Enzymatic synthesis of four stereoisomers of 3-substituted-4-hydroxypiperidines by carbonyl reductase-catalyzed reduction
Chen, Jing; Chen, Xi; Song, Jinsong; Zhang, Hongliu; Yang, Hongjiang; Feng, Jinhui; Wu, Qiaqing; Zhu, Dunming; RSC Advances 15 (2025) 21133–21141; doi:10.1039/D5RA02485D

data_7250594
_publ_section_title
;
 Enzymatic synthesis of four stereoisomers of
 3-substituted-4-hydroxypiperidines by carbonyl reductase-catalyzed
 reduction
;
_journal_issue                   26
_journal_name_full               'RSC Advances'
_journal_page_first              21133
_journal_page_last               21141
_journal_paper_doi               10.1039/D5RA02485D
_journal_volume                  15
_journal_year                    2025
_chemical_formula_moiety         'C16 H22 N O3'
_chemical_formula_sum            'C16 H22 N O3'
_chemical_formula_weight         276.34
_chemical_name_systematic        1
_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_block_doi                 10.5517/ccdc.csd.cc2mbsxp
_audit_creation_date             2024-01-26
_audit_creation_method
;
Olex2 1.3-ac4
(compiled 2020.11.27 svn.r5f609507 for Rigaku Oxford Diffraction, GUI svn.r6214)
;
_audit_update_record
;
2025-02-13 deposited with the CCDC.	2025-06-25 downloaded from the CCDC.
;
_cell_angle_alpha                90
_cell_angle_beta                 90
_cell_angle_gamma                90
_cell_formula_units_Z            4
_cell_length_a                   6.2527(6)
_cell_length_b                   13.3719(10)
_cell_length_c                   18.7005(15)
_cell_measurement_reflns_used    6915
_cell_measurement_temperature    100.00(10)
_cell_measurement_theta_max      68.9890
_cell_measurement_theta_min      3.9480
_cell_volume                     1563.6(2)
_computing_cell_refinement       'CrysAlisPro 1.171.41.122a (Rigaku OD, 2021)'
_computing_data_collection       'CrysAlisPro 1.171.41.122a (Rigaku OD, 2021)'
_computing_data_reduction        'CrysAlisPro 1.171.41.122a (Rigaku OD, 2021)'
_computing_molecular_graphics    'Olex2 1.3-ac4 (Dolomanov et al., 2009)'
_computing_publication_material  'Olex2 1.3-ac4 (Dolomanov et al., 2009)'
_computing_structure_refinement  'SHELXL 2018/3 (Sheldrick, 2015)'
_computing_structure_solution    'SHELXT  (Sheldrick, 2015)'
_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-Arc 150'
_diffrn_measured_fraction_theta_full 0.995
_diffrn_measured_fraction_theta_max 0.940
_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     85.00 131.00   0.50    0.50    --   78.20  30.00 150.00   92
  2  \w     92.00 138.00   0.50    0.50    --   85.54  30.00-120.00   92
  3  \w     73.00 118.00   0.50    0.50    --   65.83  30.00-150.00   90
  4  \w    -96.00 -33.00   0.50    0.50    --  -82.00 111.00-150.00  126
  5  \w    -98.00 -20.00   0.50    0.50    --  -69.06 125.00-120.00  156
  6  \w    -97.00 -28.00   0.50    0.50    --  -77.27 111.00   0.00  138
  7  \w    -67.00 -13.00   0.50    0.50    --  -57.83  97.00  98.00  108
  8  \w    -87.00 -33.00   0.50    0.50    --  -77.27  97.00  98.00  108
  9  \w    -91.00 -37.00   0.50    0.50    --  -82.00  97.00  98.00  108
 10  \w    -97.00 -55.00   0.50    0.50    --  -77.27 111.00 150.00   84
 11  \w    -78.00 -25.00   0.50    0.50    --  -69.06  97.00  98.00  106
 12  \w   -110.00 -65.00   0.50    0.50    --  -57.83 -30.00 -30.00   90
 13  \w   -130.00 -85.00   0.50    0.50    --  -77.27 -30.00 -30.00   90
 14  \w   -134.00 -89.00   0.50    0.50    --  -82.00 -30.00   0.00   90
 15  \w   -134.00 -89.00   0.50    0.50    --  -82.00 -30.00 -90.00   90
 16  \w   -130.00 -85.00   0.50    0.50    --  -77.27 -30.00  30.00   90
 17  \w   -130.00 -85.00   0.50    0.50    --  -77.27 -30.00  60.00   90
 18  \w   -130.00 -85.00   0.50    0.50    --  -77.27 -30.00 120.00   90
 19  \w   -110.00 -65.00   0.50    0.50    --  -57.83 -30.00 150.00   90
 20  \w   -110.00 -65.00   0.50    0.50    --  -57.83 -30.00  60.00   90
 21  \w   -130.00 -85.00   0.50    0.50    --  -77.27 -30.00 -60.00   90
 22  \w   -130.00 -85.00   0.50    0.50    --  -77.27 -30.00-120.00   90
 23  \w     22.00  74.00   0.50    0.50    --   65.83 -95.00-180.00  104
 24  \w     11.00  63.00   0.50    0.50    --   54.56 -95.00-120.00  104
 25  \w     10.00  65.00   0.50    0.50    --   54.56 -97.00  -9.00  110
 26  \w     22.00  76.00   0.50    0.50    --   65.83 -97.00  -9.00  108
 27  \w     34.00  89.00   0.50    0.50    --   78.20 -97.00  -9.00  110
