Stereoselective Synthesis of Spiropiperidines as BACE-1 Aspartyl Protease Inhibitors via Late Stage N-Arylation of a 1,8-Diazaspiro[4.5]dec-3-en-2-one Pharmacophore
Che-Wah Lee; Ricardo Lira; Jason Dutra; Kevin Ogilvie; Brian T. O'Neill; Michael Brodney; Christopher Helal; Joseph Young; Erik Lachapelle; Subas Sakya; John C. Murray; Journal of Organic Chemistry 78 (2013) 2661–2669; doi:10.1021/jo400016m

data_4028067
_publ_section_title
;
 Stereoselective Synthesis of Spiropiperidines as BACE-1 Aspartyl Protease
 Inhibitors via Late Stage N-Arylation of a
 1,8-Diazaspiro[4.5]dec-3-en-2-one Pharmacophore
;
_journal_name_full               'Journal of Organic Chemistry'
_journal_page_first              2661
_journal_page_last               2669
_journal_paper_doi               10.1021/jo400016m
_journal_volume                  78
_journal_year                    2013
_chemical_absolute_configuration ad
_chemical_formula_sum            'C16 H23 Cl N2 O4'
_chemical_formula_weight         342.81
_space_group_IT_number           19
_symmetry_cell_setting           orthorhombic
_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_method           SHELXL-97
_cell_angle_alpha                90.00
_cell_angle_beta                 90.00
_cell_angle_gamma                90.00
_cell_formula_units_Z            8
_cell_length_a                   9.1205(16)
_cell_length_b                   10.1770(17)
_cell_length_c                   39.051(7)
_cell_measurement_reflns_used    9635
_cell_measurement_temperature    296(2)
_cell_measurement_theta_max      64.16
_cell_measurement_theta_min      4.34
_cell_volume                     3624.7(11)
_computing_cell_refinement       'Bruker SAINT'
_computing_data_collection       'Bruker APEX2'
_computing_data_reduction        'Bruker SAINT'
_computing_molecular_graphics    'Bruker SHELXTL'
_computing_publication_material  'Bruker SHELXTL'
_computing_structure_refinement  'SHELXL-97 (Sheldrick, 1997)'
_computing_structure_solution    'SHELXS-97 (Sheldrick, 1990)'
_diffrn_ambient_temperature      296(2)
_diffrn_measured_fraction_theta_full 0.960
_diffrn_measured_fraction_theta_max 0.960
_diffrn_measurement_device_type  'Bruker APEX-II CCD'
_diffrn_measurement_method       '\f and \w scans'
_diffrn_radiation_monochromator  graphite
_diffrn_radiation_source         'fine-focus sealed tube'
_diffrn_radiation_type           CuK\a
_diffrn_radiation_wavelength     1.54178
_diffrn_reflns_av_R_equivalents  0.0500
_diffrn_reflns_av_sigmaI/netI    0.0490
_diffrn_reflns_limit_h_max       10
_diffrn_reflns_limit_h_min       -8
_diffrn_reflns_limit_k_max       9
_diffrn_reflns_limit_k_min       -11
_diffrn_reflns_limit_l_max       45
_diffrn_reflns_limit_l_min       -43
_diffrn_reflns_number            14602
_diffrn_reflns_theta_full        64.56
_diffrn_reflns_theta_max         64.56
_diffrn_reflns_theta_min         2.26
_diffrn_standards_number         0
_exptl_absorpt_coefficient_mu    2.043
_exptl_absorpt_correction_T_max  0.8536
_exptl_absorpt_correction_T_min  0.3737
_exptl_absorpt_correction_type   empirical
_exptl_crystal_colour            colourless
_exptl_crystal_density_diffrn    1.256
_exptl_crystal_density_meas      0
_exptl_crystal_description       PLATE
_exptl_crystal_F_000             1456
_exptl_crystal_size_max          0.60
_exptl_crystal_size_mid          0.30
_exptl_crystal_size_min          0.08
_refine_diff_density_max         0.456
_refine_diff_density_min         -0.589
_refine_diff_density_rms         0.155
_refine_ls_abs_structure_details 'Flack H D (1983), Acta Cryst. A39, 876-881'
_refine_ls_abs_structure_Flack   0.028(17)
_refine_ls_extinction_coef       0.0057(5)
_refine_ls_extinction_expression Fc^*^=kFc[1+0.001xFc^2^\l^3^/sin(2\q)]^-1/4^
_refine_ls_extinction_method     SHELXL
_refine_ls_goodness_of_fit_ref   1.059
_refine_ls_hydrogen_treatment    mixed
_refine_ls_matrix_type           full
_refine_ls_number_parameters     433
_refine_ls_number_reflns         5563
_refine_ls_number_restraints     0
_refine_ls_restrained_S_all      1.059
_refine_ls_R_factor_all          0.0672
_refine_ls_R_factor_gt           0.0584
_refine_ls_shift/su_max          0.000
_refine_ls_shift/su_mean         0.000
_refine_ls_structure_factor_coef Fsqd
_refine_ls_weighting_details
'calc w=1/[\s^2^(Fo^2^)+(0.1170P)^2^+0.0000P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1465
_refine_ls_wR_factor_ref         0.1583
_reflns_number_gt                4924
_reflns_number_total             5563
_reflns_threshold_expression     >2sigma(I)
_cod_data_source_file            jo400016m_si_003.cif
_cod_data_source_block           i891_dutra
_cod_database_code               4028067