Supporting Information

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1 Supporting Information " Enantioselective Synthesis of EFdA via Enzymatic Desymmetrization " Mark McLaughlin,* Jongrock Kong,* Kevin M. Belyk, Billy Chen, Andrew W. Gibson, Stephen P. Keen, David R. Lieberman, Erika M. Milczek, Jeffrey C. Moore, David Murray, Feng Peng, Ji Qi, Robert A. Reamer, Zhiguo J. Song, Lushi Tan, Lin Wang and Michael J. Williams Department of Process Research and Development, Merck Research Laboratories, Rahway, New Jersey 07065, USA Table of Contents Experimental Section S2 General Information S2 Optimization Tables S2 Procedures and NMR, chiral HPLC and HRMS data S3 NMR Spectra S11 Chiral HPLC spectra S25 X-Ray Crystallographic data S27

2 EXPERIMENTAL SECTION General Information Chemical reagents were used as received from suppliers. NMR spectra were taken on 400 MHz spectrometers. High resolution mass spectra (HRMS) were obtained on Accurate-Mass Time-of- Flight (TOF) mass spectrometer and reported as m/z (relative intensity). Accurate masses are reported for the molecular ion (M+1). Optimization Table of Enzymatic Desymmetrization

3 Compound 2: 2-Hydroxy-2-((triisopropylsilyl)ethynyl)propane-1,3-diyl diacetate To a cooled (-60 C ) solution of ethynyltriisopropylsilane (100 g, 548 mmol) in THF (950 ml) was added n-butyllithium solution (2.66 M in hexanes; 204 ml, 543 mmol, 0.99 equiv) over 30 minutes. The resulting solution was stirred for 30 minutes at -60 C. To this solution was added a solution of 1,3-diacetoxyacetone (97 g, 559 mmol, 1.02 equiv) in THF (300 ml), keeping the internal temperature below -60 C. The resulting solution was aged for 30 mins at -60 C. The reaction was then quenched by dropwise addition of AcOH (52 ml, 822 mmol, 1.5 equiv), keeping the internal temperature below -60 C. The resulting solution was diluted with MTBE (500 ml) and warmed to room temperature. Aqueous citric acid solution (10wt%; 750 ml) was added and the mixture stirred for 10 minutes. The layers were separated and the organic phase was washed with aqueous NaCl solution (10 wt%, 500 ml). The organic phase was concentrated under reduced pressure to yield 2 as a colorless liquid (179.7 g, 92% yield). 1 H NMR (500 MHz, CDCl 3 ): δ 4.29 (d, J = 11.3 Hz, 2H); 4.21 (d, J = 11.3 Hz, 2H); 2.80 (br s, 1H); 2.11 (s, 6H); 1.07 (s, 21H). 13 C NMR (126 MHz, CDCl 3 ): δ 170.8, 104.4, 88.3, 69.1, 67.2, 20.9, 18.6, HRMS (ES+) calc d for C 18 H 32 AgO 5 Si (M Ag ion): ; found Compound 3: (R)-2-Hydroxy-2-(hydroxymethyl)-4-(triisopropylsilyl)but-3-yn-1-yl acetate To an aqueous solution of KH 2 PO 4 /KOH (360 ml, 0.1 M, ph = 7.5) and the enzyme NovoCor AD L (120 g, 140 mmol) was added a solution of compound 2 (100 g, 280 mmol) in methanol (500 ml) at ambient temperature. The resulting mixture was stirred at 30 C for 24 hours then diluted with MTBE (800 ml) and stirred for a further 30 minutes. Aqueous NaCl solution (15 wt%, 400 ml) was added, the two-phase mixture was agitated and then the layers were allowed to settle. The lower aqueous phase was discarded and then CELITE (2.5 g) and aqueous NaCl solution (15 wt%, 400 ml) were added to the organic layer. The mixture was agitated and filtered before the lower aqueous layer was discarded. The organic phase was concentrated under reduced pressure to yield 3 as a colorless liquid (83.7 g, 95% yield). 1 H NMR (500 MHz, CDCl 3 ): δ 4.34 (d, J = 11.3 Hz, 1H); 4.22 (d, J = 11.3 Hz, 1H); 3.73 (d, J = 11.5 Hz, 1H); 3.66 (d, J = 11.5 Hz, 1H); 2.41 (br s, 2H); 2.13 (s, 3H); 1.08 (s, 21H). 13 C NMR (126 MHz, CDCl 3 ): δ

