trans-Diastereoselective Ru(II)-Catalyzed Asymmetric Transfer Hydrogenation of α-Acetamido Benzocyclic Ketones via Dynamic Kinetic Resolution

A highly efficient enantio- and diastereoselective catalyzed asymmetric transfer hydrogenation via dynamic kinetic resolution (DKR–ATH) of α,β-dehydro-α-acetamido and α-acetamido benzocyclic ketones to ent-trans-β-amido alcohols is disclosed employing a new ansa-Ru(II) complex of an enantiomerically pure syn-N,N-ligand, i.e. ent-syn-ULTAM-(CH2)3Ph. DFT calculations of the transition state structures revealed an atypical two-pronged substrate attractive stabilization engaging the commonly encountered CH/π electrostatic interaction and a new additional O=S=O···HNAc H-bond hence favoring the trans-configured products.


Computational Methods
All calculations were executed using Gaussian 09, Revision E.01. 18 The geometries of reactants, catalyst and transition states were optimized at M06-2x/6-31G(d, p) level in gas phase and in chlorobenzenne

Single-crystal X-ray diffraction of C4
Obtaining a single crystal of RuCl[syn-(3R,1'S)-ULTAM-(CH2)3Ph] (C4) was challenging. Several crystallization attempts have failed. A small single crystal (0.130 × 0.049 × 0.031 mm) of rather poor quality was finally discovered in powdered material obtained from MeOH/CH2Cl2 solution. This crystal was attached to a MiTeGen MicroMount™ (100 μm aperture size) ( Figure S3) with silicone grease (Merck) and transferred onto the magnetic base of the goniometer head. Single-crystal X-ray diffraction data were collected on an Agilent SuperNova Dual diffractometer equipped with an Atlas CCD area detector using micro-focus sealed X-ray tube with mirror monochromator. Crystal was measured with Cu Kα radiation in cold nitrogen stream at 150 K. CrysAlisPro software package 21 was used for data processing, including an empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm, and a numerical absorption correction based on Gaussian integration over a multifaceted crystal model. Crystal structure was solved and refined within OLEX2 (v. 1.2) program 22 by the SHELXT structure solution program 23 and full-matrix least-squares minimization with SHELXL (v. 2018/3), 24 respectively. Final difference Fourier map displays highest peak and deepest hole (0.443/−0.529 eÅ −3 ) located 0.74 Å from C18 and 0.75 Å from Ru, respectively (Table S3). Molecular graphics were prepared using the Diamond software. 25 Figure S3. Single crystal of RuCl[syn-(3R,1'S)-ULTAM-(CH2)3Ph] (C4) mounted on a MiTeGen MicroMount™ (100 μm aperture size) that was used for single-crystal X-ray diffraction. Crystal in the second (middle) and third (right) photo is rotated by 84° and 126°, respectively, with respect to the orientation in the first photo (left).
The aforementioned poor quality of the measured small single crystal is reflected in the low C−C bond precision (0.012 Å). However, the anisotropic refinement of the crystal structure model including all non-hydrogen atoms resulted in the difference electron density map where residual electron density maxima for all hydrogen atoms could be located at the expected positions. The sole exception was the phenyl hydrogen atom H21 attached to C21, where several Fourier peaks could be observed in the vicinity of the carbon atom. The refinement of the crystal structure with all carbon-bonded hydrogen atoms included in calculated positions using a riding model yielded the strongest residual electron density peak (0.52 eÅ −3 ) located 0.87 Å from N1, as expected for the R2N−H amine moiety. Hydrogen atom bonded to N1 was thus placed in the aforementioned position. Free refinement of this acidic H1-atom resulted in short H1−N1 distance (0.73(7) Å) and in unrealistically small Uiso (0.003(15) Å 2 ).

Single-crystal X-ray diffraction of P6
A selected needle-shaped colorless crystal was mounted on a glass fiber ( Figure S9). Single-crystal X-ray diffraction data were collected on an Agilent SuperNova Dual diffractometer equipped with an Atlas CCD area detector using micro-focus sealed X-ray tube with mirror monochromator. Crystal was measured with Cu Kα radiation in cold nitrogen stream at 150 K. CrysAlisPro software package 21 was used for data processing, including an empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm, and a numerical absorption correction based on Gaussian integration over a multifaceted crystal model. Crystal structure was solved and refined within OLEX2 (v. 1.2) program 22 by the SHELXT structure solution program 23 and full-matrix least-squares minimization with SHELXL (v. 2018/3), 24 respectively. Final difference Fourier map displays highest peak and deepest hole (0.182/−0.140 eÅ −3 ) located 0.77 Å from C3 and 0.99 Å from C8, respectively (Table S7). Molecular graphics were prepared using the Diamond software. 25 Figure S9. Single crystal of P6 mounted on a glass fiber.
Residual electron density maxima for all hydrogen atoms could be located in the difference electron density map. The hydrogen atoms located on heteroatoms (O1, N1) and chiral centers (C1, C2, C3) were freely isotropically refined. All other carbon-bonded hydrogen atoms were included in calculated positions using a riding model. Three Fourier peaks, including the strongest residual electron density peak (0.25, 0.14, 0.12 eÅ −3 ), could be observed in between the hydrogen atoms of the C17 methyl group (AFIX 137). This group was therefore modelled with hydrogen atoms disordered over the two positions rotated from one another by 56.1(3)°. The refinement of the second free variable yielded equal occupancies (0.50 (3) Figure S10. The asymmetric unit and the atom numbering scheme in the crystal structure of P6. Thermal ellipsoids are drawn at the 50% probability level and hydrogen atoms are depicted as small spheres of arbitrary radius. The methyl group H-atoms are disordered over two positions with equal occupancies (0.50 (3)).
The P6 compound crystallises in the monoclinic space group P21 with two molecules in the unit cell. The asymmetric unit is comprised of a single molecule (Figure S10, Table S8, Table S9). The absolute configuration established by anomalous dispersion (Flack x = −0.12(9), Hooft y = −0.10(9)) is S, S, R for C1, C2, and C3, respectively.
Each molecule is hydrogen-bonded to four other molecules by donating two ( (Table S10).