 28  \w     41.00  93.00   0.50    0.50    --   85.54 -97.00  -9.00  104
 29  \w     11.00  63.00   0.50    0.50    --   54.56 -95.00  90.00  104
;
_diffrn_measurement_device       'four-circle diffractometer'
_diffrn_measurement_device_type  'ROD, Synergy Custom system, HyPix-Arc 150'
_diffrn_measurement_method       '\w scans'
_diffrn_orient_matrix_type
'CrysAlisPro convention (1999,Acta A55,543-557)'
_diffrn_orient_matrix_UB_11      0.1643441000
_diffrn_orient_matrix_UB_12      0.0766221000
_diffrn_orient_matrix_UB_13      0.0277174000
_diffrn_orient_matrix_UB_21      0.1634579000
_diffrn_orient_matrix_UB_22      -0.0372298000
_diffrn_orient_matrix_UB_23      -0.0555158000
_diffrn_orient_matrix_UB_31      -0.0841462000
_diffrn_orient_matrix_UB_32      0.0774751000
_diffrn_orient_matrix_UB_33      -0.0541458000
_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  0.0967
_diffrn_reflns_av_unetI/netI     0.0450
_diffrn_reflns_Laue_measured_fraction_full 0.995
_diffrn_reflns_Laue_measured_fraction_max 0.940
_diffrn_reflns_limit_h_max       7
_diffrn_reflns_limit_h_min       -7
_diffrn_reflns_limit_k_max       16
_diffrn_reflns_limit_k_min       -15
_diffrn_reflns_limit_l_max       22
_diffrn_reflns_limit_l_min       -23
_diffrn_reflns_number            17485
_diffrn_reflns_point_group_measured_fraction_full 0.986
_diffrn_reflns_point_group_measured_fraction_max 0.922
_diffrn_reflns_theta_full        67.684
_diffrn_reflns_theta_max         73.339
_diffrn_reflns_theta_min         5.774
_diffrn_source                   'Rotating-anode X-ray tube'
_diffrn_source_type              'Rigaku (Cu) X-ray Source'
_exptl_absorpt_coefficient_mu    0.649
_exptl_absorpt_correction_T_max  1.00000
_exptl_absorpt_correction_T_min  0.60243
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details
;
CrysAlisPro 1.171.41.122a (Rigaku Oxford Diffraction, 2021)
Empirical absorption correction using spherical harmonics,
implemented in SCALE3 ABSPACK scaling algorithm.
;
_exptl_crystal_colour            'clear light colourless'
_exptl_crystal_colour_lustre     clear
_exptl_crystal_colour_modifier   light
_exptl_crystal_colour_primary    colourless
_exptl_crystal_density_diffrn    1.174
_exptl_crystal_description       block
_exptl_crystal_F_000             596
_exptl_crystal_size_max          0.1
_exptl_crystal_size_mid          0.1
_exptl_crystal_size_min          0.1
_refine_diff_density_max         0.256
_refine_diff_density_min         -0.189
_refine_diff_density_rms         0.043
_refine_ls_abs_structure_details
;
 Flack x determined using 808 quotients [(I+)-(I-)]/[(I+)+(I-)]
 (Parsons, Flack and Wagner, Acta Cryst. B69 (2013) 249-259).
;
_refine_ls_abs_structure_Flack   0.02(19)
_refine_ls_extinction_coef       0.0086(15)
_refine_ls_extinction_expression Fc^*^=kFc[1+0.001xFc^2^\l^3^/sin(2\q)]^-1/4^
_refine_ls_extinction_method     'SHELXL-2018/3 (Sheldrick 2018)'
_refine_ls_goodness_of_fit_ref   1.021
_refine_ls_hydrogen_treatment    constr
_refine_ls_matrix_type           full
_refine_ls_number_parameters     185
_refine_ls_number_reflns         2905
_refine_ls_number_restraints     0
_refine_ls_restrained_S_all      1.021
_refine_ls_R_factor_all          0.0615
_refine_ls_R_factor_gt           0.0481
_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^)+(0.0870P)^2^] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1263
_refine_ls_wR_factor_ref         0.1359
_reflns_Friedel_coverage         0.682
_reflns_Friedel_fraction_full    0.974
_reflns_Friedel_fraction_max     0.897
_reflns_number_gt                2280
_reflns_number_total             2905
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            d5ra02485d2.cif
_cod_data_source_block           exp_604_auto
_cod_database_code               7250594
_shelx_shelxl_version_number     2018/3
_shelx_estimated_absorpt_t_max   0.938
_shelx_estimated_absorpt_t_min   0.938
_reflns_odcompleteness_completeness 100.00
_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:
 C3(H3), C2(H2)
2.b Secondary CH2 refined with riding coordinates:
 C4(H4A,H4B), C1(H1A,H1B), C5(H5A,H5B)
2.c Aromatic/amide H refined with riding coordinates:
 C12(H12), C8(H8), C11(H11), C10(H10), C9(H9)
2.d Idealised Me refined as rotating group:
 C16(H16A,H16B,H16C), C18(H18A,H18B,H18C), C17(H17A,H17B,H17C)
;
_olex2_submission_original_sample_id chenjing20240126
_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 3.069
_oxdiff_exptl_absorpt_empirical_full_min 0.281