Practical Pd(II)-catalyzed C H Alkylation with Epoxides: One-step Syntheses of 3,4-Dihydroisocoumarins

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1 Practical Pd(II)-catalyzed C H Alkylation with Epoxides: One-step Syntheses of 3,4-Dihydroisocoumarins Guolin Cheng, Tuan-Jie Li, and Jin-Quan Yu* Department of Chemistry, The Scripps Research Institute, North Torrey Pines Road, La Jolla, California Table of Contents 1. General Information S2 2. Experimental Section S3-S Optimization of Reaction Conditions S3-S5 2.2 Procedure for Synthesis of 2p S6 2.3 Procedure for Gram-Scale Alkylation of 1a S6 2.4 Procedure for Synthesis of 5 S6 2.5 Procedure for Synthesis of 6a S7 2.6 General Procedure for Alkylation of Benzoic Acids with Epoxides S7-S Coupling Reactions Using Chiral (S)-(+)-epichlorohydrin S H and 13 C NMR Spectra S24 S65 4. X-ray Crystallographic Data of 4q S66 S73 5. X-ray Crystallographic Data of 4r S74 S82 S1

2 1. General Information Other solvents and chemicals were from Sigma-Aldrich, Acros and Alfa Aesar and used directly without further purification. Analytical thin layer chromatography was performed on 0.25 mm silica gel 60-F254. Visualization was carried out with UV light and Vogel s permanganate. Preparative TLC was performed on 1.0 mm silica gel (Analtech). NMR spectra were recorded on a Varian Inova 400 instrument (400 MHz for 1 H; 100 MHz for 13C), Bruker DRX-500 instrument (500 MHz for 1 H; 125 MHz for 13 C). Chemical shifts were quoted in parts per million (ppm) referenced to 0.0 ppm for tetramethylsilane. The following abbreviations (or combinations thereof) were used to explain multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, sext = sextet, m = multiplet, br = broad. Coupling constants, J, were reported in Hertz unit (Hz). Chemical shifts were reported in ppm referenced to the center line of a triplet at 77.0 ppm of chloroform-d. Melting points were obtained from a Mel-temp II apparatus (uncorrected). High-resolution mass spectra (HRMS) were recorded on an Agilent Mass spectrometer using ESI-TOF (electrospray ionization-time of flight). S2

3 2. Experimental Section 2.1 Optimization Reaction Conditions Solvent Screening a S3

4 2.1.2 Counter Cation Screening a S4

5 2.1.3 Ligand Screening a S5

6 2.2 Procedure for Synthesis of 2p m-chloroperoxybenzoic acid (70-75%, mg, 1.2 mmol) was added to a solution of ((2- methylallyl)sulfonyl)benzene (196.0 mg, 1.0 mmol) in dry dichloromethane (5.0 ml). The solution was stirred for 48 h at room temperature. After the reaction finished, the organic layer was washed with saturated aqueous sodium bicarbonate (10.0 ml), dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (ethyl acetate/hexane = 1/4) to yield the desired 2- methyl-2-((phenylsulfonyl)methyl)oxirane 2p as white solid (171.7 mg, 81%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.93 (d, J = 7.8 Hz, 2H), 7.69 (t, J = 7.4 Hz, 1H), 7.59 (t, J = 7.7 Hz, 2H), 3.54 (d, J = 14.2 Hz, 1H), 3.06 (d, J = 14.2 Hz, 1H), 2.61 (q, J = 4.7 Hz, 2H), 1.54 (s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ , , , , 63.65, 52.91, 51.97, 21.41; HRMS (ESI-TOF) Calcd for C 10 H 13 O 3 S [M+H] + : ; found: ; m.p. = C. 2.3 Procedure for Gram-Scale Alkylation of 1a A suspension of m-toluic acid 1a (1.36 g, 10.0 mmol), epoxide 2a (3.28 g, 20 mmol), KOAc (0.98 g, 10 mmol), Ac-t-leu-OH (17.3 mg, 0.1 mmol), Pd(OAc) 2 (11.2 mg, 0.05 mmol) and hexafluoroisopropanol (25 ml) in a sealed tube was stirred at 75 o C. After 48 hours, the reaction mixture was concentrated and purified by column chromatography (ethyl acetate/hexane 1/4) to give the product 3a as colorless oil (2.62 g, 93% yield). 2.4 Procedure for Synthesis of 5 S6

7 m-toluic acid 1a (136.0 mg, 1.0 mmol) was treated with KOH (32.0 mg, 0.8 mmol) in water (1.0 ml) at room temperature for 0.5 h. Then water was removed in a rotary evaporator, the white solid was washed with CH 2 Cl 2 (2.0 ml 3) to remove excess of m-toluic acid and dried under vacuum at 100 C to get potassium m-toluate (105.0 mg, 60% yield). Palladium acetate (112.0 mg, 0.5 mmol) was added to a suspension of potassium m-toluate (87.0 mg, 0.5 mmol) in 1,4-dioxane (5.0 ml, then the mixture was heated to 100 C for 2 h. The reaction mixture was filtered, and the dark residue was washed with CH 2 Cl 2 (5 ml 3) and dried under vacuum to get the palladacycle 5 (84.8 mg, 50% yield). 1 H NMR (400 MHz, DMSO) δ 7.59 (d, J = 7.8 Hz, 1H), 7.04 (s, 1H), 6.98 (d, J = 8.0 Hz, 1H), 2.33 (s, 3H), 1.85 (s, 3H); 13 C NMR (125 MHz, DMSO) δ , , , , , , , , 25.67, Procedure for Synthesis of 6a A suspension of m-toluic acid 1a (13.6 mg, 0.1 mmol), epoxide 2a (32.8 mg, 0.2 mmol), KOAc (9.8 mg, 0.1 mmol), Ac-t-leu-OH (3.46 mg, 0.02 mmol), Pd(OAc) 2 (2.23 mg 0.01 mmol,) and hexafluoroisopropanol (0.25 ml) in a sealed tube was stirred at room temperature. After 48 hours, the reaction mixture was concentrated and purified by preparative thin-layer chromatography (acetic acid/ethyl acetate/hexane 1/8/16) to give the product 6a as white solid (15.9 mg, 53% yield). 1 H NMR (500 MHz, CDCl 3 ) δ 7.76 (s, 1H), (m, 4H), (m, 2H), 7.16 (d, J = 7.8 Hz, 1H), 4.56 (s, 2H), (m, 1H), 3.56 (dd, J = 9.6, 4.0 Hz, 1H), 3.48 (dd, J = 9.6, 6.8 Hz, 1H), (m, 2H), 2.33 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , , , , , , , , 73.75, 73.34, 71.80, 37.30, 20.76; HRMS (ESI-TOF) Calcd for C 18 H 21 O 4 [M+Na] + : ; found: ; m.p. = C. 2.6 General Procedure for the Alkylation of Benzoic Acid S7

