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Electronic Supplementary Information

A Convenient Method for the Synthesis of -Carboxylate Ester Bromolactones via Bromolactonization of Alkenoic Diesters

Ying-Chieh Wong,2 Ying-Yeung Yeung1,2*

1Department of Chemistry, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China

2Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore

E-mail: yyyeung@cuhk.edu.hk; Tel: +852-3943-6377

Contents

I. General information ..................................................................................................................S2

II. Preparation of substrates.........................................................................................................S2-S7

III. Synthesis of Products............................................................................................................S7-S16

IV. Reference .................................................................................................................................S16

V. 1H & 13C NMR spectra for all substrates............................................................................ S17-S50

VI. 1H & 13C NMR spectra for all new products...................................................................... S51-S96

VII. X-ray structure of compound 6g ...............................................................................................S97

Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry.This journal is © The Royal Society of Chemistry 2016

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I. General Information

All reactions that required anhydrous conditions were carried by standard procedures under nitrogen atmosphere. Commercially available reagents were used as received. The solvents were dried by distillation over the appropriate drying reagents. Infrared spectra were recorded on a BIO-RAD FTS 165 FT-IR spectrophotometer and reported in wave numbers (cm-1). Melting points were determined on a BÜCHI B-540b melting point apparatus. 1H NMR and 13C NMR spectra were recorded on a Bruker AMX500 (500 MHz) spectrometer. Chemical shifts (δ) are reported in ppm relative to chloroform (δ 7.26) for the 1H NMR and (δ 77.0) for the 13C NMR measurements. High resolution mass spectra were obtained on a Finnigan/MAT 95XL-T spectrometer. Analytical thin layer chromatography (TLC) was performed with Merck pre-coated TLC plates, silica gel 60F-254, layer thickness 0.25 mm. Flash chromatography separations were performed on Merk 60 (0.040-0.063 mm) mesh silica gel.

II. Preparation of Substrates A. The general procedure for the synthesis of substrates 5a5l, 5n, 5o, 5p and 5q is

demonstrated as follows using 5a as a typical example.

Dimethyl 2-benzyl-2-(2-phenylallyl)malonate (5a) : A mixture of K2CO3 (0.76 g, 5.5 mmol) and dimethyl malonate (0.63 mL, 5.5 mmol) were dissolved in DMF (15 mL) and stirred under room temperature for 5 minutes. 2,3-Dibromopropene (0.49 mL, 5.0 mmol) was added to reaction mixture. The reaction temperature was then allowed to rise to 70 oC and stired for 12 h. Upon completion, the mixture was diluted with H2O (10 mL) and extrace with diethyl ether (3 × 20 mL). The combined extracts were washed with brine (15 mL), dried over MgSO4, fitered, and concentrated in vacuo. The residue was purified by flash column chromatography n-hexane/EtOAc (4/1) to yield the S1 (590 mg, 43%). To a mixture of the diester S1 (500 mg, 2.0 mmol), phenylboronic acid (0.37 g, 3.0 mmol), Pd(PPh3)4 (60 mg, 0.05 mmol), and Cs2CO3 (0.98 g, 3.0 mmol) in MeOH (20 mL) was stirred at 60 oC for 12 h. The solvent was removed under reduced pressure, and the residue was diluted with water (10 mL) and extraced with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (10 mL), dired over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatogrphy n-hexane/EtOAc (4/1) to give the corresponding diester product 9 (400 mg, 80%). The dimethyl malonate derivative 10 (400 mg, 1.6 mmol) was dissolved in THF (10 mL) stirred under ice-bath. NaH (77 mg, 1.92 mmol, 60% in mineral oil) was added slowly in portion wise into the reaction mixture and stirred for 15 minutes at 0 oC. Benzoyl bromide (0.23 mL, 1.92 mmol) in THF (5 mL) was added to the reaction mixture and stirred at room temperature for 4 h. The mixture was cooled, diluted with H2O (10 mL), and extracted with diethyl ether (3 × 10 mL). The combined extracts were washed with brine (15 mL), dried over MgSO4, fitered, and concentrated in vacuo. The residue was subjected to

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flash column chromatography n-hexane/EtOAc (3/1) to afford olefinic diester 5a as a colorless oil (476 mg, 88%); IR (neat) 3030, 2951, 1731, 1627, 1453, 1199, 1084 cm-1; 1H NMR (CDCl3, 500 MHz) : δ 7.327.31 (m, 4H), 7.267.21 (m, 4H), 7.067.05 (m, 2H), 5.31 (d, J = 1.0 Hz, 1H), 5.22 (d, J = 1.0 Hz, 1H), 3.41 (s, 6H), 3.22 (s, 2H), 3.14 (s, 2H); 13C NMR (CDCl3, 125 MHz) : δ 170.6, 144.3, 141.6, 136.0, 129.7, 127.8, 127.7, 127.1, 126.5, 126.5, 118.3, 58.4, 51.6, 38.1, 37.8; HRMS (ESI) calcd for C21H22NaO4 m/z [M + Na]+: 361.1416; found: 361.1410.

Dimethyl 2-benzyl-2-(2-(4-methoxyphenyl)allyl)malonate (5b) : White soid; 280 mg; Yield: 76%; mp 5658 oC; IR (KBr) 3055, 2987, 1732, 1265, 1034, 749 cm-1; 1H NMR (CDCl3, 500 MHz) : δ 7.287.21 (m, 5H), 7.08 (d, J = 7.5 Hz, 2H), 6.85 (d, J = 9.0 Hz, 2H), 5.27 (d, J = 1.0 Hz, 1H), 5.16 (d, J = 1.0 Hz, 1H), 3.82 (s, 3H), 3.45 (s, 6H), 3.23 (s, 2H), 3.12 (s, 2H); 13C NMR (CDCl3, 125 MHz) : δ 171.1, 159.0, 143.8, 136.3, 134.3, 129.9, 128.1, 128.0, 126.8, 117.3, 113.3, 58.7, 55.2, 51.9, 38.3, 38.1; HRMS (ESI) calcd for C22H24NaO5 m/z [M + Na]+: 391.1521; found: 391.1516.

Dimethyl 2-benzyl-2-(2-(3-methoxyphenyl)allyl)malonate (5c) : Colorless oil; 254 mg; Yield: 69%; IR (neat) 3031, 2837, 1734, 1434, 1207, 1045 cm-1; 1H NMR (CDCl3, 500 MHz) : δ 7.257.18 (m, 4H), 7.047.02 (m, 2H), 6.90 (d, J = 7.5 Hz, 1H), 6.83 (s, 1H), 6.80 (d, J = 8.0 Hz, 1H), 5.32 (s, 1H), 5.19 (s, 1H), 3.79 (s, 3H), 3.44 (s, 6H), 3.20 (s, 2H), 3.11(s, 2H); 13C NMR (CDCl3, 125 MHz) : δ 171.0, 159.2, 144.4, 143.3, 136.1, 129.9, 128.9, 128.0, 126.7, 119.4, 118.4, 112.8, 112.6, 58.7, 55.1, 51.9, 38.3, 38.0; HRMS (ESI) calcd for C22H24NaO5 m/z [M + Na]+: 391.1521; found: 391.1516.

Dimethyl 2-benzyl-2-(2-(o-tolyl)allyl)malonate (5d) : Colorless oil; 285 mg; Yield: 81%; IR (neat) 3030, 2950, 1730, 1436, 1207, 1084 cm-1; 1H NMR (CDCl3, 500 MHz) : δ 7.267.14 (m, 7H), 6.936.91 (m, 2H), 5.33 (s, 1H), 5.10 (s, 1H), 3.45 (s, 6H), 3.23 (s, 2H), 3.01 (s, 2H); 13C NMR (CDCl3, 125 MHz) : δ 170.9, 145.0, 141.7, 136.1, 135.1, 130.0, 129.9, 129.0, 128.0, 127.1, 126.7, 125.3, 120.1, 58.9, 51.9, 39.3, 38.0, 19.8; HRMS (ESI) calcd for C22H24NaO4 m/z [M + Na]+: 375.1572; found: 375.1567.