4 171.3, 105.5, 87.7, 70.5, 66.9, 66.6, 20.8, 18.6, HRMS (ES+) calc d for C 16 H 30 AgO 4 Si (M Ag ion): ; found Chiral HPLC (Phenomenex Lux Cellulose-4 column, water with 0.1% H 3 PO 4 /MeCN = 40/60, 1.0 ml/min, 210 nm); t major = 4.39 min, t minor = 4.25 min; ee = 96%. Compound 4: (S)-(2,2-Dimethyl-4-((triisopropylsilyl)ethynyl)-1,3-dioxolan-4-yl)methanol To a solution of compound 3 (108 g, 343 mmol) in MTBE (540 ml) and acetonitrile (430 ml) was added PPTS (5.91 g, 34.3 mmol, 0.1 equiv) and 2,2-dimethoxypropane (107 g, 1.03 mol, 3 equiv). The resulting solution was stirred for 2 hours at 50 C then cooled to room temperature and used directly in the methanolysis. Sodium methanolate in methanol (30 wt%; 24.7 g, 137 mmol) was added to the previous solution. The resulting mixture was stirred for an additional 20 minutes at 25 C then 10% citric acid (430 ml) was added. The layers were separated and the organic phase was washed with water (2 x 430 ml). The organic phase was concentrated under reduced pressure to yield 4 as a colorless liquid (96.5 g, 90% yield from 3). 1 H NMR (500 MHz, CDCl 3 ): δ (m, 2H); 3.72 (d, J = 11.6 Hz, 1H); 3.58 (d, J = 11.6 Hz, 1H); 1.95 (br s, 1H); 1.55 (s, 3H); 1.45 (s, 3H); 1.07 (s, 21H). 13 C NMR (126 Hz, CDCl 3 ): δ 111.3, 107.1, 87.4, 77.6, 72.0, 66.2, 26.7, 25.6, 18.7, HRMS (ES+) calc d for C 17 H 32 AgO 3 Si (M Ag ion): ; found Chiral HPLC (Phenomenex Lux Cellulose-4 column, water with 0.1% H 3 PO 4 /MeCN = 40/60, 1.0 ml/min, 210 nm); t major = min, t minor = min; ee = 93%. Compound 5: Methyl (R)-2,2-dimethyl-4-((triisopropylsilyl)ethynyl)-1,3-dioxolane-4- carboxylate To a mixture of compound 4 (87.4 g, 280 mmol) in the mixture of MTBE (2620 ml) and THF (1136 ml) was added TEMPO (49.4 g, 316 mmol), sodium chlorite (44.3 g, 489 mmol, 1.75 equiv), and NaH 2 PO 4-2H 2 O (144 g, 811 mmol, 2.9 equiv) at ambient temperature. The resulting homogenous solution was warmed to C and aqueous sodium hypochlorite solution (10

