Total synthesis of a key series of vinblastines modified at C4 that define the importance and surprising trends in activity.
Yang, Shouliang; Sankar, Kuppusamy; Skepper, Colin K.; Barker, Timothy J.; Lukesh, 3rd, John C; Brody, Daniel M.; Brütsch, Manuela M; Boger, Dale L.; Chemical science 8 (2017) 1560–1569; doi:10.1039/C6SC04146A

data_1544463
_publ_section_title
;
 Total synthesis of a key series of vinblastines modified at C4 that
 define the importance and surprising trends in activity.
;
_journal_issue                   2
_journal_name_full               'Chemical science'
_journal_page_first              1560
_journal_page_last               1569
_journal_paper_doi               10.1039/C6SC04146A
_journal_volume                  8
_journal_year                    2017
_chemical_absolute_configuration ad
_chemical_formula_moiety         'C24 H30 N2 O6, C H2 Cl2'
_chemical_formula_sum            'C25 H32 Cl2 N2 O6'
_chemical_formula_weight         527.42
_chemical_name_systematic        ysl-acid-unnatural
_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'
_symmetry_space_group_name_Hall  'P 2ac 2ab'
_symmetry_space_group_name_H-M   'P 21 21 21'
_atom_sites_solution_hydrogens   geom
_atom_sites_solution_primary     direct
_atom_sites_solution_secondary   difmap
_audit_creation_date             2016-04-19
_audit_creation_method
;
Olex2 1.2-beta
(compiled 2016.02.19 svn.r3266 for OlexSys, GUI svn.r5155)
;
_audit_update_record
;
2016-04-19 deposited with the CCDC.
2016-11-03 downloaded from the CCDC.
;
_cell_angle_alpha                90
_cell_angle_beta                 90
_cell_angle_gamma                90
_cell_formula_units_Z            4
_cell_length_a                   7.8529(8)
_cell_length_b                   15.3187(15)
_cell_length_c                   20.944(2)
_cell_measurement_reflns_used    6045
_cell_measurement_temperature    298.15
_cell_measurement_theta_max      52.791
_cell_measurement_theta_min      3.575
_cell_volume                     2519.5(4)
_computing_cell_refinement       'SAINT v8.37A (Bruker, 2016)'
_computing_data_collection       'APEX3 v2016.1-0 (Bruker, 2016)'
_computing_data_reduction        'SAINT v8.37A (Bruker, 2016)'
_computing_molecular_graphics    'Olex2 (Dolomanov et al., 2009)'
_computing_publication_material  'Olex2 (Dolomanov et al., 2009)'
_computing_structure_refinement  'ShelXL (Sheldrick, 2015)'
_computing_structure_solution    'ShelXT (Sheldrick, 2015)'
_diffrn_ambient_temperature      298.15
_diffrn_detector                 'Bruker Platinum135 CCD'
_diffrn_detector_area_resol_mean 7.9
_diffrn_detector_type            'CCD Area Detector'
_diffrn_measured_fraction_theta_full 0.993
_diffrn_measured_fraction_theta_max 0.993
_diffrn_measurement_device       'Fixed Chi Three-Circle Diffractometer'
_diffrn_measurement_device_type  'Bruker D8 Pt-135'
_diffrn_measurement_method       '\w and \f scans'
_diffrn_radiation_monochromator  'Multilayer Mirrors'
_diffrn_radiation_probe          x-ray
_diffrn_radiation_type           CuK\a
_diffrn_radiation_wavelength     1.54178
_diffrn_reflns_av_R_equivalents  0.0807
_diffrn_reflns_av_unetI/netI     0.0635
_diffrn_reflns_Laue_measured_fraction_full 0.993
_diffrn_reflns_Laue_measured_fraction_max 0.993
_diffrn_reflns_limit_h_max       8
_diffrn_reflns_limit_h_min       -8
_diffrn_reflns_limit_k_max       15
_diffrn_reflns_limit_k_min       -16
_diffrn_reflns_limit_l_max       23
_diffrn_reflns_limit_l_min       -23
_diffrn_reflns_number            18667
_diffrn_reflns_point_group_measured_fraction_full 0.991
_diffrn_reflns_point_group_measured_fraction_max 0.991
_diffrn_reflns_theta_full        59.122
_diffrn_reflns_theta_max         59.122
_diffrn_reflns_theta_min         3.575
_diffrn_source                   'Micro Focus Rotating Anode'
_diffrn_source_type              'Bruker FR-591'
_diffrn_standards_number         0
_exptl_absorpt_coefficient_mu    2.686
_exptl_absorpt_correction_T_max  0.9952
_exptl_absorpt_correction_T_min  0.8020
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details
;
SADABS-2014/5 (Bruker,2014/5) was used for absorption correction.
wR2(int) was 0.1212 before and 0.0838 after correction.
The Ratio of minimum to maximum transmission is 0.8059.
The \l/2 correction factor is Not present.
;
_exptl_crystal_colour            Colorless
_exptl_crystal_colour_primary    Colorless
_exptl_crystal_density_diffrn    1.390
_exptl_crystal_description       prism
_exptl_crystal_F_000             1112
_exptl_crystal_recrystallization_method 'Vapour deposition'
_exptl_crystal_size_max          0.223
_exptl_crystal_size_mid          0.188
_exptl_crystal_size_min          0.097
_refine_diff_density_max         0.326
_refine_diff_density_min         -0.374
_refine_diff_density_rms         0.053
_refine_ls_abs_structure_details
;
 Flack x determined using 827 quotients [(I+)-(I-)]/[(I+)+(I-)]
 (Parsons, Flack and Wagner, Acta Cryst. B69 (2013) 249-259).
;
_refine_ls_abs_structure_Flack   0.02(2)
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.027
_refine_ls_hydrogen_treatment    constr
_refine_ls_matrix_type           full
_refine_ls_number_parameters     341
_refine_ls_number_reflns         3603
_refine_ls_number_restraints     22
_refine_ls_restrained_S_all      1.082
_refine_ls_R_factor_all          0.0950
_refine_ls_R_factor_gt           0.0631
_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^)+(0.1059P)^2^+0.6059P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1638
_refine_ls_wR_factor_ref         0.1842
_reflns_Friedel_coverage         0.729
_reflns_Friedel_fraction_full    0.988
_reflns_Friedel_fraction_max     0.988
_reflns_number_gt                2521
_reflns_number_total             3603
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            c6sc04146a2.cif
_cod_data_source_block           Boger47
_cod_depositor_comments
;
The following automatic conversions were performed:

