Aza-Diels–Alder reaction between N-aryl-1-oxo-1H-isoindolium ions and tert-enamides: Steric effects on reaction outcome

• Amitabh Jha,
• Ting-Yi Chou,
• Zainab ALJaroudi,
• Bobby D. Ellis and
• T. Stanley Cameron

Beilstein J. Org. Chem. 2014, 10, 848–857, doi:10.3762/bjoc.10.81

• ]quinolin-11(5H)-ones via [4 + 2] imino-Diels–Alder cyclization from N-aryl-3-hydroxyisoindolinones and N-vinyl lactams under Lewis acid-catalysed anhydrous conditions is reported. Reactions of N-(2-substituted-aryl)-3-hydroxyisoindolinones with N-vinylpyrrolidone under identical conditions resulted in the

• fashion or otherwise) with N-(2-substituted phenyl)-1-oxo-1H-isoindolium ions. Conclusion 6,6a-Dihydroisoindolo[2,1-a]quinolin-11(5H)-one derivatives were synthesized from N-aryl-3-hydroxyisoindolinones and N-vinyl lactams under Lewis acid-catalysed anhydrous conditions in fair to good yields. As expected

• , the reaction appeared to proceed via the formation of an N-acyliminium ion which underwent an inverse-electron demand imino-Diels–Alder reaction. While reactions of this type are known to occur, this is the first report of the use of N-vinyl lactams as a dienophile for the inverse-electron demand

Synthesis of (2S,3R)-3-amino-2-hydroxydecanoic acid and its enantiomer: a non-proteinogenic amino acid segment of the linear pentapeptide microginin

• Rajendra S. Rohokale and
• Dilip D. Dhavale

Beilstein J. Org. Chem. 2014, 10, 667–671, doi:10.3762/bjoc.10.59

• -groups to olefinic acid by either asymmetric epoxidation, dihydroxylation or aminohydroxylation [10][11][12][13][14][15], (ii) the asymmetric synthesis of β-lactams by a Staudinger reaction between ketene and imine to give the corresponding amino acids [16], and (iii) the Lewis acid catalyzed

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

• ease of preparation via IMCRs [27][28][29]. First, the β-lactams will be described followed by five-membered rings varying from pyrrolidines to tetrazoles based amide bond isosteres. Examples of the six-membered rings showing peptide like-properties are the piperazines, homoprolines, dihydropyrimidones

• and triazines, whereas azepines form an important class of seven-membered cyclic peptidomimetics. Four membered ring constraints β-Lactams The smallest class of cyclic peptidomimetics is that of the β-lactams. β-lactams are effective antibiotics [30] but also show inhibitory activities against serine

• - [31], elastase- [32][33][34][35], and HIV-1 protease [36] and papain [37]. For the design of β-lactams, the Staudinger reaction involving a [2 + 2] cycloaddition of ketenes and imines is the most common method used [38]. However, Ugi reactions starting form β-amino acids are also described. In 2002

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

• 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

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

• Alexander Penger Cortney N. von Hahmann Alexander S. Filatov John T. Welch Department of Chemistry, University at Albany, SUNY, 1400 Washington Ave., Albany, NY 12222, USA 10.3762/bjoc.9.303 Abstract β-Lactams were diastereoselectively formed by the reaction of SF5-containing aldimines, or an SF5

• 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

• familiar Staudinger reaction of imines to transform readily accessible aldehydes to β-lactams has been well reviewed [30][31][32][33], yet in spite of this familiarity, the mechanism of this process remains a topic of interest [34][35][36]. Previously, it has been shown that fluorinated imines can undergo

New developments in gold-catalyzed manipulation of inactivated alkenes

• Michel Chiarucci and
• Marco Bandini

Beilstein J. Org. Chem. 2013, 9, 2586–2614, doi:10.3762/bjoc.9.294

• inactivated alkenes was also exploited for the synthesis of highly substituted lactams 59, also in a preparative scale [53]. When alkenyl β-keto amides 60 were reacted with a 1:1 mixture of phosphine-gold complex 20a and AgOTf (toluene, 50–90 °C), exo-trig hydroalkylation of the C–C double bond took place

• , affording 5-, 6-membered lactams and spiro-lactams 61 in excellent yields and high trans diastereoselectivity (Scheme 16). 4.2 The hydroarylation reaction In addition to methylene active compounds, electron-rich benzenes and heteroaromatics can be added to gold activated alkenes under suitable conditions

