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_7250592
_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_absolute_configuration ad
_chemical_formula_moiety         'C16 H22 F N O3'
_chemical_formula_sum            'C16 H22 F N O3'
_chemical_formula_weight         295.356
_chemical_name_systematic        15xia
_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_Int_Tables_number      19
_atom_sites_solution_primary     iterative
_audit_block_doi                 10.5517/ccdc.csd.cc2mnr68
_audit_creation_date             2025-02-18
_audit_creation_method
;
Olex2 1.5
(compiled 2024.02.16 svn.r378c4104 for OlexSys, GUI svn.r6928)
;
_audit_update_record
;
2025-03-21 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                   6.08342(6)
_cell_length_b                   12.36031(13)
_cell_length_c                   21.0393(2)
_cell_measurement_reflns_used    13255
_cell_measurement_temperature    99.9(4)
_cell_measurement_theta_max      74.0150
_cell_measurement_theta_min      3.5670
_cell_volume                     1582.01(3)
_computing_cell_refinement       'CrysAlisPro 1.171.42.102a (Rigaku OD, 2023)'
_computing_data_collection       'CrysAlisPro 1.171.42.102a (Rigaku OD, 2023)'
_computing_data_reduction        'CrysAlisPro 1.171.42.102a (Rigaku OD, 2023)'
_computing_molecular_graphics    'Olex2 1.5 (Dolomanov et al., 2009)'
_computing_publication_material  'Olex2 1.5 (Dolomanov et al., 2009)'
_computing_structure_refinement  'olex2.refine 1.5 (Bourhis et al., 2015)'
_computing_structure_solution    'olex2.solve 1.5 (Bourhis et al., 2015)'
_diffrn_ambient_environment      N~2~
_diffrn_ambient_temperature      99.9(4)
_diffrn_detector                 'Hybrid Pixel Array Detector'
_diffrn_detector_area_resol_mean 10.0000
_diffrn_detector_type            'HyPix-Arc 150'
_diffrn_measured_fraction_theta_full 1.0000
_diffrn_measured_fraction_theta_max 0.9631
_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    -92.00 -31.00   0.50    0.05    --  -77.31 111.00  90.00  122
  2  \w    -85.00 -16.00   0.50    0.05    --  -57.80 125.00  30.00  138
  3  \w    -98.00 -31.00   0.50    0.05    --  -77.31 119.00  15.00  134
  4  \w    -92.00 -31.00   0.50    0.05    --  -77.31 111.00 -30.00  122
  5  \w    -91.00 -32.00   0.50    0.05    --  -77.31 103.00 -68.00  118
  6  \w    -72.00 -12.00   0.50    0.05    --  -57.80 103.00 -68.00  120
  7  \w    -92.00 -31.00   0.50    0.05    --  -77.31 111.00-120.00  122
  8  \w    -92.00 -31.00   0.50    0.05    --  -77.31 111.00-180.00  122
  9  \w   -131.00 -67.00   0.50    0.05    --  -77.31 -24.00   4.00  128
 10  \w   -110.00 -65.00   0.50    0.05    --  -57.80 -30.00  60.00   90
 11  \w   -130.00 -85.00   0.50    0.05    --  -77.31 -30.00 -30.00   90
 12  \w   -121.00 -76.00   0.50    0.05    --  -68.99 -30.00-120.00   90
 13  \w   -121.00 -76.00   0.50    0.05    --  -68.99 -30.00-180.00   90
 14  \w   -130.00 -85.00   0.50    0.05    --  -77.31 -30.00-150.00   90
 15  \w   -110.00 -65.00   0.50    0.05    --  -57.80 -30.00-120.00   90
 16  \w   -130.00 -85.00   0.50    0.05    --  -77.31 -30.00 -60.00   90
 17  \w   -110.00 -72.00   0.50    0.05    --  -57.80 -30.00 -30.00   76
 18  \w   -111.00 -47.00   0.50    0.05    --  -57.80 -24.00   4.00  128
 19  \w   -121.00 -76.00   0.50    0.05    --  -68.99 -30.00 120.00   90
 20  \w   -130.00 -85.00   0.50    0.05    --  -77.31 -30.00 150.00   90
 21  \w     74.00 139.00   0.50    0.05    --   85.54  24.00 169.00  130
 22  \w     92.00 138.00   0.50    0.05    --   85.54  30.00  90.00   92
 23  \w     92.00 138.00   0.50    0.05    --   85.54  30.00 -30.00   92
 24  \w     92.00 138.00   0.50    0.05    --   85.54  30.00 -60.00   92
 25  \w      8.00  78.00   0.50    0.05    --   54.52-119.00 -69.00  140
 26  \w     11.00  63.00   0.50    0.05    --   54.52 -95.00-180.00  104
 27  \w     42.00  92.00   0.50    0.05    --   85.54 -95.00-120.00  100
 28  \w     42.00  92.00   0.50    0.05    --   85.54 -95.00  90.00  100
;
_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      0.2237472000
