Supporting Information (Part II) for ACS Combinatorial Science

Supporting Information (Part II) for ACS Combinatorial Science Application of 6,7Indole Aryne Cycloaddition and Pd(0)Catalyzed SuzukiMiyaura and BuchwaldHartwig CrossCoupling Reactions for the Preparation of Annulated Indole Libraries Paul D. Thornton, 2 Neil Brown, 1,2 David Hill, 2 Ben Neuenswander, 2 Gerald H. Lushington, 2 Conrad Santini 2 and Keith R. Buszek 1,2* 1 Department of Chemistry, University of Missouri, 5100 Rockhill Road, Kansas City, MO 64110 2 Center of Excellence in Chemical Methodologies and Library Development, University of Kansas, 2034 Becker Drive, Lawrence, KS 66047 Email: buszekk@umkc.edu Contents: 1. General experimental procedures: S2S3 a. General: S2 b. Procedure for SuzukiMiyaura CrossCoupling Reactions: S2S3 c. Procedure for BuchwaldHartwig CrossCoupling Reactions: S3 2. Tabulated 1H and 13C NMR for scaffolds and representative library members: S3S7 a. Furan scaffold, 19 b. Cyclopentadiene (Cp) scaffold, 18 c. Cp scaffold, SuzukiMiyaura members: 24{6}, 24{10}, 24{9}, 24{5}, 24{1} d. Furan scaffold, SuzukiMiyaura members: 21{28}, 21{20}, 21{24}, 21{25}, 21{18} e. Cp scaffold, BuchwaldHartwig members: 25{7}, 25{10}, 25{11}, 25{5}, 25{3}, 25{1} f. Furan scaffold, BuchwaldHartwig members: 23{10}, 23{18}, 23(11), 23{14} 3. Scaffold spectra: S8S11 a. Furan scaffold, 19 b. Cp scaffold, 18 4. Select 1H and 13C NMR data for representative library members: S12S53 S1

a. Cp scaffold, SuzukiMiyaura members: 24{6}, 24{10}, 24{9}, 24{5}, 24{1} b. Furan scaffold, SuzukiMiyaura members: 21{28}, 21{20}, 21{24}, 21{25}, 21{18} c. Cp scaffold, BuchwaldHartwig members: 25{7}, 25{10}, 25{11}, 25{5}, 25{3}, 25{1} d. Furan scaffold, BuchwaldHartwig members: 23{10}, 23{18}, 23(11), 23{14} 5. Method used for in silico analysis: See Supporting Information, Part II, S2S3. 6. Computed in silico parameters (Table 1): See Supporting Information, Part II, S4S9. 5. Method used for in silico analysis Sketched electronic versions of the library compounds were imported into the Tripos Molecular Spreadsheet [1] wherein standard Lipinski Rule of 5 parameters (molecular weight, ClogP, number of Hacceptors, and number of Hdonors[2]) plus the number of rotatable bonds and polar surface area were computed. Lipinski violations were specified according to molecular weight > 500, ClogP > 5.0, number of acceptors > 10, number of donors > 5, and number of rotatable bonds > 5. The structures were then exported into SDF format and coverted into threedimensional protonated structures via Concord [3]. Absorption, distribution, metabolism and excretion (ADME) profiles of these compounds was then generated via Volsurf [4]. Descriptors were generated using three probes (water, hydrophobic and carbonyl oxygen) with a grid space distribution of 1.0 Å. Predictions were then projected onto internal ADME models at the 5component level. Finally diversity analysis was carried out using DiverseSolutions [5] using standard H aware 3D BCUT descriptors. The library was then projected onto a chemical space defined by the following descriptors: gastchrg_invdist2_000.550_k_l, gastchrg_invdist6_000.500_k_h, haccept_invdist2_001.000_k_h, tabpolar_invdist_000.250_k_h, tabpolar_invdist_000.500_k_l and populated (for comparison) by a recent version of the MLSMR screening set (ca. 7/2010; S2