Dimethyl 2-benzyl-2-(2-(4-chlorophenyl)allyl)malonate (5e) : White solid; 260 mg; Yield: 70%; mp 6971 oC; IR (KBr) 3055, 2987, 1733, 1265, 746 cm-1; 1H NMR (CDCl3, 500 MHz): δ 7.297.24 (m, 4H), 7.22 (d, J = 8.5 Hz, 2H), 7.237.21 (m, 1H), 7.05 (d, J = 8.5 Hz, 2H), 5.30 (s, 1H), 5.23 (s, 1H), 3.44 (s, 6H), 3.21 (s, 2H), 3.10 (s, 2H); 13C NMR (CDCl3, 125 MHz): δ 171.0, 143.4, 140.3, 136.0, 133.3, 129.9, 128.3, 128.2, 128.1, 126.9, 119.1, 58.6, 52.0, 38.4, 37.9; HRMS (ESI) calcd for C21H21ClNaO4 m/z [M + Na]+: 395.1026; found: 395.1021.

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Dimethyl 2-benzyl-2-(2-(3-fluorophenyl)allyl)malonate (5f) : Colorless oil; 288 mg; Yield: 81%; IR (neat) 3032, 2952, 1731, 1435, 1213, 1085, 739 cm-1; 1H NMR (CDCl3, 500 MHz) : δ 7.297.20 (m, 3H), 7.16 (d, J = 7.0 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 7.067.01 (m, 3H), 6.96 (t, J = 8.0 Hz, 1H), 5.35 (s, 1H), 5.25 (s, 1H), 3.46 (s, 6H), 3.22 (s, 2H), 3.11 (s, 2H); 13C NMR (CDCl3, 125 MHz) : δ170.8, 162.5 (d, 1JC-F = 244.1 Hz), 144.1 (d, 3JC-F = 7.4 Hz), 143.4, 136.0, 129.9, 129.5 (d, 3JC-F = 8.3 Hz), 128.1, 126.9, 122.6 (d, 4JC-F = 2.6 Hz), 119.4, 114.2 (d, 2JC-F = 21.0 Hz), 113.8 (d, 2JC-F = 21.8 Hz), 58.6, 52.0, 38.4, 37.9; HRMS (ESI) calcd for C21H21FNaO4 m/z [M + Na]+: 379.1322; found: 379.1316.

Dimethyl 2-benzyl-2-(2-(4-(trifluoromethyl)phenyl)allyl)malonate (5g) : White solid; 292 mg; Yield: 72%; mp 8183 oC; IR (KBr) 3033, 2953, 1734, 1616, 1266, 1066 cm-1; 1H NMR (CDCl3, 500 MHz) : δ 7.56 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 7.237.20 (m, 3H), 7.047.02 (m, 2H), 5.37 (d, J = 1.0 Hz, 1H), 5.31 (d, J = 1.0 Hz, 1H), 3.41 (s, 6H), 3.22 (s, 2H), 3.13 (s, 2H); 13C NMR (CDCl3, 125 MHz) : δ 170.9, 145.5, 143.5, 135.9, 129.5 (q, 2JC-F = 32.5 Hz), 128.2, 127.3, 126.9, 126.3, 124.9 (q, 3JC-F = 3.6 Hz), 124.1 (q, 1JC-F = 270.3 Hz), 120.2, 58.6, 51.9, 38.5, 37.9; HRMS (ESI) calcd for C22H21F3NaO4 m/z [M + Na]+: 429.1290; found: 429.1284.

5h

CO2Me

CO2Me

Ph

O2N

Dimethyl 2-benzyl-2-(2-(3-nitrophenyl)allyl)malonate (5h) : Pale yellow oil; 192 mg; Yield: 50%; IR (neat) 3055, 2987, 1733, 1532, 1265, 749 cm-1; 1H NMR (CDCl3, 500 MHz) : δ 8.16 (s, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.267.21 (m, 3H), 7.047.03 (m, 2H), 5.42 (s, 1H), 5.35 (s, 1H), 3.46 (s, 6H), 3.23 (s, 2H), 3.16 (s, 2H); 13C NMR (CDCl3, 125 MHz) : δ 170.8, 148.0, 143.5, 142.6, 135.7, 132.9, 129.8, 129.0, 128.2, 127.0, 122.3, 121.6, 120.8, 58.5, 52.1, 38.6, 37.8; HRMS (ESI) calcd for C21H21NNaO6 m/z [M + Na]+: 406.1267; found: 406.1261.

Dimethyl 2-benzyl-2-(2-(4-cyanophenyl)allyl)malonate (5i) : Pale yellow solid; 250 mg; Yield: 67%; mp 102104 oC; IR (KBr) 3055, 2987, 1733, 1436, 1265 cm-1; 1H NMR (CDCl3, 500 MHz) : δ 7.60 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.267.22 (m, 3H), 7.037.02 (m, 2H), 5.39 (s, 1H), 5.34 (s, 1H), 3.44 (s, 6H), 3.21 (s, 2H), 3.11 (s, 2H); 13C NMR (CDCl3, 125 MHz) : δ 170.8, 146.5, 143.2, 135.8, 132.8, 131.9, 129.8, 128.3, 127.9, 127.6, 127.0, 121.0, 58.5, 52.1, 38.6, 37.6; HRMS (ESI) calcd for C22H21NNaO4 m/z [M + Na]+: 386.1368; found: 386.1363.

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Dimethyl 2-(2-(4-acetylphenyl)allyl)-2-benzylmalonate (5j) : Pale yellow solid; 232 mg; Yield: 61%; mp 8789 oC; IR (KBr) 3055, 2954, 1733, 1682, 1604, 1435, 1265, 749 cm-1; 1H NMR (CDCl3, 500 MHz) : δ 7.91 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.0 Hz, 1H), 7.267.22 (m, 3H), 7.05 (d, J = 6.0 Hz, 2H), 5.40 (s, 1H), 5.31 (s, 1H), 3.42 (s, 6H), 3.22 (s, 2H), 3.16 (s, 2H), 2.60 (s, 3H); 13C NMR (CDCl3, 125 MHz) : δ 197.5, 170.9, 146.6, 143.7, 136.1, 136.0, 129.9, 128.2 (2C), 127.1, 126.9, 120.2, 58.7, 52.0, 38.6, 37.8, 26.5; HRMS (ESI) calcd for C23H24NaO5 m/z [M + Na]+: 403.1521; found: 403.1516.

Dimethyl 2-(2-phenylallyl)-2-(prop-2-yn-1-yl)malonate (5k) : White solid; 237 mg; Yield: 83%; mp 7779 oC; IR (KBr) 3304, 3056, 2954, 1736, 1437, 1266, 1050, 740 cm-1; 1H NMR (CDCl3, 500 MHz) : δ 7.337.23 (m, 5H), 5.31 (s, 1H), 5.29 (s, 1H), 3.44 (s, 6H), 3.34 (s, 2H), 2.77 (d, J = 2.5 Hz, 2H), 2.04 (t, J = 2.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz) : δ 169.9, 143.8, 140.9, 128.0, 127.6, 126.9, 119.0, 79.2, 71.7, 56.4, 52.4, 36.9, 22.3; HRMS (ESI) calcd for C17H18NaO4 m/z [M + Na]+: 309.1103; found: 309.1097.

