Cerium(III) Chloride-Mediated Stereoselective Reduction of a 4-Substituted Cyclohexanone Using NaBH₄

Abstract

Several additives were screened for the stereoselective reduction of a 4-substituted cyclohexanone en route to linrodostat mesylate. It was found that the addition of sub-stoichiometric cerium(III) chloride in conjunction with sodium borohydride provided the desired trans-cyclohexanol (arising out of axial delivery of the hydride onto the carbonyl) in >16:1 selectivity and excellent conversion. The reaction was initially scaled up to 3.5 kg scale and eventually to >100 kg scale.

Structure-Guided Design of Potent Inhibitors of SARS-CoV-2 3CL Protease: Structural, Biochemical, and Cell-Based Studies

“…All trans-substituted alcohols were synthesized by reducing the precursor 4-substituted cyclohexanone with sodium borohydride/CeCl 3 . 30 …”

“…Deuterated alcohols 9 , 11 , 20 , and 22 were obtained by treatment of the precursor carboxylic acid with carbonyl diimidazole followed by the addition of sodium borodeuteride. All trans-substituted alcohols were synthesized by reducing the precursor 4-substituted cyclohexanone with sodium borohydride/CeCl 3 …”

Development of a Stereoselective and Scalable Synthesis for the Potent Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitor, BMT-297376; N-((R)-1-((cis)-4-(3-(Difluoromethyl)-2-methoxypyridin-4-yl)cyclohexyl)propyl)-6-methoxynicotinamide

“…The original reduction conditions (entry 1) gave a mixture of the products 22 and 22a in a ratio of 80:20 trans/cis with 22 isolated in 71% yield. The addition of CeCl 3 (entry 2) improved the selectivity to 90:10 but gave only a moderate 68% yield of 22 after an extended reaction time. Reduction with tetramethylammonium borohydride (1.2 equiv) in a mixture of solvent THF/MeOH (5:1) gave the best result with 90:10 trans/cis selectivity and 99% isolated yield of 22 (entry 3).…”

“…4-Chloro-2-methoxynicotinaldehyde (10). A 5 L threenecked flask was charged with i-Pr 2 NH (238 mL, 1.67 mol) and THF (1.5 L) maintained at 25 °C under an atmosphere of N 2 .…”

Structure-Guided Design of Potent Inhibitors of SARS-CoV-2 3CL Protease: Structural, Biochemical, and Cell-Based Studies.

“…All trans-substituted alcohols were synthesized by reducing the precursor 4-substituted cyclohexanone with sodium borohydride/CeCl3. 30 Compounds 1-24b/c were readily obtained by reacting each precursor alcohol with disuccinimidyl carbonate, 31 followed by coupling with amino alcohol A. The resulting product was treated with Dess-Martin periodinane to yield aldehydes 1-24b which were converted to the corresponding bisulfite adducts 1-24c upon treatment with sodium bisulfite (Scheme/panel B).…”