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_1563560
_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 H28 O3'
_chemical_formula_sum            'C15 H28 O3'
_chemical_formula_weight         256.37
_space_group_crystal_system      triclinic
_space_group_IT_number           1
_space_group_name_Hall           'P 1'
_space_group_name_H-M_alt        'P 1'
_atom_sites_solution_hydrogens   geom
_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                76.475(4)
_cell_angle_beta                 86.519(4)
_cell_angle_gamma                67.953(4)
_cell_formula_units_Z            2
_cell_length_a                   7.4494(4)
_cell_length_b                   9.7601(4)
_cell_length_c                   11.3665(6)
_cell_measurement_reflns_used    6435
_cell_measurement_temperature    100.00(10)
_cell_measurement_theta_max      72.4630
_cell_measurement_theta_min      3.9710
_cell_volume                     744.41(7)
_computing_cell_refinement       'CrysAlisPro 1.171.40.53a (Rigaku OD, 2019)'
_computing_data_collection       'CrysAlisPro 1.171.40.53a (Rigaku OD, 2019)'
_computing_data_reduction        'CrysAlisPro 1.171.40.53a (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)'
_diffrn_ambient_environment      N~2~
_diffrn_ambient_temperature      100.00(10)
_diffrn_detector                 'CCD plate'
_diffrn_detector_area_resol_mean 10.0000
_diffrn_detector_type            HyPix
_diffrn_measured_fraction_theta_full 0.996
_diffrn_measured_fraction_theta_max 0.996
_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    -35.00  29.00   0.50    0.05    --  -46.75  19.00 -60.00  128
  2  \w    -35.00  29.00   0.50    0.05    --  -46.75  19.00-150.00  128
  3  \w    -38.00 -12.00   0.50    0.08    --  -88.50  15.00 -60.00   52
  4  \w    -38.00 -12.00   0.50    0.08    --  -88.50  15.00 -90.00   52
  5  \w    -38.00 -12.00   0.50    0.08    --  -88.50  15.00-120.00   52
  6  \w    -47.00 -16.00   0.50    0.08    --  -88.50  45.00-180.00   62
  7  \w    -47.00 -16.00   0.50    0.08    --  -88.50  45.00-120.00   62
  8  \w    -38.00 -12.00   0.50    0.08    --  -88.50  15.00 -30.00   52
  9  \w    -38.00 -12.00   0.50    0.08    --  -88.50  15.00   0.00   52
 10  \w    -38.00 -12.00   0.50    0.08    --  -88.50  15.00  30.00   52
 11  \w    -47.00 -16.00   0.50    0.08    --  -88.50  45.00  30.00   62
 12  \w    -47.00 -16.00   0.50    0.08    --  -88.50  45.00  60.00   62
 13  \w    -47.00 -16.00   0.50    0.08    --  -88.50  45.00 120.00   62
 14  \w    -38.00 -12.00   0.50    0.08    --  -88.50  15.00 150.00   52
 15  \w    -35.00  29.00   0.50    0.05    --  -46.75  19.00 150.00  128
 16  \w    -47.00 -16.00   0.50    0.08    --  -88.50  45.00   0.00   62
 17  \w    -99.00 -15.00   0.50    0.05    --  -46.75 135.00  10.00  168
 18  \w     36.00 101.00   0.50    0.05    --   46.75-134.00 123.00  130
 19  \w     36.00 123.00   0.50    0.08    --  106.69-134.00 123.00  174
 20  \w     37.00 101.00   0.50    0.05    --   46.75-135.00 -55.00  128
 21  \w     37.00 124.00   0.50    0.08    --  106.69-135.00 -55.00  174
 22  \w     34.00  76.00   0.50    0.08    --  106.69 -61.00  90.00   84
 23  \w     34.00  76.00   0.50    0.08    --  106.69 -61.00 150.00   84
 24  \w     34.00 116.00   0.50    0.08    --  106.69-125.00 150.00  164
 25  \w     34.00  76.00   0.50    0.08    --  106.69 -61.00   0.00   84
 26  \w     34.00 100.00   0.50    0.08    --  106.69 -77.00 -60.00  132
 27  \w     34.00 116.00   0.50    0.08    --  106.69-125.00-150.00  164
 28  \w     34.00  76.00   0.50    0.08    --  106.69 -61.00 -90.00   84
 29  \w     34.00  76.00   0.50    0.08    --  106.69 -61.00 -30.00   84
 30  \w     34.00 100.00   0.50    0.08    --  106.69 -77.00-120.00  132
 31  \w     34.00  76.00   0.50    0.08    --  106.69 -61.00-150.00   84
 32  \w     91.00 178.00   0.50    0.08    --  106.69  30.00 -60.00  174
 33  \w     86.00 178.00   0.50    0.08    --  106.69 135.00  10.00  184
 34  \w     86.00 178.00   0.50    0.08    --  106.69 134.00-169.00  184
 35  \w     92.00 178.00   0.50    0.08    --  106.69 125.00 -30.00  172
 36  \w     92.00 178.00   0.50    0.08    --  106.69 125.00 120.00  172
 37  \w    -98.00 -15.00   0.50    0.05    --  -46.75 134.00-169.00  166
 38  \w    -98.00 -15.00   0.50    0.08    --  -88.50 134.00-169.00  166
 39  \w    -99.00 -15.00   0.50    0.08    --  -88.50 135.00  10.00  168
 40  \w   -119.00 -23.00   0.50    0.05    --  -46.75 -77.00  90.00  192
 41  \w   -119.00 -65.00   0.50    0.05    --  -46.75-134.00 123.00  108
 42  \w   -119.00 -70.00   0.50    0.05    --  -46.75-125.00   0.00   98
