# Electronic Supplementary Material (ESI) for Medicinal Chemistry Communications # This journal is © The Royal Society of Chemistry 2011 data_publication_text _journal_name_full MedChemComm _journal_coden_cambridge 1476 _publ_contact_author_name 'Mats Larhed' _publ_contact_author_address ;Uppsala University Department of Medicinal Chemistry Organic Pharmaceutical Chemistry BMC, Box 574 SE-751 23 Uppsala Sweden ; _publ_contact_author_email mats.larhed@orgfarm.uu.se _publ_contact_author_phone '+46 184714667' _publ_contact_author_fax '+46 184714474' loop_ _publ_author_name _publ_author_address '\"Ohrngren, Per' ;Uppsala University Department of Medicinal Chemistry Organic Pharmaceutical Chemistry BMC, Box 574 SE-751 23 Uppsala Sweden ; 'Wu, Xiongyu' ;Uppsala University Department of Medicinal Chemistry Organic Pharmaceutical Chemistry BMC, Box 574 SE-751 23 Uppsala Sweden ; 'Persson, Magnus' ;Uppsala University Department of Cell and Molecular Biology Structural Biology BMC, Box 596 SE-751 24 Uppsala Sweden ; 'Ekegren, Jenny K.' ;Uppsala University Department of Medicinal Chemistry Organic Pharmaceutical Chemistry BMC, Box 574 SE-751 23 Uppsala Sweden ; 'Wallberg, Hans' ;Medivir AB Lunastigen 7 SE-141 44 Huddinge Sweden ; 'Vrang, Lotta' ;Medivir AB Lunastigen 7 SE-141 44 Huddinge Sweden ; 'Rosenquist, \%Asa' ;Medivir AB Lunastigen 7 SE-141 44 Huddinge Sweden ; 'Samuelsson, Bertil' ;Medivir AB Lunastigen 7 SE-141 44 Huddinge Sweden ; 'Unge, Torsten' ;Uppsala University Department of Cell and Molecular Biology Structural Biology BMC, Box 596 SE-751 24 Uppsala Sweden ; 'Larhed, Mats' ;Uppsala University Department of Medicinal Chemistry Organic Pharmaceutical Chemistry BMC, Box 574 SE-751 23 Uppsala Sweden ; data_wu346 _database_code_depnum_ccdc_archive 'CCDC 818034' #TrackingRef 'Wu346Bnew-MedChemComm.cif' _audit_creation_date 'April 21, 2006' _audit_creation_method SHELXL-97 _chemical_name_systematic ; ? ; # start Validation Reply Form _vrf_PLAT024_wu346 ; PROBLEM: Merging of Friedel Pairs is STRONGLY Indicated RESPONSE: The anomalous dispersion effect is small, the absolute structure has been determined using the known chiral center, therefore the Friedel pairs were merged. ; _vrf_STRVA01_wu346 ; PROBLEM: Flack test results are meaningless RESPONSE: The anomalous dispersion effect is small, the absolute structure has been determined using the known chiral center, therefore the Friedel pairs were merged. ; _vrf_PLAT032_wu346 ; PROBLEM: Std. Uncertainty in Flack Parameter too High ... 0.80 RESPONSE: The anomalous dispersion effect is small. Flack's parameter did not used for absolute structure determination. The absolute structure has been determined using the known chiral center, therefore the Friedel pairs were merged. ; _vrf_PLAT390_wu346 ; PROBLEM: Deviating Methyl C20 X-C-H Bond Angle ...... 