Asymmetric synthesis of pharmaceutically relevant 1-aryl-2-heteroaryl- and 1,2-diheteroarylcyclopropane-1-carboxylates
Sharland, Jack C.; Wei, Bo; Hardee, David J.; Hodges, Timothy R.; Gong, Wei; Voight, Eric A.; Davies, Huw M. L.; Chemical Science  (2021) –; doi:10.1039/D1SC02474D

data_1564263
_publ_section_title
;
 Asymmetric synthesis of pharmaceutically relevant 1-aryl-2-heteroaryl-
 and 1,2-diheteroarylcyclopropane-1-carboxylates
;
_journal_name_full               'Chemical Science'
_journal_paper_doi               10.1039/D1SC02474D
_journal_year                    2021
_chemical_absolute_configuration ad
_chemical_formula_moiety
'C162 H128 Cl2 N6 O16 Rh2, C H2 Cl2, C5 H4 Cl N'
_chemical_formula_sum            'C168 H134 Cl5 N7 O16 Rh2'
_chemical_formula_weight         2889.88
_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             2019-10-08
_audit_creation_method
;
Olex2 1.3-alpha
(compiled 2019.09.11 svn.r3662 for OlexSys, GUI svn.r5938)
;
_audit_update_record
;
2021-03-19 deposited with the CCDC.	2021-06-29 downloaded from the CCDC.
;
_cell_angle_alpha                90
_cell_angle_beta                 90
_cell_angle_gamma                90
_cell_formula_units_Z            4
_cell_length_a                   20.07057(12)
_cell_length_b                   20.40295(11)
_cell_length_c                   41.1384(2)
_cell_measurement_reflns_used    80615
_cell_measurement_temperature    99.8(8)
_cell_measurement_theta_max      77.0630
_cell_measurement_theta_min      3.0010
_cell_volume                     16846.13(16)
_computing_cell_refinement       'CrysAlisPro 1.171.40.53 (Rigaku OD, 2019)'
_computing_data_collection       'CrysAlisPro 1.171.40.53 (Rigaku OD, 2019)'
_computing_data_reduction        'CrysAlisPro 1.171.40.53 (Rigaku OD, 2019)'
_computing_molecular_graphics    'Olex2 1.3-alpha (Dolomanov et al., 2009)'
_computing_publication_material  'Olex2 1.3-alpha (Dolomanov et al., 2009)'
_computing_structure_refinement  'ShelXL 2018/3 (Sheldrick, 2015)'
_computing_structure_solution    'ShelXT n/a (Sheldrick, 2015)'
_diffrn_ambient_environment      N~2~
_diffrn_ambient_temperature      99.8(8)
_diffrn_detector                 'CCD plate'
_diffrn_detector_area_resol_mean 10.0000
_diffrn_detector_type            HyPix
_diffrn_measured_fraction_theta_full 0.999
_diffrn_measured_fraction_theta_max 0.985
_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    153.00 178.00   0.50    5.00    --  105.75 125.00 -90.00   50
  2  \w     93.00 130.00   0.50    5.00    --  105.75 125.00 -90.00   74
  3  \w    -65.00 -33.00   0.50    5.00    --  -84.25  86.00-133.00   64
  4  \w    100.00 135.00   0.50    5.00    --  105.75  41.00  32.00   70
  5  \w    153.00 178.00   0.50    5.00    --  105.75  41.00  32.00   50
  6  \w     18.00  77.00   0.50    1.00    --   49.91-107.00  21.00  118
  7  \w    112.00 174.00   0.50    5.00    --  105.75  30.00-150.00  124
  8  \w     37.00 110.00   0.50    5.00    --  105.75 -30.00  60.00  146
  9  \w     39.00  95.00   0.50    1.00    --   49.91-125.00   0.00  112
 10  \w     34.00  59.00   0.50    5.00    --  105.75 -30.00  30.00   50
 11  \w     34.00  60.00   0.50    5.00    --  105.75 -30.00  90.00   52
 12  \w     36.00  61.00   0.50    5.00    --  105.75 -41.00-120.00   50
