Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2012

Supporting Information

Versatile Approach to α-Alkoxy Carbamate Synthesis and Stimulus-Responsive Alcohol Release

R. Adam Mosey and Paul E. Floreancig* Department of Chemistry University of Pittsburgh Pittsburgh, Pennsylvania 15260, USA

General Experimental: Proton (1H NMR) and carbon (13C NMR) nuclear magnetic resonance spectra were recorded on a Bruker Avance 400 spectrometer at 400 MHz and 100 MHz, or a Bruker Avance 500 spectrometer at 500 MHz and 125 MHz if specified. The chemical shifts are given in parts per million (ppm) on the delta (δ) scale. The solvent peak was used as a reference value, for 1H 13 NMR: CDCl3 = 7.27 ppm, C6D6 = 7.16 ppm, (CD3)2SO = 2.50 ppm, CD3CN = 1.94; for C NMR: CDCl3 = 77.0 ppm, C6D6 = 128.0 ppm (CD3)2SO = 39.5 ppm. Data are reported as follows: (s = singlet; d = doublet; t = triplet; q = quartet; p = pentet; dd = doublet of doublets; dt = doublet of triplets; br = broad). High resolution and low resolution mass spectra were recorded on a VG 7070 spectrometer. Infrared (IR) spectra were collected on a Mattson Cygnus 100 spectrometer. Samples for IR were prepared as a thin film on a NaCl plate by dissolving the compound in CH2Cl2 and then evaporating the CH2Cl2. Melting points were obtained using a Mel-Temp capillary melting point apparatus and are uncorrected. Acetonitrile and CH2Cl2 were distilled under N2 from CaH2. p-Dioxane and dimethylformamide were purchased from Sigma Aldrich and stored over 4 Ǻ molecular sieves prior to use. Phosgene (20% solution in toluene), trimethylacetonitrile, neopentyl alcohol, 4-methoxybenzonitrile, 4-(trifluoromethyl)benzonitrile, . benzyl chloroformate, 4-nitrobenzyl chloroformate, bis(pinacolato)diboron, Pd(dppf)Cl2 CH2Cl2, potassium acetate, 2,2,5,7,8-pentamethyl-6-chromanol, ammonium fluoride, N-(3- dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDCI), 4-(dimethylamino)pyridine (DMAP), (4-carboxybutyl)triphenylphosphonium bromide, urea hydrogen peroxide, DBU, and dithiothreitol were purchased from Sigma Aldrich, checked for purity, and used without further purification. Schwartz’s reagent was prepared according to a known literature procedure.1 Analytical TLC was performed on E. Merck pre-coated (25 mm) silica gel 60F-254 plates; visualization performed under UV (254 nm). Flash chromatography performed using ICN SiliTech 32-63 60 Å silica gel. Reagent grade dichloromethane, diethyl ether, ethyl acetate, methanol, and hexanes (commercial mixture) were purchased from EM Science and used without further purification for chromatography. All reactions were performed in oven or flame- dried glassware under argon with magnetic stirring unless otherwise noted.

General procedure for chloroformate synthesis. Chloroformates were prepared in accordance with a known procedure.2 A solution of a benzylic alcohol derivative in p-dioxane was treated with phosgene solution (20% in toluene, 2 equiv.), and the reaction stirred at rt for approximately 20-24 h. The reaction was concentrated to remove all volatiles and was then diluted with benzene and reconcentrated (x2) to afford the crude product. Crude chloroformates were either used immediately in a subsequent reaction, or they were stored neat or in CH2Cl2 at 0 °C over anhydrous Na2SO4 for later use.

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General procedure for α-alkoxy carbamate synthesis. This protocol was adopted from a 3 literature procedure. A solution of the nitrile in CH2Cl2 was treated with Cp2Zr(H)Cl. The reaction was stirred at rt for either 20 min (for aliphatic nitriles) or 3 h (for aromatic nitriles), after which time the reaction was cooled to 0 °C and treated with a chloroformate. The cooling bath was removed, and the mixture was stirred for 20-30 minutes. The reaction was then cooled to 0 °C and treated with a 2.0 M solution of the appropriate alcohol in CH2Cl2 (solution dried over 4 Ǻ molecular sieves). The cooling bath was removed, and the mixture was stirred for 3-4 h, after which the reaction was quenched with saturated NaHCO3 solution. The mixture was extracted with CH2Cl2, and the combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was then purified by flash chromatography to afford the desired product.

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl chloroformate (2) O Prepared according to the general chloroformate synthesis protocol with (4- B O (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol 1 (1.50 g, Cl O 6.42 mmol), 20% phosgene solution (6.4 mL, 13 mmol) and p-dioxane (3.2 O mL). After removal of volatiles, the crude product was stored in the freezer 1 over anhydrous Na2SO4 for later use. H NMR (400 MHz, C6D6) δ 1.11 (s, 12H), 4.60 (s, 2H), 13 6.95 (d, J = 8.1 Hz, 2H), 8.02 (d, J = 8.0 Hz, 2H); C NMR (100 MHz, C6D6) δ 150.3, 136.6, 135.6, 128.1, 83.9, 73.1, 24.9. The 1H NMR spectral data are consistent with those reported in the literature.4

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl (2,2- O B dimethyl-1-(neopentyloxy)propyl)carbamate (5) O H Prepared according to the general carbamate synthesis protocol with N O trimethylacetonitrile (49.7 mg, 0.598 mmol), CH2Cl2 (4.8 mL), O O Cp2Zr(H)Cl (186.0 mg, 0.721 mmol), chloroformate 2 (214.4 mg, 0.723 mmol), and neopentyl alcohol (2.0 M in CH2Cl2, 2.7 mL, 5.4 mmol). The reaction was quenched with saturated NaHCO3 (5 mL). The mixture was extracted with CH2Cl2 (3 x 10 mL), and the combined organic extracts were washed with brine (30 mL), dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (CH2Cl2 : hexanes : ether = 70:30:1) to afford the desired product (167 mg, 64%) as an oil. 1H NMR (400 MHz, CDCl3) δ 0.89 (s, 9H), 0.94 (s, 9H), 1.35 (s, 12H), 3.02 (d, J = 8.6 Hz, 1H), 3.23 (d, J = 8.6 Hz, 1H), 4.60 (d, J = 10.4 Hz, 1H), 4.97 (d, J = 10.3 Hz, 1H), 5.15 (s, 2H), 7.36 (d, J = 8.0 13 Hz, 2H), 7.82 (d, J = 8.0 Hz, 2H). C NMR (100 MHz, CDCl3) δ 156.3, 139.5, 135.0, 127.0, 88.7, 83.8, 78.4, 66.5, 35.9, 32.0, 26.7, 24.9, 24.8; IR (neat) 3326, 2956, 2864, 1715, 1362, 1217, –1 + 1089 cm ; HRMS (ESI): m/z calcd for C24H40BNO5Na (M+Na) 456.2897, found 456.2890.

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl (1-

O (neopentyloxy)ethyl)carbamate (10) B O Prepared according to the general carbamate synthesis protocol with H N O acetonitrile (25 mg, 0.61 mmol), CH2Cl2 (5.0 mL), Cp2Zr(H)Cl (181

O O mg, 0.70 mmol), chloroformate 2 (212 mg, 0.716 mmol), and neopentyl alcohol (2.0 M in CH2Cl2, 2.8 mL, 5.6 mmol). The reaction was quenched with saturated NaHCO3 (5 mL). The mixture was extracted with CH2Cl2 (3 x 10 mL), and the combined organic extracts were washed with brine (30 mL), dried (Na2SO4) and concentrated. The residue was purified by flash chromatography

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1 (1% - 2% ether in CH2Cl2) to afford the desired product (35 mg, 15%) as an oil. H NMR (400 MHz, CDCl3) δ 0.88 (s, 9H), 1.35 (s, 15H), 3.10 (d, J = 8.9 Hz, 1H), 3.25 (d, J = 8.9 Hz, 1H), 5.02 – 5.17 (m, 4H), 7.36 (d, J = 7.7 Hz, 2H), 7.81 (d, J = 7.7 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 155.6, 139.4, 135.0, 127.1, 83.8, 79.5, 78.3, 66.5, 31.7, 26.6, 24.8, 21.9; IR (neat) 3325, 2979, 2865, 1712, 1522, 1359, 1235, 1090 cm–1; HRMS (ESI): m/z calcd for + C21H34BNO5Na (M+Na) 414.2428, found 414.2437.

