Supporting Information. Discovery of Clinical Candidate CEP-37440: A Selective Inhibitor of Focal Adhesion Kinase

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1 Supporting Information Discovery of Clinical Candidate CEP-37440: A Selective Inhibitor of Focal Adhesion Kinase (FAK) and Anaplastic Lymphoma Kinase (ALK) Gregory R. Ott,,* Mangeng Cheng, Keith S. Learn, Jason Wagner, Diane E. Gingrich, Joseph G. Lisko, Matthew Curry, Eugen F. Mesaros, Arup K. Ghose, Matthew R. Quail, Weihua Wan, Lihui Lu, Pawel Dobrzanski, Mark S. Albom, Thelma S. Angeles, Kevin Wells-Knecht, Zeqi Huang, Lisa D. Aimone, Elizabeth Bruckheimer, Nathan Anderson, Jay Friedman, Sandra Fernandez, Mark A. Ator, Bruce A. Ruggeri, Bruce D. Dorsey Teva Branded Pharmaceutical Products R&D, 145 Brandywine Parkway, West Chester, PA, Champions Oncology, Inc. Champions Oncology, Inc. One University Plaza, Suite 307, Hackensack, NJ Thomas Jefferson University, 233 South 10th St, 1002 BLSB, Philadelphia, PA Table of Contents: Page S2 Table S1: DiscoveRx reported % inhibition values Page S12 Table S2: DiscoveRx Kd Values for kinases >90% inhibition at 1 µm Page S13 Table S3. Pharmacokinetic parameters of 1 in Sprague-Dawley (SD) Rats Page S14 Experimental Conditions for X-ray for compound 31 * Corresponding author: gregory.ott@tevapharm.com S1

2 Table S1: DiscoveRx reported % inhibition values of 60% at 1 µm, -- = No Hit Kinase % 1 µm AAK1 -- ABL1(E255K)-phosphorylated -- ABL1(F317I)- nonphosphorylated 74 ABL1(F317I)-phosphorylated 81 ABL1(F317L)- nonphosphorylated 80 ABL1(F317L)-phosphorylated 88 ABL1(H396P)- nonphosphorylated -- ABL1(H396P)-phosphorylated -- ABL1(M351T)- phosphorylated -- ABL1(Q252H)- nonphosphorylated -- ABL1(Q252H)- phosphorylated -- ABL1(T315I)- nonphosphorylated -- ABL1(T315I)-phosphorylated -- ABL1(Y253F)-phosphorylated -- ABL1-nonphosphorylated -- ABL1-phosphorylated -- ABL2 -- ACVR1 -- ACVR1B -- ACVR2A -- ACVR2B -- ACVRL1 -- ADCK3 -- ADCK4 -- AKT1 -- AKT2 -- AKT3 -- ALK 97 AMPK-alpha1 82 AMPK-alpha2 82 S2

3 Kinase % 1 µm ANKK1 78 ARK5 94 ASK1 -- ASK2 -- AURKA -- AURKB -- AURKC 84 AXL 94 BIKE -- BLK -- BMPR1A -- BMPR1B -- BMPR2 -- BMX -- BRAF -- BRAF(V600E) -- BRK 92 BRSK1 -- BRSK2 -- BTK -- CAMK1 -- CAMK1D -- CAMK1G -- CAMK2A -- CAMK2B -- CAMK2D -- CAMK2G -- CAMK4 80 CAMKK1 81 CAMKK2 95 CASK -- CDC2L1 -- CDC2L2 -- CDC2L5 -- CDK11 -- CDK2 -- CDK3 -- CDK4-cyclinD1 -- CDK4-cyclinD3 -- CDK5 -- CDK7 -- CDK8 -- CDK9 -- CDKL1 -- S3

4 Kinase % 1 µm CDKL2 -- CDKL3 -- CDKL5 -- CHEK1 -- CHEK2 -- CIT -- CLK1 96 CLK2 76 CLK3 -- CLK4 92 CSF1R -- CSK -- CSNK1A1 -- CSNK1A1L -- CSNK1D -- CSNK1E -- CSNK1G1 -- CSNK1G2 -- CSNK1G3 -- CSNK2A1 91 CSNK2A2 90 CTK -- DAPK1 65 DAPK2 -- DAPK3 -- DCAMKL1 -- DCAMKL2 -- DCAMKL3 -- DDR1 -- DDR2 -- DLK -- DMPK -- DMPK2 -- DRAK1 79 DRAK2 -- DYRK1A 81 DYRK1B -- DYRK2 99 EGFR 98 EGFR(E746-A7--del) 79 EGFR(G719C) -- EGFR(G719S) -- EGFR(L747-E749del, A7--P) 88 EGFR(L747-S752del, P753S) 75 S4

5 Kinase % 1 µm EGFR(L747-T751del,Sins) 75 EGFR(L858R) 84 EGFR(L858R,T790M) 83 EGFR(L861Q) 92 EGFR(S752-I759del) 67 EGFR(T790M) 97 EIF2AK1 -- EPHA1 -- EPHA2 -- EPHA3 -- EPHA4 -- EPHA5 -- EPHA6 -- EPHA7 -- EPHA8 -- EPHB1 -- EPHB2 -- EPHB3 -- EPHB4 -- EPHB6 -- ERBB2 66 ERBB3 98 ERBB4 70 ERK1 -- ERK2 -- ERK3 -- ERK4 -- ERK5 -- ERK8 -- ERN1 -- FAK 100 FER 87 FES -- FGFR1 -- FGFR2 -- FGFR3 -- FGFR3(G697C) -- FGFR4 79 FGR -- FLT1 -- FLT3 84 FLT3(D835H) 86 FLT3(D835Y) 99 FLT3(ITD) 91 S5

6 Kinase % 1 µm FLT3(K663Q) 83 FLT3(N841I) 99 FLT3(R834Q) 67 FLT4 -- FRK 80 FYN -- GAK 89 GCN2(Kin.Dom.2,S808G) 67 GRK1 -- GRK4 -- GRK7 -- GSK3A -- GSK3B -- HCK -- HIPK1 -- HIPK2 -- HIPK3 -- HIPK4 95 HPK1 -- HUNK -- ICK -- IGF1R 96 IKK-alpha -- IKK-beta -- IKK-epsilon -- INSR 91 INSRR 99 IRAK1 78 IRAK3 -- IRAK4 -- ITK -- JAK1(JH1domain-catalytic) -- JAK1(JH2domainpseudokinase) -- JAK2(JH1domain-catalytic) -- JAK3(JH1domain-catalytic) -- JNK1 99 JNK2 94 JNK3 99 KIT -- KIT(A829P) -- KIT(D816H) -- KIT(D816V) 92 KIT(L576P) -- S6

7 Kinase % 1 µm KIT(V559D) -- KIT(V559D,T670I) -- KIT(V559D,V654A) -- LATS1 -- LATS2 -- LCK -- LIMK1 -- LIMK2 -- LKB1 -- LOK -- LRRK2 79 LRRK2(G2019S) 69 LTK 100 LYN -- LZK -- MAK -- MAP3K1 -- MAP3K15 -- MAP3K2 -- MAP3K3 -- MAP3K4 -- MAP4K2 -- MAP4K3 -- MAP4K4 -- MAP4K5 -- MAPKAPK2 -- MAPKAPK5 -- MARK1 -- MARK2 -- MARK3 -- MARK4 -- MAST1 -- MEK1 -- MEK2 -- MEK3 -- MEK4 -- MEK5 -- MEK6 -- MELK 73 MERTK 69 MET 93 MET(M12--T) 80 MET(Y1235D) -- MINK -- S7

8 Kinase % 1 µm MKK7 -- MKNK1 -- MKNK2 -- MLCK -- MLK1 -- MLK2 -- MLK3 -- MRCKA -- MRCKB -- MST1 -- MST1R -- MST2 -- MST3 -- MST4 -- MTOR -- MUSK -- MYLK 96 MYLK2 -- MYLK4 -- MYO3A -- MYO3B -- NDR1 -- NDR2 -- NEK1 -- NEK11 -- NEK2 -- NEK3 -- NEK4 -- NEK5 -- NEK6 -- NEK7 -- NEK9 -- NIM1 -- NLK -- OSR1 -- p38-alpha -- p38-beta -- p38-delta -- p38-gamma -- PAK1 -- PAK2 -- PAK3 88 PAK4 -- PAK6 -- S8

9 Kinase % 1 µm PAK7 -- PCTK1 -- PCTK2 -- PCTK3 -- PDGFRA -- PDGFRB -- PDPK1 -- PFCDPK1(P.falciparum) 87 PFPK5(P.falciparum) -- PFTAIRE2 -- PFTK1 -- PHKG1 93 PHKG2 71 PIK3C2B -- PIK3C2G -- PIK3CA -- PIK3CA(C420R) -- PIK3CA(E542K) -- PIK3CA(E545A) -- PIK3CA(E545K) -- PIK3CA(H1047L) -- PIK3CA(H1047Y) -- PIK3CA(I800L) -- PIK3CA(M1043I) -- PIK3CA(Q546K) -- PIK3CB -- PIK3CD -- PIK3CG -- PIK4CB -- PIM1 -- PIM2 -- PIM3 -- PIP5K1A -- PIP5K1C -- PIP5K2B -- PIP5K2C -- PKAC-alpha -- PKAC-beta -- PKMYT1 -- PKN1 -- PKN2 -- PKNB(M.tuberculosis) -- PLK1 -- PLK2 -- S9

