Synthesis of [15,15,15-2H3]-Dihydroartemisinic Acid and Isotope Studies Support a Mixed Mechanism in the Endoperoxide Formation to Artemisinin
Varela, Kaitlyn; Arman, Hadi D.; Yoshimoto, Francis K.; Journal of Natural Products  (2021) –; doi:10.1021/acs.jnatprod.1c00246

data_1563558
_publ_section_title
;
 Synthesis of [15,15,15-2H3]-Dihydroartemisinic Acid and Isotope Studies
 Support a Mixed Mechanism in the Endoperoxide Formation to Artemisinin
;
_journal_name_full               'Journal of Natural Products'
_journal_paper_doi               10.1021/acs.jnatprod.1c00246
_journal_year                    2021
_chemical_absolute_configuration ad
_chemical_formula_moiety         'C15 H24 O2'
_chemical_formula_sum            'C15 H24 O2'
_chemical_formula_weight         236.34
_space_group_crystal_system      orthorhombic
_space_group_IT_number           19
_space_group_name_Hall           'P 2ac 2ab'
_space_group_name_H-M_alt        'P 21 21 21'
_atom_sites_solution_hydrogens   mixed
_atom_sites_solution_primary     dual
_audit_creation_date             2021-04-21
_audit_creation_method
;
Olex2 1.3
(compiled 2020.11.12 svn.r5f609507 for OlexSys, GUI svn.r6272)
;
_cell_angle_alpha                90
_cell_angle_beta                 90
_cell_angle_gamma                90
_cell_formula_units_Z            4
_cell_length_a                   6.24107(9)
_cell_length_b                   8.21018(12)
_cell_length_c                   26.5277(5)
_cell_measurement_reflns_used    5553
_cell_measurement_temperature    99.99(10)
_cell_measurement_theta_max      74.9580
_cell_measurement_theta_min      3.3190
_cell_volume                     1359.29(4)
_computing_cell_refinement       'CrysAlisPro 1.171.40.63a (Rigaku OD, 2019)'
_computing_data_collection       'CrysAlisPro 1.171.40.63a (Rigaku OD, 2019)'
_computing_data_reduction        'CrysAlisPro 1.171.40.63a (Rigaku OD, 2019)'
_computing_molecular_graphics    'Olex2 1.3 (Dolomanov et al., 2009)'
_computing_publication_material  'Olex2 1.3 (Dolomanov et al., 2009)'
_computing_structure_refinement  'SHELXL 2014/7 (Sheldrick, 2015)'
_computing_structure_solution    'SHELXT  (Sheldrick, 2015)'
_diffrn_ambient_environment      N~2~
_diffrn_ambient_temperature      99.99(10)
_diffrn_detector                 'Hybrid Pixel Array Detector'
_diffrn_detector_area_resol_mean 10.0000
_diffrn_detector_type            HyPix
_diffrn_measured_fraction_theta_full 0.998
_diffrn_measured_fraction_theta_max 0.944
_diffrn_measurement_details
;
List of Runs (angles in degrees, time in seconds):

  # Type    Start    End  Width  t~exp~   \w     \q     \k     \f   Frames
--------------------------------------------------------------------------
  1  \w   -162.00 -16.00   0.50    0.12    --  -88.50  -1.00  36.00  292
  2  \w    -91.00 -17.00   0.50    0.12    --  -88.50 132.00 -58.00  148
  3  \w   -120.00 -83.00   0.50    0.05    --  -46.87 -57.00 -30.00   74
  4  \w    -43.00  27.00   0.50    0.05    --  -46.87  37.00 150.00  140
  5  \w    -30.00  29.00   0.50    0.05    --  -46.87  19.00  90.00  118
  6  \w     83.00 120.00   0.50    0.05    --   46.87  57.00 -60.00   74
  7  \w     41.00 102.00   0.50    0.05    --   46.87-136.00 144.00  122
  8  \w   -160.00-100.00   0.50    0.12    --  -88.50 -94.00-120.00  120
  9  \w     34.00  71.00   0.50    0.12    --  106.69 -61.00  30.00   74
 10  \w     34.00  71.00   0.50    0.12    --  106.69 -61.00   0.00   74
 11  \w     34.00 105.00   0.50    0.12    --  106.69 -94.00 -30.00  142
 12  \w     41.00 120.00   0.50    0.12    --  106.69-136.00 144.00  158
 13  \w   -121.00 -32.00   0.50    0.05    --  -46.87 -37.00   0.00  178
 14  \w   -121.00 -96.00   0.50    0.05    --  -46.87 -37.00-120.00   50
 15  \w   -121.00 -32.00   0.50    0.05    --  -46.87 -37.00 150.00  178
;
_diffrn_measurement_device       'four-circle diffractometer'
_diffrn_measurement_device_type  'XtaLAB Synergy, Dualflex, HyPix'
_diffrn_measurement_method       '\w scans'
_diffrn_orient_matrix_type
'CrysAlisPro convention (1999,Acta A55,543-557)'
_diffrn_orient_matrix_UB_11      -0.0026191000
_diffrn_orient_matrix_UB_12      0.1873189000
_diffrn_orient_matrix_UB_13      -0.0033354000
_diffrn_orient_matrix_UB_21      0.0031956000
_diffrn_orient_matrix_UB_22      -0.0107697000
_diffrn_orient_matrix_UB_23      -0.0579554000
_diffrn_orient_matrix_UB_31      -0.2468852000
_diffrn_orient_matrix_UB_32      -0.0021675000
_diffrn_orient_matrix_UB_33      -0.0006931000
_diffrn_radiation_monochromator  mirror