8 A suspension of benzoic acid 1 (0.1 mmol), epoxide 2 (2 equiv), KOAc (9.8 mg, 0.1 mmol), Pd(OAc) 2 (n mol%), Ac-t-leu-OH (2n mol%), and hexafluoroisopropanol (0.25 ml) in a sealed tube was stirred at 75 o C. After 24 hours, the reaction concentrated and purified by preparative thin-layer chromatography to give the product 3 or 4. 3-(benzyloxy)-2-hydroxypropyl 3-methylbenzoate (3a`) Substrate 3a` was obtained as main product when DMF or DMSO were used as solvent. After purification by preparative TLC, 3a` was obtained as colorless oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.82 (m, 2H), (m, 7H), 4.59 (s, 2H), (m, 2H), (m, 1H), 3.65 (dd, J = 9.6, 4.4 Hz, 1H), 3.59 (dd, J = 9.6, 6.0 Hz, 1H), 2.59 (d, J = 5.0 Hz, 1H), 2.40 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ , , , , , , , , , , , 73.53, 70.89, 69.05, 65.92, 21.26; HRMS (ESI-TOF) Calcd for C 18 H 21 O 4 [M+H] + : ; found: ((benzyloxy)methyl)-7-methylisochroman-1-one (3a) Substrate 3a was alkylated following the general procedure using Pd(OAc) 2 (1 mol%) and Ac-t-leu-OH (2 mol%). After purification by preparative TLC, 3a was obtained as colorless oil (27.1 mg, 96%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.90 (s, 1H), (m, 6H), 7.14 (d, J = 7.7 Hz, 1H), (m, 3H), 3.79 (dd, J = 10.3, 4.7 Hz, 1H), 3.73 (dd, J = 10.3, 5.2 Hz, 1H), 3.11 (dd, J = 16.3, 11.5 Hz, 1H), 2.93 (dd, J = 16.3, 3.3 Hz, 1H), 2.38 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ , , , , , , , , , , , 77.25, 73.63, 71.09, 29.67, 20.94; HRMS (ESI-TOF) Calcd for C 18 H 19 O 3 [M+H] + : ; found: ; m.p. = C. 3-((benzyloxy)methyl)-6-methylisochroman-1-one (3b) S8

9 Substrate 3b was alkylated following the general procedure using Pd(OAc) 2 (1 mol%) and Ac-t-leu-OH (2 mol%). After purification by preparative TLC, 3b was obtained as colorless oil (22.3 mg, 79%). 1 H NMR (500 MHz, CDCl3) δ 7.97 (d, J = 7.9 Hz, 1H), (m, 5H), 7.19 (d, J = 8.0 Hz, 1H), 7.05 (s, 1H), (m, 3H), 3.80 (dd, J = 10.3, 4.7 Hz, 1H), 3.74 (dd, J = 10.4, 5.3 Hz, 1H), 3.13 (dd, J = 16.4, 11.5 Hz, 1H), 2.93 (dd, J = 16.4, 3.4 Hz, 1H), 2.40 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ , , , , , , , , , , , 77.08, 73.66, 71.10, 30.09, 21.74; HRMS (ESI-TOF) Calcd for C 18 H 19 O 3 [M+H] + : ; found: ((benzyloxy)methyl)-8-methylisochroman-1-one (3c) Substrate 3c was alkylated following the general procedure using Pd(OAc) 2 (1 mol%) and Ac-t-leu-OH (2 mol%). After purification by preparative TLC, 3c was obtained as colorless oil (17.0 mg, 60%). 1 H NMR (500 MHz, CDCl 3 ) δ (m, 5H), (m, 1H), 7.19 (d, J = 7.7 Hz, 1H), 7.08 (d, J = 7.5 Hz, 1H), (m, 3H), 3.79 (dd, J = 10.3, 4.8 Hz, 1H), 3.72 (dd, J = 10.3, 5.4 Hz, 1H), 3.11 (dd, J = 16.0, 11.7 Hz, 1H), 2.94 (dd, J = 16.1, 2.9 Hz, 1H), 2.67 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , , , , , , , , 76.50, 73.65, 71.09, 31.40, 22.16; HRMS (ESI-TOF) Calcd for C 18 H 19 O 3 [M+H] + : ; found: ((benzyloxy)methyl)-6-(tert-butyl)isochroman-1-one (3d) Substrate 3d was alkylated following the general procedure using Pd(OAc) 2 (1 mol%) and Ac-t-leu-OH (2 mol%). After purification by preparative TLC, 3d was obtained as colorless oil (29.2 mg, 90%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.01 (d, J = 8.2 Hz, 1H), (m, 7H), (m, 3H), 3.81 (dd, J = 10.3, 4.7 Hz, 1H), 3.75 (dd, J = 10.3, 5.3 Hz, 1H), 3.16 (dd, J = 16.3, 11.6 Hz, 1H), 2.97 (dd, J = 16.4, 3.3 Hz, 1H), 1.33 (s, 9H); 13 C NMR (100 MHz, CDCl 3 ) δ , , , , , , , , , , , 77.18, 73.64, 71.17, 35.19, 31.02, 30.45; HRMS (ESI-TOF) Calcd for C 21 H 25 O 3 [M+H] + : ; found: S9

10 3-((benzyloxy)methyl)-7-methoxyisochroman-1-one (3e) Substrate 3e was alkylated following the general procedure using Pd(OAc) 2 (1 mol%) and Ac-t-leu-OH (2 mol%). After purification by preparative TLC, 3e was obtained as colorless oil (23.8 mg, 80%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.58 (d, J = 2.7 Hz, 1H), (m, 5H), 7.16 (d, J = 8.4 Hz, 1H), 7.10 (dd, J = 8.4, 2.7 Hz, 1H), (m, 3H), (m, 5H), 3.10 (dd, J = 16.2, 11.6 Hz, 1H), 2.92 (dd, J = 16.2, 3.4 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ , , , , , , , , , , , 77.50, 73.67, 71.08, 55.59, 29.27; HRMS (ESI-TOF) Calcd for C 18 H 19 O 4 [M+H] + : ; found: N-(3-((benzyloxy)methyl)-1-oxoisochroman-6-yl)acetamide (3f) Substrate 3f was alkylated following the general procedure using Pd(OAc) 2 (2.5 mol%) and Ac-t-leu-OH (5 mol%). After purification by preparative TLC, 3f was obtained as white solid (18.8 mg, 58%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.02 (d, J = 8.5 Hz, 1H), 7.77 (s, 1H), 7.45 (brs, 1H), (m, 5H), 7.23 (d, J = 10.2 Hz, 1H), (m, 3H), 3.76 (qd, J = 10.3, 4.9 Hz, 2H), 3.16 (dd, J = 16.6, 11.6 Hz, 1H), 2.96 (dd, J = 16.5, 3.1 Hz, 1H), 2.22 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ , , , , , , , , , , , , 77.19, 73.61, 70.98, 30.24, 24.71; HRMS (ESI-TOF) Calcd for C 19 H 20 NO 4 [M+H] + : ; found: ; m.p. = C. 3-((benzyloxy)methyl)isochroman-1-one (3g) Substrate 3g was alkylated following the general procedure using Pd(OAc) 2 (1 mol%) and Ac-t-leu-OH (2 mol%). After purification by preparative TLC, 3g was obtained as colorless oil (19.8 mg, 74%). 1 H NMR (500 MHz, CDCl 3 ) δ 8.09 (d, J = 7.8 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), (m, 7H), (m, S10

11 1H), (m, 2H), 3.80 (dd, J = 10.4, 4.7 Hz, 1H), 3.75 (dd, J = 10.3, 5.3 Hz, 1H), 3.18 (dd, J = 16.3, 11.5 Hz, 1H), 2.98 (dd, J = 16.4, 3.2 Hz, 1H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , , , , , , , , 77.15, 73.68, 71.07, 30.09; HRMS (ESI- TOF) Calcd for C 17 H 17 O 3 [M+H] + : ; found: methyl 3-((benzyloxy)methyl)-1-oxoisochroman-6-carboxylate (3h) Substrate 3h was alkylated following the general procedure using Pd(OAc) 2 (2.5 mol%) and Ac-t-leu-OH (5 mol%). After purification by preparative TLC, 3h was obtained as colorless oil (21.3 mg, 65%). 1 H NMR (500 MHz, CDCl 3 ) δ 8.15 (d, J = 8.1 Hz, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.94 (s, 1H), (m, 5H), (m, 1H), (m, 2H), 3.95 (s, 3H), (m, 2H), 3.22 (dd, J = 16.5, 11.3 Hz, 1H), 3.06 (dd, J = 16.5, 3.3 Hz, 1H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , , , , , , , , , 77.25, 73.67, 70.81, 52.56, 29.91; HRMS (ESI-TOF) Calcd for C 19 H 19 O 5 [M+H] + : ; found: ((benzyloxy)methyl)-6-(trifluoromethyl)isochroman-1-one (3i) Substrate 3i was alkylated following the general procedure using Pd(OAc) 2 (5 mol%) and Ac-t-leu-OH (10 mol%). After purification by preparative TLC, 3i was obtained as white solid (24.5 mg, 73%). 1 H NMR (400 MHz, CDCl 3 ) δ 8.21 (d, J = 8.1 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.53 (s, 1H), (m, 5H), (m, 1H), (m, 2H), (m, 2H), 3.25 (dd, J = 16.4, 11.2 Hz, 1H), 3.07 (dd, J = 16.6, 3.3 Hz, 1H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , (q, J = 32.7 Hz), , , , , , (q, J = 3.6 Hz), (q, J = 3.6 Hz), (q, J = Hz), 77.13, 73.69, 70.71, 29.93; HRMS (ESI-TOF) Calcd for C 18 H 16 F 3 O 3 [M+H] + : ; found: ; m.p. = C. S11

