BODIPY-based fluorescent liposomes with sesquiterpene lactone trilobolide

• Ludmila Škorpilová,
• Silvie Rimpelová,
• Michal Jurášek,
• Miloš Buděšínský,
• Jana Lokajová,
• Roman Effenberg,
• Petr Slepička,
• Tomáš Ruml,
• Eva Kmoníčková,
• Pavel B. Drašar and
• Zdeněk Wimmer

Beilstein J. Org. Chem. 2017, 13, 1316–1324, doi:10.3762/bjoc.13.128

• theranostic applications. Keywords: BODIPY conjugates; cancer targeting; drug delivery; liposomes; natural compounds; sesquiterpene lactone trilobolide; Introduction Targeted (smart) drug delivery is a method for specific delivering of an active compound preferentially to some cells or tissues in the human

• describe the synthesis and application of a fluorescent construct (further called construct 6, depicted in Scheme 1) based on a green-emitting BODIPY dye and trilobolide–cholesterol (Tb-ChL) in a liposome formulation. Trilobolide (Tb, Figure 1) is a potent natural compound of the sesquiterpene lactone

• active construct 6 from the liposomes. Further tests are necessary to confirm this hypothesis. Conclusion In summary, in order to develop a drug delivery system for potential theranostic applications, we prepared a submicron liposome-based formulation of a cytotoxic agent, sesquiterpene lactone

Strategies in megasynthase engineering – fatty acid synthases (FAS) as model proteins

• Manuel Fischer and
• Martin Grininger

Beilstein J. Org. Chem. 2017, 13, 1204–1211, doi:10.3762/bjoc.13.119

• lactone 6-heptyl-4-hydroxypyran-2-one (6-HHP) within the scaffold of the Corynebacterium ammoniagenes FAS (a bacterial type I system). In an engineered reaction sequence, an initial FAS module was designed to produce SCFA as acyl esters, which are in a second FAS module elongated to the triketide and

• cyclized to the final lactone (Figure 4). A similar synthetic route can be found in norsolorinic acid synthesis, in which a fully reducing fungal FAS collaborates with a non-reducing PKS [4][56], as well as in resorcylic acid lactone synthesis, in which two iterative PKS systems work in sequence [57]. We

• -domain functional knockout, to synthesize the final lactone PK. The knockout in the AT-domain hinders the uptake of acetyl-CoA and encodes for modules acting in sequence. Acknowledgements M.G. thanks Dieter Oesterhelt for valuable discussions on FAS and PKS catalytic mechanisms, and continuous support

Total syntheses of the archazolids: an emerging class of novel anticancer drugs

• Stephan Scheeff and
• Dirk Menche

Beilstein J. Org. Chem. 2017, 13, 1085–1098, doi:10.3762/bjoc.13.108

• also pursued identical routes to this subunit. As shown in Scheme 5, this sequence started from L-leucine (26) which was first converted with nitrous acid to the hydroxy acid 27, which proceeds with retention of the configuration due to intermediate lactone formation after generation of the diazonium

A concise and practical stereoselective synthesis of ipragliflozin L-proline

• Shuai Ma,
• Zhenren Liu,
• Jing Pan,
• Shunli Zhang and
• Weicheng Zhou

Beilstein J. Org. Chem. 2017, 13, 1064–1070, doi:10.3762/bjoc.13.105

• other hypoglycemic agents. Only a few methods have been found in the literature about the synthesis of 1. It was reported that aryllithium reacted with per-hydroxy-protected D-glucono-1,5-lactone at −78 °C to obtain the lactol, followed by reduction with a large bulk silyl hydride in order to get high β

A strategic approach to [6,6]-bicyclic lactones: application towards the CD fragment of DHβE

• Tue Heesgaard Jepsen,
• Emil Glibstrup,
• François Crestey,
• Anders A. Jensen and
• Jesper Langgaard Kristensen

Beilstein J. Org. Chem. 2017, 13, 988–994, doi:10.3762/bjoc.13.98

• effective synthetic protocol to access [6,6]-bicyclic lactone moieties through a regio- and stereoselective intramolecular Mizoroki–Heck cross-coupling reaction followed by a 6π-electrocyclization. This method enabled the first synthesis of the elusive CD fragment of the Erythrina alkaloid DHβE. Preliminary