_diffrn_radiation_probe          x-ray
_diffrn_radiation_type           'Cu K\a'
_diffrn_radiation_wavelength     1.54184
_diffrn_reflns_av_R_equivalents  0.0325
_diffrn_reflns_av_unetI/netI     0.0267
_diffrn_reflns_Laue_measured_fraction_full 0.998
_diffrn_reflns_Laue_measured_fraction_max 0.944
_diffrn_reflns_limit_h_max       4
_diffrn_reflns_limit_h_min       -7
_diffrn_reflns_limit_k_max       9
_diffrn_reflns_limit_k_min       -8
_diffrn_reflns_limit_l_max       31
_diffrn_reflns_limit_l_min       -33
_diffrn_reflns_number            9206
_diffrn_reflns_point_group_measured_fraction_full 0.976
_diffrn_reflns_point_group_measured_fraction_max 0.911
_diffrn_reflns_theta_full        67.684
_diffrn_reflns_theta_max         76.179
_diffrn_reflns_theta_min         3.332
_diffrn_source                   'micro-focus sealed X-ray tube'
_diffrn_source_type              'PhotonJet (Cu) X-ray Source'
_exptl_absorpt_coefficient_mu    0.580
_exptl_absorpt_correction_T_max  1.000
_exptl_absorpt_correction_T_min  0.703
_exptl_absorpt_correction_type   gaussian
_exptl_absorpt_process_details
;
CrysAlisPro 1.171.40.63a (Rigaku Oxford Diffraction, 2019)
Numerical absorption correction based on gaussian integration over
			a multifaceted crystal model
Empirical absorption correction using spherical harmonics,
 implemented in SCALE3 ABSPACK scaling algorithm.
;
_exptl_crystal_colour            'clear colourless'
_exptl_crystal_colour_lustre     clear
_exptl_crystal_colour_primary    colourless
_exptl_crystal_density_diffrn    1.155
_exptl_crystal_description       block
_exptl_crystal_F_000             520
_exptl_crystal_size_max          0.216
_exptl_crystal_size_mid          0.171
_exptl_crystal_size_min          0.076
_refine_diff_density_max         0.170
_refine_diff_density_min         -0.151
_refine_diff_density_rms         0.032
_refine_ls_abs_structure_details
;
 Flack x determined using 926 quotients [(I+)-(I-)]/[(I+)+(I-)]
 (Parsons, Flack and Wagner, Acta Cryst. B69 (2013) 249-259).
;
_refine_ls_abs_structure_Flack   0.09(11)
_refine_ls_extinction_coef       0.0023(5)
_refine_ls_extinction_expression Fc^*^=kFc[1+0.001xFc^2^\l^3^/sin(2\q)]^-1/4^
_refine_ls_extinction_method     'SHELXL-2014/7 (Sheldrick 2014'
_refine_ls_goodness_of_fit_ref   1.014
_refine_ls_hydrogen_treatment    mixed
_refine_ls_matrix_type           full
_refine_ls_number_parameters     161
_refine_ls_number_reflns         2578
_refine_ls_number_restraints     0
_refine_ls_restrained_S_all      1.014
_refine_ls_R_factor_all          0.0320
_refine_ls_R_factor_gt           0.0304
_refine_ls_shift/su_max          0.000
_refine_ls_shift/su_mean         0.000
_refine_ls_structure_factor_coef Fsqd
_refine_ls_weighting_details
'w=1/[\s^2^(Fo^2^)+(0.0463P)^2^+0.1798P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.0780
_refine_ls_wR_factor_ref         0.0795
_reflns_Friedel_coverage         0.633
_reflns_Friedel_fraction_full    0.943
_reflns_Friedel_fraction_max     0.862
_reflns_number_gt                2454
_reflns_number_total             2578
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            np1c00246_si_006.cif
_cod_data_source_block           hpd206
_cod_database_code               1563558
_shelx_shelxl_version_number     2014/7
_chemical_oxdiff_formula         'C H O'
_chemical_oxdiff_usercomment     'Dihydroartemisinic acid'
_shelx_estimated_absorpt_t_max   0.957
_shelx_estimated_absorpt_t_min   0.885
_reflns_odcompleteness_completeness 99.93
_reflns_odcompleteness_iscentric 1
_reflns_odcompleteness_theta     66.97
_olex2_refinement_description
;
1. Fixed Uiso
 At 1.2 times of:
  All C(H) groups, All C(H,H) groups
 At 1.5 times of:
  All C(H,H,H) groups, All C(H,H,H,H) groups
2.a Ternary CH refined with riding coordinates:
 C6(H6), C10(H10), C7(H7), C11(H11), C1(H1)
2.b Secondary CH2 refined with riding coordinates:
 C8(H8A,H8B), C3(H3A,H3B), C2(H2A,H2B), C9(H9A,H9B)
2.c Aromatic/amide H refined with riding coordinates:
 C5(H5)
2.d Idealised Me refined as rotating group:
 C14(H14A,H14B,H14C), C12(H12A,H12B,H12C), C15(H15A,H15B,H15C)
;
_shelx_res_checksum              27140
_shelx_hkl_checksum              78588
_olex2_exptl_crystal_mounting_method 'nylon loop'
_olex2_submission_special_instructions 'No special instructions were received'
_oxdiff_exptl_absorpt_empirical_details
;
Empirical correction (ABSPACK) includes:
- Absorption correction using spherical harmonics
- Frame scaling
;
_oxdiff_exptl_absorpt_empirical_full_max 1.424
_oxdiff_exptl_absorpt_empirical_full_min 0.816