12 3-((benzyloxy)methyl)-6-fluoroisochroman-1-one (3j) Substrate 3j was alkylated following the general procedure using Pd(OAc) 2 (2.5 mol%) and Ac-t-leu-OH (5 mol%). After purification by preparative TLC, 3j was obtained as colorless oil (21.2 mg, 74%). 1 H NMR (500 MHz, CDCl 3 ) δ 8.11 (dd, J = 8.7, 5.7 Hz, 1H), (m, 5H), 7.06 (td, J = 8.6, 2.4 Hz, 1H), 6.94 (dd, J = 8.6, 2.2 Hz, 1H), (m, 1H), (m, 2H), 3.79 (dd, J = 10.4, 4.5 Hz, 1H), 3.74 (dd, J = 10.4, 5.3 Hz, 1H), 3.18 (dd, J = 16.5, 11.4 Hz, 1H), 2.98 (dd, J = 16.6, 3.3 Hz, 1H); 13 C NMR (125 MHz, CDCl 3 ) δ (d, J = Hz), , (d, J = 9.5 Hz), , (d, J = 9.9 Hz), , , , (d, J = 2.8 Hz), (d, J = 22.2 Hz), (d, J = 22.3 Hz), 76.94, 73.69, 70.81, 30.17; HRMS (ESI-TOF) Calcd for C 17 H 16 FO 3 [M+H] + : ; found: ((benzyloxy)methyl)-7-fluoroisochroman-1-one (3k) Substrate 3k was alkylated following the general procedure using Pd(OAc) 2 (2.5 mol%) and Ac-t-leu-OH (5 mol%). After purification by preparative TLC, 3k was obtained as colorless oil (21.7 mg, 78%). 1 H NMR (500 MHz, CDCl 3 ) δ 7.77 (d, J = 8.3 Hz, 1H), (m, 7H), (m, 1H), (m, 2H), 3.80 (dd, J = 10.4, 4.6 Hz, 1H), 3.75 (dd, J = 10.4, 5.2 Hz, 1H), (m, 1H), 2.98 (dd, J = 16.4, 3.4 Hz, 1H); 13 C NMR (125 MHz, CDCl 3 ) δ (d, J = 2.8 Hz), (d, J = Hz), , , (d, J = 7.4 Hz), , , , (d, J = 7.8 Hz), (d, J = 22.0 Hz), (d, J = 23.3 Hz), 77.40, 73.70, 70.87, 29.38; HRMS (ESI-TOF) Calcd for C 17 H 16 FO 3 [M+H] + : ; found: ((benzyloxy)methyl)-7-chloroisochroman-1-one (3l) S12

13 Substrate 3l was alkylated following the general procedure using Pd(OAc) 2 (1 mol%) and Ac-t-leu-OH (2 mol%). After purification by preparative TLC, 3l was obtained as white solid (24.8 mg, 82%). 1 H NMR (500 MHz, CDCl 3 ) δ 8.07 (d, J = 2.1 Hz, 1H), 7.50 (dd, J = 8.1, 2.2 Hz, 1H), (m, 5H), 7.21 (d, J = 8.1 Hz, 1H), (m, 1H), (m, 2H) (m, 2H), 3.14 (dd, J = 16.5, 11.3 Hz, 1H), 2.98 (dd, J = 16.5, 3.4 Hz, 1H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , , , , , 127.9, , , 77.21, 73.73, 70.86, 29.53; HRMS (ESI-TOF) Calcd for C 17 H 16 ClO 3 [M+H] + : ; found: ; m.p. = C. 3-((benzyloxy)methyl)-6-chloroisochroman-1-one (3m) Substrate 3m was alkylated following the general procedure using Pd(OAc) 2 (1 mol%) and Ac-t-leu-OH (2 mol%). After purification by preparative TLC, 3m was obtained as colorless oil (22.4 mg, 74%). 1 H NMR (500 MHz, CDCl 3 ) δ 8.02 (d, J = 8.4 Hz, 1H), (m, 6H), (m, 1H), (m, 1H), (m, 2H), (m, 2H), 3.17 (dd, J = 16.5, 11.3 Hz, 1H), 2.97 (dd, J = 16.6, 3.4 Hz, 1H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , , , , , , , , 77.25, 73.71, 70.79, 29.90; HRMS (ESI-TOF) Calcd for C 17 H 16 ClO 3 [M+H] + : ; found: ((benzyloxy)methyl)-6,7-dimethylisochroman-1-one (3n) Substrate 3n was alkylated following the general procedure using Pd(OAc) 2 (1 mol%) and Ac-t-leu-OH (2 mol%). After purification by preparative TLC, 3n was obtained as white solid (26.7 mg, 90%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.84 (s, 1H), (m, 5H), 7.00 (s, 1H), (m, 3H), (m, 2H), 3.08 (dd, J = 16.2, 11.5 Hz, 1H), 2.89 (dd, J = 16.3, 3.4 Hz, 1H), 2.30 (s, 3H), 2.28 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ , , , , , , , , , , , 77.21, 73.60, 71.13, 29.56, 20.04, 19.28; HRMS (ESI-TOF) Calcd for C 19 H 21 O 3 [M+H] + : ; found: ; m.p. = C. S13

14 3-((benzyloxy)methyl)-7-methoxy-6-methylisochroman-1-one (3o) Substrate 3o was alkylated following the general procedure using Pd(OAc) 2 (1 mol%) and Ac-t-leu-OH (2 mol%). After purification by preparative TLC, 3o was obtained as white solid (26.8 mg, 86%). 1 H NMR (500 MHz, CDCl 3 ) δ 7.49 (s, 1H), (m, 4H), (m, 1H), 7.00 (s, 1H), (m, 3H), 3.86 (s, 3H), (m, 2H), 3.06 (dd, J = 16.2, 11.5 Hz, 1H), 2.87 (dd, J = 16.3, 3.4 Hz, 1H), 2.26 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , , , , , , , , 77.46, 73.65, 71.15, 55.62, 29.17, 16.59; HRMS (ESI-TOF) Calcd for C 19 H 21 O 4 [M+H] + : ; found: ; m.p. = C. 3-((benzyloxy)methyl)-6-fluoro-8-methylisochroman-1-one (3p) Substrate 3p was alkylated following the general procedure using Pd(OAc) 2 (1 mol%) and Ac-t-leu-OH (2 mol%). After purification by preparative TLC, 3p was obtained as white solid (24.1 mg, 80%). 1 H NMR (500 MHz, CDCl 3 ) δ (m, 5H), 6.89 (dd, J = 9.6, 2.3 Hz, 1H), 6.78 (dd, J = 8.2, 2.1 Hz, 1H), (m, 3H), 3.77 (dd, J = 10.3, 4.7 Hz, 1H), 3.71 (dd, J = 10.3, 5.4 Hz, 1H), 3.11 (dd, J = 16.2, 11.6 Hz, 1H), 2.93 (dd, J = 16.3, 2.9 Hz, 1H), 2.67 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ (d, J = Hz), , (d, J = 9.6 Hz), (d, J = 9.6 Hz), , , , , , (d, J = 21.2 Hz), (d, J = 21.6 Hz), 76.14, 73.66, 70.83, 31.55, 22.44; HRMS (ESI- TOF) Calcd for C 18 H 18 FO 3 [M+H] + : ; found: ; m.p. = C. 3-((benzyloxy)methyl)-6-chloro-8-methylisochroman-1-one (3q) Substrate 3q was alkylated following the general procedurev. After purification by preparative TLC, 3q was obtained as white solid (23.4 mg, 74%). 1 H NMR (500 MHz, CDCl 3 ) δ (m, 5H), 7.19 (s, S14