Towards stereochemical control: A short formal enantioselective total synthesis of pumiliotoxins 251D and 237A

• Jie Zhang,
• Hong-Kui Zhang and
• Pei-Qiang Huang

Beilstein J. Org. Chem. 2013, 9, 2358–2366, doi:10.3762/bjoc.9.271

• mixture of lactams. Without separation, the mixture was treated with TBAF in dichloromethane to produce alcohols 18 and 20 (combined yield: 62% over 3 steps) in a ratio of 95:5 (determined by 1H NMR), along with the keto-amide 21 in 13% yield (Scheme 7). Separation of the mixture by column chromatography

Diastereoselective radical addition to γ-alkyl-α-methylene-γ-butyrolactams and the synthesis of a chiral pyroglutamic acid derivative

• Tomoko Yajima,
• Eriko Yoshida and
• Masako Hamano

Beilstein J. Org. Chem. 2013, 9, 1432–1436, doi:10.3762/bjoc.9.161

• Tomoko Yajima Eriko Yoshida Masako Hamano Department of Chemistry, Ochanomizu University, Otsuka, Bunkyo-ku, Tokyo, 112-8610, Japan 10.3762/bjoc.9.161 Abstract The cis- and trans-stereoselective radical additions to α-methylene-γ-alkyl- γ-lactams were investigated and the scope and limitation of

• the reaction were also revealed. This stereoselective radical reaction was used for synthesis of chiral pyroglutamic acid derivatives starting from a commercially available chiral amino acid. Keywords: chelation controlled reaction; diastereoselective reaction; free radical; lactams; pyroglutamic

• acid derivative; radical alkylation; Introduction γ-Lactams exist in many natural products and biologically active compounds and are one of the most important classes of compounds for drug discovery [1][2][3]. Substituted γ-lactams, in particular, have potential application in drug synthesis, but the

α-Bromodiazoacetamides – a new class of diazo compounds for catalyst-free, ambient temperature intramolecular C–H insertion reactions

• Åsmund Kaupang and
• Tore Bonge-Hansen

Beilstein J. Org. Chem. 2013, 9, 1407–1413, doi:10.3762/bjoc.9.157

• thermolysis perform intramolecular C–H insertions to produce α-halo-β-lactams. When carried out with α-bromodiazoacetamides bearing cyclic side chains, the thermolysis reaction affords bicyclic α-halo-β-lactams, in some cases in excellent yields, depending on the ring size and substitution pattern of the

• -bromodiazoacetamides to form α-bromo-β-lactams. Results The diazoacetamides 3a–f were synthesised from α-bromoacetamides 2a–f using a protocol published by Toma et al. [40], modified by exchanging the base employed in the original procedure (DBU) for 1,1,3,3-tetramethylguanidine (TMG). The use of TMG allowed for a

• -bromodiazoacetamides will rapidly lose their bright red colour at temperatures above 0 °C. As can be seen in Table 1, the obtained yields of the α-bromo-β-lactams 5a–f vary significantly throughout the series. Among the derivatives with aliphatic amide side chains, the yields increase dramatically with ring size

A construction of 4,4-spirocyclic γ-lactams by tandem radical cyclization with carbon monoxide

• Mitsuhiro Ueda,
• Yoshitaka Uenoyama,
• Nozomi Terasoma,
• Shoko Doi,
• Shoji Kobayashi,
• Ilhyong Ryu and
• John A. Murphy

Beilstein J. Org. Chem. 2013, 9, 1340–1345, doi:10.3762/bjoc.9.151

• Technology, 5-16-1 Ohmiya, Asahi-ku, Osaka 535-8585, Japan Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, UK 10.3762/bjoc.9.151 Abstract A straightforward synthesis of 4,4-spirocyclic indol γ-lactams by tandem radical cyclization of iodoaryl allyl

• azides with CO was achieved. The reaction of iodoaryl allyl azides, TTMSS and AIBN under CO pressure (80 atm) in THF at 80 °C gave the desired 4,4-spirocyclic indoline, benzofuran, and oxindole γ-lactams in moderate to good yields. Keywords: 4,4-spirocyclic indol γ-lactams; carbon monoxide; free radical

• ; iodoaryl allyl azides; tandem radical cyclization; Introduction 4,4-Spirocyclic oxindole γ-lactams containing a quaternary carbon center are key structures for the synthesis of biologically active natural products and the related analogues [1][2][3][4]. Therefore, the development of an efficient synthesis

