Novel Aspects on the Preparation of Spirocyclic and Fused Unusual β-Lactams

Capítulo 1, pp 1-48β-Lactam antibiotics have occupied a central role in the fight against pathogenic bacteria and the subsequent rise in quality of life for the world population as a whole. However, the extensive use of common β-lactam antibiotics such as penicillins and cephalosporins in medicine has resulted in an increasing number of resistant strains of bacteria through mutation and β-lactamase gene transfer. The resistance of bacteria to the classical β-lactam antibiotics can be overcome, e.g., by using novel β-lactam moieties in drugs which show much higher stability towards these resistance bacteria. In addition, there are many important nonantibiotic uses of 2-azetidinones in fields ranging from enzyme inhibition to gene activation. These biological activities, combined with the use of these products as starting materials to prepare α- and β-amino acids, alkaloids, heterocycles, taxoids, and other types of compounds of biological and medicinal interest, provide the motivation to explore new methodologies for the synthesis of substances based on the β-lactam core. The aim of this chapter is to provide a survey of the types of reactions used to prepare non-conventional spirocyclic and fused β-lactams, concentrating on the advances that have been made in the last decade, and in particular in the last five years. We will draw special attention to radical cyclizations, cycloaddition reactions, and transition metal-catalyzed reactions.Peer reviewe

Intramolecular Azide to Alkene Cycloadditions for the Construction of Pyrrolobenzodiazepines and Azetidino-Benzodiazepines

The coupling of proline- and azetidinone-substituted alkenes to 2-azidobenzoic and 2-azidobenzenesulfonic acid gives precursors that undergo intramolecular azide to alkene 1,3-dipolar cycloadditions to give imine-, triazoline- or aziridine-containing pyrrolo[1,4]benzodiazepines (PBDs), pyrrolo[1,2,5]benzothiadiazepines (PBTDs), and azetidino[1,4]benzodiazepines. The imines and aziridines are formed after loss of nitrogen from a triazoline cycloadduct. The PBDs are a potent class of antitumour antibiotics

Doctor of Philosophy

dissertationTransition metal-catalyzed synthesis of carbocycles and heterocycles is described. A Ni/NHC catalyst couples diynes to the C(a)-C(B) double bond of tropone, a type of reactions that is unprecedented for metal-catalyzed cycloadditions with aromatic tropone. Many different diynes were efficiently coupled to afford [5-6-7] fused tricyclic products, while [5-7-6] fused tricyclic compounds were obtained as minor byproducts in a few cases. The reaction has broad substrate scope and tolerates a wide range of functional groups, and excellent regioselectivity is found with unsymmetrical diynes. The mechanism of this interesting cycloaddition has been investigated using DFT calculations and it reveals an interesting 8p-insertion of tropone to afford [5-6-7] and [5-7-6] fused tricyclic products. A unique and catalytic way to synthesize challenging eight-membered heterocycles is disclosed. The Ni/P(p-tol)3 catalyst promoted the cycloaddition of a variety of 1,3-dienes with 3-azetidinones and 3-oxetanones to afford both monocyclic and bicyclic azocine and oxocine ring systems, respectively. Interestingly, the cycloaddition with 1,3-diene conjugated with a p-methoxylphenyl group led to a 3-piperidinone product instead of the azocine ring. The synthesis of the these interesting eight-membered heterocycles involved the challenging steps of C(sp2)-C(sp3) bond activation and C(sp3)-C(sp3) reductive elimination. An efficient and convenient procedure that generates the active Ni(0) catalyst in situ from cheap, air stable Ni(II) precursors is developed for the [4+2]-cycloaddition of alkynes and 3-azetidinones. The reaction affords useful 3-dehydropiperidinones in comparable yields to the reported Ni(0) procedure. Additionally, the cycloaddition with 3-oxetanone afforded the 3-dehydropyranone product. The application of this methodology to the total synthesis of (+)-septicine is also described. A protocol for the Suzuki-Miyaura coupling of heteroaryl boronic acids and vinyl chlorides that minimizes protodeboronation is disclosed. A combination of catalytic amounts of Pd(OAc)2 and SPhos in conjunction with CsF in isopropanol effectively affords a variety of coupled products. Surprisingly, a dramatic temperature dependence in product selectivity was observed