116 Deg. RESPONSE: The hydrogen atom of the methyl group was located from Fourier difference synthesis. ; # end Validation Reply Form _chemical_name_common ? _chemical_formula_moiety 'C19 H26 N2 O4' _chemical_formula_sum 'C19 H26 N2 O4' _chemical_formula_weight 346.42 loop_ _atom_type_symbol _atom_type_description _atom_type_scat_dispersion_real _atom_type_scat_dispersion_imag _atom_type_scat_source C C 0.0033 0.0016 'International Tables Vol C Tables 4.2.6.8 and 6.1.1.4' H H 0.0000 0.0000 'International Tables Vol C Tables 4.2.6.8 and 6.1.1.4' N N 0.0061 0.0033 'International Tables Vol C Tables 4.2.6.8 and 6.1.1.4' O O 0.0106 0.0060 'International Tables Vol C Tables 4.2.6.8 and 6.1.1.4' _symmetry_cell_setting Orthorhombic _symmetry_space_group_name_H-M 'P 21 21 21 ' _symmetry_space_group_name_Hall 'P 2ac 2ab ' loop_ _symmetry_equiv_pos_as_xyz 'x, y, z' '-x+1/2, -y, z+1/2' 'x+1/2, -y+1/2, -z' '-x, y+1/2, -z+1/2' _cell_length_a 9.8793(1) _cell_length_b 11.1873(2) _cell_length_c 17.4480(4) _cell_angle_alpha 90.00 _cell_angle_beta 90.00 _cell_angle_gamma 90.00 _cell_volume 1928.40(6) _cell_formula_units_Z 4 _cell_measurement_temperature 293 _cell_measurement_reflns_used 3405 _cell_measurement_theta_min 0.99 _cell_measurement_theta_max 30.00 _chemical_absolute_configuration rm _exptl_crystal_description Prism _exptl_crystal_colour Colourless _exptl_crystal_size_max 0.48 _exptl_crystal_size_mid 0.42 _exptl_crystal_size_min 0.33 _exptl_crystal_density_meas ? _exptl_crystal_density_diffrn 1.193 _exptl_crystal_density_method 'not measured' _exptl_crystal_F_000 744 _exptl_absorpt_coefficient_mu 0.084 _exptl_absorpt_correction_type none _exptl_absorpt_correction_T_min ? _exptl_absorpt_correction_T_max ? _exptl_special_details ; ? ; _diffrn_ambient_temperature 293(2) _diffrn_radiation_wavelength 0.71073 _diffrn_radiation_type MoK\a _diffrn_radiation_source 'fine-focus sealed tube' _diffrn_radiation_monochromator graphite _diffrn_measurement_device_type 'Nonius KappaCCD' _diffrn_measurement_method '\f and \w scans' _diffrn_detector_area_resol_mean ? _diffrn_standards_number ? _diffrn_standards_interval_count ? _diffrn_standards_interval_time ? _diffrn_standards_decay_% ? _diffrn_reflns_number 16378 _diffrn_reflns_av_R_equivalents 0.0307 _diffrn_reflns_av_sigmaI/netI 0.0354 _diffrn_reflns_limit_h_min -13 _diffrn_reflns_limit_h_max 13 _diffrn_reflns_limit_k_min -13 _diffrn_reflns_limit_k_max 15 _diffrn_reflns_limit_l_min -23 _diffrn_reflns_limit_l_max 24 _diffrn_reflns_theta_min 2.37 _diffrn_reflns_theta_max 30.0 _reflns_number_total 5607 _reflns_number_gt 4484 _reflns_threshold_expression >2sigma(I) _computing_data_collection 'KappaCCD (Nonius, 1999)' _computing_cell_refinement 'HKL Scalepack (Otwinowski & Minor 1997)' _computing_data_reduction 'Denzo and Scalepak (Otwinowski & Minor, 1997)' _computing_structure_solution 'SIR92 (Altomare et al., 1994)' _computing_structure_refinement 'SHELXL-97 (Sheldrick, 1997)' _computing_molecular_graphics ? _computing_publication_material ? _refine_special_details ; Refinement of F^2^ against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F^2^, conventional R-factors R are based on F, with F set to zero for negative F^2^. The threshold expression of F^2^ > 2sigma(F^2^) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F^2^ are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger. ; _refine_ls_structure_factor_coef Fsqd _refine_ls_matrix_type full _refine_ls_weighting_scheme calc _refine_ls_weighting_details 'calc w=1/[\s^2^(Fo^2^)+(0.0951P)^2^+0.0312P] where P=(Fo^2^+2Fc^2^)/3' _atom_sites_solution_primary direct _atom_sites_solution_secondary difmap _atom_sites_solution_hydrogens 'geom, diff' _refine_ls_hydrogen_treatment refall _refine_ls_extinction_method none _refine_ls_extinction_coef ? _refine_ls_abs_structure_details 'Flack H D (1983), Acta Cryst. A39, 876-881' _refine_ls_abs_structure_Flack -0.1(8) _refine_ls_number_reflns 5607 _refine_ls_number_parameters 330 _refine_ls_number_restraints 0 _refine_ls_R_factor_all 0.0639 _refine_ls_R_factor_gt 0.0471 _refine_ls_wR_factor_ref 0.1451 _refine_ls_wR_factor_gt 0.1314 _refine_ls_goodness_of_fit_ref 1.040 _refine_ls_restrained_S_all 1.040 _refine_ls_shift/su_max 0.004 _refine_ls_shift/su_mean 0.001 loop_ _atom_site_label _atom_site_type_symbol _atom_site_fract_x _atom_site_fract_y _atom_site_fract_z _atom_site_U_iso_or_equiv _atom_site_adp_type _atom_site_occupancy _atom_site_calc_flag _atom_site_refinement_flags _atom_site_disorder_assembly _atom_site_disorder_group O1 O 0.44163(10) 0.12320(10) 0.48467(7) 0.0409(3) Uani 1 d . . . O23 O 0.33441(11) -0.23175(13) 0.49398(9) 0.0543(3) Uani 1 d . . . N16 N 0.24246(13) -0.01847(12) 0.44423(8) 0.0381(3) Uani 1 d . . . H16 H 0.329(2) -0.0392(19) 0.4475(11) 0.043(5) Uiso 1 d . . . O15 O 0.08627(12) 0.12938(12) 0.44703(10) 0.0588(4) Uani 1 d . . . O6 O 0.55151(17) 0.07656(15) 0.59185(9) 0.0651(4) Uani 1 d . . . N24 N 0.12226(13) -0.28517(14) 0.52553(9) 0.0437(3) Uani 1 d . . . H24 H 0.038(3) -0.273(2) 0.5227(11) 0.048(5) Uiso 1 d . . . C14 C 0.20358(14) 0.09530(14) 0.45064(9) 0.0380(3) Uani 1 d . . . C18 C 0.13847(17) -0.16312(17) 0.35104(10) 0.0438(4) Uani 1 d . . . C25 C 0.1630(3) -0.3858(2) 0.57267(17) 0.0642(6) Uani 1 d . . . H25A H 0.251(6) -0.386(5) 0.581(3) 0.094(17) Uiso 1 d . . . H25B