D-Fructose-based spiro-fused PHOX ligands: synthesis and application in enantioselective allylic alkylation

• Michael R. Imrich,
• Jochen Kraft,
• Cäcilia Maichle-Mössmer and
• Thomas Ziegler

Beilstein J. Org. Chem. 2018, 14, 2082–2089, doi:10.3762/bjoc.14.182

• ligands are prepared in two steps from readily available 1,2-O-isopropylidene protected β-D-fructopyranoses by the BF3·OEt2-promoted Ritter reaction with 2-bromobenzonitrile to construct the oxazoline moiety followed by Ullmann coupling of the resulting aryl bromides with diphenylphosphine. Both steps

• acetate as model substrate. Keywords: Fürst–Plattner rule; oxazoline; Ritter reaction; Tsuji–Trost reaction; Ullmann coupling; Introduction The vast majority of biologically active compounds like vitamins and natural products occur as single enantiomers in nature. Usually only one enantiomer generates

• -glucosamine and the sugar was linked to the aromatic system via an annulated oxazoline. Palladium complexes of 2 were used in allylic substitution of allyl acetates with dimethyl malonate as nucleophile and ee values from 69% to 98% were obtained [19]. Recently, we presented the synthesis of carbohydrate

Chiral bisoxazoline ligands designed to stabilize bimetallic complexes

• Deepankar Das,
• Rudrajit Mal,
• Nisha Mittal,
• Zhengbo Zhu,
• Thomas J. Emge and
• Daniel Seidel

Beilstein J. Org. Chem. 2018, 14, 2002–2011, doi:10.3762/bjoc.14.175

• to form a five-membered metallacycle, subtending N(2)–Ni(1)–N(3) and N(5)–Ni(2)–N(6) angles of 81.53° and 80.34°, respectively. Additionally, the nitrogen atoms on the oxazoline and amide moieties form six-membered rings with the nickel(ΙΙ) center with N(1)–Ni(1)–N(2) and N(4)–Ni(2)–N(5) angles of

• backbone of complex 16·Ni2(OAc)2 shows a helical arrangement. This helicity is facilitated by the innate stereogenic centers of the oxazoline moieties which is further extended by the flexibility afforded by the amide connections. Naphthyridine ligand 22-H2 was designed as an analogue of ligand 16-H2 that

• an acetate anion. The nitrogen atoms from pyrazole and amide moieties coordinate to the two nickel centers to form five-membered metallacycles, subtending N(1)–Ni(1)–N(2) and N(4)–Ni(2)–N(5) angles of 84.0° and 85.0°, respectively. Similarly, the nitrogen atoms on amide and oxazoline moieties form

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 tyrosine derivatives to spirolactams using iodine(III) reagents. In this reaction, oxazoline derivatives 41 were cyclized to spirocyclic products 42 using PIDA (15) as an electrophile in trifluoroethanol at room temperature for 30 minutes. The desired products 42 were isolated in moderate yields

• (Scheme 12). Additionally, the same research group [81] reported the oxidative cyclization of a phenolic substrate to a spirolactam using PIDA as electrophile. In this methodology, oxazoline 43 was cyclized to spirolactam 44 in 50% yield using PIDA (15) in trifluoroethanol at room temperature (Scheme 13

• same research group [104]. In this report, spirocyclic oxazoline 93 was prepared by starting from para-substituted phenolic compound 92 under the reaction conditions mentioned in Scheme 32 (Scheme 33). In 2002, Honda and co-workers [105] reported the synthesis of naturally occurring (−)-TAN1251A (95

DFT calculations on the mechanism of copper-catalysed tandem arylation–cyclisation reactions of alkynes and diaryliodonium salts

• Tamás Károly Stenczel,
• Ádám Sinai,
• Zoltán Novák and
• András Stirling

Beilstein J. Org. Chem. 2018, 14, 1743–1749, doi:10.3762/bjoc.14.148

• in the order of the oxazoline ring formation and the aryl transfer steps. In our model transformation, it was found that the reaction generally features the aryl transfer–ring closing sequence and this sequence shows very limited sensitivity to the variation of the substituent of the reactants. On