5 wt%; 502 g, 674 mmol, 2.41 equiv) was slowly added over 3 hours. The resulting reaction solution was stirred for 14 hours. The reaction was cooled to ambient temperature, and additional MTBE (1000 ml) was charged to the reaction. Agitation was ceased and the lower aqueous layer was discarded. The organic layer was washed sequentially with aqueous Na 2 SO 3 solution (6 wt%, 1748 ml), aqueous citric acid solution (10 wt%, 2447 ml) and water (2622 ml). The final organic layer was concentrated under reduced pressure. The concentrated crude was dissolved 2-Me-THF (874 ml). CDI (68 g, 419 mmol, 1.5 mmol) was added at ambient temperature. The mixture was stirred for 2 h and then MeOH (175 ml) was added. After a further 5 h, the mixture was washed sequentially with 0.5 M aqueous HCl (435 ml) then aqueous NaCl (2 x 435 ml of 10 wt% solution). The final organic layer was concentrated under reduced pressure to yield 5 as a colorless oil (76.9 g, 81% yield from 4). 1 H NMR (400 MHz, CDCl 3 ): δ 4.45 (d, J = 8.6 Hz, 1H); 4.19 (d, J = 8.6 Hz, 1H); 3.80 (s, 3H); 1.52 (s, 3H); 1.44 (s, 3H); 1.05 (s, 21H). 13 C NMR (101 MHz, CDCl 3 ): δ 169.2, 112.8, 103.2, 88.3, 76.3, 73.9, 53.1, 26.1, 25.5, 18.4, HRMS (ES+) calc d for C 18 H 33 O 4 Si (M+H): ; found Compound 6: tert-butyl (R)-3-(2,2-dimethyl-4-((triisopropylsilyl)ethynyl)-1,3-dioxolan-4-yl)-3- oxopropanoate To a -20 C solution of N,N-diisopropylamine (85 g, 840 mmol) in THF (715 ml) was added n- BuLi (2.5 M in hexanes; 336 ml, 840 mmol) over 40 minutes with internal temperature maintained below 0 C. The resulting solution was then aged at 0 C for 10 minutes before it was cooled to -68 C. tert-butyl acetate (101 g, 861 mmol) was added over 15 minutes, keeping the temperature below -60 C. The resulting mixture was stirred for 30 minutes at -60 C). Next, a solution of compound 5 (143 g, 420 mmol) in THF (425 ml) was added over 30 minutes. After an additional 25 minutes at -60 C, the reaction was quenched by the addition of a solution of acetic acid (76 g, 1260 mmol) in THF (225 ml). The mixture was diluted with 750 ml of MTBE, warmed to room temperature and washed sequentially with aqueous citric acid solution (10 wt%, 1400 ml), aqueous sodium hydrogen carbonate solution (5 wt%, 700 ml) and aqueous NaCl (10 wt%, 1400 ml). The final organic layer was concentrated under reduced pressure to yield 6 as a colorless liquid (169.4 g, 95% yield). 1 H NMR (400 MHz, CDCl 3 ): δ 4.32 (d, J = 12.0 Hz, 1H), 4.11 (d, J = 12.0 Hz, 1H), 3.73 (d, J = 16.0 Hz, 1H), 3.62 (d, J = 16.0 Hz, 1H), 1.50 (s, 3H), 1.46 (s, 3H), 1.45 (s, 9H), 1.06 (s, 21H). 13 C NMR (101 MHz, CDCl 3 ): δ 197.1, 166.0, 112.7, 103.3, 90.3,

6 81.8, 81.0, 72.1, 27.9, 26.2, 25.1, 18.5, HRMS (ES+) calc d for C 23 H 40 NaO 5 Si (M+Na): ; found Compound 7: tert-butyl (S)-3-((R)-2,2-dimethyl-4-((triisopropylsilyl)ethynyl)-1,3-dioxolan-4- yl)-3-hydroxypropanoate To a solution of compound 6 (47.0 g, 111 mmol) in THF (600 ml) was added (S,S)-Ts-DENEB (0.162 g, mmol). To a separate flask containing a cooled (10 C) solution of Et 3 N (15.3 ml, 110 mmol) in THF (50 ml) was added formic acid (13.2 ml, 274 mmol). After 15 min, the solution of triethylammonium formate was added to the substrate/catalyst solution and the mixture was stirred at 38 C. After 24 hours, the reaction mixture was cooled to 22 C, and slowly charged MTBE (470 ml) to the reaction over 0.5 hour. The organic layer was washed sequentially with aqueous citric acid solution (10 wt%, 310 ml) and aqueous NaCl (10 wt%, 310 ml). The final organic layer was treated with Ecosorb C-941 (11.8 g) for 1 h and then filtered. The filtrate was concentrated under reduced pressure to yield 7 as a colorless liquid (44.9 g, 95%; > 99:1 dr). 1 H NMR (400 MHz, CDCl 3 ): δ 4.22 (d, J = 8.0 Hz, 1H), 4.12 (d, J = 8.0 Hz, 1H), (m, 1H), (m, 2H), 2.42 (dd, J = 16.0, 8.0 Hz, 1H), 1.51 (s, 3H), 1.48 (s, 9H), 1.42 (s, 3H), 1.09 (s, 21H). 13 C NMR (101 MHz, CDCl 3 ): δ 171.4, 111.3, 106.0, 88.2, 81.1, 79.3, 72.2, 71.6, 38.5, 28.2, 26.6, 25.5, 18.6, HRMS (ES+) calc d for C 23 H 42 O 5 SiNa (M+Na): ; found Compound 8: tert-butyl (S)-3-((R)-4-ethynyl-2,2-dimethyl-1,3-dioxolan-4-yl)-3- hydroxypropanoate To a solution of compound 7 (5.12 g, 12.0 mmol) in THF (26 ml) was added 1 M TBAF in THF (12 ml, 12.0 mmol) dropwise with stirring at 10 C. After addition was complete, the mixture was warmed to 25 C and quenched with water (26 ml). The resulting mixture was extracted with MTBE (52 ml) then the organic layer was washed sequentially with water (26 ml) and aqueous