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl O ((neopentyloxy)(4-(trifluoromethyl)phenyl)methyl)carbamate F C B 3 O H (11) N O Prepared according to the general carbamate synthesis protocol O O with 4-(trifluoromethyl)benzonitrile (96 mg, 0.56 mmol), CH2Cl2 (4.0 mL), Cp2Zr(H)Cl (176 mg, 0.684 mmol), chloroformate 2 (195 mg, 0.658 mmol), and neopentyl alcohol (2.0 M in CH2Cl2, 2.6 mL, 5.2 mmol). The reaction was quenched with saturated NaHCO3 (5 mL). The mixture was extracted with CH2Cl2 (3 x 10 mL), and the combined organic extracts were washed with brine (30 mL), dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (CH2Cl2 : hexanes : ether = 80:20:2) to afford the desired product (97 mg, 33%) as a foamy solid 1 (m.p. = 45 – 47 °C). H NMR (400 MHz, CDCl3) δ 0.97 (s, 9H), 1.36 (s, 12H), 3.26 (d, J = 8.7 Hz, 1H), 3.43 (d, J = 8.7 Hz, 1H), 5.20 (s, 2H), 5.34 (d, J = 9.8 Hz, 1H), 6.05 (d, J = 9.9 Hz, 1H), 7.38 (d, J = 7.8 Hz, 2H), 7.56 – 7.65 (m, 4 H), 7.82 (d, J = 7.9 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 155.9, 143.7, 139.0, 135.0, 130.5 (q, J = 33 Hz), 127.1, 126.4, 125.4, 124.0 (q, J = 270 Hz), 83.9, 82.2, 78.7, 67.0, 32.0, 26.7, 24.8; IR (neat) 3318, 2974, 2860, 1712, 1360, 1328, 1238, –1 + 1127 cm . HRMS (ESI): m/z calcd for C20H35BF3NO5Na (M+Na) 544.2458, found 544.2449.

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl ((4- O MeO B methoxyphenyl)(neopentyloxy)methyl)carbamate (12) O H N O Prepared according to the general carbamate synthesis protocol with 4-methoxybenzonitrile (74 mg, 0.56 mmol), CH2Cl2 (4.0 O O mL), Cp2Zr(H)Cl (173 mg, 0.672 mmol), chloroformate 2 (201 mg, 0.679 mmol), and neopentyl alcohol (2.0 M in CH2Cl2, 2.5 mL, 5.0 mmol). The reaction was quenched with saturated NaHCO3 (5 mL). The mixture was extracted with CH2Cl2 (3 x 10 mL), and the combined organic extracts were washed with brine (30 mL), dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (CH2Cl2 : hexanes : ether = 80:20:0 to 80:20:2) to afford the desired product with some impurities. Additional purification via column chromatography (CH2Cl2 : hexanes : TEA : ether = 50:50:0.5:0 to 50:50:0.5:2 as eluent) afforded the desired product (41 mg, 15%) as an oil. 1H NMR (400 MHz, C6D6) δ 0.95 (s, 9H), 1.11 (s, 12H), 3.23 (d, J = 8.5 Hz, 1H), 3.29 (s, 3H), 3.46 (d, J = 8.4 Hz, 1H), 4.96 – 5.12 (m, 3H), 6.19 (d, J = 9.7 Hz, 1H), 6.73 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 7.4 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 8.13 (d, J = 7.7 Hz, 2H); 13C NMR (100 MHz, C6D6) δ 160.0, 156.0, 140.3, 135.5, 132.7, 128.5, 127.5, 114.0, 83.8, 83.1, 78.6, 66.7, 54.8, 32.1, 26.9, 24.9; IR (neat) 3321, 2966, 2864, 1720, 1507, 1364, 1246, 1091 cm–1; HRMS (ESI): m/z + calcd for C27H38BNO6Na (M+Na) 506.2690, found 506.2689.

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(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol O B (S1) O 1 HO H NMR (400 MHz, CDCl3) δ 1.34 (s, 12H), 2.68 (s, 1H), 4.64 (s, 2H), 7.00 F (d, J = 10.2 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 7.66 (dd, J = 7.4, 6.4 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 167.3 (d, J = 249 Hz), 147.2 (d, J = 8 Hz), 136.8 (d, J = 8 Hz), 121.4 (d, J = 2 Hz), 113.1 (d, J = 25 Hz), 83.9, 64.0, 24.7. The 1H NMR spectral data are consistent with those reported in the literature.5

3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl O chloroformate (S2) B O Prepared according to the general chloroformate synthesis protocol with S1 Cl O F (140 mg, 0.556 mmol), 20% phosgene solution (0.65 mL, 1.31 mmol) and O p-dioxane (0.50 mL). After removal of volatiles, crude product was diluted in CH2Cl2 (0.40 mL) and dried over anhydrous Na2SO4 for 1 h prior to use (title compound was 1 used as solution in CH2Cl2). H NMR (400 MHz, C6D6) δ 1.10 (s, 12H), 4.43 (s, 2H), 6.62 (d, J = 13 8.6 Hz, 2H), 7.85 (t, J = 6.8 Hz, 1H); C NMR (100 MHz, C6D6) δ 167.8 (d, J = 250 Hz), 150.2, 139.3 (d, J = 8 Hz), 137.7 (d, J = 8 Hz), 123.8 (d, J = 3 Hz), 115.8 (d, J = 25 Hz), 84.4, 72.2 (d, J = 2 Hz), 25.2.

3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl (2,2- O dimethyl-1-(neopentyloxy)propyl)carbamate (13) B O H Prepared according to the general carbamate synthesis protocol with N O F trimethylacetonitrile (38 mg, 0.46 mmol), CH2Cl2 (3.5 mL), O O Cp2Zr(H)Cl (145 mg, 0.564 mmol), S2 (0.556 mmol), and neopentyl alcohol (2.0 M in CH2Cl2, 2.1 mL, 4.2 mmol). The reaction was quenched with saturated NaHCO3 (5 mL). The mixture was extracted with CH2Cl2 (3 x 10 mL), and the combined organic extracts were washed with brine (30 mL), dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (CH2Cl2 : hexanes : ether = 80:20:1 to 80:20:2) to afford the desired product (62 mg, 30%) as an oil. 1H NMR (400 MHz, CDCl3) δ 0.89 (s, 9H), 0.94 (s, 9H), 1.36 (s, 12H) 3.01 (d, J = 8.6 Hz, 1H), 3.23 (d, J = 8.5 Hz, 1H), 4.58 (d, J = 10.4 Hz, 1H), 4.97 (d, J = 10.2 Hz, 1H), 5.13 (d, J = 2.7 Hz, 2H), 7.03 (d, J = 9.9 Hz, 1H), 7.11 (d, J = 7.5 Hz, 1H), 7.73 (t, J = 6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 167.3 (d, J = 250 Hz), 156.1, 142.5 (d, J = 8 Hz), 137.0 (d, J = 9 Hz), 122.4 (d, J = 3 Hz), 114.1 (d, J = 25 Hz), 88.8, 83.9, 78.5, 65.5, 35.9, 32.0, 26.7, 24.9, 24.8; IR (neat) 3338, –1 2957, 2864, 1717, 1508, 1357, 1146, 1068 cm ; HRMS (ESI): m/z calcd for C24H39BFNO5Na (M+Na)+ 474.2803, found 474.2802.

Br O O a B b B HO O O HO Cl O OMe OMe O OMe S3 S4 S5 Reagents and conditions a) Bis(pinacolato)diboron, Pd(dppf)Cl2•CH2Cl2, KOAc, DMF, 80 °C. b) Cl2CO, p-dioxane.

