Preparation of chiral isoxazole carbinols via catalytic asymmetric Corey-Bakshi-Shibata reduction.

Abstract

Dedicated in Honor of Dr. Bruce E. Maryanoff and Dr. Cynthia A. Maryanoff on the occasion of their outstanding contributions to organic chemistry as industrial chemists Abstract A diverse set of isoxazoles, with activity in three different disease categories, was reduced asymmetrically from pro-chiral ketones to chiral alcohols using the Corey-Bakshi-Shibata methodology at the α, β, and γ positions relative to the C-5-methyl of the isoxazole. The experiments described provide an easy route to hydroxylated isoxazoles that represent the common CYP-450 3A4 metabolic site.

Synthesis and Structure of Unsymmetrical Anthracenyl-Isoxazole Antitumor Agents Via the Diastereoselective Bromination of 3-(9′-Anthryl)-Isoxazole Esters

“…A second potential use for unsymmetrically halogenated AIMs was suggested during our consideration of the plausible metabolic fates of the anthracene. One of our planned roles for the isoxazoles was to direct Cyp3A4 metabolism away from potentially toxic metabolites at the anthracene ring, and both prior models in the literature [11] and Smart-Cyp density function computations [12] suggest that hydroxylation at the C-5 alkyl group of the isoxazole is a reasonable route; however, the docking of the alkoxy AIM shown presents the side of the anthracene directly over the heme of the Cyp [13] (Figure 3B). We decided that we should anticipate this by using the tactic of blocking the position with a halogen, and a bromine could provide either a metabolism blocking effect intrinsically (as in Vandetanib [14]) or serve as a precursor to the strategically positioned fluorine [15,16]. )…”

Syntheses and crystal structures of a nitro–anthracene–isoxazole and its oxidation product

“…Usually, anthracenes are oxidized in vivo predominantly by cytochrome P450, leading to a potentially toxic arene oxide (Silverman et al, 2014). The rationale for the isoxazole series is that the C-5 isoxazole methyl group represents an opportunity for safer metabolism (Natale et al, 2010). The observation in this manuscript suggests that intramolecular dioxygenation, which would likely be mediated in vivo by mono amine oxidase (MAO), is another plausible route (Silverman, 2002).…”

Leveraging Limited Experimental Data with Machine Learning: Differentiating a Methyl from an Ethyl Group in the Corey–Bakshi–Shibata Reduction

“…The CBS reduction of prochiral ketones has been widely employed in organic syntheses due to their generally high enantioselectivity and broad substrate scope using, e.g., lactones, alkaloids, and steroids. 3−5 For instance, it has been employed in the preparation of chiral isoxazole carbinols, 6 the synthesis of (R)-phenylephrine, 7 as well as the enantioselective syntheses of massadine, 8 FR901464, and spliceostatin A. 9 The lessons learned from such a challenging transformation could potentially be applied to other instances.…”

“…This catalyst coordinates to borane (BH 3 ), the reducing agent, and together, they facilitate the reduction of the ketone in an enantioselective manner. The CBS reduction of prochiral ketones has been widely employed in organic syntheses due to their generally high enantioselectivity and broad substrate scope using, e.g., lactones, alkaloids, and steroids. − For instance, it has been employed in the preparation of chiral isoxazole carbinols, the synthesis of ( R )-phenylephrine, as well as the enantioselective syntheses of massadine, FR901464, and spliceostatin A …”