Multicomponent reactions driving the discovery and optimization of agents targeting central nervous system pathologies

• Lucía Campos-Prieto,
• Aitor García-Rey,
• Eddy Sotelo and
• Ana Mallo-Abreu

Beilstein J. Org. Chem. 2024, 20, 3151–3173, doi:10.3762/bjoc.20.261

• concentrations in the later stages of this pathology, has been gaining attention for the treatment of this disease. In 2021, Brandão et al. [33] developed a series of molecules inspired by the oxoindole-β-lactam core, a structural motif, present in many acetylcholinesterase inhibitor drugs, through the Ugi

• active oxoindole-β-lactam compounds developed by Brãndao et al. [33]. The most promising hybrids synthesized via the Ugi-azide multicomponent reaction reported by Kushwaha et al. [34]. Most potent antioxidant compounds obtained through the Ugi four-component reaction developed by Pachón-Angona et al. [35

• of best derivatives obtained by Hasaninejad et al. [49]. Best DRD2 compounds synthesized using a multicomponent strategy. Oxoindole-β-lactam core produced in a U4C-3CR. Ugi-azide synthesis of benzofuran, pyrazole and tetrazole hybrids. Four-component Ugi reaction for the synthesis of novel

Photoredox-catalyzed intramolecular nucleophilic amidation of alkenes with β-lactams

• Valentina Giraldi,
• Giandomenico Magagnano,
• Daria Giacomini,
• Pier Giorgio Cozzi and
• Andrea Gualandi

Beilstein J. Org. Chem. 2024, 20, 2461–2468, doi:10.3762/bjoc.20.210

• reactions limit the utility of this approach. Herein, we report an intramolecular photoredox cyclization of alkenes with β-lactams in the presence of an acridinium photocatalyst. The approach uses an intramolecular nucleophilic addition of the β-lactam nitrogen atom to the radical cation photogenerated in

• the linked alkene moiety, followed by hydrogen transfer from the hydrogen atom transfer (HAT) catalyst. This process was used to successfully prepare 2-alkylated clavam derivatives. Keywords: β-lactam; acridinium photocatalyst; alkenes; amides; intramolecular radical reaction; photoredox catalysis

• ]. Through tailored molecular design, it is possible to enhance the oxidation capability of these catalysts, enabling the utilization of less reactive alkenes and even aromatic molecules such as toluene [32]. Until now, heterocyclic amides such as β-lactam compounds have not been employed in alkene

Efficacy of radical reactions of isocyanides with heteroatom radicals in organic synthesis

• Akiya Ogawa and
• Yuki Yamamoto

Beilstein J. Org. Chem. 2024, 20, 2114–2128, doi:10.3762/bjoc.20.182

• lack of geometrical isomerization of the C–N double bond of the dithiolation products [32]. The thioselenation product 6’, an imine derivative, can be converted to a β-lactam derivative by [2 + 2] cycloaddition with ketene generated in situ. For example, thioselenation of RNC (R = (EtO)2P(O)–CH2) gave

• imine 6’ (96%), which underwent [2 + 2] cycloaddition with methoxyketene to afford β-lactam derivative 7 (79%) (Scheme 4). Selective replacement of the PhSe group of 7 with a 3-butanonyl group (34%) and the subsequent intramolecular Horner–Emmons reaction successfully led to carbacephem skeleton 8 (96

Access to 2-oxoazetidine-3-carboxylic acid derivatives via thermal microwave-assisted Wolff rearrangement of 3-diazotetramic acids in the presence of nucleophiles

• Ivan Lyutin,
• Vasilisa Krivovicheva,
• Grigory Kantin and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2024, 20, 1894–1899, doi:10.3762/bjoc.20.164

• well as a wide range of nucleophiles provides access to a structural diversity of medically relevant 2-oxoazetidine-3-carboxylic acid amides and esters. Keywords: β-lactams; diazotetramic acids; nucleophiles; spirocycles; thermolysis; Wolff rearrangement; Introduction The importance of the β-lactam

• versatile methods for the preparation of structurally diverse β-lactam derivatives is of great importance and relevance. Continuing the investigation of the reactivity and synthetic potential of diazotetramic acids (1), we have recently shown that these diazo reagents can act as precursors of β-lactam

• reported in the literature are based on the construction of the β-lactam ring (Scheme 1). The main methods include the [2 + 2] cycloaddition of acyl ketenes, generated by various methods, with imines [11][12][13][14] and the Wolff rearrangement of γ-amino-α-diazo-β-ketoesters followed by intramolecular