10 Kinase % 1 µm PLK3 -- PLK4 95 PRKCD -- PRKCE -- PRKCH -- PRKCI -- PRKCQ -- PRKD1 65 PRKD2 -- PRKD3 71 PRKG1 74 PRKG2 87 PRKR -- PRKX -- PRP4 -- PYK2 100 QSK -- RAF1 -- RET -- RET(M918T) -- RET(V804L) -- RET(V804M) -- RIOK1 -- RIOK2 -- RIOK3 -- RIPK1 -- RIPK2 -- RIPK4 -- RIPK5 -- ROCK1 -- ROCK2 -- ROS1 84 RPS6KA4(Kin.Dom.1-Nterminal) -- RPS6KA4(Kin.Dom.2-Cterminal) -- RPS6KA5(Kin.Dom.1-Nterminal) -- RPS6KA5(Kin.Dom.2-Cterminal) -- RSK1(Kin.Dom.1-N-terminal) 100 RSK1(Kin.Dom.2-C-terminal) -- RSK2(Kin.Dom.1-N-terminal) 100 RSK3(Kin.Dom.1-N-terminal) 99 S10

11 Kinase % 1 µm RSK3(Kin.Dom.2-C-terminal) -- RSK4(Kin.Dom.1-N-terminal) 98 RSK4(Kin.Dom.2-C-terminal) -- S6K1 -- SBK1 -- SgK SGK3 -- SIK -- SIK2 -- SLK -- SNARK 76 SNRK -- SRC -- SRMS 72 SRPK1 -- SRPK2 -- SRPK3 -- STK16 -- STK STK35 -- STK36 -- STK39 -- SYK -- TAK1 -- TAOK1 -- TAOK2 -- TAOK3 -- TBK1 -- TEC -- TESK1 -- TGFBR1 -- TGFBR2 -- TIE1 -- TIE2 -- TLK1 -- TLK2 -- TNIK -- TNK1 100 TNK2 -- TNNI3K -- TRKA -- TRKB -- TRKC -- TRPM6 -- S11

12 Kinase % 1 µm TSSK1B -- TTK 70 TXK -- TYK2(JH1domain-catalytic) -- TYK2(JH2domainpseudokinase) -- TYRO3 -- ULK1 -- ULK2 -- ULK3 -- VEGFR2 -- VRK2 -- WEE1 -- WEE2 -- YANK1 -- YANK2 -- YANK3 -- YES -- YSK1 -- YSK4 83 ZAK -- ZAP70 -- Table S2: DiscoveRx Kd Values for kinases >90% inhibition at 1 µm Kinase % Inhibition Kd (nm) a ALK a ARK a AXL ± 26 BRK ± 14 CAMKK ± 8 CLK ± 23 CLK ± 62 CSNK2A ± 27 CSNK2A ± 25 DYRK ± 58 EGFR ± 220 EGFR(L861Q) ± 36 EGFR(T790M) ± 6 ERBB c FAK ± 1.7 FLT3(D835Y) ± 4 FLT3(ITD) ± 15 FLT3(N841I) ± 26 S12

13 HIPK ± 32 IGF1R ± 37 INSR ± 15 INSRR ± 23 JNK ± 7 JNK ± 61 JNK ± 6 KIT(D816V) ± 40 LTK ± 4 MET ± 67 MYLK ± 34 PHKG ± 35 PLK ± 10 PYK ± 1.5 RSK1 (Kin.Dom.1-Nterminal) ± 1.3 RSK2 (Kin.Dom.1-Nterminal) ± 0.3 RSK3 (Kin.Dom.1-Nterminal) ± 20 RSK4 (Kin.Dom.1-Nterminal) ± 22 STK ± 2.2 TNK ± 3.7 a n=4, mean ± SD unless otherwise noted b mean, n=2 false positive in single-point profile Table S3. Pharmacokinetic parameters of 1 in Sprague-Dawley (SD) Rats PK parameters SD Rat a i.v. Dose b (mg/kg) 1 t 1/2 (h) 0.9 ± 0.2 AUC 0- (ng*h/ml) 989 ± 127 Vd (L/kg) 1.3 ± 0.2 CL (ml/min/kg) 17 ± 0.2 p.o. Dose b (mg/kg) 5 C max (ng/ml) 360 ± 57 t max (h) 1.7 ± 0.3 AUC 0- (ng*h/ml) 1232 ± 224 F% 25 ± 5 S13

14 a Values ± SEM are means from three animals. b Formulated as solutions i.v.: 3% DMSO, 30% solutol, 67% PBS; p.o.: dh 2 O Experimental Conditions for X-ray for compound 31 All reflection intensities were measured using a KM4/Xcalibur (detector: Sapphire3) with enhance graphite-monochromated Mo Kα radiation (λ = Å) under the program CrysAlisPro (Version , Oxford Diffraction Ltd., 2009). The program CrysAlisPro (Version , Oxford Diffraction Ltd., 2009) was used to refine the cell dimensions. Data reduction was done using the program CrysAlisPro (Version , Oxford Diffraction Ltd., 2009). The structure was solved with the program SHELXS-97 (Sheldrick, 2008) and was refined on F 2 with SHELXL-97 (Sheldrick, 2008). Semi-empirical absorption corrections (multi-scan) were applied to the data using CrysAlisPro (Version , Oxford Diffraction Ltd., 2009). The temperature of the data collection was controlled using the system Cryojet (manufactured by Oxford Instruments). The H-atoms were placed at calculated positions using the instructions AFIX 13, AFIX 23, AFIX 43 or AFIX 137 with isotropic displacement parameters having values 1.2 or 1.5 times Ueq of the attached C and N1X (X = A, B, C, D) atoms. Data were collected at 110(2) K after the crystal had been flash-cooled from room temperature. The structure of the compound C 32 H 35 Br 2 N 3 O (H 2 O) was solved and refined in the noncentrosymmetric space group P1 with Z = 4. The structure of 31 is mostly ordered. The fragments N2C(N2E) C23C(C23E) and C24D(C24F) C26D(C26F) are disordered. The occupancy factors of the major components of the disorder refine to 0.512(7) and 0.585(9), respectively. Lattice water molecules are also found in the crystal lattice. One solvent molecule (O1W) has full occupancy, whereas the occupancy factor of the second solvent molecule (O2W) refines to 0.47(2). The H-atoms of the lattice water molecules could not be found from difference maps [note: checkcif/platon report suggests intermolecular contacts of type D H A (hydrogen bonds) around O1W and O2W]. These solvent molecules are likely to be disordered (at least the H atoms) mainly because there are always three potential H-bond acceptors around O1W and O2W. These acceptors are N3A, O4B, Br8 for O1W, and N3C, O4D(O4F), Br4 for O2W. The S14

15 four crystallographically independent molecules have one chiral carbon atoms (C18X, X= A, B, C, D). The absolute configuration was established by anomalous-dispersion effects in diffraction measurements on the crystal, and all C18X atoms have the R configuration (the test in the checkcif report fails to report the R configuration for moiety C because the fragment N2C C23C is disordered. Without taking into account the disorder, the atom C18C has the R configuration as well). The Flack parameter refines to 0.003(8). Crystals of 31 are found to be non-merohedrally twinned. The twin relationship corresponds to a twofold axis along the a direction. The BASF parameter refines to 0.296(2). The final refinement against F 2 was fair. The R factor [F 2 > 2σ(F 2 )] is about The final difference Fourier map was relatively flat, and the residual peaks were found no larger than 0.92 e Å -3. The largest residual peaks are always found to be around the Br atoms. C 32 H 35 Br 2 N 3 O (H 2 O), Fw , colorless blade, mm 3, triclinic, P1 (no. 1), a = (2), b = (5), c = (5) Å, α = (2), β = (2), γ = (2), V = (13) Å 3, Z = 4, D x = g cm 3, µ = mm 1, abs. corr. range: Reflections were measured up to a resolution of (sin θ/λ) max = 0.59 Å Reflections were unique (R int = ), of which were observed [I > 2σ(I)] Parameters were refined with 302 restraints. R1/wR2 [I > 2σ(I)]: / R1/wR2 [all refl.]: / S = Residual electron density found between 0.81 and 0.92 e Å 3. Table 1. Sample and Crystal Data for 31. Crystallization solvents Crystallization method MeOH Slow evaporation Chemical formula C 32 H 35 N 3 O 4 Br 2 + water Empirical formula C 32 H 35 N 3 O 4 Br 2 + water Formula weight Temperature 110(2) K Wavelength Å Crystal size 0.60 x 0.23 x 0.10 mm S15