• pharmacological evaluations support the notion that the key pharmacophores of DHβE are located in the A and B rings. Keywords: DhβE; Mizoroki–Heck cross-coupling reaction; 6π-electrocyclization; [6,6]-bicyclic lactone; vinyl halide; Introduction The neuronal nicotinic acetylcholine receptors (nAChRs) have been

• ring and the B–C ring, which contrasts a mutational-computational study by Bermudez and co-workers suggesting that the lactone carbonyl is a hydrogen bond acceptor and hence locating the key pharmacophores in the C and D rings [9]. In order to weigh these hypotheses against one another, we have

Transition-metal-catalyzed synthesis of phenols and aryl thiols

• Yajun Liu,
• Shasha Liu and
• Yan Xiao

Beilstein J. Org. Chem. 2017, 13, 589–611, doi:10.3762/bjoc.13.58

• phosphonates were compatible with the hydroxylation condtions, while monoalkyl phosphonate gave the phosphoryl lactone as product. Exploration of substrate scope showed that both electron-donating groups (such as Me, OMe) and electron-withdrawing groups (such as F, Cl, Br, CF3) are tolerable. 1.2.2.3 Phenol as

Synthesis of 1-indanones with a broad range of biological activity

• Marika Turek,
• Dorota Szczęsna,
• Marek Koprowski and
• Piotr Bałczewski

Beilstein J. Org. Chem. 2017, 13, 451–494, doi:10.3762/bjoc.13.48

• , 1-indanone has been obtained in 80% yield. Interestingly, when aluminum chloride was added to the lactone in benzene, the yield of this reaction decreased (30%) [34]. Irradiation of esters 44 possessing the photoremovable 2,5-dimethylphenacyl group in benzene or cyclohexane solutions led to free

Biosynthetic origin of butyrolactol A, an antifungal polyketide produced by a marine-derived Streptomyces

• Enjuro Harunari,
• Hisayuki Komaki and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2017, 13, 441–450, doi:10.3762/bjoc.13.47

• system bearing a γ-lactone terminus constitutes the right half of the molecule. To date, no structurally related natural products are known except for its demethyl congener butyrolactol B that was also isolated from the same strain and has an isopropyl group instead of the tert-butyl terminus [9]. Very

• intriguing feature of this molecule is the highly oxygenated carbon chain in which eight hydroxy groups, one of which is used for lactone formation, are contiguously aligned. A 1,3-diol is a common structural element in aliphatic polyketides because the incorporation of malonate-precursors gives rise to the

• with a parameter set optimized for 1JCC 50 Hz, cross peaks derived from the intact 13C2 acetate units were detected for the carbon pairs mentioned above (Table 1, Figure 4a). According to the incorporation result of the doubly labeled acetate, malonyl-CoA is not the extender unit for the lactone (C-1

Polyketide stereocontrol: a study in chemical biology

• Kira J. Weissman

Beilstein J. Org. Chem. 2017, 13, 348–371, doi:10.3762/bjoc.13.39

• stage. This modification results in an experimentally tractable δ-lactone 9 instead of the 14-membered macrolide, 6-deoxyerythronolide B. Notably, the two methyl centers in the lactone have opposite configurations (for clarity, that at C-2 will be referred to as D-configured, and that at C-4 as L), and

• (Figure 9), (2RS)-[2-2H]methylmalonyl-CoA (10) was prepared and provided to DEBS 1-TE (along with starter unit butyryl-CoA (11) and NADPH (12)), knowing that solely the (2S)- isomer would be utilized. Analysis by mass spectrometry and NMR of the triketide lactone product 13 showed that only a single

• lactone product). Sequestering of intermediates by the ACP domains has been proposed as a source of configurational stability at C-2 [82]. However, as all direct study of this question to date by NMR has failed to reveal any direct contact between modular PKS ACP domains and their attached substrates [83