 13  \w     34.00  59.00   0.50    5.00    --  105.75 -45.00   0.00   50
 14  \w     59.00  89.00   0.50    1.00    --   49.91-125.00 -90.00   60
 15  \w     34.00  60.00   0.50    5.00    --  105.75 -45.00 150.00   52
 16  \w     35.00  60.00   0.50    5.00    --  105.75 -45.00  60.00   50
 17  \w     36.00  69.00   0.50    5.00    --  105.75 -61.00-180.00   66
 18  \w   -115.00 -77.00   0.50    1.00    --  -49.35-125.00 -90.00   76
 19  \w     35.00  68.00   0.50    5.00    --  105.75 -61.00-120.00   66
 20  \w     37.00  62.00   0.50    5.00    --  105.75 -61.00  90.00   50
 21  \w   -120.00 -71.00   0.50    1.00    --  -49.35-125.00-180.00   98
 22  \w     36.00  68.00   0.50    5.00    --  105.75 -61.00 120.00   64
 23  \w   -114.00 -70.00   0.50    1.00    --  -49.35-125.00  30.00   88
 24  \w     35.00  70.00   0.50    5.00    --  105.75 -61.00 150.00   70
 25  \w     48.00  79.00   0.50    5.00    --  105.75 -77.00 -60.00   62
 26  \w     34.00  95.00   0.50    5.00    --  105.75-107.00  21.00  122
;
_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      0.0252952000
_diffrn_orient_matrix_UB_12      -0.0656859000
_diffrn_orient_matrix_UB_13      -0.0137459000
_diffrn_orient_matrix_UB_21      0.0700502000
_diffrn_orient_matrix_UB_22      0.0146878000
_diffrn_orient_matrix_UB_23      0.0134364000
_diffrn_orient_matrix_UB_31      -0.0184761000
_diffrn_orient_matrix_UB_32      -0.0342131000
_diffrn_orient_matrix_UB_33      0.0321528000
_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  0.0491
_diffrn_reflns_av_unetI/netI     0.0428
_diffrn_reflns_Laue_measured_fraction_full 0.999
_diffrn_reflns_Laue_measured_fraction_max 0.985
_diffrn_reflns_limit_h_max       24
_diffrn_reflns_limit_h_min       -25
_diffrn_reflns_limit_k_max       25
_diffrn_reflns_limit_k_min       -25
_diffrn_reflns_limit_l_max       51
_diffrn_reflns_limit_l_min       -36
_diffrn_reflns_number            123357
_diffrn_reflns_point_group_measured_fraction_full 0.997
_diffrn_reflns_point_group_measured_fraction_max 0.968
_diffrn_reflns_theta_full        67.684
_diffrn_reflns_theta_max         77.155
_diffrn_reflns_theta_min         2.449
_diffrn_source                   'micro-focus sealed X-ray tube'
_diffrn_source_type              'PhotonJet (Cu) X-ray Source'
_exptl_absorpt_coefficient_mu    2.780
_exptl_absorpt_correction_T_max  1.000
_exptl_absorpt_correction_T_min  0.198
_exptl_absorpt_correction_type   gaussian
_exptl_absorpt_process_details
'CrysAlisPro 1.171.40.53 (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            red
_exptl_crystal_colour_primary    red
_exptl_crystal_density_diffrn    1.139
_exptl_crystal_description       prism
_exptl_crystal_F_000             5976
_exptl_crystal_recrystallization_method
'The material was recrystallised from --- by as supplied'
_exptl_crystal_size_max          0.553
_exptl_crystal_size_mid          0.405
_exptl_crystal_size_min          0.15
_refine_diff_density_max         1.126
_refine_diff_density_min         -1.091
_refine_diff_density_rms         0.079
_refine_ls_abs_structure_details
;
 Flack x determined using 14370 quotients [(I+)-(I-)]/[(I+)+(I-)]
 (Parsons, Flack and Wagner, Acta Cryst. B69 (2013) 249-259).