Syntheses and medicinal chemistry of spiro heterocyclic steroids

• Laura L. Romero-Hernández,
• Ana Isabel Ahuja-Casarín,
• Penélope Merino-Montiel,
• Sara Montiel-Smith,
• José Luis Vega-Báez and
• Jesús Sandoval-Ramírez

Beilstein J. Org. Chem. 2024, 20, 1713–1745, doi:10.3762/bjoc.20.152

• as a 1:1 mixture of diastereomers (Scheme 4). The same procedure was also applied to estrone to insert the spiro moiety at C-17 in 70% yield [14]. Spiro-β-lactam steroids A novel one-pot procedure to build spiro-β-lactams from enamides was described by Liu et al. The research group had previously

• reported the formation of an α,α-dicyanoalkene from dehydroepiandrosterone (DHEA) and its efficient transformation to dienamides 15 in a single step via a cascade reaction [15][16]. The construction of the β-lactam ring involved a cascade 4-endo N-cyclization/aerobic oxidation sequence in presence of

Clauson–Kaas pyrrole synthesis using diverse catalysts: a transition from conventional to greener approach

• Dileep Kumar Singh and
• Rajesh Kumar

Beilstein J. Org. Chem. 2023, 19, 928–955, doi:10.3762/bjoc.19.71

• ). This process has many advantages such as ease of operation, short reaction times, high to excellent product yields, and stable, readily available and green catalysts. Moreover, this protocol is also useful for the preparation of N-substituted compounds with β-lactam fragments. The authors also proposed

Palladium-catalyzed enantioselective three-component synthesis of α-arylglycine derivatives from glyoxylic acid, sulfonamides and aryltrifluoroborates

• Bastian Jakob,
• Nico Schneider,
• Luca Gengenbach and
• Georg Manolikakes

Beilstein J. Org. Chem. 2023, 19, 719–726, doi:10.3762/bjoc.19.52

• , e.g., the antiplatelet drug clopidogrel [7] or the β-lactam antibiotic amoxicillin [8] (Figure 1). Therefore, the chemical synthesis of α-aryglycines has received considerable attention. Among the different methods introduced over time, multicomponent reactions utilizing an in situ generated reactive

On drug discovery against infectious diseases and academic medicinal chemistry contributions

• Yves L. Janin

Beilstein J. Org. Chem. 2022, 18, 1355–1378, doi:10.3762/bjoc.18.141

• human pharmacology. Moreover, preparing fully artificial β-lactam analogues is also an active research field since, for instance aztreonam (61), is produced by total synthesis [304][305]. Amongst other issues, the main concern in this domain remains the design of compounds capable of resisting the

• human use has slowed down but it has yet to stop. Could the use of very recent chemistry allow to go beyond the current [303][306][307][308][309][310] state of the art? Aside from these rather thoroughly investigated β-lactam antibiotics (more than 40,000 tons are produced every year), one could

Efficient and regioselective synthesis of dihydroxy-substituted 2-aminocyclooctane-1-carboxylic acid and its bicyclic derivatives

• İlknur Polat,
• Selçuk Eşsiz,
• Uğur Bozkaya and
• Emine Salamci

Beilstein J. Org. Chem. 2022, 18, 77–85, doi:10.3762/bjoc.18.7

• -oxabicyclo[5.2.1]decan-10-yl)carbamate was confirmed by X-ray diffraction. Keywords: aminocyclitol; azidolysis; bicyclic β-lactam; bicyclic lactone; cyclic β-amino acids; DFT; Introduction Cyclic β-amino acids have for the past few decades aroused widespread synthetic interest owing to their diverse

• . Results and Discussion Initially, we focused on the synthesis of β-lactam 2, which was prepared by the cycloaddition of chlorosulfonyl isocyanate (CSI) to cis,cis-1,3-cyclooctadiene, as described in the literature [26]. β-Lactam 2 was transformed into cis-amino ester 3 by cleavage of the lactam ring with

• epoxide 7, the relative free energy of 7b is higher by 10.3 kcal mol−1 than that of 7a (Figure 5). Conclusion In summary, we successfully synthesized hydroxylated cyclooctane β-amino acid 6 and its derivatives 8, 10, and 13 starting from β-lactam 2. The regioselective synthesis of lactone 8, which is a

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

• Joseane A. Mendes,
• Paulo R. R. Costa,
• Miguel Yus,
• Francisco Foubelo and
• Camilla D. Buarque