Identification, synthesis and mass spectrometry of a macrolide from the African reed frog Hyperolius cinnamomeoventris

• Markus Menke,
• Pardha Saradhi Peram,
• Iris Starnberger,
• Walter Hödl,
• Gregory F.M. Jongsma,
• David C. Blackburn,
• Mark-Oliver Rödel,
• Miguel Vences and
• Stefan Schulz

Beilstein J. Org. Chem. 2016, 12, 2731–2738, doi:10.3762/bjoc.12.269

• ; pheromones; Introduction The lactone motif is found in many compounds that are used in chemical communication. Among them, macrocyclic lactones are an important class because of their biosynthetic availability and their inherent compound properties. During the biosynthesis of macrocyclic lactones, a fatty

Evidence for an iterative module in chain elongation on the azalomycin polyketide synthase

• Hui Hong,
• Yuhui Sun,
• Yongjun Zhou,
• Emily Stephens,
• Markiyan Samborskyy and
• Peter F. Leadlay

Beilstein J. Org. Chem. 2016, 12, 2164–2172, doi:10.3762/bjoc.12.206

• gene cluster for biosynthesis of the polyketide β-lactone ebelactone in Streptomyces aburaviensis has shown that, contrary to a recently-published proposal, the ebelactone polyketide synthase faithfully follows the colinear modular paradigm. Keywords: colinearity; ebelactone; enzyme catalysis

• the third is the PKS for the β-lactone ebelactone, a potent esterase inhibitor from Streptomyces aburaviensis 2a,b (Figure 1) [30]. These examples are particularly interesting as potential model systems because the chemical outcome of the two successive extensions catalysed by the iterative module is

The direct oxidative diene cyclization and related reactions in natural product synthesis

• Juliane Adrian,
• Leona J. Gross and
• Christian B. W. Stark

Beilstein J. Org. Chem. 2016, 12, 2104–2123, doi:10.3762/bjoc.12.200

• diastereoisomeric lactone 52 in 76% yield. This lactone (52) was converted to enediol 53 in a further few steps. The second THF ring was then established using an epoxidation–cyclization sequence. Thus, asymmetric Sharpless epoxidation (SAE) [103][104] yielded an intermediary oxirane (not shown in Scheme 12) which

Diastereoselective synthesis of 3,4-dihydro-2H-pyran-4-carboxamides through an unusual regiospecific quasi-hydrolysis of a cyano group

• Mikhail Yu. Ievlev,
• Oleg V. Ershov,
• Mikhail Yu. Belikov,
• Angelina G. Milovidova,
• Viktor A. Tafeenko and
• Oleg E. Nasakin

Beilstein J. Org. Chem. 2016, 12, 2093–2098, doi:10.3762/bjoc.12.198

• presence thereof, but all acids promote only the iminolactone decyclization process without traces of lactone derivative 4 (Table 2). It is also important to note that during the reaction pathway (Scheme 3) a carbonyl-assisted carbonitrile hydration effect (CACHE) was occured. The carbonyl group, through

Rearrangements of organic peroxides and related processes

• Ivan A. Yaremenko,
• Vera A. Vil’,
• Dmitry V. Demchuk and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2016, 12, 1647–1748, doi:10.3762/bjoc.12.162

• for the oxidative production of valuable intermediates [264][265][266][267][268][269]. The asymmetric oxidation of 3-substituted cyclopentane-1,2-diones 87a–f is an efficient tool in organic synthesis for the preparation of unsymmetrical γ-lactone acids 88a–f with high optical purity and good yields

• (Table 6). These γ-lactone acids are valuable substrates for the synthesis of compounds with potentially useful pharmacological properties, such as homocitrates, alkyl- and aryl-substituted nucleosides [270][271][272]. The reaction starts with an asymmetric epoxidation of the substituted cyclopentane-1,2

• -dione 87a to form epoxide 89a. The second step involves the Baeyer–Villiger oxidation of epoxide 89a to peroxide 90a followed by the rearrangement into intermediate 91a. The latter is hydrolyzed by H2O to form dicarboxylic acid 92a, which is cyclized under the acidic conditions to γ-lactone acid 88a

