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1 Supplementary information doi: /nchem.215 Concise Synthesis of a Ricciocarpin A and Discovery of a More Potent Analogue Anna Michrowska and Benjamin List Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, D Mülheim an der Ruhr, Germany list@mpi-muelheim.mpg.de General: Unless otherwise stated, all reagents were purchased from commercial suppliers and used without further purification. All solvents used in the reactions were distilled from appropriate drying agents prior to use. Analytical thin-layer chromatography (TLC) was performed on silica gel precoated glass plates (0.25 mm thickness, 60F-254, E. Merck). Visualization was accomplished by irradiation with a UV light at 254 nm. Flash chromatography was performed using silica gel 60 ( mm) from Merck. Proton and carbon NMR spectra were recorded on a Bruker AV-400, Bruker AV-500 spectrometer in CDCl 3. Proton chemical shifts are reported in ppm ( ) relative to tetramethylsilane (TMS) with the solvent resonance employed as the internal standard (CDCl 3, 7.26 ppm). Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, q = quartet, m = multiplet), coupling constants (Hz) and integration. 13 C chemical shifts are reported in ppm from tetramethylsilane (TMS) with the solvent resonance as the internal standard (CDCl 3, 77.0 ppm). Mass spectra were obtained on a Finnigan MAT 8200 (70 ev), accurate mass determinations were done on a Bruker APEX III FT-MS (7 T magnet). The enantiomeric excesses were determined by HPLC analysis employing a chiral stationary phase column (Daicel Co. Chiralcel unless otherwise noted) specified in the individual experiment, by comparing the samples with the appropriate racemic mixtures. Compounds 3, 1 6, 1 9, 2 10, 3 and catalyst 7 4 are known and the spectroscopic data are in agreement with the literature. Compounds: 4, 5, Grubbs second generation catalyst, and Sm(O i Pr) 3 are commercially available. For the young B. glabrata snails (not specified whether albino or pigmented) of average shell diameter size 8mm which were feed with lettuce and fish food pellets it is reported that LC 100 of (+)-Ricciocarpin A is 11 g/ml. 5 1 K. Agapiou, M. J. Krische, Org. Lett., 2003, 5, J.Woon Yang, B. List, Org. Lett. 2006, 8, Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, K. Grela, S. Harutyunyan, A. Michrowska, Angew. Chem. Int. Ed. 2002, 41, Wurzel, G., Becker, H., Eicher, H. T. & Tiefensee, K. Planta Med. 1990, 56, nature chemistry 1