Dimethyl 2-(2-bromoallyl)-2-(2-phenylallyl)malonate (5l) : Colorless oil; 808 mg; Yield: 38% (two steps); IR (neat) 3024, 2951, 1744, 1626, 1436, 1216, 700 cm-1; 1H NMR (CDCl3, 500 MHz) : δ 7.297.27 (m, 4H), 7.247.22 (m, 1H), 5.56 (s, 1H), 5.54 (s, 1H), 5.27 (s, 1H), 5.22 (s, 1H), 3.44 (s, 6H), 3.30 (s, 2H), 3.13 (s, 2H); 13C NMR (CDCl3, 125 MHz) : δ 170.2, 144.1, 141.4, 127.9, 127.4, 126.9, 121.7, 118.9, 56.5, 52.2, 42.5, 36.9; HRMS (ESI) calcd for C17H19BrNaO4 m/z [M + Na]+: 389.0364; found: 389.0359.

Diethyl 2-benzyl-2-(2-phenylallyl)malonate (5n) : Colorless oil; 495 mg; Yield: 20% (three steps); IR (neat) 3031, 2981, 1731, 1204, 1042 cm-1; 1H NMR (CDCl3, 500 MHz) : δ 7.337.27 (m, 4H), 7.267.17 (m, 4H), 7.087.07 (m, 2H), 5.31 (s, 1H), 5.22 (s, 1H), 3.943.87 (m, 2H), 3.843.78 (m, 2H), 3.22 (s, 2H), 3.13 (m, 2H), 1.10 (t, J = 7.0 Hz, 6H); 13C NMR (CDCl3, 125 MHz) : δ 170.7, 144.7, 142.1, 136.4, 130.0, 128.0, 127.9, 127.4, 126.9, 126.7, 118.3, 61.0, 58.5, 38.1, 37.8, 13.7; HRMS (ESI) calcd for C23H26NaO4 m/z [M + Na]+: 389.1729; found: 389.1723.

Dimethyl 2-benzyl-2-(2-methylallyl)malonate (5o) : Colorless oil; 213 mg; Yield: 77%; IR (enat) 3031, 2952, 1732, 1436, 1205, 1086, 702 cm-1; 1H NMR (CDCl3, 500 MHz) : δ 7.287.21 (m, 3H), 7.167.11 (m, 2H), 4.92 (s, 1H), 4.80 (s, 1H), 3.68 (s, 6H), 3.31 (s, 2H), 2.65 (s, 2H), 2.65 (s, 3H); 13C NMR (CDCl3, 125 MHz) : δ 171.5, 140.9, 136.2, 129.9, 128.1, 126.9, 115.0, 58.6, 52.2, 40.3, 38.8, 23.6; HRMS (ESI) calcd for C16H20NaO4 m/z [M + Na]+: 299.1259; found: 299.1254.

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5p

PhCO2Me

CO2Me

Dimethyl 2-ethyl-2-(2-phenylallyl)malonate (5p) : Colorless oil; 246 mg; Yield: 89%; IR (neat) 3082, 2952, 1734, 1445, 1224, 1028, 699 cm-1; 1H NMR (CDCl3, 500 MHz) : δ 7.297.27 (m, 4H), 7.247.23 (m, 1H), 5.23 (s, 1H), 5.11 (s, 1H), 3.44 (s, 3H), 3.16 (s, 2H), 1.85 (q, J = 7.5 Hz, 2H), 0.75 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz) : δ 171.2, 144.5, 141.4, 127.8, 127.2, 126.7, 118.0, 57.6, 51.7, 36.7, 24.5, 8.3; HRMS (ESI) calcd for C16H20NaO4 m/z [M + Na]+: 299.1259; found: 299.1254. B. General procedure for the preparation of alkenoic dicarboxylic acid 11

2-Benzyl-2-(2-phenylallyl)malonic acid (1) : The alkenoic diester 5a (500 mg, 1.5 mmol) was dissolved in MeOH (10 mL) and H2O (10 mL). Then LiOH•H2O (630 mg, 15 mmol) was added. The mixture was heated at 65 oC for 24 h. Then 2 M HCl (15 mL) and 50 mL of Et2O were added. The layers were sepqrated and the organic layers were washed with brine (15 mL), dried over MgSO4, fitered, and concentrated in vacuo to afford alkenoic dicarboxylic acid 1 as a white solid (372 mg, 80% yield), mp 132134 oC; IR (KBr) 3441, 3055, 2987, 1758, 1629, 1422 cm-1; 1H NMR (CDCl3, 500 MHz) : δ 7.357.14 (m, 10H), 5.28 (s, 1H), 5.19 (s, 1H), 3.35 (s, 2H), 3.34 (s, 2H); 13C NMR (CDCl3, 125 MHz) : δ 176.4, 144.0, 140.8, 134.8, 129.5, 128.5, 128.2, 128.0, 127.5, 126.9, 117.6, 59.3, 42.7, 42.0; HRMS (ESI) calcd for C19H18NaO4 m/z [M + Na]+: 333.1103; found: 333.1097. C. General procedure for the preparation of tri-substituted diester 5m

Et2O, 0 to 25 oC, 48 h

NaH, THF0 to 25 oC

S2

PhOH

3MeO-C6H4MgBr, CuI

Et2O, 0 to 25 oC

PBr3

S3

MeO2C CO2Me

Ph 7

5m

CO2Me

CO2Me

Ph

Ph

MeO

Ph

MeO OH

Ph

MeO Br

Dimethyl (Z)-2-benzyl-2-(2-(3-methoxyphenyl)-3-phenylallyl)malonate (5m) : The desired allylic alcohol S2 was first prepared via a literature procedure using the corresponding propargyl alchols.2

The allylic alcohol S2 (1.0 g, 6.76 mmol) was first dissolved in THF (30 mL) and stirred under an ice-

bath. PBr3 (0.32 mL, 3.38 mmol) was added dropwise into the solution over 15 minutes. The reaction was allowed to warm to 25 oC and stirred for additional 4 h. Upon completion, saturated sodium bicarbonate solution was added dropwise to quench the reaction. The mixture was then partitioned between saturated sodium bicarbonate solution (20 mL) and diethyl ether (10 mL). The aqueous layer was further extracted

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with diethyl ether (2 x 20 mL) and the combined organic extract was dried over sodium sulfate, filtered, and concentrated to dryness. The crude product S3was used directly in the next step.

2-Benzyl dimethyl malonate 7 (800 mg, 3.23 mmol) was dissolved in THF (20 mL) and stirred under

ice-bath. NaH (194 mg, 4.85 mmol) was added slowly in portion wise. The reaction mixture was then stirred under ice-bath for a further 15 min. A solution of crude allylic bromide S3 in THF (5 mL) was then added dropwise into the reaction mixture over 10 minutes. Thereafter, the reaction was allowed to warm to 25 oC and stirred for additional 4 h. Upon completion, water (10 mL) was added and the aqueous layer was extracted with EtOAc (3 x 20 mL). The organic extracts were combined, dried over MgSO4, filtered, and concentrated to dryness. The residue was purified over silica gel chromatography with n-hexane/ethyl acetate (4:1) to yield 5m as a colorless oil; 851 mg; Yield: 60%; IR (neat) 3028, 2951, 2837, 1731, 1576, 1434, 1248, 1047 cm-1; 1H NMR (CDCl3, 500 MHz) : δ 7.297.21 (m, 4H), 7.137.10 (m, 3H), 7.06 (d, J = 7.5 Hz, 2H), 6.92 (d, J = 7.5 Hz, 2H), 6.846.81 (m, 2H), 6.76 (s, 1H), 6.50 (s, 1H), 3.75 (s, 3H), 3.52 (s, 6H), 3.30 (s, 2H), 3.22 (s, 2H); 13C NMR (CDCl3, 125 MHz) : δ 171.0, 159.5, 141.2, 137.3, 136.6, 136.2, 131.8, 129.9, 129.3, 128.9, 128.0, 127.8, 126.7, 126.6, 121.8, 114.5, 113.2, 59.0, 55.1, 51.9, 42.4, 38.4; HRMS (ESI) calcd for C28H28NaO5 m/z [M + Na]+: 467.1834; found: 467.1829.