16 Crystal habit Crystal system Space group P 1 Colorless blade Triclinic Unit cell dimensions a = (2) Å α= (2) Volume (13) Å 3 Z 4 Density (calculated) Mg/m 3 Absorption coefficient mm -1 b = (5) Å β= (2) c = (5) Å γ = (2) F(000) 1412 S16

17 Table 2. Data Collection and Processing for 31. Diffractometer Radiation source Generator power Detector distance 50 Data collection method Oxford Instruments KM4/Xcalibur Goniometer: Sapphire3 detector Enhance (Mo) X-ray Source, MoKα 2 kw (50 kv, 40 ma) omega scans Theta range for data collection 1.95 to Index ranges -11 h 11, -20 k 20, -21 l 21 Reflections collected Independent reflections [R(int) = ] Coverage of independent reflections 99.9 % Variation in check reflections Absorption correction Max. and min. transmission and n/a Semi-empirical from equivalents S17

18 Table 3. Structure Solution and Refinement for 31. Structure solution technique Direct methods Structure solution program SHELXS-97 (Sheldrick, 1990) Refinement technique Full-matrix least-squares on F 2 Refinement program SHELXL-97 (Sheldrick, 1997) Function minimized Σ w(fo 2 - Fc 2 ) 2 Data / restraints / parameters(+) / 302 / 1578 Goodness-of-fit on F /σ max Final R indices(*) 1989 data; I>2s (I) R1 = , wr2 = all data R1 = , wr2 = Weighting scheme w = 1/[σ 2 (Fo 2 ) +[(0.08P) P] where P = [MAX(F o 2,0) + 2Fc 2 ]/3 Absolute structure parameter 0.003(8) Largest diff. peak and hole and eå -3 R.M.S. deviation from the mean eå -3 * R = Σ Fo - Fc / Σ Fo & wr2 = Σ w(fo 2 - Fc 2 ) 2 / Σ (Fo 2 ) 2 + Refinement summary: Ordered Non-H atoms, XYZ Ordered Non-H atoms, U H atoms (on carbon), XYZ H atoms (on carbon), U H atoms (on heteroatoms), XYZ H atoms (on heteroatoms), U Disordered atoms Freely refined Anisotropic Idealized positions riding on attached atom Appropriate constant times Ueq of attached atom Idealized positions riding on attached atom Appropriate constant times Ueq of attached atom (see Occupancy Table below) S18

19 Table 4. Atomic Coordinates and Equivalent Isotropic Atomic Displacement Parameters (Å 2 ) for 31. U(eq) is defined as one third of the trace of the orthogonalized U ij tensor. x/a y/b z/c U(eq) Br (8) (5) (4) (2) Br (11) (6) (5) (3) C1A (8) (4) (4) (18) C2A (8) (5) (4) (18) C3A (8) (4) (4) (18) C4A (8) (4) (4) (17) C5A (8) (5) (4) (18) C6A (8) (5) (5) (19) C7A (9) (5) (4) (19) C8A (7) (4) (4) (17) C9A (7) (5) (4) (17) C10A (8) (5) (5) (18) C11A (7) (4) (4) (16) C12A (8) (4) (4) (17) C13A (7) (4) (4) (17) C14A (8) (5) (5) 0.034(2) C15A (8) (5) (5) 0.033(2) C16A (8) (5) (4) (18) C17A (9) (5) (5) 0.037(2) C18A (8) (4) (4) (17) C19A (8) (5) (4) (18) C20A (9) (5) (4) (19) C21A (8) (5) (4) (18) C22A (8) (5) (5) 0.035(2) C23A (8) (5) (4) (19) C24A (8) (5) (4) (19) C25A (9) (5) (4) (19) C26A (8) (5) (4) (19) C27A (8) (4) (4) (17) C28A (9) (5) (5) 0.038(2) C29A (10) (5) (5) 0.044(2) C30A (10) (5) (4) 0.038(2) C31A (10) (5) (5) 0.041(2) C32A (9) (5) (4) 0.037(2) N1A (6) (4) (3) (15) N2A (7) (4) (4) (16) N3A (6) (4) (3) (15) O1A (6) (5) (3) 0.056(2) O2A (6) (3) (3) (13) O3A (6) (3) (3) (13) O4A (6) (4) (3) (15) Br (9) (5) (5) (2) Br (10) (5) (5) (3) C1B (9) (5) (4) (19) C2B (8) (5) (5) (19) C3B (8) (5) (4) (17) S19

20 C4B (7) (4) (4) (16) C5B (8) (5) (5) (19) C6B (8) (5) (5) 0.034(2) C7B (8) (4) (4) (17) C8B (7) (5) (4) (17) C9B (7) (4) (4) (16) C10B (7) (5) (4) (17) C11B (8) (4) (4) (17) C12B (7) (4) (4) (17) C13B (7) (4) (4) (16) C14B (9) (6) (5) 0.040(2) C15B (9) (5) (5) 0.035(2) C16B (8) (5) (5) (19) C17B (8) (5) (5) (19) C18B (7) (4) (4) (17) C19B (8) (5) (4) (19) C20B (9) (5) (5) 0.037(2) C21B (9) (5) (5) 0.039(2) C22B (9) (5) (4) (19) C23B (8) (5) (5) (19) C24B (9) (5) (5) 0.035(2) C25B (9) (5) (5) 0.039(2) C26B (10) (5) (5) 0.042(2) C27B (10) (5) (5) 0.042(2) C28B (10) (5) (5) 0.040(2) C29B (10) (5) (5) 0.041(2) C30B (11) (5) (5) 0.044(2) C31B (11) (5) (5) 0.046(3) C32B (9) (5) (5) 0.039(2) N1B (6) (4) (4) (15) N2B (6) (4) (3) (15) N3B (7) (4) (4) (16) O1B (5) (3) (3) (13) O2B (5) (3) (3) (13) O3B (7) (4) (3) (15) O4B (7) (4) (4) (17) Br (10) (6) (5) (3) Br (10) (5) (5) (3) C1C (9) (5) (5) 0.034(2) C2C (8) (5) (5) (19) C3C (8) (5) (4) (19) C4C (7) (5) (4) (17) C5C (7) (5) (5) (18) C6C (8) (5) (4) (19) C7C (8) (4) (4) (17) C8C (7) (5) (4) (17) C9C (8) (5) (4) (18) C10C (8) (5) (4) (18) C11C (8) (5) (4) (18) C12C (7) (4) (4) (17) C13C (7) (5) (4) (17) C14C (9) (5) (5) 0.039(2) C15C (9) (5) (5) 0.042(2) C16C (9) (5) (5) 0.041(2) S20

21 C17C (9) (5) (5) 0.038(2) C18C (8) (5) (5) 0.037(2) C19C (8) (5) (4) (18) N2C (16) (9) (6) 0.038(2) C20C (16) (12) (8) 0.039(2) C21C (15) (11) (8) 0.043(3) N3C (13) (8) (6) 0.036(2) C22C (17) (10) (8) 0.034(2) C23C (16) (8) (8) 0.031(3) N2E (16) (10) (6) 0.038(2) C20E (17) (12) (9) 0.039(2) C21E (18) (9) (8) 0.036(3) N3E (13) (8) (7) 0.036(2) C22E (15) (11) (8) 0.034(2) C23E (16) (11) (9) 0.044(3) C24C (9) (6) (5) 0.042(2) C25C (10) (8) (5) 0.059(3) C26C (9) (5) (5) 0.038(2) C27C (8) (5) (5) 0.033(2) C28C (9) (5) (5) 0.037(2) C29C (10) (5) (5) 0.038(2) C30C (10) (5) (5) 0.040(2) C31C (10) (5) (5) 0.039(2) C32C (9) (5) (5) 0.034(2) N1C (6) (4) (3) (15) O1C (5) (3) (3) (13) O2C (5) (3) (3) (13) O3C (6) (4) (3) (16) O4C (6) (4) (3) (17) Br (9) (5) (5) (2) Br (10) (6) (5) (3) C1D (8) (5) (4) (18) C2D (8) (5) (4) (19) C3D (8) (5) (4) (18) C4D (8) (5) (4) (17) C5D (8) (5) (4) 0.035(2) C6D (8) (5) (5) 0.037(2) C7D (8) (5) (5) (19) C8D (7) (4) (4) (17) C9D (7) (5) (4) (17) C10D (7) (5) (4) (17) C11D (7) (4) (4) (16) C12D (8) (5) (4) (17) C13D (7) (4) (4) (16) C14D (9) (5) (5) 0.037(2) C15D (9) (5) (4) 0.035(2) C16D (10) (6) (5) 0.039(2) C17D (10) (5) (5) 0.044(2) C18D (8) (5) (4) (18) C19D (8) (4) (4) (18) C20D (9) (5) (4) (19) C21D (10) (6) (5) 0.047(2) C22D (9) (5) (4) 0.042(2) C23D (9) (5) (4) (19) S21