2 Experimental procedures: I. Stepwise synthesis of Ricciocarpin A: (2E, 7E)-9-(furan-3-yl)-6,6-dimethyl-9-oxononan-2,7-dienal (3) To a solution of 6 (0.23 g, 1.09 mmol) and crotonaldehyde (8, 0.23 g, 3.28 mmol, 0.27 ml) in CH 2 Cl 2 (10 ml, c = 0.1M) was added a solution of a Ru-catalyst 7 (0.01 g, 0.02 mmol, 2 mol%) in CH 2 Cl 2 (1 ml). The resulting mixture was stirred at 40 C for 24 h. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (10% AcOEt/hexane) to give 0.24 g (90% yield) of 3 as an oil. (1S, 2R)-2-(2-(furan-3-yl)-2-oxoethyl)-3,3-dimethylcyclohexanecarbaldehyde (2) To a solution of enal enone 3 (0.05 g, 0.21 mmol) and imidazolidinone organocatalyst 9 (0.02 g, 0.04 mmol, 20 mol%) in dry 1,4-dioxane (5 ml) was added Hantzsch ester 10 (0.71 g, 0.23 mmol). The reaction mixture was stirred at room temperature for 48 h, after which the solvent was removed and residue was purified by flash chromatography on silica gel (10% AcOEt/hexane) to give 0.04 g of pure product 2 as a white solid (79% yield, mixture of cis : trans = 2:1). The enantiomeric excess was determined to be trans-er = 57.3 and cis-er = by chiral HPLC (ChiralPak AS-H column, 5% i- PrOH/heptane, 0.5 ml/min, 264 nm, t R trans (minor 23.4 min), t R trans (major 53.1 min), t R cis (minor 26.8 min), t R cis (major 30.6 min). The synthesis of the racemic compound was performed according to the above mentioned procedure at room temperature using dibenzylammonium trifluoroacetate (20 mol%) as the catalyst. 1 H NMR (CDCl 3, 400 MHz): 0.81 (s, 3H, cis), 0.87 (s, 3H, trans), 0.91 (s, 3H, trans), 1.07 (s, 3H, cis) 1.22 ± 1.31 (m, 2H), 1.31 ± 1.40 (m, 2H), 1.41 ± 1.55 (m, 4H), 1.55 ± 1.64 (m, 2H), 1.64 ± 1.77 (m, 2H), 2.16 (ddd, J = 4.3 Hz, J = 8.6 Hz, J = 11.0 Hz,1H, trans), 2.37 (ddd, J = 3.4 Hz, J = 6.9 Hz, J = 11.0 Hz, 1H, trans), 2.54 (m, 1H, trans), 2.60 (dd, J = 5.9 Hz, J = 17.4 Hz, 1H, cis), 2.66 ± 2.79 (m, 2H), 2.83 (dd, J = 3.3 Hz, J = 18.2 Hz, 1H, trans), 2.90 (dd, J = 5.9 Hz, J = 17.4 Hz, 1H, cis), 6.73 (apparent dd, J = 0.7 Hz, J = 1.9 Hz, 1H, trans), 6.75 (apparent dd, apparent dd, J = 0.7 Hz, J = 1.9 Hz, 1H cis), 7.41 (apparent t, J = 1.6 Hz, 1H, trans), 7.42 (apparent t, J = 1.6 Hz, 1H cis), 8.01 (apparent t, J = 1.1 Hz, 1H, trans), 8.04 nature chemistry 2

3 (apparent t, J = 1.1 Hz, 1H cis), 9.35 (d, J = 4.3 Hz, 1H, trans), 9.72 (s, 1H, cis); 13 C NMR (CDCl 3, 125 MHz): 20.21, 20.27, 20.40, 22.28, 26.38, 27.78, 28.20, 30.25, 32.93, 33.54, 37.56, 39.11, 40.27, 40.65, 49,79, 53.65, , , , , , , , , , , ; MS (GC/MS, 70 ev): m/z (%) = 248 (2) [M + ], 220 (13), 110 (100), 95 (57); MS (EI) m/z 248 (M + ); HRMS calculated for (C 15 H 20 O 3 Na 1 ) , found Ricciocarpin A ((+)-1) A solution of keto aldehyde 2 (19.9 mg, mmol) in dry toluene at 0 C was treated with diisobutylaluminium methoxide (prepared by addition of excess of MeOH to DIBAL {1M solution in toluene, 1.2 equiv.