Enantioenriched γ-Aminoalcohols, β-Amino Acids, β-Lactams, and Azetidines Featuring Tetrasubstituted Fluorinated Stereocenters via Palladacycle-Catalyzed Asymmetric Fluorination of Isoxazolinones

Abstract

Enantiopure fluorine containing β-amino acids are of large biological and pharmaceutical interest. Strategies to prepare β-amino acid derivatives possessing a F-containing tetrasubstituted stereocenter at the α-C atom in a catalytic asymmetric sense are rare, in particular using an enantioselective electrophilic C–F bond formation. In the present study, a highly enantioselective palladacycle-catalyzed fluorination of isoxazolinones was developed. It is demonstrated that isoxazolinones are useful precursors toward enantiopure β-amino acid derivatives by diastereo- and chemoselective reduction. The formed γ-aminoalcohols served as valuable precursors toward β-amino acids, β-amino acid esters, and β-lactams, all featuring tetrasubstituted fluorinated stereocenters. In addition, by this work, enantioenriched fluorinated azetidines were accessible for the first time.

Catalytic Asymmetric Chlorination of Isoxazolinones

“…Moreover, it was found that variations of the aromatic residues R 1 at the imino C atom are possible (entries [12][13][14]. However, as a limitation we found that substrates with a simple alkyl group R 1 such as methyl permitted only poor enantioselectivity, whereas the product yields were still good (not shown).…”

“…We assume that the reaction mechanism is very similar to those previously suggested for our 1,4 additions and fluorinations of isoxazolinones, applying the same type of catalyst. [14,17,21] It should involve coordination of the substrate by its N-atom to the azaphilic Pd(II) center thus triggering substrate enolization, that might be facilitated by HOAc. Due to the acidic conditions we think that the formation of an enolate intermediate is unlikely in this method.…”

“…[22] The stereochemical outcome might be explained by our previously reported working models. [14,17] To showcase the synthetic value of the reaction products, we studied the option of an S N 2 displacement. Prior to use, the chlorination product 2 a was crystallized in order to get almost enantiopure material.…”

“…The investigation was started by surveying the impact of different chlorination agents A-E using the chloride bridged planar chiral ferrocenyl palladacycle [PPFIPÀ Cl] 2 [16] (PPFIP: 1 ' ,2 ' ,3 ' ,4 ' ,5 ' -pentaphenylferrocenyl imidazoline palladacycle) as precatalyst (entries 1-5). In previous work we found that ferrocene based imidazoline palladacycle catalysts are capable of efficiently activating pronucleophiles featuring C,N-π-bonds in α-position to a C,H-acidic C atom, such as isoxazolinones, [17,14] in asymmetric catalysis with high compatibility of functional groups. [18] [PPFIPÀ Cl] 2 C1 (2.5 mol%) was activated with AgOTs (5 mol%) by a chloride/tosylate exchange in the presence of MeCN prior to use.…”

“…In contrast, for the structurally related isoxazolinones (systemic name: isoxazol‐5‐(4H)‐ones) [12] catalytic asymmetric chlorinations have not been reported. These cyclic 5‐membered oxime esters are also biologically interesting heterocycles [13] which, in addition, can be regarded as versatile β‐aminoacid precursors [14] . Enantioselective chlorination of the isoxazolinones’ 4‐position might thus create new possibilities for the synthesis of enantiopure pharmacologically interesting β‐aminoacid derivatives [15]…”