'_diffrn_radiation_probe' value 'X-ray' changed to 'x-ray' according
to
/usr/data/users/saulius/crontab/automatic-downloads/rss-feeds/RSC/lib/dictionaries/cif_core.dic
dictionary named 'cif_core.dic' version 2.4.2 from 2011-04-26.

Automatic conversion script
Id: cif_fix_values 4268 2015-11-12 08:31:59Z antanas 

 Adding full bibliography for 1544462--1544465.cif.

 Adding full bibliography for 1544462--1544465.cif.
;
_cod_original_cell_volume        2519.4(4)
_cod_database_code               1544463
_shelx_estimated_absorpt_t_max   0.781
_shelx_estimated_absorpt_t_min   0.586
_olex2_refinement_description
;
1. Fixed Uiso
 At 1.2 times of:
  All C(H) groups, All C(H,H) groups, All C(H,H,H,H) groups
 At 1.5 times of:
  All C(H,H,H) groups, All O(H) groups
2. Restrained distances
 Cl2S-C1S = Cl2B-C1S = Cl1S-C1S = Cl1B-C1S
 1.8 with sigma of 0.02
3. Rigid body (RIGU) restrains
 Cl1S, Cl2S, Cl1B, Cl2B, C1S
 with sigma for 1-2 distances of 0.002 and sigma for 1-3 distances of 0.002
4. Others
 Sof(Cl1S)=Sof(Cl2S)=Sof(H1SD)=Sof(H1SC)=1-FVAR(1)
 Sof(Cl1B)=Sof(Cl2B)=Sof(H1SB)=Sof(H1SA)=FVAR(1)
5.a Ternary CH refined with riding coordinates:
 C5(H5), C7(H7), C9(H9)
5.b Secondary CH2 refined with riding coordinates:
 C1(H1A,H1B), C11(H11A,H11B), C13(H13A,H13B), C14(H14A,H14B), C1S(H1SB,H1SA),
 C1S(H1SD,H1SC)
5.c Aromatic/amide H refined with riding coordinates:
 C2(H2), C3(H3A), C17(H17), C19(H19), C20(H20)
5.d Idealised Me refined as rotating group:
 C12(H12A,H12B,H12C), C22(H22A,H22B,H22C), C23(H23A,H23B,H23C), C24(H24A,H24B,
 H24C)
5.e Idealised tetrahedral OH refined as rotating group:
 O1(H1), O3(H3)
;
_shelx_res_checksum              1756
_shelx_shelxl_version_number     2014/7
_olex2_submission_special_instructions 'No special instructions were received'