} at 0 C). 6 The reaction mixture was allowed to warm to RT and stirred for 4 h. Solvent was removed in vacuo. Water and diethyl ether was added, water phase was extracted twice with diethyl ether. The combined organic layer were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (10% AcOEt/hexane) to give 19.0 mg (96% yield) of (+)-1 as a white crystalline solid. All analytical data proved to be identical to that of the naturally occurring enantiomer of ricciocarpin A, natural (+)-1: [ ] D 20 = (c=1.18 in CH 2 Cl 2 ), mp= o C: [ ] D 20 = (c 0.5, CH 2 Cl 2 ) [natural 1 7 : [ ] D 25 = (c 1.18, CH 2 Cl 2 )]; mp 109 C; IR (neat): max 2967, 2937, 1718, 1501, 1368, 1275, 1235, 1185 cm -1 ; 1 H NMR (CDCl 3, 500 MHz): 0.92 (s, 6H), 1.19 (apparent dt, Jd = 4.1 Hz, Jt = 14.3 Hz, 1H), 1.34 (apparent qd, Jd = 4.5 Hz, Jq = 13.6 Hz, 1H), 1.43 ± 1.59 (m, 3H), 1.62 ± 1.70 (m, 1H), 1.93 (ddd, J = 4.6 Hz, J = 6.9 Hz, J = 14.3 Hz, 1H), 2.06 (apparent td, Jt = 9.3 Hz, Jd =14.3 Hz, 1H), 2.16 ± 2.24 (m, 1H), 2.41 (apparent dt, Jd = 3.5 Hz, Jt = 12.3 Hz, 1H), 5.27 (dd, J = 4.6 Hz, J = 9.5 Hz, 1H), 6.41 (s, 1H), 7.42 (s, 1H), 7.45 (s, 1H); 13 C NMR (CDCl 3, 125 MHz): (CH), (CH 2 ), (CH 2 ), (CH), (CH 2 ), 33.71, (CH), (CH 2 ), (CH), (CH), (CH), , (CH), (CH), ; MS (EI) m/z 248 (M + ); HRMS calculated for (C 15 H 20 O 3 ) , found ; elemental analysis calcd (%) for C 15 H 20 O 3 : C 72.55, H 8.12, O found: C 72.30, H 8.16, O HPLC: er = 1249 The er was measured with Chiralpak AS-RH column, mobile phase was MeOH/H 2 O = 90:10 (v/v), flow: 0.5 ml/min, UV detector: 220 nm. Major enantiomer t1 = 7.82 minor enantiomer t2 = 8.76 min. 6 G. L. Lange, M. G. Organ, Synlett, 1991, G. Wurzel, H. Becker, Phytochemistry 1990, 29, nature chemistry 3

4 II. One pot synthesis of Ricciocarpin A: Keto aldehyde 3 (0.05 g, 0.21 mmol) was dissolved in dry dioxane (5 ml) and treated with 9 (0.01 g, 0.04 mmol, 20%) and 10 (0.07 g, 0.23 mmol, 1.1 equiv.). The resulting reaction mixture was stirred at room temperature until the starting material had disappeared (72h). Next, solid Sm(OiPr) 3 (0.08 g, 0.24 mmol, 1.2 equiv.) was added and the reaction was stirred for an additional 4h. The solution was then concentrated in vacuo and purified by chromatography on silica gel (10% AcOEt/hexane). Lactone (+)-1 was obtained as a white crystalline solid (0.02 g, 0.10 mmol, 48%). Ricciocarpin A analogues: O O (-)-1 O The compound was prepared using the same one pot method as (+)-1, white crystalline solid (43%). [ ] 20 D = 17.1 (c 0.86, CH 2 Cl 2 ); mp 110 C; all other analytical data proved to be identical to (+)-ricciocarpin A HPLC: er = 906 The er was measured with Chiralpak AS-RH column, mobile phase