7 NaCl (10 wt%, 26 ml). The final organic layer was concentrated under reduced pressure to yield 8 as a colorless liquid (3.08 g, 95% yield). 1 H NMR (400 MHz, CDCl 3 ): δ 4.22 (d, J = 8.0 Hz, 1H), 4.12 (d, J = 8.0 Hz, 1H), (m, 1H), (m, 2H), 2.42 (dd, J = 16.0, 8.0 Hz, 1H), 1.51 (s, 3H), 1.48 (s, 9H), 1.42 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ): δ 171.9, 111.5, 82.1, 81.4, 78.5, 74.7, 72.4, 71.3, 37.8, 28.1, 26.6, HRMS (ES+) calc d for C 14 H 22 O 5 Na (M+Na): ; found Compound 9: (4S,5R)-5-Ethynyl-4-hydroxy-5-(hydroxymethyl)dihydrofuran-2(3H)-one To a solution of compound 8 (10.9 g, 30.4 mmol) in 1,2-DME (110 ml) was added hydrochloric acid (37%; 7.5 ml, 91.0 mmol, 3 equiv). After the mixture was stirred at 45 C for 1 hour it was dried azeotropically by continuous distillation of 1,2-DME then the solvent was changed to isopropyl acetate and final volume adjusted to 50 ml. Upon cooling to room temperature, crystallization occurred and the solid was collected by filtration to give compound 9 as a sand colored solid (4.0 g, 85% yield; > 99:1 dr). 1 H NMR (400 MHz, DMSO-d 6 ) δ 4.36 (dd, J = 6.9, 4.2 Hz, 1H), 3.66 (s, 1H), 3.62 (d, J = 2.2 Hz, 2H), 2.90 (dd, J = 17.7, 6.9 Hz, 1H), 2.37 (dd, J = 17.7, 4.2 Hz, 1H). 13 C NMR (101 MHz, DMSO-d 6 ) δ 174.9, 87.1, 81.1, 78.9, 69.1, 65.2, HRMS (ES+) calc d for C 7 H 8 O 4 Na (M+Na): ; found Compound 10: (2R,3S)-2-Ethynyl-2-(((4-methylbenzoyl)oxy)methyl)-5-oxotetrahydrofuran-3- yl 4-methylbenzoate To a solution of compound 9 (7.5 g, 48.0 mmol, 1 equiv) in pyridine (38 ml) was added toluoyl chloride (15.2 g, 98.0 mmol, 2.04 equiv) at 0 C. The resulting mixture was stirred for 2 hours at