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

• imine at the α-position (Table 1, entry 9). By using [RhCl(cod)]2, the α,β-unsaturated lactone was also converted to the product with a small improvement in the yield (Table 1, entry 11). Acrylamide 2i also gave the corresponding β-aminoamide 4Ai in a low yield (Table 1, entry 12). In the reaction using

• 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

• ). BF3·Et2O was found to be the most suitable Lewis acid, and the desired β-lactam (anti-3Bh) was obtained in moderate yield (Table 2, entry 9). Based on these results, we applied this reaction to the synthesis of ezetimibe (Scheme 3). The reaction of imine 1B with lactone 2j proceeded smoothly and gave

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

• annelated with a δ-lactone and a cyclopentanone or oxidation products of the latter. Aflatoxin biosynthesis has been studied since the late 1960s and has attracted attention, because the polyketide undergoes a series of oxidative rearrangements, which drastically alter the molecular scaffold. Due to the

• lactone that is decarboxylated towards the xanthone [103]. Studies with recombinant AflM and a lack of isolatable intermediates however made it clear that the order of steps in demethylsterigmatocystin (107) formation needs to be carefully re-evaluated [100]. Methylation by an O-methyltransferase and

• isoprenoid biosynthesis. The designated branching modules of lactone and glutarimide-producing PKS show similar designs: a branching domain (B or X), which is flanked by a KS and an ACP domain (Scheme 20b and c). In vitro reconstitution experiments with the branching module of the macrolide rhizoxin (130

Discovery of an inhibitor of the production of the Pseudomonas aeruginosa virulence factor pyocyanin in wild-type cells

• Bernardas Morkunas,
• Balint Gal,
• Warren R. J. D. Galloway,
• James T. Hodgkinson,
• Brett M. Ibbeson,
• Yaw Sing Tan,
• Martin Welch and
• David R. Spring

Beilstein J. Org. Chem. 2016, 12, 1428–1433, doi:10.3762/bjoc.12.137

• types of quorum sensing systems. Two of the QS signaling systems in P. aeruginosa utilise N-acylated-L-homoserine lactones (AHLs) as signalling molecules [20][21][22]. The rhl system utilises N-butanoyl-L-homoserine lactone (BHL) and it’s cognate receptor RhlR [20][21][22]. The las system utilises N-(3

• -oxododecanoyl)-L-homoserine lactone (OdDHL) and it’s cognate receptor LasR (Figure 1) [20][21][22]. Interlinking these two AHL signalling systems is a third signaling system utilising a quinolone signalling molecule (termed Pseudomonas quinolone signal, PQS) [20] to form an intricate hierarchical signaling

Stereoselective synthesis of tricyclic compounds by intramolecular palladium-catalyzed addition of aryl iodides to carbonyl groups

• Jakub Saadi,
• Christoph Bentz,
• Kai Redies,
• Dieter Lentz,
• Reinhold Zimmer and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2016, 12, 1236–1242, doi:10.3762/bjoc.12.118

• configurational assignment is ambiguous in this case, the NMR data and the fact that no γ-lactone is formed strongly support the trans-arrangement of the two functional groups as depicted. Under similar conditions (5 mol % Pd(PPh3)4, 90 °C, 3 d) the isopropyl-substituted ketone 2 furnished a mixture of the

Towards the total synthesis of keramaphidin B

• Pavol Jakubec,
• Alistair J. M. Farley and
• Darren J. Dixon

Beilstein J. Org. Chem. 2016, 12, 1096–1100, doi:10.3762/bjoc.12.104

• favoured attack at the more reactive δ-lactone carbonyl instead of that of the methyl ester. Pleasingly, this was indeed realised at the next stage; performing a nitro-Mannich lactamisation cascade on 13 with formaldehyde and butylamine in methanol afforded lactam 15 in 63% yield, possessing the

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

• the ring flip and transannular insertion by an axially disposed ketocarbene into an axial C–H bond. Magnus noted that 46 bears a striking resemblance to the bridged polycyclic lactone core of irroratin and proposed that this method could be used for its synthesis. The discovery by Du Bois that