H 0.112(5) -0.384(5) 0.613(3) 0.092(16) Uiso 1 d . . . H25C H 0.147(5) -0.456(5) 0.546(3) 0.093(15) Uiso 1 d . . . C5 C 0.31892(14) 0.18717(14) 0.46238(10) 0.0383(3) Uani 1 d . . . C22 C 0.21088(13) -0.21840(14) 0.48803(9) 0.0362(3) Uani 1 d . . . C13 C 0.5010(2) 0.1279(2) 0.30758(12) 0.0560(5) Uani 1 d . . . H13 H 0.575(3) 0.129(3) 0.3467(18) 0.078(8) Uiso 1 d . . . C8 C 0.37795(18) 0.18690(17) 0.31740(11) 0.0477(4) Uani 1 d . . . C21 C 0.2773(2) -0.1727(2) 0.31352(13) 0.0588(5) Uani 1 d . . . H21A H 0.321(3) -0.095(3) 0.3155(17) 0.081(9) Uiso 1 d . . . H21B H 0.267(3) -0.197(3) 0.261(2) 0.088(9) Uiso 1 d . . . H21C H 0.330(3) -0.231(3) 0.3401(18) 0.078(8) Uiso 1 d . . . C19 C 0.0668(3) -0.2843(3) 0.34776(14) 0.0670(6) Uani 1 d . . . H19A H -0.016(3) -0.276(2) 0.3742(15) 0.060(7) Uiso 1 d . . . H19B H 0.125(3) -0.337(3) 0.3704(18) 0.080(9) Uiso 1 d . . . H19C H 0.043(3) -0.302(3) 0.2926(18) 0.085(8) Uiso 1 d . . . C17 C 0.15234(13) -0.12092(13) 0.43616(9) 0.0338(3) Uani 1 d . . . H17 H 0.0658(17) -0.0957(15) 0.4558(9) 0.024(4) Uiso 1 d . . . C7 C 0.3475(2) 0.25835(16) 0.38903(12) 0.0494(4) Uani 1 d . . . H7A H 0.413(3) 0.321(3) 0.4067(17) 0.082(8) Uiso 1 d . . . H7B H 0.270(3) 0.313(3) 0.3780(18) 0.091(9) Uiso 1 d . . . C2 C 0.45985(18) 0.12808(16) 0.56235(11) 0.0471(4) Uani 1 d . . . C4 C 0.28758(18) 0.26896(17) 0.53066(11) 0.0483(4) Uani 1 d . . . H4A H 0.330(2) 0.346(2) 0.5253(12) 0.043(5) Uiso 1 d . . . H4B H 0.196(3) 0.283(2) 0.5328(13) 0.062(7) Uiso 1 d . . . C3 C 0.3498(2) 0.2023(2) 0.59769(11) 0.0557(4) Uani 1 d . . . H3A H 0.293(3) 0.146(2) 0.6258(14) 0.059(6) Uiso 1 d . . . H3B H 0.394(2) 0.246(2) 0.6376(14) 0.051(6) Uiso 1 d . . . C11 C 0.4312(3) 0.0609(3) 0.18236(15) 0.0740(7) Uani 1 d . . . H11 H 0.445(3) 0.020(3) 0.135(2) 0.089(9) Uiso 1 d . . . C12 C 0.5272(3) 0.0649(2) 0.24031(14) 0.0688(6) Uani 1 d . . . H12 H 0.616(3) 0.028(3) 0.2336(18) 0.082(8) Uiso 1 d . . . C9 C 0.2831(2) 0.1806(2) 0.25842(13) 0.0633(5) Uani 1 d . . . H9 H 0.191(3) 0.226(2) 0.2652(14) 0.062(7) Uiso 1 d . . . C10 C 0.3099(3) 0.1184(3) 0.19147(14) 0.0754(7) Uani 1 d . . . H10 H 0.245(4) 0.120(4) 0.151(2) 0.086(12) Uiso 1 d . . . C20 C 0.0521(2) -0.0721(3) 0.30816(12) 0.0604(5) Uani 1 d . . . H20A H -0.029(4) -0.061(3) 0.3261(18) 0.085(9) Uiso 1 d . . . H20B H 0.042(3) -0.091(3) 0.2507(17) 0.073(8) Uiso 1 d . . . H20C H 0.094(3) -0.002(3) 0.3081(16) 0.068(7) Uiso 1 d . . . loop_ _atom_site_aniso_label _atom_site_aniso_U_11 _atom_site_aniso_U_22 _atom_site_aniso_U_33 _atom_site_aniso_U_23 _atom_site_aniso_U_13 _atom_site_aniso_U_12 O1 0.0310(5) 0.0373(6) 0.0543(7) -0.0007(5) -0.0009(4) -0.0004(4) O23 0.0270(5) 0.0597(8) 0.0763(9) 0.0153(7) -0.0052(5) 0.0004(5) N16 0.0280(6) 0.0343(6) 