• the basis of the mechanism the origin of the stereoselectivity is ascribed to the interaction of the Cu ion with the oxazoline oxygen driving the ring-closure step selectively. Keywords: catalysis; DFT calculation; iodonium salts; reaction mechanism; tandem arylation–cyclisation; Introduction

• before the C–O bond formation in the ring closing step (see Scheme 1). As an example of the catalytic arylation–cyclisation strategy, an efficient procedure to form substituted oxazoline derivatives from alkyl and aryl propargylamides has been developed. The process involves a 5-exo-dig cyclisation and

Recent applications of chiral calixarenes in asymmetric catalysis

• Mustafa Durmaz,
• Erkan Halay and
• Selahattin Bozkurt

Beilstein J. Org. Chem. 2018, 14, 1389–1412, doi:10.3762/bjoc.14.117

• selectivity was the chiral oxazoline unit and not the inherent chirality of calixarene skeleton. Asymmetric hydrogenation Starting with distally O-dialkylated calixarene precursors, a series of BINOL-derived calix[4]arene-diphosphite ligands 40a–g were synthesized by Liu and Sandoval through phosphorylation

• achieve reusable catalysts for batch and continuous-flow studies. Inherently chiral calix[4]arene-based phase-transfer catalysts. Calix[4]arene-amides used as phase-transfer catalysts. Proposed transition state model of asymmetric Henry reaction. Structure of inherently chiral oxazoline calix[4]arenes

Synthesis of chiral 3-substituted 3-amino-2-oxindoles through enantioselective catalytic nucleophilic additions to isatin imines

• Hélène Pellissier

Beilstein J. Org. Chem. 2018, 14, 1349–1369, doi:10.3762/bjoc.14.114

• pyridine-oxazoline ligand In-Pyrox was found optimal to provide a wide variety of chiral 3-amino-2-oxindoles 62 in moderate to high yields (51–97%) and uniformly excellent enantioselectivities (91–98% ee). As shown in Scheme 21, the reaction performed at 70 °C in TFE as solvent proceeded well in the

• enantioselectivities (up to 94% ee) by using chiral nickel and palladium complexes with imidazoline and pyridine-oxazoline ligands while the first additions of enaminones to isatin imines catalyzed by chiral phosphoric acids provided even higher enantioselectivities (up to 97% ee). In spite of these significant

A survey of chiral hypervalent iodine reagents in asymmetric synthesis

• Soumen Ghosh,
• Suman Pradhan and
• Indranil Chatterjee

Beilstein J. Org. Chem. 2018, 14, 1244–1262, doi:10.3762/bjoc.14.107

• spirocyclization of naphthol carboxylic acid [34]. Later Birman et al. reported a new variation of a chiral I(V) reagent, namely 2-(o-iodoxyphenyl)oxazoline derivative 28 [35]. The reagent was applied to an asymmetric [4 + 2] Diels–Alder dimerization of phenolic derivatives 29 to construct tricyclic derivatives 30

• with moderate enantioselectivity (Scheme 4). Although modest ees were obtained, this chiral oxazoline-based compound demonstrated encouraging potential as a new class of chiral hypervalent iodine reagent. Fujita et al. synthesized non C2-symmetric chiral iodoarene reagents 9a derived from lactic acid

Fluorocyclisation via I(I)/I(III) catalysis: a concise route to fluorinated oxazolines

• Felix Scheidt,
• Christian Thiehoff,
• Gülay Yilmaz,
• Stephanie Meyer,
• Constantin G. Daniliuc,
• Gerald Kehr and
• Ryan Gilmour

Beilstein J. Org. Chem. 2018, 14, 1021–1027, doi:10.3762/bjoc.14.88

• -ray crystallographic analysis of a representative example. Given the importance of fluorine in drug discovery, its ability to modulate conformation, and the prevalence of the 2-oxazoline scaffold in Nature, this strategy provides a rapid entry into an important bioisostere class. Keywords: catalysis

• ; cyclisation; fluorination; gauche effect; hypervalent iodine; oxazolines; Introduction Marine and terrestrial natural product bioprospecting has established a broad spectrum of structurally complex, bioactive metabolites containing the venerable 2-oxazoline unit [1][2]. This diversity is exemplified by the