15 1H), 7.08 (s, 1H), (m, 3H), (m, 2H), 3.10 (dd, J = 16.2, 11.5 Hz, 1H), 2.91 (dd, J = 16.2, 2.9 Hz, 1H), 2.64 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , , , , , , , , 76.25, 73.66, 70.79, 31.21, 22.09; HRMS (ESI-TOF) Calcd for C 18 H 18 ClO 3 [M+H] + : ; found: ; m.p. = C. 3-((benzyloxy)methyl)-6-fluoro-7-methylisochroman-1-one (3r) Substrate 3r was alkylated following the general procedure using Pd(OAc) 2 (1 mol%) and Ac-t-leu-OH (2 mol%). After purification by preparative TLC, 3r was obtained as white solid (26.5 mg, 88%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.95 (d, J = 7.7 Hz, 1H), (m, 5H), 6.88 (d, J = 9.3 Hz, 1H), (m, 3H), (m, 2H), 3.13 (dd, J = 16.4, 11.4 Hz, 1H), 2.92 (dd, J = 16.5, 3.4 Hz, 1H), 2.29 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ (d, J = Hz), , (d, J = 9.6 Hz), , (d, J = 7.2 Hz), , , , (d, J = 18.2 Hz), (d, J = 3.2 Hz), (d, J = 23.4 Hz), 77.08, 73.66, 70.88, 29.73, (d, J = 3.5 Hz); HRMS (ESI-TOF) Calcd for C 18 H 18 FO 3 [M+H] + : ; found: ; m.p. = C. 3-((benzyloxy)methyl)-6-fluoro-7-methoxyisochroman-1-one (3s) Substrate 3s was alkylated following the general procedure using Pd(OAc) 2 (1 mol%) and Ac-t-leu-OH (2 mol%). After purification by preparative TLC, 3s was obtained as colorless oil (28.4 mg, 90%). 1 H NMR (500 MHz, CDCl 3 ) δ 7.68 (d, J = 8.5 Hz, 1H), (m, 5H), 6.96 (d, J = 10.7 Hz, 1H), (m, 3H), 3.93 (s, 3H), (m, 2H), 3.11 (dd, J = 16.4, 11.5 Hz, 1H), 2.89 (dd, J = 16.4, 3.4 Hz, 1H); 13 C NMR (125 MHz, CDCl 3 ) δ , (d, J = Hz), (d, J = 11.1 Hz), , (d, J = 8.0 Hz), , , , (d, J = 3.1 Hz), (d, J = 19.6 Hz), (d, J = 3.6 Hz), 77.36, 73.71, 70.88, 56.39, 29.22; HRMS (ESI-TOF) Calcd for C 18 H 18 FO 4 [M+H] + : ; found: S15

16 3-((benzyloxy)methyl)-6-bromo-7-methylisochroman-1-one (3t) Substrate 3t was alkylated following the general procedure using Pd(OAc) 2 (2.5 mol%) and Ac-t-leu-OH (5 mol%). After purification by preparative TLC, 3t was obtained as white solid (27.1 mg, 75%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.93 (s, 1H), 7.45 (s, 1H), (m, 5H), (m, 3H), (m, 2H), 3.12 (dd, J = 16.4, 11.3 Hz, 1H), 2.92 (dd, J = 16.4, 3.4 Hz, 1H), 2.42 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ , , , , , , , , , , , 77.19, 73.67, 70.84, 29.28, 22.54; HRMS (ESI-TOF) Calcd for C 18 H 18 BrO 3 [M+H] + : ; found: ; m.p. = C. 7-methylisochroman-1-one (4a) Substrate 4a was alkylated following the general procedure using Pd(OAc) 2 (1 mol%) and Ac-t-leu-OH (2 mol%). After purification by preparative TLC, 4a was obtained as colorless oil (13.0 mg, 80%). 1 H NMR (500 MHz, CDCl 3 ) δ 7.91 (s, 1H), 7.35 (d, J = 7.7 Hz, 1H), 7.15 (d, J = 7.7 Hz, 1H), 4.52 (t, J = 6.0 Hz, 2H), 3.01 (t, J = 6.0 Hz, 2H), 2.39 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , , , , 67.40, 27.44, ,7-dimethylisochroman-1-one (4b) Substrate 4b was alkylated following the general procedure using Pd(OAc) 2 (1 mol%) and Ac-t-leu-OH (2 mol%). After purification by preparative TLC, 4b was obtained as colorless oil (15.0 mg, 85%). 1 H NMR (500 MHz, CDCl 3 ) δ 7.91 (s, 1H), 7.34 (dd, J = 7.7 Hz, 1.2 Hz, 1H), 7.12 (d, J = 7.7 Hz, 1H), (m, 1H), (m, 2H), 2.38 (s, 3H), 1.51 (d, J = 6.3 Hz, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , , , , 75.16, 34.51, 20.96, S16

17 3-hexyl-7-methylisochroman-1-one (4c) Substrate 4c was alkylated following the general procedure using Pd(OAc) 2 (2.5 mol%) and Ac-t-leu-OH (5 mol%). After purification by preparative TLC, 4c was obtained as white solid (20.6 mg, 84%). 1 H NMR (500 MHz, CDCl 3 ) δ 7.91 (s, 1H), 7.33 (d, J = 7.6 Hz, 1H), 7.12 (d, J = 7.7 Hz, 1H), (m, 1H), (m, 2H), 2.38 (s, 3H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 6H), 0.89 (t, J = 6.8 Hz, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , , , , 78.87, 34.96, 32.83, 31.65, 29.03, 24.87, 22.53, 20.94, 14.01; HRMS (ESI-TOF) Calcd for C 16 H 23 O 2 [M+H] + : ; found: ; m.p. = C. 3-decyl-7-methylisochroman-1-one (4d) Substrate 4d was alkylated following the general procedure using Pd(OAc) 2 (2.5 mol%) and Ac-t-leu-OH (5 mol%). After purification by preparative TLC, 4d was obtained as white solid (24.2 mg, 80%). 1 H NMR (500 MHz, CDCl 3 ) δ 7.90 (s, 1H), 7.33 (d, J = 7.4 Hz, 1H), 7.12 (d, J = 7.7 Hz, 1H), (m, 1H), (m, 2H), 2.38 (s, 3H), (m, 1H), (m, 1H), (m, J = 18.4, 11.1 Hz, 1H), (m, 1H), (m, 14H), 0.88 (t, J = 6.9 Hz, 3H); 13 C NMR (125MHz, CDCl 3 ) δ , , , , , , , 78.87, 34.97, 32.83, 31.87, 29.56, 29.53, 29.46, 29.38, 29.28, 24.92, 22.65, 20.95, 14.07; HRMS (ESI-TOF) Calcd for C 20 H 31 O 2 [M+H] + : ; found: ; m.p. = C. 3-benzyl-7-methylisochroman-1-one (4e) Substrate 4e was alkylated following the general procedure using Pd(OAc) 2 (2.5 mol%) and Ac-t-leu-OH (5 mol%). After purification by preparative TLC, 4e was obtained as colorless oil (21.9 mg, 87%). 1 H S17