0.0520(7) -0.0011(5) 0.0002(5) -0.0016(4) O15 0.0347(5) 0.0439(7) 0.0976(11) -0.0066(7) -0.0027(6) 0.0048(5) O6 0.0682(9) 0.0568(8) 0.0704(9) 0.0128(7) -0.0178(7) -0.0004(7) N24 0.0300(6) 0.0459(8) 0.0550(8) 0.0108(6) -0.0047(5) -0.0072(5) C14 0.0333(6) 0.0367(7) 0.0441(8) -0.0018(6) 0.0020(6) -0.0005(5) C18 0.0423(8) 0.0463(9) 0.0428(8) -0.0021(7) -0.0002(6) -0.0050(7) C25 0.0592(12) 0.0518(12) 0.0816(16) 0.0230(11) -0.0114(11) -0.0108(9) C5 0.0316(6) 0.0317(7) 0.0517(9) -0.0006(6) 0.0011(5) 0.0005(5) C22 0.0266(6) 0.0372(7) 0.0448(8) -0.0006(6) -0.0032(5) -0.0024(5) C13 0.0492(9) 0.0588(12) 0.0599(11) 0.0121(9) 0.0101(8) -0.0010(8) C8 0.0488(9) 0.0430(9) 0.0514(9) 0.0155(7) 0.0068(7) -0.0025(7) C21 0.0549(11) 0.0716(14) 0.0498(11) -0.0072(10) 0.0092(8) 0.0036(10) C19 0.0847(16) 0.0639(14) 0.0524(12) -0.0090(10) -0.0096(11) -0.0287(13) C17 0.0263(6) 0.0349(7) 0.0402(7) 0.0001(6) 0.0000(5) -0.0027(5) C7 0.0512(9) 0.0365(8) 0.0605(10) 0.0092(7) 0.0059(8) -0.0016(7) C2 0.0474(8) 0.0400(8) 0.0540(10) 0.0058(7) -0.0027(7) -0.0090(7) C4 0.0429(8) 0.0404(9) 0.0615(11) -0.0109(7) 0.0046(7) 0.0011(7) C3 0.0599(10) 0.0576(12) 0.0495(10) -0.0049(9) 0.0079(8) -0.0073(9) C11 0.0964(18) 0.0748(16) 0.0509(12) 0.0074(11) 0.0164(12) -0.0033(14) C12 0.0681(14) 0.0681(15) 0.0702(14) 0.0083(11) 0.0239(11) 0.0046(11) C9 0.0631(12) 0.0712(14) 0.0555(11) 0.0174(10) 0.0004(9) 0.0073(11) C10 0.0874(16) 0.0862(18) 0.0525(12) 0.0126(12) -0.0038(11) 0.0030(14) C20 0.0592(12) 0.0743(15) 0.0477(11) 0.0052(10) -0.0110(9) 0.0025(11) _geom_special_details ; All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes. ; loop_ _geom_bond_atom_site_label_1 _geom_bond_atom_site_label_2 _geom_bond_distance _geom_bond_site_symmetry_2 _geom_bond_publ_flag O1 C2 1.368(2) . ? O1 C5 1.4605(17) . ? O23 C22 1.2339(18) . ? N16 C14 1.334(2) . ? N16 C17 1.4581(19) . ? N16 H16 0.89(2) . ? O15 C14 1.2217(19) . ? O6 C2 1.190(2) . ? N24 C22 1.324(2) . ? N24 C25 1.451(3) . ? N24 H24 0.85(2) . ? C14 C5 1.548(2) . ? C18 C20 1.525(3) . ? C18 C21 1.524(3) . ? C18 C19 1.531(3) . ? C18 C17 1.564(2) . ? C25 H25A 0.89(6) . ? C25 H25B 0.86(5) . ? C25 H25C 0.93(5) . ? C5 C7 1.534(2) . ? C5 C4 1.534(2) . ? C22 C17 1.531(2) . ? C13 C8 1.394(3) . ? C13 C12 1.393(3) . ? C13 H13 1.00(3) . ? C8 C9 1.393(3) . ? C8 C7 1.514(3) . ? C19 H19A 0.95(3) . ? C19 H19B 0.91(3) . ? C19 H19C 1.01(3) . ? C17 H17 0.963(17) . ? C7 H7A 1.01(3) . ? C2 C3 1.501(3) . ? C4 C3 1.517(3) . ? C4 H4A 0.97(2) . ? C4 H4B 0.92(3) . ? C3 H3A 0.97(3) . ? C3 H3B 0.96(2) . ? C11 C10 1.369(4) . ? C11 C12 1.387(4) . ? C11 H11 0.95(3) . ? C12 H12 0.98(3) . ? C9 C10 1.385(4) . ? C9 H9 1.05(3) . ? C10 H10 0.95(4) . ? C20 H20A 0.87(3) . ? C20 H20B 1.03(3) . ? C20 H20C 0.88(3) . ? loop_ _geom_angle_atom_site_label_1 _geom_angle_atom_site_label_2 _geom_angle_atom_site_label_3 _geom_angle _geom_angle_site_symmetry_1 _geom_angle_site_symmetry_3 _geom_angle_publ_flag C2 O1 C5 110.69(12) . . ? C14 N16 C17 125.60(13) . . ? C14 N16 H16 121.5(14) . . ? C17 N16 H16 112.8(14) . . ? C22 N24 C25 122.30(16) . . ? C22 N24 H24 122.1(15) . . ? C25 N24 H24 115.6(15) . . ? O15 C14 N16 124.51(15) . . ? O15 C14 C5 119.85(14) . . ? N16 C14 C5 115.63(13) . . ? C20 C18 C21 109.88(18) . . ? C20 C18 C19 108.34(18) . . ? C21 C18 C19 109.7(2) . . ? C20 C18 C17 108.25(15) . . ? C21 C18 C17 110.51(14) . . ? C19 C18 C17 110.08(15) . . ? N24 C25 H25A 116(4) . . ? N24 C25 H25B 106(3) . . ? H25A C25 H25B 116(5) . . ? N24 C25 H25C 109(3) . . ? H25A C25 H25C 100(4) . . ? H25B C25 H25C 109(4) . . ? O1 C5 C7 108.90(13) . . ? O1 C5 C4 104.66(13) . . ? C7 C5 C4 112.06(14) . . ? O1 C5 C14 108.71(12) . . ? C7 C5 C14 111.70(14) . . ? C4 C5 C14 110.50(13) . . ? O23 C22 N24 122.97(15) . . ? O23 C22 C17 120.64(14) . . ? N24 C22 C17 116.39(12) . . ? C8 C13 C12 120.3(2) . . ? C8 C13 H13 123.2(17) . . ? C12 C13 H13 116.5(17) . . ? C9 C8 C13 118.1(2) . . ? C9 C8 C7 120.18(18) . . ? C13 C8 C7 121.66(18) . . ? C18 C21 H21B 109.5(18) . . ? C18 C19 H19A 107.3(17) . . ? C18 C19 H19B 105(2) . . ? H19A C19 H19B 114(3) . . ? C18 C19 H19C 108.7(19) . . ? H19A C19 H19C 106(2) . . ? H19B C19 H19C 116(3) . . ? N16 C17 C22 105.80(11) . . ? N16 C17 C18 112.48(12) . . ? C22 C17 C18 112.29(13) . . ? N16 C17 H17 106.1(10) . . ? C22 C17 H17 109.5(10) . . ? C18 C17 H17 110.3(9) . . ? C8 C7 C5 116.83(14) . . ? C8 C7 H7A 119.6(17) . . ? C5 C7 H7A 103.1(18) . . ? O6 C2 O1 120.59(18) . . ? O6 C2 C3 129.89(19) . . ? O1 C2 C3 109.50(15) . . ? C3 C4 C5 102.93(15) . . ? C3 C4 H4A 109.8(12) . . ? C5 C4 H4A 111.8(12) . . ? C3 C4 H4B 116.9(15) . . ? C5 C4 H4B 109.5(15) . . ? H4A C4 H4B 106(2) . . ? C2 C3 C4 104.40(15) . . ? C2 C3 H3A 105.6(15) . . ? C4 C3 H3A 118.2(14) . . ? C2 C3 H3B 104.9(13) . . ? C4 C3 H3B 119.4(14) . . ? H3A C3 H3B 103.0(19) . . ? C10 C11 C12 119.9(2) . . ? C10 C11 H11 117(2) . . ? C12 C11 H11 123(2) . . ? C11 C12 C13 120.2(2) . . ? C11 C12 H12 120.8(18) . . ? C13 C12 H12 118.9(18) . . ? C10 C9 C8 121.3(2) . . ? C10 C9 H9 120.3(13) . . ? C8 C9 H9 118.3(14) . . ? C11 C10 C9 120.1(2) . . ? C11 C10 H10 121(2) . . ? C9 C10 H10 119(2) . . ? C18 C20 H20A 116(2) . . ? C18 C20 H20B 113.1(17) . . ? H20A C20 H20B 107(3) . . ? C18 C20 H20C 109.5(19) . . ? H20A C20 H20C 107(3) . . ? H20B C20 H20C 103(3) . . ? _diffrn_measured_fraction_theta_max 0.993 _diffrn_reflns_theta_full 30.0 _diffrn_measured_fraction_theta_full 0.993 _refine_diff_density_max 0.187 _refine_diff_density_min -0.195 _refine_diff_density_rms 0.041