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Br (4-bromo-2-methoxyphenyl)methanol (S3) HO 1 H NMR (500 MHz, CDCl3) δ 2.10 (br s, 1H), 3.87 (s, 3H), 4.64 (s, 2H), 7.02 (d, J 13 OMe = 1.7 Hz, 1H), 7.10 (dd, J = 8.0, 1.8 Hz, 1H), 7.17 (d, J = 7.9 Hz, 1H); C NMR 1 (125 MHz, CDCl3) δ 157.9, 129.7, 128.2, 123.6, 122.0, 113.9, 61.4, 55.6. The H NMR spectral data are consistent with those reported in the literature.6

(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- O yl)phenyl)methanol (S4) B O A mixture of S3 (609 mg, 2.81 mmol), bis(pinacolato)diboron (871 mg, 3.43 HO . mmol), Pd(dppf)Cl2 CH2Cl2 (116 mg, 0.142 mmol), and KOAc (860 mg, 8.77 OMe mmol) in degassed DMF (13.0 mL) was stirred at 80 °C in a sealed vial for 6 h. The reaction was allowed to cool to rt and was then diluted with a THF/EtOAc mixture (1:4, 50 mL). The reaction mixture was washed successively with a water/brine mixture (1:1, 50 mL) and brine (2 x 50 mL) before being passed through a silica plug consisting of (from top to bottom): celite, activated charcoal, silica, Na2SO4, and MgSO4. The plug was washed generously with a CH2Cl2/ether mixture (1:1), and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (CH2Cl2 : EtOAc : ether = 90:10:0 to 90:10:5 as eluent) to afford the desired prduct (646 mg, 87%) as a light orange solid (m.p. = 96 – 98 °C). 1H NMR (400 MHz, CDCl3) δ 1.34 (s, 12H), 2.97 (s, 1H), 3.85 (s, 3H), 4.67 (s, 2H), 7.28 (s, 1H), 7.31 (d, 13 J = 7.3 Hz, 1H), 7.42 (d, J = 7.3 Hz, 1H). C NMR (100 MHz, CDCl3) δ 156.4, 132.3, 127.5, 127.3, 115.3, 83.6, 61.2, 55.1, 24.6; IR (neat) 3416, 2978, 2860, 1401, 1356, 1148, 1029 cm–1; + HRMS (EI): m/z calcd for C14H21BO4 (M ) 264.1533, found 264.1532.

2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl O chloroformate (S5) B O Prepared according to the general chloroformate synthesis protocol with S4 Cl O (205 mg, 0.775 mmol), 20% phosgene solution (0.77 mL, 1.6 mmol) and p- O OMe dioxane (0.38 mL). After removal of volatiles, crude product was diluted in CH2Cl2 (0.30 mL) and dried over anhydrous Na2SO4 for 1 h prior to use (title compound was 1 used as solution in CH2Cl2). H NMR (400 MHz, C6D6) δ 1.14 (s, 12H), 3.18 (s, 3H), 5.05 (s, 2H), 7.07 (d, J = 7.4 Hz, 1H), 7.45 (s, 1H), 7.71 (dd, J = 7.3, 0.7 Hz, 1H); 13C NMR (100 MHz, C6D6) δ 157.6, 150.4, 130.3, 125.2, 116.6, 84.0, 69.2, 54.8, 24.9.

2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl

O (2,2-dimethyl-1-(neopentyloxy)propyl)carbamate (14) B O Prepared according to the general carbamate synthesis protocol with H N O trimethylacetonitrile (46 mg, 0.55 mmol), CH2Cl2 (4.0 mL), O O OMe Cp2Zr(H)Cl (170 mg, 0.661 mmol), S5 (0.775 mmol), and neopentyl alcohol (2.0 M in CH2Cl2, 2.4 mL, 4.8 mmol). The reaction was quenched with saturated NaHCO3 (5 mL). The mixture was extracted with CH2Cl2 (3 x 10 mL), and the combined organic extracts were washed with brine (30 mL), dried (Na2SO4) and concentrated. The residue was purified by column chromatography (CH2Cl2 : hexanes : ether = 80:20:1 to 80:20:2) to afford the desired product (153 mg, 60%) as a foamy 1 solid (m.p. = 38 – 41 °C). H NMR (400 MHz, CDCl3) δ 0.89 (s, 9H), 0.94 (s, 9H), 1.35 (s, 12H), 3.03 (d, J = 8.6 Hz, 1H), 3.25 (d, J = 8.6 Hz, 1H), 3.89 (s, 3H), 4.61 (d, J = 10.4 Hz, 1H), 4.96 (d, J = 10.3 Hz, 1H), 5.22 (d, J = 3.6 Hz, 2H), 7.30 (s, 1H), 7.34 (d, J = 7.4 Hz, 1H), 7.42 13 (d, J = 7.4 Hz, 1H); C NMR (100 MHz, CDCl3) δ 156.7, 156.5, 128.3, 128.0, 127.1, 115.8,

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88.6, 83.8, 78.3, 62.0, 55.5, 35.9, 32.0, 26.7, 25.0, 24.8; IR (neat) 3333, 2954, 2864, 1710, 1508, –1 + 1403, 1358, 1238, 1047 cm ; HRMS (ESI): m/z calcd for C25H42BNO6Na (M+Na) 486.3003, found 486.3006.

1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanol (S6) O 1 B H NMR (400 MHz, CDCl3) δ 1.34 (s, 12H), 1.45 (d, J = 6.5 Hz, 3H), 2.74 (s, O HO 1H), 4.85 (q, J = 6.4 Hz, 1H), 7.34 (d, J = 7.9 Hz, 1H), 7.78 (d, J = 7.9 Hz, 13 1H); C NMR (100 MHz, CDCl3) δ 149.0, 134.8, 124.6, 83.6, 70.0, 25.1, 24.7. The NMR spectral data are consistent with those reported in the literature.7

1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl O B chloroformate (S7) O Cl O Prepared according to the general chloroformate synthesis protocol with S6

O (187 mg, 0.752 mmol), 20% phosgene solution (0.75 mL, 1.5 mmol) and p- dioxane (0.38 mL). After removal of volatiles, crude product was used without purification for the synthesis of 11.

1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl (2,2- O B dimethyl-1-(neopentyloxy)propyl)carbamate (15) O H Prepared according to the general carbamate synthesis protocol with N O trimethylacetonitrile (48 mg, 0.58 mmol), CH2Cl2 (4.7 mL), O O Cp2Zr(H)Cl (179 mg, 0.695 mmol), S7 (0.752 mmol), and neopentyl alcohol (2.0 M in CH2Cl2, 2.6 mL, 5.2 mmol). The reaction was quenched with saturated NaHCO3 (5 mL). The mixture was extracted with CH2Cl2 (3 x 10 mL), and the combined organic extracts were washed with brine (30 mL), dried (Na2SO4) and concentrated. The residue was purified by column chromatography (CH2Cl2 : hexanes : ether = 85:15:1 to 85:15:2) to afford the desired product (35 mg, 14%) as an oil in a 1 1:1 diastereomeric ratio. H NMR (400 MHz, CDCl3) δ 0.80 – 0.96 (m, 18H), 1.34 (s, 12H), 1.52 – 1.58 (m, 3H), 2.88 (d, J = 8.6 Hz, 0.5H), 2.99 – 3.07 (m, 1H), 3.28 (d, J = 8.6 Hz, 0.5H), 4.49 – 4.58 (m, 1H), 4.84 – 4.96 (m, 1H), 5.80 (q, J = 6.6 Hz, 1H), 7.36 (t, J = 7.2 Hz, 2H), 7.80 (dd, J 13 = 8.0, 1.4 Hz, 2H); C NMR (100 MHz, CDCl3) δ 155.91, 155.87, 145.3, 135.0, 125.1, 125.0, 88.58, 88.55, 83.75, 83.74, 78.5, 78.2, 72.76, 72.71, 35.8, 32.1, 31.9, 26.8, 26.7, 25.0, 24.84, 24.80, 22.4, 22.3; IR (neat) 3344, 2956, 2870, 1714, 1516, 1362, 1145, 1089 cm–1; HRMS (ESI): + m/z calcd for C25H42BNO5Na (M+Na) 470.3054, found 470.3067.

