Electronic Supplementary Information. Discovery of 7-hydroxyaporphines as conformational restricted

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1 Electronic Supplementary Material (ESI) for MedChemComm. This journal is The Royal Society of Chemistry 208 Electronic Supplementary Information Discovery of 7-hydroxyaporphines as conformational restricted ligands for beta- and beta-2 adrenergic receptors Angela F. Ku and Gregory D. Cuny a a Department of Pharmacological and Pharmaceutical Sciences, University of ouston, Science and Research Building 2, ouston, Texas 77204, United States. Content. General Experimental Conditions S2 2. Functional Assays S3 S4 3. Synthetic Procedures S5 S5 4. Copies of the and 3 C MR spectra S6 S33 S

2 . General Experimental Conditions All reactions involving air-sensitive reagents were carried out in oven-dried glassware equipped with a magnetic stir bar and fitted with rubber septa under argon unless otherwise stated. All commercially available chemicals and reagent grade solvents were used directly without further purification unless otherwise specified. All reactions were monitored by thinlayer chromatography (TLC) on Baker-flex silica gel plates (IB2-F) using UV-light (254 and 365 nm) detection or visualizing agents (ninhydrin or phosphomolybdic acid stain). Flash column chromatography was conducted on silica gel ( mesh) using Teledyne Isco CombiFlash Rf. Melting points were measured using a Thomas oover Uni-Melt capillary melting point apparatus and are uncorrected. MR spectra were recorded at room temperature using a JEL ECA-500 ( MR at 500 Mz and 3 C MR at 25 Mz) or a JEL ECX-400P ( MR at 400 Mz and 3 C MR at 00 Mz) with tetramethylsilane (TMS) as an internal standard. Chemical shifts (δ) are given in parts per million (ppm) with reference to solvent signals [ -MR: CD 3 (7.26 ppm), CD 3 D (3.3 ppm), DMS-d 6 (2.50 ppm); 3 C-MR: CD 3 (77.0 ppm), CD 3 D (49.5 ppm), DMS-d 6 (39.5 ppm)]. Signal patterns are reported as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and br (broad). Coupling constants (J) are given in z. igh resolution mass spectra (RMS) were performed by the University of Texas Mass Spectrometry facility using a quadrupole time-of-flight (Q-TF) mass spectrometer with electrospray ionization (ESI). The spectra were reported as m/z (relative intensity) for the molecular ion [M]. ptical rotations were measured on ATAG's polarimeter (PLAX-2L). Specific rotation [α] D values are given in units of 0 deg cm 2 g. S2

3 2. Functional Assays The functional assays were conducted by Eurofins Panlab Discovery Service. Compound 2 was tested for both agonist and antagonist activities of the adrenergic receptor subtypes β and β 2 using conditions described in Table S. For functional antagonism, the β -adrenergic receptor was first agonized with isoproterenol to release camp. The agonism, detected by camp accumulation, was subsequently blocked through the treatment with either compound 2 (IC 50 = 0.07 ± 0.04 μm) or the positive control, atenolol (IC 50 = 0.40 ± μm) as shown in Figure S. Following a similar protocol, 2 and the positive control, ICI-8,55, inhibited the procaterol-induced camp increase at the β 2 -adrenergic receptor with IC 50 values of ± μm and ± μm, respectively (Figure S2). In the absence of or 2 agonists, compound 2 had no effect. Table S. Methods for β and β 2 -adrenergic receptor functional assays Adrenergic β, adenylyl cyclase Adrenergic β 2, adenylyl cyclase Target uman C-K cells uman C cells Quantitation method TRF quantitation of camp accumulation TRF quantitation of camp accumulation Vehicle 0.40% DMS 0.40% DMS Incubation time/temp 5 37 C C Incubation buffer BSS, 5 mm EPES, 0.% BSA, 00 µm IBMX, p 7.4 BSS, 5 mm EPES, 0.% BSA, 00 µm IBMX, p 7.4 2, IC 50 = M Atenolol, IC 50 = 0.37 M 2, IC 50 = 0.03 M Atenolol, IC 50 = 0.43 M Figure S. Dose-response curves of 2 and atenolol (positive control) for inhibition of isoproterenol-induced camp increase in a β -adrenergic receptor functional assay. S3

4 2, IC 50 = 9.53 nm ICI-8,55, IC 50 = 0.79 nm 2, IC 50 = 4.2 nm ICI-8,55, IC 50 = 0.55 nm Figure S2. Dose-response curves of 2 and ICI-8,55 (positive control) for inhibition of isoproterenol-induced camp increase in a β 2 -adrenergic receptor functional assay. S4