Methyl 4-phenylpent-4-enoate (8) : Methyl triphenylphosphonium bromide (4.5 g, 12.5 mmol) was suspended in THF (50 mL) at 0 oC, sodium tert-butoxide (1.92 g, 20.0 mmol) was added and stirred 30 mins at the same temperature. 4-Oxo-4-phenylbutyric acid methyl ester (2.0 g, 10.0 mmol) was added and the reaction mixture allowed to warm to room temperature and heated to reflux for 24 h. The reaction was quenched with satureated aqueous NH4Cl solution and extracted with EtOAc (2 x 50 mL). The organic extracts were combined, dried over MgSO4, filtered, and concentrated to dryness. The residue was purified over silica gel chromatography with n-hexane/ethyl acetate (4:1) to yield 7 (1.0 g; Yield: 50%) as colorless oil.3

Dimethyl 2-(2-phenylallyl)malonate (10) : Colorless oil; 476 mg; Yield: 88%.4

III. Synthesis of Products A. Bromolactonization of alkenoic dicarboxylic acid 1.

3-Benzyl-5-(bromomethyl)-2-oxo-5-phenyltetrahydrofuran-3-carboxylic acid (2) : To a solution of alkenoic dicarboxylic acid 1 (31 mg, 0.1 mmol) in dichloromethane (1 mL) at 0 oC in dark was added N-bromosuccinimide (27 mg, 0.15 mmol). The resulting mixture was stirred at room temperature for 12 h. The reaction was quenched with saturated Na2SO3 (0.5 mL) and diluted with water. The mixture was then basified by adding aqueous NaOH solution to pH 14 and extracted with dichloromethane (3 × 10 mL). The aqueous fraction was acidified with 2 M HCl to pH 2 and extracted with dichloromethane (3 × 10 mL). The combined organic extracts were washed with brine (5 mL), dried with MgSO4, filtered, and

S8

concentrated in vacuo to give the compound 2 [17 mg, 45% yield, a mixture of diastereomers in a ratio of 1:2 (syn : anti)] as a colorless oil; IR (neat) 3450, 3055, 2987, 1779, 1265, 740 cm-1; 1H NMR (CDCl3, 500 MHz) (syn + anti): δ 7.357.25 (m, 16H), 7.127.11 (m, 2H), 7.077.05 (m, 1H), 6.966.95 (m, 1H), 3.78, 3.74 (ABq, J = 12.0 Hz, 1H each), 3.63, 3.37 (ABq, J = 12.5 Hz, 1H each), 3.43, 3.29 (ABq, J = 13.5 Hz, 1H each), 3.32, 2.57 (ABq, J = 14.0 Hz, 1H each), 3.18, 3.12 (ABq, J = 13.5 Hz, 1H each), 2.90 (s, 2H); 13C NMR (CDCl3, 125 MHz) (syn + anti): δ 174.8, 173.9, 173.0, 172.9, 140.2, 139.5, 134.9, 134.2, 130.2, 130.1, 128.7, 128.5, 128.46, 128.41, 128.1, 127.9, 127.6, 127.4, 124.9, 124.2, 87.7, 87.2, 68.8, 68.1, 58.0, 57.3, 41.4, 40.2, 37.9, 36.5; HRMS (ESI) calcd for C19H17BrNaO4 m/z [M + Na]+: 411.0208; found: 411.0202.

B. The general procedure for the synthesis of products 6a6q is demonstrated as follows using 6a as a typical example.

Methyl 3-benzyl-5-(bromomethyl)-2-oxo-5-phenyltetrahydrofuran-3-carboxylate (X = Br; 6a + 6a′) : To a solution of olefinoic diester 3 (36 mg, 0.1 mmol) and H2O (1.8 l, 0.1 mmol) in THF (1 mL) at 0 oC in dark was added N-bromosuccinimide (27 mg, 0.15 mmol). The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated Na2SO3 (0.5 mL) and the solution was diluted with water (0.5 ml) and extracted with EtOAc (3 × 5 mL). The combined extracts were washed with brine (5 mL), dried with MgSO4, filtered, and concentrated in vacuo. The residue was subjected to purification by flash chromatography on silica gel n-hexane/EtOAc (4/1) to afford the compound 6a and 6a′ [40 mg, 95% yield, a mixture of diastereomers in a ratio of 10:1 (syn : anti)] as a colorless oil. IR (neat) 3056, 2956, 1783, 1736, 1450, 1265, 1018, 747, 704 cm-1; 1H NMR (CDCl3, 500 MHz) 6a (syn): δ 7.347.27 (m, 3H), 7.187.16 (m, 2H), 7.087.07 (m, 2H), 6.856.83 (m, 2H), 3.88 (s, 3H), 3.69 (s, 2H), 3.37, 2.48 (ABq, J = 14.0 Hz, 1H each), 3.29, 3.00 (ABq, J = 14.0 Hz, 1H each); 13C NMR (CDCl3, 125 MHz) 6a (syn): δ 172.5, 169.7, 140.8, 134.4, 129.8, 128.6, 128.5, 128.3, 127.4, 124.6, 84.2, 57.6, 53.4, 40.7, 40.6, 39.5; HRMS (ESI) calcd for C20H19BrNaO4 m/z [M + Na]+: 425.0364; found: 425.0359.

Methyl 3-benzyl-5-(chloromethyl)-2-oxo-5-phenyltetrahydrofuran-3-carboxylate (X = Cl; 6a + 6a′) : A mixture of diastereomers in a ratio of 2.5:1 (syn : anti) was obtained as a colorless oil; 26 mg; Yield: 74%; IR (neat) 3031, 2955, 1782, 1736, 1450, 1194, 733 cm-1; 1H NMR (CDCl3, 500 MHz) 6a (syn): δ 7.307.28 (m, 3H), 7.177.15 (m, 2H), 7.087.07 (m, 2H), 6.876.85 (m, 2H), 3.87 (s, 3H), 3.79, 3.75 (ABq, J = 12.0 Hz, 1H each), 3.36, 2.63 (ABq, J = 14.0 Hz, 1H each), 3.28, 3.03 (ABq, J = 14.0 Hz, 1H each); 13C NMR (CDCl3, 125 MHz) 6a (syn): δ 172.7, 169.8, 140.6, 134.4, 129.9, 128.6, 128.4, 128.3, 127.4, 124.5, 84.7, 57.5, 53.4, 51.5, 40.8, 38.7; HRMS (ESI) calcd for C20H19ClNaO4 m/z [M + Na]+: 381.0870; found: 381.0864.

S9

Methyl 3-benzyl-5-(iodomethyl)-2-oxo-5-phenyltetrahydrofuran-3-carboxylate (X = I; 6a + 6a′) : A mixture of diastereomers in a ratio of 5:1 (syn : anti) was obtained as a white solid; 44 mg; Yield: 98%; mp 7981 oC; IR (KBr) 3064, 2955, 1782, 1736, 1449, 1173, 1013, 744, 700 cm-1; 1H NMR (CDCl3, 500 MHz) 6a (syn): δ 7.357.28 (m, 3H), 7.187.16 (m, 2H), 7.107.08 (m, 2H), 6.846.82 (m, 2H), 3.88 (s, 3H), 3.63, 3.61 (ABq, J = 11.0 Hz, 1H each), 3.31, 2.74 (ABq, J = 14.0 Hz, 1H each), 3.31, 2.95 (ABq, J = 14.0 Hz, 1H each); 13C NMR (CDCl3, 125 MHz) 6a (syn): δ 172.2, 169.8, 141.5, 134.7, 129.8, 128.5, 128.4, 128.2, 127.4, 124.6, 83.8, 57.9, 53.3, 40.7, 40.5, 38.7, 15.9; HRMS (ESI) calcd for C20H19INaO4 m/z [M + Na]+: 473.0226; found: 473.0220.