8 0 C. Water (45 ml) was added slowly at 0-5 C, causing the product to crystallize. The mixture was filtered, the filter cake was washed with ice water, and then dried to afford compound 11 as a white solid (17.9 g, 95% yield). 1 H NMR (500 MHz, CDCl 3 ): δ (m, 2H); (m, 2H); (m, 4H); 5.85 (dd, J = 5.0, 5.0 Hz, 1H); 4.76 (d, J = 10.0 Hz, 2H); 4.71 (d, J = 15.0 Hz, 2H); 3.24 (dd, J = 20.0, 10.0 Hz, 1H); 2.92 (m, 1H); 2.75 (s, 1H); 2.45 (d, J = 5.0 Hz, 6H). 13 C NMR (125 MHz, CDCl 3 ): δ 172.0, 165.3, 165.3, 144.8, 144.6, 130.0, 129.8, 129.4, 129.3, 126.1, 126.0, 82.3, 79.6, 75.2, 70.8, 66.6, 35.2, 21.8, HRMS (ES+) calc d for C 23 H 21 O6 (M+H): ; found Compound 11: (2R,3S)-5-Acetoxy-2-ethynyl-2-(((4-methylbenzoyl)oxy) methyl) tetrahydrofuran-3-yl 4-methylbenzoate To a solution of compound 10 (15.5 g, 39.5 mmol) in toluene (233 ml) and DCM (102 ml) was added sodium bis(2-methoxyethoxy)aluminum hydride solution in toluene (73% w/w, g, 35.6 mmol, 0.9 equiv) dropwise with stirring at -70 C over 22 min. The mixture was stirred at the same temperature for an additional 30 min and then the reaction was quenched by adding a solution of acetic acid (22.6 ml, 395 mmol, 10 equiv) in DCM (15.5 ml) over 20 minutes, keeping the temperature below -60 C. After warming to ambient temperature, the mixture was washed sequentially with aqueous sulfuric acid (1 M, 74 ml) and aqueous NaCl solution (10 wt%, 74 ml). The final organic layer was solvent switched into toluene and used directly in the ensuing acetylation. The toluene solution was cooled to 0 o C. Solid 4-(dimethylamino)pyridine (0.81 g, 6.6 mmol, 0.17 equiv) and triethylamine (6.3 ml, 46.2 mmol, 1.17 equiv) was added. The mixture was maintained below 5 o C. Acetic anhydride (3.74 ml, 39.6 mmol, 1.00 equiv) was added over 10 min maintaining the internal temperature below 5 o C. After 1 h, the reaction was quenched by addition of water (5.1 ml) over 10 min. The resulting mixture was warmed to ambient temperature and washed sequentially with aqueous citric acid solution (10 wt%, 2 x 78 ml), aqueous sodium bicarbonate solution (5 wt%, 78 ml) and water (78 ml). The final organic layer was dried via azeotropic distillation using toluene, the volume was adjusted to 31 ml toluene solution (33.2 g solution containing g of compound 11, 80% yield) and the solution was used directly in the preparation of compound 12. Analytical data for the major

9 anomer is provided: 1 H NMR (500 MHz, CD 2 Cl 2 ) δ (m, 4H), (m, 4H), 6.47 (d, J = 4.2 Hz, 1H), 5.86 (t, J = 7.4 Hz, 1H), 4.74 (d, J = 11.6 Hz, 1H), 4.53 (d, J = 11.6 Hz, 1H), 2.76 (d, J = 4.5 Hz, 1H), 2.68 (dd, J = 7.6, 3.9 Hz, 2H), 2.45 (d, J = 10.4 Hz, 4H), 1.92 (s, 1H). 13 C NMR (126 MHz, CD 2 Cl2) δ 169.5, 165.5, 165.5, 144.5, 144.2, 129.7, 129.7, 129.2, 129.1, 126.9, 126.7, 96.3, 82.1, 78.3, 77.2, 72.9, 66.2, 37.3, 21.4, 21.4, HRMS (ES+) calc d for C 25 H 24 NaO 7 (M+Na): ; found Compound 12: (2R,3S,5R)-2-Ethynyl-5-(2-fluoro-6-((trimethylsilyl)amino)-9H-purin-9-yl)-2-(((4- methylbenzoyl)oxy)methyl)tetrahydrofuran-3-yl 4-methylbenzoate To a slurry of 2-fluoro-7H-purin-6-amine (4.05 g, 26.5 mmol, 1.1 equiv) in MeCN (105 ml) was added N,O-bis(trimethylsilyl)acetamide (14.68 g, 72.2 mmol, 3 equiv). The mixture was heated to 70 C for 1 hour and dissolution of the solids was observed. After cooling to ambient temperature, TMSOTf (5.99 g, 26.9 mmol, 1.12 equiv) was added and the mixture was reheated to 70 C. The previously prepared solution of compound 11 in toluene (10.5 g, 24.1 mmol, 1 equiv) was diluted with MeCN (105 ml) and then transferred into the reaction mixture at 70 C over 1 h. The batch was concentrated to around 105 ml via simple distillation. The batch was cooled to 60 C and seeded with the desired β-anomer of compound 12 (10.5 mg, 0.1 wt%). After aging for 60 min, the slurry was cooled to room temperature and held for a further 7.5 hour. The slurry was cooled to 0 C over 60 min and finally aged at 0 C for 80 min. After filtration, washing with cold MeCN (10 ml) and drying under vacuum, compound 12 was obtained as a white solid (6.95 g, 48% yield). 1 H NMR (500 MHz, CD 2 Cl 2 ) δ 8.06 (d, J = 5.0 Hz, 2H), 7.92 (d, J = 10.0 Hz, 2H), 7.89 (s, 1H), 7.34 (d, J = 10.0 Hz, 2H), 7.27 (d, J = 10.0 Hz, 2H), (m, 1H),, 6.12 (dd, J = 5.0 Hz, 5.0 Hz, 1H), 5.68 (s, 1H), 4.81 (d, J = 15.0 Hz, 1H), 4.66 (d, J = 15.0 Hz, 1H), (m, 1H), (m, 1H), 2.80 (s, 1H), 2.42 (d, J = 15.0 Hz, 6H), 0.43 (s, 9H). 13 C NMR (126 MHz, CD 2 Cl 2 ) δ 165.6, 165.4, 159.9, 159.8, 159.6, 144.5, 144.3, 139.1, 129.8, 129.6, 129.2, 129.2, 126.6, 120.5, 83.6, 81.7, 78.0, 77.6, 73.2, 65.8, 36.2, 21.5, 21.4, HRMS (ESI+) calc d for C 31 H 32 FN 5 O 5 Si (M+H): ; found