18 NMR (500 MHz, CDCl 3 ) δ 7.90 (s, 1H), (m, 3H), (m, 3H), 7.06 (d, J = 7.7 Hz, 1H), (m, 1H), 3.25 (dd, J = 13.8, 5.7 Hz, 1H), 3.01 (dd, J = 13.8, 7.5 Hz, 1H), 2.90 (dd, J = 16.2, 11.0 Hz, 1H), 2.81 (dd, J = 16.2, 3.4 Hz, 1H), 2.37 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , , , 129.5, 128.6, , , , 79.15, 77.25, 31.90, 20.95; HRMS (ESI-TOF) Calcd for C 17 H 17 O 2 [M+H] + : ; found: (n-butoxymethyl)-7-methylisochroman-1-one (4f) Substrate 4f was alkylated following the general procedure using Pd(OAc) 2 (1 mol%) and Ac-t-leu-OH (2 mol%). After purification by preparative TLC, 4f was obtained as colorless oil (23.6 mg, 95%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.90 (s, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.15 (d, J = 7.7 Hz, 1H), (m, 1H), 3.74 (dd, J = 10.4, 4.7 Hz, 1H), 3.67 (dd, J = 10.4, 5.4 Hz, 1H), 3.53 (t, J = 6.6 Hz, 2H), 3.09 (dd, J = 16.3, 11.4 Hz, 1H), 2.94 (dd, J = 16.3, 3.4 Hz, 1H), 2.38 (s, 3H), (m, 2H), (m, 2H), 0.92 (t, J = 7.4 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ , , , , , 127.3, , 71.75, 71.69, 31.65, 29.72, 20.94, 19.21, 13.86; HRMS (ESI-TOF) Calcd for C 15 H 21 O 3 [M+H] + : ; found: methyl-3-(phenoxymethyl)isochroman-1-one (4g) Substrate 4g was alkylated following the general procedure using Pd(OAc) 2 (1 mol%) and Ac-t-leu-OH (2 mol%). After purification by preparative TLC, 4g was obtained as colorless oil (22.9 mg, 85%). 1 H NMR (500 MHz, CDCl 3 ) δ 7.93 (s, 1H), 7.37 (d, J = 7.7 Hz, 1H), (m, 2H), 7.18 (d, J = 7.7 Hz, 1H), 6.99 (t, J = 7.4 Hz, 1H), 6.93 (d, J = 7.9 Hz, 2H), (m, 1H), 4.30 (dd, J = 9.9, 4.6 Hz, 1H), 4.20 (dd, J = 9.9, 5.9 Hz, 1H), 3.21 (dd, J = 16.2, 11.4 Hz, 1H), 3.09 (dd, J = 16.3, 3.5 Hz, 1H), 2.40 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , , , , , , , , 76.23, 68.69, 29.80, 20.9; HRMS (ESI-TOF) Calcd for C 17 H 17 O 3 [M+H] + : ; found: S18

19 7-methyl-3-((o-tolyloxy)methyl)isochroman-1-one (4h) Substrate 4h was alkylated following the general procedure using Pd(OAc) 2 (1 mol%) and Ac-t-leu-OH (2 mol%). After purification by preparative TLC, 4h was obtained as colorless oil (24.5 mg, 87%). 1 H NMR (500 MHz, CDCl 3 ) δ 7.94 (s, 1H), 7.37 (d, J = 7.8 Hz, 1H), (m, 3H), 6.90 (t, J = 7.4 Hz, 1H), 6.82 (d, J = 7.7 Hz, 1H), (m, 1H), 4.30 (dd, J = 10.0, 4.4 Hz, 1H), 4.21 (dd, J = 9.9, 5.8 Hz, 1H), 3.25 (dd, J = 16.1, 11.3 Hz, 1H), 3.11 (dd, J = 16.3, 3.6 Hz, 1H), 2.40 (s, 3H), 2.22 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ 165.1, , , , , , , , , , , , , 76.34, 68.80, 29.84, 21.00, 16.18; HRMS (ESI-TOF) Calcd for C 18 H 19 O 3 [M+H] + : ; found: (((tert-butyldimethylsilyl)oxy)methyl)-7-methylisochroman-1-one (4i) Substrate 4i was alkylated following the general procedurev. After purification by preparative TLC, 4i was obtained as white solid (18.7 mg, 61%). 1 H NMR (500 MHz, CDCl 3 ) δ 7.90 (s, 1H), 7.34 (d, J = 7.7 Hz, 1H), 7.16 (d, J = 7.7 Hz, 1H), (m, 1H), 3.91 (dd, J = 10.7, 4.2 Hz, 1H), 3.84 (dd, J = 10.7, 6.0 Hz, 1H), 3.08 (dd, J = 16.3, 10.9 Hz, 1H), 2.95 (dd, J = 16.3, 3.5 Hz, 1H), 2.38 (s, 3H), 0.90 (s, 9H), 0.08 (d, J = 5.2 Hz, 6H); 13 C NMR (125 MHz, CDCl) δ , , , , , , , 78.44, 64.42, 29.34, 25.81, 20.95, 18.27, (d, J = 2.1 Hz); HRMS (ESI-TOF) Calcd for C 17 H 27 O 3 Si [M+H] + : ; found: ; m.p. =55-56 C. 3-(hydroxymethyl)-7-methylisochroman-1-one (4j) Substrate 4j was alkylated following the general procedure using Pd(OAc) 2 (1 mol%) and Ac-t-leu-OH (2 mol%). After purification by preparative TLC, 4j was obtained as colorless oil (12.5 mg, 65%). 1 H NMR S19

20 (400 MHz, CDCl 3 ) δ 7.91 (s, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.17 (d, J = 7.7 Hz, 1H), (m, 1H), 3.96 (dd, J = 12.3, 3.0 Hz, 1H), 3.85 (dd, J = 12.3, 5.2 Hz, 1H), 3.17 (dd, J = 16.2, 12.5 Hz, 1H), 2.82 (dd, J = 16.3, 3.0 Hz,, 1H), 2.39 (s, 3H), 2.27 (brs, 1H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , , , , 79.10, 64.36, 28.75, 20.97; HRMS (ESI-TOF) Calcd for C 11 H 13 O 3 [M+H] + : ; found: (S)-3-(chloromethyl)-7-methylisochroman-1-one (4k) Substrate 4k was alkylated following the general procedure using Pd(OAc) 2 (1 mol%) and Ac-t-leu-OH (2 mol%). After purification by preparative TLC, 4k was obtained as white solid (16.4 mg, 78%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.91 (s, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.18 (d, J = 7.8 Hz, 1H), (m, 1H), 3.83 (dd, J = 11.5, 4.6 Hz, 1H), 3.74 (dd, J = 11.5, 6.7 Hz, 1H), (m, 2H), 2.40 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , , , , 77.10, 44.72, 30.19, 20.98; HRMS (ESI-TOF) Calcd for C 11 H 12 ClO 2 [M+H] + : ; found: ; m.p. = C. 2-((7-methyl-1-oxoisochroman-3-yl)methyl)isoindoline-1,3-dione (4l) Substrate 4l was alkylated following the general procedure using Pd(OAc) 2 (2.5 mol%) and Ac-t-leu-OH (5 mol%). After purification by preparative TLC, 4l was obtained as white solid (24.4 mg, 76%). 1 H NMR (400 MHz, CDCl 3 ) δ (m, 3H), (m, 2H), 7.34 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 7.7 Hz, 1H), (m, 1H), 4.18 (dd, J = 14.1, 7.5 Hz, 1H), 3.93 (dd, J = 14.1, 5.5 Hz, 1H), 3.02 (d, J = 6.9 Hz, 2H), 2.37 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ , , , , , , , , , , , 74.97, 41.05, 30.59, 20.97; HRMS (ESI-TOF) Calcd for C 19 H 16 NO 4 [M+H] + : ; found: ; m.p. = C. S20

