An Aldol-Based Build/Couple/Pair Strategy for the Synthesis of Medium- and Large-Sized Rings: Discovery of Macrocyclic Histone Deacetylase Inhibitors
Lisa A. Marcaurelle; Eamon Comer; Sivaraman Dandapani; Jeremy R. Duvall; Baudouin Gerard; Sarathy Kesavan; Maurice D. Lee; Haibo Liu; Jason T. Lowe; Jean-Charles Marie; Carol A. Mulrooney; Bhaumik A. Pandya; Ann Rowley; Troy D. Ryba; Byung-Chul Suh; Jingqiang Wei; Damian W. Young; Lakshmi B. Akella; Nathan T. Ross; Yan-Ling Zhang; Daniel M. Fass; Surya A. Reis; Wen-Ning Zhao; Stephen J. Haggarty; Michelle Palmer; Michael A. Foley; Journal of the American Chemical Society 132 (2010) 16962–16976; doi:10.1021/ja105119r

data_4103579
_publ_section_title
;
 An Aldol-Based Build/Couple/Pair Strategy for the Synthesis of Medium-
 and Large-Sized Rings: Discovery of Macrocyclic Histone Deacetylase
 Inhibitors
;
_journal_name_full               'Journal of the American Chemical Society'
_journal_page_first              16962
_journal_page_last               16976
_journal_paper_doi               10.1021/ja105119r
_journal_volume                  132
_journal_year                    2010
_chemical_absolute_configuration ad
_chemical_formula_sum            'C29 H45 N5 O6'
_chemical_formula_weight         559.70
_space_group_IT_number           4
_symmetry_cell_setting           monoclinic
_symmetry_space_group_name_Hall  'P 2yb'
_symmetry_space_group_name_H-M   'P 1 21 1'
_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                 92.4280(10)
_cell_angle_gamma                90.00
_cell_formula_units_Z            2
_cell_length_a                   10.7412(3)
_cell_length_b                   9.4434(2)
_cell_length_c                   14.6583(4)
_cell_measurement_reflns_used    9741
_cell_measurement_temperature    100(2)
_cell_measurement_theta_max      68.45
_cell_measurement_theta_min      3.02
_cell_volume                     1485.51(7)
_computing_cell_refinement       'SAINT 7.46A (Bruker-AXS, 2009)'
_computing_data_collection       'APEX2 v2009.9.0 (Bruker-AXS, 2009)'
_computing_data_reduction        'SAINT 7.46A (Bruker-AXS, 2009)'
_computing_molecular_graphics    'Bruker SHELXTL'
_computing_publication_material  'Bruker SHELXTL'
_computing_structure_refinement  'SHELXL-97 (Sheldrick, 2008)'
_computing_structure_solution    'SHELXS-97 (Sheldrick, 2008)'
_diffrn_ambient_temperature      100(2)
_diffrn_detector_area_resol_mean 8.3
_diffrn_measured_fraction_theta_full 0.961
_diffrn_measured_fraction_theta_max 0.961
_diffrn_measurement_device_type  'Bruker Smart APEX CCD'
_diffrn_measurement_method       'omega and phi 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  0.0184
_diffrn_reflns_av_sigmaI/netI    0.0117
_diffrn_reflns_limit_h_max       9
_diffrn_reflns_limit_h_min       -12
_diffrn_reflns_limit_k_max       11
_diffrn_reflns_limit_k_min       -11
_diffrn_reflns_limit_l_max       17
_diffrn_reflns_limit_l_min       -17
_diffrn_reflns_number            28376
_diffrn_reflns_theta_full        67.54
_diffrn_reflns_theta_max         67.54
_diffrn_reflns_theta_min         4.12
_exptl_absorpt_coefficient_mu    0.717
_exptl_absorpt_correction_T_max  0.9515
_exptl_absorpt_correction_T_min  0.7247
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details   'SADABS (Sheldrick, 2009)'
_exptl_crystal_colour            colourless
_exptl_crystal_density_diffrn    1.251
_exptl_crystal_density_method    'not measured'
_exptl_crystal_description       plate
_exptl_crystal_F_000             604
_exptl_crystal_size_max          0.48
_exptl_crystal_size_mid          0.25
_exptl_crystal_size_min          0.07
_refine_diff_density_max         0.152
_refine_diff_density_min         -0.138
_refine_diff_density_rms         0.029
_refine_ls_abs_structure_details 'Flack H D (1983), Acta Cryst. A39, 876-881'
_refine_ls_abs_structure_Flack   0.01(10)
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.029
_refine_ls_hydrogen_treatment    constr
_refine_ls_matrix_type           full
_refine_ls_number_parameters     368
_refine_ls_number_reflns         5144
_refine_ls_number_restraints     1
_refine_ls_restrained_S_all      1.029
_refine_ls_R_factor_all          0.0249
_refine_ls_R_factor_gt           0.0248
_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^)+(0.0373P)^2^+0.2913P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.0636
_refine_ls_wR_factor_ref         0.0637
_reflns_number_gt                5114
_reflns_number_total             5144
_reflns_threshold_expression     >2sigma(I)
_cod_data_source_file            ja105119r_si_005.cif
_cod_data_source_block           d09076
_cod_database_code               4103579