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

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

• cyclic amide side chains. Keywords: α-halo-β-lactam; diazo; halocarbonylcarbene; halogenation; thermolysis; Introduction Diazocarbonyl compounds are popular precursors for carbonylcarbenes and -carbenoids, the synthetic utility of which is thoroughly established through their successful employment in

• N-methylene groups of the amide [44]. With the exception of the piperazine derivative 5d, the observed diastereomeric ratio in the β-lactam products was approximately 6:1, favouring the diastereomer in which the bromine atom and the ring fragment are in a trans relationship (hereafter referred to as

• interpreted from Table 1, the dominant reaction pathway in the high-yielding reactions (Table 1, entries 2–3), is apparently the intramolecular C–H insertion to form a β-lactam. The preferential formation of intramolecular products from N,N’-disubstituted diazoacetamides, as compared to diazoacetates has

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

• encapsulated in the two addition reactions presented in Scheme 7 [22]. β-Lactam xanthates such as 31 and 33 can be readily added without harm to the fragile azetidinone motif and, if desired, the xanthate group may be reduced off by a number of methods, the mildest perhaps relying on tris(trimethylsilyl)silane

• as the reducing agent [23]. Its use is illustrated by the synthesis of the β-lactam-sugar conjugate 35, which also highlights the possibility of cleanly removing an oxalyl group from adduct 34 without destruction of the azetidinone [24]. The synthesis of complex compounds such 32 and 35 would be very

• (±)-fortucine. Model radical sequence for the synthesis of quadrone. Radical cascade using the Barton decarboxylation. Simplified mechanism for the xanthate addition to alkenes. Synthesis of β-lactam derivatives. Sequential additions to three different alkenes (PhthN = phthalimido). Key cascade in the total

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

• site presumably by accessing a hydrophobic binding pocket [29][30]. A similar effect was seen with the substituted β-lactam analogue of PLG, compound 13, developed by Palomo et al. [31]. Other scaffolds have been employed successfully to generate PLG peptidomimetics. A β-amino acid approach to the

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

• -dimethylpenta-2,3-diene), at ice-bath temperature and obtained, after aqueous work-up, a mixture of the β-lactam 68 and the cross-conjugated amide 69; other alkylated allenes reacted similarly (Scheme 14) [36][37]. To rationalize their findings they proposed the initial generation of a zwitterionic intermediate

• importance are its amide bands (3515 and 1679 cm−1) in the IR spectrum and the absorption maximum at 284 nm in the electronic spectrum (triene chromophore). The central double bond of the triene system is trans-configured (3J = 15.2 Hz) [35]. The main product is the β-lactam derivate 71. Since this primary

• data (Supporting Information File 1) also agree with the structural proposal 72. For the formation of the two reaction products we suggest the pathways given in Scheme 14. The initial adduct of CSI to 2 is again a zwitterion 70. This either cycloisomerizes to the β-lactam 71 or undergoes an

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

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

• . Because of their interesting biological activities, their widespread occurrence in many natural products [28], and their broad synthetic utility, γ-lactam ring systems have received considerable attention in organic chemistry. Recent strategies toward the construction of the γ-lactam motif comprise β

• -lactam to γ-lactam ring expansions [29][30], aziridine ring openings followed by cyclization with enolates [31], palladium-catalyzed cyclizations [32], cycloadditions [33], multicomponent reactions [34], and even NHC catalysis [35][36]. Nevertheless, the methodology developed by Rovis indisputably

Synthesis of highly functionalized β-aminocyclopentanecarboxylate stereoisomers by reductive ring opening reaction of isoxazolines

• Melinda Nonn,
• Loránd Kiss,
• Reijo Sillanpää and
• Ferenc Fülöp

Beilstein J. Org. Chem. 2012, 8, 100–106, doi:10.3762/bjoc.8.10

• Peramivir analogues has recently been investigated as potential antiviral agents [46][47]. Results and Discussion We recently reported a regio- and stereoselective procedure for the formation of a series of isoxazoline-fused cispentacin and transpentacin regio- and stereoisomers (2–6) from bicyclic β-lactam

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

• cycloaddition and avoided formation of a β-lactam as shown before (Scheme 5) [5]. The palladium-catalyzed trans-addition-alkylative cyclization (anti-Wacker cyclization) of o-ethynylbenzaldehyde with organoboron reagents in the presence of secondary amines was accomplished by Tsukamoto and coworkers [6]. This

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

• Vaclav Jurcik Alexandra M. Z. Slawin David O'Hagan EASTChem School of Chemistry and Centre for Biomolecular Sciences, University of St Andrews, North Haugh, St Andrews, Fife, KY16 9ST, UK 10.3762/bjoc.7.86 Abstract The first synthesis of α-(trifluoromethyl)-β-lactam ((S)-1) is reported. The route

• starts from α-(trifluoromethyl)acrylic acid (2). Conjugate addition of α-(p-methoxyphenyl)ethylamine ((S)-3b), generated an addition adduct 4b which was cyclised to β-lactam 5b. Separation of the diastereoisomers by chromatography gave ((αS,3S)-5b). N-Debenzylation afforded the desired α-(trifluoromethyl

• )-β-lactam ((S)-1). The absolute stereochemistry of diastereoisomers 5 was determined by X-ray crystallographic determination of a close structural analogue, (αS,3S)-5c, and then 1H and 19F NMR correlation to the individual diastereoisomers of 5a and 5b. Keywords: enantiomeric resolution

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

• occupies the most important place in the treatment of fungal diseases. The triazole derivatives noted below were synthesized by various groups and show antifungal activity. Novel 1,2,3-triazole-linked with β-lactam–bile acid conjugates were prepared via 1,3-dipolar cycloaddition reactions of azido β

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

• four-membered ring, using the chirality and functionalization of the β-lactam ring as a stereo-controlling element [29][30]. This overview focuses on gold-catalyzed heterocyclization reactions of allenic and alkynic β-lactams which rely on the activation of the allene and alkyne component. The

• palladium-based catalysts such as Pd(OAc)2, PdCl2, [Pd(PPh3)4], and [Pd2(dba)3]·CHCl3 failed to give the desired cyclized products, exposure of allenyl-β-lactams 1 to 5 mol % AuCl3 in CH2Cl2 produced the bicyclic β-lactam products, i.e., the Δ1-carbapenems 2 (Scheme 1). The desired products were produced in