Some aspects of radical chemistry in the assembly of complex molecular architectures

• Béatrice Quiclet-Sire and
• Samir Z. Zard

Beilstein J. Org. Chem. 2013, 9, 557–576, doi:10.3762/bjoc.9.61

• by the rich array of lactams 159a–f [67]. In the case of ketoester 159c, the reaction was carried out at room temperature [68]. The formation of unsaturated lactam 159f is particularly interesting, since it involves the use of a mild oxidant (cupric acetate) in a reducing medium [69]. Another

• formally produced in these transformations, the addition of sodium acetate to buffer the medium is often beneficial. The easy access to unsaturated lactams such as 165 and 166 may be exploited to construct complex structures by subsequent application of radical, ionic, or organometallic transformations

• agents. Radical allylations using allylic alcohol derivatives. Synthesis of variously substituted lactams. Nickel-mediated synthesis of unsaturated lactams. Total synthesis of (±)-3-demethoxy-erythratidinone. Generation and capture of an iminyl radical from an oxime ester. Acknowledgements We are

Development of peptidomimetic ligands of Pro-Leu-Gly-NH₂ as allosteric modulators of the dopamine D₂ receptor

• Swapna Bhagwanth,
• Ram K. Mishra and
• Rodney L. Johnson

Beilstein J. Org. Chem. 2013, 9, 204–214, doi:10.3762/bjoc.9.24

• β-turn that is mimicked is dictated by the chirality of C-3. Lactams 1, 2, 4–6, and 9 (Figure 2) were active in enhancing the binding of the dopamine receptor agonist 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (ADTN) to dopamine receptors, while 3, 7, and 8 were inactive [19][20]. The

• Freidinger lactams that employs the piperidin-2-one scaffold yielded the active PLG peptidomimetic 14 [32]. Another example is the pyridine-based PLG peptidomimetics developed by Saitton et al. [33][34] and illustrated by 15. Peptidomimetic 15 cannot adopt a type II β-turn, but rather exists in an extended

Polar reactions of acyclic conjugated bisallenes

• Reiner Stamm and
• Henning Hopf

Beilstein J. Org. Chem. 2013, 9, 36–48, doi:10.3762/bjoc.9.5

• transformations. Keywords: β-lactams; conjugated bisallenes; cyclopentenones; epoxidation; halogen addition; hydrohalogenation; ionic additions; metalation; Introduction Whereas the use of hexa-1,2,4,5-tetraene (1) and its derivatives in pericyclic reactions is well documented [2][3][4][5][6], relatively little

Flow photochemistry: Old light through new windows

• Jonathan P. Knowles,
• Luke D. Elliott and
• Kevin I. Booker-Milburn

Beilstein J. Org. Chem. 2012, 8, 2025–2052, doi:10.3762/bjoc.8.229

Automated three-component synthesis of a library of γ-lactams

• Erik Fenster,
• David Hill,
• Oliver Reiser and
• Jeffrey Aubé

Beilstein J. Org. Chem. 2012, 8, 1804–1813, doi:10.3762/bjoc.8.206

• , Germany 10.3762/bjoc.8.206 Abstract A three-component method for the synthesis of γ-lactams from commercially available maleimides, aldehydes, and amines was adapted to parallel library synthesis. Improvements to the chemistry over previous efforts include the optimization of the method to a one-pot

• process, the management of by-products and excess reagents, the development of an automated parallel sequence, and the adaption of the method to permit the preparation of enantiomerically enriched products. These efforts culminated in the preparation of a library of 169 γ-lactams. Keywords: γ-lactam

• been significant in the treatment of epilepsy [6][7], HIV [8][9], neurodegenerative disease and depression [10][11]. Having identified the lactam ring as a target of opportunity in chemical-screening efforts, we previously reported a method to prepare γ-lactams from readily available maleimides

Stereoselective, nitro-Mannich/lactamisation cascades for the direct synthesis of heavily decorated 5-nitropiperidin-2-ones and related heterocycles

• Pavol Jakubec,
• Dane M. Cockfield,
• Madeleine Helliwell,
• James Raftery and
• Darren J. Dixon

Beilstein J. Org. Chem. 2012, 8, 567–578, doi:10.3762/bjoc.8.64

• ester 6c, provided moderate yields of the desired δ-lactams 1b and 1c as single diastereoisomers in both cases. The diastereoselectivity in the latter case is notable, as the quaternary stereogenic centre is created in the lactamisation step. The relative stereochemical configurations of 1a–c were