5 3. Synthetic Procedures triphosgene TBS 8 (R) 2 toluene 00 C, h S 2, C 3 TBS 0 Me C Et 3, 0 0 C to rt, 6 h C 2 2, rt, 6 h 99% 55% TBS 7 9 Methyl (R)-2-(2-chlorophenyl)-2-hydroxyacetate (9) To a solution of (R)-( )-2- chloromandelic acid (7) (7.38 g, 39.5 mmol) in C 3 (5 ml) was added S 2 (3.2 ml, 44 mmol) at 0 o C under argon. After being stirred at room temperature for 6 h, the reaction mixture was poured into saturated aqueous ac 3 (00 ml). The mixture was then evaporated in vacuo to remove C 3. The aqueous layer was extracted with EtAc (2 50 ml), and the combined organic extracts were washed with brine, dried over anhydrous a 2 S 4, filtered and concentrated to afford 9 (7.9 g, 99%) as a colorless oil; MR (CD 3, 500 Mz) (2, m), (2, m), 5.57 (, s), 3.78 (3, s); 3 C MR (CD 3, 25 Mz) 73.7, 35.9, 33.5, 30.0, 29.8, 28.8, 27.2, 70.3, 53.2; RMS (ESI/Q-TF) m/z [M + a] + calculated for C a ; found The crude product was used directly in the next step. Methyl (R)-2-(((4-((tert-butyldimethylsilyl)oxy)-3-methoxyphenethyl)carbamoyl)oxy)-2- (2-chlorophenyl)acetate () To a solution of triphosgene (630 mg, 2. mmol) in anhydrous toluene (5 ml) was added a solution of 8 (850 mg, 3.0 mmol) in anhydrous toluene (5 ml) under argon. The mixture was stirred at room temperature for 30 min and heated to 00 o C for another h. The resulting mixture was then allowed to cool to room temperature and slowly added into a suspension of 9 (400 mg, 2.0 mmol) and triethylamine (340 μl, 2.4 mmol) in anhydrous C 2 2 (5 ml) under argon. After being stirred at room temperature for 6 h, the reaction was quenched by the addition of saturated aqueous 4, evaporated in vacuo to remove excess toluene and C 2 2, and then partitioned between 2 and EtAc. Following neutralization with saturated aqueous ac 3, the organic layer was washed with brine, dried over anhydrous a 2 S 4, filtered and concentrated. The residue was purified by column chromatography on silica gel (EtAc/hexane, 5:95 to 7:93 to 0:90) to afford (560 mg, 55%) as a colorless oil; [ ] 24 D 67 (c.5, C 3 ); MR (CD 3, 500 Mz) (2, m), (2, m), 6.76 (, d, J = 8.0 z), 6.67 (, d, J = 2.0 z), 6.62 (, dd, J = 8.0, 2.0 z), 6.45 (, s), 4.98 (, S5

6 br, ), 3.77 (3, s), 3.75 (3, s), (2, m), 2.75 (2, t, J = 7.0 z), 0.99 (9, s), 0.4 (6, s); 3 C MR (CD 3, 25 Mz) 69.6, 55.0, 50.9, 43.6, 34., 32.5, 3.8, 30.4, 29.9, 29.4, 27., 20.9, 20.8, 2.6, 7.2, 55.4, 52.7, 42.5, 35.5, 25.7 (3 ), 8.4, 4.7 (2 ); RMS (ESI/Q-TF) m/z [M + a] + calculated for C Sia ; found TBS ) (i) DIBAL-, C 2 2, 78 o C, h (ii) C 3, 20 o C, 0 min + (iii) BF 3 Et 2, 20 o C to rt, h 2) TBAF, C 2 2, rt, 0 min 64% (2-anti / 2-syn = 67:33) 2-anti 2-syn 2 To a solution of (308 mg, 0.6 mmol) in anhydrous C 2 2 (0 ml) was added dropwise a solution of DIBAL- (25% in toluene, 800 μl,.2 mmol) at 78 o C under argon, and the mixture was stirred at 78 o C for h. Then, C 3 (500 μl) was added, and the reaction was stirred at 20 o C for 0 min. Following the addition of BF 3 Et 2 (740 μl, 6 mmol), the resulting mixture was stirred at room temperature for another h. This reaction mixture was quenched with 2 (5 ml), evaporated in vacuo to remove excess C 3, and then partitioned between 2 and EtAc. After neutralization with saturated aqueous ac 3, the organic layer was washed with brine, dried over anhydrous a 2 S 4, filtered and concentrated. To the crude mixture in anhydrous C 2 2 (5 ml) was added TBAF (.0 M in TF, 470 μl, 4.7 mmol) under argon. After being stirred at room temperature for 0 min, the reaction was evaporated in vacuo. The residue was purified by column chromatography on silica gel (EtAc/hexane, 30:70 to 40:60) to afford 2 (32 mg, 64%) as a mixture of diastereomers (dr 67:33 for the anti/syn isomers). Anti-isomer 2-anti could be obtained after several recrystalizations with EtAc and hexane. (R,0bR)--(2-Chlorophenyl)-9-hydroxy-8-methoxy-5,6-dihydro--oxazolo[4,3- a]isoquinolin-3(0b)-one (2-anti) White prisms; mp o C; [ ] 26 D 60 (c 2.4, C 3 ); MR (CD 3, 500 Mz) 7.55 (, dd, J = 7.0, 2.5 z), (, m), (2, m), 6.89 (, s), 6.6 (, s), 5.73 (, d, J = 4.5 z), 5.66 (, s, Ph), 4.82 (, d, J = 4.5 z), 4. (, ddd, J = 3.0, 6.0,.5 z), 3.88 (3, s), 3.20 (, td, J = 3.0, 4.0 z), 3.0 (, td, J = 6.0, 6.0 z), 2.6 (, dd, J = 6.0, 4.0 z); 3 C MR (CD 3, 25 Mz) 57.6, 46.2, 44.7, 35.7, 32.3, 30.2, 30.2, 28., 27.5, 26.3, 25.5,.2, 0.9, 79.4, 6.4, 55.9, 39.4, 26.8; RMS (ESI/Q-TF) m/z [M + ] + calculated for C ; S6