Marine-derived myxobacteria of the suborder Nannocystineae: An underexplored source of structurally intriguing and biologically active metabolites

• Antonio Dávila-Céspedes,
• Peter Hufendiek,
• Max Crüsemann,
• Till F. Schäberle and
• Gabriele M. König

Beilstein J. Org. Chem. 2016, 12, 969–984, doi:10.3762/bjoc.12.96

• of the molecule. However, the complete natural product has not yet been synthesized [61]. The enhygrolide group of compounds comprises enhygrolide A (27) and B (28). These molecules resemble cyanobacteria-derived metabolites, known as nostoclides and cyanobacterin, which also have a γ-lactone-moiety

• testing, revealed that the lactone moiety and the configuration of the methoxyacrylate partial structure are crucial for antifungal activity. The latter structural motif is well known from a range of antifungal compounds produced by fungi and myxobacteria, e.g., the strobilurins and the melithiazols [67

1H-Imidazol-4(5H)-ones and thiazol-4(5H)-ones as emerging pronucleophiles in asymmetric catalysis

• Antonia Mielgo and
• Claudio Palomo

Beilstein J. Org. Chem. 2016, 12, 918–936, doi:10.3762/bjoc.12.90

• therapeutical candidates because of their high lipophilicity and membrane permeability [44][51]. A major catalytic entry to α,α-disubstituted (quaternary) amino acids is the α-functionalization of an appropriate template as, for instance, an α-imino ester or lactone, followed by hydrolysis [49][52][53]; but

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

• synthesis of (−)-maoecrystal V [63]. During this study, the authors observed an unexpected result when ortho–halosubstituted diazo compounds were used. Here the formation of a β-lactone by the carbenoid insertion into the C(sp3)–H bond of the alkyl substituent of the alkoxy moiety of the ester (Scheme 21

Indenopyrans – synthesis and photoluminescence properties

• Andreea Petronela Diac,
• Ana-Maria Ţepeş,
• Albert Soran,
• Ion Grosu,
• Anamaria Terec,
• Jean Roncali and
• Elena Bogdan

Beilstein J. Org. Chem. 2016, 12, 825–834, doi:10.3762/bjoc.12.81

• constants, typically observed for geminal protons. Noteworthy, in case of isomer 3''b, the specific methylene protons connected to the enol-lactone moiety display more deshielded signals than those of isomer 2''b (Figure 2). Once the 1,4-disubstituted indenopyrone derivatives were synthesized and their

• time, most of the isomer 2'a was recovered and traces of derivative 4a could only be detected in the NMR spectrum. Using the same procedure, the enol-lactone isomeric mixture 2'c/3'c was subjected to the dehydrogenation reaction yielding the regioisomers 4c and 5c (Scheme 2). The 1H NMR spectrum

• revealed the formation of the fully oxidized derivative 6c in small amounts that could not be isolated. However, silica gel column chromatography of the reaction mixture allowed the recovery of the starting enol-lactone derivative 2'c in 50% yield. The 1H NMR spectra of α-pyrones 4c and 5c (Figure S4

Muraymycin nucleoside-peptide antibiotics: uridine-derived natural products as lead structures for the development of novel antibacterial agents

• Daniel Wiegmann,
• Stefan Koppermann,
• Marius Wirth,
• Giuliana Niro,
• Kristin Leyerer and
• Christian Ducho

Beilstein J. Org. Chem. 2016, 12, 769–795, doi:10.3762/bjoc.12.77

• muraymycins (Scheme 5) [98]. A fully protected ureidomuraymycidine tripeptide was prepared through lactone opening followed by urea formation and a final Mitsunobu ring closure as key steps. A Strecker reaction of the benzylimine 34 followed by several steps afforded the alcohol 35. A thermal lactonisation as

• a first key step of the synthesis led to a 1:1 mixture of the two epimers 36 and 37, and the undesired lactone 37 could be epimerised and converted into 36 by treatment with DBU [98]. Epimerisation and simultaneous lactone opening could be achieved in another key step using L-valine tert-butyl ester