OH 2-neopentylphenol (S8) 1 H NMR (400 MHz, CDCl3) δ 7.06 – 7.14 (m, 2H), 6.87 (td, J = 7.4, 1.2 Hz, 1H), 6.79 (dd, J = 8.0, 1.0 Hz, 1H), 4.62 (s, 1H), 2.54 (s, 2H), 0.97 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 154.0, 132.8, 127.3, 125.5, 120.2, 115.4, 43.0, 32.7, 29.5. The NMR spectral data are consistent with those reported in the literature.8

S6 Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2012

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl (2,2- O dimethyl-1-(2-neopentylphenoxy)propyl)carbamate (16) B O Prepared according to the general carbamate synthesis protocol with H N O trimethylacetonitrile (30 mg, 0.36 mmol), CH2Cl2 (2.8 mL), O O Cp2Zr(H)Cl (116 mg, 0.450 mmol), chloroformate 2 (131 mg, 0.442 mmol), and S8 (120 mg diluted in 0.40 mL CH2Cl2, 0.731 mmol). The reaction was quenched with saturated NaHCO3 (5 mL). The mixture was extracted with CH2Cl2 (3 x 10 mL), and the combined organic extracts were washed with brine (30 mL), dried (Na2SO4) and concentrated. The residue was purified by column chromatography (0% to 2% ether in CH2Cl2) to afford the desired 1 product (33 mg, 18%) as a foamy solid (m.p. = 42 - 46 °C). H NMR (400 MHz, CDCl3) δ 0.93 (s, 9H), 1.08 (s, 9H), 1.38 (s, 12H), 2.45 (d, J = 12.8 Hz, 1H), 2.69 (d, J = 12.8 Hz, 1H), 5.02 – 5.18 (m, 3H), 5.53 (d, J = 10.4 Hz, 1H), 6.91 (t, J = 7.2 Hz, 1H), 7.07 – 7.21 (m, 3H), 7.29 (d, J 13 = 8.0 Hz, 2H), 7.79 (d, J = 8.0 Hz, 2H); C NMR (100 MHz, CDCl3) δ 155.6, 154.7, 139.2, 135.0, 132.5, 128.8, 127.3, 127.0, 120.5, 113.1, 85.5, 83.8, 66.8, 42.6, 36.4, 32.6, 29.6, 25.0, 24.8; IR (neat) 3322, 2962, 2856, 1712, 1360, 1234, 1144 cm–1; HRMS (ESI): m/z calcd for + C30H44BNO5Na (M+Na) 532.3210, found 532.3202.

(E)-3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-ol (S9) 1 O H NMR (500 MHz, CDCl3) δ 1.25 (s, 12H), 2.23 (broad s, 1 H), 4.20 (d, J = 2.4 HO B 1 O Hz, 2H), 5.68 (d, J = 18.4 Hz, 1H), 6.71 (dd, J = 3.6, 18.0 Hz, 1H). The H NMR spectral data are consistent with those reported in the literature.9

(E)-3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)allyl chloroformate O Cl O B (S10) O Prepared according to the general chloroformate synthesis protocol with S9 O (1.012 g, 5.50 mmol), 20% phosgene solution (5.6 mL, 11 mmol) and p- dioxane (2.7 mL). After removal of volatiles, the crude product was stored in the freezer over 1 anhydrous Na2SO4 for later use. H NMR (400 MHz, C6D6) δ 1.04 (s, 12H), 4.18 (d, J = 5.0 Hz, 13 2H), 5.71 (d, J = 18.0 Hz, 1H), 6.46 (dt, J = 18.0, 5.0 Hz, 1H); C NMR (100 MHz, CDCl3) δ 150.1, 143.2, 83.5, 72.3, 24.8; IR (neat) 2974, 2933, 1777, 1646, 1368, 1348, 1140 cm–1.

(E)-3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)allyl (2,2- O H N O B dimethyl-1-(neopentyloxy)propyl)carbamate (17) O O O Prepared according to the general carbamate synthesis protocol with trimethylacetonitrile (48 mg, 0.58 mmol), CH2Cl2 (4.3 mL), Cp2Zr(H)Cl (176 mg, 0.68 mmol), chloroformate S10 (180 mg, 0.73 mmol), and neopentyl alcohol (2.0 M in CH2Cl2, 2.6 mL, 5.2 mmol). The reaction was quenched with saturated NaHCO3 (10 mL). The mixture was extracted with CH2Cl2 (3 x 10 mL), dried (Na2SO4), and concentrated. The residue was purified by flash chromatography (CH2Cl2 : Hexanes : ether = 80:20:1 to 80:20:2) to afford the desired product (110 mg, 50%) as an oil. 1H NMR (500 MHz, CDCl3) δ 0.90 (s, 9H), 0.93 (s, 9H), 1.27 (s, 12H), 3.02 (d, J = 8.6 Hz, 1H), 3.25 (d, J = 8.6 Hz, 1H), 4.57 (d, J = 10.4 Hz, 1H), 4.68 (dd, J = 4.6, 1.7 Hz, 2H), 4.89 (d, J = 10.3 Hz, 1H), 5.70 (dt, J = 18.1, 1.7 Hz, 1H), 6.64 (dt, J = 18.2, 4.6 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 156.1, 146.6, 88.7, 83.4, 78.5, 65.9, 35.9, 32.1, 26.7, 25.0, 24.8; IR (neat) 3338, –1 2958, 2864, 1712, 1646, 1352, 1324, 1148 cm ; HRMS (ESI): m/z calcd for C20H38BNO5Na (M++Na) 406.2741, found 406.2735.

S7 Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2012

H (2,2-dimethyl-1-(neopentyloxy)propyl)carbamate (18) N O Prepared according to the general carbamate synthesis protocol with O O trimethylacetonitrile (44 mg, 0.53 mmol), CH2Cl2 (4.1 mL), Cp2Zr(H)Cl (173 mg, 0.672 mmol), benzyl chloroformate (0.090 mL, 0.63 mmol), and neopentyl alcohol (2.0 M in CH2Cl2, 2.4 mL, 4.8 mmol). The reaction was quenched with saturated NaHCO3 (5 mL). The mixture was extracted with CH2Cl2 (3 x 10 mL), and the combined organic extracts were washed with brine (30 mL), dried (Na2SO4) and concentrated. The residue was purified by column chromatography (50% to 0% hexanes in 1 CH2Cl2) to afford the desired product (108 mg, 67%) as an oil. H NMR (400 MHz, CDCl3) δ 0.90 (s, 9H), 0.95 (s, 9H), 3.04 (d, J = 8.6 Hz, 1H), 3.25 (d, J = 8.6 Hz, 1H), 4.62 (d, J = 10.4 Hz, 1H), 4.96 (d, J = 10.2 Hz, 1H), 5.15 (d, J = 4.1 Hz, 2H), 7.30 – 7.41 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 156.4, 136.4, 128.5, 128.1, 128.0, 88.7, 78.4, 66.7, 35.9, 32.0, 26.7, 25.0. IR (neat) 3330, 2956, 2868, 1707, 1520, 1225, 1095, 1047 cm–1; HRMS (ESI): m/z calcd for + C18H29NO3Na (M+Na) 330.2045, found 330.2068.

OAc 4-(acetoxy)benzyl chloroformate (S11) Cl O The title compound was prepared according to the general chloroformate

O synthesis protocol with the following amounts of reagents: 4-acetoxybenzyl alcohol (433 mg, 2.61 mmol), 20% phosgene solution (2.60 mL, 5.26 mmol) and p-dioxane (1.30 1 mL). After removal of volatiles, crude product was dried over anhydrous Na2SO4 prior to use. H NMR (400 MHz, C6D6) δ 1.71 (s, 3H), 4.57 (s, 2H), 6.82 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 13 2H); C NMR (100 MHz, C6D6) δ 168.1, 151.8, 150.4, 130.9, 130.2, 122.1, 72.5, 20.4. The NMR spectral data are consistent with those reported in the literature.10

4-((((2,2-dimethyl-1- OAc H (neopentyloxy)propyl)carbamoyl)oxy)methyl)phenyl acetate (19) N O Prepared according to the general carbamate synthesis protocol with O O trimethylacetonitrile (49 mg, 0.59 mmol), CH2Cl2 (4.5 mL), Cp2Zr(H)Cl (186 mg, 0.723 mmol), S11 (161 mg, 0.704 mmol), and neopentyl alcohol (2.0 M in CH2Cl2, 2.65 mL, 5.3 mmol). The reaction was quenched with saturated NaHCO3 (5 mL). The mixture was extracted with CH2Cl2 (3 x 10 mL), and the combined organic extracts were washed with brine (30 mL), dried (Na2SO4) and concentrated. The residue was purified by column chromatography (0% to 3% EtOAc in CH2Cl2) to afford the 1 desired product (123 mg, 57%) as an oil. H NMR (400 MHz, CDCl3) δ 0.88 (s, 9H), 0.93 (s, 9H), 2.29 (s, 3H), 3.02 (d, J = 8.6 Hz, 1H), 3.23 (d, J = 8.6 Hz, 1H), 4.59 (d, J = 10.4 Hz, 1H), 4.97 (d, J = 10.3 Hz, 1H), 5.11 (s, 2H), 7.08 (d, J = 8.6 Hz, 2H), 7.38 (d, J = 8.5 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 169.3, 156.3, 150.4, 134.0, 129.2, 121.6, 88.7, 78.4, 65.9, 35.8, 32.0, 26.7, 24.9, 21.0; IR (neat) 3334, 2956, 2864, 1769, 1716, 1510, 1217, 1197, 1046 cm–1; HRMS + (ESI): m/z calcd for C20H31NO5Na (M+Na) 388.2100, found 388.2106.