Beilstein J. Org. Chem. 2021, 17, 1096–1140, doi:10.3762/bjoc.17.86

• the asymmetric synthesis of a variety of aromatic, heteroaromatic, and aliphatic 1-substituted 2,6-diazaspiro[3.3]heptanes 48, with overall yields ranging from 74 to 94% (Scheme 16). Asymmetric synthesis of β–lactams β-Lactam antibiotics are important drug class of antibacterial agents [83] and in the

• the stereoselective synthesis of spiro β-lactam 57 from chiral (RS)-N-tert-butanesulfinyl isatin ketimine 53 (R1 = H), with a bulky trityl protecting group bonded to the nitrogen indolic atom (Tr = triphenylmethyl), and ethyl bromoacetate. The Zn/Cu-mediated Reformatsky-type reaction furnished

• the synthesis of (–)-AG-041R, a gastrin/cholecyctokinin-B receptor antagonist. In addition, amino ester 55 was transformed into the fully unprotected amino acid 56 under basic conditions in MeOH, and after that, further treatment with of MsCl and NaHCO3 in MeCN at 80 °C led to spiro-β-lactam

β-Lactamase inhibition profile of new amidine-substituted diazabicyclooctanes

• Zafar Iqbal,
• Lijuan Zhai,
• Yuanyu Gao,
• Dong Tang,
• Xueqin Ma,
• Jinbo Ji,
• Jian Sun,
• Jingwen Ji,
• Yuanbai Liu,
• Rui Jiang,
• Yangxiu Mu,
• Lili He,
• Haikang Yang and
• Zhixiang Yang

Beilstein J. Org. Chem. 2021, 17, 711–718, doi:10.3762/bjoc.17.60

• , Jinfeng District, Yinchuan, Ningxia 750002, P.R. China College of Pharmacy, Ningxia Medical University, Shengli Street, Xingqing District, Yinchuan, Ningxia 750004, P.R. China 10.3762/bjoc.17.60 Abstract The diazabicyclooctane (DBO) scaffold is the backbone of non-β-lactam-based second generation β

• in Escherichia coli clinical isolates [14][15]. The diazabicyclooctane (DBO) [16] ring suggested as an alternative to the β-lactam ring [17] by the Hoechst researchers [16] could not prove its antibacterial strength in early experiments rather it showed β-lactamase inhibition activity. This discovery

• led the researchers to develop second generation β-lactamase inhibitors, finally succeeded with the approval of avibactam and relebactam as non-β-lactam-based BLIs. Avibactam proved potent as inhibitor of Klebsiella pneumoniae carbapenemases (KPCs), AmpCs and some of class D β-lactamases [18] is now

α,γ-Dioxygenated amides via tandem Brook rearrangement/radical oxygenation reactions and their application to syntheses of γ-lactams

• Mikhail K. Klychnikov,
• Radek Pohl,
• Ivana Císařová and
• Ullrich Jahn

Beilstein J. Org. Chem. 2021, 17, 688–704, doi:10.3762/bjoc.17.58

• -lactams are important lead compounds, e.g., derivatives with antibacterial activity were discovered, what gains importance with respect to the increasing bacterial resistance toward traditional β-lactam antibiotics [35][36][37][38][39]. Various synthetic pathways can be applied for the construction of the

Recent synthesis of thietanes

• Jiaxi Xu

Beilstein J. Org. Chem. 2020, 16, 1357–1410, doi:10.3762/bjoc.16.116

• to proceed via an n–π* triplet-excited state [96] (Scheme 70). In 1993, the same group first attempted to prepare a chiral thietane-fused β-lactam 356a from an achiral monothioimide 355a using a chiral crystal environment through a topochemically controlled intramolecular photochemical [2 + 2

Steroid diversification by multicomponent reactions

• Leslie Reguera,
• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Daniel G. Rivera

Beilstein J. Org. Chem. 2019, 15, 1236–1256, doi:10.3762/bjoc.15.121

• steroid derivatization methods using MCRs was reported by the Ugi laboratory in 1995 (Scheme 1) [14]. The occurrence of pachystermin A, an unusual natural steroid isolated from the boxaceous plant Pachysandra terminalis and having a β-lactam moiety in ring A, inspired these authors to obtain a steroidal β

• -lactam, albeit functionalized in the side chain. The one-pot synthesis of the β-lactam steroid was achieved via the Ugi 3-component-4-center reaction using the dehydrocholic aldehyde 1 as carbonyl component. This variation of the Ugi reaction including a β-amino acid component allows the formation of the