Methyl 3-benzyl-5-(bromomethyl)-5-(4-methoxyphenyl)-2-oxotetrahydrofuran-3-carboxylate (6b + 6b′) : A mixture of diastereomers in a ratio of 10:1 (syn : anti) was obtained as a colorless oil; 31 mg; Yield: 72%; IR (neat) 2961, 1780, 1736, 1514, 1259, 1019 cm-1; 1H NMR (CDCl3, 500 MHz) 6b (syn): δ 7.127.08 (m, 5H), 6.886.85 (m, 2H), 6.82 (d, J = 8.5 Hz, 2H), 3.87 (s, 3H), 3.81 (s, 3H), 3.68, 3.64 (ABq, J = 11.5 Hz, 1H each), 3.36, 2.66 (ABq, J = 14.0 Hz, 1H each), 3.30, 2.99 (ABq, J = 14.0 Hz, 1H each); 13C NMR (CDCl3, 125 MHz) 6b (syn): δ 172.6, 169.7, 159.4, 134.6, 132.7, 129.9, 128.5, 127.4, 126.0, 113.9, 84.1, 57.6, 55.3, 53.4, 40.7, 40.6, 39.3; HRMS (ESI) calcd for C21H21BrNaO5 m/z [M + Na]+: 455.0470; found: 455.0465.

Methyl 3-benzyl-5-(bromomethyl)-5-(3-methoxyphenyl)-2-oxotetrahydrofuran-3-carboxylate (6c + 6c′) : A mixture of diastereomers in a ratio of 10:1 (syn : anti) was obtained as a white solid; 37 mg; Yield: 85%; mp 8587 oC; IR (KBr) 3055, 2987, 1783, 1737, 1435, 1265, 1020, 748, 705 cm-1; 1H NMR (CDCl3, 500 MHz) 6c (syn): δ 7.23 (t, J = 8.0 Hz, 1H), 7.097.07 (m, 3H), 6.886.85 (m, 2H), 6.82 (dd, J = 8.0 and 2.0 Hz, 1H), 6.52 (d, J = 8.0 Hz, 1H), 6.71 (t, J = 2.0 Hz, 1H), 3.87 (s, 3H), 3.79 (s, 3H), 3.67 (s, 2H), 3.36, 2.69 (ABq, J = 14.0 Hz, 1H each), 3.28, 3.01 (ABq, J = 14.0 Hz, 1H each); 13C NMR (CDCl3, 125 MHz) 6c (syn): δ 172.5, 169.7, 159.6, 142.4, 134.4, 129.9, 129.7, 128.4, 127.4, 116.8, 113.7, 110.5, 84.1, 57.6, 55.3, 53.4, 40.7, 40.6, 39.6; HRMS (ESI) calcd for C21H21BrNaO5 m/z [M + Na]+: 455.0470; found: 455.0465.

S10

Methyl 3-benzyl-5-(bromomethyl)-2-oxo-5-(o-tolyl)tetrahydrofuran-3-carboxylate (6d + 6d′) : A mixture of diastereomers in a ratio of 10:1 (syn : anti) was obtained as a pale yellow oil; 38mg; Yield: 91%; IR (neat) 3030, 2927, 1780, 1733, 1455, 1016, 764 cm-1; 1H NMR (CDCl3, 500 MHz) 6d (syn): δ 7.257.24 (m, 1H), 7.187.17 (m, 1H), 7.047.03 (m, 3H), 6.806.79 (m, 1H), 3.87 (s, 3H), 3.80, 3.73 (ABq, J = 11.5 Hz, 1H each), 3.41, 2.73 (ABq, J = 14.0 Hz, 1H each), 3.27, 2.99 (ABq, J = 14.0 Hz, 1H each); 13C NMR (CDCl3, 125 MHz) 6d (syn): δ 172.3, 169.7, 138.5, 134.3, 132.6, 132.5, 132.3, 129.7, 128.4, 127.4, 126.3, 125.6, 84.9, 57.3, 53.4, 41.1, 39.6, 39.1, 21.1; HRMS (ESI) calcd for C21H21BrNaO4 m/z [M + Na]+: 439.0521; found: 439.0515.

Methyl 3-benzyl-5-(bromomethyl)-5-(4-chlorophenyl)-2-oxotetrahydrofuran-3-carboxylate (6e + 6e′) : A mixture of diastereomers in a ratio of > 20:1 (syn : anti) was obtained as a colorless oil; 35 mg; Yield: 81%; IR (neat) 3031, 2959, 1783, 1736, 1258, 1014, 702 cm-1; 1H NMR (CDCl3, 500 MHz) 6e (syn): δ 7.22 (d, J = 8.5 Hz, 2H), 7.107.05 (m, 3H), 7.02 (d, J = 8.5 Hz, 2H), 6.896.88 (m, 2H), 3.88 (s, 3H), 3.64 (s, 2H), 3.32, 2.65 (ABq, J = 14.0 Hz, 1H each), 3.21, 3.15 (ABq, J = 14.0 Hz, 1H each); 13C NMR (CDCl3, 125 MHz) 6e (syn): δ 172.4, 169.7, 139.3, 134.2, 134.1, 129.9, 128.6, 128.5, 127.5, 126.0, 83.7, 57.6, 53.5, 40.7, 40.3, 39.6; HRMS (ESI) calcd for C20H18BrClNaO4 m/z [M + Na]+: 458.9975; found: 458.9969.

Methyl 3-benzyl-5-(bromomethyl)-5-(3-fluorophenyl)-2-oxotetrahydrofuran-3-carboxylate (6f + 6f′) : A mixture of diastereomers in a ratio of > 20:1 (syn : anti) was obtained as a white solid; 37 mg; Yield: 88%; mp 9395 oC; IR (KBr) 3055, 2987, 1785, 1736, 1444, 1264, 749 cm-1; 1H NMR (CDCl3, 500 MHz) 6f (syn): δ 7.24 (td, J = 8.0 and 6.0 Hz, 1H), 7.087.06 (m, 3H), 6.95 (td, J = 8.5 and 2.5 Hz, 1H), 6.906.87 (m, 3H), 6.77 (dt, J = 10.0 and 4.0 Hz, 1H), 3.89 (s, 3H), 3.66 (s, 2H), 3.32, 2.67 (ABq, J = 14.0 Hz, 1H each), 3.21, 3.16 (ABq, J = 14.0 Hz, 1H each); 13C NMR (CDCl3, 125 MHz) 6f (syn): δ 172.4, 169.8, 162.5 (d, 1JC-F = 245.9 Hz), 143.4 (d, 3JC-F = 7.1 Hz), 134.1, 130.2 (d, 3JC-F = 8.1 Hz), 129.9, 128.5, 127.6, 120.1 (d, 4JC-F = 3.0 Hz), 115.2 (d, 2JC-F = 20.9 Hz), 112.1 (d, 2JC-F = 23.6 Hz), 83.6, 57.7, 53.6, 40.8, 40.3, 39.8; HRMS (ESI) calcd for C20H18BrFNaO4 m/z [M + Na]+: 443.0270; found: 443.0265.