10 EFdA: (2R,3S,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl) tetrahydrofuran-3-ol To a cooled (0 C) solution of compound 12 (5.66 g, 9.40 mmol) in THF (56 ml) was added sodium methoxide stock solution in methanol (28 ml) (25.5 mg of 30 wt% in MeOH was diluted with 28 ml MeOH; 25.5 mg, 0.14 mmol, equiv.). The mixture was stirred at room temperature overnight. The resulting reaction solution was quenched with acetic acid (0.043 ml, 0.75 mmol, 0.08 equiv.), and the reaction was aged at room temperature over 1 hour. The resulting solution was concentrated under reduced pressure. The crude material was redissolved in wet MeCN (56 ml with 8 vol% water content). Upon seeding, crystallization occurred and the solid was collected by filtration to give EFdA as an off-white solid (2.48 g, 90% yield). 1 H-NMR: (300 MHz, DMSO-d 6, ppm): δ 7.68 (br s, 2H), 7.32 (d, J = 2.0 Hz, 1H), 6.44 (t, J = 5.8 Hz, 1H), 5.52 (d, J = 5.6 Hz, 1H), 5.27 (t, J = 6.0 Hz, 1H), 4.44 (q, J = 6.4 Hz, 1H), 3.60 (q, J = 6.0 Hz, 1H), 3.53 (q, J = 6.4 Hz, 1H), 3.48 (s, 1H), (m, 1H), (m, 1H). 13 C NMR ( MHz, d 6 -DMSO, ppm) δ (d, J CF = 203.5), (d, J CF = 21.2), (d, J CF = 20.2), (d, J CF = 2.4), (d, J CF = 4.0), 85.1, 82.0, 81.4, 78.7, 70.1, 64.2, F-NMR: (282 MHz, d 6 -DMSO, ppm): δ (s, 1F). LC-MS: (ES, m/z): calc d for C 12 H 12 FN 5 O 3 (M+Na): ; found Optical rotation was measured in MeOH at 25 C and 10 mg/ml concentration.

11 AcO OH OAc 2 TIPS

12

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17 1H NMR spectrum from NaBH 4 reduction of ketoester 6 showing both diastereomers (major is undesired diastereomer here).

18 1H NMR spectrum from diastereoselective reduction of ketoester 6 showing > 99:1 diastereoselectivity favoring the desired diasteromer.