• siderophore antibiotic D-fluviabactin, the cytotoxic agent westiellamide, the antifungal macrodiolide leupyrrin A1 and the antitumour compound BE-70016 (Figure 1). In addition, synthetic polymers based on the 2-oxazoline building block constitute versatile platforms for a range of biomedical applications

Nanoreactors for green catalysis

• M. Teresa De Martino,
• Loai K. E. A. Abdelmohsen,
• Floris P. J. T. Rutjes and
• Jan C. M. van Hest

Beilstein J. Org. Chem. 2018, 14, 716–733, doi:10.3762/bjoc.14.61

• synthesis of dendrimers and their applications as nanoreactors and catalyst carriers have been extensively studied over the last decades [94][95][96]. Fan and co-workers incorporated a bis(oxazoline)-copper(II) complex in the hydrophobic core of a polyether dendrimer [11]. The copper catalytic complex was

Heterogeneous Pd catalysts as emulsifiers in Pickering emulsions for integrated multistep synthesis in flow chemistry

• Katharina Hiebler,
• Georg J. Lichtenegger,
• Manuel C. Maier,
• Eun Sung Park,
• Renie Gonzales-Groom,
• Bernard P. Binks and
• Heidrun Gruber-Woelfler

Beilstein J. Org. Chem. 2018, 14, 648–658, doi:10.3762/bjoc.14.52

• palladium by ligands which are covalently bound to the support material [12]. One example of such a catalyst was reported by our group using a bis(oxazoline) ligand bonded to 3-mercaptopropyl-functionalised silica [20]. Alternatively, the use of unsupported Pd nanoparticles or encapsulated Pd complexes are

Synthetic and semi-synthetic approaches to unprotected N-glycan oxazolines

• Antony J. Fairbanks

Beilstein J. Org. Chem. 2018, 14, 416–429, doi:10.3762/bjoc.14.30

• chloride (DMC), and related reagents, which can direct convert an oligosaccharide with a 2-acetamido sugar at the reducing terminus directly into the corresponding oxazoline in water. Therefore, oxazoline formation can now be achieved in water as the final step of any synthetic sequence, obviating the need

• these materials, in concert with DMC-mediated oxazoline formation as a final step, allow access to a selection of N-glycan oxazoline structures both in larger quantities and in a more expedient fashion than is achievable by total synthesis. Keywords: DMC, ENGase; glycosyl oxazolines; N-glycans

• ] (ENGases, EC 3.2.1.96), a class of enzyme which specifically cleave between the innermost two GlcNAc residues of N-glycans attached to N-linked glycoproteins, all operate via a two-step mechanism involving neighbouring group participation of the 2-acetamide group and an oxazoline as a high energy

Fluorination of some highly functionalized cycloalkanes: chemoselectivity and substrate dependence

• Attila Márió Remete,
• Melinda Nonn,
• Santos Fustero,
• Matti Haukka,
• Ferenc Fülöp and
• Loránd Kiss

Beilstein J. Org. Chem. 2017, 13, 2364–2371, doi:10.3762/bjoc.13.233

• treatment of dihydroxylated amino acid ester (±)-1 with 1.5 equiv of Deoxofluor after 70 min afforded through intramolecular cyclization a compound which was identified on the basis of 2D NMR analysis as oxazoline derivative (±)-2 as the sole product in 71% yield. When the same reaction was carried out in

• amide O-atom. Increasing the amount of Deoxofluor to 4 equiv resulted in the exclusive formation of the fluorine-containing oxazoline derivative (±)-3. Note that the addition of DBU did not have a significant effect on this reaction. When isolated hydroxyoxazoline (±)-2 is subjected to the fluorination

• , namely oxazoline derivative (±)-21 (Scheme 10). This is in high contrast to the transformation of (±)-14 (Scheme 7). Interestingly, when (±)-20 is treated with Deoxofluor in excess, again, differently from its all-cis counterpart (±)-14, two fluorinated oxazolines in nearly 1:1 ratio are obtained: (±)-22