7 found XPhos precat. (0 mol %) Cs 2C 3, DMA 0 C, 40 min + 2 (dr 67:33) 3-anti (70%) 3-syn (24%) To 2 (dr 67:33) (39 mg, 0. mmol), Cs 2 C 3 ( mg, 0.34 mmol) and XPhos precatalyst (8 mg, 0.0 mmol) was added anhydrous DMA (500 μl) under argon. The reaction was stirred at room temperature for 5 min and then put into a preheated oil bath (0 o C) for another 40 min. After being quenched by the addition of (aq), the aqueous layer was extracted with EtAc (2 30 ml). Following neutralization with saturated aqueous ac 3, the combined organic extracts were washed with brine, dried over anhydrous a 2 S 4, filtered and concentrated. The residue was purified by column chromatography on silica gel (EtAc/hexane, 25:75 to 30:70 to 35:65 to 50:50) to afford 3-anti (24 mg, 70%) and 3-syn (8 mg, 24%) in a combined yield of 94%. (3 R,2bR)-8-ydroxy-7-methoxy-3,4,5,2b-tetrahydro-2-dibenzo[de,g]oxazolo[5,4,3- ij]quinolin-2-one (3-anti) White prisms; mp o C; [ ] 25 D 03 (c 0.97, C 3 ); MR (CD 3, 500 Mz) 8.39 (, d, J = 8.0 z), 7.47 (, d, J = 7.5 z), 7.43 (, t, J = 8.0 z), 7.35 (, t, J = 7.5 z), 6.68 (, s), 6.34 (, s, Ph), 4.79 (, d, J = 3.0 z), 4.7 (, d, J = 3.0 z), (, m), 3.94 (3, s), (, m), (, m), (, m); 3 C MR (CD 3, 25 Mz) 57.8, 47.3, 42.7, 33.5, 30.4, 29.6, 27.8, 27.7, 2.9, 2.3, 20., 6.0, 09.5, 8.6, 56.5, 56.2, 37.8, 26.7; RMS (ESI/Q-TF) m/z [M + ] + calculated for C ; found (3 S,2bR)-8-ydroxy-7-methoxy-3,4,5,2b-tetrahydro-2-dibenzo[de,g]oxazolo[5,4,3- ij]quinolin-2-one (3-syn) White prisms; mp o C; [ ] 24 D 80 (c 0.5, C 3 ); MR (CD 3, 500 Mz) 8.78 (, d, J = 8.0 z), (2, m), 7.35 (, td, J = 7.5,.0 z), 6.76 (, s), 6.45 (, s, Ph), 5.56 (, d, J = 7.0 z), 4.70 (, d, J = 7.0 z), 3.95 (3, s), 3.67 (, dd, J =.0, 7.5 z), 3.52 (, td, J =.0, 6.5 z), (2, m); 3 C MR (CD 3, 25 Mz) 60.4, 46.9, 42.6, 32. (2 ), 30.7, 29., 27.7, 26.9, 26.5, 23.6, 5.8, 0., 73.2, 56.5, 52.6, 40.4, 27.; RMS (ESI/Q-TF) m/z [M + a] + calculated for C a ; found S7

