Recent Advances in the Synthesis of Spiro‐β‐Lactams and Spiro‐δ‐Lactams

Abstract

Spirocyclic molecules are widely recognized for their complex three-dimensional features and structural rigidity. Among this class of molecules, the spiro-lactams subclass stands out, being extensively explored due to its bioactivity and utility in a variety of scientific fields such as drug design and organic synthesis. Given the recognition of spirocyclic lactams' broad potential, several efforts have been engaged on the pursuit of new synthetic strategies towards these molecules. The present review gathers advances on the synthesis of both spiroβ-lactams (spiroazetidin-2-ones) and spiro-δ-lactams (spiropiperidon-2-ones) reported since 2015. The work is divided into two distinct parts, each one dedicated to one of these types of spiro-lactam, with the approach used for building the spirocyclic system being extensively discussed, according to the meth-

Synthesis of novel chiral spiro-β-lactams from nitrile oxides and 6-(Z)-(benzoylmethylene)penicillanate: batch, microwave-induced and continuous flow methodologies

“…It is known that due to the bicyclic β-lactam-thiazolidine ring system of the penicillin core which exists in a butterfly-like structure, the approach of a given reactant usually occurs by the convex face (α-side) of the penicillin derivative. 3–5 This is in agreement with the observed stereoselectivity, with both compounds 6a and 7a resulting from the addition of the dipole to the less sterically hindered α-side of the penicillanates. The stereoselectivity observed in the formation of compound 8a can be rationalized by an approach of the dipole through the β-side of the penicillanate, with the regioselective formation of the cycloadduct where the dipole's oxygen adds to the forthcoming spirocyclic carbon.…”

“…Thus, many researchers have turned their focus to the development of alternative synthetic approaches aiming at the synthesis of novel spiro-β-lactam derivatives. 3 The synthesis of chiral spirocyclic β-lactams derived from 6-aminopenicillanic acid (6-APA) has been explored by our research group, leading to a library of chiral spiro-β-lactams with significant structural diversity. Among the synthesized spiro-β-lactams, several were identified with potent activity against both HIV and Plasmodium , the causative agents of AIDS and malaria, respectively ( Fig.…”

Visible-light-mediated sequential Wolff rearrangement and Staudinger cycloaddition enabling the assembly of spiro-pyrazolone-β-lactams

“…)-mediated cyclization, 12 and other types of cyclization, 13 have been successively developed and have made significant progress (Scheme 1C). 14 However, limited substrate scope, toxicity and removal of metal catalysts, and relatively harsh reaction conditions of the above methods further restrict the synthesis and application of the desired spirocyclic β-lactam. Compared with the established approaches, visiblelight photoactivation demonstrates a powerful ability to address these problems and provide unique access in organic synthesis to deliver targeted molecules that are difficult to obtain through conventional thermal approaches (Scheme 1C).…”

Palladium-Catalyzed Access to Benzocyclobutenone-Derived Ketonitrones via C(sp2)–H Functionalization

“… 25 In particular, cyclobutenone-derived ketonitrones could serve as substrates for the straightforward preparation of the azaspiro[3.3]heptane skeleton, which is an emerging privileged structural motif in medicinal chemistry. 26 Indeed, 1,3-dipolar cycloaddition between BCBn 2n and 2 H -pentafluoropropene (PFP) afforded isoxazolidine 7 in 72% yield ( Scheme 4 ). Subsequent hydrogenation of isoxazolidine 7 led to fluorinated, spirocyclic β-lactams 8, 8′ (85% 7.5:1) which could be readily separated by chromatography.…”

“…Nitrones are also excellent precursors of β-lactams . In particular, cyclobutenone-derived ketonitrones could serve as substrates for the straightforward preparation of the azaspiro­[3.3]­heptane skeleton, which is an emerging privileged structural motif in medicinal chemistry . Indeed, 1,3-dipolar cycloaddition between BCBn 2n and 2 H -pentafluoropropene (PFP) afforded isoxazolidine 7 in 72% yield (Scheme ).…”