Iodoarene-catalyzed cyclizations of N-propargylamides and β-amidoketones: synthesis of 2-oxazolines

• Somaia Kamouka and
• Wesley J. Moran

Beilstein J. Org. Chem. 2017, 13, 1823–1827, doi:10.3762/bjoc.13.177

• [32][33][34][35][36]. Gao and co-workers described the I2-catalyzed cyclization of β-acylaminoketones using tert-butyl hydroperoxide as the oxidant; notably, adding DBU led to oxazole formation whereas adding K2CO3 generated oxazolines [37][38]. Our proposed new approaches to oxazoline formation

• 2-oxazoline formation through the iodoarene-catalyzed cyclization of β-amidoketones 5. These are readily prepared by alkylation of the corresponding β-ketoester followed by decarboxylation (Scheme 4) [40][41]. The cyclization of β-amidoketones 5 was successful with the same conditions as

• could be improved to 5:1 by substituting p-toluenesulfonic acid with trifluoroacetic acid albeit with a loss of yield. When the p-nitrophenylamide 5p was subjected to the reaction conditions, the expected oxazoline 6p was not observed (Scheme 6). Instead, alcohol 8 was isolated in 66% yield. Presumably

Strategies toward protecting group-free glycosylation through selective activation of the anomeric center

• A. Michael Downey and
• Michal Hocek

Beilstein J. Org. Chem. 2017, 13, 1239–1279, doi:10.3762/bjoc.13.123

• ]. The two most successful saccharide donors to date are 1-fluoroglycosides or oxazoline derivatives (Scheme 2). In addition to the aforementioned enzymes, thioglycoligases and thioglycosynthases have also been developed for the synthesis of thioglycosides as reviewed by Withers et al. [12]. An elegant

• ligation of an oxazoline donor and commercially available RNase B protein (with the glycans curtailed to a single GlcNAc moiety [17]) as the acceptor [16]. The beauty of this work extends beyond the enzymatic glycosylation reaction. We point out that the oxazoline functionality was installed chemically in

• 1,6-anhydrosugars: The treatment of a 2-deoxy-2-N-acetylated sugar with DMC and an amine base in the absence of any nucleophile provides the observable (by 1H NMR) or even isolatable (LacNAc) corresponding oxazoline derivative in moderate to very good yield (Scheme 21, pathway A) [68][69]. It is

Correction: Inherently chiral calix[4]arenes via oxazoline directed ortholithiation: synthesis and probe of chiral space

• Simon A. Herbert,
• Laura J. van Laeren,
• Dominic C. Castell and
• Gareth E. Arnott

Beilstein J. Org. Chem. 2017, 13, 347–347, doi:10.3762/bjoc.13.38

• Simon A. Herbert Laura J. van Laeren Dominic C. Castell Gareth E. Arnott Department of Chemistry and Polymer Science, Stellenbosch University, Private Bag X1, Matieland 7602, South Africa 10.3762/bjoc.13.38 Keywords: calix[4]arene; inherently chiral; ortholithiation; oxazoline; Tsuji–Trost; In

Chromium(II)-catalyzed enantioselective arylation of ketones

• Gang Wang,
• Shutao Sun,
• Ying Mao,
• Zhiyu Xie and
• Lei Liu

Beilstein J. Org. Chem. 2016, 12, 2771–2775, doi:10.3762/bjoc.12.275

• asymmetric addition to ketones remains a big challenge probably due to the decreased reactivity and selectivity [36][37]. A breakthrough was made by the Sigman group who reported the catalytic enantioselective addition of allylic bromides and propargyl halides to arylaliphatic ketones using oxazoline ligands

• ) was selected as the model reaction for optimization employing Kishi’s oxazoline/sulfonamides as the chiral ligands. A series of oxazoline/sulfonamide ligands (L1–L8) were tested and the results were summarized in Table 1. Four subgroups of R1 were studied (entries 1–4, Table 1) and isopropyl

• substituted oxazoline proved to be the best ligand with a 42% ee. Afterwards, R2 (Table 1, entries 2, 5 and 6) and R3 (Table 1, entries 6–8) substituents were also examined, and L8 bearing a methyl group in both R2 and R3 gave the best enantiocontrol. The solvent effect was then investigated, and 1,2