8 C 3I, Cs 2C 3 LA DMF, rt, 6 h 93% TF, 0 o C to rt, h 83% 3-syn S (3 S,2bR)-7,8-Dimethoxy-3,4,5,2b-tetrahydro-2-dibenzo[de,g]oxazolo[5,4,3-ij]quinolin- 2-one (S) To a solution of 3-syn (64 mg, 0.20 mmol) and Cs 2 C 3 (82 mg, 0.25 mmol) in anhydrous DMF ( ml) was added C 3 I (6 μl, 0.25 mmol) under argon, and the mixture was stirred at room temperature for 6 h. After being quenched with 2 (0 ml), the aqueous layer was extracted with EtAc (2 20 ml). The combined organic extracts were washed with brine, dried over anhydrous a 2 S 4, filtered and concentrated. The residue was purified by column chromatography on silica gel (EtAc/C 2 2, 0:00 to 2:98) to afford S (62 mg, 93%) as a white solid; mp o C; [ ] 24 D 78 (c.4, C 3 ); MR (CD 3, 500 Mz) 8.77 (, d, J = 8.0 z), (2, m), (, m), 6.80 (, s), 5.5 (, d, J = 7.5 z), 4.67 (, d, J = 7.5 z), 3.9 (3, s), 3.72 (3, s), (, m), (, m), (2, m); 3 C MR (CD 3, 25 Mz) 60.4, 53.7, 46.0, 32.2, 3.9, 3.5, 3., 28.7, 28.2, 27.3, 23.4, 23.0, 2., 73., 60.2, 56.0, 52.5, 40.4, 27.3; RMS (ESI/Q-TF) m/z [M + a] + calculated for C a ; found (6aS,7R)-,2-Dimethoxy-5,6,6a,7-tetrahydro-4-dibenzo[de,g]quinolin-7-ol () To a solution of S (7 mg, mmol) in TF (3 ml) was added a solution of lithium aluminum hydride (LA) (.0 M in TF, 260 μl) at 0 o C under argon, and the mixture was stirred at room temperature for h. After being quenched with saturated aqueous sodium potassium tartrate (5 ml) for 30 min, the aqueous layer was extracted with C 2 2 (2 0 ml). Following neutralization with saturated aqueous ac 3, the combined organic extracts were washed with brine, dried over anhydrous a 2 S 4, filtered and concentrated. The residue was purified by column chromatography on silica gel (C 3 /C 2 2, 5:95 to 0:90) to afford (3 mg, 83%) as a pale yellow solid; mp 8 82 o C; [ ] 22 D 45 (c., C 3 ); MR (CD 3, 500 Mz) 8.50 (, d, J = 7.0 z), 7.43 (, td, J = 7.0,.5 z), 7.38 (, dd, J = 7.5,.0 z), 7.29 (, td, J = 7.5,.5 z), 6.66 (, s), 4.54 (, d, J = 2.5 z), 3.97 (, s), 3.89 (3, s), 3.69 (3, s), 3.42 (, dd, J = 2.0, 5.0 z), 3.3 (, td, J = 2.0, 4.0 z), 2.99 (, td, J = 6.0, 5.0 z), 2.70 (, dd, J = 6.0, 4.0 z); 3 C MR (CD 3, 25 Mz) 52.4, 45.2, 36.3, 3.3, 3.3, 29.4, 29.0, 28.9, 27.8, 25.6, 23.4, 2., 7., 60.2, 57., 55.8, 42.8, 29.0; RMS (ESI/Q-TF) m/z [M + ] + calculated for C ; found S8

9 C 3I, Cs 2C 3 2 a (aq) DMF, rt, 2 h 75% TF, 70 o C, 2 days 82% 3-anti S2 2 (3 R,2bR)-7,8-Dimethoxy-3,4,5,2b-tetrahydro-2-dibenzo[de,g]oxazolo[5,4,3-ij]quinolin- 2-one (S2) To a solution of 3-anti (8 mg, mmol) and Cs 2 C 3 (23 mg, 0.07 mmol) in anhydrous DMF (0.5 ml) was added C 3 I (5 μl, 0.07 mmol) under argon, and the mixture was stirred at room temperature for 2 h. After being quenched with 2 (5 ml), the aqueous layer was extracted with EtAc (2 20 ml). The combined organic extracts were washed with brine, dried over anhydrous a 2 S 4, filtered and concentrated. The residue was purified by column chromatography on silica gel (EtAc/hexane, 20:80 to 25:75) to afford S2 (4 mg, 75%) as a white solid; mp o C; [ ] 23 D 70 (c.0, C 3 ); MR (CD 3, 500 Mz) 8.40 (, dd, J = 7.0,.5 z), 7.48 (, d, J = 7.0 z), (2, m), 6.76 (, s), 4.82 (, d, J = 3.5 z), 4.6 (, d, J = 3.5 z), (, m), 3.9 (3, s), 3.75 (3, s), (, m), (2, m); 3 C MR (CD 3, 25 Mz) 57.7, 53.7, 46.5, 34.0, 30.2, 29.6, 28.2, 28., 25.0, 23.7, 2.7, 2.3,.6, 8.5, 60.4, 56.2, 56., 37.7, 27.0; RMS (ESI/Q-TF) m/z [M + ] + calculated for C ; found (6aR,7R)-,2-Dimethoxy-5,6,6a,7-tetrahydro-4-dibenzo[de,g]quinolin-7-ol (2) To a solution of S2 (0 mg, 0.03 mmol) in TF (2 ml) was added 2 a (aq) ( ml), and the mixture was stirred at 70 o C for 2 days. After being quenched with 2 (0 ml), the aqueous layer was extracted with EtAc (2 20 ml). The combined organic extracts were washed with brine, dried over anhydrous a 2 S 4, filtered and concentrated. The residue was purified by column chromatography on silica gel (C 3 /C 2 2, 5:95 to 0:90) to afford 2 (7.6 mg, 82%) as a pale yellow solid; mp 89 9 o C; [ ] 24 D +78 (c 0.58, C 3 ); MR (CD 3, 500 Mz) (, m), (, m), (2, m), 6.65 (, s), 4.55 (, d, J =.5 z), 3.88 (3, s), 3.67 (, d, J =.5 z), 3.64 (3, s), (, m), (, m), 2.98 (, td, J =.5, 3.5 z), 2.73 (, d, J = 6.0 z); 3 C MR (CD 3, 25 Mz) 52.5, 45., 39.0, 30.2, 29.4, 28., 27.8, 27.4, 25.9, 24.3, 23.,.8, 72.0, 60.3, 59.0, 55.9, 42.0, 28.9; RMS (ESI/Q-TF) m/z [M + ] + calculated for C ; found S9