22 C24D (15) (10) (7) 0.040(3) C25D (15) (10) (7) 0.039(3) O3D (12) (7) (5) 0.040(2) C26D (18) (12) (7) 0.038(3) O4D (11) (9) (6) 0.047(3) C24F 0.088(2) (11) (8) 0.038(3) C25F 0.075(2) (12) (9) 0.040(3) O3F (16) (10) (7) 0.038(3) C26F 0.016(2) (15) (9) 0.036(3) O4F (17) (11) (9) 0.037(3) C27D (11) (6) (5) 0.049(3) C28D (13) (6) (6) 0.065(3) C29D (9) (5) (5) 0.043(2) C30D (9) (5) (5) 0.033(2) C31D (9) (5) (5) 0.037(2) C32D (10) (6) (5) 0.044(2) N1D (6) (4) (3) (16) N2D (6) (4) (3) (14) N3D (8) (5) (4) 0.054(2) O1D (6) (4) (3) (16) O2D (6) (3) (3) (14) O1W (8) (5) (5) 0.075(2) O2W (2) (11) (9) 0.085(8) S22

23 Table 5. Selected Bond Lengths (Å) for 31. Br1-C1A 1.906(7) Br2-C30A 1.916(8) C1A-C6A 1.355(11) C1A-C2A 1.391(11) C2A-C3A 1.378(11) C3A-C4A 1.387(11) C4A-C5A 1.385(11) C4A-C7A 1.508(10) C5A-C6A 1.405(11) C7A-O1A 1.222(10) C7A-N1A 1.339(10) C8A-C9A 1.381(11) C8A-C13A 1.385(10) C8A-N1A 1.421(9) C9A-C10A 1.377(10) C10A-C11A 1.380(11) C11A-C12A 1.396(11) C11A-C19A 1.539(10) C12A-C13A 1.412(10) C12A-C15A 1.490(11) C13A-O2A 1.397(9) C14A-O2A 1.429(9) C15A-C16A 1.537(11) C16A-C17A 1.538(11) C17A-C18A 1.524(11) C18A-N2A 1.488(9) C18A-C19A 1.544(11) C20A-N2A 1.479(10) C20A-C21A 1.515(10) C21A-N3A 1.482(9) C22A-N3A 1.462(10) C22A-C23A 1.501(11) C23A-N2A 1.478(10) C24A-N3A 1.476(10) C24A-C25A 1.511(11) C25A-O3A 1.443(9) C26A-O4A 1.190(10) C26A-O3A 1.348(9) C26A-C27A 1.495(11) C27A-C28A 1.385(11) C27A-C32A 1.390(12) C28A-C29A 1.369(12) C29A-C30A 1.375(13) C30A-C31A 1.354(12) C31A-C32A 1.395(11) Br3-C1B 1.898(8) Br4-C30B 1.901(9) C1B-C2B 1.374(11) C1B-C6B 1.408(11) C2B-C3B 1.394(11) C3B-C4B 1.398(10) C4B-C5B 1.380(11) C4B-C7B 1.504(10) C5B-C6B 1.368(11) C7B-O1B 1.231(9) C7B-N1B 1.362(9) C8B-C9B 1.376(10) C8B-C13B 1.389(11) C8B-N1B 1.401(9) C9B-C10B 1.366(10) C10B-C11B 1.405(10) C11B-C12B 1.391(10) C11B-C19B 1.507(10) C12B-C13B 1.423(10) C12B-C15B 1.505(11) C13B-O2B 1.368(9) C14B-O2B 1.424(10) C15B-C16B 1.530(12) C16B-C17B 1.543(11) C17B-C18B 1.495(11) C18B-N2B 1.478(9) C18B-C19B 1.558(10) C20B-N2B 1.466(10) C20B-C21B 1.502(11) C21B-N3B 1.464(11) C22B-N3B 1.453(10) C22B-C23B 1.513(10) C23B-N2B 1.465(10) C24B-N3B 1.434(10) C24B-C25B 1.548(12) C25B-O3B 1.455(10) C26B-O4B 1.204(11) C26B-O3B 1.342(11) C26B-C27B 1.480(13) C27B-C28B 1.383(13) C27B-C32B 1.398(12) C28B-C29B 1.374(13) C29B-C30B 1.369(12) C30B-C31B 1.429(14) C31B-C32B 1.378(13) Br5-C1C 1.883(8) Br6-C30C 1.901(9) C1C-C6C 1.368(12) C1C-C2C 1.393(12) C2C-C3C 1.363(11) C3C-C4C 1.406(11) C4C-C5C 1.396(10) C4C-C7C 1.515(10) C5C-C6C 1.397(11) C7C-O1C 1.233(9) C7C-N1C 1.328(10) C8C-C13C 1.381(11) S23

24 C8C-C9C 1.384(11) C8C-N1C 1.443(9) C9C-C10C 1.377(10) C10C-C11C 1.394(11) C11C-C12C 1.393(11) C11C-C19C 1.536(10) C12C-C13C 1.405(10) C12C-C15C 1.478(11) C13C-O2C 1.375(9) C14C-O2C 1.433(10) C15C-C16C 1.561(12) C16C-C17C 1.512(12) C17C-C18C 1.535(12) C18C-N2C 1.463(13) C18C-N2E 1.471(14) C18C-C19C 1.546(11) N2C-C23C 1.466(18) N2C-C20C 1.528(16) C20C-C21C 1.541(17) C21C-N3C 1.439(16) N3C-C24C 1.469(14) N3C-C22C 1.665(15) C22C-C23C 1.491(17) N2E-C23E 1.456(18) N2E-C20E 1.528(16) C20E-C21E 1.537(17) C21E-N3E 1.462(16) N3E-C24C 1.500(14) N3E-C22E 1.653(16) C22E-C23E 1.489(18) C24C-C25C 1.487(13) C25C-O3C 1.449(10) C26C-O4C 1.212(10) C26C-O3C 1.363(10) C26C-C27C 1.475(12) C27C-C28C 1.391(12) C27C-C32C 1.392(12) C28C-C29C 1.406(12) C29C-C30C 1.376(13) C30C-C31C 1.379(13) C31C-C32C 1.392(12) Br7-C1D 1.889(8) Br8-C30D 1.882(8) C1D-C6D 1.381(11) C1D-C2D 1.389(11) C2D-C3D 1.372(11) C3D-C4D 1.406(10) C4D-C5D 1.373(11) C4D-C7D 1.508(10) C5D-C6D 1.377(11) C7D-O1D 1.211(10) C7D-N1D 1.341(10) C8D-C9D 1.402(10) C8D-N1D 1.405(9) C8D-C13D 1.407(10) C9D-C10D 1.388(10) C10D-C11D 1.385(10) C11D-C12D 1.416(10) C11D-C19D 1.512(10) C12D-C13D 1.397(10) C12D-C15D 1.483(11) C13D-O2D 1.385(9) C14D-O2D 1.449(10) C15D-C16D 1.525(12) C16D-C17D 1.522(12) C17D-C18D 1.515(11) C18D-N2D 1.468(9) C18D-C19D 1.544(11) C20D-N2D 1.469(10) C20D-C21D 1.511(11) C21D-N3D 1.472(12) C22D-N3D 1.409(12) C22D-C23D 1.520(10) C23D-N2D 1.456(10) C24D-N3D 1.468(14) C24D-C25D 1.543(17) C25D-O3D 1.463(14) O3D-C26D 1.299(18) C26D-O4D 1.227(19) C26D-C27D 1.557(16) C24F-C25F 1.537(19) C24F-N3D 1.562(16) C25F-O3F 1.454(16) O3F-C26F 1.30(2) C26F- O4F 1.20(2) C26F-C27D 1.513(17) C27D-C32D 1.336(14) C27D-C28D 1.407(16) C28D-C29D 1.357(14) C29D-C30D 1.409(12) C30D-C31D 1.362(12) C31D-C32D 1.405(12) S24