~330,000 unique chemical structures). Diversity scores (div(a)) for our library were then generated for each of our compounds (A) according to the expression: div( A) = pop[ Cell( A)] pop( i) /! i" Occ N occ where N occ is the number of cells occupied by PubChem compounds in an evenly distributed 10 10 10 10 10 grid decomposition of the chemistry space, and pop(i) is the population of cell i. REFERENCES [1] SYBYL 8.0, The Tripos Associates, St. Louis MO, 2008. [2] Lipinski, C.A., Lombardo, F., Dominy, B.W., Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Delivery Rev. 1997, 23, 325. [3] Concord 8.0, The Tripos Associates, St. Louis MO, 2008. [4] Cruciani, G., Meniconi, M., Carosati, E., Zamora, I., Mannhold, R. VOLSURF: A Tool for Drug ADMEProperties Prediction. In: Methods and Principles in Medicinal Chemistry. Eds. van de Waterbeemd, H., Lennernäs, H., Artursson, P. (WileyVCH Verlag GmbH & Co., Weinheim, 2003). [5] Pearlman, R.S.; Smith, K.M. Metric Validation and the ReceptorRelevant Subspace Concept. J. Chem. Inf. Comput. Sci. 1999, 39, 2835. 6. Computed in silico parameters (Table 1) S3

Molecule CLOGP Mol.Wt H acc H don 2501 4.70 287.36 1 1 2 0 87.09 0.16 1.20 2502 6.23 327.34 0 1 2 1 43.77 0.23 0.63 2503 3.85 260.33 1 2 1 0 71.04 0.23 1.61 2504 4.97 305.35 1 1 2 0 87.01 0.16 0.27 2505 5.91 305.44 0 1 2 1 62.43 0.07 1.57 2506 5.63 295.33 0 1 1 1 43.77 0.23 0.53 2507 4.37 302.37 1 2 1 0 131.03 1.83 0.85 2508 5.49 277.34 0 1 1 1 43.77 0.23 1.17 2509 4.71 289.37 1 1 2 0 50.16 0.78 1.56 2510 5.27 317.38 2 1 1 1 77.14 0.53 1.00 2511 5.02 310.39 1 2 1 1 71.04 0.23 1.22 2512 7.17 315.45 0 1 2 1 43.77 0.17 2.01 2513 5.49 277.34 0 1 1 1 43.77 0.23 1.23 2514 5.55 273.37 0 1 1 1 43.77 0.53 1.64 2515 5.09 303.35 2 1 3 1 146.54 2.00 0.48 2516 6.52 309.40 0 1 1 1 43.77 0.02 1.67 2517 5.81 293.79 0 1 1 1 43.77 0.22 1.94 2518 3.86 302.37 1 2 1 0 152.18 1.29 0.56 2519 5.27 289.37 1 1 2 1 61.64 0.78 1.33 Rot Bond viols PSA DIVS BBB SOLY CACO2 SP_S SP_P PB VD HERG SD MS 4.47 1.34 0.10 1.22 98.04 4.89 0.98 0.03 0.95 100.39 4.35 1.45 0.04 1.19 98.32 4.20 1.17 0.06 0.88 93.47 5.42 1.50 0.31 1.30 91.68 4.87 1.32 0.17 0.81 96.73 4.81 1.20 0.18 1.13 97.03 4.89 1.43 0.04 1.16 101.37 5.21 1.52 0.16 1.15 97.66 5.13 1.46 0.22 1.00 98.20 5.20 1.65 0.37 1.28 106.15 6.04 1.26 0.35 1.35 95.33 4.93 1.48 0.01 1.07 96.89 5.29 1.39 0.17 1.33 94.27 4.10 1.03 0.05 0.92 93.27 6.05 1.59 0.50 1.43 107.88 5.13 1.51 0.36 1.35 97.44 4.14 1.11 0.09 0.96 92.51 5.01 1.51 0.20 1.15 93.66 0.53 1.02 0.02 0.39 0.96 0.69 0.24 0.16 0.55 0.83 0.06 0.31 0.48 1.03 0.83 0.24 0.94 0.36 0.15 0.14 0.39 0.44 0.64 0.12 0.39 0.97 0.30 0.28 0.71 0.74 0.10 0.10 0.68 0.24 0.13 0.10 0.70 0.34 0.15 0.16 0.67 0.58 0.25 0.17 0.78 0.40 0.07 0.06 0.62 0.34 0.11 0.02 0.71 0.47 0.22 0.17 0.05 0.69 1.22 0.61 0.85 0.41 0.38 0.15 0.88 0.01 0.08 0.10 0.17 0.68 0.89 0.73 0.81 0.44 0.43 0.01 S4

