodium thiosulphate for 5 min. It was transferred to separatory funnel and shaken vigorously. Organic layer was extracted with CH 2 Cl 2 (30 ml X 2). The combined CH 2 Cl 2 extracts were dried over anhydrous Na 2 SO 4, filtered and concentrated using rotator evaporator under vacuum. The crude products were purified by flash chromatography (9:1 hexanes/etoac) to afford 8.2 g of compound 26 in 99% yields. Step 2: Same as discussed for the synthesis of 6a-b (step 5). 1-bromo-2,4,5-trimethoxybenzene (26): 99% yield as colorless solid, R f = 0.6 (20% EtOAc in hexane); 1 H NMR (400 MHz, CDCl 3 ) δ: 7.01 (s, 1H), 6.54 (s, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 3.81 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 150.3, 149.1, 143.8, 116.5, 101.1, 98.9, 57.2, 56.6, 56.3; IR (film) υ max 2927, 2874, 2360, 1456, 1363, 1238, 1149, 1038, 976, 850, 735 cm -1 ; HRMS (ESI) m/z 268.9794 [(M + Na)] + ; calculated for [C 9 H 11 BrO 3 + Na] + : 268.9784. S14

((4aS,8aS)-2,5,5,8a-tetramethyl-3,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)(2,4,5- trimethoxyphenyl)methanol (9d): 68% yield as colorless solid (359 mg), R f = 0.5 (30% EtOAc in hexane); 1 H NMR (400 MHz, DMSO-D 6 ) δ: 6.90 (s, 1H), 6.6 (s, 1H), 5.42 (d, J = 4.6Hz, 1H), 4.48 (d, J = 4.7 Hz, 1H), 3.73 (s, 3H), 3.69 (s, 3H), 3.6 (s, 3H) 3.33 (s, (H 2 O)), 2.46 (DMSO), 1.98-1.94 (m, 3H), 1.61-1.45 (m, 3H), 1.41-1.39 (m, 2H), 1.37 (s, 3H), 1.34-1.31 (m, 2H), 1.10-1.07 (m, 1H), 0.91 (s, 3H), 0.85 (s, 3H), 0.79 (s, 3H); 13 C NMR (100 MHz, DMSO-D 6 ) δ: 151.5, 148.6, 142.2, 141.2, 130.0, 125.5, 114.2, 98.8, 65.8, 56.8, 56.5, 56.2, 52.2, 41.8, 39.3, 37.2, 35.1, 33.9, 33.5, 22.1, 22.0, 20.9, 19.2, 19.16; IR (film) υ max 3407, 2910, 1424, 1328, 1259, 1177, 1118, 1057, 1011, 960, 805, 744, 740 cm -1 ; LRMS (ESI) m/z 411.2505 [(M + Na)] + ; calculated for [C 24 H 36 O 4 + Na] + 19.3 ºC : 411.2506, [α] 589 = 27.05 (c = 0.2366, CH 2 Cl 2 ). Procedure for synthesis of arylvinylcarbinol 6e from carbaldehyde 15: (2,3-Dimethoxyphenyl)((4aS,8aS)-2,5,5,8a-tetramethyl-3,4,4a,5,6,7,8,8aoctahydronaphthalen-1-yl)methanol (6e): A flame-dried round-bottom flask was charged with veratrole (260 mg, 2.01 mmol) under nitrogen atmosphere in Dry THF (10 ml) was added 1.6 M solution of n-buli in cyclohexane (1.6 ml, 2.61 mmol) in portions via syringe at 0 C and at the same temperature TMEDA (400 µl, 2.61 mmol) was added dropwise via syringe. The reaction mixture was allowed to stand for continuous stirring for 1 hour then compound 11 (400, 1.69 mmol, 1.0 equiv) was added and reaction mixture was allowed to stand on stirring for additional 4 h. The mixture was treated with saturated aq. solution of NH 4 Cl solution. Organic layer was extracted with EtOAc (10 ml X 2) and transferred to the separatory funnel and shaken vigorously. The organic layer was separated and dried over anhydrous Na 2 SO 4 and concentrated by rotatory evaporator under vacuum. The crude product was purified by column chromatography (9:1, hexane/ EtOAc) to afford 447 mg of compound 6e in 74% yield as colorless oil, R f = 0.5 (10% EtOAc in hexane); 1 H NMR (500 MHz, CDCl 3 ) δ: 7.0 (t, J = 8.0 Hz, 1H), 6.84 (dd, J = 8.1, 1.3 Hz, 1H), 6.82-6.80 (m, 1H), 5.73 (s, 1H), 3.98 (d, J = 2.3 Hz, 1H), 3.93 (s, 3H), 3.87 (s, 3H), 2.21-2.14 (m, 1H), 2.11-2.03 S15