4-azidobenzyl chloroformate (S12) N3 Cl O Prepared according to the general chloroformate synthesis protocol with 4- azidobenzyl alcohol (147 mg, 0.988 mmol), 20% phosgene solution (1.00 mL, O 2.02 mmol) and p-dioxane (0.50 mL). After removal of volatiles, the crude 1 product was dried over anhydrous Na2SO4 prior to use. H NMR (400 MHz, C6D6) δ 4.50 (s, 13 2H), 6.52 (d, J = 8.3 Hz, 2H), 6.68 (d, J = 8.2 Hz, 2H); C NMR (100 MHz, C6D6) δ 150.4,

S8 Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2012

141.3, 130.7, 130.0, 119.3, 72.5. The NMR spectral data are consistent with those reported in the literature.11

(2,2-dimethyl-1-(neopentyloxy)propyl)carbamate (20) N3 H N O Prepared according to the general carbamate synthesis protocol with trimethylacetonitrile (44 mg, 0.53 mmol), CH Cl (4.1 mL), Cp Zr(H)Cl O O 2 2 2 (167 mg, 0.647 mmol), S12 (142 mg, 0.672 mmol), and neopentyl alcohol (2.0 M in CH2Cl2, 2.4 mL, 4.8 mmol). The reaction was quenched with saturated NaHCO3 (5 mL). The mixture was extracted with CH2Cl2 (3 x 10 mL), and the combined organic extracts were washed with brine (30 mL), dried (Na2SO4) and concentrated. The residue was purified by column chromatography (50% to 0% Hexanes in CH2Cl2) to afford 1 the desired product (134.2 mg, 73%) as an oil. H NMR (400 MHz, CDCl3) δ 0.88 (s, 9H), 0.93 (s, 9H), 3.01 (d, J = 8.6 Hz, 1H), 3.21 (d, J = 8.6 Hz, 1H), 4.59 (d, J = 10.4 Hz, 1H), 4.98 (d, J = 10.3 Hz, 1H), 5.09 (s, 2H), 7.01 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 156.3, 139.9, 133.2, 129.6, 119.0, 88.7, 78.4, 66.0, 35.8, 32.0, 26.6, 24.9; IR (neat) 3326, 2956, 2860, 2116, 1713, 1509, 1287, 1047 cm–1; HRMS (ESI): m/z calcd for + C18H29N4O3 (M+H) 349.2240, found 349.2290.

4-nitrobenzyl (2,2-dimethyl-1-(neopentyloxy)propyl)carbamate (21) NO2 H Prepared according to the general carbamate synthesis protocol with N O trimethylacetonitrile (45 mg, 0.54 mmol), CH2Cl2 (4.2 mL), Cp2Zr(H)Cl O O (171 mg, 0.662 mmol), 4-nitrobenzyl chloroformate (147 mg, 0.682 mmol), and neopentyl alcohol (2.0 M in CH2Cl2, 2.5 mL, 5.0 mmol). The reaction was quenched with saturated NaHCO3 (5 mL). The mixture was extracted with CH2Cl2 (3 x 10 mL), and the combined organic extracts were washed with brine (30 mL), dried (Na2SO4) and concentrated. The residue was purified by column chromatography (33% to 0% hexanes in CH2Cl2) to afford the desired product (147 mg, 76%) as a solid (m.p. = 1 72 – 74 °C). H NMR (500 MHz, CDCl3) δ 0.88 (s, 9H), 0.94 (s, 9H), 3.02 (d, J = 8.6 Hz, 1H), 3.22 (d, J = 8.6 Hz, 1H), 4.58 (d, J = 10.3 Hz, 1H), 5.03 (d, J = 10.2 Hz, 1H), 5.22 (s, 2H), 7.51 13 (d, J = 8.7 Hz, 2H), 8.21 (d, J = 8.7 Hz, 2H); C NMR (125 MHz, CDCl3) δ 155.9, 147.6, 143.9, 128.0, 123.7, 88.9, 78.6, 65.1, 35.9, 32.0, 26.6, 24.9; IR (neat) 3334, 2956, 2864, 1717, 1523, –1 + 1346, 1221, 1049 cm ; HRMS (ESI): m/z calcd for C18H28N2O5Na (M+Na) 375.1896, found 375.1911.

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl (2,2- O dimethyl-1-(3-((4-methyl-2-oxo-2H-chromen-7- B O H yl)oxy)propoxy)propyl)carbamate (22) N O Prepared according to the general carbamate synthesis protocol with O O trimethylacetonitrile (62 mg, 0.75 mmol), CH2Cl2 (6.0 mL), O O O Cp2Zr(H)Cl (233 mg, 0.903 mmol), chloroformate 2 (254 mg, 0.858 mmol), and alcohol 23 (602 mg, 2.57 mmol). The reaction was quenched with saturated NaHCO3 (5 mL). The mixture was extracted with CH2Cl2 (3 x 15 mL), and the combined organic extracts were washed with brine (45 mL), dried (Na2SO4) and concentrated. The residue was purified by column chromatography (2% to 4% ether in CH2Cl2) to afford the desired product (132 mg, 30%) as a foamy solid (m.p. = 74 – 1 78 °C). H NMR (400 MHz, CDCl3) δ 0.91 (s, 9H), 1.33 (s, 12H), 1.97 – 2.09 (m, 2H), 2.36 (s, 3H), 3.58 (dt, J = 9.7, 6.0 Hz, 1H), 3.78 (dt, J = 9.8, 5.9 Hz, 1H), 4.08 (t, J = 6.3 Hz, 2H), 4.64

S9 Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry This journal is © The Royal Society of Chemistry 2012

(d, J = 10.4 Hz, 1H), 5.04 – 5.21 (m, 3H), 6.10 (s, 1H), 6.76 – 6.84 (m, 2H), 7.33 (d, J = 7.8 Hz, 13 2H), 7.43 (d, J = 8.7 Hz, 1H), 7.79 (d, J = 7.9 Hz, 2H). C NMR (100 MHz, CDCl3) δ 162.0, 161.2, 156.3, 155.1, 152.5, 139.2, 134.9, 126.9, 125.4, 113.3, 112.7, 111.7, 101.1, 88.5, 83.7, 66.5, 65.3, 64.2, 35.5, 29.1, 24.9, 24.8, 18.6; IR (neat) 3334, 2974, 2872, 1724, 1610, 1360, –1 + 1144, 1091 cm ; HRMS (ESI): m/z calcd for C32H43BNO8 (M+H) 580.3082, found 580.3094.

OH 7-(3-hydroxypropoxy)-4-methyl-2H-chromen-2-one (23) 1 O O O H NMR (400 MHz, (CD3)2SO) δ 1.88 (p, J = 6.2 Hz, 2H), 2.38 (s, 3H), 3.56 (dd, J = 11.5, 6.0 Hz, 2H), 4.13 (t, J = 6.4 Hz, 2H), 4.60 (t, J = 5.1 Hz, 1H), 6.18 (d, J = 0.7 Hz, 1H), 6.92 – 6.96 (m, 2H), 7.65 (d, J = 9.4 Hz, 1H); 13C NMR (100 MHz, (CD3)2SO) δ 161.8, 160.2, 154.7, 153.4, 126.4, 113.0, 112.4, 111.1, 101.1, 65.4, 57.1, 31.9, 18.1. The NMR spectral data are consistent with those reported in the literature.12

TBSO 5-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpentanenitrile (25) 1 CN H NMR (500 MHz, CDCl3) δ 0.04 (s, 6H), 0.89 (s, 9H), 1.34 (s, 6H), 1.56 – 1.61 (m, 2H), 1.65 – 1.72 (m, 2H), 3.64 (t, J = 6.0 Hz, 2H); 13C NMR (125 MHz, 1 CDCl3) δ 125.0, 62.5, 37.5, 32.1, 28.5, 26.6, 25.9, 18.2, -5.4. The H NMR spectral data are consistent with those reported in the literature.13