2520 4.67 290.36 2 2 2 0 75.42 0.78 1.19 2521 5.27 289.37 1 1 2 1 61.58 0.78 1.43 2522 4.31 289.37 1 2 3 0 97.55 0.29 0.59 2523 6.40 328.24 0 1 1 1 43.77 0.22 2.03 2524 5.01 319.40 2 1 3 1 68.13 0.11 1.34 2525 4.08 278.32 1 2 1 0 70.71 0.23 0.82 2526 6.29 303.37 0 1 2 1 43.77 0.23 0.91 2527 5.35 307.36 1 1 2 1 61.58 0.78 0.55 2601 3.17 289.33 2 1 2 0 106.78 0.07 0.26 2602 4.70 329.32 1 1 2 0 63.46 0.23 0.45 2605 4.38 307.41 1 1 2 0 82.12 0.04 0.76 2606 4.10 297.30 1 1 1 0 59.52 0.14 0.32 2607 2.84 304.34 2 2 1 0 150.72 1.83 0.13 2608 3.96 279.31 1 1 1 0 63.46 0.14 0.63 2609 3.18 291.34 2 1 2 0 59.21 0.26 1.02 2610 3.74 319.35 3 1 1 0 96.83 0.33 0.83 2611 3.50 312.36 2 2 1 0 79.98 0.23 0.22 2612 5.64 317.42 1 1 2 1 63.46 0.01 1.17 2614 4.02 275.34 1 1 1 0 52.32 0.33 1.26 2615 3.56 305.33 3 1 3 0 166.23 1.19 0.24 4.55 1.40 0.15 1.05 95.21 5.11 1.53 0.22 1.19 97.57 4.39 1.03 0.14 0.96 91.06 5.87 1.60 0.61 1.39 104.03 5.35 1.42 0.26 1.14 95.05 4.36 1.26 0.03 1.02 97.47 6.11 1.26 0.36 1.21 103.25 5.06 1.34 0.16 1.05 101.25 3.99 1.27 0.01 0.78 89.50 4.42 0.65 0.14 0.68 87.97 4.15 1.27 0.07 1.14 90.52 4.41 0.74 0.36 0.51 83.96 4.20 1.09 0.05 0.77 91.82 3.94 1.23 0.11 0.76 89.04 4.34 1.30 0.09 1.06 92.36 4.69 1.15 0.00 0.83 91.80 4.55 1.47 0.25 0.91 99.86 5.20 1.32 0.07 1.24 103.29 4.24 1.40 0.09 1.24 94.87 3.69 0.69 0.09 0.49 75.15 0.55 0.59 0.03 0.09 0.86 0.53 0.48 0.03 0.56 0.84 1.00 0.36 1.13 0.34 0.46 0.01 0.83 0.64 0.15 0.28 0.39 0.94 0.61 0.15 0.54 0.46 0.74 0.20 0.87 0.89 0.12 0.06 0.62 1.24 0.35 0.47 0.58 0.22 0.44 0.17 0.60 0.33 0.69 0.32 0.38 0.90 0.82 0.00 0.52 1.30 0.79 0.54 0.56 0.51 0.43 0.34 0.43 0.89 0.65 0.12 0.61 0.64 0.18 0.08 0.74 0.92 0.24 0.29 0.49 0.59 0.29 0.16 0.46 0.72 0.46 0.35 0.07 0.87 1.61 0.70 S5

