Crystal Structure of (2S,5R)-2-(tert-Butyl)-5-phenyl-5-(cyclopentyl-1-ol)-1,3-dioxolan-4-one

Abstract

Tertiary hydroxy acids and esters are highly important components in the asymmetric synthesis of a variety of natural products and medicinal agents.1,2 Our recent drug candidate, 9α-(3-azabicyclo[3,3,1]nonanyl)-2′-cyclopentyl-2′-hydroxy-2′-phenylacetate, is a potent selective M1 antagonist. It is composed of a tertiary hydroxy acid as a key component, like the majority of muscarinic receptor antagonists. It exhibits classical antimuscarine side effects, such as dry mouth. The biology results suggest that the (S)-conformation compound displays an improved therapeutic profile compared to its racemic counterpart. In our efforts to production of enantiopure tertiary acid, (2S,5R)-2-(tert-butyl)-5-phenyl-5-(cyclopentyl-1-ol)-1,3-dioxolan-4-one has been synthesized by (S)-mandelic acid as a chiral controller. It can be effectively transferred to tertiary hydroxy acid. (2S,5R)-2-(tert-Butyl)-5-phenyl-1,3-dioxolan-4-one was synthesized by (S)-mandelic acid with pivaldehyde, as described in the literature. 3 The title compound was prepared by a homogenized mixture of lithium bis(trimethylsilyl)amide and (2S,5R)-2-(tert-butyl)-5-phenyl-1,3-dioxolan-4-one in THF at -78˚C. The reaction mixture was stirred for 0.5 h followed by the addition of cyclopentanone. After stirring for 1 h, a saturated NaHPO4 solution was added. The reaction mixture was poured into the saturated NH4Cl solution. The aqueous layer was separated and extracted with ethyl acetate. After being concentrated in a vacuum, the crude product was obtained as a white solid. Crystals of the title complex suitable for X-ray analysis were recrystallized from heptane.A colorless cubic crystal with dimensions of 0.36 mm × 0.34 mm × 0.30 mm was mounted on a BRUKER SMART 1000 CCD diffractometer equipped with a graphite monochromator for data collection.The determination of the unit-cell parameters and data collections were performed with Mo Kα radiation (λ = 0.71073 Å). A total of 9530 reflections with 3388 independent ones with Rint = 0.0273 with I > 2σ(I) were collected in the range of 2.12 < θ < 26.42˚ by an ω/θ scan mode at 298(2)K. All data were corrected by using the SADABS method. The structure was solved by direct methods with the SHELXS-97 program.4 The final refinement was performed by full-matrix least-squares methods with anisotropic thermal parameters for non-hydrogen atoms on F 2 . The hydrogen atoms were added theoretically, riding on the concerned atoms and being refined with fixed thermal factors. The weighting scheme was w = 1/[σ 2 (Fo 2 ) + (0.0323P) 2 + 0.1107P], where P = (Fo 2 + 2Fc 2 )/3. The refinement converged to the final R = 0.0358 and wR = 0.0711. S = 1.050. Molecular graphics were drawn with the program package XP. Full crystallographic details have been deposited with the Cambridge Crystallographic Data Center, and were allocated the deposition number CCDC-219010. Crystallographic data and experimental details for structural analyses are summarized in Table 1. Positional parameters and atomic coordinates are given in Table 2 (2S,5R)-2-(te...