(m, 2H), 1.74-1.70 (m, 1H), 1.61 (tt, J = 13.7, 3.5 Hz, 1H), 1.55-1.49 (m, 2H), 1.50 (s, 3H), 1.46-1.40 (m, 1H), 1.29 (dd, J = 12.5, 1.7 Hz, 1H), 1.21 (td, J = 13.3, 4.2 Hz, 1H), 0.98 (s, 3H), 0.92 (s, 3H), 0.86 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ: 152.4, 147.3, 139.3, 137.6, 133.8, 123.4, 120.8, 111.4, 68.2, 60.5, 55.8, 52.1, 41.5, 39.0, 36.8, 34.8, 33.42, 33.40, 22.3, 21.7, 20.5, 19.2, 19.1; IR (film) υ max 3444, 3048, 2919, 1438, 1224, 1096, 1011, 992, 899, 865, 835, 744, 699 cm -1 ; HRMS (ESI) m/z 381.2717 [(M + Na)] + ; calculated for [C 23 H 34 O 3 + Na] + 22.2 ºC : 381.2400, [α] 589 = 14.993 (c = 0.0667, CH 2 Cl 2 ). Procedure for synthesis of arylvinyl carbinol (6f) from carbaldehyde 11: Step 1: A flame-dried round-bottom flask was charged with p-vanillin (3000 mg, 19.7 mmol, 1.0 equiv) under nitrogen atmosphere in CCl 4 (40 ml) was added silica (6.0 gm) and ceric ammonium nitrate (26 mg, 0.024 mmol) at 0 C and at the same temperature Bromine (1.0 ml, 19.71 mmol) was added dropwise via syringe. The reaction mixture was allowed to stand for continuous stirring for 4 h. The mixture was treated with saturated aq. solution of sodium thiosulphate solution and then filtered through celite filtere. Organic layer was extracted with CH 2 Cl 2 (50 ml X 2) and transferred to the separatory funnel and shaken vigorously. The organic layer was separated and dried over anhydrous Na 2 SO 4 and concentrated by rotatory evaporator under vacuum. Step 2: Clean and dry round-bottom flask was charged with crude Compound in Acetone (50 ml) was added K 2 CO 3 (4.08 g, 29.58 mmol) followed by addition of dimethylsulphate (2.8 ml, 29.58 mmol) at room temperature and kept on stirring for 6 h at 45 C. It was transferred to the separatory funnel and shaken vigorously. The organic layer was extracted with DCM (50 ml X 2) and dried over anhydrous Na 2 SO 4, concentrated using rotator evaporator under vacuum. The crude products were purified by flash chromatography (8:2 hexanes/etoac) to afford 3.89 g of pure bromoaldehyde in 80% yield over two steps. S16

Step 3: A flame-dried round-bottom flask was charged with bromoaldehyde (2000 mg, 8.15 mmol) in MeOH (20 ml) was added NaBH 4 (370 mg, 9.78 mmol) in portions at 0 C. The reaction mixture was allowed to stand for continuous stirring for 1 h. The mixture was treated with saturated aq. solution of NH 4 Cl solution. Organic layer was extracted with CH 2 Cl 2 (40 ml X 2) and transferred to the separatory funnel and shaken vigorously. The organic layer was separated and dried over anhydrous Na 2 SO 4 and concentrated by rotatory evaporator under vacuum. The crude product was purified by column chromatography (6:4, hexane/ EtOAc) to afford 1927 mg of benzyl alcohol 27b in 95% yield. Step 4: Clean and dry round-bottom flask was charged with benzyl alcohol (616 mg, 2.50 mmol) dissolved in diethylether (15 ml) was added phosphorous tribromide ( 94 µl, 0.99 mmol) at 0 C and kept on stirring for 10 min. The mixture was treated with saturated aq. solution of NaHCO 3. It was transferred to the