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

• -ethyl-2-oxazoline in methanol [69]. Additionally, acylnitroso compounds can be generated by the rearrangement of diazonitroalkanes 26 [70], the photochemical cleavage of 1,2,4-oxadiazole-4-oxides 25 [71] and the cycloreversion of 9,10-dimethylantracene adducts 27 (Scheme 7) [72][73]. Dienes: There is a

• ). Recent research of the Whiting group revealed a wide spectrum of results on the reactions of hydroxamic acid analogues 35 with various dienes 37 using the copper/oxazoline/air catalytic system (Scheme 10) [69]. Conclusions of an experimental as well as a computational approach to understanding the

• reactions of acylnitroso compounds in [4 + 2] cycloadditions indicate several facts. The copper–oxazoline complex behaves as an excellent catalyst for the aerobic oxidation of acylhydroxamic acids. However, this system is useful only for hydroxamic acids containing a heteroatom between the aryl and carbonyl

Biosynthesis of oxygen and nitrogen-containing heterocycles in polyketides

• Franziska Hemmerling and
• Frank Hahn

Beilstein J. Org. Chem. 2016, 12, 1512–1550, doi:10.3762/bjoc.12.148

Conjugate addition–enantioselective protonation reactions

• James P. Phelan and
• Jonathan A. Ellman

Beilstein J. Org. Chem. 2016, 12, 1203–1228, doi:10.3762/bjoc.12.116

• (Scheme 2) [15][16][17]. A Mg-(bis)oxazoline complex serves as both a Lewis acid for the activation of α-substituted acrylates 6 towards radical addition and as a chiral template for an enantioselective hydrogen atom transfer from Bu3SnH to the α-ester radical intermediate. The authors found that the

• stoichiometric chiral Mg-(bis)oxazoline complex was required to achieve high enantioselectivity. Higher enantioselectivity was generally observed for reactions using secondary or tertiary alkyl halides. When performing radical conjugate additons to give 2-hydroxymethyl esters 7c, the authors observed a complete

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

• intermediate is a NeoPHOX derivative bearing a methoxycarbonyl group at the stereogenic center next to the oxazoline N atom. The addition of methylmagnesium chloride leads to a tertiary alcohol, which can be acylated or silylated to produce NeoPHOX ligands with different sterical demand. The new NeoPHOX

• efficiency and excellent enantioselectivity. Among the many oxazoline-derived ligands that have been reported in the literature, SimplePHOX [17] and ThrePHOX [18] have emerged as some of the most versatile and most easily accessible ligand classes. However, although iridium complexes derived from these

• state-of-the-art oxazoline-based ligands is the high cost of tert-leucinol as starting material, which reduces their potential for industrial-scale application. We therefore thought of ways to replace the tert-butyloxazoline ring by an equally effective oxazoline unit derived from a less expensive

Catalytic asymmetric synthesis of biologically important 3-hydroxyoxindoles: an update

• Bin Yu,
• Hui Xing,
• De-Quan Yu and
• Hong-Min Liu

Beilstein J. Org. Chem. 2016, 12, 1000–1039, doi:10.3762/bjoc.12.98

• allylated product in 93% yield and 72% ee value when cat. 2 was used (Scheme 2). Kesavan and co-workers described that the Pd/bis(oxazoline) (L1) complex can catalyze the asymmetric allylation of 3-O-Boc-oxindole, yielding the 3-allyl-3-hydroxyoxindoles in good yields (up to 93% yield) and with high

• the Cu(OTf)2 as the catalyst (10 mol %) and a fluorinated bis(oxazoline) L2 as the ligand (10 mol %), affording the products in moderate yields (up to 66% yield) and with good to excellent enantioselectivities (up to 92% ee). Interestingly, the fluorinated bis(oxazoline) L2 can be recovered and reused