21 3-(((4-methoxyphenyl)sulfonyl)methyl)-7-methylisochroman-1-one (4m) Substrate 4m was alkylated following the general procedure using Pd(OAc) 2 (2.5 mol%) and Ac-t-leu-OH (5 mol%). After purification by preparative TLC, 4m was obtained as white solid (33.2 mg, 96%). 1 H NMR (500 MHz, CDCl 3 ) δ (m, 3H), 7.38 (d, J = 6.7 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H), (m, 2H), (m, 1H), 3.90 (s, 3H), 3.66 (dd, J = 14.4, 4.9 Hz, 1H), 3.46 (dd, J = 14.4, 7.4 Hz, 1H), 3.28 (dd, J = 16.3, 3.3 Hz, 1H), 3.10 (dd, J = 16.2, 10.8 Hz, 1H), 2.38 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , , , , , , 124.2, , 72.64, 60.29, 55.73, 32.61, 20.96; HRMS (ESI-TOF) Calcd for C 18 H 19 O 5 S [M+H] + : ; found: ; m.p. = C. methyl 7-methyl-1-oxoisochroman-3-carboxylate (4n) Substrate 4n was alkylated following the general procedure using Pd(OAc) 2 (2.5 mol%) and Ac-t-leu-OH (5 mol%). After purification by preparative TLC, 4n was obtained as white solid (15.8 mg, 72%). 1 H NMR (500 MHz, CDCl 3 ) δ 7.92 (s, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.14 (d, J = 7.7 Hz, 1H), 5.15 (t, J = 5.6 Hz, 1H), 3.73 (s, 3H), 3.40 (dd, J = 16.4, 5.4 Hz, 1H), 3.25 (dd, J = 16.4, 5.7 Hz, 1H), 2.39 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , , , , , 74.98, 52.86, 29.79, ((benzyloxy)methyl)-3,7-dimethylisochroman-1-one (4o) Substrate 4o was alkylated following the general procedure using Pd(OAc) 2 (10 mol%) and Ac-t-leu-OH (20 mol%). After purification by preparative TLC, 4o was obtained as colorless oil (23.7 mg, 80%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.89 (s, 1H), (m, 6H), 7.11 (d, J = 7.7 Hz, 1H), 4.54 (s, 2H), 3.58 (d, J = 9.6 Hz, 1H), 3.50 (d, J = 9.7 Hz, 1H), 3.29 (d, J = 16.3 Hz, 1H), 2.88 (d, J = 16.4 Hz, 1H), 2.38 (s, 3H), 1.43 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ , , , , , , , S21

22 127.92, , , , 81.85, 74.87, 73.54, 34.46, 23.40, 20.96; HRMS (ESI-TOF) Calcd for C 19 H 21 O 3 [M+H] + : ; found: ,7-dimethyl-3-((phenylsulfonyl)methyl)isochroman-1-one (4p) Substrate 4p was alkylated following the general procedure using Pd(OAc) 2 (10 mol%) and Ac-t-leu-OH (20 mol%). After purification by preparative TLC, 4p was obtained as white solid (16.5 mg, 50%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.86 (d, J = 7.7 Hz, 2H), 7.82 (s, 1H), 7.67 (t, J = 7.4 Hz, 1H), 7.56 (t, J = 7.7 Hz, 2H), 7.38 (d, J = 7.7 Hz, 1H), 7.16 (d, J = 7.7 Hz, 1H), 3.59 (d, J = 16.4 Hz, 1H), 3.49 (s, 2H), 3.21 (d, J = 16.5 Hz, 1H), 2.38 (s, 3H), 1.73 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ , , 137.8, , , , , , , , 80.20, 62.85, 36.81, 26.10, 20.97; HRMS (ESI- TOF) Calcd for C 18 H 19 O 4 S [M+H] + : ; found: ; m.p. = C. (4a,10b-trans)-8-methyl-2,3,4,4a-tetrahydro-1H-benzo[c]chromen-6(10bH)-one (4q) Substrate 4q was alkylated following the general procedure using Pd(OAc) 2 (10 mol%) and Ac-t-leu-OH (20 mol%). After purification by preparative TLC, 4q was obtained as white solid (11.9 mg, 55%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.92 (s, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.19 (d, J = 7.9 Hz, 1H), 4.07 (td, J = 11.4, 4.3 Hz, 1H), 2.78 (td, J = 11.5, 4.0 Hz, 1H), (m, 1H), 2.39 (s, 3H), (m, 1H), (m, 2H), (m, 1H), (m, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ , , , , , , , 81.65, 40.07, 31.68, 27.04, 24.89, 24.00, 20.89; HRMS (ESI- TOF) Calcd for C 14 H 17 O 2 [M+H] + : ; found: ; m.p. = C. (3a,9b-trans)-7-methyl-1,3,3a,9b-tetrahydrocyclopenta[c]isochromen-5(2H)-one (4r) S22

23 Substrate 4r was alkylated following the general procedure using Pd(OAc) 2 (10 mol%) and Ac-t-leu-OH (20 mol%). After purification by preparative TLC, 4r was obtained as white solid (8.5 mg, 42%). 1 H NMR (500 MHz, CDCl 3 ) δ 7.89 (s, 1H), 7.36 (d, J = 7.0 Hz, 1H), 7.08 (d, J = 7.7 Hz, 1H), (m, 1H), (m, 1H), 2.39 (s, 3H), (m, 1H), (m, 1H), (m, 1H), (m, 2H), (m, 1H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , , , , 83.63, 42.60, 27.94, 22.94, 21.04, 19.58; HRMS (ESI-TOF) Calcd for C 13 H 15 O 2 [M+H] + : ; found: ; m.p. = C. 2.7 Coupling Reactions Using Chiral (S)-(+)-epichlorohydrin The enantiomeric excess of (S)-4K was determined by HPLC (chiral column: CHIRALPAK AD-H; solvent: hexane/2-propanol = 20/1; flow rate: 0.3 ml/min; detection: at 254 nm) analysis in comparision with authentic racemic material: Retention time = 54.4 min (R) and 58.8 min (S) H and 13 C NMR Spectra S23

24 S24

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44 S44

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46 S46

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51 S51

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66 4. X-ray Crystallographic Data of 4q Table 1. Crystal data and structure refinement for Yu42. Report date Identification code 4q Empirical formula C14 H16 O2 Molecular formula C14 H16 O2 Formula weight Temperature K Wavelength Å Crystal system Monoclinic Space group P 1 21/n 1 Unit cell dimensions a = (11) Å b = (6) Å c = (2) Å Volume (2) Å 3 Z 4 Density (calculated) Mg/m 3 Absorption coefficient mm -1 F(000) 464 Crystal size x x mm 3 Crystal color, habit Colorless Block Theta range for data collection to S66

67 Index ranges -11<=h<=11, -7<=k<=7, -22<=l<=22 Reflections collected 7956 Independent reflections 2000 [R(int) = ] Completeness to theta = % Absorption correction Semi-empirical from equivalents Max. and min. transmission and Refinement method Full-matrix least-squares on F 2 Data / restraints / parameters 2000 / 0 / 146 Goodness-of-fit on F Final R indices [I>2sigma(I)] R1 = , wr2 = R indices (all data) R1 = , wr2 = Extinction coefficient n/a Largest diff. peak and hole and e.å -3 S67