2616 4.99 311.38 1 1 1 0 52.64 0.23 0.90 2618 2.33 304.34 2 2 1 0 171.87 1.29 0.31 2619 3.74 291.34 2 1 2 0 81.33 0.26 0.70 2620 3.14 292.33 3 2 2 0 95.11 0.26 0.49 2621 3.74 291.34 2 1 2 0 81.27 0.26 0.62 2622 2.78 291.34 2 2 3 0 117.24 0.15 0.23 2623 4.87 330.21 1 1 1 0 59.52 0.17 1.45 2624 3.48 321.37 3 1 3 0 87.82 0.26 0.69 2625 2.55 280.30 2 2 1 0 90.40 0.14 0.29 2626 4.77 305.35 1 1 2 0 66.60 0.23 0.27 2627 3.82 309.33 2 1 2 0 81.27 0.26 0.23 2628 3.81 300.35 1 2 1 0 103.62 0.14 0.59 2801 6.28 322.83 1 2 2 1 49.70 0.03 1.47 2802 5.71 306.38 1 2 2 1 49.70 0.07 1.35 2803 4.86 280.41 0 2 1 0 49.59 0.08 1.78 2804 3.74 252.35 0 2 1 0 49.44 0.20 1.87 2805 4.30 266.38 0 2 1 0 49.45 0.14 1.81 2806 4.68 254.37 0 2 3 0 49.26 0.76 1.85 2807 2.92 268.35 1 2 1 0 65.40 0.20 1.06 2808 3.86 283.41 1 3 4 0 54.56 0.26 1.20 4.85 1.49 0.23 1.31 106.60 4.22 1.07 0.03 0.60 84.37 4.16 1.25 0.05 1.02 90.09 4.26 1.14 0.00 0.69 84.12 3.97 1.24 0.01 0.99 88.36 4.16 0.91 0.28 0.50 83.06 4.70 1.51 0.37 1.27 102.28 4.42 1.21 0.05 0.96 88.64 4.14 0.92 0.13 0.55 86.65 4.91 1.35 0.19 0.83 99.50 4.03 1.06 0.05 0.81 87.04 4.33 1.39 0.21 1.11 96.42 5.62 1.26 0.46 1.32 97.33 5.30 1.45 0.11 1.12 99.81 4.57 1.38 0.04 1.09 89.02 4.10 1.33 0.20 1.07 86.90 4.31 1.37 0.11 1.08 89.16 3.98 1.34 0.19 1.15 83.82 3.60 1.17 0.29 0.94 85.98 4.08 1.24 0.11 0.87 85.00 0.57 0.54 0.30 0.31 0.27 1.07 1.00 0.66 0.51 0.70 0.51 0.26 0.66 0.95 0.16 0.16 0.54 0.59 0.65 0.37 0.46 0.83 1.48 0.47 0.83 0.29 0.09 0.17 0.82 0.95 0.37 0.10 0.54 1.18 0.43 0.22 0.49 0.05 0.02 0.28 0.53 0.76 0.69 0.27 0.64 0.36 0.34 0.55 0.84 0.26 0.43 0.06 0.63 0.28 0.14 0.20 0.81 0.27 0.08 0.07 0.53 0.48 0.31 0.30 0.77 0.42 0.21 0.08 0.55 0.67 0.12 0.13 0.35 0.73 1.01 0.32 0.47 0.43 0.76 0.00 S6

2809 2.10 333.38 3 2 3 0 151.45 0.04 0.73 2810 5.42 318.41 2 2 3 1 56.29 0.74 1.71 2811 5.39 302.41 0 2 3 1 49.22 0.29 1.44 2812 5.71 306.38 1 2 2 1 49.70 0.07 1.07 2813 7.06 378.51 0 2 5 1 51.86 0.00 1.38 2814 5.72 316.44 0 2 4 1 49.29 0.29 0.98 2815 5.66 294.43 0 2 2 1 49.04 0.61 1.71 2816 5.66 294.43 0 2 5 1 49.20 0.65 1.59 2817 6.19 366.84 3 2 2 1 85.85 0.03 0.42 2818 7.75 376.49 1 2 1 1 51.07 0.00 1.43 2819 5.92 316.44 0 2 4 1 49.26 0.93 1.47 2820 3.14 238.33 0 2 1 0 50.13 0.62 1.79 2821 4.15 240.34 0 2 2 0 49.35 0.56 1.78 2822 3.18 238.33 0 2 1 0 49.68 0.15 1.74 2823 4.86 268.40 0 2 2 0 49.11 0.61 1.63 2824 7.42 356.50 1 2 3 1 49.38 0.11 1.82 2825 5.42 294.43 0 2 1 1 49.92 0.08 1.75 2901 4.75 324.80 2 2 2 0 58.61 0.03 0.69 2902 4.18 308.35 2 2 2 0 58.61 0.07 0.57 2903 3.33 282.38 1 2 1 0 69.10 0.08 0.90 5.40 1.10 0.22 1.03 95.71 5.81 1.36 0.29 1.22 99.71 5.39 1.35 0.13 1.16 105.42 5.26 1.38 0.07 1.11 99.51 7.26 1.46 0.69 1.36 121.61 5.64 1.38 0.29 1.21 108.91 4.86 1.38 0.00 1.15 94.79 4.63 1.25 0.05 1.16 87.92 5.50 1.27 0.41 1.00 106.95 6.03 1.44 0.69 1.26 114.99 5.56 1.36 0.19 1.18 104.65 3.89 1.34 0.23 1.05 84.73 3.77 1.32 0.25 1.12 85.12 3.62 1.27 0.26 1.06 79.97 4.43 1.36 0.23 1.09 87.92 6.84 0.79 0.47 1.32 83.24 4.77 1.35 0.07 1.08 87.63 4.61 1.32 0.20 1.24 101.76 4.51 1.18 0.12 0.88 94.15 4.02 1.22 0.31 0.93 85.57 0.82 0.46 0.09 0.15 0.73 0.28 0.14 0.13 0.57 0.14 0.14 0.26 0.59 0.43 0.06 0.21 0.92 0.05 0.11 0.42 0.67 0.20 0.44 0.18 0.73 0.38 0.00 0.17 0.74 0.57 0.21 0.18 0.84 0.07 0.48 0.32 0.80 0.09 0.33 0.47 0.62 0.12 0.07 0.38 0.65 0.63 0.24 0.32 0.49 0.76 0.32 0.26 0.61 0.68 0.38 0.39 0.48 0.41 0.30 0.12 0.61 0.03 1.80 0.17 0.86 0.08 0.12 0.19 0.70 0.05 0.47 0.16 0.48 0.53 0.66 0.04 0.49 0.53 0.79 0.09 S7