N-Heterocyclic carbene/Brønsted acid cooperative catalysis as a powerful tool in organic synthesis

• Rob De Vreese and
• Matthias D’hooghe

Beilstein J. Org. Chem. 2012, 8, 398–402, doi:10.3762/bjoc.8.43

• functionalized pyrrolidin-2-ones as valuable scaffolds in heterocyclic chemistry. This Commentary will briefly highlight the concept of N-heterocyclic carbene/Brønsted acid cooperative catalysis as a new and powerful methodology in organic chemistry. Keywords: Brønsted acids; cooperative catalysis; γ-lactams; N

• the search for suitable combinations and, if one of both partners is chiral, the development of enantioselective catalytic processes. Selected examples of the successful deployment of cooperative catalysis in organic synthesis comprise the preparation of chiral γ-lactams from N-acyl hydrazones and α,β

• formed homoenolate 10 with the activated iminium salt 12 to provide a new entry into the class of pyrrolidin-2-ones 13 (Scheme 4), which is potentially complementary to other methods in terms of stereochemistry. However, the formation of lactones instead of lactams through the intervention of aldehydes

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

• Matthias D’hooghe,
• Stéphanie Vandekerckhove,
• Karen Mollet,
• Karel Vervisch,
• Stijn Dekeukeleire,
• Liesbeth Lehoucq,
• Carmen Lategan,
• Peter J. Smith,
• Kelly Chibale and
• Norbert De Kimpe

Beilstein J. Org. Chem. 2011, 7, 1745–1752, doi:10.3762/bjoc.7.205

• variety of 2-amino-3-arylpropan-1-ols, anti-2-amino-3-aryl-3-methoxypropan-1-ols and anti-2-amino-1-arylpropan-1,3-diols were prepared selectively through elaboration of trans-4-aryl-3-chloro-β-lactams. In addition, a number of 2-(azidomethyl)aziridines was converted into novel 2-[(1,2,3-triazol-1-yl

• antiplasmodial activity against both a chloroquine-sensitive and a chloroquine-resistant strain of Plasmodium falciparum with IC50-values of ≤25 μM. Keywords: aminopropanes; antimalarial activity; aziridines; β-lactams; ring opening; Introduction Malaria remains a major issue in health control, especially in

• efforts have been devoted to the preparation of structurally diverse analogues bearing a functionalized propane skeleton [6][7][8]. In that respect, we have been engaged in the stereoselective synthesis of syn-2-alkoxy-3-amino-3-arylpropan-1-ols 1 by reductive ring opening of the corresponding β-lactams

Amines as key building blocks in Pd-assisted multicomponent processes

• Didier Bouyssi,
• Nuno Monteiro and
• Geneviève Balme

Beilstein J. Org. Chem. 2011, 7, 1387–1406, doi:10.3762/bjoc.7.163

• addition of acetic acid and 15 equivalents of ammonium acetate to the crude mixture resulted in a postcyclization leading to imidazolones 4, with spontaneous elimination of the initial chloroformate substituent (Scheme 2). Arndtsen also demonstrated that 3-amido-substituted β-lactams 7 can be obtained

• to the mesoionic compound 5 under these conditions. Subsequent addition of a second, different imine produced β-lactams 9 in good yields, after heating at 55 °C for 24 h (Scheme 4) [4]. As mentioned above, imidazolinium salts 12 can be obtained by a dipolar cycloaddition of münchnone intermediates

• cyclofunctionalization of the allyl moiety by carbopalladation/reductive elimination [22]. It is interesting to note that 3-sulfonylpyrolidin-2-ones (γ-lactams) 48 may also be accessed in high yield as single trans-diastereomers upon simple treatment of N-allyl- or N-methylpyrrolidines with 2-mercaptobenzoic acid in

Gold(I)-catalyzed synthesis of γ-vinylbutyrolactones by intramolecular oxaallylic alkylation with alcohols

• Michel Chiarucci,
• Mirko Locritani,
• Gianpiero Cera and
• Marco Bandini

Beilstein J. Org. Chem. 2011, 7, 1198–1204, doi:10.3762/bjoc.7.139

• alkylation procedure to obtain valuable precursors (i.e., lactams and lactones) of podophyllotoxin analogs [39][40]. However, to the best of our knowledge, no examples of metal-catalyzed lactonization through direct activation of allylic alcohols have been described so far. Results and Discussion At the