S11

Methyl 3-benzyl-5-(bromomethyl)-2-oxo-5-(4-(trifluoromethyl)phenyl)tetrahydrofuran-3-carboxyl- ate (6g + 6g′) : A mixture of diastereomers in a ratio of > 20:1 (syn : anti) was obtained as a white solid; 39 mg; Yield: 84%; mp 118120 oC; IR (KBr) 3055, 2987, 1785, 1642, 1736, 1265, 702 cm-1; 1H NMR (CDCl3, 500 MHz) 6g (syn): δ 7.46 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 7.006.98 (m, 3H), 6.876.86 (m, 2H), 3.90 (s, 3H), 3.66 (s, 2H), 3.34, 2.69 (ABq, J = 14.0 Hz, 1H each), 3.26, 3.14 (ABq, J = 14.0 Hz, 1H each); 13C NMR (CDCl3, 125 MHz) 6g (syn): δ 172.4, 169.8, 144.8, 134.0, 130.3 (q, 2JC-F

= 32.4 Hz), 129.9, 128.5, 127.6, 125.4 (q, 3JC-F = 3.6 Hz), 125.0, 123.8 (q, 1JC-F = 270.5 Hz), 83.7, 57.7, 53.6, 40.7, 40.1, 40.0; HRMS (ESI) calcd for C21H18BrF3NaO4 m/z [M + Na]+: 493.0238; found: 493.0233.

Methyl 3-benzyl-5-(bromomethyl)-5-(3-nitrophenyl)-2-oxotetrahydrofuran-3-carboxylate (6h + 6h′) : A mixture of diastereomers in a ratio of > 20:1 (syn : anti) was obtained as a white solid; 29 mg; Yield: 65%; mp 127129 oC; IR (KBr) 3055, 2928, 1788, 1736, 1535, 1268 cm-1; 1H NMR (CDCl3, 500 MHz) 6h (syn): δ 8.07 (d, J = 8.0 Hz, 2H), 7.81 (s, 1H), 7.427.35 (m, 2H), 6.986.90 (m, 5H), 3.91 (s, 3H), 3.68 (s, 2H), 3.38, 2.72 (ABq, J = 14.0 Hz, 1H each), 3.34, 3.08 (ABq, J = 14.0 Hz, 1H each); 13C NMR (CDCl3, 125 MHz) 6h (syn): δ 172.3, 169.8, 148.0, 143.0, 133.9, 130.6, 130.0, 129.5, 128.5, 127.5, 123.0, 119.8, 83.3, 57.7, 53.8, 40.6, 40.1, 29.7; HRMS (ESI) calcd for C20H18BrNNaO6 m/z [M + Na]+: 470.0215; found: 470.0210.

6i (major) 6i' (minor)

O

O

CO2Me

Ph

+

Br

O

O

CO2Me

Br

Ph

NC NC

Methyl 3-benzyl-5-(bromomethyl)-5-(4-cyanophenyl)-2-oxotetrahydrofuran-3-carboxylate (6i + 6i′) : A mixture of diastereomers in a ratio of 10:1 (syn : anti) was obtained as a white solid; 29 mg; Yield: 69%; mp 133135 oC; IR (KBr) 3054, 2987, 2305, 1785, 1735, 1422, 1264, 748 cm-1; 1H NMR (CDCl3, 500 MHz) 6i (syn): δ 7.50 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 8.5 Hz, 2H), 7.067.01 (m, 3H), 6.906.89 (m, 2H), 3.90 (s, 3H), 3.68, 3.65 (ABq, J = 11.0 Hz, 1H each), 3.32, 2.66 (ABq, J = 14.0 Hz, 1H each), 3.30, 3.13 (ABq, J = 14.0 Hz, 1H each); 13C NMR (CDCl3, 125 MHz) 6i (syn): δ 172.2, 169.7, 145.9, 134.0, 132.2, 129.9, 128.6, 127.6, 125.4, 118.1, 112.1, 83.5, 57.6, 53.7, 40.6, 39.9, 39.8; HRMS (ESI) calcd for C21H18BrNNaO4 m/z [M + Na]+: 450.0317; found: 450.0311.

S12

Methyl 5-(4-acetylphenyl)-3-benzyl-5-(bromomethyl)-2-oxotetrahydrofuran-3-carboxylate (6j + 6j′) : A mixture of diastereomers in a ratio of 10:1 (syn : anti) was obtained as a white solid; 42 mg; Yield: 95%; mp 119121 oC; IR (KBr) 3055, 2987, 1785, 1737, 1686, 1422, 1265, 747, 703 cm-1; 1H NMR (CDCl3, 500 MHz) 6j (syn): δ 7.83 (d, J = 8.5 Hz, 2H), 7.20 (d, J = 8.5 Hz, 2H), 7.057.03 (m, 3H), 6.896.87 (m, 2H), 3.89 (s, 3H), 3.69 (s, 2H), 3.35, 2.69 (ABq, J = 14.0 Hz, 1H each), 3.21, 3.16 (ABq, J = 14.0 Hz, 1H each); 13C NMR (CDCl3, 125 MHz) 6j (syn): δ 197.2, 172.3, 169.6, 145.7, 136.6, 134.1, 129.8, 128.5, 128.4, 127.4, 124.8, 83.9, 57.2, 53.6, 40.6, 40.0, 39.7, 26.6; HRMS (ESI) calcd for C22H21BrNaO5 m/z [M + Na]+: 467.0470; found: 467.0465.

Methyl 5-(bromomethyl)-2-oxo-5-phenyl-3-(prop-2-yn-1-yl)tetrahydrofuran-3-carboxylate (6k + 6k′) : A mixture of diastereomers in a ratio of 2:1 (syn : anti) was obtained as a colorless oil; 32 mg; Yield: 90%; IR (neat) 3302, 3059, 1956, 1784, 1741, 1266, 703, 653 cm-1; 1H NMR (CDCl3, 500 MHz) 6k (syn): δ 7.447.35 (m, 5H), 3.87 (s, 3H), 3.80, 3.75 (ABq, J = 11.5 Hz, 1H each), 3.50, 2.98 (ABq, J = 14.0 Hz, 1H each), 2.85 (dd, J = 16.5 and 2.5 Hz, 1H), 2.49 (dd, J = 16.5 and 2.5 Hz, 1H), 1.78 (t, J = 2.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz) 6k (syn): δ 171.5, 168.7, 140.7, 128.6 (3C), 124.9, 84.8, 77.9, 71.9, 55.7, 53.7, 40.4, 40.3, 25.3; HRMS (ESI) calcd for C16H15BrNaO4 m/z [M + Na]+: 373.0051; found: 373.0046.

Methyl 3-(2-bromoallyl)-5-(bromomethyl)-2-oxo-5-phenyltetrahydrofuran-3-carboxylate (6l + 6l′) : A mixture of diastereomers in a ratio of 5:1 (syn : anti) was obtained as a white solid; 42 mg; Yield: 97%; mp 8284 oC; IR (neat) 3055, 2956, 1785, 1738, 1436, 1265, 748 cm-1; 1H NMR (CDCl3, 500 MHz) 6l (syn): δ 7.427.37 (m, 5H), 5.41 (d, J = 2.0 Hz, 1H), 5.18 (s, 1H), 3.86 (s, 3H), 3.76, 3.73 (ABq, J = 11.5 Hz, 1H each), 3.65, 2.84 (ABq, J = 14.0 Hz, 1H each), 3.37, 2.59 (ABq, J = 15.0 Hz, 1H each); 13C NMR (CDCl3, 125 MHz) 6l (syn): δ 171.5, 168.5, 140.7, 128.8, 128.7, 126.1, 124.9, 122.3, 84.6, 55.8, 53.7, 45.2, 40.2, 38.8; HRMS (ESI) calcd for C16H16Br2NaO4 m/z [M + Na]+: 452.9313; found: 452.9308.