25 Table 6. Selected bond angles ( ) for 31. C6A-C1A-C2A 121.6(7) C6A-C1A-Br (6) C2A-C1A-Br (6) C3A-C2A-C1A 119.0(7) C2A-C3A-C4A 120.4(7) C5A-C4A-C3A 119.9(7) C5A-C4A-C7A 123.3(7) C3A-C4A-C7A 116.8(7) C4A-C5A-C6A 119.7(7) C1A-C6A-C5A 119.3(7) O1A-C7A-N1A 122.4(7) O1A-C7A-C4A 120.2(7) N1A-C7A-C4A 117.4(7) C9A-C8A-C13A 119.6(7) C9A-C8A-N1A 121.0(7) C13A-C8A-N1A 119.4(7) C10A-C9A-C8A 118.8(7) C9A-C10A-C11A 122.4(8) C10A-C11A-C12A 120.0(7) C10A-C11A-C19A 120.3(7) C12A-C11A-C19A 119.6(7) C11A-C12A-C13A 117.0(7) C11A-C12A-C15A 121.6(7) C13A-C12A-C15A 121.4(7) C8A-C13A-O2A 117.5(6) C8A-C13A-C12A 122.1(7) O2A-C13A-C12A 120.3(6) C12A-C15A-C16A 113.0(7) C15A-C16A-C17A 112.8(7) C18A-C17A-C16A 115.1(6) N2A-C18A-C17A 114.8(6) N2A-C18A-C19A 109.9(6) C17A-C18A-C19A 111.3(6) C11A-C19A-C18A 113.6(6) N2A-C20A-C21A 111.1(7) N3A-C21A-C20A 109.3(6) N3A-C22A-C23A 108.6(7) N2A-C23A-C22A 110.3(6) N3A-C24A-C25A 110.8(6) O3A-C25A-C24A 106.7(6) O4A-C26A-O3A 123.9(7) O4A-C26A-C27A 125.9(7) O3A-C26A-C27A 110.3(7) C28A-C27A-C32A 119.8(8) C28A-C27A-C26A 118.8(8) C32A-C27A-C26A 121.2(7) C29A-C28A-C27A 120.9(9) C28A-C29A-C30A 118.0(8) C31A-C30A-C29A 123.2(8) C31A-C30A-Br (7) C29A-C30A-Br (6) C30A-C31A-C32A 118.8(9) C27A-C32A-C31A 119.2(7) C7A-N1A-C8A 125.0(7) C23A-N2A-C20A 110.0(6) C23A-N2A-C18A 112.7(6) C20A-N2A-C18A 112.2(6) C22A-N3A-C24A 112.9(6) C22A-N3A-C21A 107.9(6) C24A-N3A-C21A 109.7(6) C13A-O2A-C14A 115.7(6) C26A-O3A-C25A 116.3(6) C2B-C1B-C6B 121.2(7) C2B-C1B-Br (6) C6B-C1B-Br (6) C1B-C2B-C3B 118.1(7) C2B-C3B-C4B 121.2(7) C5B-C4B-C3B 119.2(7) C5B-C4B-C7B 123.8(7) C3B-C4B-C7B 117.0(7) C6B-C5B-C4B 120.7(7) C5B-C6B-C1B 119.5(7) O1B-C7B-N1B 122.5(6) O1B-C7B-C4B 121.3(6) N1B-C7B-C4B 116.2(6) C9B-C8B-C13B 119.7(7) C9B-C8B-N1B 121.1(7) C13B-C8B-N1B 119.0(7) C10B-C9B-C8B 120.3(7) C9B-C10B-C11B 122.0(7) C12B-C11B-C10B 118.4(7) C12B-C11B-C19B 121.1(7) C10B-C11B-C19B 120.5(7) C11B-C12B-C13B 119.2(7) C11B-C12B-C15B 120.8(7) C13B-C12B-C15B 120.0(7) O2B-C13B-C8B 119.3(6) O2B-C13B-C12B 120.4(6) C8B-C13B-C12B 120.4(7) C12B-C15B-C16B 112.8(7) C15B-C16B-C17B 113.9(7) C18B-C17B-C16B 115.9(6) N2B-C18B-C17B 109.6(6) N2B-C18B-C19B 113.6(6) C17B-C18B-C19B 112.5(6) C11B-C19B-C18B 116.4(6) N2B-C20B-C21B 111.1(7) N3B-C21B-C20B 109.4(7) N3B-C22B-C23B 110.0(6) N2B-C23B-C22B 110.0(6) N3B-C24B-C25B 117.1(7) O3B-C25B-C24B 104.7(7) S25

26 O4B-C26B-O3B 124.4(9) O4B-C26B-C27B 125.1(9) O3B-C26B-C27B 110.4(9) C28B-C27B-C32B 119.3(9) C28B-C27B-C26B 122.3(8) C32B-C27B-C26B 118.3(9) C29B-C28B-C27B 121.7(8) C30B-C29B-C28B 118.7(9) C29B-C30B-C31B 121.7(9) C29B-C30B-Br (8) C31B-C30B-Br (7) C32B-C31B-C30B 117.7(8) C31B-C32B-C27B 120.8(9) C7B-N1B-C8B 122.1(6) C23B-N2B-C20B 109.9(6) C23B-N2B-C18B 114.0(6) C20B-N2B-C18B 114.0(6) C24B-N3B-C22B 114.7(6) C24B-N3B-C21B 114.8(7) C22B-N3B-C21B 109.6(7) C13B-O2B-C14B 112.3(6) C26B-O3B-C25B 115.8(7) C6C-C1C-C2C 121.1(7) C6C-C1C-Br (6) C2C-C1C-Br (6) C3C-C2C-C1C 119.2(8) C2C-C3C-C4C 121.4(7) C5C-C4C-C3C 118.3(7) C5C-C4C-C7C 123.4(7) C3C-C4C-C7C 118.3(7) C4C-C5C-C6C 120.3(7) C1C-C6C-C5C 119.6(7) O1C-C7C-N1C 123.9(7) O1C-C7C-C4C 119.2(7) N1C-C7C-C4C 117.0(6) C13C-C8C-C9C 119.8(7) C13C-C8C-N1C 120.1(7) C9C-C8C-N1C 120.0(7) C10C-C9C-C8C 119.3(7) C9C-C10C-C11C 121.5(7) C10C-C11C-C12C 119.7(7) C10C-C11C-C19C 119.2(7) C12C-C11C-C19C 121.2(7) C11C-C12C-C13C 118.1(7) C11C-C12C-C15C 121.6(7) C13C-C12C-C15C 120.3(7) O2C-C13C-C8C 118.4(7) O2C-C13C-C12C 120.1(7) C8C-C13C-C12C 121.5(7) C12C-C15C-C16C 111.2(7) C17C-C16C-C15C 114.9(8) C16C-C17C-C18C 116.6(7) N2C-C18C-C17C 103.7(8) N2E-C18C-C17C 119.0(9) N2C-C18C-C19C 119.3(9) N2E-C18C-C19C 105.9(9) C17C-C18C-C19C 112.1(7) C11C-C19C-C18C 112.7(6) C18C-N2C-C23C 110.3(11) C18C-N2C-C20C 112.3(11) C23C-N2C-C20C 98.3(13) N2C-C20C-C21C 115.1(11) N3C-C21C-C20C 110.3(13) C21C-N3C-C24C 110.9(11) C21C-N3C-C22C 93.0(10) C24C-N3C-C22C 103.1(10) C23C-C22C-N3C 116.3(11) N2C-C23C-C22C 109.0(11) C23E-N2E-C18C 115.3(13) C23E-N2E-C20E 99.2(12) C18C-N2E-C20E 109.2(12) N2E-C20E-C21E 110.5(11) N3E-C21E-C20E 110.5(13) C21E-N3E-C24C 108.2(11) C21E-N3E-C22E 89.5(11) C24C-N3E-C22E 98.5(10) C23E-C22E-N3E 112.7(11) N2E-C23E-C22E 112.9(13) N3C-C24C-C25C 114.4(8) C25C-C24C-N3E 113.5(8) O3C-C25C-C24C 105.9(7) O4C-C26C-O3C 123.7(8) O4C-C26C-C27C 125.4(8) O3C-C26C-C27C 110.9(8) C28C-C27C-C32C 120.1(8) C28C-C27C-C26C 121.3(8) C32C-C27C-C26C 118.5(8) C27C-C28C-C29C 119.4(9) C30C-C29C-C28C 119.7(9) C29C-C30C-C31C 121.1(9) C29C-C30C-Br (7) C31C-C30C-Br (7) C30C-C31C-C32C 119.8(8) C31C-C32C-C27C 119.9(8) C7C-N1C-C8C 120.8(6) C13C-O2C-C14C 114.5(6) C26C-O3C-C25C 115.7(7) C6D-C1D-C2D 121.0(7) C6D-C1D-Br (6) C2D-C1D-Br (6) C3D-C2D-C1D 118.5(7) C2D-C3D-C4D 121.0(7) C5D-C4D-C3D 119.2(7) C5D-C4D-C7D 122.5(7) C3D-C4D-C7D 118.3(7) C4D-C5D-C6D 120.4(7) C5D-C6D-C1D 119.8(8) O1D-C7D-N1D 123.5(7) S26