10 Me C 3I, Cs 2C 3 Me sat. K (aq) Me DMF, rt, 6 h 90% TF, 75 o C, 3 days 59% 4 S3 3 rel-(3 S,2bS)-7,8-Dimethoxy-3 -methyl-3,4,5,2b-tetrahydro-2dibenzo[de,g]oxazolo[5,4,3-ij]quinolin-2-one (S3) To a solution of 4 (22 mg, mmol) and Cs 2 C 3 (26 mg, 0.08 mmol) in anhydrous DMF ( ml) was added C 3 I (5 μl, 0.08 mmol) under argon, and the mixture was stirred at room temperature for 6 h. After being quenched with 2 (0 ml), the aqueous layer was extracted with EtAc (2 20 ml). The combined organic extracts were washed with brine, dried over anhydrous a 2 S 4, filtered and concentrated. The residue was purified by column chromatography on silica gel (EtAc/hexane, 20:80 to 25:75) to afford S3 (20.7 mg, 90%) as a pale yellow foam; MR (CD 3, 500 Mz) 8.37 (, d, J = 8.5 z), (3, m), 6.74 (, s), 5.07 (, s), (4, m), 3.73 (3, s), 3.6 (, dt, J = 2.5, 7.5 z), (2, m), 0.95 (3, s); 3 C MR (CD 3, 25 Mz) 57.2, 53.4, 46.7, 32.6, 30.7, 29.3, 28.2, 28., 27.9, 24.6, 23.2, 2.9,.7, 84.3, 60.4, 56.3, 56., 36.2, 26.6, 6.6; RMS (ESI/Q-TF) m/z [M + ] + calculated for C ; found rel-(6as,7s)-,2-dimethoxy-6a-methyl-5,6,6a,7-tetrahydro-4-dibenzo[de,g]quinolin-7-ol (3) To a solution of S3 (22 mg, mmol) in TF ( ml) was added saturated K (aq) ( ml), and the mixture was stirred at 75 o C for 3 days. After being quenched with 2 (0 ml), the aqueous layer was extracted with EtAc (2 20 ml). The combined organic extracts were washed with brine, dried over anhydrous a 2 S 4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (C 3 /C 2 2, 5:95 to 0:90) to afford 3 (2 mg, 59%) as a white solid; mp > 250 o C (decomposed); MR (CD 3 D, 400 Mz) (, m), (, m), (2, m), 6.90 (, s), 4.90 (, s), 3.90 (3, s), 3.65 (3, s), (2, m), (, m), (, m),.7 (3, s); 3 C MR (CD 3 D, 00 Mz) 55.3, 47.5, 38.9, 3., 29.6 (2 ), 29., 27.4, 26.4, 25.6, 25.3, 3.5, 74.0, 60.9, 60.7, 56.6, 38.0, 26.0, 5.9; RMS (ESI/Q-TF) m/z [M + ] + calculated for C ; found S0