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27 X-ray Crystal Data and Structure Refinement for Compound 10 ( ) A single crystal grown from 1:1 hexane: EtOAc by solvent evaporation was selected for single crystal X-ray data analysis. The crystal was a cut block with dimensions of 0.34 mm x 0.10 mm x 0.07mm. Data collection was performed on a Bruker Apex II system at 100K. The unit cell was determined to be monoclinic in space group P2 1. The structure contained one molecule in the crystallographic asymmetric unit. Absolute configuration was established by anomalous-dispersion effects in diffraction measurements on the crystal and confirmed that the stereochemistry was as shown. Crystallographic data is summarized in Table S1. Figure S1 shows a thermal ellipsoid representation of Compound 10 with thermal ellipsoids set at the 50% probability level. Coordinates, refinement details and structure factors have been deposited with the Cambridge Crystallographic Data Centre (CCDC ). Table S1. Crystal Data and Structure Refinement for Compound 9 [CCDC ] Identification code Empirical formula mdh071 C23 H20 O6 Formula weight Temperature Wavelength Crystal system Space group P (2) K Å Monoclinic Unit cell dimensions a = (16) Å α= 90. Volume (3) Å 3 Z 2 Density (calculated) g/cm 3 Absorption coefficient mm -1 F(000) 414 b = (10) Å β= (10). c = (4) Å γ = 90. Crystal size x x mm 3 Theta range for data collection 1.93 to Index ranges Reflections collected <=h<=10, -6<=k<=4, -27<=l<=27 Independent reflections 3007 [R(int) = ] Completeness to theta = % Absorption correction Semi-empirical from equivalents Max. and min. transmission and

28 Refinement method Full-matrix least-squares on F 2 Data / restraints / parameters 3007 / 1 / 264 Goodness-of-fit on F Final R indices [I>2sigma(I)] R1 = , wr2 = R indices (all data) R1 = , wr2 = Absolute structure parameter [Flack] 0.10(16) Absolute structure parameter [Hooft y / P2true] 0.03(8) / 1.00 Largest diff. peak and hole and e.å -3 Figure S1: Thermal ellipsoid representation of Compound 10 with thermal ellipsoids set at the 50% probability level.

29 X-ray Crystal Data and Structure Refinement for Compound 12 (CCDC ) A single crystal grown from acetonitrile by solvent evaporation was selected for single crystal X- ray data analysis. The crystal was a plate with dimensions of 0.35 mm x 0.19 mm x 0.06mm. Data collection was performed on a Bruker Apex II system at 100K. The unit cell was determined to be orthorhobic in space group P The structure contained one molecule in the crystallographic asymmetric unit. Absolute configuration was established by anomalous-dispersion effects in diffraction measurements on the crystal and confirmed that the stereochemistry was as shown. Crystallographic data is summarized in Table S2. Figure S2shows a thermal ellipsoid representation of Compound 12 with thermal ellipsoids set at the 50% probability level. Coordinates, refinement details and structure factors have been deposited with the Cambridge Crystallographic Data Centre (CCDC ). Table S2. Crystal Data and Structure Refinement for Compound 12 [CCDC ] Identification code Empirical formula mdi011 Formula weight Temperature Wavelength Crystal system C31 H32 F N5 O5 Si 100(2) K Å Orthorhombic Space group P Unit cell dimensions a = (8) Å α= 90. Volume (6) Å 3 Z 4 Density (calculated) g/cm 3 Absorption coefficient mm -1 F(000) 1264 b = (13) Å β= 90. c = (4) Å γ = 90. Crystal size 0.35 x 0.19 x 0.06 mm 3 Theta range for data collection 3.84 to Index ranges Reflections collected <=h<=8, -13<=k<=14, -39<=l<=41 Independent reflections 5226 [R(int) = ] Completeness to theta = % Absorption correction Semi-empirical from equivalents Max. and min. transmission and

30 Refinement method Full-matrix least-squares on F 2 Data / restraints / parameters 5226 / 0 / 393 Goodness-of-fit on F Final R indices [I>2sigma(I)] R1 = , wr2 = R indices (all data) R1 = , wr2 = Absolute structure parameter [Flack] 0.03(3) Largest diff. peak and hole and e.å -3 Figure S2: Thermal ellipsoid representation of Compound 12 with thermal ellipsoids set at the 50% probability level.