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_1563559
_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 H22 O5'
_chemical_formula_sum            'C15 H22 O5'
_chemical_formula_weight         282.32
_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   geom
_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                   6.3116(2)
_cell_length_b                   23.9499(6)
_cell_length_c                   9.3031(3)
_cell_measurement_reflns_used    11600
_cell_measurement_temperature    100.00(10)
_cell_measurement_theta_max      76.3180
_cell_measurement_theta_min      3.6580
_cell_volume                     1406.28(7)
_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 2018/2 (Sheldrick, 2018)'
_diffrn_ambient_environment      N~2~
_diffrn_ambient_temperature      100.00(10)
_diffrn_detector                 'Hybrid Pixel Array Detector'
_diffrn_detector_area_resol_mean 10.0000
_diffrn_detector_type            HyPix
_diffrn_measured_fraction_theta_full 1.000
_diffrn_measured_fraction_theta_max 0.986
_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    -26.00  62.00   0.50    0.50    --   46.12 -55.00  72.00  176
  2  \w     34.00  63.00   0.50    2.00    --  106.69 -55.00  72.00   58
  3  \w     34.00 101.00   0.50    2.00    --  106.69 -77.00 120.00  134
  4  \w     34.00 111.00   0.50    2.00    --  106.69-125.00   0.00  154
  5  \w     34.00  71.00   0.50    2.00    --  106.69 -61.00 150.00   74
  6  \w     34.00  71.00   0.50    2.00    --  106.69 -61.00 120.00   74
  7  \w     34.00 105.00   0.50    2.00    --  106.69 -94.00  60.00  142
  8  \w     34.00  71.00   0.50    2.00    --  106.69 -61.00 -30.00   74
  9  \w     34.00  71.00   0.50    2.00    --  106.69 -61.00 -90.00   74
 10  \w     34.00  71.00   0.50    2.00    --  106.69 -61.00-150.00   74
 11  \w     91.00 178.00   0.50    2.00    --  106.69  30.00 -60.00  174
 12  \w     95.00 178.00   0.50    2.00    --  106.69 125.00 -60.00  166
 13  \w     91.00 178.00   0.50    2.00    --  106.69  55.00-144.00  174
 14  \w     91.00 178.00   0.50    2.00    --  106.69  61.00   0.00  174
 15  \w     91.00 178.00   0.50    2.00    --  106.69  61.00 -30.00  174
 16  \w     92.00 178.00   0.50    2.00    --  106.69  45.00 -90.00  172
 17  \w     91.00 178.00   0.50    2.00    --  106.69  30.00 150.00  174
 18  \w     31.00 118.00   0.50    0.50    --   46.12  55.00-144.00  174
 19  \w     31.00 118.00   0.50    0.50    --   46.12  52.00 -45.82  174
 20  \w     31.00 118.00   0.50    0.50    --   46.12  54.00 118.78  174
 21  \w     31.00 118.00   0.50    0.50    --   46.12  54.00 170.23  174
 22  \w     31.00 120.00   0.50    0.50    --   46.12  37.00 120.00  178
 23  \w     31.00 118.00   0.50    0.50    --   46.12  52.00  -1.15  174
 24  \w     31.00 118.00   0.50    0.50    --   46.12  53.00 -85.44  174
 25  \w     34.00  95.00   0.50    0.50    --   46.12-125.00 -90.00  122
 26  \w    -51.00 -16.00   0.50    2.00    --  -88.50  45.00 -60.00   70
 27  \w    -51.00 -16.00   0.50    2.00    --  -88.50  45.00 -90.00   70
 28  \w    -62.00  27.00   0.50    0.50    --  -46.12  55.00-144.00  178
 29  \w    -63.00 -15.00   0.50    2.00    --  -88.50  55.00-144.00   96
 30  \w    -51.00 -16.00   0.50    2.00    --  -88.50  45.00  30.00   70
 31  \w    -51.00 -16.00   0.50    2.00    --  -88.50  45.00  60.00   70
 32  \w   -118.00 -30.00   0.50    0.50    --  -46.12 -55.00  72.00  176
 33  \w   -118.00 -87.00   0.50    0.50    --  -46.12-125.00  30.00   62
 34  \w   -118.00 -30.00   0.50    0.50    --  -46.12 -54.00  -6.02  176
 35  \w   -118.00 -87.00   0.50    0.50    --  -46.12-125.00-180.00   62
 36  \w   -118.00 -87.00   0.50    0.50    --  -46.12-125.00-150.00   62
 37  \w   -118.00 -30.00   0.50    0.50    --  -46.12 -55.00 -51.43  176
 38  \w   -118.00 -31.00   0.50    0.50    --  -46.12 -53.00 165.49  174
 39  \w   -160.00 -73.00   0.50    2.00    --  -88.50 -55.00  72.00  174
 40  \w   -160.00 -74.00   0.50    2.00    --  -88.50 -49.00 -99.31  172
 41  \w   -160.00 -73.00   0.50    2.00    --  -88.50 -52.00 -60.15  174