11 C 3I, Cs 2C 3 sat. K (aq) DMF, rt, 6 h TF, 75 o C, day 89% 72% 2-anti 5 4 (R,0bR)--(2-Chlorophenyl)-8,9-dimethoxy-5,6-dihydro--oxazolo[4,3-a]isoquinolin- 3(0b)-one (5) To a solution of 2-anti (35 mg, 0.0 mmol) and Cs 2 C 3 (39 mg, 0.2 mmol) in anhydrous DMF ( ml) was added C 3 I (8 μl, 0.2 mmol) under argon, and the mixture was stirred at room temperature for 6 h. After being quenched with 2 (0 ml), the aqueous layer was extracted with EtAc (2 20 ml). The combined organic extracts were washed with brine, dried over anhydrous a 2 S 4, filtered and concentrated. The residue was purified by column chromatography on silica gel (EtAc/hexane, 20:80 to 25:75) to afford 5 (32 mg, 89%) as a white solid; mp o C; [ ] 24 D 38 (c.3, C 3 ); MR (CD 3, 500 Mz) 7.59 (, dd, J = 7.5,.5 z), 7.47 (, dd, J = 7.5,.5 z), (2, m), 6.79 (, s), 6.62 (, s), 5.78 (, d, J = 5.0 z), 4.83 (, d, J = 5.0 z), 4.5 (, dd, J = 2.5, 5.5 z), 3.87 (3, s), 3.82 (3, s), 3.20 (, td, J = 2.5, 4.0 z), 3.0 (, td, J = 6.0, 5.5 z), 2.62 (, dd, J = 6.0, 4.0 z); 3 C MR (CD 3, 25 Mz) 57.5, 48.5, 48., 36., 3.9, 30.3, 30., 28.2, 27.8, 26.0, 25.4,.8, 07.9, 79.2, 62.0, 55.9, 55.9, 39.3, 26.7; RMS (ESI/Q-TF) m/z [M + ] + calculated for C ; found (R)-(2-Chlorophenyl)((R)-6,7-dimethoxy-,2,3,4-tetrahydroisoquinolin--yl)methanol (4) To a solution of 5 (9 mg, 0.05 mmol) in TF (3 ml) was added saturated K (aq) ( ml), and the mixture was stirred at 75 o C for day. After being quenched with 2 (0 ml), the aqueous layer was extracted with C 2 2 (2 20 ml). The combined organic extracts were washed with brine, dried over anhydrous a 2 S 4, filtered and concentrated. The residue was purified by column chromatography on silica gel (C 3 /C 2 2, 0:00 to 4:96) to afford 4 (2 mg, 72%) as a white foam; [ ] 22 D +8 (c 0.58, C 3 ); MR (CD 3, 400 Mz) 7.64 (, d, J = 6.4 z), (2, m), (, m), 6.58 (, s), 6.43 (, s), 5.32 (, d, J = 4.0 z), 4.6 (, d, J = 4.0 z), 3.85 (3, s), 3.66 (3, s), (, m), (, m), (, m), (, m); 3 C MR (CD 3, 00 Mz) 47.7, 47., 39.8, 32.9, 29.4, 28.6, 28.2, 27.9, 27.0, 26.3,.3, 09.4, 7.9, 59.3, 55.8, 55.5, 40.2, 29.; RMS (ESI/Q-TF) m/z [M + ] + calculated for C ; found S

12 triphosgene 7 2 toluene 00 C, h 8 Me C Et 3, 8 C 2 2, rt, 6 h 43% 6 9 (R)-Methyl 2-(3,4-dimethoxyphenethylcarbamoyloxy)-2-phenylacetate (9) To a solution of triphosgene (252 mg, 0.85 mmol) in anhydrous toluene (3 ml) was added a solution of 3,4- dimethoxyphenethylamine (7) (70 μl,.0 mmol) in anhydrous toluene (3 ml) under argon. The mixture was stirred at room temperature for 30 min and heated to 00 o C for another h. The resulting mixture was then allowed to cool to room temperature and slowly added into a suspension of 6 (66 mg,.0 mmol) and triethylamine (70 μl,.2 mmol) in anhydrous C 2 2 (5 ml) under argon. After being stirred at room temperature for 6 h, the reaction was quenched by the addition of saturated aqueous 4, evaporated in vacuo to remove excess toluene and C 2 2, and then partitioned between 2 and EtAc. Following neutralization with saturated aqueous ac 3, the organic layer was washed with brine, dried over anhydrous a 2 S 4, filtered and concentrated. The residue was purified by column chromatography on silica gel (EtAc/hexane, 20:80 to 25:75 to 30:70) to afford 9 (6 mg, 43%) as a colorless oil; [ ] 22 D 67 (c.8, C 3 ); MR (CD 3, 500 Mz) (5, m), 6.79 (, d, J = 8.0 z), (2, m), 5.92 (, s), 5.06 (, br, ), 3.85 (6, s), 3.72 (3, s), (2, m), (2, m); 3 C MR (CD 3, 25 Mz) 70.0, 55.2, 48.9, 47.6, 34., 30.9, 29., 28.7 (2 ), 27.6 (2 ), 20.6,.8,.2, 74.5, 55.8, 55.8, 52.5, 42.4, 35.4; RMS (ESI/Q-TF) m/z [M + a] + calculated for C a ; found (i) DIBAL-, C 2 2, 78 o C, h (ii) C 3, 20 o C, 0 min (iii) BF 3 Et 2, 20 o C to rt, h 52% 9 20 (R,0bR)-8,9-Dimethoxy--phenyl-5,6-dihydro--oxazolo[4,3-a]isoquinolin-3(0b)-one (20) To a solution of 9 (30 mg, 0.35 mmol) in anhydrous toluene (0 ml) was added dropwise a solution of DIBAL- (25% in toluene, 470 μl, 0.7 mmol) at 78 o C under argon, and the mixture was stirred at 78 o C for h. Then, C 3 (280 μl) was added, and the reaction was S2