Enantioselective carbenoid insertion into C(sp³)–H bonds

• J. V. Santiago and
• A. H. L. Machado

Beilstein J. Org. Chem. 2016, 12, 882–902, doi:10.3762/bjoc.12.87

• (sp3)–H bond has gained special attention, as in the works of Muler and Boléa [9], Flynn [10], Stattery [11] and their respective co-workers. The most selective copper carbenoids are those generated from chiral bis(oxazoline) ligands in the presence of copper(I) triflate (CuOTf) (Figure 3). The rhodium

• transformation was regio and stereoselective where the main product was trans-γ-lactam (56). The chiral rhodium complexes (S)-17, (S)-18 and (S)-23 were also evaluated and yielded similar regio- and diastereoselectivity, however, with lower enantioselectivity when compared to the bis(oxazoline)/CuCl2/NaBARF

• carbene, triplet carbene and carbenoids. Classification of the carbenoid intermediates by the electronic nature of the groups attached to the divalent carbene carbon. Chiral bis(oxazoline) ligands used in enantioselective copper carbenoid insertion. Chemical structures of complexes (R)-18 and (S)-18

Synthesis and in vitro cytotoxicity of acetylated 3-fluoro, 4-fluoro and 3,4-difluoro analogs of D-glucosamine and D-galactosamine

• Štěpán Horník,
• Lucie Červenková Šťastná,
• Petra Cuřínová,
• Jan Sýkora,
• Kateřina Káňová,
• Roman Hrstka,
• Ivana Císařová,
• Martin Dračínský and
• Jindřich Karban

Beilstein J. Org. Chem. 2016, 12, 750–759, doi:10.3762/bjoc.12.75

• acetal with acetic anhydride gave a mixture containing 1,2-oxazoline 41 as the main product (Scheme 5). The structure of oxazoline 41 was confirmed by single crystal X-ray diffraction analysis which also confirmed the retention of configuration during the preceding fluorine introduction. To prevent

• oxazoline formation, the order of reactions was reversed, and triethylsilyl triflate (TESOTf)-catalyzed [58] acetolysis of the 1,6-anhydro bridge in 19 gave 42 (Table 1) as a mixture of anomers from which the α-anomer crystallized. TESOTf as a catalyst for acetolysis gave better results than sulfuric acid

• 8, and oxazoline 41 was therefore tested for 24 h on the human prostate cancer PC-3 cell line, and human ovarian cancer A2780 cell line using the MTT assay, and the obtained IC50 values were compared with those obtained for cisplatin and 5-fluorouracil. All of the tested compounds induced only

Antibiotics from predatory bacteria

• Juliane Korp,
• María S. Vela Gurovic and
• Markus Nett

Beilstein J. Org. Chem. 2016, 12, 594–607, doi:10.3762/bjoc.12.58

• possess antioxidative properties and might thus confer resistance towards oxidative stress [63]. Structurally, the DKxanthenes harbor a hydrophilic asparagine moiety attached to a hydrophobic polyene chain bearing an additional oxazoline and pyrrol ring system. Their production seems to be universal among

Spiro-fused carbohydrate oxazoline ligands: Synthesis and application as enantio-discrimination agents in asymmetric allylic alkylation

• Jochen Kraft,
• Martin Golkowski and
• Thomas Ziegler

Beilstein J. Org. Chem. 2016, 12, 166–171, doi:10.3762/bjoc.12.18

• present work, we describe a convenient synthesis of spiro-fused D-fructo- and D-psico-configurated oxazoline ligands and their application in asymmetric catalysis. The ligands were synthesized from readily available 3,4,5-tri-O-benzyl-1,2-O-isopropylidene-β-D-fructopyranose and 3,4,5-tri-O-benzyl-1,2-O

• benzylation, fully characterized and subjected to palladium catalyzed Suzuki–Miyaura coupling with 2-pyridineboronic acid N-phenyldiethanolamine ester to give the corresponding 2-pyridyl spiro-oxazoline (PyOx) ligands. The spiro-oxazoline ligands showed high asymmetric induction (up to 93% ee) when applied as

• for metal-catalyzed asymmetric syntheses [16] we recently described the preparation of spiro-fused oxazoline ligands of type C from D-fructose [17]. We could demonstrate that our oxazoline ligands, in contrast to A, were able to form air and moisture-stable palladium complexes of type D upon reaction