Accelerated Development of a Scalable Ring-Closing Metathesis to Manufacture AMG 176 Using a Combined High-Throughput Experimentation and Computational Modeling Approach
St-Pierre, Gabrielle; Cherney, Alan H.; Chen, Wencan; Dong, Xiaofei; Dornan, Peter K.; Griffin, Daniel J.; Houk, K. N.; Lin, Janice B.; Osgood, Stephen; Silva Elipe, Maria V.; Timmons, Heath C.; Xie, Yong; Tedrow, Jason S.; Thiel, Oliver R.; Smith, Austin G.; Organic Process Research & Development  (2020) –; doi:10.1021/acs.oprd.0c00416

data_1559553
_publ_section_title
;
 Accelerated Development of a Scalable Ring-Closing Metathesis to
 Manufacture AMG 176 Using a Combined High-Throughput Experimentation and
 Computational Modeling Approach
;
_journal_name_full               'Organic Process Research &amp; Development'
_journal_paper_doi               10.1021/acs.oprd.0c00416
_journal_year                    2020
_chemical_absolute_configuration ad
_chemical_formula_moiety         'C39 H42 Br Cl N2 O6 S'
_chemical_formula_sum            'C39 H42 Br Cl N2 O6 S'
_chemical_formula_weight         782.16
_space_group_crystal_system      orthorhombic
_space_group_IT_number           20
_space_group_name_Hall           'C 2c 2'
_space_group_name_H-M_alt        'C 2 2 21'
_atom_sites_solution_hydrogens   mixed
_atom_sites_solution_primary     dual
_audit_creation_date             2018-09-12
_audit_creation_method
;
Olex2 1.2
(compiled 2018.05.29 svn.r3508 for OlexSys, GUI svn.r5506)
;
_cell_angle_alpha                90
_cell_angle_beta                 90
_cell_angle_gamma                90
_cell_formula_units_Z            8
_cell_length_a                   12.0049(8)
_cell_length_b                   17.7292(12)
_cell_length_c                   35.641(2)
_cell_measurement_reflns_used    7603
_cell_measurement_temperature    173(2)
_cell_measurement_theta_max      23.56
_cell_measurement_theta_min      2.29
_cell_volume                     7585.7(8)
_computing_cell_refinement       'SAINT v8.34A (Bruker, 2013)'
_computing_data_collection       'COSMO (BRUKER, V1.61, 2009)'
_computing_data_reduction        'SAINT v8.34A (Bruker, 2013)'
_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      173(2)
_diffrn_detector_area_resol_mean 8.36
_diffrn_measured_fraction_theta_full 1.000
_diffrn_measured_fraction_theta_max 0.999
_diffrn_measurement_device_type  'Bruker APEX-II CCD'
_diffrn_measurement_method       '\f and \w scans'
_diffrn_radiation_monochromator  graphite
_diffrn_radiation_type           MoK\a
_diffrn_radiation_wavelength     0.71073
_diffrn_reflns_av_R_equivalents  0.0793
_diffrn_reflns_av_unetI/netI     0.0827
_diffrn_reflns_Laue_measured_fraction_full 1.000
_diffrn_reflns_Laue_measured_fraction_max 0.999
_diffrn_reflns_limit_h_max       14
_diffrn_reflns_limit_h_min       -14
_diffrn_reflns_limit_k_max       21
_diffrn_reflns_limit_k_min       -21
_diffrn_reflns_limit_l_max       42
_diffrn_reflns_limit_l_min       -42
_diffrn_reflns_number            31066
_diffrn_reflns_point_group_measured_fraction_full 1.000
_diffrn_reflns_point_group_measured_fraction_max 0.999
_diffrn_reflns_theta_full        25.242
_diffrn_reflns_theta_max         25.385
_diffrn_reflns_theta_min         1.143
_diffrn_source                   'sealed tube'
_diffrn_standards_number         0
_exptl_absorpt_coefficient_mu    1.257
_exptl_absorpt_correction_T_max  0.7452
_exptl_absorpt_correction_T_min  0.6861
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details
'SADABS-2014/5 (Bruker,2014/5) was used for absorption correction. wR2(int) was 0.0840 before and 0.0758 after correction. The Ratio of minimum to maximum transmission is 0.9207. The \l/2 correction factor is 0.00150.'
_exptl_crystal_colour            colourless
_exptl_crystal_colour_primary    colourless
_exptl_crystal_density_diffrn    1.370
_exptl_crystal_description       plate
_exptl_crystal_F_000             3248
_exptl_crystal_recrystallization_method 'used as received'
_exptl_crystal_size_max          0.153
_exptl_crystal_size_mid          0.142
_exptl_crystal_size_min          0.05
_refine_diff_density_max         0.351
_refine_diff_density_min         -0.255
_refine_diff_density_rms         0.059
_refine_ls_abs_structure_details
;
 Flack x determined using 1734 quotients [(I+)-(I-)]/[(I+)+(I-)]
 (Parsons, Flack and Wagner, Acta Cryst. B69 (2013) 249-259).
;
_refine_ls_abs_structure_Flack   -0.001(7)
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.005
_refine_ls_hydrogen_treatment    mixed
_refine_ls_matrix_type           full
_refine_ls_number_parameters     457
_refine_ls_number_reflns         6958
_refine_ls_number_restraints     0
_refine_ls_restrained_S_all      1.005
_refine_ls_R_factor_all          0.0778
_refine_ls_R_factor_gt           0.0451
_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^)+6.9589P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.0827
_refine_ls_wR_factor_ref         0.0944
_reflns_Friedel_coverage         0.815
_reflns_Friedel_fraction_full    0.999
_reflns_Friedel_fraction_max     0.998
_reflns_number_gt                5027
_reflns_number_total             6958
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            op0c00416_si_003.cif
_cod_data_source_block           agx918b
_cod_original_cell_volume        7585.7(9)
_cod_database_code               1559553
_shelx_shelxl_version_number     2018/3
_shelx_estimated_absorpt_t_max   0.940
_shelx_estimated_absorpt_t_min   0.831
_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:
 C21(H21), C22(H22), C25(H25), C29(H29), C30(H30)
2.b Secondary CH2 refined with riding coordinates:
 C8(H8A,H8B), C10(H10A,H10B), C11(H11A,H11B), C12(H12A,H12B), C13(H13A,H13B),
 C20(H20A,H20B), C23(H23A,H23B), C24(H24A,H24B), C28(H28A,H28B)
2.c Aromatic/amide H refined with riding coordinates:
 C3(H3), C4(H4), C7(H7), C16(H16), C17(H17), C19(H19), C26(H26), C27(H27),
 C35(H35), C36(H36), C38(H38), C39(H39)
2.d Idealised Me refined as rotating group:
 C31(H31A,H31B,H31C), C32(H32A,H32B,H32C)
;
_shelx_res_checksum              36080
_shelx_hkl_checksum              80583
_olex2_diffrn_ambient_temperature_device 'Oxford Cryosystems'
_olex2_exptl_crystal_mounting_method
'The crystal was mounted on a nylon loop with paratone oil'
_olex2_submission_original_sample_id AR310875-1
_olex2_submission_special_instructions 'No special instructions were received'