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

Application of cyclic phosphonamide reagents in the total synthesis of natural products and biologically active molecules

• Thilo Focken and
• Stephen Hanessian

Beilstein J. Org. Chem. 2014, 10, 1848–1877, doi:10.3762/bjoc.10.195

• eight benzyl protecting groups was accomplished using Pearlman’s catalyst under mild acidic conditions to give fumonisin B2 (20) [45][46][47][84]. Tricylic β-lactams (1997) β-Lactam antibiotics are the most prescribed and successful class of antibiotics developed and used in clinical practice. This

• broad class of antibiotics shares a highly reactive four-membered β-lactam ring and includes penicillin derivatives, cephalosporins, monobactams, carbapenems, and other related compounds [85][86][87]. Approved drugs such as imipenem (111) and meropenem (112) (Figure 6) belong to the subclass of

• carbapenem-resistant enterobacteriaceae such as Klebsiella pneumoniae [90][91]. In the 1990’s, scientists at GlaxoWellcome developed sanfetrinem (113), a member of a novel class of tricyclic β-lactam antibiotics known as trinems [92][93]. Eventually the development of sanfetrinem was stopped in 2009 after

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

• Gijs Koopmanschap,
• Eelco Ruijter and
• Romano V.A. Orru

Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50

• β-amino acids, in which the ring was varied, were combined with a variety of aldehydes and isocyanides in methanol to obtain the desired β-lactams. In Scheme 6, a plausible mechanism of this reaction is shown. The β-lactam ring herein is formed via a ring contraction of the seven-membered

• media. In a variation, the same group constructed a 10-membered library of oxabicyclo β-lactam derivatives (17, Scheme 7) from the bifunctional heteronorborene 16 in either water or methanol [42]. It was shown that both solvents gave similar results with regard to the yield (43–76% vs. 50–96%), whereas

• the diastereoselectivity, the group of Sureshbabu utilized chiral Nβ-Fmoc-amino alkyl isocyanides (obtained from Nβ-Fmoc-amino acids) and L-aspartic acid α-methyl esters as Ugi-substrates (Scheme 10) [46]. The resulting β-lactam-linked peptidomimetics were obtained in good yields (53–78%) with high

Stereoselectively fluorinated N-heterocycles: a brief survey

• Xiang-Guo Hu and
• Luke Hunter

Beilstein J. Org. Chem. 2013, 9, 2696–2708, doi:10.3762/bjoc.9.306

• . Fluorination has also been shown to influence reactivity in four-membered N-heterocycles (Scheme 1). Kanerva and co-workers [18] investigated a series of β-lactam derivatives (4a–c) in a lipase-catalysed methanolysis process. While the non-fluorinated derivative 4a was found to be unreactive under the reaction

• Enzyme catalysis was presented earlier (Scheme 1) as a strategy for synthesising fluorinated β-lactams (4) [18]. At that time, we were interested in the effect that the fluorine substituents had on the reactivity of the β-lactam derivatives. However this work now merits further attention, because it also

• illustrates a strategy for achieving stereoselectivity in C–F bond formation. The racemic β-lactam 4b was synthesised as a single diastereoisomer from the Schiff base 79 (Scheme 11), by a Reformatsky addition followed by spontaneous cyclisation; removal of the amine protecting group under oxidative conditions

Diastereoselectivity in the Staudinger reaction of pentafluorosulfanylaldimines and ketimines

• Alexander Penger,
• Cortney N. von Hahmann,
• Alexander S. Filatov and
• John T. Welch

Beilstein J. Org. Chem. 2013, 9, 2675–2680, doi:10.3762/bjoc.9.303

• control of the C–N ketimine geometry was reflected in the stereochemistry of the product β-lactam. Cyclization of imines with a stereogenic center bearing SF5 was reflected in the 1,2-lk,lk selectivity of the β-lactam. Keywords: aldimine; Cornforth transition state; diastereoselectivity; β-lactam; organo

• minimization of unfavourable hydrophobic interactions. Results and Discussion The use of fluoroalkylimines to form β-lactams has proven especially useful in synthesis [24][25][26] especially in the Ojima β-lactam synthon method [27][28][29] used to prepare docetaxel analogs [26]. The general utility of the

• desired product β-lactam 7 was a minor constituent. However, the yields of 7 are of product purified by silica gel chromatography and crystallization. The only other fluorinated products observed prior to purification were unreacted imine 5 and the tentatively designated N-acylenamine 8. In the case of 7b

Synthesis and antibacterial activity of monocyclic 3-carboxamide tetramic acids

• Yong-Chul Jeong and
• Mark G. Moloney

Beilstein J. Org. Chem. 2013, 9, 1899–1906, doi:10.3762/bjoc.9.224

• was highly effective against erythromycin resistant S. pneumoniae Pn31 (MIC = 0.125 µg/mL). By way of comparison, the activities of moxifloxacin (a fourth generation fluoroquinolone) to S. aureus Sa18 (MIC = 32 µg/mL), amoxicillin (β-lactam) to S. pneumoniae Pn7, Pn10 and Pn11 (MIC = 4 µg/mL