separatory funnel and shaken vigorously. The organic layer was extracted with EtOAc (10 ml X 2) and dried over anhydrous Na 2 SO 4, concentrated using rotator evaporator under vacuum. Step 5: A flame-dried round-bottom flask was charged with crude benzyl bromide (769 mg, 2.49 mmol) under nitrogen atmosphere in THF (10 ml) was added LiAlH 4 (113 mg, 2.99 mmol) at room temperature for 20 min. The mixture was treated with 2M aq. solution of NaOH and compound was extracted by using EtOAc and dried over anhydrous Na 2 SO 4, concentrated using rotator evaporator under vacuum. The crude products were purified by flash chromatography (15:1 hexanes/etoac) to afford 358 mg of pure compound 27c in 62% yields over steps. Step 6: Same as discussed for the synthesis of 6a-b (step 5). (3-bromo-4,5-dimethoxyphenyl)methanol (27b): 95% yield as colorless solid, R f = 0.5 (40% EtOAc in hexane); 1 H NMR (400 MHz, CDCl 3 ) δ: 7.08 (d, J = 1.6 Hz, 1H), 6.85 (d, J = 1.5 Hz, 1H), 4.58 (s, 2H), 3.84 (s, 3H), 3.81 (s, 3H), 1.90 (brs, 1H (OH)); 13 C NMR (100 MHz, CDCl 3 ) δ: 153.7, 145.7, 138.1, 122.9, 117.5, 110.2, 64.5, 60.6, 56.1; IR (film) υ max S17

3392, 2907, 1595, 1569, 1415, 1276, 1235, 1139, 1048, 817, 774 cm -1 ; HRMS (ESI) m/z 268.9799 [(M + Na)] + ; calculated for [C 9 H 11 BrO 3 + Na] + : 268.9784. 1-bromo-2,3-dimethoxy-5-methylbenzene (27c): 62% yield as colorless liquid, R f = 0.5 (5% EtOAc in hexane); 1 H NMR (400 MHz, CDCl 3 ) δ: 6.93 (s, 1H), 6.64 (s, 1H), 3.83 (s, 3H), 3.80 (s, 3H), 2.27 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ: 153.3, 144.2, 135.1, 124.9, 117.2, 112.6, 60.6, 56.0, 21.0; IR (film) υ max 2922, 1568, 1471, 1303, 1236, 1142, 1048, 1004, 815 cm -1 ; HRMS (ESI) m/z 228.9857 [(M - H)] + ; calculated for [C 9 H 11 BrO 2 - H] + : 228.9859. (2,3-dimethoxy-5-methylphenyl)((4aS,8aS)-2,5,5,8a-tetramethyl-3,4,4a,5,6,7,8,8aoctahydronaphthalen-1-yl)methanol (6f): 83% yield as colorless solid (210 mg, 0.68 mmol), R f = 0.5 (20% EtOAc in hexane); 1 H NMR (400 MHz, DMSO-D 6 ) δ: 6.85 (s, 1H), 6.66 (s, 1H), 5.37 (d, J = 5.02 Hz 1H), 4.68 (d, J = 5.4 Hz, 1H), 3.72 (s, 3H), 3.56 (s, 3H), 2.29 (brs, (H 2 O)), 2.47-2.46 (m, DMSO), 2.20 (s, 3H), 1.95-1.93 (m, 3H), 1.59-1.49 (m, 3H), 1.36-1.33 (m, 2H), 1.30 (s, 3H), 1.11-1.06 (m, 2H), 1.00 (s, 3H), 0.85 (s, 3H), 0.80 (s, 3H); 13 C NMR (100 MHz, DMSO-D 6 ) δ: 152.2, 143.9, 141.9, 139.7, 131.9, 129.4, 120.8, 112.1, 66.4, 59.7, 56.0, 52.2, 41.8, 39.6, 37.3, 35.2, 33.9, 33.5, 22.1, 21.8, 21.78, 20.5, 19.2, 19.1; IR (film) υ max 3481, 2920, 1588, 1464, 1314, 1237, 1145, 1078, 1007, 837, 742 cm -1 ; HRMS (ESI) m/z 395.2557 [(M + Na)] + ; calculated for [C 24 H 36 O 3 + Na] + 19.9 ºC : 395.2557, [α] 589 = +41.652 (c = 0.566, CH 2 Cl 2 ). Procedure for synthesis of arylvinylcarbinol 6g from carbaldehyde 11: S18