Synthesis of novel 5-alkyl/aryl/heteroaryl substituted diethyl 3,4-dihydro-2H-pyrrole-4,4-dicarboxylates by aziridine ring expansion of 2-[(aziridin-1-yl)-1-alkyl/aryl/heteroaryl-methylene]malonic acid diethyl esters

• Satish S. More,
• T. Krishna Mohan,
• Y. Sateesh Kumar,
• U. K. Syam Kumar and
• Navin B. Patel

Beilstein J. Org. Chem. 2011, 7, 831–838, doi:10.3762/bjoc.7.95

• ], pyrrolines [10][11][12][13][14], imidazolidinones [15], β-lactams [16][17][18] and azepines [19][20][21]. There is ample evidence in the literature to confirm that the syntheses and applications of the N-acyl, N-sulfonamide or N-benzyl protected C-vinylaziridines are of considerable interest in organic

Single enantiomer synthesis of α-(trifluoromethyl)-β-lactam

• Václav Jurčík,
• Alexandra M. Z. Slawin and
• David O'Hagan

Beilstein J. Org. Chem. 2011, 7, 759–766, doi:10.3762/bjoc.7.86

• ; organofluorine building blocks; α-(trifluoromethyl)-β-lactam; Introduction β-Lactams (azetidin-2-ones) have played a prominent role in medicinal chemistry and many structural variants have been prepared and elaborated [1]. Similarly, the CF3 group is an ubiquitous substituent in pharmaceutical research, where

• -substituted β-lactams 5 would give a mixture of two stereoisomers which might be separated into their individual diastereoisomers 5 by chromatography. N-Benzyl deprotection of the individual diastereoisomers would then provide β-lactam 1 as a single enantiomer. At the outset, (S)-(α-phenyl)ethylamine (3a) was

• nitrate (CAN) oxidation offered a milder deprotection method [15]. The aza-Michael reaction proved straightforward to generate 4b and then cyclisation again using thionyl chloride and triethylamine gave β-lactams 5b in a 40% de, presumably again a thermodynamically biased isomer ratio. The

Advances in synthetic approach to and antifungal activity of triazoles

• Kumari Shalini,
• Nitin Kumar,
• Sushma Drabu and
• Pramod Kumar Sharma

Beilstein J. Org. Chem. 2011, 7, 668–677, doi:10.3762/bjoc.7.79

• -lactams and terminal alkynes of bile acids in the presence of a Cu(I) catalyst (click chemistry) by Vatmurge et al. The synthesized compounds were evaluated for their antifungal activity against different fungal strains such as Candida albicans, Cryptococcus neoformans, Benjaminiella poitrasii, Yarrowia

Gold-catalyzed heterocyclizations in alkynyl- and allenyl-β-lactams

• Benito Alcaide and
• Pedro Almendros

Beilstein J. Org. Chem. 2011, 7, 622–630, doi:10.3762/bjoc.7.73

• Científicas (CSIC), Juan de la Cierva 3, 28006-Madrid, Spain 10.3762/bjoc.7.73 Abstract New gold-catalyzed methods using the β-lactam scaffold have been recently developed for the synthesis of different sized heterocycles. This overview focuses on heterocyclization reactions of allenic and alkynic β-lactams

• which rely on the activation of the allene and alkyne component. The mechanism as well as the regio- and stereoselectivity of the cyclizations are also discussed. Keywords: alkynes; allenes; gold; heterocyclizations; β-lactams; Introduction The chemistry of alkynes and allenes has been extensively

• (endo versus exo cyclizations) as well as it being one of the most rapid and convenient methods for the preparation of heterocycles. On the other hand, in addition to the key role that β-lactams play in medicinal chemistry, namely, their action against pathogenic bacteria, enzyme inhibition, or gene

Palladium- and copper-mediated N-aryl bond formation reactions for the synthesis of biological active compounds

• Carolin Fischer and
• Burkhard Koenig

Beilstein J. Org. Chem. 2011, 7, 59–74, doi:10.3762/bjoc.7.10

• ], benzimidazoles [40][41], sulfonamides [38], pyrroles [42] and lactams [43]. The three typical methods for N-arylation have been extensively reviewed concerning scope and limitation of these reactions [4][44][45][46][47][48]. However, the application of palladium- and copper-mediated N-arylation reactions in the