Enantioselective synthesis of α,α-difluoro-β-lactams using amino alcohol ligands

Abstract

A practical and highly enantioselective Reformatsky reaction of ethyl bromodifluoroacetate with imines using a cheap and commercially available amino alcohol ligand is described. A variety of α,α-difluoro-β-lactams were obtained in up to 74% yield with high enantioselectivity in excess of 99% ee. The use of ethyl bromodifluoroacetate provides for ease of operation because of the inherent chemical stability of this reagent.

Cobalt‐Catalyzed α‐Arylation of Substituted α‐Bromo α‐Fluoro β‐Lactams with Diaryl Zinc Reagents: Generalization to Functionalized Bromo Derivatives

“…Among these methods, we chose the Staudinger (2+2)‐cycloaddition between α‐bromo acetyl bromide ( A ) and the aryl imines B which allows the access to α‐bromo β‐lactams 1′a – d (Scheme ). A Reformatsky‐type reaction, involving ethyl dibromofluoroacetate ( A’ ) and imines B , in the presence of an excess of Et 2 Zn was utilized to synthesize α‐bromo α‐fluoro β‐lactams ( 1 a – 1 j ). The relative configuration was reported to be cis (related to the position of F/H) with a coupling constant of 3 J ≈10.3 Hz between the fluorine atom at C3 and the proton of C4 and the structure of 1 h was confirmed by X‐ray diffraction (see Supporting Information).…”

The Asymmetric Difluoro‐Reformatsky Reaction

“…After in‐situ condensation α,α‐difluoro‐β‐lactams 79 were obtained in good chemical yields and high enantioselectivity (Scheme 16). [61] In order to rationalize the preferred attack to the Si ‐face of the imine 77 , the authors postulate transition state model 78 . It involves a deprotonation of the amino alcohol 64 f under formation of a zinc chelate, where the metal furthermore coordinates to the imine nitrogen.…”

“…In addition, the metal of the Reformatsky reagent, assumed to exist as C‐bound tautomer, coordinates to the alkoxide oxygen atom of the chiral additive. Thus, an ensemble is created that guarantees ‘multiple chiral induction’ resulting in high enantioselectivity [61] …”

Recent developments in the asymmetric Reformatsky-type reaction

“…As an extension of the precedent methodology, the same ligand (1 R ,2 S )- 59 was applied to promote the enantioselective domino aza-Reformatsky/cyclization reaction of aromatic imines 60a – h with ethyl bromodifluoroacetate ( 26 ) [ 48 ]. In this case, a stoichiometric amount of this ligand was required to achieve at room temperature the corresponding chiral α,α-difluoro-β-lactams ( R )- 63a – h in moderate to good yields (45–76%) and high to excellent enantioselectivities (86–99% ee), as shown in Scheme 24 .…”

“… Domino aza-Reformatsky/cyclization reactions of imines with ethyl bromodifluoroacetate in the presence of a stoichiometric amount of chiral 1,2-amino alcohol ligands [ 48 ]. …”