A Ugi Straightforward Access to Bis‐β‐lactam Derivatives

Abstract

THe Ugi reaction of β‐amino acids with aromatic aldehydes affords β‐lactams which may be used as starting materials in a second β‐lactam formation following a base triggered diiodomethane addition. The sequence may be conducted in a one‐pot fashion affording a straightforward access to bis‐β‐lactams.

Advances in Base‐Mediated Post‐Ugi Transformations via Peptidyl Anion Trapping

“…In continuation with the same theme, El Kaïm and coworkers in 2019 reported a one‐pot protocol for the formation of bis‐β‐lactam derivatives 119 (Scheme 40). [74] Ugi reaction of β‐amino acids with aromatic aldehydes afforded β‐lactams 118 , which underwent a second β‐lactam formation following a base‐triggered diiodomethane addition.…”

“…The resulting anion can be trapped by various electrophiles, as demonstrated by El Kaïm and coworkers. [70][71][72][73][74] Using this strategy, the research group synthesized densely functionalized pyrrolines 115 by addition of Ugi adducts 114 to acrylonitrile under microwave irradiation (Scheme 38). [70] Plausible reaction mechanism involved the unexpected formation of El Kaïm and coworkers in 2017 demonstrated a novel post-Ugi modification strategy involving [3 + 1]-cyclization of amide dianions with diiodomethane, which furnished a wide range of β-lactams 117 in 34-72% yields (Scheme 39).…”

“…Aromatic aldehyde derived Ugi adducts are relatively acidic at the peptidyl position and may undergo deprotonation under basic conditions. The resulting anion can be trapped by various electrophiles, as demonstrated by El Kaïm and coworkers [70–74] . Using this strategy, the research group synthesized densely functionalized pyrrolines 115 by addition of Ugi adducts 114 to acrylonitrile under microwave irradiation (Scheme 38).…”

Synthesis of Lactams via Isocyanide-Based Multicomponent Reactions

“…Later, in 2019, El Kaïm 46 reported the two-step synthesis of bis -lactams 67 in poor to good yields (28-61%) via an Ugi-3CR followed by a base-mediated diiodomethane cyclocondensation reaction at room temperature (Scheme 15). The amino acid 65 on reaction with an isocyanide and an aldehyde at 120 °C under microwave irradiation was readily converted into -lactam 66.…”

Diastereoselective Synthesis of β-Lactams by Ligand-Controlled Stereodivergent Intramolecular Tsuji–Trost Allylation

“…In addition to the cyclization of β-amino acids, synthetic methods for the construction of β-lactams include the Staudinger reaction (i.e., the formal [2 + 2] cycloaddition of ketenes and imines), the Kinugasa reaction, intramolecular carbene insertion, and various other methods . In addition, several methods for the synthesis of β-lactams based on the U4CR have been reported, − but these do not offer the same flexibility, substitution pattern, and stereocontrol. Given the mild conditions of our (likely kinetically controlled) reaction and opportunities to fine-tune the reaction outcome via the Pd ligand, we set about to investigate possibilities to control the relative stereochemistry of the process.…”