S13

O

O

CO2Me

6m (syn-major)

Br Ph

+

MeOO

O

CO2Me

Br Ph

MeO

6m' (anti-minor)

Ph

Ph

Methyl-3-benzyl-5-(bromo(phenyl)methyl)-5-(3-methoxyphenyl)-2-oxotetrahydrofuran-3-carboxyl- ate (6m + 6m′) : A mixture of diastereomers in a ratio of 2:1 (syn : anti) was obtained as a white solid; 46 mg; Yield: 90%; mp 6062 oC; IR (KBr) 3055, 2987, 1784, 1738, 1423, 1265, 740 cm-1; 1H NMR (CDCl3, 500 MHz) 6m (syn): δ 7.237.11 (m, 5H), 7.077.04 (m, 3H), 6.98 (d, J = 7.0 Hz, 1H), 6.81 (dd, J = 8.0 and 2.0 Hz, 1H), 6.766.75 (m, 2H), 6.70 (t, J = 8.0 Hz, 1H), 6.54 (s, 1H), 5.14 (s, 1H), 3.73 (s, 3H), 3.68 (s, 3H), 3.50, 2.74 (ABq, J = 14.0 Hz, 1H each), 3.26, 2.70 (ABq, J = 14.0 Hz, 1H each); 13C NMR (CDCl3, 125 MHz) 6m (syn): δ 172.1, 169.8, 158.9, 139.8, 136.0, 134.7, 130.4, 129.8, 129.3, 128.8, 128.6, 128.1, 127.5, 118.9, 114.2, 112.2, 87.3, 60.4, 57.3, 55.2, 52.6, 40.4, 39.6; HRMS (ESI) calcd for C27H25BrNaO5 m/z [M + Na]+: 531.0783; found: 531.0778.

6n (syn-major) 6n' (anti-minor)

O

O

CO2Et

Ph Ph

O

O

CO2EtPh

Ph

+

Br Br

Ethyl 3-benzyl-5-(bromomethyl)-2-oxo-5-phenyltetrahydrofuran-3-carboxylate (6n + 6n′) : A mixture of diastereomers in a ratio of > 20:1 (syn : anti) was obtained as a pale yellow solid; 34 mg; Yield: 82%; mp 8991 oC; IR (KBr) 3055, 1986, 1783, 1731, 1265, 738, 703 cm-1; 1H NMR (CDCl3, 500 MHz) 6n (syn): δ 7.307.27 (m, 3H), 7.177.15 (m, 2H), 7.087.06 (m, 2H), 6.876.86 (m, 2H), 4.33 (q, J = 7.5 Hz, 2H), 3.72, 3.70 (ABq, J = 7.0 Hz, 1H each), 3.36, 2.67 (ABq, J = 14.0 Hz, 1H each), 3.29, 3.02 (ABq, J = 14.0 Hz, 1H each), 1.36 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz) 6n (syn): δ 172.7, 169.2, 140.8, 134.6, 129.9, 128.5, 128.4, 128.2, 127.4, 124.6, 84.1, 62.7, 57.6, 40.5, 39.6, 14.0; HRMS (ESI) calcd for C21H21BrNaO4 m/z [M + Na]+: 439.0521; found: 439.0515.

Methyl 3-benzyl-5-(bromomethyl)-5-methyl-2-oxotetrahydrofuran-3-carboxylate (6o + 6o′) : A mixture of diastereomers in a ratio of 1.4:1 (syn : anti) was obtained as a colorless oil; 29 mg; Yield: 85%; IR (neat) 3031, 2955, 1773, 1734, 1437, 1168, 703 cm-1; 1H NMR (CDCl3, 500 MHz) 6o (syn): δ 7.347.29 (m, 3H), 7.217.18 (m, 2H), 3.84 (s, 3H), 3.50, 3.14 (ABq, J = 14.0 Hz, 1H each), 3.46, 3.41 (ABq, J = 10.5 Hz, 1H each), 2.85, 2.15 (ABq, J = 14.5 Hz, 1H each), 0.92 (s, 3H); 13C NMR (CDCl3, 125 MHz) 6o (syn): δ 173.3, 170.4, 135.0, 130.3, 128.8, 127.6, 82.4, 58.1, 53.4, 40.2, 38.9, 38.2, 25.4; HRMS (ESI) calcd for C15H17BrNaO4 m/z [M + Na]+: 363.0208; found: 363.0202.

S14

Methyl 5-(bromomethyl)-3-ethyl-2-oxo-5-phenyltetrahydrofuran-3-carboxylate (6p + 6p′) : A mixture of diastereomers in a ratio of 3:1 (syn : anti) was obtained as a colorless oil; 30 mg; Yield: 88%; IR (neat) 3030, 2972, 1782, 1743, 1449, 1245, 703 cm-1; 1H NMR (CDCl3, 500 MHz) 6p (syn): δ 7.427.34 (m, 5H), 3.85 (s, 3H), 3.74, 3.69 (ABq, J = 11.0 Hz, 1H each), 3.46, 2.60 (ABq, J = 13.5 Hz, 1H each), 1.95 (sext, J = 7.5 Hz, 1H), 1.68 (sext, J = 7.5 Hz, 1H), 0.77 (t, J = 7.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz) 6p (syn): δ 172.7, 170.0, 141.1, 128.7, 128.5, 124.7, 84.0, 56.5, 53.2, 40.7, 40.6, 29.1, 9.1; HRMS (ESI) calcd for C15H17BrNaO4 m/z [M + Na]+: 363.0208; found: 363.0202.

O

O

Ph

Br 9a 5-(Bromomethyl)-5-phenyldihydrofuran-2(3H)-one (9a) : Colorless oil; 15 mg; Yield: 58%.5

Methyl 5-bromo-4-hydroxy-4-phenylpentanoate (9b) : Colorless oil; 7 mg; Yield: 25%; IR (neat) 3491, 3028, 2952, 1732, 1446, 1201, 703 cm-1; 1H NMR (CDCl3, 500 MHz) : δ 7.417.35 (m, 4H), 7.317.28 (m, 1H), 3.75 (s, 2H), 3.61 (s, 3H), 3.72, 2.452.34 (m, 2H), 2.202.10 (m, 2H); 13C NMR (CDCl3, 125 MHz) : δ 174.3, 141.7, 128.5, 127.6, 125.3, 74.8, 51.7, 45.8, 34.7, 28.8; HRMS (ESI) calcd for C12H15BrNaO3 m/z [M + Na]+: 309.0102; found: 309.0097.