;
_refine_ls_abs_structure_Flack   0.055(3)
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.028
_refine_ls_hydrogen_treatment    constr
_refine_ls_matrix_type           full
_refine_ls_number_parameters     1847
_refine_ls_number_reflns         34540
_refine_ls_number_restraints     2461
_refine_ls_restrained_S_all      1.018
_refine_ls_R_factor_all          0.0503
_refine_ls_R_factor_gt           0.0483
_refine_ls_shift/su_max          0.007
_refine_ls_shift/su_mean         0.000
_refine_ls_structure_factor_coef Fsqd
_refine_ls_weighting_details
'w=1/[\s^2^(Fo^2^)+(0.0577P)^2^+32.0731P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1244
_refine_ls_wR_factor_ref         0.1270
_reflns_Friedel_coverage         0.834
_reflns_Friedel_fraction_full    0.995
_reflns_Friedel_fraction_max     0.948
_reflns_number_gt                33360
_reflns_number_total             34540
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            d1sc02474d2.cif
_cod_data_source_block           jcs-pyridine-tppttl-coxtal-xtal2
_cod_original_cell_volume        16846.11(16)
_cod_database_code               1564263
_shelx_shelxl_version_number     2018/3
_chemical_oxdiff_formula         'C704  H576  Cl48  N32  O64  Rh8  '
_shelx_estimated_absorpt_t_max   0.681
_shelx_estimated_absorpt_t_min   0.309
_reflns_odcompleteness_completeness 99.92
_reflns_odcompleteness_iscentric 1
_reflns_odcompleteness_theta     68.13
_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. Uiso/Uaniso restraints and constraints
Uanis(C41_10) \\sim Ueq, Uanis(C40_10) \\sim Ueq: with sigma of 0.002 and sigma
for terminal atoms of 0.004
Uanis(N2_10) \\sim Ueq: with sigma of 0.002 and sigma for terminal atoms of
0.004
Uanis(C17_1) \\sim Ueq, Uanis(C18_1) \\sim Ueq, Uanis(C19_1) \\sim Ueq,
Uanis(C20_1) \\sim Ueq, Uanis(C21_1) \\sim Ueq, Uanis(C22_1) \\sim Ueq: with
sigma of 0.002 and sigma for terminal atoms of 0.004
Uanis(C39_13) = Uanis(C39_10)
Uanis(N2_13) = Uanis(N2_10)
3. Rigid body (RIGU) restrains
 Cl1_6, Cl2_6, C1_6
 with sigma for 1-2 distances of 0.002 and sigma for 1-3 distances of 0.004
 O1_1, O2_1, O3_1, O4_1, N1_1, C1_1, C2_1, C3_1, C4_1, C5_1, C6_1, C7_1, C8_1,
 C9_1, C10_1, C11_1, C12_1, C13_1, C14_1, C15_1, C16_1, C17_1, C18_1, C19_1,
 C20_1, C21_1, C22_1, C23_1, C24_1, C25_1, C26_1, C27_1, C28_1, C29_1, C30_1,
 C31_1, C32_1, C33_1, C34_1, C35_1, C36_1, C37_1, C38_1