was MeOH/H 2 O = 90:10 (v/v), flow: 0.5 ml/min, UV detector: 220 nm. Major enantiomer t1 = 8.76 minor enantiomer t2 = 7.84 min. H O O H 11 O The compound was prepared using the same one pot method as (+)-1, white crystalline solid (42%). [ ] D 20 = (c 0.85, CHCl 3 ) ; 1 H NMR (CDCl 3, 500 MHz): 0.91 (s, 3H), 0.93 (s, 3H), 1.15 ± 1.25 (m, 2H), 1.34 (apparent qd, Jd = 4.5 Hz, Jq = 13.6 Hz, 1H), 1.43 ± 1.49 (m, 2H), 1.54 ± 1.62 (m, 1H), 1.62 ± 1.69 (m, 1H), 1.92 (ddd, J = 4.8 Hz, J =7.1 Hz, J = 11.7 Hz, 1H), 2.16 ± 2.22 (m, 1H), 2.30 (dt, Jt = 9.3 Hz, Jd =14.4 Hz, 1H), 2.38 (apparent td, Jt = 3.7 Hz, Jd =12.4 Hz, 1H), 5.29 (dd, J = 4.8 Hz, J = 9.7 Hz, 1H), 6.33 ± 6.39 (m, 2H)), 7.40 (s, 1H); 13 C NMR (CDCl 3, 125 MHz): 18.51, 20.96, 27.17, 27.31, 29.63, 33.70, 38.86, 40.46, 42.27, 71.76, , , , , ; MS (EI) m/z 248 (M + ); HRMS (ESI) calculated for (C 15 H 20 O 3 Na + ) , found nature chemistry 4

5 HPLC: dr = 48; Diastereoseletivity was determined by HPLC analysis using an achiral separation with reversed-phase column Nucleodur C 18ec (125 x 4.0 mm), mobile phase MeOH/H 2 O = 70:30 (v/v), flow: 0.5 ml/min, UV detector: 220 nm. Major isomer: t1 = 9.96 min, minor isomer t2 = 9.12 min. In a second run this diastereoisomers were switched by a column switching valve, directly to the chiral column. Trans-er = 81 (major); The er was measured with Chiralpak AS-RH column, mobile phase was MeOH/H 2 O = 90:10 (v/v), flow: 0.5 ml/min, UV detector: 220 nm. Major enantiomer trans, t1 = 12.18, minor enantiomer trans t2 = min, enantiomer cis t3 = min. H O O H 12 S The compound was prepared using the same one pot method as (+)-1, white crystalline solid (40%). 1 H NMR (CDCl 3, 500 MHz): 0.93 (s, 6H), 1.19 (apparent dt, Jd = 4.2 Hz, Jt = 13.4 Hz, 1H), 1.34 (apparent dq, Jd = 4.2 Hz, Jq = 13.4 Hz, 1H), 1.43 ± 1.49 (m, 2H), 1.57 ± 1.63 (m, 1H), 1.63 ± 1.70 (m, 1H), 2.05 (ddd, J = 5.1 Hz, J = 7.0 Hz, J = 12.4 Hz, 1H), 2.16 ± 2.26 (m, 2H), 2.43 (apparent dt, Jd = 3.9 Hz, Jt = 12.4 Hz, 1H), 5.51 (dd, J = 4.5 Hz, J = 10.2 Hz, 1H), 7.00 (apparent t, J = 3.9 Hz, 1H), 7.05 (apparent d, J = 3.4 Hz, 1H), 7.31 (d, J = 5.1 Hz, 1H); 13 C NMR (CDCl 3, 125 MHz): (CH), (CH 2 ), (CH 2 ), (CH), (CH 2 ), 33.79, (CH), (CH 2 ), (CH), (CH), (CH), (CH), (CH), , ; MS (EI) m/z 264 (M + ); HRMS (ESI) calculated for (C 15 H 20 O 2 SNa + ) , found ; HPLC: dr = 6; Diastereoseletivity was determined by HPLC analysis using an achiral separation with reversed-phase column Nucleodur C 18ec (125 x 4.0 mm), mobile phase MeOH/H 2 O = 75:25 (v/v), flow: 0.5 ml/min, UV detector: 220 nm. Major isomer: t1 = 8.68 min, minor isomer t2 = 7.84 min. In a second run this diastereoisomers were switched by a column