68 Table 2. Atomic coordinates ( x 10 4 ) and equivalent isotropic displacement parameters (Å 2 x 10 3 ) for Yu42. U(eq) is defined as one third of the trace of the orthogonalized U ij tensor. x y z U(eq) O(1) 4028(1) 7413(2) 6957(1) 24(1) O(2) 3945(1) 9302(2) 5947(1) 28(1) C(8) 5555(2) 6310(3) 6080(1) 20(1) C(7) 5799(2) 4288(3) 6416(1) 19(1) C(6) 5047(2) 3769(3) 7058(1) 21(1) C(9) 4477(2) 7800(3) 6309(1) 22(1) C(13) 6237(2) 6909(3) 5494(1) 22(1) C(12) 7180(2) 5509(3) 5226(1) 22(1) C(10) 6711(2) 2872(3) 6129(1) 22(1) C(1) 4830(2) 5866(3) 7450(1) 21(1) C(11) 7382(2) 3468(3) 5546(1) 24(1) C(4) 4978(2) 1809(3) 8237(1) 25(1) C(5) 5815(2) 2163(3) 7604(1) 23(1) C(3) 4747(2) 3936(3) 8621(1) 26(1) C(14) 7972(2) 6171(3) 4616(1) 27(1) C(2) 4013(2) 5589(3) 8084(1) 25(1) S68

69 Table 3. Bond lengths [Å] and angles [ ] for Yu42. O(1)-C(9) 1.359(2) O(1)-C(1) 1.460(2) O(2)-C(9) 1.213(2) C(8)-C(7) 1.403(2) C(8)-C(9) 1.483(2) C(8)-C(13) 1.397(2) C(7)-C(6) 1.512(2) C(7)-C(10) 1.391(2) C(6)-H(6) C(6)-C(1) 1.516(2) C(6)-C(5) 1.528(2) C(13)-H(13) C(13)-C(12) 1.388(2) C(12)-C(11) 1.396(2) C(12)-C(14) 1.506(2) C(10)-H(10) C(10)-C(11) 1.387(2) C(1)-H(1) C(1)-C(2) 1.513(2) C(11)-H(11) C(4)-H(4A) C(4)-H(4B) C(4)-C(5) 1.529(2) C(4)-C(3) 1.527(2) C(5)-H(5A) C(5)-H(5B) C(3)-H(3A) C(3)-H(3B) C(3)-C(2) 1.525(3) C(14)-H(14A) C(14)-H(14B) C(14)-H(14C) S69

70 C(2)-H(2A) C(2)-H(2B) C(9)-O(1)-C(1) (13) C(7)-C(8)-C(9) (15) C(13)-C(8)-C(7) (15) C(13)-C(8)-C(9) (15) C(8)-C(7)-C(6) (14) C(10)-C(7)-C(8) (15) C(10)-C(7)-C(6) (15) C(7)-C(6)-H(6) C(7)-C(6)-C(1) (14) C(7)-C(6)-C(5) (14) C(1)-C(6)-H(6) C(1)-C(6)-C(5) (14) C(5)-C(6)-H(6) O(1)-C(9)-C(8) (15) O(2)-C(9)-O(1) (15) O(2)-C(9)-C(8) (16) C(8)-C(13)-H(13) C(12)-C(13)-C(8) (16) C(12)-C(13)-H(13) C(13)-C(12)-C(11) (16) C(13)-C(12)-C(14) (15) C(11)-C(12)-C(14) (15) C(7)-C(10)-H(10) C(11)-C(10)-C(7) (16) C(11)-C(10)-H(10) O(1)-C(1)-C(6) (13) O(1)-C(1)-H(1) O(1)-C(1)-C(2) (13) C(6)-C(1)-H(1) C(2)-C(1)-C(6) (14) C(2)-C(1)-H(1) S70

71 C(12)-C(11)-H(11) C(10)-C(11)-C(12) (16) C(10)-C(11)-H(11) H(4A)-C(4)-H(4B) C(5)-C(4)-H(4A) C(5)-C(4)-H(4B) C(3)-C(4)-H(4A) C(3)-C(4)-H(4B) C(3)-C(4)-C(5) (14) C(6)-C(5)-C(4) (14) C(6)-C(5)-H(5A) C(6)-C(5)-H(5B) C(4)-C(5)-H(5A) C(4)-C(5)-H(5B) H(5A)-C(5)-H(5B) C(4)-C(3)-H(3A) C(4)-C(3)-H(3B) H(3A)-C(3)-H(3B) C(2)-C(3)-C(4) (14) C(2)-C(3)-H(3A) C(2)-C(3)-H(3B) C(12)-C(14)-H(14A) C(12)-C(14)-H(14B) C(12)-C(14)-H(14C) H(14A)-C(14)-H(14B) H(14A)-C(14)-H(14C) H(14B)-C(14)-H(14C) C(1)-C(2)-C(3) (14) C(1)-C(2)-H(2A) C(1)-C(2)-H(2B) C(3)-C(2)-H(2A) C(3)-C(2)-H(2B) H(2A)-C(2)-H(2B) S71

72 Table 4. Anisotropic displacement parameters (Å 2 x 10 3 ) for Yu42. The anisotropic displacement factor exponent takes the form: - 2 [ h 2 a* 2 U h k a* b* U 12 ] U 11 U 22 U 33 U 23 U 13 U 12 O(1) 26(1) 22(1) 25(1) 2(1) 6(1) 5(1) O(2) 31(1) 23(1) 31(1) 5(1) 5(1) 6(1) C(8) 17(1) 21(1) 21(1) -2(1) 0(1) 0(1) C(7) 17(1) 20(1) 20(1) -1(1) -1(1) -2(1) C(6) 18(1) 21(1) 24(1) 1(1) 2(1) -1(1) C(9) 23(1) 21(1) 23(1) 0(1) 3(1) -4(1) C(13) 21(1) 20(1) 23(1) 1(1) 0(1) -1(1) C(12) 21(1) 24(1) 20(1) -2(1) 1(1) -1(1) C(10) 24(1) 18(1) 24(1) 2(1) 1(1) 1(1) C(1) 21(1) 20(1) 22(1) 3(1) 2(1) 1(1) C(11) 23(1) 23(1) 24(1) -3(1) 3(1) 2(1) C(4) 25(1) 25(1) 25(1) 6(1) 2(1) 0(1) C(5) 24(1) 21(1) 25(1) 1(1) 2(1) 0(1) C(3) 28(1) 26(1) 23(1) 1(1) 5(1) -3(1) C(14) 27(1) 28(1) 26(1) 0(1) 7(1) 1(1) C(2) 26(1) 22(1) 28(1) -1(1) 9(1) 1(1) S72

73 Table 5. Hydrogen coordinates ( x 10 4 ) and isotropic displacement parameters (Å 2 x 10 3 ) for Yu42. x y z U(eq) H(6) H(13) H(10) H(1) H(11) H(4A) H(4B) H(5A) H(5B) H(3A) H(3B) H(14A) H(14B) H(14C) H(2A) H(2B) S73

74 5. X-ray Crystallographic Data of 4r Table 1. Crystal data and structure refinement for Yu43. Report date Identification code 4r Empirical formula C13 H14 O2 Molecular formula C13 H14 O2 Formula weight Temperature K Wavelength Å Crystal system Monoclinic Space group P 1 21/n 1 Unit cell dimensions a = (4) Å b = (10) Å c = (10) Å Volume (13) Å 3 Z 4 Density (calculated) Mg/m 3 Absorption coefficient mm -1 F(000) 432 Crystal size x x mm 3 Crystal color, habit Colorless Block S74

75 Theta range for data collection to Index ranges -7<=h<=6, -14<=k<=14, -16<=l<=16 Reflections collected 8581 Independent reflections 1876 [R(int) = ] Completeness to theta = % Absorption correction Semi-empirical from equivalents Max. and min. transmission and Refinement method Full-matrix least-squares on F 2 Data / restraints / parameters 1876 / 0 / 144 Goodness-of-fit on F Final R indices [I>2sigma(I)] R1 = , wr2 = R indices (all data) R1 = , wr2 = Extinction coefficient n/a Largest diff. peak and hole and e.å -3 S75

