Use of functionalized β-lactams as building blocks in heterocyclic chemistry

Abstract

β-Lactams represent flexible building blocks suitable for the preparation of a large variety of nitrogen-containing target compounds. In the present study, the formerly neglected synthetic potential of 4-haloalkyl-β-lactams has been elaborated in detail with a focus on the preparation of different mono-and bicyclic heterocycles. A first approach involved ring transformations of these halogenated building blocks toward stereodefined aziridines, azetidines, pyrrolidines, and piperidines via intermediate aziridinium or azetidinium ions. In a second part, novel and stereoselective entries into 1,4-and 3,4-fused bicyclic β-lactams were developed through either a radical or an ionic cyclization protocol. Furthermore, the ring enlarge ment of halogenated β-lactams into functionalized mono-and bicyclic pyrrolidin-2-ones was established as the aza-analog of the cyclobutylmethylcarbenium ion to cyclopentylcarbenium ion rearrangement. Finally, chiral versions toward azetidin-2-ones and ring transformation products were elaborated, involving the synthesis of 3(S)-alkoxy-4(S)-[1(S)-chloroethyl]azetidin-2-ones and the preparation of bicyclic β-lactams annelated to piperazines, morpholines, and diazepanes.

Short Synthesis of Enantiopure trans-3-Arylpiperazine-2-carboxylic Acid Derivatives via Diaza-Cope Rearrangement

“…Although many reports exist for the synthesis of optically active piperazine-2-carboxylic acid derivatives, preparation of stereodefined 3-, 5-, or 6-substituted piperazine-2-carboxylic acid derivatives in an enantiomerically pure form is still a challenging synthetic problem. Previously, chiral piperazine-2-carboxylic acid derivatives have been synthesized through cyclizations, multicomponent synthesis, amino-acid-based synthesis, enzymatic resolution, asymmetric hydrogenation of pyrazine derivatives, α-lithiation of piperazine using s -BuLi/(−)-sparteine, and Pd-catalyzed asymmetric allylic allylation . However, some of these methods suffer from shortcomings such as the problem of catalyst traces remaining in final product(s), low enantiomeric purities of final compounds, and low yields resulting from complicated multistep syntheses.…”

Synthesis of 2-amino-3-arylpropan-1-ols and 1-(2,3-diaminopropyl)-1,2,3-triazoles and evaluation of their antimalarial activity

“…Within azaheterocyclic chemistry, aziridines [ 9 – 17 ] and β-lactams [ 18 – 27 ] are extraordinary classes of strained compounds with diverse synthetic and biological applications. In previous works, we have elaborated the synthetic potential of 3-chloroazetidin-2-ones with a focus on stereoselectivity, thus providing convenient entries into, e.g., aziridines, azetidines and β-aminoalcohols [ 28 – 31 ].…”

Transition metal-free one-pot synthesis of nitrogen-containing heterocycles

“…Antibiotics containing azetidine have been known for decades for their unsurpassed clinical efficacy and safety. The Spartan architecture of these heterocycles has been acknowledged as classical building blocks in the synthesis of other heterocyclic compounds [31]. Recently, a highly stereoselective synthesis of azitidine derivatives 18 was reported by Miao et al [32] in the presence of tetramethylguanidine (TMG), comprising iodine catalyzed condensation of Michael adduct formed in situ from [2 + 2] cycloaddition of α-amidomalonates 16 and enones 17.…”