 43  \w   -119.00 -64.00   0.50    0.05    --  -46.75-135.00 -55.00  110
 44  \w   -119.00 -23.00   0.50    0.05    --  -46.75 -77.00 -30.00  192
 45  \w   -119.00 -23.00   0.50    0.05    --  -46.75 -77.00-150.00  192
 46  \w   -160.00 -65.00   0.50    0.08    --  -88.50-134.00 123.00  190
;
_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      -0.0734340000
_diffrn_orient_matrix_UB_12      -0.0369624000
_diffrn_orient_matrix_UB_13      0.1286938000
_diffrn_orient_matrix_UB_21      -0.1921873000
_diffrn_orient_matrix_UB_22      0.0129176000
_diffrn_orient_matrix_UB_23      -0.0537377000
_diffrn_orient_matrix_UB_31      0.0865951000
_diffrn_orient_matrix_UB_32      -0.1704700000
_diffrn_orient_matrix_UB_33      0.0006713000
_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  0.0706
_diffrn_reflns_av_unetI/netI     0.0521
_diffrn_reflns_Laue_measured_fraction_full 0.996
_diffrn_reflns_Laue_measured_fraction_max 0.996
_diffrn_reflns_limit_h_max       8
_diffrn_reflns_limit_h_min       -8
_diffrn_reflns_limit_k_max       9
_diffrn_reflns_limit_k_min       -11
_diffrn_reflns_limit_l_max       12
_diffrn_reflns_limit_l_min       -13
_diffrn_reflns_number            11239
_diffrn_reflns_point_group_measured_fraction_full 0.741
_diffrn_reflns_point_group_measured_fraction_max 0.741
_diffrn_reflns_theta_full        62.487
_diffrn_reflns_theta_max         62.487
_diffrn_reflns_theta_min         4.002
_diffrn_source                   'micro-focus sealed X-ray tube'
_diffrn_source_type              'PhotonJet (Cu) X-ray Source'
_exptl_absorpt_coefficient_mu    0.612
_exptl_absorpt_correction_T_max  1.00000
_exptl_absorpt_correction_T_min  0.03564
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details
;
CrysAlisPro 1.171.40.53a (Rigaku Oxford Diffraction, 2019)
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    1.144
_exptl_crystal_description       plate
_exptl_crystal_F_000             284
_exptl_crystal_size_max          0.25
_exptl_crystal_size_mid          0.2
_exptl_crystal_size_min          0.02
_refine_diff_density_max         0.348
_refine_diff_density_min         -0.308
_refine_diff_density_rms         0.069
_refine_ls_abs_structure_details
;
 Flack x determined using 936 quotients [(I+)-(I-)]/[(I+)+(I-)]
 (Parsons, Flack and Wagner, Acta Cryst. B69 (2013) 249-259).
;
_refine_ls_abs_structure_Flack   0.3(4)
_refine_ls_extinction_coef       0.0076(9)
_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   1.085
_refine_ls_hydrogen_treatment    constr
_refine_ls_matrix_type           full
_refine_ls_number_parameters     338
_refine_ls_number_reflns         3514
_refine_ls_number_restraints     7
_refine_ls_restrained_S_all      1.114
_refine_ls_R_factor_all          0.0700
_refine_ls_R_factor_gt           0.0663
_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^)+(0.0100P)^2^+1.7000P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1495
_refine_ls_wR_factor_ref         0.1514
_reflns_Friedel_coverage         0.487
_reflns_Friedel_fraction_full    0.485
_reflns_Friedel_fraction_max     0.485
_reflns_number_gt                3254
_reflns_number_total             3514
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            np1c00246_si_004.cif
_cod_data_source_block           hpd007c
_cod_database_code               1563560
_shelx_shelxl_version_number     2014/7
_chemical_oxdiff_formula         C20H20O4
_chemical_oxdiff_usercomment     KV11-005
_shelx_estimated_absorpt_t_max   0.988
_shelx_estimated_absorpt_t_min   0.862
_reflns_odcompleteness_completeness 99.47
_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 O(H) groups
2. Restrained distances
 H3-O1_$1
 1.95 with sigma of 0.02
 H1-O2
 1.95 with sigma of 0.02
 H4-O5
 1.95 with sigma of 0.02
 H6A-O4_$2
 2.05 with sigma of 0.02
3.a Ternary CH refined with riding coordinates:
 C21(H21), C6(H6), C1(H1A), C7(H7), C5(H5), C16(H16), C11(H11), C20(H20),
 C10(H10), C25(H25), C22(H22), C26(H26)
3.b Secondary CH2 refined with riding coordinates:
 C3(H3A,H3B), C17(H17A,H17B), C2(H2A,H2B), C23(H23A,H23B), C8(H8A,H8B),
 C27(H27A,H27B), C24(H24A,H24B), C18(H18A,H18B), C9(H9A,H9B), C12(H12A,H12B)
3.c Idealised Me refined as rotating group:
 C15(H15A,H15B,H15C), C14(H14A,H14B,H14C), C13(H13A,H13B,H13C), C28(H28A,H28B,
 H28C), C30(H30A,H30B,H30C), C29(H29A,H29B,H29C)
3.d Idealised tetrahedral OH refined as rotating group:
 O1(H1), O5(H5A), O2(H2), O4(H4), O6(H6A), O3(H3)
;
_shelx_res_checksum              57125
_shelx_hkl_checksum              25482
_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 23.927
_oxdiff_exptl_absorpt_empirical_full_min 0.429