27 O1D-C7D-C4D 122.0(7) N1D-C7D-C4D 114.5(7) C9D-C8D-N1D 122.6(7) C9D-C8D-C13D 118.6(6) N1D-C8D-C13D 118.7(6) C10D-C9D-C8D 118.5(7) C11D-C10D-C9D 123.7(7) C10D-C11D-C12D 118.2(6) C10D-C11D-C19D 120.8(6) C12D-C11D-C19D 121.0(6) C13D-C12D-C11D 118.6(7) C13D-C12D-C15D 120.4(7) C11D-C12D-C15D 121.0(6) O2D-C13D-C12D 121.1(6) O2D-C13D-C8D 116.5(6) C12D-C13D-C8D 122.2(7) C12D-C15D-C16D 115.8(7) C17D-C16D-C15D 115.3(7) C18D-C17D-C16D 114.9(7) N2D-C18D-C17D 108.8(6) N2D-C18D-C19D 113.0(6) C17D-C18D-C19D 114.0(7) C11D-C19D-C18D 115.3(6) N2D-C20D-C21D 109.2(7) N3D-C21D-C20D 109.7(7) N3D-C22D-C23D 110.0(7) N2D-C23D-C22D 110.4(7) N3D-C24D-C25D 107.1(10) O3D-C25D-C24D 103.5(11) C26D-O3D-C25D 119.5(13) O4D-C26D-O3D 121.7(12) O4D-C26D-C27D 130.1(13) O3D-C26D-C27D 108.1(13) C25F-C24F-N3D 106.6(12) O3F-C25F-C24F 110.9(14) C26F-O3F-C25F 117.1(16) O4F-C26F-O3F 126.2(16) O4F-C26F-C27D 111.7(16) O3F-C26F-C27D 122.0(17) C32D-C27D-C28D 120.8(9) C32D-C27D-C26F 134.3(13) C28D-C27D-C26F 104.7(12) C32D-C27D-C26D 109.8(11) C28D-C27D-C26D 128.8(10) C29D-C28D-C27D 120.2(9) C28D-C29D-C30D 118.8(9) C31D-C30D-C29D 120.5(8) C31D-C30D-Br (6) C29D-C30D-Br (7) C30D-C31D-C32D 119.6(8) C27D-C32D-C31D 119.8(9) C7D-N1D-C8D 124.9(6) C23D-N2D-C18D 115.3(6) C23D-N2D-C20D 110.0(6) C18D-N2D-C20D 114.2(6) C22D-N3D-C24D 126.7(9) C22D-N3D-C21D 111.0(7) C24D-N3D-C21D 110.7(9) C22D-N3D-C24F 95.1(9) C21D-N3D-C24F 113.3(11) C13D-O2D-C14D 116.3(6) S27

28 Table 7. Selected torsion angles ( ) for 31. C18C-N2C-C20C-C21C 158.8(13) C23C-N2C-C20C-C21C 42.8(19) N2C-C20C-C21C-N3C 35(2) C20C-C21C-N3C-C24C (12) C20C-C21C-N3C-C22C -71.5(14) C21C-N3C-C22C-C23C 43.1(18) C24C-N3C-C22C-C23C 155.4(14) C18C-N2C-C23C-C22C 171.9(13) C20C-N2C-C23C-C22C -70.5(15) N3C-C22C-C23C-N2C 30(2) N2C- C18C-N2E-C23E -47(3) C17C-C18C-N2E-C23E -67.0(15) C19C-C18C-N2E-C23E 165.8(11) N2C-C18C-N2E-C20E 64(3) C17C- C18C-N2E-C20E 43.7(17) C19C-C18C-N2E-C20E -83.6(15) C23E-N2E-C20E-C21E -35(2) C18C-N2E-C20E-C21E (14) N2E-C20E-C21E-N3E -45(2) C20E-C21E-N3E-C24C 179.7(13) C20E-C21E-N3E-C22E 80.9(14) C21E-N3E-C22E-C23E -43.5(15) C24C-N3E-C22E-C23E (13) C18C-N2E-C23E-C22E (13) C20E-N2E-C23E-C22E 70.9(17) N3E-C22E-C23E-N2E -30(2) C21C- N3C-C24C-C25C -53.9(14) C22C-N3C-C24C-C25C (11) C21C-N3C-C24C-N3E 41.0(14) C22C-N3C-C24C-N3E -57.4(14) C21E-N3E-C24C-N3C -32.9(13) C22E-N3E-C24C-N3C 59.4(14) C21E-N3E-C24C-C25C 65.4(14) C22E-N3E-C24C-C25C 157.7(11) N3C-C24C-C25C-O3C (9) N3E-C24C-C25C-O3C 167.5(9) O4C-C26C-C27C-C28C (9) O3C-C26C-C27C-C28C 24.0(11) O4C-C26C-C27C-C32C 22.5(13) O3C-C26C-C27C-C32C (8) C32C-C27C-C28C-C29C -2.6(12) C26C-C27C-C28C-C29C 175.4(8) C27C-C28C-C29C-C30C 1.7(12) C28C-C29C-C30C-C31C 0.2(12) C28C-C29C-C30C-Br (6) C29C-C30C-C31C-C32C -1.1(13) Br6-C30C-C31C-C32C 179.0(6) C30C-C31C-C32C-C27C 0.2(13) C28C-C27C-C32C-C31C 1.7(13) C26C-C27C-C32C-C31C (8) O1C-C7C-N1C-C8C -8.6(12) C4C-C7C-N1C-C8C 171.0(7) C13C-C8C-N1C-C7C -68.4(10) C9C-C8C-N1C-C7C 114.7(8) C8C-C13C-O2C-C14C -91.0(8) C12C-C13C-O2C-C14C 88.8(8) O4C-C26C-O3C-C25C 2.1(13) C27C-C26C-O3C-C25C (8) C24C-C25C-O3C-C26C (8) C6D-C1D-C2D-C3D 2.8(12) Br7-C1D-C2D-C3D (6) C1D-C2D-C3D-C4D -1.8(12) C2D-C3D-C4D-C5D 1.7(12) C2D-C3D-C4D-C7D (7) C3D-C4D-C5D-C6D -2.5(13) C7D-C4D-C5D-C6D 178.6(8) C4D-C5D-C6D-C1D 3.4(13) C2D-C1D-C6D-C5D -3.6(13) Br7-C1D-C6D-C5D 179.2(7) C5D-C4D-C7D-O1D (9) C3D-C4D-C7D-O1D 37.2(12) C5D-C4D-C7D-N1D 35.7(11) C3D-C4D-C7D-N1D (8) N1D-C8D-C9D-C10D 176.8(7) C13D-C8D-C9D-C10D -0.5(11) C8D-C9D-C10D-C11D 1.7(11) C9D-C10D-C11D-C12D 0.3(11) C9D-C10D-C11D-C19D 179.9(7) C10D-C11D-C12D-C13D -3.5(10) C19D-C11D-C12D-C13D 176.9(7) C10D-C11D-C12D-C15D 176.2(7) C19D-C11D-C12D-C15D -3.4(11) C11D-C12D-C13D-O2D 179.6(6) C15D-C12D-C13D-O2D -0.1(11) C11D-C12D-C13D-C8D 4.8(11) C15D-C12D-C13D-C8D (7) C9D-C8D-C13D-O2D (7) N1D-C8D-C13D-O2D 4.7(10) C9D-C8D-C13D-C12D -2.7(11) N1D-C8D-C13D-C12D 179.8(7) C13D-C12D-C15D-C16D (8) C11D-C12D-C15D-C16D 64.8(10) C12D-C15D-C16D-C17D -78.5(10) C15D-C16D-C17D-C18D 62.4(11) C16D-C17D-C18D-N2D 169.1(8) C16D-C17D-C18D-C19D -63.9(10) C10D-C11D-C19D-C18D 119.6(8) C12D-C11D-C19D-C18D -60.8(9) N2D-C18D-C19D-C11D (6) C17D-C18D-C19D-C11D 79.9(8) N2D-C20D-C21D-N3D 58.2(10) N3D-C22D-C23D-N2D -58.4(9) S28

29 N3D-C24D-C25D-O3D 165.8(12) C24D-C25D-O3D-C26D (15) C25D-O3D-C26D-O4D -7(3) C25D-O3D-C26D-C27D 175.6(13) N3D-C24F-C25F-O3F (15) C24F-C25F-O3F-C26F -79(2) C25F- O3F-C26F-O4F -1(4) C25F-O3F-C26F-C27D 175.3(18) O4F-C26F-C27D-C32D -1(3) O3F-C26F-C27D-C32D (15) O4F-C26F-C27D-C28D (18) O3F-C26F-C27D-C28D 7(2) O4F- C26F-C27D-C26D 28.1(19) O3F-C26F-C27D-C26D -149(4) O4D- C26D-C27D-C32D 7(2) O3D-C26D-C27D-C32D (12) O4D-C26D-C27D-C28D 177.2(17) O3D-C26D-C27D-C28D -6(2) O4D- C26D-C27D-C26F -152(4) O3D-C26D-C27D-C26F 25(2) C32D- C27D-C28D-C29D 4.1(16) C26F-C27D-C28D-C29D (13) C26D-C27D-C28D-C29D (13) C27D-C28D-C29D-C30D -1.3(15) C28D-C29D-C30D-C31D -3.4(14) C28D-C29D-C30D-Br (7) C29D-C30D-C31D-C32D 5.4(13) Br8-C30D-C31D-C32D (6) C28D-C27D-C32D-C31D -2.0(14) C26F-C27D-C32D-C31D (16) C26D-C27D-C32D-C31D 169.4(10) C30D-C31D-C32D-C27D -2.7(13) O1D-C7D-N1D-C8D -1.2(13) C4D-C7D-N1D-C8D 179.2(7) C9D-C8D-N1D-C7D 47.0(11) C13D-C8D-N1D-C7D (8) C22D-C23D-N2D-C18D (7) C22D-C23D-N2D-C20D 58.1(8) C17D-C18D-N2D-C23D 74.4(8) C19D-C18D-N2D-C23D -53.2(9) C17D-C18D-N2D-C20D (7) C19D-C18D-N2D-C20D 75.6(8) C21D-C20D-N2D-C23D -58.4(8) C21D-C20D-N2D-C18D 170.2(7) C23D-C22D-N3D-C24D (10) C23D-C22D-N3D-C21D 58.8(10) C23D-C22D-N3D-C24F 176.1(11) C25D-C24D-N3D-C22D -69.4(16) C25D-C24D-N3D-C21D 70.0(14) C25D-C24D-N3D-C24F -31.6(15) C20D-C21D-N3D-C22D -59.6(10) C20D-C21D-N3D-C24D 154.4(9) C20D-C21D-N3D-C24F (10) C25F-C24F-N3D-C22D (15) C25F-C24F-N3D-C24D 30.0(15) C25F-C24F-N3D-C21D -64.1(18) C12D-C13D-O2D-C14D 72.4(9) C8D-C13D-O2D-C14D (7) S29