(5-(hydroxymethyl)-2,3-dimethoxyphenyl)((4aS,8aS)-2,5,5,8a-tetramethyl- 3,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)methanol (6g): A flame-dried round-bottom flask was charged with bromoarene 27b [369 mg, 1.5 mmol, 1.1 equiv.] under nitrogen atmosphere in dry THF (7 ml for per mmol) and cooled to -78 ºC on a julabo. The n-butyl lithium solution [2.0 ml, 3.2 mmol, 2.4 equiv.(1.6 M in cyclohexane)] was added drop wise to the reaction mixture by a syringe and allowed to stirred for 10 min followed by dropwise addition of compound 11 (300 mg, 1.36 mmol, 1.0 equiv) The stirring was continued till TLC showed complete consumption of starting materials. The reaction mixture was quenched by saturated NH 4 Cl solution and then diluted with 20 ml of EtOAc. The whole reaction mixture was taken in a separatory funnel and extracted with 20 ml of water. The organic filtrate was separated and the aqueous part was again washed with 10 ml EtOAc, the combined organic filtrate dried over anhydrous Na 2 SO 4 and concentrated in a rotary evaporator under vacuum. The crude products were purified by flash chromatography (7:3 hexanes/etoac) to afford 306 mg of pure 6g in 58% yield as colorless gel, R f = 0.45 (50% EtOAc in hexane); 1 H NMR (400 MHz, DMSO-D 6 ) δ: 7.00 (s, 1H), 6.81 (s, 1H), 5.39 (d, J = 5.4 Hz, 1H), 5.07 (t, J = 5.7 Hz, 1H), 4.71 (d, J = 5.5 Hz, 1H), 4.37 (d, J = 5.7 Hz, 2H) 3.74 (s, 3H), 3.57 (s, 3H), 3.35 (s, H 2 O), 2.46 (m, DMSO), 1.95-1.92 (m, 3H), 1.60-1.48 (m, 3H), 1.40-1.32 (m, 4H), 1.29 (s, 3H), 1.09-1.00 (m, 1H), 0.84 (s, 3H), 0.79 (s, 3H); 13 C NMR (100 MHz, DMSO-D 6 ) δ: 157.0, 149.6, 144.4, 142.0, 134.3, 123.3, 114.4, 57.0, 46.5, 44.4, 42.1, 40.0, 38.6, 38.3, 26.9, 26.6, 25.2, 23.9, 23.89; IR (film) υ max 3432, 2920, 1466, 1445, 1383, 1213, 1106, 1052, 1033, 859, 856, 818 cm -1 ; HRMS (ESI) m/z 411.2519 [(M + Na)] + ; calculated for [C 24 H 36 O 4 + Na] + 20.5 ºC : 411.2506, [α] 589 = +55.287 (c = 0.233, CH 2 Cl 2 ). Procedure for synthesis of arylvinylcarbinol 6h from carbaldehyde 11: S19

Step 1: A flame-dried round-bottom flask was charged with compound 27b (350 mg, 1.45 mmol, 1.0 equiv.) under nitrogen atmosphere in DMF (5 ml) was added sodium hydride (60% in mineral oil) (68 mg, 1.68 mmol) in portions at 0 C and at the same temperature methyl iodide (100 µl, 1.45 mmol) was added dropwise via syringe. The reaction mixture was allowed to stand for continuous stirring for 1 h. The mixture was diluted with water (20 ml) and was extracted with 20% EtOAc in hexane (10 ml X 2) and transferred and organic layer was separated and dried over anhydrous Na 2 SO 4 and concentrated by rotatory evaporator under vacuum. The crude product was purified by column chromatography (8:2, hexane/ EtOAc) to afford 363 mg of compound 27d in 96% yields. Step 2: Same as discussed for the synthesis of 6a-b (step 5). 1-bromo-2,3-dimethoxy-5-(methoxymethyl)benzene (27d): 96% yield as colorless solid, R f = 0.5 (10% EtOAc in hexane); 1 H NMR (400 MHz, CDCl 3 ) δ: 7.06 (d, J = 1.6 Hz, 1H), 6.83 (d, J = 1.5 Hz, 1H), 4.33 (s, 2H), 3.84 (s, 3H), 3.81 (s, 3H), 3.36 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 153.7, 145.8, 135.4, 123.7, 117.4, 110.9, 73.8, 60.5, 58.2, 26.1; IR (film) υ max 3021, 2923, 1669, 1449, 1380, 1211, 1107, 1023, 857, 822, 753 cm -1 ; HRMS (ESI) m/z 282.9970 [(M + Na)] + ; calculated for [C 10 H 13 BrO 3 + Na] + : 282.9940. (2,3-dimethoxy-5-(methoxymethyl)phenyl)((4aS,8aS)-2,5,5,8a-tetramethyl- 3,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)methanol (6h): 73% yield as colorless gel S20