CO2Me

Br

HOPh

CO2Me

Dimethyl 2-(3-bromo-2-hydroxy-2-phenylpropyl)malonate (11) : Colorless oil; 29 mg; Yield: 85%; IR (neat) 3506, 3029, 2954, 1734, 1437, 1246, 1157, 703 cm-1; 1H NMR (CDCl3, 500 MHz) : δ 7.417.36 (m, 4H), 7.327.31 (m, 1H), 3.76, 3.71 (ABq, J = 10.5 Hz, 1H each), 3.74 (s, 3H), 3.53 (s, 3H), 3.30 (dd, J = 8.5 and 4.5 Hz, 1H), 2.82 (dd, J = 14.5 and 8.5 Hz, 1H), 2.77 (s, 1H), 2.50 (dd, J = 14.5 and 4.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz) : δ 170.4, 169.4, 140.7, 128.5, 127.8, 125.4, 74.5, 52.7, 52.5, 47.5, 45.5, 38.5; HRMS (ESI) calcd for C14H17BrNaO5 m/z [M + Na]+: 367.0157; found: 367.0152. C. Chemical transformation of -ester bromolactone

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3,8-bis(Bromomethyl)-3-(3-fluorophenyl)-8-phenyl-2,7-dioxaspiro[4.4]nonane-1,6-dione (11) : To

a mixture of the -ester bromolactone 6l [100 mg, 0.23 mmol, a ratio of 5:1 (syn : anti)], 3-Fluorophenylboronic acid (39 mg, 0.28 mmol), Pd(PPh3)4 (21 mg, 0.02 mmol), and Cs2CO3 (91 mg, 0.28 mmol) in MeOH (10 mL) was stirred at 60 oC for 6 h. The solvent was removed under reduced pressure, and the residue was diluted with water (10 mL) and extraced with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (10 mL), dired over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatogrphy n-hexane/EtOAc (5/1) to give the coupling product S4 + S4′ [59 mg, 58% yield, a mixture of diastereomers in a ratio of 2:1 (syn : anti)] was obtained as a colorless oil; IR (enat) 3063, 2954, 1788, 1739, 1581, 1448, 1224, 1018, 703 cm-1; 1H NMR (CDCl3, 500 MHz) S4 + S4′ (syn+anti): δ 7.407.28 (m, 5 + 3H), 7.187.14 (m, 1 + 0.5H), 7.07 (d, J = 10,5 Hz, 0.5H), 6.99 (t, J = 8.5 Hz, 0.5H), 6.92 (t, J = 8.0 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.63 (d, J = 10 Hz, 1H), 5.41 (s, 0.5H), 5.28 (s, 0.5H), 5.16 (s, 1H), 4.88 (s, 1H), 3.68, 3.57 (ABq, J = 11.5 Hz, 0.5H each), 3.68, 3.64 (ABq, J = 12.0 Hz, 1H each), 3.63 (s, 3H), 3.41, 3.08 (ABq, J = 14.0 Hz, 0.5H each), 3.38, 2.64 (ABq, J = 14.0 Hz, 1H each), 3.31, 2.71 (ABq, J = 14.5 Hz, 1H each), 3.11 (s, 1.5H), 3.03, 2.75 (ABq, J = 13.5 Hz, 0.5H each); 13C NMR (CDCl3, 125 MHz) S4 + S4′ (syn+anti): δ 172.2, 172.1, 169.0, 168.5, 162.7 (d, 1JC-F = 244.8 Hz), 162.5 (d, 1JC-F = 244.9 Hz), 143.0 (d, 3JC-F = 7.4 Hz), 142.7 (d, 3JC-F = 7.4 Hz), 142.4 (d, J = 1.3 Hz,), 142.3 (d, J = 1.8 Hz), 140.9, 139.2, 129.8 (d, 3JC-F = 8.4 Hz), 129.7 (d, 3JC-F = 8.1 Hz), 128.7, 128.6 (2C), 128.5, 125.1, 124.8, 122.3 (d, 4JC-F = 2.8 Hz), 122.2 (d, 4JC-F = 2.6 Hz), 119.5, 119.2, 114.7 (d, 2JC-F = 20.9 Hz), 114.6 (d, 2JC-F = 21.0 Hz), 113.7 (d, 2JC-F = 21.8 Hz), 113.6 (d, 2JC-F = 21.9 Hz), 84.3, 84.1, 56.1, 53.4, 53.2, 52.6, 40.6, 40.5, 40.4, 40.0, 39.8, 38.9; HRMS (ESI) calcd for C22H20BrFNaO4 m/z [M + Na]+: 469.0427; found: 469.0421.

To a solution of coupling product S4 + S4′ (59 mg, 0.13 mmol) and H2O (2.0 l, 0.13 mmol) in THF (1

mL) at 0 oC in dark was added N-bromosuccinimide (36 mg, 0.20 mmol). The resulting mixture was stirred at room temperature for 2 h. The reacion was quenched with saturated Na2SO3 (1.0 mL) and the solution was diluted with water (1.0 ml) and extracted with EtOAc (3 × 10 mL). The combined extracts were washed with brine (10 mL), dried with MgSO4, filtered, and concentrated in vacuo. The residue was subjected to purification by flash chromatography on silica gel n-hexane/EtOAc (4/1) to afford the compound 7 + 7′ (40 mg, 59% yield, a mixture of diastereomers in a ratio of 2:1:1:0) was obtained as a white solid; mp 8991 oC; IR (enat) 3062, 1965, 1790, 1770, 1591, 1446, 1264, 1194, 739 cm-1; 1H NMR (CDCl3, 500 MHz) : δ 7.487.29 (m, 12H), 7.217.03 (m, 6H), 3.913.87 (m, 3H), 3.803.71 (m, 5H), 3.653.66 (m, 3H), 3.41 (t, J = 13.5 Hz, 0.5H), 3.173.12 (m, 1H), 3.022.94 (m, 2H), 2.82, 2.56 (ABq, J = 14.0 Hz, 0.5H each), 2.69, 2.50 (ABq, J = 14.0 Hz, 1H each), 2.30 (d, J = 13.5 Hz, 0.5H), 2.20 (d, J = 13.5 Hz, 0.5H); 13C NMR (CDCl3, 125 MHz) major : δ 172.2, 172.1, 162.8 (d, 1JC-F = 247.4 Hz), 139.9 (d, 3JC-F = 9.8 Hz), 139.6, 130.7 (d, 3JC-F = 8.1 Hz), 129.1, 125.1, 124.5, 120.3 (d, 4JC-F = 3.9 Hz), 116.0 (d,

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2JC-F = 20.8 Hz), 112.2 (d, 2JC-F = 23.8 Hz), 85.8, 84.5, 53.7, 45.0, 44.2, 41.6, 39.1; HRMS (ESI) calcd for C21H17Br2FNaO4 m/z [M + Na]+: 532.9375; found: 532.9370. IV. Reference (1) N. T. Barczak and E. R. Jarvo, Chem. Eur. J., 2011, 17, 12912. (2) A. V. Malkov, L. Czemerys and D. A. Malyshev, J. Org. Chem., 2009, 74, 3350. (3) D. C. Braddock, G. Cansell and S. A. Hermitage, Chem. Commun., 2006, 2483. (4) Z. Ke, C, K, Tan and Y.-Y. Yeung, J. Am. Chem. Soc., 2014, 136, 5627. (5) L. Zhou, C. K. Tan, X. Jiang, F. Chen and Y.-Y. Yeung, J. Am. Chem. Soc., 2010, 132, 15474.

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V. 1H & 13C NMR spectra for all substrates

S18

S19

S20

S21

S22

S23

S24

S25

S26

S27

S28

S29

S30

S31

S32

S33

S34

S35

S36

S37

S38

S39

S40

S41

S42

S43

S44

S45

S46

S47

S48

S49

S50

S51

VI. 1H & 13C NMR spectra for all new products

O

O

CO2H

PhPh

2 (syn+anti)

Br

S52

O

O

CO2H

PhPh

2 (syn+anti)

Br

S53

O

O

CO2Me

Ph Ph

6a (syn-major)

O

O

CO2MePh

Ph

+

6a' (anti-minor)Br Br

S54

O

O

CO2Me

Ph Ph

6a (syn-major)

O

O

CO2MePh

Ph

+

6a' (anti-minor)Br Br

S55

S56

S57

S58

S59

S60

S61

S62

S63

S64

S65

S66

S67

S68

S69

S70

S71

S72

S73

S74

S75

S76

S77

S78

S79

S80

S81

S82

S83

S84

S85

S86

S87

S88

S89

S90

S91

S92

S93

S94

S95

S96

S97

VII. X-Ray structure of compound 6g (CCDC 1049123)