76 Table 2. Atomic coordinates ( x 10 4 ) and equivalent isotropic displacement parameters (Å 2 x 10 3 ) for Yu43. U(eq) is defined as one third of the trace of the orthogonalized U ij tensor. x y z U(eq) O(1) 5669(2) 4989(1) 2339(1) 24(1) O(2) 8033(2) 6325(1) 2117(1) 27(1) C(2) 2859(3) 3549(1) 2610(1) 29(1) C(3) 877(3) 3541(1) 3240(1) 26(1) C(4) 1191(3) 4556(1) 3906(1) 20(1) C(6) 3937(2) 6236(1) 3851(1) 19(1) C(7) 5918(2) 6538(1) 3461(1) 18(1) C(8) 6639(2) 5962(1) 2602(1) 20(1) C(9) 3278(3) 6834(1) 4621(1) 21(1) C(10) 4543(3) 7713(1) 4994(1) 22(1) C(11) 6498(3) 8032(1) 4604(1) 23(1) C(12) 7167(3) 7432(1) 3834(1) 22(1) C(13) 7839(3) 9008(1) 4988(1) 35(1) C(1) 4296(3) 4487(1) 3029(1) 20(1) C(5) 2650(3) 5307(1) 3360(1) 17(1) C(1B) 3320(40) 5029(19) 2605(17) 20(1) C(5B) 3620(50) 4980(20) 3633(18) 17(1) S76

77 Table 3. Bond lengths [Å] and angles [ ] for Yu43. O(1)-C(8) (19) O(1)-C(1) (19) O(1)-C(1B) 1.49(2) O(2)-C(8) (18) C(2)-H(2A) C(2)-H(2B) C(2)-C(3) 1.548(2) C(2)-C(1) 1.517(2) C(2)-C(1B) 1.82(2) C(3)-H(3A) C(3)-H(3B) C(3)-C(4) 1.552(2) C(4)-H(4AA) C(4)-H(4AB) C(4)-H(4BC) C(4)-H(4BD) C(4)-C(5) 1.523(2) C(4)-C(5B) 1.63(2) C(6)-C(7) 1.405(2) C(6)-C(9) 1.391(2) C(6)-C(5) 1.501(2) C(6)-C(5B) 1.57(2) C(7)-C(8) 1.494(2) C(7)-C(12) 1.396(2) C(9)-H(9) C(9)-C(10) 1.386(2) C(10)-H(10) C(10)-C(11) 1.397(2) C(11)-C(12) 1.394(2) C(11)-C(13) 1.508(2) C(12)-H(12) C(13)-H(13A) C(13)-H(13B) C(13)-H(13C) C(1)-H(1) C(1)-C(5) 1.509(2) C(5)-H(5) S77

78 C(1B)-H(1B) C(1B)-C(5B) 1.44(3) C(5B)-H(5B) C(8)-O(1)-C(1) (12) C(8)-O(1)-C(1B) 107.2(9) H(2A)-C(2)-H(2B) C(3)-C(2)-H(2A) C(3)-C(2)-H(2B) C(3)-C(2)-C(1B) 97.7(7) C(1)-C(2)-H(2A) C(1)-C(2)-H(2B) C(1)-C(2)-C(3) (13) C(2)-C(3)-H(3A) C(2)-C(3)-H(3B) C(2)-C(3)-C(4) (12) H(3A)-C(3)-H(3B) C(4)-C(3)-H(3A) C(4)-C(3)-H(3B) C(3)-C(4)-H(4AA) C(3)-C(4)-H(4AB) C(3)-C(4)-H(4BC) C(3)-C(4)-H(4BD) C(3)-C(4)-C(5B) 99.8(8) H(4AA)-C(4)-H(4AB) H(4BC)-C(4)-H(4BD) C(5)-C(4)-C(3) (12) C(5)-C(4)-H(4AA) C(5)-C(4)-H(4AB) C(5B)-C(4)-H(4BC) C(5B)-C(4)-H(4BD) C(7)-C(6)-C(5) (13) C(7)-C(6)-C(5B) 105.8(9) C(9)-C(6)-C(7) (14) C(9)-C(6)-C(5) (14) C(9)-C(6)-C(5B) 128.6(9) C(6)-C(7)-C(8) (13) C(12)-C(7)-C(6) (14) C(12)-C(7)-C(8) (13) S78

79 O(1)-C(8)-C(7) (13) O(2)-C(8)-O(1) (14) O(2)-C(8)-C(7) (14) C(6)-C(9)-H(9) C(10)-C(9)-C(6) (14) C(10)-C(9)-H(9) C(9)-C(10)-H(10) C(9)-C(10)-C(11) (14) C(11)-C(10)-H(10) C(10)-C(11)-C(13) (15) C(12)-C(11)-C(10) (14) C(12)-C(11)-C(13) (15) C(7)-C(12)-H(12) C(11)-C(12)-C(7) (14) C(11)-C(12)-H(12) C(11)-C(13)-H(13A) C(11)-C(13)-H(13B) C(11)-C(13)-H(13C) H(13A)-C(13)-H(13B) H(13A)-C(13)-H(13C) H(13B)-C(13)-H(13C) O(1)-C(1)-H(1) O(1)-C(1)-C(5) (13) C(2)-C(1)-H(1) C(5)-C(1)-C(2) (13) C(5)-C(1)-H(1) C(4)-C(5)-H(5) C(6)-C(5)-C(4) (13) C(6)-C(5)-C(1) (14) C(6)-C(5)-H(5) C(1)-C(5)-C(4) (13) C(1)-C(5)-H(5) O(1)-C(1B)-C(2) 96.6(12) O(1)-C(1B)-H(1B) C(2)-C(1B)-H(1B) C(5B)-C(1B)-O(1) 102.5(19) C(5B)-C(1B)-C(2) 87.6(16) C(5B)-C(1B)-H(1B) S79

80 C(4)-C(5B)-H(5B) C(6)-C(5B)-C(4) 111.0(16) C(6)-C(5B)-H(5B) C(1B)-C(5B)-C(4) 102.7(19) C(1B)-C(5B)-C(6) 98.9(18) C(1B)-C(5B)-H(5B) S80

81 Table 4. Anisotropic displacement parameters (Å 2 x 10 3 ) for Yu43. The anisotropic displacement factor exponent takes the form: - 2 [ h 2 a* 2 U h k a* b* U 12 ] U 11 U 22 U 33 U 23 U 13 U 12 O(1) 23(1) 29(1) 22(1) -5(1) 7(1) -1(1) O(2) 24(1) 34(1) 26(1) 6(1) 10(1) 2(1) C(2) 28(1) 27(1) 33(1) -11(1) 6(1) -2(1) C(3) 26(1) 24(1) 28(1) -7(1) 1(1) -4(1) C(4) 20(1) 21(1) 21(1) -2(1) 3(1) -3(1) C(6) 21(1) 17(1) 19(1) 2(1) 3(1) -1(1) C(7) 18(1) 20(1) 16(1) 5(1) 1(1) 3(1) C(8) 16(1) 26(1) 19(1) 5(1) 1(1) 4(1) C(9) 22(1) 21(1) 21(1) 1(1) 7(1) -1(1) C(10) 28(1) 19(1) 18(1) 0(1) 3(1) 1(1) C(11) 26(1) 21(1) 21(1) 4(1) -4(1) -4(1) C(12) 18(1) 26(1) 22(1) 7(1) 1(1) -3(1) C(13) 40(1) 29(1) 34(1) -1(1) 0(1) -13(1) C(1) 20(1) 22(1) 19(1) 0(1) 5(1) 1(1) C(5) 17(1) 18(1) 16(1) 0(1) 1(1) 2(1) C(1B) 20(1) 22(1) 19(1) 0(1) 5(1) 1(1) C(5B) 17(1) 18(1) 16(1) 0(1) 1(1) 2(1) S81

82 Table 5. Hydrogen coordinates ( x 10 4 ) and isotropic displacement parameters (Å 2 x 10 3 ) for Yu43. x y z U(eq) H(2A) H(2B) H(3A) H(3B) H(4AA) H(4AB) H(4BC) H(4BD) H(9) H(10) H(12) H(13A) H(13B) H(13C) H(1) H(5) H(1B) H(5B) S82