(265 mg, 0.91 mmol), R f = 0.45 (30% EtOAc in hexane); 1 H NMR (400 MHz, DMSO-D 6 ) δ: 7.04 (s, 1H), 6.79 (d, J = 1.2 Hz, 1H), 5.39 (d, J = 4.4 Hz, 1H), 4.76 (d, J = 5.3 Hz, 1H), 4.29 (s, 2H), 3.74 (s, 3H), 3.58 (s, 3H), 3.33 (s, H 2 O), 3.20 (s, 3H) 2.46 (m, DMSO), 1.95-1.92 (m, 3H), 1.60-1.50 (m, 2H), 1.39-1.32 (m, 3H), 1.27 (s, 3H), 1.09-1.06 (m, 1H), 1.02 (s, 3H), 0.84 (s, 3H), 0.79 (s, 3H); 13 C NMR (100 MHz, DMSO-D 6 ) δ: 152.3, 145.4, 141.9, 139.9, 132.9, 129.5, 119.9, 110.8, 74.4, 66.4, 59.7, 57.5, 56.0, 52.2, 41.8, 39.7, 37.3, 35.2, 33.9, 33.5, 22.1, 21.7, 20.5, 19.2, 19.1; IR (film) υ max 3520, 2904, 1591, 1448, 1378, 1261, 1142, 1026, 850, 808, 766 cm -1 ; HRMS (ESI) m/z 425.2644 [(M + Na)] + ; calculated for [C 25 H 38 O 4 + Na] + : 22.3 ºC 425.2662, [α] 589 = +38.4 (c = 0.3333, CH 2 Cl 2 ). Procedure for synthesis of arylvinylcarbinol 6i from carbaldehyde 11: Step 1: First step of bromination same as discussed for during synthesis of 6f. Step 2: A flame-dried round-bottom flask was charged with bromo-hydroxy aldehyde (2000 mg, 8.15 mmol, 1.0 Equiv.) in MeOH (20 ml) was added NaBH 4 (370 mg, 9.78 mmol) in portions at 0 C. The reaction mixture was allowed to stand for continuous stirring for 1 h. The mixture was treated with saturated aq. solution of NH 4 Cl. Organic layer was extracted with CH 2 Cl 2 (40 ml X 2) and transferred to the separatory funnel and shaken vigorously. The organic layer was separated and dried over anhydrous Na 2 SO 4 and concentrated by rotatory evaporator under vacuum. The crude product was purified by column chromatography (6:4, hexane/ EtOAc) to afford bromobenzyl alcohol 1.8 g in 95% yield. Step 3: A flame-dried round-bottom flask was charged with bromobenzyl alcohol (1265 mg, 5.53 mmol, 1.0 equiv.) under nitrogen atmosphere in DMF (15 ml) was added sodium hydride (60% in mineral oil) (487 mg, 12.18 mmol ) in portions at 0 C and at the same temperature benzyl bromide (1400 µl, 11.72 mmol) was added dropwise via syringe. The reaction mixture was allowed to stand for continuous stirring for 1 h. The mixture was diluted S21

with water (50 ml) and was extracted with 10% EtOAc in hexane (40 ml X 2) and transferred and organic layer was separated and dried over anhydrous Na 2 SO 4 and concentrated by rotatory evaporator under vacuum. The crude product was purified by column chromatography (9:1, hexane/ EtOAc) to afford 2215 mg of compound 27e in 97% yield. Step 4: Same as discussed for the synthesis of 6a-b (step 5). 2-(benzyloxy)-5-((benzyloxy)methyl)-1-bromo-3-methoxybenzene (27e): 97% yield as colorless liquid, R f = 0.5 (5% EtOAc in hexane); 1 H NMR (400 MHz, CDCl 3 ) δ: 7.58-7.56 (m, 2H), 7.41-7.32 (m, 8H), 7.15 (d, J = 1.4 Hz, 1H), 6.91 (d, J = 1.4 Hz, 1H), 5.04 (s, 2H), 4.58 (s, 2H), 4.49 (s, 2H), 3.87 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 153.9, 144.7, 137.9, 137.2, 135.6, 128.5, 128.3, 128.1, 127.9, 127.8, 123.9, 117.9, 111.1, 74.7, 72.4, 71.3, 56.1; IR (film) υ max 2918, 1723, 1563, 1464, 1385, 1340, 1286, 1109, 1089, 1018, 918, 857, 744 cm -1 ; HRMS (ESI) m/z 435.0592 [(M + Na)] + ; calculated for [C 22 H 21 BrO 3 + Na] + : 435.0566. (2-(benzyloxy)-5-((benzyloxy)methyl)-3-methoxyphenyl)((4aS,8aS)-2,5,5,8a-tetramethyl- 