2904 2.21 254.33 1 2 1 0 70.95 0.15 0.95 2905 2.77 268.35 1 2 1 0 69.87 0.14 0.85 2906 3.15 256.34 1 2 3 0 57.84 0.76 0.78 2907 1.39 270.33 2 2 1 0 85.82 0.20 0.63 2908 2.33 285.38 2 3 4 0 61.14 0.26 0.43 2909 0.57 335.36 4 2 3 0 160.36 0.01 0.27 2910 3.89 320.39 3 2 3 0 65.20 0.19 0.78 2911 3.86 304.39 1 2 3 0 70.35 0.56 0.51 2912 4.18 308.35 2 2 2 0 58.61 0.07 0.27 2913 5.53 380.48 1 2 5 1 56.58 0.00 0.32 2914 4.19 318.41 1 2 4 0 56.00 0.29 0.43 2915 4.13 296.41 1 2 2 0 56.79 0.38 0.65 2916 4.13 296.41 1 2 5 0 56.96 0.65 0.70 2917 4.66 368.81 4 2 2 0 99.39 0.03 0.45 2918 6.22 378.47 2 2 1 1 59.00 0.09 0.93 2919 4.39 318.41 1 2 4 0 57.79 0.93 0.58 2920 1.61 240.30 1 2 1 0 72.66 0.62 0.79 2921 2.62 242.32 1 2 2 0 57.87 0.26 0.97 2922 1.65 240.30 1 2 1 0 71.38 0.15 0.85 2923 3.33 270.37 1 2 2 0 57.64 0.38 0.79 3.66 1.19 0.47 0.81 81.12 3.93 1.23 0.37 0.88 86.07 3.71 1.18 0.40 0.81 77.82 3.75 0.95 0.47 0.51 72.37 3.98 0.96 0.35 0.53 72.42 4.73 0.94 0.04 0.77 90.55 4.76 1.28 0.02 1.13 101.06 5.22 1.27 0.06 0.91 106.87 4.28 1.13 0.14 0.75 87.61 6.03 1.32 0.41 1.21 117.25 5.09 1.28 0.13 1.01 105.11 4.59 1.18 0.20 0.85 88.69 4.49 1.17 0.27 0.87 84.09 4.81 1.13 0.19 0.77 94.36 5.69 1.36 0.48 1.09 113.26 5.32 1.28 0.01 0.98 106.21 3.54 1.17 0.49 0.80 81.63 3.59 1.25 0.48 0.71 74.93 3.31 1.16 0.51 0.78 76.35 4.33 1.29 0.39 0.77 85.89 0.23 0.82 0.93 0.39 0.47 0.73 0.87 0.16 0.34 0.94 1.06 0.18 0.20 0.63 1.19 0.27 0.26 0.69 1.11 0.01 0.56 0.01 0.47 0.21 0.49 0.57 0.58 0.14 0.39 0.41 0.89 0.12 0.50 0.44 0.74 0.12 0.72 0.35 0.53 0.35 0.56 0.64 0.82 0.09 0.62 0.69 0.88 0.25 0.55 0.79 0.76 0.16 0.69 0.05 0.27 0.03 0.71 0.34 0.10 0.53 0.47 0.37 0.68 0.20 0.33 1.04 1.05 0.43 0.29 0.93 0.64 0.17 0.34 0.98 0.93 0.47 0.29 0.65 1.01 0.15 S8

2924 5.90 358.48 2 2 3 1 57.14 0.17 1.00 5.78 1.31 0.24 1.22 114.42 0.57 0.06 0.18 0.31 2925 3.89 296.41 1 2 1 0 68.84 0.08 0.63 4.08 1.14 0.20 0.98 86.65 0.59 0.34 0.99 0.02 4.45 300.05 1 2 2 0 70.54 0.35 0.97 4.70 1.26 0.03 1.01 93.81 0.58 0.53 0.41 0.10 1.37 30.99 1 1 1 0 29.49 0.39 0.55 0.75 0.19 0.27 0.22 9.82 0.20 0.34 0.47 0.26 S9