_diffrn_orient_matrix_UB_12      -0.0018801000
_diffrn_orient_matrix_UB_13      -0.0342593000
_diffrn_orient_matrix_UB_21      -0.1138642000
_diffrn_orient_matrix_UB_22      -0.0383495000
_diffrn_orient_matrix_UB_23      -0.0614166000
_diffrn_orient_matrix_UB_31      -0.0331797000
_diffrn_orient_matrix_UB_32      0.1185747000
_diffrn_orient_matrix_UB_33      -0.0203998000
_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  0.0345
_diffrn_reflns_av_unetI/netI     0.0196
_diffrn_reflns_Laue_measured_fraction_full 1.0000
_diffrn_reflns_Laue_measured_fraction_max 0.9631
_diffrn_reflns_limit_h_max       7
_diffrn_reflns_limit_h_min       -7
_diffrn_reflns_limit_k_max       15
_diffrn_reflns_limit_k_min       -11
_diffrn_reflns_limit_l_max       26
_diffrn_reflns_limit_l_min       -25
_diffrn_reflns_number            17784
_diffrn_reflns_point_group_measured_fraction_full 0.9979
_diffrn_reflns_point_group_measured_fraction_max 0.9387
_diffrn_reflns_theta_full        67.6840
_diffrn_reflns_theta_max         74.39
_diffrn_reflns_theta_min         4.15
_diffrn_source                   'Rotating-anode X-ray tube'
_diffrn_source_type              'Rigaku (Cu) X-ray Source'
_exptl_absorpt_coefficient_mu    0.768
_exptl_absorpt_correction_T_max  1.00000
_exptl_absorpt_correction_T_min  0.76047
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details
;
CrysAlisPro 1.171.42.102a (Rigaku Oxford Diffraction, 2023)
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    1.240
_exptl_crystal_description       block
_exptl_crystal_F_000             634.290
_exptl_crystal_preparation       single
_exptl_crystal_recrystallization_method 'vapor diffusion'
_exptl_crystal_size_max          0.1
_exptl_crystal_size_mid          0.1
_exptl_crystal_size_min          0.1
_refine_diff_density_max         0.1579
_refine_diff_density_min         -0.1715
_refine_diff_density_rms         0.0350
_refine_ls_abs_structure_details
'Hooft, R.W.W., Straver, L.H., Spek, A.L. (2010). J. Appl. Cryst., 43, 665-668.'
_refine_ls_abs_structure_Flack   -0.08(4)
_refine_ls_d_res_high            0.8005
_refine_ls_d_res_low             10.6573
_refine_ls_goodness_of_fit_ref   0.7816
_refine_ls_hydrogen_treatment    constr
_refine_ls_matrix_type           full
_refine_ls_number_constraints    35
_refine_ls_number_parameters     194
_refine_ls_number_reflns         3045
_refine_ls_number_restraints     0
_refine_ls_restrained_S_all      0.7816
_refine_ls_R_factor_all          0.0291
_refine_ls_R_factor_gt           0.0278
_refine_ls_shift/su_max          -0.0008
_refine_ls_shift/su_mean         0.0001
_refine_ls_structure_factor_coef Fsqd
_refine_ls_weighting_details
'w=1/[\s^2^(Fo^2^)+(0.1P)^2^] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.0859
_refine_ls_wR_factor_ref         0.0877
_reflns_Friedel_coverage         0.904
_reflns_limit_h_max              7
_reflns_limit_h_min              -7
_reflns_limit_k_max              15
_reflns_limit_k_min              -15
_reflns_limit_l_max              26
_reflns_limit_l_min              -25
_reflns_number_gt                2920
_reflns_number_total             3045
_reflns_threshold_expression     I>=2u(I)
_cod_data_source_file            d5ra02485d2.cif
_cod_data_source_block           15-xia_auto
_cod_original_sg_symbol_Hall     ' P 2ac 2ab'
_cod_database_code               7250592
_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, All O(H) groups
2.a Ternary CH refined with riding coordinates:
 C008(H008), C00A(H00A)
2.b Secondary CH2 refined with riding coordinates:
 C00B(H00b,H00c), C00F(H00g,H00h), C00G(H00i,H00j)
2.c Aromatic/amide H refined with riding coordinates:
 C00H(H00k), C00E(H00f), C00C(H00d), C00D(H00e)
2.d Idealised Me refined as rotating group:
 C00J(H00l,H00m,H00n), C00K(H00o,H00p,H00q), C00L(H00r,H00s,H00t)
2.e Idealised tetrahedral OH refined as rotating group:
 O002(H002)
;
_olex2_exptl_crystal_mounting_method loop
_olex2_submission_original_sample_id 15xia
_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 1.697
_oxdiff_exptl_absorpt_empirical_full_min 0.551