3,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)methanol (6i): 68% yield as colorless gel (256 mg, 0.68 mmol), R f = 0.45 (10% EtOAc in hexane); 1 H NMR (400 MHz, CDCl 3 ) δ: 7.41-7.40 (m, 2H), 7.34-7.26 (m, 8H), 6.95 (s, 1H), 6.90 (s, 1H), 5.45 (d, J = 4.1 Hz, 1H), 5.03 (d, J = 11.1 Hz, 1H), 4.87 (d, J = 11.2 Hz, 1H), 4.60 (d, J = 4.3 Hz, 1H), 4.45 (s, 2H), 4.44 (s, 2H), 3.79 (s, 3H), 1.97-1.95 (m, 2H), 1.82-1.79 (m, 1H), 1.59-1.56 (m, 1H), 1.45 (m, 1H), 1.40 (s, 3H), 1.36-1.29 (m, 3H), 1.23-1.18 (m, 1H), 1.10 (m, 1H), 1.05 (m, 1H), 0.82 (s, 3H), 0.74 (s, 3H), 0.73 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 152.4, 145.1, 141.1, 139.0, 138.99, 138.5, 133.2, 130.5, 128.7, 128.5, 128.2, 127.8, 127.7, 120.0, 111.1, 74.1, 72.0, 71.3, 66.7, 56.2, 52.1, 41.7, 39.2, 37.0, 35.0, 33.8, 33.5, 22.2, 22.0, 21.0, 19.1, 19.09; IR (film) υ max 3522, 2910, 1588, 1451, 1360, 1311, 1143, 1075, 1028, 849, 746 cm -1 ; HRMS (ESI) S22

m/z 577.3289 [(M + Na)] + ; calculated for [C 37 H 46 O 4 + Na] + 20.5 ºC : 577.3288, [α] 589 = 43.50 (c = 0.400, CH 2 Cl 2 ). Procedure for synthesis of arylvinylcarbinol 6j from carbaldehyde 11: Note: Procedure followed for synthesis 28b and 28c as similar as synthesis of 27b. Procedure for synthesis of 6j: Same as discussed for the synthesis of 6g. 5-bromo-2,3-dimethoxybenzaldehyde (28b): 76% yield over two steps as colorless solid, R f = 0.5 (20% EtOAc in hexane); 1 H NMR (400 MHz, CDCl 3 ) δ: 10.31 (s, 1H), 7.49 (d, J = 2.3 Hz, 1H), 7.19 (d, J = 2.3 Hz, 1H), 3.94 (s, 3H), 3.88 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 188.6, 153.9, 151.9, 130.5, 121.7, 121.0, 117.0, 62.4, 56.3; IR (film) υ max 2919, 2842, 1682, 1598, 1466, 1387, 1340, 1289, 1202, 1126, 1086, 1040, 1007, 863, 744 cm -1 ; HRMS (ESI) m/z 266.9644 [(M + Na)] + ; calculated for [C 9 H 9 BrO 3 + Na] + : 266.9627. (5-bromo-2,3-dimethoxyphenyl)methanol (28c): 92% yield as colorless gel (927 mg, 4.1 mmol), R f = 0.5 (40% EtOAc in hexane); 1 H NMR (400 MHz, CDCl 3 ) δ: 7.08 (d, J = 2.2 Hz, 1H), 6.96 (d, J = 2.2 Hz, 1H), 4.64 (s, 2H), 3.84 (s, 3H), 3.83 (s, 3H), 2.00 (brs, 1H (OH)); 13 C NMR (100 MHz, CDCl 3 ) δ: 153.1, 145.9, 136.1, 123.2, 116.5, 115.4, 60.9, 60.8, 56.1; IR (film) υ max 3396, 2834, 1590, 1517, 1458, 1416, 1263, 1233, 1152, 1138, 1026, 853, 810, 761, 759 cm -1 ; HRMS (ESI) m/z 268.9797 [(M + Na)] + ; calculated for [C 9 H 11 BrO 3 + Na] + : 268.9784. S23

(3-(hydroxymethyl)-4,5-dimethoxyphenyl)((4aS,8aS)-2,5,5,8a-tetramethyl- 3,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)methanol (6j): 49% yield as colorless gel (216 mg, 1.13 mmol), R f = 0.4 (40% EtOAc in hexane); 1 H NMR (400 MHz, CDCl 3 ) δ: 6.98 (s, 1H), 6.86 (s, 1H), 5.31 (s, 1H), 4.63 (s, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 2.39 (brs, 1H (OH)), 2.04-1.94 (m, 3H), 1.71-1.58 (m, 2H), 1.53-1.38 (m, 4H), 1.34-1.31 (m, 1H), 1.26 (s, 3H), 1.20-1.13 (m, 2H), 1.09 (s, 3H), 1.20-1.13 (m, 2H), 1.09 (s, 3H), 0.90 (s, 3H), 0.86 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 152.1, 145.0, 143.3, 142.1, 133.8, 133.5, 117.5, 109.7, 69.3, 62.0, 60.9, 55.8, 52.5, 41.5, 39.0, 37.0, 34.8, 33.4, 33.4, 21.7, 20.5, 19.1, 18.9; IR (film) υ max 33396, 2910, 1590, 1462, 1310, 1140, 1094, 1012, 764 cm -1 ; HRMS (ESI) m/z 411.2523 [(M + Na)] + ; calculated for [C 24 H 36 O 4 + Na] + 18.5 ºC : 411.2506, [α] 589 = +67.203 (c = 0.166, CH 2 Cl 2 ). Procedure for synthesis of arylvinylcarbinol 6k from carbaldehyde 11: Step 1: First step of bromination same as discussed for during synthesis of 6f. Step 2: Second step of reduction same as discussed for during synthesis of 27b. Step 3: A flame-dried round-bottom flask was charged with bromo benzylalcohol (3250 mg, 21.09 mmol) in DMF (30 ml) was added Cs 2 (CO 3 ) (8.22 g, 25.3 mmol ) at room temperature followed by addition of dibromomethane (1.77 ml, 25.3 mmol) dropwise via syringe. The reaction mixture was allowed to stand for continuous stirring for overnight at 110 C. The mixture was treated with saturated aq. Solution of NaHCO 3. Organic layer was extracted with 20% EtOAc in hexane (50 ml X 2). The organic layer was separated and dried over anhydrous Na 2 SO 4 and concentrated by rotatory evaporator under vacuum. The crude S24

product was purified by column chromatography (8:2, hexane/ EtOAc) to afford compound 24b in 44% yield overall 3 steps. Step 4: Same as discussed for the synthesis of 6a-b (step 5). 6-bromo-8-methoxy-4H-benzo[d][1,3]dioxine (29b): 44% yield (over 3 steps) as colorless gel, R f = 0.6 (10% EtOAc in hexane); 1 H NMR (400 MHz, CDCl 3 ) δ: 6.85 (d, J = 1.5 Hz, 1H), 6.71 (s, 1H), 5.25 (s, 2H), 4.82 (s, 2H), 3.85 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 148.9, 141.3, 123.3, 119.6, 113.4, 113.2, 91.5, 65.4, 56.2; IR (film) υ max 3021, 1578, 1475, 1345, 1267, 1239, 1158, 1092, 990, 946, 849, 797, 726 cm -1. (8-methoxy-4H-benzo[d][1,3]dioxin-6-yl)((4aS,8aS)-2,5,5,8a-tetramethyl- 3,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl)methanol (6k): 69% yield as colorless gel (145 mg, 0.54 mmol), R f = 0.4 (20% EtOAc in hexane); 1 H NMR (400 MHz, DMSO-D 6 ) δ: 6.75 (s, 1H), 6.51 (s, 1H), 5.17 (s, 2H) 5.12-5.11 (m, 1H), 4.78 (s, 2H), 3.71-3.68 (m, 1H), 3.66 (m, 3H), 3.33 (s, H 2 O), 2.46 (m, DMSO), 1.99-1.87 (m, 3H), 1.62-1.46 (m, 3H), 1.43-1.32 (m, 4H), 1.26 (s, 3H), 1.09 (s, 1H), 1.05 (s, 3H), 0.85 (s, 3H), 0.80 (s, 3H); 13 C NMR (100 MHz, DMSO-D 6 ) δ: 147.5, 143.0, 140.3, 139.9, 121.7, 113.9, 108.3, 91.2, 66.0, 55.8, 52.4, 41.8, 38.9, 36.4, 34.5, 33.8, 33.5, 22.1, 21.4, 21.2, 19.1, 19.0; IR (film) υ max 3521, 2910, 1597, 1470, 1350, 1239, 1140, 996, 743 cm -1 ; HRMS (ESI) m/z 425.2116 [(M + K)] + ; calculated for [C 24 H 34 O 4 + K] + 19.2 ºC : 425.2089, [α] 589 = +49.202 (c = 0.1666, CH 2 Cl 2 ). General procedure for metal triflate-catalyzed cyclization of arylvinylcarbinols 6a-e. In an oven-dried round-bottom flask, arylcarbinol 6 (0.25 mmol; 1.0 equiv.) and Sn(OTf) 2 (0.005 mmol; 2 mol%) [Condition A] or Bi(OTf) 3 (0.005 mmol; 2 mol%) [Condition B] were taken in dichloroethane (DCE) (3 ml). The round-bottom flask was stirred at 80 ºC for indicated time (2 h). Upon completion of the reactions, (TLC showed complete consumption S25

