Studies directed toward the exploitation of vicinal diols in the synthesis of (+)-nebivolol intermediates

Abstract

While the exploitation of the Sharpless asymmetric dihydroxylation as the source of chirality in the synthesis of acyclic molecules and saturated heterocycles has been tremendous, its synthetic utility toward chiral benzo-annulated heterocycles is relatively limited. Thus, in the search for wider applications of Sharpless asymmetric dihydroxylation-derived diols for the synthesis of benzo-annulated heterocycles, we report herein our studies in the asymmetric synthesis of (R)-1-((R)-6-fluorochroman-2-yl)ethane-1,2-diol, (R)-1-((S)-6-fluorochroman-2-yl)ethane-1,2-diol and (S)-6-fluoro-2-((R)-oxiran-2-yl)chroman, which have been used as late-stage intermediates for the asymmetric synthesis of the antihypertensive drug (S,R,R,R)-nebivolol. Noteworthy is that a large number of racemic and asymmetric syntheses of nebivolol and their intermediates have been described in the literature, however, the Sharpless asymmetric dihydroxylation has never been employed as the sole source of chirality for this purpose.

Stereochemistry of Chiral 2-Substituted Chromanes: Twist of the Dihydropyran Ring and Specific Optical Rotation

“…The theoretical SORs for compounds 66 and 67 calculated using the BL approach in methanol were +128.1 and −129.8, respectively, concordant with the SOR sign predicted based on the correlation. The AC of compound 67 was further inspected by Snatzke's method and ECD calculations [71][72][73][74][75][76][77][78][79][80][81]. The positive CE sign at approximately 310 nm verified its (R,R)-configuration.…”

“…BL: PCM/B3LYP/Aug-cc-pVDZ//B3LYP/6-311G(d,p), M6: PCM/M06-2X/Aug-cc-pVDZ//M06-2X/TZVP. Experimental SOR data were collected from references [11,48,[72][73][74][75][76][77][78].…”

Carboazidation of Terminal Alkenes with Trimethylsilyl Azide and Cyclic Ethers Catalyzed by Copper Powder under Oxidative Conditions

“…Among the difunctionalization methods developed, the azide group has been found to be an ideal coupling partner to access nitrogen-containing substances . Therefore, the introduction of azide groups into alkenes with cyclic ethers is a straightforward way to synthesize important β-nitrogen-substituted cyclic ether scaffolds such as pamamycin and nebivolol…”

Biocatalytic Stereoselective Synthesis of Chiral Precursors for Liposoluble β1 Receptor Blocker Nebivolol

“…Nebivolol is a third-generation selective β 1 -adrenergic receptor (β 1 -AR) blocker and is prescribed to treat primary hypertension, ischemic heart disease, and congestive heart failure through improving lipid and glucose metabolism in obese individuals. d - and l -nebivolols exhibit distinct pharmaceutical potency. , d -Nebivolol (SRRR) reduces heart rate and blood pressure, whereas l -nebivolol (RSSS) regulates vasodilation through endogenous NO release. , Retrosynthetic analysis revealed d - and l -nebivolol consisted of ( R , S )-, ( S , S )-, ( S , R )-, and ( R , R )- 2-chloro-1-(6-fluorochroman-2-yl)­ethan-1-ol (NEB-8) (Figure A). − Various synthetic methods have been proposed, including chemical kinetic resolution, asymmetric reduction, and chemical synthesis. Asymmetric reduction of 2-chloro-1-(6-fluorochroman-2-yl)­ethan-1-one (NEB-7) is the most economic and efficient approach for the synthesis of NEB-8.…”