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl (5- O ((tert-butyldimethylsilyl)oxy)-2,2-dimethyl-1-((2,2,5,6,8- TBSO B O H pentamethylchroman-7-yl)oxy)pentyl)carbamate (26) N O Prepared according to the general carbamate synthesis protocol O O with nitrile 25 (290 mg, 1.20 mmol), CH2Cl2 (8.5 mL), O Cp2Zr(H)Cl (388 mg, 1.51 mmol), chloroformate 2 (629 mg, 2.12 mmol), and 2,2,5,7,8-pentamethyl-6-chromanol (1.22 g, 5.53 mmol). The reaction was quenched with saturated NaHCO3 (15 mL). The mixture was extracted with CH2Cl2 (3 x 20 mL), and the combined organic extracts were washed with brine (60 mL), dried (Na2SO4) and concentrated. Excess 2,2,5,7,8-pentamethyl-6-chromanol was removed via crystallization from hexanes, after which the filtrate was concentrated. The residue was purified by column chromatography (0% to 4% ether in CH2Cl2) to afford the desired product (506 mg, 58%) as a foam. The product appeared as ~3:1 mixture of rotamers by 1H 1 NMR. H NMR (400 MHz, CDCl3) δ 0.08 (s, 6H), 0.92 (s, 9H), 1.12 (s, 3H), 1.18 (s, 3H), 1.27 – 1.40 (m, 18H), 1.44 – 1.68 (m, 4H), 1.79 (t, J = 7.0 Hz, 2H), 1.99 – 2.11 (m, 9H), 2.42 – 2.67 (m, 2H), 3.63 (dd, J = 12.0, 5.6 Hz, 2H), 4.33 (d, J = 12.6 Hz, 0.27H), 4.77 (d, J = 12.8 Hz, 0.72H), 4.85 – 4.98 (m, 1.31H), 5.04 (d, J = 11.2 Hz, 0.71H), 5.13 (d, J = 11.4 Hz, 0.30H), 5.29 (d, J = 13 11.2 Hz, 0.70H), 6.98 – 7.10 (m, 2H), 7.78 (d, J = 7.8 Hz, 2H); C NMR (100 MHz, CDCl3) δ 155.7, 155.5, 148.0, 143.9, 143.7, 139.4, 138.9, 134.9, 134.8, 128.5, 126.7, 126.5, 126.4, 126.3, 122.9, 122.7, 117.3, 117.2, 88.6, 88.4, 83.7, 72.6, 66.8, 66.1, 63.84, 63.76, 38.3, 38.2, 34.4, 34.2, 32.9, 27.2, 27.0, 26.6, 26.3, 26.0, 24.8, 22.6, 22.4, 22.2, 22.0, 21.0, 18.3, 13.8, 13.6, 12.9, 12.8, 11.8, -5.3; IR (neat) 3452, 3359, 3289, 2925, 2852, 1712, 1462, 1364, 1091 cm–1; HRMS (ESI): + m/z calcd for C41H66BNO7NaSi (M+Na) 746.4599, found 746.4606.

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4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl (5- O hydroxy-2,2-dimethyl-1-((2,2,5,6,8-pentamethylchroman-7- HO B O yl)oxy)pentyl)carbamate (S13) H N O A solution of 26 (55 mg, 0.076 mmol) in MeOH (0.5 mL) was O O treated with NH4F (50 mg, 1.4 mmol), and the reaction mixture stirred in a sealed vial for 3 d. The mixture was concentrated in O vacuo, after which the residue was diluted in CH2Cl2 (5 mL) and H2O (5 mL). The mixture was extracted with CH2Cl2 (3 x 5 mL), and the pooled organic layers were washed successively with H2O and brine before being dried (Na2SO4) and concentrated. The residue was purified by column chromatography (14% ether in CH2Cl2) to afford the desired product (34 mg, 74%) as a foamy soid (m.p. = 81 – 85 °C). The product 1 1 appeared as ~3:1 mixture of rotamers by H NMR. H NMR (400 MHz, CDCl3) δ 1.12 (s, 3H), 1.16 – 1.21 (m, 3H), 1.26 – 1.39 (m, 19H), 1.47 – 1.82 (m, 6H), 1.99 – 2.19 (m, 9H), 2.42 – 2.65 (m, 2H), 3.58 – 3.70 (m, 2H), 4.31 (d, J = 12.6 Hz, 0.26H), 4.77 (d, J = 12.8 Hz, 0.72H), 4.89 (dd, J = 12.8, 3.2 Hz, 1 H), 4.98 – 5.16 (m, 1.34 H), 5.30 (d, J = 11.1 Hz, 0.72H), 7.00 (d, J = 7.9 13 Hz, 0.57H), 7.06 (d, J = 7.9 Hz, 1.44H), 7.06 (d, J = 7.9 Hz, 2H); C NMR (100 MHz, CDCl3) δ 155.7, 155.6, 148.0, 143.8, 143.6, 139.3, 138.9, 134.9, 134.8, 128.4, 126.5, 126.4, 123.0, 122.8, 117.3, 117.2, 88.5, 88.2, 83.8, 83.7, 72.6, 66.8, 66.2, 63.5, 63.4, 38.3, 38.2, 34.2, 32.9, 27.1, 27.0, 26.8, 26.3, 24.8, 22.6, 22.5, 22.0, 21.8, 20.9, 13.8, 13.6, 12.8, 11.8; IR (neat) 3452, 3346, 2974, –1 + 2868, 1712, 1364, 1148, 1086 cm ; HRMS (ESI): m/z calcd for C35H52BNO7Na (M+Na) 632.3735, found 632.3770.

Carbamate phosphonium ion 28 PPh Br 3 O A mixture containing S13 (70 mg, 0.11 mmol), 27 (55 mg, 0.12 O B O H mmol), EDCI (38 mg, 0.20 mmol), 4-(dimethylamino)pyridine O N O (1.6 mg, 0.013 mmol), and CH2Cl2 (4.0 mL) stirred at rt in a O O sealed vial for 4.5 h. The reaction was quenched with ice water O and extracted with CH2Cl2 (3 x 10 mL). The pooled extracts were dried (Na2SO4) and concentrated, and the residue was purified by column chromatography (2% to 5% MeOH in CH2Cl2) to afford the desired product (92 mg, 78%) as a foamy solid (m.p. = 120 – 124 °C). The product appeared as ~3:1 mixture of 1 rotamers by NMR. H NMR (400 MHz, CDCl3) δ 1.03 – 1.14 (m, 6H), 1.20 – 1.29 (m, 9H), 1.33 (s, 12H), 1.40 – 1.78 (m, 8H), 1.92 – 2.15 (m, 11H), 2.38 (t, J = 6.8 Hz, 2H), 2.43 – 2.59 (m, 2H), 3.82 – 4.01 (m, 4H), 4.30 (d, J = 12.6 Hz, 0.23H), 4.71 (d, J = 12.8 Hz, 0.68H), 4.78 – 4.93 (m, 1.24H), 4.99 (d, J = 11.2 Hz, 0.67H), 5.07 (d, J = 11.4 Hz, 0.30H), 5.23 (d, J = 11.2 Hz, 0.69H), 6.94 (d, J = 7.9 Hz, 0.55H), 7.01 (d, J = 7.9 Hz, 1.46H), 7.64 – 7.87 (m, 17H); 13C NMR (100 MHz, CDCl3) δ 173.1, 155.5, 148.0, 143.7, 143.5, 139.2, 138.7, 134.9, 134.8, 133.7, 133.6, 130.4, 130.3, 128.3, 126.4, 126.34, 126.27, 122.8, 118.6, 117.8, 117.3, 88.3, 88.0, 83.8, 83.7, 72.6, 66.8, 66.2, 65.0, 38.2, 34.3, 33.2, 32.8, 29.6, 27.0, 26.6, 26.5, 26.2, 25.4, 25.2, 24.8, 23.1, 22.7, 22.4, 22.2 22.1, 22.0, 21.8, 20.9, 13.7, 12.8, 11.8; IR (neat) 3362, 2972, 2926, 1724, 1361, –1 + 1087 cm ; HRMS (ESI): m/z calcd for C58H74BNO8P (M-Br) 954.5245, found 954.5256.

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TBSO Benzyl (5-((tert-butyldimethylsilyl)oxy)-2,2-dimethyl-1-((2,2,5,7,8- H N O pentamethylchroman-6-yl)oxy)pentyl)carbamate (S14)

O O Prepared according to the general carbamate synthesis protocol with nitrile 25 (102 mg, 0.424 mmol), CH2Cl2 (3.0 mL), Cp2Zr(H)Cl (142 O mg, 0.549 mmol), benzyl chloroformate (0.11 mL, 0.77 mmol), and 2,2,5,7,8-pentamethyl-6-chromanol (425 mg, 1.93 mmol). The reaction was quenched with

saturated NaHCO3 (15 mL). The mixture was extracted with CH2Cl2 (3 x 20 mL), and the

combined organic extracts were washed with brine (60 mL), dried (Na2SO4) and concentrated. Excess 2,2,5,7,8-pentamethyl-6-chromanol was removed via crystallization from hexanes, after which the filtrate was concentrated. The residue was purified by column chromatography (1% to

2% ether in CH2Cl2) to afford the desired product (104 mg, 41%) as a foam. By NMR, the 1 product appeared as ~3:1 mixture of rotamers. H NMR (400 MHz, CDCl3) δ 0.08 (s, 6H), 0.92 (s, 9H), 1.12 (s, 3H), 1.17 (s, 3H), 1.26 – 1.34 (m, 6H), 1.43 – 1.66 (m, 4H), 1.78 (t, J = 6.9 Hz, 2H), 1.99 – 2.20 (m, 9H), 2.40 – 2.65 (m, 2H), 3.52 – 3.70 (m, 2H), 4.35 (d, J = 12.4 Hz, 0.24H), 4.76 (d, J = 12.4 Hz, 0.66H), 4.82 – 4.97 (m, 1.24H), 5.03 (d, J = 11.2 Hz, 0.65H), 5.13 (d, J = 11.6 Hz, 0.33H), 5.30 (d, J = 11.2 Hz, 0.64H), 7.01 (dd, J = 7.6, 1.7 Hz, 0.50H), 7.07 (dd, J = 13 8.4, 1.7 Hz, 1.28H), 7.28 – 7.36 (m, 3H); C NMR (100 MHz, CDCl3) δ 155.8, 155.6, 148.0, 143.9, 143.8, 136.4, 135.9, 128.6, 128.5, 128.3, 128.2, 128.1, 127.8, 127.5, 127.4, 127.2, 126.8, 126.6, 122.9, 122.7, 117.3, 117.2, 88.6, 88.3, 72.6, 66.9, 66.3, 63.9, 63.8, 38.33, 38.26, 34.4, 34.2, 32.92, 32.88, 27.2, 27.1, 26.8, 26.6, 26.3, 26.0, 22.6, 22.4, 22.2, 22.0, 21.0, 20.9, 18.3, 13.8, 13.6, 12.8, 11.9, 11.8, -5.3; IR (neat) 3452, 3289, 2950, 2852, 1708, 1450, 1254, 1099 cm–1; + HRMS (ESI): m/z calcd for C35H55NO5NaSi (M +Na) 620.3747, found 620.3782.

HO Benzyl (5-hydroxy-2,2-dimethyl-1-((2,2,5,7,8- H N O pentamethylchroman-6-yl)oxy)pentyl)carbamate (S15)

O O A solution of S14 (80 mg, 0.13 mmol) in MeOH (0.80 mL) was treated with NH4F (50 mg, 1.4 mmol), and the reaction mixture stirred in a O sealed vial for 3 days. The reaction was concentrated in vacuo, after which the residue was diluted in CH2Cl2 (5 mL) and H2O (5 mL). The mixture was extracted with CH2Cl2 (3 x 5 mL), and the pooled organic layers were washed successively with H2O and brine before being dried (Na2SO4) and concentrated. The residue was purified by column chromatography (15% ether in CH2Cl2) to afford the desired product (61 mg, 94%) as a foam. By NMR, the product appeared as ~3:1 mixture of rotamers. 1H NMR (400 MHz, CDCl3) δ 1.12 (s, 3H), 1.17 – 1.21 (m, 3H), 1.26 – 1.32 (m, 6H), 1.47 – 1.57 (m, 3H), 1.60 – 1.71 (m, 2H), 1.73 – 1.82 (m, 2H), 1.98 – 2.20 (m, 9H), 2.42 – 2.64 (m, 2H), 3.52 – 3.70 (m, 2H), 4.34 (d, J = 12.4 Hz, 0.23H), 4.76 (d, J = 12.5 Hz, 0.67H), 4.84 – 4.93 (m, 1H), 4.99 (d, J = 11.4 Hz, 0.27H), 5.05 (d, J = 11.2 Hz, 0.66H), 5.13 (d, J = 11.7 Hz, 0.38H), 5.31 (d, J = 11.2 Hz, 13 0.66H), 6.98 – 7.09 (m, 2H), 7.28 – 7.36 (m, 3H); C NMR (100 MHz, CDCl3) δ 155.8, 155.7, 148.0, 143.9, 143.7, 136.3, 135.8, 128.6, 128.5, 128.3, 128.2, 128.1, 127.9, 127.8, 127.7, 127.4, 127.2, 126.7, 126.5, 122.9, 122.7, 117.3, 117.2, 88.4, 88.1, 72.6, 66.9, 66.3, 63.50, 63.46, 38.4, 38.3, 34.3, 32.9, 27.2, 27.1, 26.7, 26.6, 26.3, 22.6, 22.5, 22.1, 21.8, 20.9, 13.8, 13.6, 12.8, 11.84, 11.80; IR (neat) 3453, 3337, 2936, 2872, 1703, 1459, 1223, 1058 cm–1; HRMS (ESI): m/z calcd + for C29H41NO5Na (M +Na) 506.2882, found 506.2904.

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Carbamate 29 PPh Br 3 A mixture containing S15 (49 mg, 0.10 mmol), 27 (56 mg, 0.13 O H mmol), EDCI (36 mg, 0.19 mmol), 4-(dimethylamino)pyridine (3 mg, O N O 0.03 mmol), and CH2Cl2 (4.0 mL) stirred at room temperature in a O O sealed vial for 1.5 hours. The reaction was quenched with ice water O and extracted with CH2Cl2 (3 x 10 mL). The pooled extracts were dried (Na2SO4) and concentrated, and the residue was purified by column chromatography (3.5% to 5% MeOH in CH2Cl2) to afford the desired product (82 mg, 88%) as a foam. By NMR, the product appeared as ~3:1 mixture of rotamers. 1H NMR (400 MHz, CDCl3) δ 1.01 – 1.08 (m, 3H), 1.11 (s, 3H), 1.20 – 1.28 (m, 6H), 1.36 – 1.49 (m, 2H), 1.54 – 1.77 (m, 6H), 1.91 – 2.14 (m, 11H), 2.35 (t, J = 6.8 Hz, 2H), 2.51 (t, J = 6.3 Hz, 2H), 3.82 (dd, J = 15.9, 13.0 Hz, 2H), 3.93 (t, J = 6.6 Hz, 2H), 4.29 (d, J = 12.4 Hz, 0.22H), 4.69 (d, J = 12.5 Hz, 0.67H), 4.75 – 4.86 (m, 1H), 4.89 (d, J = 11.5 Hz, 0.26H), 4.97 (d, J = 11.2 Hz, 0.67H), 5.06 (d, J = 11.4 Hz, 0.32H), 5.22 (d, J = 11.4 Hz, 0.64H), 6.90 – 7.03 (m, 2H), 7.22 – 7.30 (m, 3H), 13 7.62 – 7.86 (m, 15H); C NMR (100 MHz, CDCl3) δ 172.9, 155.5, 147.9, 143.5, 136.1, 135.6, 134.89, 134.86, 133.6, 133.5, 130.4, 130.3, 128.34, 128.29, 128.2, 128.1, 127.7, 127.5, 127.2, 127.0, 126.4, 122.8, 122.6, 118.5, 117.6, 117.2, 88.2, 87.9, 72.5, 66.8, 66.2, 64.9, 64.7, 38.2, 38.1, 34.2, 33.1, 32.7, 27.0, 26.6, 26.5, 26.1, 25.3, 25.1, 23.0, 22.7, 22.3, 22.2, 22.0, 21.8, 20.8, 13.6, 13.5, 12.7, 11.7, ; IR (neat) 3355, 2931, 2872, 1723, 1439, 1226, 1062 cm–1; HRMS (ESI): + m/z calcd for C52H63NO6P (M -Br) 828.4393, found 828.4373.