 42  \w   -160.00 -73.00   0.50    2.00    --  -88.50 -52.00 -20.87  174
 43  \w   -160.00 -73.00   0.50    2.00    --  -88.50 -55.00 159.08  174
 44  \w   -161.00 -73.00   0.50    2.00    --  -88.50 -43.00   4.53  176
 45  \w   -160.00 -78.00   0.50    2.00    --  -88.50 -56.00 -72.77  164
 46  \w   -160.00 -73.00   0.50    2.00    --  -88.50 -52.00 -43.47  174
 47  \w   -161.00 -73.00   0.50    2.00    --  -88.50 -43.00 -50.12  176
;
_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      0.1232319000
_diffrn_orient_matrix_UB_12      0.0434576000
_diffrn_orient_matrix_UB_13      -0.0888025000
_diffrn_orient_matrix_UB_21      0.2099455000
_diffrn_orient_matrix_UB_22      -0.0218916000
_diffrn_orient_matrix_UB_23      0.0629847000
_diffrn_orient_matrix_UB_31      0.0181646000
_diffrn_orient_matrix_UB_32      -0.0420502000
_diffrn_orient_matrix_UB_33      -0.1247899000
_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  0.0392
_diffrn_reflns_av_unetI/netI     0.0146
_diffrn_reflns_Laue_measured_fraction_full 1.000
_diffrn_reflns_Laue_measured_fraction_max 0.986
_diffrn_reflns_limit_h_max       7
_diffrn_reflns_limit_h_min       -7
_diffrn_reflns_limit_k_max       27
_diffrn_reflns_limit_k_min       -30
_diffrn_reflns_limit_l_max       11
_diffrn_reflns_limit_l_min       -11
_diffrn_reflns_number            29337
_diffrn_reflns_point_group_measured_fraction_full 1.000
_diffrn_reflns_point_group_measured_fraction_max 0.977
_diffrn_reflns_theta_full        67.684
_diffrn_reflns_theta_max         76.382
_diffrn_reflns_theta_min         3.691
_diffrn_source                   'micro-focus sealed X-ray tube'
_diffrn_source_type              'PhotonJet (Cu) X-ray Source'
_exptl_absorpt_coefficient_mu    0.820
_exptl_absorpt_correction_T_max  1.000
_exptl_absorpt_correction_T_min  0.708
_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    1.333
_exptl_crystal_description       block
_exptl_crystal_F_000             608
_exptl_crystal_size_max          0.169
_exptl_crystal_size_mid          0.096
_exptl_crystal_size_min          0.062
_refine_diff_density_max         0.283
_refine_diff_density_min         -0.259
_refine_diff_density_rms         0.063
_refine_ls_abs_structure_details
;
 Flack x determined using 1107 quotients [(I+)-(I-)]/[(I+)+(I-)]
 (Parsons, Flack and Wagner, Acta Cryst. B69 (2013) 249-259).
;
_refine_ls_abs_structure_Flack   -0.01(5)
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.099
_refine_ls_hydrogen_treatment    constr
_refine_ls_matrix_type           full
_refine_ls_number_parameters     184
_refine_ls_number_reflns         2876
_refine_ls_number_restraints     0
_refine_ls_restrained_S_all      1.099
_refine_ls_R_factor_all          0.0518
_refine_ls_R_factor_gt           0.0505
_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^)+(0.0300P)^2^+2.6000P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1340
_refine_ls_wR_factor_ref         0.1346
_reflns_Friedel_coverage         0.689
_reflns_Friedel_fraction_full    0.999
_reflns_Friedel_fraction_max     0.965
_reflns_number_gt                2770
_reflns_number_total             2876
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            np1c00246_si_002.cif
_cod_data_source_block           hpd205
_cod_database_code               1563559
_shelx_shelxl_version_number     2014/7
_chemical_oxdiff_formula         'C H O'
_chemical_oxdiff_usercomment     Peroxide
_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
2.a Ternary CH refined with riding coordinates:
 C1(H1), C7(H7), C11(H11), C10(H10), C5(H5)
2.b Secondary CH2 refined with riding coordinates:
 C8(H8A,H8B), C2(H2A,H2B), C9(H9A,H9B), C3(H3A,H3B)
2.c Idealised Me refined as rotating group:
 C13(H13A,H13B,H13C), C15(H15A,H15B,H15C), C14(H14A,H14B,H14C)
;
_shelx_res_checksum              92144
_shelx_hkl_checksum              39828
_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
- B-factor correction
;
_oxdiff_exptl_absorpt_empirical_full_max 1.872
_oxdiff_exptl_absorpt_empirical_full_min 0.649