 O1_2, O2_2, O3_2, O4_2, N1_2, C1_2, C2_2, C3_2, C4_2, C5_2, C6_2, C7_2, C8_2,
 C9_2, C10_2, C11_2, C12_2, C13_2, C14_2, C15_2, C16_2, C17_2, C18_2, C19_2,
 C20_2, C21_2, C22_2, C23_2, C24_2, C25_2, C26_2, C27_2, C28_2, C29_2, C30_2,
 C31_2, C32_2, C33_2, C34_2, C35_2, C36_2, C37_2, C38_2
 O1_3, O2_3, O3_3, O4_3, N1_3, C1_3, C2_3, C3_3, C4_3, C5_3, C6_3, C7_3, C8_3,
 C9_3, C10_3, C11_3, C12_3, C13_3, C14_3, C15_3, C16_3, C17_3, C18_3, C19_3,
 C20_3, C21_3, C22_3, C23_3, C24_3, C25_3, C26_3, C27_3, C28_3, C29_3, C30_3,
 C31_3, C32_3, C33_3, C34_3, C35_3, C36_3, C37_3, C38_3
 O1_4, O2_4, O3_4, O4_4, N1_4, C1_4, C2_4, C3_4, C4_4, C5_4, C6_4, C7_4, C8_4,
 C9_4, C10_4, C11_4, C12_4, C13_4, C14_4, C15_4, C16_4, C17_4, C18_4, C19_4,
 C20_4, C21_4, C22_4, C23_4, C24_4, C25_4, C26_4, C27_4, C28_4, C29_4, C30_4,
 C31_4, C32_4, C33_4, C34_4, C35_4, C36_4, C37_4, C38_4
 with sigma for 1-2 distances of 0.002 and sigma for 1-3 distances of 0.004
 Cl3_8, N2_8, C39_8, C40_8, C41_8, C42_8, C43_8
 Cl3_9, N2_9, C39_9, C40_9, C41_9, C42_9, C43_9
 Cl3_10, N2_10, C39_10, C40_10, C41_10, C42_10, C43_10
 Cl3_13, N2_13, C39_13, C40_13, C41_13, C42_13, C43_13
 with sigma for 1-2 distances of 0.0002 and sigma for 1-3 distances of 0.0004
4. Same fragment restrains
{Cl3_9, N2_9, C39_9, C40_9, C41_9, C42_9, C43_9}
{Cl3_10, N2_10, C39_10, C40_10, C41_10, C42_10, C43_10}
{Cl3_13, N2_13, C39_13, C40_13, C41_13, C42_13, C43_13}
as
{Cl3_8, N2_8, C39_8, C40_8, C41_8, C42_8, C43_8} sigma for 1-2: 0.002 1-3: 0.004
{O1_2, O2_2, O3_2, O4_2, N1_2, C1_2, C2_2, C3_2, C4_2, C5_2, C6_2, C7_2, C8_2,
C9_2, C10_2, C11_2, C12_2, C13_2, C14_2, C15_2, C16_2, C17_2, C18_2, C19_2,
C20_2, C21_2, C22_2, C23_2, C24_2, C25_2, C26_2, C27_2, C28_2, C29_2, C30_2,
C31_2, C32_2, C33_2, C34_2, C35_2, C36_2, C37_2, C38_2}
{O1_3, O2_3, O3_3, O4_3, N1_3, C1_3, C2_3, C3_3, C4_3, C5_3, C6_3, C7_3, C8_3,
C9_3, C10_3, C11_3, C12_3, C13_3, C14_3, C15_3, C16_3, C17_3, C18_3, C19_3,
C20_3, C21_3, C22_3, C23_3, C24_3, C25_3, C26_3, C27_3, C28_3, C29_3, C30_3,
C31_3, C32_3, C33_3, C34_3, C35_3, C36_3, C37_3, C38_3}
{O1_4, O2_4, O3_4, O4_4, N1_4, C1_4, C2_4, C3_4, C4_4, C5_4, C6_4, C7_4, C8_4,
C9_4, C10_4, C11_4, C12_4, C13_4, C14_4, C15_4, C16_4, C17_4, C18_4, C19_4,
C20_4, C21_4, C22_4, C23_4, C24_4, C25_4, C26_4, C27_4, C28_4, C29_4, C30_4,
C31_4, C32_4, C33_4, C34_4, C35_4, C36_4, C37_4, C38_4}
as