30 Table 8. Anisotropic atomic displacement parameters (Å 2 ) for 31. The anisotropic atomic displacement factor exponent takes the form: -2π 2 [ h 2 a* 2 U hka* b* U 12 ] U 11 U 22 U 33 U 23 U 13 U 12 Br (5) (4) (4) (3) (3) (4) Br (7) (6) (5) (4) (4) (5) C1A 0.030(5) 0.020(4) 0.027(4) (3) 0.004(4) 0.000(3) C2A 0.021(4) 0.045(5) 0.022(4) (4) (3) (4) C3A 0.013(4) 0.034(4) 0.035(4) (4) (3) (3) C4A 0.015(4) 0.031(4) 0.025(4) (3) (3) 0.003(3) C5A 0.016(4) 0.039(5) 0.029(4) (4) (3) (3) C6A 0.020(4) 0.038(5) 0.032(5) (4) 0.003(4) (4) C7A 0.027(5) 0.037(4) 0.029(4) (4) (4) (4) C8A 0.018(4) 0.032(4) 0.025(4) (3) 0.003(3) (3) C9A 0.011(4) 0.037(4) 0.026(4) (3) (3) (3) C10A 0.017(4) 0.037(5) 0.033(4) (4) (3) 0.001(3) C11A 0.018(4) 0.036(4) 0.019(4) (3) 0.001(3) (3) C12A 0.021(4) 0.033(4) 0.030(4) (3) (3) 0.000(3) C13A 0.019(4) 0.033(4) 0.029(4) (3) (3) 0.002(3) C14A 0.021(5) 0.037(5) 0.044(5) (4) 0.001(4) 0.006(4) C15A 0.027(5) 0.034(4) 0.038(5) (4) (4) 0.001(4) C16A 0.034(5) 0.029(4) 0.031(4) (3) (4) 0.007(4) C17A 0.030(5) 0.035(5) 0.040(5) (4) (4) 0.008(4) C18A 0.028(4) 0.027(4) 0.016(3) 0.001(3) (3) (3) C19A 0.036(5) 0.030(4) 0.034(4) (3) (4) (4) C20A 0.042(5) 0.038(5) 0.019(4) (3) (4) (4) C21A 0.033(5) 0.037(4) 0.017(4) (3) 0.003(3) (4) C22A 0.026(5) 0.041(5) 0.032(4) (4) (4) (4) C23A 0.028(5) 0.051(5) 0.019(4) (4) (3) (4) C24A 0.025(5) 0.044(5) 0.027(4) (4) (4) (4) C25A 0.033(5) 0.043(5) 0.020(4) (3) (3) (4) C26A 0.022(5) 0.041(5) 0.023(4) (3) 0.006(3) 0.000(4) C27A 0.037(5) 0.023(4) 0.015(4) (3) 0.006(3) (3) C28A 0.030(5) 0.057(6) 0.028(5) (4) 0.007(4) (4) C29A 0.042(6) 0.051(6) 0.032(5) (4) 0.005(4) (5) C30A 0.063(7) 0.030(4) 0.020(4) (3) (4) (4) C31A 0.035(5) 0.054(6) 0.036(5) (4) 0.002(4) (4) C32A 0.046(6) 0.052(5) 0.015(4) (4) 0.008(4) (4) N1A 0.016(3) 0.044(4) 0.022(3) (3) (3) 0.007(3) N2A 0.032(4) 0.033(4) 0.029(4) (3) (3) (3) N3A 0.025(4) 0.032(3) 0.025(3) (3) (3) (3) O1A 0.023(4) 0.105(6) 0.019(3) 0.008(3) 0.008(3) 0.007(4) O2A 0.028(3) 0.042(3) 0.025(3) (2) (2) 0.011(3) O3A 0.038(3) 0.043(3) 0.020(3) (2) (2) (3) O4A 0.034(4) 0.058(4) 0.027(3) (3) (3) (3) Br (6) (5) (4) (4) (4) (4) Br (7) (5) (4) (4) (4) (5) C1B 0.033(5) 0.036(4) 0.028(4) (4) (4) 0.009(4) C2B 0.026(5) 0.032(4) 0.032(4) (4) 0.002(4) 0.000(4) S30

31 C3B 0.023(4) 0.037(4) 0.018(4) (3) 0.005(3) (4) C4B 0.017(4) 0.028(4) 0.025(4) (3) 0.002(3) 0.003(3) C5B 0.017(4) 0.035(4) 0.045(5) (4) 0.000(4) 0.002(3) C6B 0.015(4) 0.040(5) 0.047(5) (4) (4) 0.000(4) C7B 0.021(4) 0.031(4) 0.020(4) (3) 0.002(3) 0.001(3) C8B 0.015(4) 0.037(4) 0.025(4) (3) 0.006(3) (3) C9B 0.017(4) 0.024(4) 0.025(4) (3) 0.001(3) 0.002(3) C10B 0.010(4) 0.037(4) 0.037(5) (4) (3) (3) C11B 0.020(4) 0.032(4) 0.028(4) (3) 0.005(3) 0.001(3) C12B 0.015(4) 0.031(4) 0.032(4) (3) 0.002(3) 0.003(3) C13B 0.012(4) 0.037(4) 0.030(4) (3) 0.001(3) 0.001(3) C14B 0.036(5) 0.059(6) 0.032(5) (4) 0.001(4) (4) C15B 0.038(5) 0.036(5) 0.034(5) (4) 0.003(4) 0.002(4) C16B 0.029(5) 0.029(4) 0.042(5) (4) (4) (4) C17B 0.020(4) 0.034(4) 0.037(5) (4) (4) (3) C18B 0.019(4) 0.029(4) 0.027(4) (3) (3) 0.003(3) C19B 0.027(5) 0.036(4) 0.032(4) (4) (3) (4) C20B 0.036(5) 0.038(5) 0.037(5) (4) (4) 0.011(4) C21B 0.042(5) 0.037(5) 0.038(5) (4) (4) 0.001(4) C22B 0.037(5) 0.032(4) 0.029(4) (3) (4) 0.009(4) C23B 0.026(5) 0.045(5) 0.037(5) (4) (4) 0.005(4) C24B 0.029(5) 0.045(5) 0.034(5) (4) (4) 0.001(4) C25B 0.039(6) 0.044(5) 0.030(5) (4) (4) (4) C26B 0.044(6) 0.032(5) 0.048(6) (4) 0.002(5) 0.012(4) C27B 0.052(6) 0.025(4) 0.044(5) (4) 0.003(5) 0.004(4) C28B 0.052(6) 0.033(5) 0.026(5) 0.003(4) 0.014(4) 0.000(4) C29B 0.059(6) 0.029(4) 0.034(5) (4) 0.006(4) (4) C30B 0.064(7) 0.038(5) 0.029(5) (4) 0.002(5) 0.012(5) C31B 0.069(7) 0.026(4) 0.037(5) (4) 0.019(5) 0.005(5) C32B 0.043(5) 0.036(5) 0.036(5) (4) 0.010(4) (4) N1B 0.011(3) 0.040(4) 0.028(3) (3) (3) 0.003(3) N2B 0.020(4) 0.036(4) 0.029(3) (3) (3) 0.003(3) N3B 0.030(4) 0.033(4) 0.034(4) (3) (3) 0.003(3) O1B 0.013(3) 0.054(4) 0.026(3) (3) 0.002(2) (3) O2B 0.028(3) 0.040(3) 0.031(3) (2) 0.002(2) (3) O3B 0.051(4) 0.044(4) 0.025(3) (3) 0.002(3) (3) O4B 0.055(5) 0.044(4) 0.053(4) (3) 0.002(3) (3) Br (6) (6) (4) (4) (4) (5) Br (7) (5) (5) (4) (5) (5) C1C 0.035(5) 0.042(5) 0.031(4) (4) 0.002(4) 0.000(4) C2C 0.025(5) 0.048(5) 0.028(4) (4) (4) (4) C3C 0.019(4) 0.035(4) 0.031(4) (4) (4) (4) C4C 0.014(4) 0.038(4) 0.021(4) (3) 0.000(3) 0.002(3) C5C 0.010(4) 0.033(4) 0.042(5) (4) (3) 0.001(3) C6C 0.021(4) 0.040(5) 0.028(4) (4) 0.016(4) (4) C7C 0.022(5) 0.027(4) 0.027(4) (3) 0.003(3) 0.003(3) C8C 0.011(4) 0.040(5) 0.021(4) (3) (3) (3) C9C 0.026(5) 0.028(4) 0.026(4) (3) (3) (3) C10C 0.026(5) 0.037(5) 0.023(4) (3) 0.000(3) 0.009(4) C11C 0.020(4) 0.037(4) 0.029(4) (4) 0.003(3) 0.006(3) C12C 0.010(4) 0.033(4) 0.034(4) (3) (3) 0.002(3) C13C 0.013(4) 0.037(4) 0.036(4) (4) (3) 0.003(3) C14C 0.036(5) 0.043(5) 0.035(5) (4) 0.002(4) 0.016(4) C15C 0.031(5) 0.046(5) 0.045(5) (4) (4) (4) S31