13 stirred at 20 o C for 0 min. Following the addition of BF 3 Et 2 (430 μl, 3.5 mmol), the resulting mixture was stirred at room temperature for another h. This reaction mixture was quenched with 2 (5 ml), evaporated in vacuo to remove excess C 3, and then partitioned between 2 and EtAc. After neutralization with saturated aqueous ac 3, the organic layer was washed with brine, dried over anhydrous a 2 S 4, filtered and concentrated. The residue was purified by column chromatography on silica gel (EtAc/hexane, 20:80 to 30:70) to afford 20 (60 mg, 52%) as a white solid; mp o C; [ ] 22 D 26 (c 3.5, C 3 ); MR (CD 3, 500 Mz) (5, m), 6.63 (, s), 6.30 (, s), 5.3 (, d, J = 7.5 z), 4.85 (, d, J = 7.5 z), 4.7 (, dd, J = 3.0, 5.5 z), 3.85 (3, s), 3.69 (3, s), 3.5 (, td, J = 3.0, 3.0 z), 3.0 (, td, J = 6.0, 5.5 z), 2.65 (, dd, J = 6.0, 3.0 z); 3 C MR (CD 3, 25 Mz) 56.6, 48.3, 48.0, 37.7, 29.4, 29.0 (2 ), 27.0 (2 ), 25.7, 25.0,.9, 07.3, 83.9, 6.5, 55.8, 55.7, 38.5, 27.6; RMS (ESI/Q-TF) m/z [M + ] + calculated for C ; found sat. K (aq) TF, 75 o C, day 43% 20 5 (R)-((R)-6,7-Dimethoxy-,2,3,4-tetrahydroisoquinolin--yl)(phenyl)methanol (5) To a solution of 20 (30 mg, 0.09 mmol) in TF (2 ml) was added saturated K (aq) ( ml), and the mixture was stirred at 75 o C for day. After being quenched with 2 (0 ml), the aqueous layer was extracted with C 2 2 (2 20 ml). The combined organic extracts were washed with brine, dried over anhydrous a 2 S 4, filtered and concentrated. The residue was purified by column chromatography on silica gel (C 3 /C 2 2, 5:95 to 0:90) to afford 5 (2 mg, 43%) as a pale yellow solid; mp o C; [ ] 22 D +30 (c 0.83, C 3 ); MR (CD 3 D, 500 Mz) (5, m), 6.68 (, s), 5.58 (, s), 4.80 (, d, J = 8.0 z), 4.04 (, d, J = 8.0 z), 3.76 (3, s), (, m), 3.24 (3, s), (, m), (, m), (, m); 3 C MR (CD 3 D, 25 Mz) 49.6, 47.6, 43.6, 29.6 (2 ), 29.2 (3 ), 28., 25.6, 3., 2.8, 75.5, 62.3, 56.4, 55.8, 39.0, 28.5; RMS (ESI/Q-TF) m/z [M + ] + calculated for C ; found S3

14 Me ) Li, TF, 2, rt, 4 h 2) 7, EDC, Bt, DMF, rt, 6 h 69% over twp steps 6 2 (R)--(3,4-Dimethoxyphenethyl)-2-hydroxy-2-phenylacetamide (2) To a solution of methyl (R)-( )-mandelate (6) (332 mg, 2.0 mmol) in TF (3 ml) and 2 (3 ml) was added Li 2 (672 mg, 6.0 mmol), and the mixture was stirred at room temperature for 4 h. After being quenched with 2 (0 ml), the aqueous layer was extracted with EtAc (2 20 ml). The combined organic extracts were washed with brine, dried over anhydrous a 2 S 4, filtered and concentrated to afford the mandelic acid as the crude product. To a solution of this crude product, 3,4-dimethoxyphenethylamine (7) (370 μl, 2.2 mmol) and Bt hydrate (337 mg, 2.2 mmol) in anhydrous DMF (4 ml) was added EDC (422 mg, 2.2 mmol) under argon. The resulting mixture was stirred at room temperature for 6 h and then quenched by the addition of (aq). The aqueous layer was extracted with EtAc (2 20 ml). Following neutralization with saturated aqueous ac 3, the combined organic extracts were washed with brine, dried over anhydrous a 2 S 4, filtered and concentrated. The residue was purified by column chromatography on silica gel (EtAc/hexane, 40:60) to afford 2 (433 mg, 69%) as a pale yellow oil; [ ] 22 D 39 (c.9, C 3 ); MR (CD 3, 400 Mz) (5, m), 6.73 (, d, J = 8.4 z), 6.62 (, d, J = 2.0 z), 6.56 (, dd, J = 8.4, 2.0 z), 6.25 (, br, ), 4.94 (, s), 3.84 (3, s), 3.80 (4, s, C 3 and ), (2, m), (2, m); 3 C MR (CD 3, 00 Mz) 72.3, 48.7, 47.4, 39.4, 30.8, 28.4 (2 ), 28.2, 26.5 (2 ), 20.5,.6,., 73.8, 55.7, 55.6, 40.3, 34.9; RMS (ESI/Q-TF) m/z [M + a] + calculated for C a ; found (i) ab 4, BF 3 Et 2 0 o C to 55 o C, 3 h (ii), 55 o C, h 92% 6 (R)-2-(3,4-Dimethoxyphenethylamino)--phenylethanol (6) To a solution of 2 (80 mg, 0.57 mmol) in TF (5 ml) was added ab 4 (45 mg,.2 mmol) at 0 o C under argon. Following the addition of BF 3 Et 2 (300 μl, 2.4 mmol) dropwise at 0 o C under argon, the resulting mixture was stirred at 55 o C for 3 h. After completion of the reaction, the mixture was cooled to 0 o C, treated with 2 (5 ml) and 6 (aq) (5 ml), and then heated at 55 o C for another h. The S4