{O1_1, O2_1, O3_1, O4_1, N1_1, C1_1, C2_1, C3_1, C4_1, C5_1, C6_1, C7_1, C8_1,
C9_1, C10_1, C11_1, C12_1, C13_1, C14_1, C15_1, C16_1, C17_1, C18_1, C19_1,
C20_1, C21_1, C22_1, C23_1, C24_1, C25_1, C26_1, C27_1, C28_1, C29_1, C30_1,
C31_1, C32_1, C33_1, C34_1, C35_1, C36_1, C37_1, C38_1} sigma for 1-2: 0.002
1-3: 0.004
5. Others
 Sof(Cl3)=Sof(N2)=Sof(C39)=Sof(C40)=Sof(H40)=Sof(C41)=Sof(H41)=Sof(C42)=
 Sof(H42)=Sof(C43)=Sof(H43)=1-FVAR(1)
 Sof(Cl3)=Sof(N2)=Sof(C39)=Sof(C40)=Sof(H40)=Sof(C41)=Sof(H41)=Sof(C42)=
 Sof(H42)=Sof(C43)=Sof(H43)=FVAR(1)
6.a Ternary CH refined with riding coordinates:
 C2(H2), C2(H2), C2(H2), C2(H2)
6.b Secondary CH2 refined with riding coordinates:
 C1(H1A,H1B)
6.c Aromatic/amide H refined with riding coordinates:
 C12(H12), C13(H13), C14(H14), C15(H15), C16(H16), C18(H18), C19(H19),
 C20(H20), C21(H21), C22(H22), C24(H24), C25(H25), C26(H26), C27(H27), C28(H28),
  C30(H30), C31(H31), C32(H32), C33(H33), C34(H34), C12(H12), C13(H13),
 C14(H14), C15(H15), C16(H16), C18(H18), C19(H19), C20(H20), C21(H21), C22(H22),
  C24(H24), C25(H25), C26(H26), C27(H27), C28(H28), C30(H30), C31(H31),
 C32(H32), C33(H33), C34(H34), C12(H12), C13(H13), C14(H14), C15(H15), C16(H16),
  C18(H18), C19(H19), C20(H20), C21(H21), C22(H22), C24(H24), C25(H25),
 C26(H26), C27(H27), C28(H28), C30(H30), C31(H31), C32(H32), C33(H33), C34(H34),
  C12(H12), C13(H13), C14(H14), C15(H15), C16(H16), C18(H18), C19(H19),
 C20(H20), C21(H21), C22(H22), C24(H24), C25(H25), C26(H26), C27(H27), C28(H28),
  C30(H30), C31(H31), C32(H32), C33(H33), C34(H34), C40(H40), C41(H41),
 C42(H42), C43(H43), C40(H40), C41(H41), C42(H42), C43(H43), C40(H40), C41(H41),
  C42(H42), C43(H43), C40(H40), C41(H41), C42(H42), C43(H43)
6.d Idealised Me refined as rotating group:
 C36(H36A,H36B,H36C), C37(H37A,H37B,H37C), C38(H38A,H38B,H38C), C36(H36A,H36B,
 H36C), C37(H37A,H37B,H37C), C38(H38A,H38B,H38C), C36(H36A,H36B,H36C), C37(H37A,
 H37B,H37C), C38(H38A,H38B,H38C), C36(H36A,H36B,H36C), C37(H37A,H37B,H37C),
 C38(H38A,H38B,H38C)
;
_smtbx_masks_void_probe_radius   0.3
_smtbx_masks_void_truncation_radius 1.2
_shelx_res_checksum              23046
_shelx_hkl_checksum              94578
_shelx_fab_checksum              98492
_olex2_exptl_crystal_mounting_method
'The crystal was mounted on a loop with paratone oil'
_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 1.120
_oxdiff_exptl_absorpt_empirical_full_min 0.854