• 4-membered ring of the β-lactam moiety, which is difficult to obtain through other traditional methods like the cyclization of acyclic precursors because of both the Baeyer strain of the newly formed ring and conformational effects [15]. However, the readily formation of the 4-membered ring by this

Ring-opening metathesis of some strained bicyclic systems; stereocontrolled access to diolefinated saturated heterocycles with multiple stereogenic centers

• Zsanett Benke,
• Melinda Nonn,
• Márton Kardos,
• Santos Fustero and
• Loránd Kiss

Beilstein J. Org. Chem. 2018, 14, 2698–2707, doi:10.3762/bjoc.14.247

• functionalized derivatives such as bicyclic lactones, γ-lactams or isoxazolines, derived from various cyclodienes and to evaluate their chemical behavior under Ru-catalyzed ring-opening conditions (Scheme 2). First, the ring opening of racemic bicyclic γ-lactone (±)-3 (derived from cyclodiene 1 via β-lactam

Synthesis of spirocyclic scaffolds using hypervalent iodine reagents

• Fateh V. Singh,
• Priyanka B. Kole,
• Saeesh R. Mangaonkar and
• Samata E. Shetgaonkar

Beilstein J. Org. Chem. 2018, 14, 1778–1805, doi:10.3762/bjoc.14.152

• of DMAP base. The spirocyclization reactions were performed in MeOH for 2 h at 0 °C and spirocyclic products 56 were isolated in good yields (Scheme 18). Additionally, fused bicyclic compounds 57 were also observed in few reactions in traces. The structure of the spiro β-lactam was confirmed by

• 2014, Xu and Abdellaoui [93] reported a nucleophilic intramolecular cyclization of phenylacetamides 65 to spirocyclic lactams 66 via iodine(III)-mediated spirocarbocyclizations. In literature, there are limited methods available for the synthesis of spiro-β-lactam-3-carbonitrile which is widely used as

• an antibiotic [94]. In this methodology, N-(p-hydroxyphenyl)cyanoacetamides 65 were cyclized to corresponding 4-spiro-β-lactam-3-carbonitriles 66 in useful yields using PIDA (15) as an electrophile in the presence of KOH as base in anhydrous ethanol at room temperature (Scheme 22). In 2014, Fan and

Isoxazole derivatives as new nitric oxide elicitors in plants

• Anca Oancea,
• Emilian Georgescu,
• Florentina Georgescu,
• Alina Nicolescu,
• Elena Iulia Oprita,
• Catalina Tudora,
• Lucian Vladulescu,
• Marius-Constantin Vladulescu,
• Florin Oancea and
• Calin Deleanu

Beilstein J. Org. Chem. 2017, 13, 659–664, doi:10.3762/bjoc.13.65

• ], antinociceptive [12] and anticancer [13] activities. Several isoxazole derivatives have GABAA antagonist [14] and T-type Ca2+ channel blocking activities [15]. Commercial drugs featuring an isoxazole moiety include the COX-2 inhibitor Valdecoxib and the β-lactam antibiotics Cloxacillin and Dicloxacillin. An

Stereo- and regioselectivity of the hetero-Diels–Alder reaction of nitroso derivatives with conjugated dienes

• Lucie Brulíková,
• Aidan Harrison,
• Marvin J. Miller and
• Jan Hlaváč

Beilstein J. Org. Chem. 2016, 12, 1949–1980, doi:10.3762/bjoc.12.184

• regioselectivity. On the other hand, its isomer 106 gave two regioisomers in a ratio of 2:1 [88][95] (Scheme 21). This was proposed to be due to an increased steric interaction between the phenyl ring at position 4 on the β-lactam ring in 107 and the nitrosobenzene (47) during the formation of product 108. For the

Rh-Catalyzed reductive Mannich-type reaction and its application towards the synthesis of (±)-ezetimibe

• Motoyuki Isoda,
• Kazuyuki Sato,
• Yurika Kunugi,
• Satsuki Tokonishi,
• Atsushi Tarui,
• Masaaki Omote,
• Hideki Minami and
• Akira Ando

Beilstein J. Org. Chem. 2016, 12, 1608–1615, doi:10.3762/bjoc.12.157

• -reduction of an α,β-unsaturated ester to give a Reformatsky-type reagent, which in turn, reacted with an imine to give the syn-β-lactam. Additionally, the reaction was applied to the synthesis of (±)-ezetimibe, a potent β-lactamic cholesterol absorption inhibitor. Keywords: β-lactam; ezetimibe; reductive