15 reaction mixture was cooled to room temperature, treated with 0% a (aq) to adjust the p value to 0 2, and evaporated in vacuo to remove excess TF. After being partitioned between 2 and C 2 2, the organic layer was washed with brine, dried over anhydrous a 2 S 4, filtered and concentrated. The residue was purified by column chromatography on silica gel (C 3 /C 2 2, 5:95 to 0:90) to afford 6 (58 mg, 92%) as a white solid; mp o C; [ ] 22 D 38 (c 3.9, C 3 ); MR (CD 3, 500 Mz) (5, m), 6.79 (, d, J = 8.0 z), (2, m), 4.78 (, dd, J = 9.0, 3.5 z), 3.87 (3, s), 3.86 (3, s), 3.7 (, br), (3, m), (3, m); 3 C MR (CD 3, 25 Mz) 48.9, 47.5, 42., 3.7, 28.4 (2 ), 27.6, 25.8 (2 ), 20.6,.8,.2, 7.3, 56.7, 55.9, 55.8, 50.6, 35.5; RMS (ESI/Q-TF) m/z [M + ] + calculated for C ; found S5

16 4. Copies of the and 3 C MR spectra Me MR (CD 3, 500 Mz) spectra of 9 Me 3 C MR (CD 3, 25 Mz) spectra of 9 S6

17 TBS MR (CD 3, 500 Mz) spectrum of TBS 3 C MR (CD 3, 25 Mz) spectrum of S7

18 MR (CD 3, 500 Mz) spectrum of 2-anti 3 C MR (CD 3, 25 Mz) spectrum of 2-anti S8

19 MR (CD 3, 500 Mz) spectrum of 3-anti 3 C MR (CD 3, 25 Mz) spectrum of 3-anti S9

20 MR (CD 3, 500 Mz) spectrum of 3-syn 3 C MR (CD 3, 25 Mz) spectrum of 3-syn S20

21 MR (CD 3, 500 Mz) spectrum of S 3 C MR (CD 3, 25 Mz) spectrum of S S2

22 MR (CD 3, 500 Mz) spectrum of 3 C MR (CD 3, 25 Mz) spectrum of S22

23 MR (CD 3, 500 Mz) spectrum of S2 3 C MR (CD 3, 25 Mz) spectrum of S2 S23

24 MR (CD 3, 500 Mz) spectrum of 2 3 C MR (CD 3, 25 Mz) spectrum of 2 S24

25 Me MR (CD 3, 500 Mz) spectrum of S3 Me 3 C MR (CD 3, 25 Mz) spectrum of S3 S25

26 Me MR (CD 3 D, 400 Mz) spectrum of 3 Me 3 C (CD 3 D, 00 Mz) MR spectrum of 3 S26

27 MR (CD 3, 500 Mz) spectraum of 5 3 C MR (CD 3, 25 Mz) spectrum of 5 S27

28 MR (CD 3, 400 Mz) spectrum of 4 3 C MR (CD 3, 00 Mz) spectrum of 4 S28

29 MR (CD 3, 500 Mz) spectrum of 9 3 C MR (CD 3, 25 Mz) spectrum of 9 S29

30 MR (CD 3, 500 Mz) spectrum of 20 3 C MR (CD 3, 25 Mz) spectrum of 20 S30

31 MR (CD 3 D, 500 Mz) spectrum of 5 3 C MR (CD 3 D, 25 Mz) spectrum of 5 S3

32 MR (CD 3, 400 Mz) spectrum of 2 3 C MR (CD 3, 00 Mz) spectrum of 2 S32

33 MR (CD 3, 500 Mz) spectrum of 6 3 CMR (CD 3, 25 Mz) spectrum of 6 S33