32 C16C 0.031(5) 0.035(5) 0.051(6) (4) (4) (4) C17C 0.037(5) 0.026(4) 0.042(5) 0.002(4) (4) (4) C18C 0.021(5) 0.042(5) 0.034(5) 0.007(4) (4) (4) C19C 0.021(4) 0.041(5) 0.028(4) (3) 0.003(3) 0.002(3) N2C 0.026(3) 0.043(5) 0.034(3) 0.006(3) (3) (3) C20C 0.027(4) 0.044(5) 0.033(3) 0.005(3) (3) (3) C21C 0.031(5) 0.052(5) 0.034(5) 0.005(5) (5) (5) N3C 0.024(4) 0.044(4) 0.032(3) (4) (3) (3) C22C 0.024(4) 0.040(4) 0.035(4) (4) (3) (4) C23C 0.027(5) 0.037(5) 0.026(5) (4) (4) (4) N2E 0.026(3) 0.043(5) 0.034(3) 0.006(3) (3) (3) C20E 0.027(4) 0.044(5) 0.033(3) 0.005(3) (3) (3) C21E 0.029(5) 0.041(5) 0.031(5) 0.002(4) (4) (4) N3E 0.024(4) 0.044(4) 0.032(3) (4) (3) (3) C22E 0.024(4) 0.040(4) 0.035(4) (4) (3) (4) C23E 0.028(5) 0.047(5) 0.046(5) 0.002(5) (5) (5) C24C 0.030(5) 0.054(6) 0.038(5) (4) (4) (4) C25C 0.036(6) 0.107(9) 0.032(5) (5) (4) (6) C26C 0.038(6) 0.045(5) 0.025(4) (4) (4) 0.008(4) C27C 0.021(5) 0.038(5) 0.042(5) (4) (4) 0.008(4) C28C 0.030(5) 0.039(5) 0.042(5) (4) (4) 0.003(4) C29C 0.044(6) 0.031(4) 0.040(5) (4) (4) (4) C30C 0.054(6) 0.022(4) 0.042(5) (4) (5) 0.002(4) C31C 0.045(6) 0.041(5) 0.033(5) (4) 0.005(4) (4) C32C 0.031(5) 0.043(5) 0.031(5) (4) (4) 0.008(4) N1C 0.014(3) 0.046(4) 0.015(3) (3) 0.000(3) (3) O1C 0.012(3) 0.054(3) 0.023(3) (3) 0.002(2) (2) O2C 0.020(3) 0.036(3) 0.044(3) (3) (2) (2) O3C 0.034(4) 0.073(4) 0.034(3) (3) (3) 0.005(3) O4C 0.027(4) 0.076(5) 0.037(3) (3) (3) (3) Br (6) (6) (4) (4) (4) (4) Br (6) (6) (5) (4) (4) (5) C1D 0.024(5) 0.035(4) 0.026(4) (3) (3) (4) C2D 0.024(5) 0.055(5) 0.023(4) (4) 0.007(3) (4) C3D 0.016(4) 0.040(4) 0.025(4) (3) 0.000(3) (3) C4D 0.024(4) 0.036(4) 0.011(3) (3) 0.007(3) (3) C5D 0.020(5) 0.062(6) 0.020(4) (4) (3) 0.003(4) C6D 0.017(4) 0.057(5) 0.031(5) (4) (4) 0.000(4) C7D 0.021(4) 0.031(4) 0.035(5) (3) (4) (3) C8D 0.019(4) 0.035(4) 0.016(4) (3) 0.005(3) 0.002(3) C9D 0.013(4) 0.034(4) 0.026(4) (3) 0.002(3) (3) C10D 0.010(4) 0.043(5) 0.027(4) (4) 0.001(3) 0.000(3) C11D 0.017(4) 0.024(4) 0.027(4) (3) 0.002(3) 0.004(3) C12D 0.022(4) 0.035(4) 0.019(4) (3) 0.004(3) 0.004(3) C13D 0.016(4) 0.037(4) 0.019(4) (3) 0.003(3) 0.000(3) C14D 0.041(6) 0.051(5) 0.026(4) (4) 0.003(4) (4) C15D 0.048(6) 0.036(5) 0.024(4) (4) (4) (4) C16D 0.045(6) 0.045(5) 0.025(4) (4) (4) (4) C17D 0.050(6) 0.045(5) 0.032(5) 0.002(4) (4) (5) C18D 0.028(5) 0.033(4) 0.025(4) (3) 0.000(3) (3) C19D 0.032(5) 0.031(4) 0.022(4) (3) (3) (3) C20D 0.032(5) 0.041(5) 0.026(4) (4) (4) 0.003(4) C21D 0.037(6) 0.061(6) 0.045(5) (5) (4) 0.012(5) C22D 0.037(5) 0.058(6) 0.023(4) (4) 0.002(4) 0.006(4) S32

33 C23D 0.046(5) 0.034(4) 0.017(4) (3) (4) 0.000(4) C24D 0.039(7) 0.058(7) 0.021(5) (5) (5) (5) C25D 0.041(6) 0.058(6) 0.018(5) (5) (4) (5) O3D 0.039(5) 0.060(5) 0.019(4) (4) 0.001(4) (4) C26D 0.035(7) 0.058(7) 0.018(5) (5) 0.007(5) (6) O4D 0.028(6) 0.074(8) 0.031(6) (6) (5) (6) C24F 0.044(7) 0.052(7) 0.020(6) (6) (6) (6) C25F 0.043(6) 0.056(6) 0.018(5) (5) (5) (5) O3F 0.040(7) 0.055(7) 0.017(5) (5) (5) (5) C26F 0.037(7) 0.053(7) 0.018(5) (6) 0.003(6) (6) O4F 0.033(8) 0.050(8) 0.028(7) (7) (6) 0.006(7) C27D 0.043(6) 0.064(6) 0.031(5) (5) 0.001(5) 0.030(5) C28D 0.079(9) 0.063(7) 0.033(6) 0.002(5) 0.022(6) 0.024(6) C29D 0.025(5) 0.046(5) 0.054(6) (5) 0.002(4) (4) C30D 0.039(6) 0.031(4) 0.033(5) (4) (4) (4) C31D 0.045(6) 0.034(5) 0.025(4) (4) (4) 0.003(4) C32D 0.039(6) 0.056(6) 0.042(5) (5) (4) 0.014(5) N1D 0.013(3) 0.053(4) 0.022(3) (3) (3) (3) N2D 0.025(4) 0.032(3) 0.025(3) (3) 0.001(3) (3) N3D 0.045(5) 0.085(6) 0.039(4) (4) (4) 0.022(4) O1D 0.020(3) 0.070(4) 0.029(3) 0.002(3) (3) (3) O2D 0.042(4) 0.050(3) 0.020(3) (3) 0.008(3) (3) O1W 0.066(5) 0.083(5) 0.069(5) (4) (4) 0.003(4) O2W 0.119(18) 0.090(14) 0.060(12) (10) (10) (11) S33

34 Table 9. Hydrogen atom coordinates and isotropic atomic displacement parameters (Å 2 ) for 31. x/a y/b z/c U H2A H3A H5A H6A H9A H10A H14A H14B H14C H15A H15B H16A H16B H17A H17B H18A H19A H19B H20A H20B H21A H21B H22A H22B H23A H23B H24A H24B H25A H25B H28A H29A H31A H32A H1A H2B H3B H5B H6B H9B H10B H14D H14E H14F H15C H15D S34

35 H16C H16D H17C H17D H18B H19C H19D H20C H20D H21C H21D H22C H22D H23C H23D H24C H24D H25C H25D H28B H29B H31B H32B H1B H2C H3C H5C H6C H9C H10C H14G H14H H14I H15E H15F H16E H16F H17E H17F H18C H19E H19F H20E H20F H21E H21F H22E H22F H23E H23F H20G H20H H21G H21H S35