O B O H OH N O O O O O O

O O O

Procedure for release of 23 from 22. A mixture of 22 (66 mg, 0.11 mmol) in 2.5 mM pH 8.0 phosphate buffer (9.0 mL) and acetonitrile (9.0 mL) was treated with 3 M H2O2-urea solution (0.56 mL, 1.7 mmol), and the reaction stirred at room temperature for 1 hour. The reaction was quenched by addition of saturated NaHCO3 solution (5 mL). The mixture was extracted with EtOAc (3 x 20 mL), and the combined organic extracts were dried (MgSO4) and concentrated. The residue was purified by column chromatography (33% to 20% hexanes in EtOAc) to afford desired product 23 (22 mg, 82%).

General Procedure for Monitoring Alcohol Release via 1H NMR Spectroscopy. The NMR spectrometer was programmed to acquire 2 scans every 120 s. Buffer solutions were prepared 14 15, 16 according to Gomori and Sorensen with D2O used in place of water.

Representative Procedure for Sample Preparation. Compound 5 (5.2 mg, 12 mmol) was dissolved in CD3CN (0.98 mL), pH 8.0 phosphate buffer (2.5 mM in D2O, 1.0 mL), and a 1.5 M solution of THF (internal standard) in CD3CN (20.0 µL). An aliquot of the mixture (0.60 mL) was then transferred to an NMR tube. Sample preparation was modeled after the procedure by Phillips and coworkers.17

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Representative procedure for controlled release of neopentyl alcohol or neopentylphenol from 5 or 10-18 in response to hydrogen peroxide exposure. The release of neopentyl alcohol from 5 was monitored via 1H NMR at 300 K. NMR samples were prepared according to the representative procedure for sample preparation. An initial 1H spectrum was acquired to obtain baseline integration values relative to the internal standard (THF was the internal standard for all samples except 16, which contained 1,2-dimethoxyethane as an internal standard). The NMR sample was treated with a solution of H2O2-urea (3.0 M in D2O, 18.5 µL, 15 equiv.), and mixing was achieved by inverting the NMR tube three times. The final concentration of 5 was 6 mM and of H2O2 was 90 mM. The NMR tube was returned to the spectrometer and the programmed NMR experiment was initiated.

The release of neopentyl alcohol from 5 was measured by integrating the neopentyl alcohol methylene peak relative to the internal standard. The chemical shift of the methylene peak changed during conversion of starting ether to product alcohol as follows: methylene peaks for 5 were observed at 2.86 ppm (d, J = 8.5 Hz) and 3.06 ppm (d, J = 8.6 Hz); the methylene peaks for intermediate phenol were observed at 2.89 ppm (d, J = 8.8 Hz) and 3.08 ppm (d, J = 8.7 Hz); the methylene peak for neopentyl phenol was observed at 3.13 ppm (s).

Release of PMC (24) from 28 in response to H2O2 exposure. To an eppendorf tube containing 950 µL of 2.0 mM phosphate buffer (pH = 7.2 or 8.0) and 50 µL of EtOH was added 4.0 µL of a solution of 28 (10 mM in EtOH), and the mixture was agitated at 37 °C on an eppendorf Thermomixer for 15 minutes. An aqueous solution of H2O2 was then added (5.0 µL of 2.0 mM H2O2 added to make [H2O2] = 10 µM, 4.0 µL of 5.0 mM H2O2 added to make [H2O2] = 20 µM, and 8.0 µL of 5.0 mM H2O2 added to make [H2O2] = 40 µM), and the reaction mixture continued agitating at 37 °C for the remainder of the experiment. At specified time points, 30 µL aliquots were removed from the reaction mixture and injected into an HPLC equipped with an Ultrasphere ODS column (4.6 mm x 25 cm) and an electrochemical detector (flow rate = 1.0 mL/min, mobile phase consisted of 90% MeOH and 10% 20 mM LiClO4 solution (aq)).

Monitoring PMC release from exposure of 29 to H2O2 was performed in the same manner, with 4.0 µL of a solution of 29 (10 mM in EtOH) being added to the aforementioned phosphate buffer/EtOH mixture. After agitating at 37 °C for 15 minutes, the mixture was treated with 8.0 µL of a 5.0 mM aqueous H2O2 solution, and aliquots of the reaction were removed and analyzed as described above.

References:

1. S. L. Buchwald, S. J. LaMaire, R. B. Nielsen, B. T. Watson, and S. M. King, Tetrahedron Lett. 1987, 28, 3895. 2. W. R. Waterfield, J. Chem. Soc. 1963, 2731. 3. S. Wan, M. E. Green, J.-H. Park, and P. E. Floreancig, Org. Lett. 2007, 9, 5385. 4. C. Chung, D. Srikun, C. S. Lim, C. J. Chang, and B. R. Cho, Chem. Commun. 2011, 9618. 5. H. Hagen, P. Marzenell, E. Jentzsch, F. Wenz, M. R. Veldwijk, and A. Mokhir, J. Med. Chem. 2012, 55, 924.

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6. M. Gensini, M. Altamura, T. Dimoulas, V. Fedi, D. Giannotti, S. Giuliani, A. Guidi, N. J. S. Harmat, S. Meini, R. Nannicini, F. Pasqui, M. Tramontana, A. Triolo, and C. A. Maggi, ChemMedChem 2010, 5, 65. 7. L. H. Andrade, and T. Barcellos, Org. Lett. 2009, 11, 3052. 8. R. B. Bates and T. J. Siahaan, J. Org. Chem. 1986, 51, 1432. 9. H. Jang, A. R. Zhugralin, Y. Lee, and A. H. Hoveyda, J. Am. Chem. Soc. 2011, 133, 7859. 10. E. Nägele, M. Schelhaas, N. Kuder, and H. Waldmann, J. Am. Chem. Soc. 1998, 120, 6889. 11. R. J. Griffin, E. Evers, R. Davison, A. E. Gibson, D. Layton, and W. J. Irwin, J. Chem. Soc. Perkin Trans. 1 1996, 1205. 12. M. J. Brites, C. Santos, S. Nascimento, B. Gigante, H. Luftmann, A. Fedorov, and M. N. Berberan-Santos, New J. Chem. 2006, 30, 1036. 13. J. Ciesielski, D. P. Canterbury, and A. J. Frontier, Org. Lett. 2009, 11, 4374. 14. G. Gomori, Methods Enzymol. 1955, 138. 15. S. P. L. Sörensen, Biochem. Zeit. 1909, 22, 352. 16. S. P. L. Sörensen, Biochem. Zeit. 1909, 21, 131. 17. S. A. Nuñez, K. Yeung, N. S. Fox, and S. T. Phillips, J. Org. Chem. 2011, 76, 10099.

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Release of neopentyl alcohol from 10, as monitored by kinetic 1H NMR:

Release of neopentyl alcohol from 11, as monitored by kinetic 1H NMR:

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Release of neopentyl alcohol from 12, as monitored by kinetic 1H NMR:

Release of neopentyl alcohol from 13, as monitored by kinetic 1H NMR:

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Release of neopentyl alcohol from 14, as monitored by kinetic 1H NMR:

Release of neopentyl alcohol from 15, as monitored by kinetic 1H NMR:

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Release of 2-neopentylphenol (S8) from 16, as monitored by kinetic 1H NMR:

Release of neopentyl alcohol from 17, as monitored by kinetic 1H NMR:

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Release of neopentyl alcohol from 18, as monitored by kinetic 1H NMR:

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Release of neopentyl alcohol from 5 at different initial concentrations of 5 and H2O2.

60 [5]0 = 3 mM, [H2O2]0 = 30 mM

[5]0 = 6 mM, [H2O2]0 = 90 mM

40

20

Released (%) ROH

0 0 10 20 30 Time (min)

Release of neopentyl alcohol from 14 at different initial concentrations of 14 and H2O2.

80

60 [14]0 = 3 mM, [H2O2]0 = 30 mM

[14] = 6 mM, [H O ] = 90 mM 0 2 2 0 40

Released (%) ROH 20

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HPLC spectra of PMC standards:

PMC Standard Curve:

3000000

2500000 y = 63971x - 32025

2000000 R² = 0.9991

1500000

Peak Area Peak 1000000

500000

0 0 20 40

[PMC]

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Release of PMC from 28 (40 μM) in response to H2O2 (40 μM), as monitored by HPLC:

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