switching valve, directly to the chiral column. trans-er = 41 (major), cis-er = 120 (minor ); The er was measured with Chiralpak AS-RH column, mobile phase was MeOH/H 2 O = 90:10 (v/v), flow: 0.5 ml/min, UV detector: 220 nm. Major enantiomer trans, t1 = 21.24, minor enantiomer trans t2 = min, major enantiomer cis t3 = min, minor enantiomer ci t2 = A one pot procedure where diisobutylaluminium methoxide was used instead of Sm(OiPr) 3 HPLC: dr = 42; Diastereoseletivity was determined by HPLC analysis using an achiral separation with reversed-phase column Nucleodur C 18ec (125 x 4.0 mm), mobile phase MeOH/H 2 O = 75:25 (v/v), flow: 0.5 ml/min, UV detector: 220 nm. Major isomer: t1 = 8.29 min, minor isomer t2 = 7.52 min. In a second run this diastereoisomers were switched by a column switching valve, directly to the chiral column. Trans-er = 28 (major), cis-er >999 (minor ); The er was measured with Chiralpak AS-RH column, mobile phase was MeOH/H 2 O = 90:10 (v/v), flow: 0.5 ml/min, UV detector: 220 nm. Major enantiomer trans, t1 = 21.21, minor enantiomer trans t2 = min, major enantiomer cis t3 = min. nature chemistry 5

6 The compound was prepared using the same one pot method as (+)-1, white crystalline solid (30%). 1 H NMR (CDCl 3, 500 MHz): 1.09 ± 1.36 (m, 4H), 1.51 ± 1.62 (m, 1H), 1.63 ± 1.71 (m, 1H), 1.72 ± 1.82 (m, 1H), 2.04 ± 2.20 (m, 3H), 5.34 (dd, J = 5.3 Hz, J = 9.2 Hz, 1H), 7.20 ± 7.32 (m, 5H); 13 C NMR (CDCl 3, 125 MHz): 25.54, 25.61, 26.77, 34.03, 34.26, 37.24, 43.77, 77.74, , , , 140.0, ; MS (EI) m/z 230 (M + ). HRMS calculated for (C 15 H 18 O 2 ) , found; ; HPLC: dr = 140; Diastereoseletivity was determined by HPLC analysis using an achiral separation with reversed-phase column Nucleodur C 18ec (125 x 4.0 mm), mobile phase MeOH/H 2 O = 70:30 (v/v), flow: 0.5 ml/min, UV detector: 220 nm. Major isomer: t1 = 9.70 min, minor isomer t2 = 8.64 min. In a second run this diastereoisomers were switched by a column switching valve, directly to the chiral column. Trans-er = 999; The er was measured with Chiralcel OD-RH column, mobile phase was MeOH/H 2 O = 90:10 (v/v), flow: 0.5 ml/min, UV detector: 220 nm. Major enantiomer, t1 = The compound was prepared using the same one pot method as (+)-1, white crystalline solid (30%). 1 H NMR (CDCl 3, 500 MHz): 0.87 (s, 3H), 1.00 (s, 3H), 1.33 ± 1.42 (m, 1H), 1.51 ± 1.55 (m, 2H), 1.83 ± 1.92 (m, 1H), 2.03 ± 2.26 (m, 3H), 2.26 (ddd, J = 2.7 Hz, J = 7.3 Hz, J = 14.2 Hz, 1H), 2.98 (q, J = 10.0 Hz, 1H), 5.57 ± 5.61 (m, 1H), 6.30 ± 6.33 (m, 1H), 6.35 ± 6.38 (m, 1H), 7.40 (s, 1H); 13 C NMR (CDCl 3, 125 MHz): 22.84, 26.24, 26.81, 28.13, 39.45, 41.62, 41.84, 43.99, 73.78, , , ; MS (EI) m/z 234 (M + ); HRMS (ESI) calculated for (C 14 H 18 O 3 Na + ) , found HPLC: dr = 1810; Diastereoseletivity was determined by HPLC analysis using an achiral separation with reversed-phase column Nucleodur C 18ec (125 x 4.0 mm), mobile phase MeOH/H 2 O = 70:30 (v/v), flow: 0.5 ml/min, UV detector: 220 nm. Major isomer: t1 = 7.44 min, minor isomer t2 = 6.86 min. In a second run this diastereoisomers were switched by a column switching valve, directly to the chiral column. Trans-er = 12; The er was measured with Chiralcel AS-RH column, mobile phase was MeOH/H 2 O = 80:20 (v/v), flow: 0.5 ml/min, UV detector: 220 nm. Major enantiomer, t1 = min, minor enantiomer trans t2 = min. nature chemistry 6

7 X-ray Crystal Structure Analysis of trans-2: C 15 H 20 O 3, M r = g mol -1, colorless plate, crystal size 0.12 x 0.04 x 0.01 mm, orthorhombic, space group P , a = (10) Å, b = (3) Å, c = (3) Å, V = (4) Å 3, Z = 4, D calc = g cm -3, (Mo-K ) = mm -1, = Å, T = 100 K, 2 max = 33.13, measured reflections, 2888 independent reflections, R int = R = 0.042, wr 2 = 0.115, residual electron density 0.6 / -0.6 e Å -3. FR591 rotating anode with graded multilayer mirror and Nonius KappaCCD diffractometer. Structure solution by direct methods and refinement by full-matrix least-squares against F 2, H atoms riding. Absolute structure could not be determined. The following crystal structure has been deposited at the Cambridge Crystallographic Data Centre and allocated the deposition number CCDC C14 O3 C10 C9 C8 C13 C2 O1 C11 C12 C15 C7 C6 C5 O2 C1 C4 C3 nature chemistry 7

8 Table 1. Crystal data and structure refinement Identification code 6065 Empirical formula C 15 H 20 O 3 Color colorless Formula weight g mol -1 Temperature 100 K Wavelength Å Crystal system Orthorhombic Space group P , (no. 19) Unit cell dimensions a = (10) Å = 90. b = (3) Å = 90. c = (3) Å = 90. Volume (4) Å 3 Z 4 Density (calculated) Mg m -3 Absorption coefficient mm -1 F(000) 536 e Crystal size 0.12 x 0.04 x 0.01 mm 3 range for data collection 3.01 to Index ranges -8 h 8, -23 k 23, -23 l 23 Reflections collected Independent reflections 2888 [R int = ] Reflections with I>2 (I) 2620 Completeness to = % Absorption correction Empirical Max. and min. transmission 0.86 and 0.77 Refinement method Full-matrix least-squares on F 2 Data / restraints / parameters 2888 / 0 / 165 Goodness-of-fit on F Final R indices [I>2 (I)] R1 = wr 2 = R indices (all data) R1 = wr 2 = Absolute structure parameter 0.5(11) Largest diff. peak and hole and e Å -3 nature chemistry 8