of starting material) the reaction mixture was quenched by saturated NaHCO 3 solution and diluted with 5 ml of dichloromethane. The whole reaction mixture was taken in a separatory funnel and extracted with 5 ml of water. The organic filtrate was dried over Na 2 SO 4 and concentrated in a rotary evaporator under vacuum. The crude products were purified by flash chromatography (10:1 hexanes/etoac) to afford Friedel-crafts alkylation product. Table1: Selected optimization of Nazarov type reaction of 6a. S. N. Lewis acid (mol%) solvent temp time % of 7a a,b % of 12a a,b 1 5 mol% BF 3.OEt 2 CH 2 Cl 2 25ºC 0.5 h 27% 60% c 2 5 mol% Sn(OTf) 2 CH 2 Cl 2 25ºC 1 h 00% 94% 3 5 mol% In(OTf) 3 CH 2 Cl 2 25ºC 1 h 00% 89% 4 5 mol% Bi(OTf) 3 CH 2 Cl 2 25ºC 1 h 00% 93% 5 5 mol% Bi(OTf) 3 (CH 2 Cl) 2 80ºC 2 h 95% 00% 6 5 mol% Sn(OTf) 2 (CH 2 Cl) 2 80ºC 2 h 93% 00% 7 5 mol% In(OTf) 3 (CH 2 Cl) 2 80ºC 2 h 92% 00% 8 5 mol% Zn(OTf) 2 (CH 2 Cl) 2 80ºC 20 h 79% 12% c 9 5 mol% Yb(OTf) 3 (CH 2 Cl) 2 80ºC 20 h 49% 41% c 10 5 mol%cu(otf) 2 (CH 2 Cl) 2 80ºC 2 h 93% 00% 11 2 mol% In(OTf) 3 (CH 2 Cl) 2 80ºC 2 h 88% 08% 12 2 mol% Sn(OTf) 2 (CH 2 Cl) 2 80ºC 2 h 92% d 00% 13 2 mol% Cu(OTf) 2 (CH 2 Cl) 2 80ºC 2 h 71% 18% c 14 2 mol% Bi(OTf) 3 (CH 2 Cl) 2 80ºC 2 h 93% e 00% a reactions were carried out on a 0.25 mmol of (6a) in 3 ml of solvent. b isolated yields reported after column chromatography. c determined from 1 H-NMR of impure materials. d condition A (2 mol% of Sn(OTf) 2 ). e condition B (2 mol% of Bi(OTf) 3 ). S26

Note: (In case of arylvinylcarbinols (6f-k) reaction was done at room temperature) (4aS,6aR,11bS)-9-isopropyl-7,8,10-trimethoxy-4,4,6a,11b-tetramethyl- 2,3,4,4a,5,6,6a,11b-octahydro-1H-benzo[a]fluorine (7a): 95% yield as colorless gel (98 mg), R f = 0.5 (2.5% EtOAc in hexane); 1 H NMR (400 MHz, CDCl 3 ) δ: 6.21 (s, 1H), 3.83 (s, 3H), 3.80 (s, 3H), 3.79 (s, 3H), 3.46-3.39 (m, 1H), 2.47 (td, J = 12.7, 3.0 Hz, 1H), 1.85-1.82 (m, 1H), 1.76-1.70 (m, 2H), 1.66-1.51 (m, 1H), 1.46 (s, 3H), 1.31 (d, J = 7.2 Hz, 6H), 1.23 (s, 3H), 1.16-1.11 (m, 1H), 0.98-0.95 (m, 1H), 0.92 (s, 3H), 0.83 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 166.8, 149.3, 147.3, 144.5, 132.7, 130.4, 113.8, 61.9, 60.5, 60.2, 56.6, 52.6, 42.3, 39.3, 38.4, 37.8, 33.7, 33.6, 29.7, 25.7, 22.8, 22.2, 21.6, 19.5, 19.1, 18.6; IR (film) υ max 2915, 1580, 1491, 1451, 1373, 1325, 128, 1148, 109, 1015, 831, 782 cm -1 ; HRMS (ESI) m/z 413.3055 [(M + H)] + ; calculated for [C 27 H 40 O 3 + H] + 19.8 ºC : 413.3050, [α] 589 = 58.559 (c = 0.0666, CH 2 Cl 2 ). (4aS,8aS,E)-5-(3-isopropyl-2,4,5-trimethoxybenzylidene)-1,1,4a,6-tetramethyl- 1,2,3,4,4a,5,8,8a-octahydronaphthalene (12a): 94% yield as colorless gel, R f = 0.6 (2.5% EtOAc in hexane); 1 H NMR (400 MHz, CDCl 3 ) δ: 6.50 (s, 1H), 6.27 (s, 1H), 5.58 (s, 1H), 3.79 (s, 3H), 3.76 (s, 3H), 3.63 (s, 3H), 3.48-3.41 (m, 1H), 2.29-2.24 (m, 1H), 2.09-2.01 (m, 1H), 1.85-1.82 (m, 1H), 1.70-1.60 (m, 2H), 1.52 (m, 3H), 1.48-1.42 (m, 2H), 1.31 (t, J = 7.1 Hz, 6H), 1.21-1.12 (m, 2H), 1.02 (s, 3H), 0.94 (s, 3H), 0.87 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 150.6, 150.1, 148.6, 146.9, 134.1, 131.4, 128.8, 128.7, 116.5, 112.7, 61.0, 60.9, 56.0, 48.1, 42.4, 38.8, 38.3, 33.8, 32.6, 25.7, 25.3, 22.9, 22.1, 22.0, 21.9, 19.7, 19.3; IR (film) υ max 2917, 1595, 1469, 1397, 1311, 1261, 1213, 1057, 988, 832, 746, 658 cm -1. S27