• bulkiness of the β-position (Table 1, entries 1–8). It is interesting that ethyl sorbate (2g) gave the corresponding anti-β-lactam 3Ag in a moderate yield but with an anti-β-lactam stereochemistry indicating that the reaction proceeded via 1,6-reduction, then the resulting nucleophile was trapped by the

• α,β-unsaturated lactone 2h, the β-lactam anti-3Ah that has a hydroxy group on the side chain was obtained in a low yield (Table 1, entry 11). This result was of interest because the reaction is applicable to the synthesis of ezetimibe. Ezetimibe is an inhibitor of the cholesterol transporter Niemann

NeoPHOX – a structurally tunable ligand system for asymmetric catalysis

• Jaroslav Padevět,
• Marcus G. Schrems,
• Robin Scheil and
• Andreas Pfaltz

Beilstein J. Org. Chem. 2016, 12, 1185–1195, doi:10.3762/bjoc.12.114

• to the threonine methyl ester or N-protected derivatives were also briefly investigated, but failed. Grignard addition to the chloro amide 11 was not attempted because earlier studies with chloro amide 15 had shown that an undesired β-lactam 16 was formed upon treatment with Grignard reagents (Scheme

• anions were omitted for clarity. Retrosynthetic analysis for NeoPHOX ligands. Synthesis of 1st generation NeoPHOX Ir-complexes [19]. Synthesis of a C(5)-disubstituted NeoPHOX-Ir complex. Revisited synthetic strategy for the preparation of a threonine-based NeoPHOX ligand. Undesired β-lactam formation

The synthesis of functionalized bridged polycycles via C–H bond insertion

• Jiun-Le Shih,
• Po-An Chen and
• Jeremy A. May

Beilstein J. Org. Chem. 2016, 12, 985–999, doi:10.3762/bjoc.12.97

• diazoacetamides (Scheme 8) [61]. He found an important example of a transformation where the ratio of gamma vs beta-lactam formation could be controlled to a significant extent by catalyst choice. In particular, Rh2(4S-MEOX)4 favored the bridged γ-lactam 41 over the fused β-lactam 42 in about a 3:1 ratio. The

Selected synthetic strategies to cyclophanes

• Sambasivarao Kotha,
• Mukesh E. Shirbhate and
• Gopalkrushna T. Waghule

Beilstein J. Org. Chem. 2015, 11, 1274–1331, doi:10.3762/bjoc.11.142

Novel stereocontrolled syntheses of tashiromine and epitashiromine

• Loránd Kiss,
• Enikő Forró and
• Ferenc Fülöp

Beilstein J. Org. Chem. 2015, 11, 596–603, doi:10.3762/bjoc.11.66

• stereocontrolled approach has been developed for the syntheses of tashiromine and epitashiromine alkaloids from cyclooctene β-amino acids. The synthetic concept is based on the azetidinone opening of a bicyclic β-lactam, followed by oxidative ring opening through ring C–C double bond and reductive ring-closure

• pyrrolizidine alkaloids [45]. Results and Discussion We describe here a novel access route for the synthesis of tashiromine and epitashiromine by starting from an unsaturated bicyclic β-lactam. The retrosynthetic concept of the synthesis is represented on Scheme 1 and was based on the lactam ring opening, in

• continuation followed by oxidative ring opening of the formed β-amino esters and by reductive ring closure as key steps. Bicyclic β-lactam (±)-1 [53][54] was first transformed by azetidinone opening to the corresponding amino ester hydrochloride (±)-2 [53][54], N-protection of which with benzyl chloroformate

Natural phenolic metabolites with anti-angiogenic properties – a review from the chemical point of view

• Qiu Sun,
• Jörg Heilmann and
• Burkhard König

Beilstein J. Org. Chem. 2015, 11, 249–264, doi:10.3762/bjoc.11.28

• amide bond and evaluated their efficacy as modulators for β-lactam resistance in S. aureus. Landis-Piwowar et al. [68] and Wang et al. [69] protected the hydroxy groups through peracetylation. These analogs behave as prodrugs and the acetyl group is removed by cellular cytosolic esterases. Liao et al

Cross-dehydrogenative coupling for the intermolecular C–O bond formation

• Igor B. Krylov,
• Vera A. Vil’ and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2015, 11, 92–146, doi:10.3762/bjoc.11.13