9 Table 2. Atomic coordinates and equivalent isotropic displacement parameters (Å 2 ). U eq is defined as one third of the trace of the orthogonalized U ij tensor. x y z U eq C(1) (2) (1) (1) 0.015(1) C(2) (2) (1) (1) 0.017(1) C(3) (3) (1) (1) 0.019(1) C(4) (3) (1) (1) 0.018(1) C(5) (2) (1) (1) 0.016(1) C(6) (2) (1) (1) 0.017(1) C(7) (2) (1) (1) 0.015(1) C(8) (3) (1) (1) 0.019(1) C(9) (3) (1) (1) 0.023(1) C(10) (3) (1) (1) 0.026(1) C(11) (3) (1) (1) 0.022(1) C(12) (2) (1) (1) 0.016(1) C(13) (3) (1) (1) 0.024(1) C(14) (3) (1) (1) 0.023(1) C(15) (3) (1) (1) 0.023(1) O(1) (2) (1) (1) 0.019(1) O(2) (2) (1) (1) 0.022(1) O(3) (3) (1) (1) 0.036(1) nature chemistry 9

10 Table 3. Bond lengths [Å] and angles [ ]. C(1)-C(2) (19) C(1)-C(4) (18) C(1)-C(5) (17) C(2)-O(1) (15) C(3)-C(4) 1.349(2) C(3)-O(1) (19) C(5)-O(2) (18) C(5)-C(6) (18) C(6)-C(7) (17) C(7)-C(8) (18) C(7)-C(12) (17) C(8)-C(13) 1.504(2) C(8)-C(9) (19) C(9)-C(10) 1.525(2) C(10)-C(11) 1.528(2) C(11)-C(12) (19) C(12)-C(15) (19) C(12)-C(14) 1.539(2) C(13)-O(3) 1.208(2) C(2)-C(1)-C(4) (11) C(2)-C(1)-C(5) (12) C(4)-C(1)-C(5) (12) C(1)-C(2)-O(1) (12) C(4)-C(3)-O(1) (11) C(3)-C(4)-C(1) (13) O(2)-C(5)-C(1) (12) O(2)-C(5)-C(6) (12) C(1)-C(5)-C(6) (12) C(5)-C(6)-C(7) (11) C(6)-C(7)-C(8) (10) C(6)-C(7)-C(12) (11) C(8)-C(7)-C(12) (10) C(13)-C(8)-C(9) (12) C(13)-C(8)-C(7) (11) C(9)-C(8)-C(7) (11) C(10)-C(9)-C(8) (12) nature chemistry 10

11 C(9)-C(10)-C(11) (11) C(10)-C(11)-C(12) (11) C(15)-C(12)-C(14) (13) C(15)-C(12)-C(11) (11) C(14)-C(12)-C(11) (12) C(15)-C(12)-C(7) (11) C(14)-C(12)-C(7) (12) C(11)-C(12)-C(7) (11) O(3)-C(13)-C(8) (15) C(2)-O(1)-C(3) (11) nature chemistry 11

12 Table 4. Anisotropic displacement parameters (Å 2 ). The anisotropic displacement factor exponent takes the form: -2 2 [ h 2 a* 2 U h k a* b* U 12 ]. U 11 U 22 U 33 U 23 U 13 U 12 C(1) 0.017(1) 0.013(1) 0.013(1) 0.000(1) 0.000(1) 0.000(1) C(2) 0.019(1) 0.016(1) 0.015(1) 0.001(1) 0.000(1) 0.001(1) C(3) 0.023(1) 0.017(1) 0.017(1) 0.002(1) 0.002(1) 0.000(1) C(4) 0.020(1) 0.017(1) 0.017(1) 0.002(1) 0.001(1) (1) C(5) 0.017(1) 0.016(1) 0.014(1) 0.001(1) 0.000(1) (1) C(6) 0.015(1) 0.019(1) 0.017(1) 0.005(1) (1) (1) C(7) 0.015(1) 0.015(1) 0.014(1) 0.001(1) 0.001(1) (1) C(8) 0.020(1) 0.019(1) 0.016(1) (1) 0.000(1) 0.001(1) C(9) 0.026(1) 0.028(1) 0.017(1) 0.000(1) (1) 0.002(1) C(10) 0.032(1) 0.031(1) 0.016(1) 0.007(1) 0.002(1) 0.001(1) C(11) 0.024(1) 0.020(1) 0.023(1) 0.008(1) 0.003(1) 0.001(1) C(12) 0.016(1) 0.015(1) 0.018(1) 0.002(1) 0.002(1) (1) C(13) 0.029(1) 0.023(1) 0.019(1) (1) (1) (1) C(14) 0.017(1) 0.024(1) 0.027(1) 0.002(1) 0.004(1) (1) C(15) 0.027(1) 0.018(1) 0.025(1) (1) 0.004(1) (1) O(1) 0.021(1) 0.020(1) 0.017(1) 0.002(1) (1) 0.002(1) O(2) 0.017(1) 0.027(1) 0.021(1) 0.006(1) (1) (1) O(3) 0.043(1) 0.019(1) 0.046(1) (1) (1) 0.000(1) nature chemistry 12

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