Stereoselective cyanation of 4-formyl and 4-imino-β-lactams: Application to the synthesis of polyfunctionalized γ-lactams

The stereoselective reaction of 4-oxoazetidine-2-carbaldehydes and their corresponding imines with cyanide-based reagents give β-lactam α-aminonitriles, which are chameleonic building blocks for the controlled synthesis of a variety of new compounds including functionalized γ-lactams, succinimide derivatives, and diamino-lactams derivatives in optically pure form. © 2012 Elsevier Ltd. All rights reserved.Peer Reviewe

Silver(I) Salts as Useful Reagents in Pyrazole Synthesis

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An Expeditious Iodine-Catalyzed Synthesis of 3-Pyrrole-Substituted 2-Azetidinones

2-Azetidinones and pyrroles are two highly important classes of molecules in organic and medicinal chemistry. A green and practical method for the synthesis of 3-pyrrole-substituted 2-azetidinones using catalytic amounts of molecular iodine under microwave irradiation has been developed. Following this method, a series of 3-pyrrole-substituted 2-azetidinones have been synthesized with a variety of substituents at N-1 and at C-4. The procedure is equally effective for mono-as well as polyaromatic groups at the N-1 position of the 2-azetidinone ring. The C-4 substituent has no influence either on the yield or the rate of the reaction. Optically pure 3-pyrrole-substituted 2-azetidinones have also been synthesized following this methodology. No deprotection/ rearrangement has been identified in this process, even with highly acid sensitive group-containing substrates. A plausible mechanistic pathway has also been suggested based on the evidence obtained from 1H-NMR spectroscopy. The extreme rapidity with excellent reaction yields is believed to be the result of a synergistic effect of the Lewis acid catalyst (molecular iodine) and microwave irradiation

Investigation of ring transformations of diaryl-β-lactams condensed with 1,3-benzothiazines

Reactions of derivatives of the isoquinoline analog trans-2,2a-diaryl-2,2a-dihydro-5,6-dimethoxy-1H,8H-azeto[2,1-b][1,3]benzothiazin-1-one were studied under basic conditions. Their treatment with sodium methoxide in methanol resulted first in alcoholysis of the beta-lactam ring, followed by opening of the thiazine ring and oxidation of the thiol moiety to disulfide. Thus, the corresponding beta-amino acid derivatives, disulfides of N-(ortho-mercaptobenzyl)substituted diaryl-3-aminoacrylic acid methyl esters, were obtained in good yields. The structures of the new molecules were proved by means of NMR and IR spectroscopy. Geometric isomerism investigations indicated the presence of the Z forms of the acrylic acid moiety

Substituted azetidine-2 carboxylic acid synthesis

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal

Biocatalysis as Useful Tool in Asymmetric Synthesis: An Assessment of Recently Granted Patents (2014–2019)

The broad interdisciplinary nature of biocatalysis fosters innovation, as different technical fields are interconnected and synergized. A way to depict that innovation is by conducting a survey on patent activities. This paper analyses the intellectual property activities of the last five years (2014–2019) with a specific focus on biocatalysis applied to asymmetric synthesis. Furthermore, to reflect the inventive and innovative steps, only patents that were granted during that period are considered. Patent searches using several keywords (e.g., enzyme names) have been conducted by using several patent engine servers (e.g., Espacenet, SciFinder, Google Patents), with focus on granted patents during the period 2014–2019. Around 200 granted patents have been identified, covering all enzyme types. The inventive pattern focuses on the protection of novel protein sequences, as well as on new substrates. In some other cases, combined processes, multi-step enzymatic reactions, as well as process conditions are the innovative basis. Both industries and academic groups are active in patenting. As a conclusion of this survey, we can assert that biocatalysis is increasingly recognized as a useful tool for asymmetric synthesis and being considered as an innovative option to build IP and protect synthetic routes